Textbook of Psychopharmacology

Psychopharmacology has developed as a medical discipline over approximately the past five decades. The discoveries of the earlier effective antidepressants, antipsychotics, and mood stabilizers were invariably based on serendipitous observations. The repeated demonstration of efficacy of these agents then served as an impetus for considerable research into the neurobiological bases of their therapeutic effects and of emotion and cognition themselves, as well as the biological basis of the major psychiatric disorders. Moreover, the emergence of an entire new multidisciplinary field, neuropsychopharmacology, which has led to newer specific agents to alter maladaptive central nervous system processes or activity, was another by-product of these early endeavors. The remarkable proliferation of information in this area—coupled with the absence of any comparable, currently available text—led us to edit the first edition of The American Psychiatric Press Textbook of Psychopharmacology, published in 1995. The response to that edition was overwhelmingly positive. In the second edition, published in 1998, we expanded considerably on the first edition, covering a number of areas in much greater detail, adding several new chapters, and updating all of the previous material. Again, the response was positive. We then presented a third edition in 2004 with virtually all new material, and now this fourth edition has updated the previous material and added several chapters on important (often emerging) areas not previously covered. In order for the reader to appreciate and integrate the rich amount of information about pharmacological agents, we have attempted in all editions to provide sufficient background material to understand more easily how drugs work and why, when, and in whom they should be used. For this fourth edition, we have updated all the material, often adding new contributors as well as adding several new chapters, and thus expanding the scope and length of the text. The textbook consists of five major parts. The first section, “Principles of Psychopharmacology,” was edited by Robert Malenka and provides a theoretical background for the ensuing parts. It includes chapters on neurotransmitters; signal transduction and second messengers; molecular biology; chemical neuroanatomy; electrophysiology; animal models of psychiatric disorders; psychoneuroendocrinology, pharmacokinetics; and pharmacodynamics; psychoneuroimmunology; brain imaging in psychopharmacology; and statistics/clinical trial design. The second part, “Classes of Psychiatric Treatments: Animal and Human Pharmacology,” presents information by classes of drugs and is coedited by K. Ranga Rama Krishnan and Dennis Charney. For each drug within a class, data are reviewed on preclinical and clinical pharmacology, pharmacokinetics, indications, dosages, and cognate issues. This section is pharmacopoeia-like. Individual chapters are now generally dedicated to individual agents (e.g., paroxetine, venlafaxine). We include data not only on currently available drugs in the United States but also on medications that will in all likelihood become available in the near future. We have not only updated all the material but invited new authors on many chapters to provide fresh insights. The third part, “Clinical Psychobiology and Psychiatric Syndromes,” edited by David Kupfer, reviews data on the biological underpinnings of specific disorders—for example, major depression, bipolar disorder, and panic disorder. The chapter authors in this section comprehensively review the biological alterations described for each of the major psychiatric disorders, allowing the reader to better understand current psychopharmacological approaches as well as to anticipate future developments. The fourth part, “Psychopharmacological Treatment,” edited by David Dunner, reviews state-of-the-art therapeutic approaches to patients with major psychiatric disorders as well as to those in specific age groups or circumstances: childhood disorders, emergency psychiatry, pregnancy and postpartum, and so forth. Here, too, new contributors provide fresh looks at important clinical topics. This section provides the reader with specific information about drug selection and prescription. We have added a new chapter on chronic pain syndromes. Last, we have added a new chapter on ethical considerations in psychopharmacological treatment and research, providing the reader with a thoughtful overview of this important area. This textbook would not have been possible without the superb editorial work of the section editors—as well as, of course, the authors of the chapters, who so generously gave of their time. In addition, we wish to thank Editorial Director John McDuffie of American Psychiatric Publishing and his staff for their editorial efforts. In particular, we appreciate the major efforts of Bessie Jones, Acquisitions Coordinator; Greg Kuny, Managing Editor; Tammy J. Cordova, Graphic Design Manager; Susan Westrate, Prepress Coordinator; Judy Castagna, Manufacturing Manager; Melissa Coates, Assistant Editor; and Rebecca Richters, Senior Editor. Finally, we extend our thanks to Tina ColtriMarshall at the University of California–Davis, Rebecca Wyse at Stanford University, and Janice Dell at Emory University for their invaluable editorial assistance.

y Alan F. Schatzberg, M.D. Charles B. Nemeroff, M.D., Ph.D.

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Steven T. Szabo, Todd D. Gould, Husseini K. Manji: Chapter 1. Neurotransmitters, Receptors, Signal Transduction, and Second Messengers in Psychiatric Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.407001. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 1. Neurotransmitters, Receptors, Signal Transduction, and Second Messengers in Psychiatric Disorders NEUROTRANSMITTERS, RECEPTORS, SIGNAL TRANSDUCTION, AND SECOND MESSENGERS IN PSYCHIATRIC DISORDERS: INTRODUCTION This chapter serves as a primer on the recent advances in our understanding of neural function both in health and in disease. It is beyond the scope of this chapter to cover these important areas in extensive detail, and readers are referred to outstanding textbooks that are entirely devoted to the topic (Cooper et al. 2001; Kandel et al. 2000; Nestler et al. 2001; Squire et al. 2003). Here, we focus on the principles of neurotransmission and second-messenger generation that we believe are critical for an understanding of the biological bases of major psychiatric disorders, as well as the mechanisms by which effective treatments may exert their beneficial effects. In particular, it is our goal to lay the groundwork for the subsequent chapters, which focus on individual disorders and their treatments. Although this chapter is intended to provide a general overview on neurotransmitter and second-messenger function, whenever possible we emphasize the neuropsychiatric relevance of specific observations. In the chapter proper, we outline principles that are of utmost importance to the study and practice of psychopharmacology; in the figure legends, we provide additional details for the interested reader. [The work presented in this chapter was undertaken under the auspices of the National Institute of Mental Health Intramural Program. Dr. Manji is now at Johnson & Johnson Pharmaceutical Research & Development. The authors thank Ioline Henter for assistance in the preparation of this chapter.]

WHAT ARE NEUROTRANSMITTERS? Several criteria have been established for a neurotransmitter, including 1) it is synthesized and released from neurons; 2) it is released from nerve terminals in a chemically or pharmacologically identifiable form; 3) it interacts with postsynaptic receptors and brings about the same effects as are seen with stimulation of the presynaptic neuron; 4) its interaction with the postsynaptic receptor displays a specific pharmacology; and 5) its actions are terminated by active processes (Kandel et al. 2000; Nestler et al. 2001). However, our growing appreciation of the complexity of the central nervous system (CNS) and of the existence of numerous molecules that exert neuromodulatory and neurohormonal effects has blurred the classical definition of neurotransmitters somewhat, and even well-known neurotransmitters do not meet all these criteria under certain situations (Cooper et al. 2001). Most neuroactive compounds are small polar molecules that are synthesized in the CNS via local machinery or are able to permeate the blood–brain barrier. To date, more than 50 endogenous substances have been found to be present in the brain that appear to be capable of functioning as neurotransmitters. There are many plausible explanations for why the brain would need so many transmitters and receptor subtypes to transmit messages. Perhaps the simplest explanation is that the sheer complexity of the CNS results in many afferent nerve terminals impinging on a single neuron. This requires a neuron to be able to distinguish the multiple information conveying inputs. Although this can be accomplished partially by spatial segregation, it is accomplished in large part by chemical coding of the inputs—that is, different chemicals convey different information. Moreover, as we discuss in detail later, the evolution of multiple receptors for a single neurotransmitter means that the same chemical can convey different messages depending on the receptor subtypes it acts on. Additionally, the firing pattern of neurons is also a means of conveying information; thus, the firing activities of neurons in the brain differ widely, and a single neuron firing at different frequencies can even release different neuroactive compounds depending on the firing rate (e.g., the release of peptides often occurs at higher firing rates than that which is required to release monoamines). These multiple mechanisms to enhance the diversity of responses —chemical coding, spatial coding, frequency coding—are undoubtedly critical in endowing the CNS with its complex repertoire of physiological and behavioral responses (Kandel et al. 2000; Nestler et al. 2001). Finally, the existence of multiple neuroactive compounds also provides built-in safeguards to ensure that vital brain circuits are able to partially compensate for loss of function of particular neurotransmitters.

RECEPTORS An essential property of any living cell is its ability to recognize and respond to external stimuli. Cell surface receptors have two major functions: recognition of specific molecules (neurotransmitters, hormones, growth factors, and even sensory signals) and activation of "effectors." Binding of the appropriate agonist (i.e., neurotransmitter or hormone) externally to the receptor alters the conformation (shape) of the protein. Cell surface receptors use a variety of membrane-transducing mechanisms to transform an agonist's message into cellular responses. In neuronal systems, the most typical responses ultimately (in some cases rapidly, in others more slowly) involve changes in transmembrane voltage and hence neuronal changes in excitability. Collectively, the processes are referred to as transmembrane signaling or signal transduction mechanisms. These processes are not restricted to neurons. For example, astrocytes, which were once thought to be unrelated to neurotransmission, have recently been demonstrated to possess voltage-regulated anion channels (VRAC), which not only transport Cl– but also allow efflux of amino acids such as taurine, glutamate, and aspartate (Mulligan and MacVicar 2006). Interestingly, although increasing numbers of potential neuroactive compounds and receptors continue to be identified, it has become clear that translation of the extracellular signals (into a form that can be interpreted by the complex intracellular enzymatic machinery) is achieved through a relatively small number of cellular mechanisms. Generally speaking, these transmembrane signaling systems, and the receptors that utilize them, can be divided into four major groups (Figure 1–1): Those that are relatively self-contained in structure and whose message takes the form of transmembrane ion fluxes (ionotropic) Those that are multicomponent in nature and generate intracellular second messengers (G protein–coupled) Those that contain intrinsic enzymatic activity (receptor tyrosine kinases and phosphatases) Those that are cytoplasmic and translocate to the nucleus to directly regulate transcription (gene expression) after they are activated by lipophilic molecules (often hormones) that enter the cell (nuclear receptors) FIGURE 1–1. Major receptor subtypes in the central nervous system.

This figure depicts the four major classes of receptors in the CNS. (A) Ionotropic receptors. These receptors comprise multiple protein subunits that are combined in such a way as to create a central membrane pore through this complex, allowing the flow of ions. This type of receptor has a very rapid response time (milliseconds). The consequences of receptor stimulation (i.e., excitatory or inhibitory) depend on the types of ions that the receptor specifically allows to enter the cell. Thus, for example, Na+ entry through the NMDA (N-methyl-D-aspartate) receptor depolarizes the neuron and brings about an excitatory response, whereas Cl– efflux through the -aminobutyric acid type A (GABAA) receptor hyperpolarizes the neuron and brings about an inhibitory response. Illustrated here is the NMDA receptor regulating a channel permeable to Ca2+, Na+, and K+ ions. The NMDA receptors also have binding sites for glycine, Zn2+, phencyclidine (PCP), MK801/ketamine, and Mg2+; these molecules are able to regulate the function of this receptor. (B) G protein–coupled receptors (GPCRs). The majority of neurotransmitters, hormones, and even sensory signals mediate their effects via seven transmembrane domain–spanning receptors that are G protein–coupled. The amino terminus of the G protein is on the outside of the cell and plays an important role in the recognition of specific ligands; the third intracellular loop and carboxy terminus of the receptor play an important role in coupling to G proteins and are sites of regulation of receptor function (e.g., by phosphorylation). All G proteins are heterotrimers (consisting of , moieties (fatty acid) via their

, and

subunits). The G proteins are attached to the membrane by isoprenoid

subunits. Compared with the ionotropic receptors, GPCRs mediate a slower response (on the order of seconds). Detailed depiction of the

activation of G protein–coupled receptors is given in Figure 1–2. Here we depict a receptor coupled to the G protein Gs (the s stands for stimulatory to the enzyme adenylyl cyclase [AC]). Activation of such a receptor produces activation of AC and increases in cAMP levels. G protein–coupled pathways exhibit major amplification properties, and, for example, in model systems researchers have demonstrated a 10,000-fold amplification of the original signal. The effects of cAMP are mediated largely by activation of protein kinase A (PKA). One major downstream target of PKA is CREB (cAMP response element–binding protein), which may be important to the mechanism of action of antidepressants. (C) Receptor tyrosine kinases. These receptors are activated by neurotrophic factors and are able to bring about acute changes in synaptic function, as well as long-term effects on neuronal growth and survival. These receptors contain intrinsic tyrosine kinase activity. Binding of the ligand triggers receptor dimerization and transphosphorylation of tyrosine residues in its cytoplasmic domain, which then recruits cytoplasmic signaling and scaffolding proteins. The recruitment of effector molecules generally occurs via interaction of proteins with modular binding domains SH2 and SH3 (named after homology to the src oncogenes–src homology domains); SH2 domains are a stretch of about 100 amino acids that allows high-affinity interactions with certain phosphotyrosine motifs. The ability of multiple effectors to interact with phosphotyrosines is undoubtedly one of the keys to the pleiotropic effects that neurotrophins can exert. Shown here is a tyrosine kinase receptor type B (TrkB), which upon activation produces effects on the Raf, MEK (mitogen-activated protein kinase/ERK), extracellular response kinase (ERK), and ribosomal S6 kinase (RSK) signaling pathway. Some major downstream effects of RSK are CREB and stimulation of factors that bind to the AP-1 site (c-Fos and c-Jun). (D) Nuclear receptors. These receptors are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Many hormones (including glucocorticoids, gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane, because of their lipophilic composition, and thereby directly interact with these cytoplasmic receptors inside the cell. Upon activation by a hormone, the nuclear receptor–ligand complex translocates to the nucleus, where it binds to specific DNA sequences, referred to as hormone responsive elements (HREs), and regulates gene transcription. Nuclear receptors often interact with a variety of coregulators that promote transcriptional activation when recruited (coactivators) and those that attenuate promoter activity (corepressors). However, nongenomic effects of neuroactive steroids have also been documented, with the majority of evidence suggesting modulation of ionotropic receptors. This figure illustrates both the genomic and the nongenomic effects. ATF1 = activation transcription factor 1; BDNF = brain-derived neurotrophic factor; CaMKII = Ca2+/calmodulin–dependent protein kinase II; CREM = cyclic adenosine 5'-monophosphate response element modulator; D1 = dopamine1 receptor; D5 = dopamine5 receptor; ER = estrogen receptor; GR = glucocorticoid receptor; GRK = G protein–coupled receptor kinase; P = phosphorylation; PR = progesterone receptor.

Ionotropic Receptors

The first class of receptors contains in their molecular complex an intrinsic ion channel. Receptors of this class include those for a number of amino acids, including glutamate (e.g., the NMDA [N-methyl-D-aspartate] receptor) and GABA ( -aminobutyric acid via the GABAA receptor), as well as the nicotinic acetylcholine (ACh) receptor and the serotonin3 (5-HT3) receptor. Ion channels are integral membrane proteins that are directly responsible for the electrical activity of the nervous system by virtue of their regulation of the movement of ions across membranes. Receptors containing intrinsic ion channels have been called ionotropic and are generally composed of four or five subunits that open transiently when neurotransmitter binds, allowing ions to flow into (e.g., Na+, Ca2+, Cl–) or out of (e.g., K+) the neuron, thereby generating synaptic potential (see Figure 1–1). Often, the ionotropic receptors can be composed of different compositions of the different subunits, thereby providing the system with considerable flexibility. For example, there is extensive research into the potential development of an anxiolytic that is devoid of sedative effects by targeting GABAA receptor subunits present in selected brain regions. In general, neurotransmission that is mediated by ionotropic receptors is very fast, with ion channels opening and closing within milliseconds, and regulates much of the tonic excitatory (e.g., glutamate-mediated) and inhibitory (e.g., GABA-mediated) activity in the CNS; as we discuss below, many of the classical neurotransmitters (e.g., monoamines) exert their effects on a slower time scale and are therefore often considered to be modulatory in their effects.

G Protein–Coupled Receptors Most receptors in the CNS do not have intrinsic ionic conductance channels within their structure but instead regulate cellular activity by the generation of various "second messengers." Receptors of this class do not generally interact directly with the various second-messenger-generating enzymes but instead transmit information to the appropriate "effector" by the activation of interposed coupling proteins. These are the G protein–coupled receptor families. The G protein–coupled receptors (GPCRs, which constitute more than 80% of all known receptors in the body, and number about 300) all span the plasma membrane seven times (see Figure 1–1). GPCRs have been the focus of extensive research in psychiatry in recent years (Catapano and Manji 2007). The amino terminus is on the outside of the cell and plays a critical role in recognition of the ligand; the carboxy terminus and third intracellular loop are inside the cell and regulate not only coupling to different G proteins but also "cross talk" between receptors and desensitization (see Figure 1–1). G proteins are so named because of their ability to bind the guanine nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). Receptors coupled to G proteins include those for catecholamines, serotonin, ACh, various peptides, and even sensory signals such as light and odorants (Table 1–1). As we discuss later in the chapter, multiple subtypes of G proteins are known to exist, and they play critical roles in amplifying and integrating signals. TABLE 1–1. Key features of G protein subunits G protein class Members i

G i1–3, G o

Effector(s)/Functions

Examples of receptors

AC (+)

2,

Ligand-type Ca2+ channels (+) G z , G t1–2

D2, A1, , M2, 5-HT1A

Olfactory signals

K+ channels (+) Ca2+ channels (–)a

GABAB

Cyclic GMP

Retinal rods, cones (rhodopsins)

Phosphodiesterase (+) (G t1–2 ) q

G q, G 11 , G 14, G 15 , G 16 PLC- (+)

TxA2, 5-HT2C , M1, M3 , M5,

12

G 12,G 13

TxA2, thrombin

b

(x5)

RGS domain–containing rho exchange factors

1

AC type I (–); AC types II, IV (potentiation) PLC (+) Receptor kinases (+) Inactivates s

(x12)

required for interaction of

Note. AC = adenylyl cyclase; A1, A2 = adenosine receptor subtypes; 1,

1,

subunit with receptor 2

= adrenergic receptor subtypes; C = cholera toxin; D1 , D2 = dopamine receptor subtypes; G t

= olfactory, but also found in limbic areas; G s = stimulatory; G t = transducin; GABAB = -aminobutyric acid receptor subtype; 5-HT1A, 5-HT2C = serotonin receptor subtypes; M1 , M2, M3, M5 = muscarinic receptor subtypes; = opioid receptor; P = pertussis toxin; PLC = phospholipase C; RGS = regulators of G protein signaling; TxA2 = thromboxane A2 receptor. a

Although regulation of Na+/H+ exchange and Ca2+ channels by G 1–2 and G 1–3 has been demonstrated in artificial systems in vitro, these findings await definitive

confirmation. b

Effectors are regulated by

subunits as a dimer.

Autoreceptors and Heteroreceptors Autoreceptors are receptors located on neurons that produce the endogenous ligand for that particular receptor (e.g., a serotonergic receptor on a serotonergic neuron). By contrast, heteroreceptors are receptor subtypes that are present on neurons that do not contain an endogenous ligand for that particular receptor subtype (e.g., a serotonergic receptor located on a dopaminergic neuron). Two major classes of autoreceptors play very important roles in fine-tuning neuronal activity. Somatodendritic autoreceptors are present on cell bodies and dendrites and exert critical roles in regulating the firing rate of neurons. In general, activation of somatodendritic autoreceptors (e.g.,

2-adrenergic

receptors for noradrenergic neurons, serotonin1A [5-HT1A] receptors for serotonergic neurons, dopamine2 [D2] receptors for dopaminergic neurons) inhibits the firing rate of the neurons by opening K+ channels and by reducing cyclic adenosine monophosphate (cAMP) levels, both of which may be important in psychiatric disease. For example, TREK-1 is a background K+ channel regulator protein important in 5-HT transmission and potentially in mood-like behavior regulation in mice (Heurteaux et al. 2006). Fundamental mechanisms of neuronal transmission—such as K+ channels, which regulate membrane potentials—may relate to global alterations in brain functioning relevant to psychiatry. The second major class of autoreceptors, nerve terminal autoreceptors, play an important role in regulating the amount of neurotransmitter released per nerve impulse, generally by closing nerve terminal Ca2+ channels. Both of these types of autoreceptors are typically members of the G protein–coupled receptor family. Neurotransmitter release is known to be triggered by influx and alterations of intracellular calcium, with the functioning of three types of SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein [SNAP] receptor) proteins exerting critical roles. Recent advances in our understanding of the distinct kinetics of neurotransmitter release modulators, such as botulinum and tetanus neurotoxins, suggest that these induce prominent alterations in synaptobrevin and syntaxin, leading to calcium-independent mechanisms of neurotransmitter regulation (Sakaba et al. 2005). Most synapses are dependent on influx of Ca2+ through voltage-gated calcium channels for presynaptic neurotransmitter release; in the retina, however, this

influx of calcium occurs via glutamatergic AMPA receptors (Chavez et al. 2006). Beyond the receptor level, presynaptic SAD, an intracellular serine threonine kinase, is associated with the active zone cytomatrix that regulates neurotransmitter release (Inoue et al. 2006). These recent data further exemplify the dynamic nature and ongoing advancement of our knowledge pertaining to basic processes involved in neurotransmitter regulation that may possibly aid in advancing treatment of psychopathology.

G Protein–Coupled Receptor Regulation and Trafficking The mechanism by which GPCRs translate extracellular signals into cellular changes was once envisioned as a simple linear model. It is now known, however, that the activity of GPCRs is subject to at least three additional principal modes of regulation: desensitization, downregulation, and trafficking (Carman and Benovic 1998) (Figure 1–2). Desensitization, the process by which cells rapidly adapt to stimulation by agonists, is generally believed to occur by two major mechanisms: homologous and heterologous. FIGURE 1–2. G protein–coupled receptors and G protein activation.

All G proteins are heterotrimers consisting of ,

, and

subunits. The receptor shuttles between a low-affinity form that is not coupled to a G protein and a high-affinity form

that is coupled to a G protein. (A) At rest, G proteins are largely in their inactive state, namely, as

heterotrimers, which have GDP (guanosine diphosphate) bound to the

subunit. (B) When a receptor is activated by a neurotransmitter, it undergoes a conformational (shape) change, forming a transient state referred to as a high-affinity ternary complex, comprising the agonist, receptor in a high-affinity state, and G protein. A consequence of the receptor interaction with the G protein is that the GDP comes off the G protein

subunit, leaving a very transient empty guanine nucleotide binding domain. (C) Guanine nucleotides (generally GTP) quickly bind to this nucleotide binding

domain; thus, one of the major consequences of active receptor–G protein interaction is to facilitate guanine nucleotide exchange—this is basically the "on switch" for the G protein cycle. (D) A family of GTPase-activating proteins for G protein–coupled receptors has been identified, and they are called regulators of G protein signaling (RGS) proteins. Since activating GTPase activity facilitates the "turn off" reaction, these RGS proteins are involved in dampening the signal. Binding of GTP to the proteins results in subunit dissociation, whereby the generally function as dimers. The

-GTP and

-GTP dissociates from the

subunits. Although not covalently bound, the

and

subunit of G

subunits remain tightly associated and

subunits are now able to activate multiple diverse effectors, thereby propagating the signal. While they are in their active

states, the G protein subunits can activate multiple effector molecules in a "hit and run" manner; this results in major signal amplification (i.e., one active G protein subunit can activate multiple effector molecules; see Figure 1–11). The activated G protein subunits also dissociate from the receptor, converting the receptor to a low-affinity conformation and facilitating the dissociation of the agonist from the receptor. The agonist can now activate another receptor, and this also results in signal amplification. Together, these processes have been estimated to produce a 10,000-fold amplification of the signal in certain models. (E) Interestingly, the activity, which cleaves the third phosphate group from GTP (G-P-P-P) to GDP (G-P-P). Since mechanism, and this is the "turn off" reaction. (F) The reassociation of -GDP with

subunit has intrinsic GTPase

-GDP is an inactive state, the GTPase activity serves as a built-in timing

is thermodynamically favored, and the reformation of the inactive heterotrimer (

)

completes the G protein cycle. Homologous desensitization is receptor specific; that is, only the receptor actively being stimulated becomes desensitized. This form of desensitization occurs via a family of kinases known as G protein–coupled kinases (GRKs). When a receptor activates a G protein and causes dissociation of the from the

subunits (discussed in detail later), the

subunit

subunits are able to provide an "anchoring surface" for the GRKs to allow them to come into the

proximity of the activated receptor and phosphorylate it. This phorphorylation then recruits another family of proteins known as arrestins, which physically interfere with the coupling of the phosphorylated receptor and the G protein, thereby dampening the signal. This form of desensitization is very rapid and usually transient (i.e., the receptors get dephosphorylated and return to the baseline state). However, if the stimulation of the receptor is excessive and prolonged, it leads to an internalization of the receptor, and often its degradation, a process referred to as downregulation. Heterologous desensitization is not receptor specific and is mediated by second-messenger kinases such as protein kinase A (PKA) and protein kinase C (PKC). Thus, when a receptor activates PKA, the activated PKA is capable of phosphorylating (and thereby desensitizing) not only that particular receptor but also other receptors that are present in proximity and have the correct phosphorylation motif, thereby producing heterologous desensitization. Upon prolonged or repeated activation of receptors by agonist ligands, the process of receptor downregulation is observed. Downregulation is associated with a reduced number of receptors detected in cells or tissues, thereby leading to attenuation of cellular responses (Carman and Benovic 1998). The process of GPCR sequestration is mediated by a well-characterized endocytic pathway involving the concentration of receptors in clathrin-coated pits and subsequent internalization and recycling back to the plasma membrane (Tsao and von Zastrow 2000). Endocytosis can thus clearly serve as a primary mechanism to attenuate signaling by rapidly and reversibly removing receptors from the cell surface. However, emerging evidence suggests additional functions of endocytosis and receptor trafficking in mediating GPCR signaling by way of certain effector pathways, most notably mitogen-activated protein (MAP) kinase cascades (discussed in greater detail later). There is also evidence that endocytosis of GPCRs may be required for certain signal transduction pathways leading to the nucleus (Tsao and von Zastrow 2000). These diverse functions of GPCR endocytosis and trafficking are leading to unexpected insights into the biochemical and functional properties of endocytic vesicles. Indeed, there is considerable excitement about our growing understanding of the diverse molecular mechanisms for signaling specificity and receptor trafficking, and the possibility that this knowledge could lead to highly selective therapeutics.

Receptor Tyrosine Kinases

The receptor tyrosine kinases, as their name implies, contain intrinsic tyrosine kinase activity and are generally utilized by growth factors, such as neurotrophic factors, and cytokines. Binding of an agonist initiates receptor dimerization and transphosphorylation of tyrosine residues in its cytoplasmic domain (Patapoutian and Reichardt 2001) (see Figure 1–1). The phosphotyrosine residues of the receptor function as binding sites for recruiting specific cytoplasmic signaling and scaffolding proteins. The ability of multiple effectors to interact with phosphotyrosines is undoubtedly one of the keys to the pleiotropic effects that neurotrophins can exert. These pleiotropic and yet distinct effects of growth factors are mediated by varying degrees of activation of three major signaling pathways: the MAP kinase pathway, the phosphoinositide-3 (PI3) kinase pathway, and the phospholipase C (PLC)– 1 pathway (see Figure 1–9 later in this chapter).

Nuclear Receptors Nuclear receptors are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Many hormones (including glucocorticoids, gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane, because of their lipophilic composition, and thereby directly interact with these cytoplasmic receptors inside the cell (see Figure 1–1). Upon activation by a hormone, the nuclear receptor–ligand complex translocates to the nucleus, where it binds to specific DNA sequences referred to as hormone-responsive elements (HREs), and subsequently regulates gene transcription (Mangelsdorf et al. 1995; Truss and Beato 1993). Nuclear receptors often interact with a variety of coregulators that promote transcriptional activation when recruited (coactivators) and those that attenuate promoter activity (corepressors). With this overview of neurotransmitters and receptor subtypes, we now turn to a discussion of selected individual neurotransmitters and neuropeptides before discussing the intricacies of cellular signal transduction systems.

NEUROTRANSMITTER AND NEUROPEPTIDE SYSTEMS Serotonergic System Largely on the basis of the observation that most current effective antidepressants and antipsychotics target these systems, the monoaminergic systems (e.g., serotonin, norepinephrine, dopamine) have been extensively studied. Serotonin (5-HT) was given that name because of its activity as an endogenous vasoconstrictor in blood serum (Rapport et al. 1947). It was later acknowledged as being the same molecule (secretin) found in the intestinal mucosa and that is "secreted" by chromaffin cells (Brodie 1900). Following these findings, 5-HT soon became characterized as being a neurotransmitter in the CNS (Bogdansky et al. 1956). 5-HT-producing cell bodies in the brain are localized in the central gray, in the surrounding reticular formation, and in cell clusters located in the center, and thus the name raphe (from Latin, meaning midline) was adopted (Figure 1–3A) (discussed more extensively in Chapter 4, "Chemical Neuroanatomy of the Primate Brain"). The dorsal raphe (DR), the largest brain stem 5-HT nucleus, contains approximately 50% of the total 5-HT neurons in the mammalian CNS; in contrast, the medial raphe (MR) comprises 5% (Descarries et al. 1982; Wiklund and Bjorklund 1980). Serotonergic neurons project widely throughout the CNS rather than to discrete anatomical locations (as the dopaminergic neurons appear to do; see Figure 1–4A later in this chapter), leading to the suggestion that 5-HT exerts a major modulatory role throughout the CNS (Reader 1980). Interestingly, evidence suggests that infralimbic and prelimbic regions of the ventral medial prefrontal cortex (mPFCv) in rats are responsible for detecting whether a stressor is under the organism's control. When a stressor is controllable, stress-induced activation of the dorsal raphe nucleus is inhibited by the mPFCv, and the behavioral sequelae of the uncontrollable stress response are blocked (Amat et al. 2005). The organism's ability to regulate 5-HT neuron activity and function has been a major ongoing focus of psychiatric disorder research and treatments. FIGURE 1–3. The serotonergic system.

This figure depicts the location of the major serotonin (5-HT)–producing cells (raphe nuclei) innervating brain structures (A), and various cellular regulatory processes involved in serotonergic neurotransmission (B). 5-HT neurons project widely throughout the CNS and innervate virtually every part of the neuroaxis. L-Tryptophan, an amino acid actively transported into presynaptic 5-HT-containing terminals, is the precursor for 5-HT. It is converted to 5-hydroxytryptophan (5-HTP) by the rate-limiting enzyme tryptophan hydroxylase (TrpH). This enzyme is effectively inhibited by the drug p-chlorophenylalanine (PCPA). Aromatic amino acid decarboxylase (AADC) converts 5-HTP to 5-HT. Once released from the presynaptic terminal, 5-HT can interact with a variety (15 different types) of presynaptic and postsynaptic receptors. Presynaptic regulation of 5-HT neuron firing activity and release occurs through somatodendritic 5-HT1A (not shown) and 5-HT1B,1D autoreceptors, respectively, located on nerve terminals. Sumatriptan is a 5-HT1B,1D receptor agonist. (The antimigraine effects of this agent are likely mediated by local activation of this receptor subtype on blood vessels, which results in their constriction.) Buspirone is a partial 5-HT1A agonist that activates both pre- and postsynaptic receptors. Cisapride is a preferential 5-HT4 receptor agonist that is used to treat irritable bowel syndrome as well as nausea associated with antidepressants. The binding of 5-HT to G protein receptors (Go , Gi, etc.) that are coupled to adenylyl cyclase (AC) and phospholipase C– (PLC- ) will result in the production of a cascade of second-messenger and cellular effects. Lysergic acid diethylamide (LSD) likely interacts with numerous 5-HT receptors to mediate its effects. Pharmacologically this ligand is often used as a 5-HT2 receptor agonist in receptor binding experiments. Ondansetron is a 5-HT3 receptor antagonist that is marketed as an antiemetic agent for chemotherapy patients but is also given to counteract side effects produced by antidepressants in some patients. 5-HT has its action terminated in the synapse by rapidly being taken back into the presynaptic neuron through 5-HT transporters (5-HTT). Once inside the neuron, it can either be repackaged into vesicles for reuse or undergo enzymatic catabolism. The selective 5-HT reuptake inhibitors (SSRIs) and oldergeneration tricyclic antidepressants (TCAs) are able to interfere/block the reuptake of 5-HT. 5-HT is then metabolized to 5-hydroxyindoleacetic acid (5-HIAA) by monoamine oxidase (MAO), located on the outer membrane of mitochondria or sequestered and stored in secretory vesicles by vesicle monoamine transporters (VMATs). Reserpine causes a depletion of 5-HT in vesicles by interfering with uptake and storage mechanisms (depressive-like symptoms have been reported with this agent). Tranylcypromine is an MAO inhibitor (MAOI) and an effective antidepressant. Fenfluramine (an anorectic agent) and MDMA ("Ecstasy") are able to facilitate 5-HT release by altering 5-HTT function. DAG = diacylglycerol; 5-HTT = serotonin transporter; IP3 = inositol-1,4,5-triphosphate. Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nestler et al. 2001. FIGURE 1–4. The dopaminergic system.

This figure depicts the dopaminergic projections throughout the brain (A) and various regulatory processes involved in dopaminergic neurotransmission (B). The amino acid L-tyrosine

is actively transported into presynaptic dopamine (DA) nerve terminals, where it is ultimately converted into DA. The rate-limiting step is conversion of L-tyrosine

to L-dihydroxyphenylalanine (L-dopa) by the enzyme tyrosine hydroxylase (TH).

-Methyl-p-tyrosine (AMPT) is a competitive inhibitor of tyrosine hydroxylase and has been

used to assess the impact of reduced catecholaminergic function in clinical studies. The production of DA requires that L-aromatic amino acid decarboxylase (AADC) act on L-dopa.

Thus, the administration of L-dopa to patients with Parkinson's disease bypasses the rate-limiting step and is able to produce DA quite readily. DA has its action

terminated in the synapse by rapidly being taken back into the presynaptic neuron through DA transporters (DATs). DA is then metabolized to dihydroxyphenylalanine (DOPAC) by intraneuronal monoamine oxidase (MAO; preferentially by the MAO-B subtype) located on the outer membrane of mitochondria, or is sequestered and stored in secretory vesicles by vesicle monoamine transporters (VMATs). Reserpine causes a depletion of DA in vesicles by interfering and irreversibly damaging uptake and storage mechanisms. -Hydroxybutyrate inhibits the release of DA by blocking impulse propagation in DA neurons. Pargyline inhibits MAO and may have efficacy in treating parkinsonian symptoms by augmenting DA levels through inhibition of DA catabolism. Other clinically used inhibitors of MAO are nonselective and thus likely elevate the levels of DA, norepinephrine, and serotonin. Once released from the presynaptic terminal (because of an action potential and calcium influx), DA can interact with five different G protein–coupled receptors (D1 –D5), which belong to either the D1 or D2 receptor family. Presynaptic regulation of DA neuron firing activity and release occurs through somatodendritic (not shown) and nerve terminal D2 autoreceptors, respectively. Pramipexole is a D2/D3 receptor agonist and has been documented to have efficacy as an augmentation strategy in cases of treatment-resistant depression and in the management of Parkinson's disease. The binding of DA to G protein receptors (Go , Gi, etc.) positively or negatively coupled to adenylyl cyclase (AC) results in the activation or inhibition of this enzyme, respectively, and the production of a cascade of secondmessenger and cellular effects (see diagram). Apomorphine is a D1 /D2 receptor agonist that has been used clinically to aid in the treatment of Parkinson's disease. (SKF-82958 is a pharmacologically selective D1 receptor agonist.) SCH-23390 is a D1/D5 receptor antagonist. There are likely physiological differences between D1 and D5 receptors, but the current unavailability of selective pharmacological agents has precluded an adequate differentiation thus far. Haloperidol is a D2 receptor antagonist, and clozapine is a nonspecific D2 /D4 receptor antagonist (both are effective antipsychotic agents). Once inside the neuron, DA can either be repackaged into vesicles for reuse or undergo enzymatic catabolism. Nomifensine is able to interfere/block the reuptake of DA. The antidepressant bupropion has affinity for the dopaminergic system, but it is not known whether this agent mediates its effects through DA or possibly by augmenting other monoamines. DA can be degraded to homovanillic acid (HVA) through the sequential action of catechol-O-methyltransferase (COMT) and MAO. Tropolone is an inhibitor of COMT. Evidence suggests that the COMT gene may be linked to schizophrenia (Akil et al. 2003). Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. The precursor for 5-HT synthesis is l-tryptophan, an amino acid that comes primarily from the diet and crosses the blood–brain barrier through a carrier for large neutral amino acids. Tryptophan hydroxylase (TrpH) is the rate-limiting enzyme in serotonin biosynthesis (Figure 1–3B), and polymorphisms in this

enzyme have been extensively investigated in psychiatric disorders, with equivocal results to date. A more fruitful research strategy in humans has been tryptophan depletion via dietary restriction to study the role of serotonin in the pathophysiology and treatment of psychiatric disorders (Bell et al. 2001). These studies have indicated that tryptophan depletion produces a rapid depressive relapse in patients treated with selective serotonin reuptake inhibitors (SSRIs) but not in those treated with norepinephrine reuptake inhibitors; the data suggesting induction of depressive symptoms in remitted patients or individuals with family histories of mood disorders are more equivocal (Bell et al. 2001).

Serotonin Transporters As is the case for many classical neurotransmitters, termination of the effects of 5-HT in the synaptic cleft is brought about in large part by an active reuptake process mediated by the 5-HT transporter (5-HTT). 5-HT is taken up into the presynaptic terminals, where it is metabolized by the enzyme monoamine oxidase (MAO) or sequestered into secretory vesicles by the vesicle monoamine transporter (see Figure 1–3B). This presumably underlies the mechanism by which MAO inhibitors initiate their therapeutic effects; that is, the blockade of monoamine breakdown results in increasing the available pool for release when an action potential invades the nerve terminal. It is now well established that many tricyclic antidepressants and SSRIs exert their initial primary pharmacological effects by binding to the 5-HTT and blocking 5-HT reuptake, thereby increasing the intrasynaptic levels of 5-HT, which initiates a cascade of downstream effects (see Figure 1–3B for details). It has been hypothesized that the first step in 5-HT transport involves the binding of 5-HT to the 5-HTT and then a cotransport with Na+, while the second step involves the translocation of K+ across the membrane to the outside of the cell. SSRIs bind to the same site on the transporter as 5-HT itself. Recently, elegant biochemical and mutagenesis experiments have elucidated a leucine transporter from bacterial species, providing information that may aid in unraveling the complex process by which mammalian transporters couple ions and substrates to mediate neurotransmitter clearance (Henry et al. 2006). In the brain, 5-HTTs have been radiolabeled with [3H]-imipramine (Hrdina et al. 1985; Langer et al. 1980) and with SSRIs such as [3H]cyanoimipramine (Wolf and Bobik 1988), [3H]paroxetine (Habert et al. 1985), and [3H]citalopram (D'Amato et al. 1987). The regional distribution of 5-HTT corresponds to discrete regions of rat brain known to contain cell bodies of 5-HT neurons and synaptic axon terminals, most notably the cerebral cortex, neostriatum, thalamus, and limbic areas (Cooper et al. 2001; Hrdina et al. 1990; Madden 2002). The specific cellular localization of 5-HTT in the CNS has also been accomplished by using site-specific antibodies (Lawrence et al. 1995a). Immunohistochemical studies utilizing antibodies against the 5-HT carrier have revealed both neuronal and glial staining in areas of the rat brain containing 5-HT somata and terminals (i.e., DR and hippocampus) (Lawrence et al. 1995b). Experimental alterations of 5-HTT in young mice for a brief period during early development indicate abnormal emotional behavior in the same mice later in life, similar to the phenotype in mice where 5-HTT is deficient throughout life (Ansorge et al. 2004). This suggests the necessity of 5-HT early in emotional development and provides a possible mechanism by which genetic changes in the 5-HTT system may lead to susceptibility to developing psychiatric diseases such as depression (Caspi et al. 2003). Furthermore, 5-HT uptake ability has been documented in primary astrocyte cultures (Kimelberg and Katz 1985) and has been postulated to account for considerable 5-HT uptake in the frontal cortex and periventricular region (Ravid et al. 1992). Since 5-HTT is transcribed from a single copy gene, abnormalities in platelet 5-HTT have been postulated to reflect CNS abnormalities (Owens and Nemeroff 1998). A number of studies on platelet 5-HTT density have been undertaken using [3H]imipramine binding or [3H]paroxetine binding in mood disorders. Although the results of these studies are not entirely consistent, in toto the results suggest that the Bmax value for platelet 5-HT density is significantly lower in depressed subjects compared with healthy control subjects (Owens and Nemeroff 1998).

Serotonin Receptors In 1957, the existence of two separate 5-HT receptors was first proposed primarily because of the opposing phenomenon this neurotransmitter produces in reference to cholinergic mediation of smooth muscle contraction (Gaddum and Picarelli 1957). Today, through the use of more precise molecular cloning and pharmacological and biochemical studies, seven distinct 5-HT receptor families have been identified (5-HT1–7), many of which contain several subtypes. With the exception of the 5-HT3 receptor, which is an excitatory ionotropic receptor, all the other 5-HT receptors are GPCRs. The 5-HT1A,B,D,E,F receptors are negatively coupled to adenylyl cyclase, the 5-HT2A,B,C subtypes are positively coupled to PLC, and the 5-HT4, 5-HT5, 5-HT6, and 5-HT7 subtypes are positively coupled to adenylyl cyclase (see Figure 1–3B) (Humphrey et al. 1993).

5-HT1 receptors 5-HT1A receptors are found in particularly high density in several limbic structures, including the hippocampus, septum, amygdala, and entorhinal cortex, as well as on serotonergic neuron cell bodies, where they serve as autoreceptors regulating 5-HT neuronal firing rates (Blier et al. 1998; Cooper et al. 2001; Pazos and Palacios 1985). The highest density of labeling is found in the DR, with lower densities observed in the remaining raphe nuclei (Pazos and Palacios 1985). The density and mRNA expression of 5-HT1A receptors appear insensitive to reductions in 5-HT transmission associated with lesioning the raphe or administering the serotonin-depleting agent p-chlorophenylalanine (PCPA). Similarly, elevation of 5-HT transmission resulting from chronic administration of an SSRI or monoamine oxidase inhibitor (MAOI) does not consistently alter 5-HT1A receptor density or mRNA in the cortex, hippocampus, amygdala, or hypothalamus. In contrast to the insensitivity to 5-HT, 5-HT1A receptor density is downregulated by adrenal steroids. Postsynaptic 5-HT1A receptor gene expression is under tonic inhibition by adrenal steroids in the hippocampus and some other regions. Thus, in rodents, hippocampal 5-HT1A receptor mRNA expression is increased by adrenalectomy and decreased by corticosterone administration or chronic stress. The stress-induced downregulation of 5-HT1A receptor expression is prevented by adrenalectomy. Mineralocorticoid receptor stimulation has the most potent effect on downregulating 5-HT1A receptors, although glucocorticoid receptor stimulation also contributes to this effect. In addition to being expressed on neurons, postsynaptic 5-HT1A receptors are also abundantly expressed by astrocytes and some other glia (WhitakerAzmitia et al. 1990) (see Figure 1–7 later in this chapter). Stimulation of astrocyte-based 5-HT1A sites causes astrocytes to acquire a more mature morphology and to release the trophic factor S-100 , which promotes growth and arborization of serotonergic axons. Administration of 5-HT1A receptor antagonists, antibodies to S-100 , or agents that deplete 5-HT produces similar losses of dendrites, spines, and/or synapses in adult and developing animals—effects that are blocked by administration of 5-HT1A receptor agonists or SSRIs. These observations have led to the hypothesis that a reduction of 5-HT1A receptor function may play an important role in mood disorders that are known to be associated with glial reductions (Manji et al. 2001). The use of conditional knockouts of the 5-HT1A receptor, in which gene expression is altered only in particular anatomical regions and/or during particular times, has illustrated the caution necessary in attributing complex behaviors to simple "too much" or "too little" neurotransmitter/receptor hypotheses. Using a knockout/rescue approach with regional and temporal specificity, Gross et al. (2002) demonstrated that the anxiety-related effect of the 5-HT1A receptor knockout was actually developmental. Specifically, expression limited to the hippocampus and cortex during early postnatal development was sufficient to counteract the anxious phenotype of the mutant, even though the receptor was still absent in adulthood (Gross et al. 2002). As is discussed in the chapters on antidepressants and axiolytics (see Chapters 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26), there is growing interest in the observation that antidepressants enhance hippocampal neurogenesis (Duman 2002; Malberg et al. 2000). It is noteworthy that preliminary data suggest that 5-HT1A receptor activation is required for SSRI-induced hippocampal neurogenesis in mice (Jacobs et al. 2000). Altering 5-HT levels with the SSRI fluoxetine does not affect division of stem cells in the dentate gyrus, but rather increases symmetric divisions of an early progenitor cell class that exists after stem cell division (Encinas et al. 2006). 5-HT1A receptors are now known to utilize a variety of signaling mechanisms to bring about their effects in distinct brain areas. Thus, somatodendritic 5-HT1A receptors appear to inhibit the firing of serotonergic neurons by opening a K+ channel through a pertussis toxin–sensitive G protein (likely Go, discussed later in the section on G proteins) (Andrade et al. 1986), as well as by reducing cAMP levels. Postsynaptic 5-HT1A receptors appear to exert many of their effects by inhibiting adenylyl cyclase via Gi (De Vivo and Maayani 1990) but have also been demonstrated to potentiate the activity of certain

adenylyl cyclases (Bourne and Nicoll 1993) and to stimulate inositol-1,4,5-triphosphate (IP3) production and activate PKC (Y. F. Liu and Albert 1991). 5-HT1D receptors are virtually absent in the rodent but have been detected in guinea pig and man (Bruinvels et al. 1993). On the basis of an approximately 74% sequence homology, it has been proposed that 5-HT1B receptors are the rodent homolog of 5-HT1D receptors (see Saxena et al. 1998). Furthermore, the distribution of the 5-HT1D receptors in guinea pig and man is roughly equivalent to that of the 5-HT1B receptors in the rat (Bruinvels et al. 1993). Both 5-HT1B and 5-HT1D receptors have been proposed to represent the major nerve terminal autoreceptors regulating the amount of 5-HT released per nerve impulse (Pineyro and Blier 1999) (see Figure 1–3B). Like 5-HT1A receptors, 5-HT1B and 5-HT1D receptors inhibit cAMP formation and stimulate IP3 production and activate PKC (Schoeffter and Bobirnac 1995). As we discuss later, this appears to be the case for many receptors coupled to Gi and Go (see Table 1–1). The

subunits of the G protein ( i and

o)

inhibit adenylyl cyclase and regulate ion channels, respectively, whereas the

subunits activate PLC

isozymes to stimulate IP3 production and activate PKC. Finally, it should be noted that the 5-HT1C receptor classification has been revoked, as these receptors have structural and transductional similarities to the 5-HT2 receptor class (Hoyer et al. 1986; Saxena et al. 1998).

5-HT2 receptors There are three subtypes of 5-HT2 receptors: 5-HT2A, 5-HT2B, and 5-HT2C. The highest level of 5-HT2A binding sites and mRNA for these receptors exists in the cortex, and these receptors have been implicated in the psychotomimetic effects of agents like lysergic acid diethylamide (LSD) (for a review, see Aghajanian and Marek 1999). In addition, lesioning of 5-HT neurons with 5,7-DHT does not reduce the 5-HT2 receptor density reported in brain regions (Hoyer et al. 1986), indicating that these receptors are primarily (if not exclusively) postsynaptic. Autoradiography performed with the potent and selective radioligand [3H]MDL 100,907 has localized 5-HT2A receptors to many similar brain regions in the rat and primate brain (Lopez-Gimenez et al. 1997). Recent experiments show that mice expressing 5-HT2A receptors only in the frontal cortex have conserved receptor signaling and behavioral responses to hallucinogenic drugs similar to those of wild-type littermates, suggestive of cortical importance (Gonzalez-Maeso et al. 2007). Competition studies with other radioligands (Westphal and Sanders-Bush 1994) and their mRNA distribution indicate that 5-HT2C receptors are considerably widespread throughout the CNS, with the highest density in the choroid plexus (Hoffman and Mezey 1989). 5-HT2B receptors are detected sparingly in the brain and are more prominently located in the fundus, gut, kidney, lungs, and heart (Hoyer et al. 1986). Several antidepressants (e.g., mianserin, mirtazapine) and antipsychotics (e.g., clozapine) bind to 5-HT2 receptors, raising the possibility that blockade of 5-HT2 receptors may play an important role in the therapeutic efficacy of these agents. Indeed, a leading hypothesis concerning the mechanism of action of atypical antipsychotic agents suggests that the ratio of D2/5-HT2 blockade confers "atypicality" properties on many currently available antipsychotic agents (Meltzer 2002). Evidence from animal experiments in which cortical 5-HT2A receptors are disrupted indicates a specific role of these receptors in modulation of conflict anxiety without affecting fear conditioning and depression-like behaviors (Weisstaub et al. 2006). Furthermore, chronic administration of many antidepressants downregulates 5-HT2 receptors, suggesting that this effect may be important for their efficacy (J. A. Scott and Crews 1986); however, chronic electroconvulsive shock (ECS) appears to upregulate 5-HT2 expression, precluding a simple mechanism for antidepressant efficacy. The obesity seen in 5-HT2C knockout animals suggests that in addition to histamine receptor blockade, 5-HT2C blockade may play a role in the weight gain observed with certain psychotropic agents; this is an area of considerable current research. In keeping, recent evidence suggests that the weight gain "orexigenic" properties of atypical antipsychotics are likely due to potent activation of hypothalamic AMP-kinase through histamine1 (H1) receptors (Kim et al. 2007). The regulation of 5-HT2 receptors is intriguing, as not only is it important in psychiatric disorders and therapeutic benefit, but both agonists and antagonists appear to cause an internalization of the receptor. Moreover, emerging data suggest that mRNA editing may play an important role in regulating the levels and activity of this receptor subtype (Niswender et al. 1998). All of the 5-HT2 receptor subtypes are linked to the phosphoinositide signaling system, and their activation produces IP3 and diacylglycerol (DAG), via PLC activation (Conn and Sanders-Bush 1987) (see Figure 1–3B). An exciting recent pharmacogenetic investigation searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and prospectively assessed (McMahon et al. 2006). In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. A significant and reproducible association was detected between treatment outcome and a marker in HTR2A (P = 1 x 10–6 to 3.7 x 10–5 in the total sample). The "A" allele (associated with better outcome) was six times more frequent in white than in black participants, for whom treatment was also less effective in this sample (McMahon et al. 2006). The "A" allele may thus contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.

5-HT3–7 receptors Unlike the other 5-HT receptors, 5-HT3 receptors are ligand-gated ion channels capable of mediating fast synaptic responses (see Figure 1–3B). The cis-trans isomerization and molecular rearrangement at proline 8 is the structural mechanism that opens the 5-HT3 receptor protein pore (Lummis et al. 2005). 5-HT3 receptors are present in multiple brain areas, including the hippocampus, dorsal motor nucleus of the solitary tract, and area postrema (Laporte et al. 1992). The 5-HT3 receptor is effectively modulated by a variety of compounds, such as alcohols and anesthetics, and antagonists against this receptor are used as effective antiemetics in patients who are undergoing chemotherapy (e.g., ondansetron). 5-HT4, 5-HT6, and 5-HT7 are GPCRs that are preferentially coupled to Gs and activate adenylyl cyclases (see Figure 1–3B). 5-HT4 receptors are able to modulate the release of monoamines and GABA in the brain. 5-HT5 receptors are located in the hypothalamus, hippocampus, corpus callosum, cerebral ventricles, and glia (Hoyer et al. 2002). The 5-HT5A receptor is negatively coupled to adenylyl cyclase, whereas the 5-HT5B receptor does not involve cAMP accumulation or phosphoinositide turnover. 5-HT6 receptors are located in the striatum, amygdala, nucleus accumbens, hippocampus, cortex, and olfactory tubercle (Hoyer et al. 2002). Of interest, many antipsychotic agents and antidepressants have high affinity for 5-HT6 receptors and act as antagonists at this receptor. 5-HT7 receptors have been localized to the cerebral cortex, medial thalamic nuclei, substantia nigra, central gray, and dorsal raphe nucleus (Hoyer et al. 2002). It appears that chronic treatment with antidepressants is able to downregulate this receptor, whereas acute stress has been reported to alter 5-HT7 expression (Sleight et al. 1995; Yau et al. 2001).

Dopaminergic System Dopamine (DA) was originally thought to simply be a precursor of norepinephrine (NE) and epinephrine synthesis, but the demonstration that its distribution in the brain was quite distinct to that of NE led to extensive research demonstrating its role as a unique critical neurotransmitter. DA synthesis requires transport of the amino acid L-tyrosine across the blood–brain barrier and into the cell. Once tyrosine enters the neuron, the rate-limiting step for DA synthesis is conversion of L-tyrosine to L -dihydroxyphenylalanine (L-dopa) by the enzyme tyrosine hydroxylase (TH); L-dopa is readily converted to dopamine and, hence, is used as a precursor strategy to correct a dopamine deficiency in the treatment of Parkinson's disease (Figure 1–4B). The activity of TH can be regulated by many factors, including the activity of catecholamine neurons; furthermore, catecholamines function as end-product inhibitors of TH by competing with a tetrahydrobiopterin cofactor (Cooper et al. 2001). In contrast to the widespread 5-HT and NE projections, DA neurons form more discrete circuits, with the nigrostriatal, mesolimbic, tuberoinfundibular, and tuberohypophysial pathways comprising the major CNS dopaminergic circuits (Figure 1–4A). The nigrostriatal circuit is composed of DA neurons from the mesencephalic reticular formation (region A8) and the pars compacta region of the substantia nigra (region A9) of the mesencephalon. These neurons give

rise to axons that travel via the medial forebrain bundle to innervate the caudate nucleus and putamen (see Anden et al. 1964; Ungerstedt 1971). The DA neurons that make up the nigrostriatal circuit have been assumed to be critical for maintaining normal motor control, since destruction of these neurons is associated with Parkinson's disease; however, it is now clear that these projections subserve a variety of additional functions. For example, recent evidence from human brain imaging studies indicates that a subject's ability to choose rewarding actions during instrumental learning tasks can be modulated by administration of drugs that enhance or reduce striatal DA receptor activation. This further implies that the DA reward pathway in the brain is likely convergent on many discrete brain circuits and neurotransmitter alterations, and it shows that striatal activity can also account for how the human brain proceeds toward making future decisions based on reward prediction (Pessiglione et al. 2006). The mesolimbic DA circuit consists of DA neurons located in the midbrain just medial to the A9 cells in an area termed the ventral tegmental area (VTA) (Cooper et al. 2001; Nestler et al. 2001; Squire et al. 2003). This circuit shares some similarities to the nigrostriatal circuit in that it is a parallel circuit consisting of axons that make up the medial forebrain bundle. However, these axons ascend through the lateral hypothalamus and project to the nucleus accumbens, olfactory tubercle, bed nucleus of the stria terminalis, lateral septum, and frontal, cingulate, and entorhinal regions of the cerebral cortex (Cooper et al. 2001). This circuit innervates many limbic structures known to play critical roles in motivational, motor, and reward pathways and has therefore been implicated in a variety of clinical conditions, including psychosis and drug abuse (Cooper et al. 2001). Data also suggest a potential role for dopamine—and, in particular, mesolimbic pathways—in the pathophysiology of bipolar mania as well as bipolar and unipolar depression (Beaulieu et al. 2004; Dunlop and Nemeroff 2007; Goodwin and Jamison 2007; Roybal et al. 2007). It is perhaps surprising that the role of the dopaminergic system in the pathophysiology of mood disorders has not received greater study, since it represents a prime candidate on a number of theoretical grounds. The motoric changes in bipolar disorder are perhaps the most defining characteristics of the illness, ranging from the near-catatonic immobility of depressive states to the profound hyperactivity of manic states. Similarly, loss of motivation is one of the central features of depression, whereas anhedonia and "hyperhedonic states" are among the most defining characteristics of bipolar depression and mania, respectively. In this context, it is noteworthy that the midbrain dopaminergic system is known to play a critical role in regulating not only motoric activity but also motivational and reward circuits. It is clear that motivation and motor function are closely linked and that motivational variables can influence motor output both qualitatively and quantitatively. Furthermore, there is considerable evidence that the mesolimbic dopaminergic pathway plays a crucial role in the selection and orchestration of goal-directed behaviors, particularly those elicited by incentive stimuli (Goodwin and Jamison 2007). The firing pattern of mesolimbic DA neurons appears to be an important regulatory mechanism; thus, in rats, electrical or glutamatergic stimulation of medial prefrontal cortex elicits a burst firing pattern of dopaminergic cells in the VTA and increases DA release in the nucleus accumbens (Murase et al. 1993; Taber and Fibiger 1993). The burst firing of DA cell activity elicits more terminal DA release per action potential than the nonbursting pacemaker firing pattern (Roth et al. 1987). The phasic burst firing of DA neurons and accompanying rise in DA release normally occur in response to primary rewards (until they become fully predicted) and reward-predicting stimuli. Such a role has also been postulated to provide a neural mechanism by which prefrontal cortex dysfunction could alter hedonic perceptions and motivated behavior in mood disorders (Drevets et al. 2002). Recent studies indicate that the amygdala is important in learning new cocaine drug-seeking responses as well as the habit-forming properties of cocaine (Lee et al. 2005), expanding our knowledge of drug addiction circuits in the brain.

Dopamine Transporters As with serotonin, the DA signal in the synaptic cleft is terminated primarily by reuptake into the presynaptic terminal. The dopamine transporter (DAT) comprises 12 putative transmembrane domains and is located somatodendritically as well as on DA nerve terminals (see Figure 1–4B). Like other monoamine transporters, the DAT functions as a Na+/K+ pump to clear DA from the synaptic cleft upon its release. However, data suggest that many drugs of abuse are capable of altering the function of these transporters. Thus, the amphetamines are thought to mediate their effects, in part, by reversing the direction of the transporter so that it releases DA. Cocaine is capable of blocking the reuptake of DAT, leading to an increase in DA in the synaptic cleft. Of interest, altered neuronal long-term potentiation in the VTA in response to chronic cocaine exposure has been recently linked to drug-associated memory and likely contributes to the powerful addictive potential of this drug of abuse (Q. S. Liu et al. 2005). DA in the medial frontal cortex is taken up predominantly by the NE transporter. Although the precise functional significance of this finding is not currently known, it goes against the dogma of transporters being able to selectively take up only their respective neurotransmitter. Furthermore, this provides a mechanism by which NE reuptake– inhibiting antidepressants may also increase synaptic levels of DA in the frontal cortex, effects that may be therapeutically very important.

Dopaminergic Receptors The existence of two subtypes of DA receptors, dopamine1 (D1) and dopamine2 (D2), was initially established using classic pharmacological techniques in the 1970s (Stoof and Kebabian 1984). Subsequent molecular biological studies have shown that the D1 family contains both the D1 and dopamine5 (D5) receptors, whereas the D2 family contains the D2, dopamine3 (D3), and dopamine4 (D4) receptors (Cooper et al. 2001). D1 receptor family members were originally defined solely on the ability to stimulate adenylyl cyclase (AC), while the D2 family inhibited the enzyme. Interestingly, DA receptors complexed with subunits from other subclasses of DA receptors within a receptor family are able to form distinct hetero-oligomeric receptors (also termed "kissing cousin receptors"). Notably, hetero-oligomeric D1–D2 receptor complexes in the brain require binding to active sites of both receptor subtypes to induce activation of the hetero-oligomeric receptor complex. These receptors have been demonstrated to use traditional D1 receptor intracellular signaling components of Gq/11 and Ca2+/calmodulin–dependent protein kinase II (CaMKII) second-messenger activation as demonstrated in the nucleus accumbens (Rashid et al. 2007). This work suggests possible avenues through which the brain might use different receptor subunit proportions to further fine-tune brain neurophysiology.

D1 and D5 receptors The D1 and D5 receptors stimulate adenylyl cyclase activity via the activation of Gs or Golf (a G protein originally thought to be present exclusively in olfactory tissue but now known to be abundantly present in limbic areas) (see Figure 1–4B). Other second-messenger pathways have also been reported to be activated by D1 receptors, effects that may play a role in the reported D1–D2 cross-talk (Clark and White 1987). The frontal cortex contains almost exclusively D1 receptors (Clark and White 1987), suggesting that this receptor may play an important role in higher cognitive function and perhaps in the actions of medications like methylphenidate. The D5 receptor is a neuron-specific receptor that is located primarily in limbic areas of the brain.

D2 receptors Four types of D2 receptors have been identified. The two subtypes of D2 receptors (the short and long forms, D2S and D2L, respectively) are derived from alternative splicing of the D2 gene. Although a seemingly identical pharmacological profile for these receptors exists, there are undoubtedly (yet to be discovered) physiological differences between the two subtypes. D2 receptors mediate their cellular effects via the Gi/Go proteins and thereby several effectors (see Figure 1–4B). In addition to the well-characterized inhibition of adenylyl cyclase, D2 receptors in different brain areas also regulate PLC, bring changes in K+ and Ca2+ currents, and possibly regulate phospholipase A2. D2 receptors are located on cell bodies and nerve terminals of DA neurons and function as autoreceptors. Thus, activation of somatodendritic D2 receptors reduces DA neuron firing activity, likely via opening of K+ channels, whereas activation of nerve-terminal D2 autoreceptors reduces the amount of DA released per nerve impulse, in large part by closing voltage-gated Ca2+ channels. As discussed extensively in Chapters 27 and 46, D2 receptors have long been implicated in the pathophysiology and treatment of schizophrenia. Recently, transgenic mice overexpressing D2 receptors in the striatum have been found to display many phenotypic hallmarks of schizophrenia (Kellendonk et al. 2006).

D3 receptors D3 receptors possess a different anatomical distribution than do D2 receptors and, because of their preferential limbic expression, have been postulated to represent an important target for antipsychotic drugs. Numerous studies have investigated the position association of a polymorphism in the coding sequence of the D3 receptor with schizophrenia, with equivocal results. It has been suggested that brain-derived neurotrophic factor (BDNF) may regulate behavioral sensitization via its effects on D3 receptor expression (Guillin et al. 2001).

D4 receptors The D4 receptor has received much interest in psychopharmacological research in recent years because of the fact that clozapine has a high affinity for this receptor. Studies are currently underway that are investigating more selective D4 antagonists as adjunctive agents in the treatment of schizophrenia. Furthermore, considerable attention has focused on the possibility that genetic D4 variants may be associated with thrill-seeking behavior (Zuckerman 1985), attention-deficit/hyperactivity disorder (Roman et al. 2001), and responsiveness to clozapine (Van Tol et al. 1992).

Noradrenergic System Named sympathine because it was initially encountered as being released by sympathetic nerve terminals, the molecule was later given the name norepinephrine after meeting the criteria for a neurotransmitter in the CNS (see Cooper et al. 2001). NE is produced from the amino acid precursor L -tyrosine

found in neurons in the brain, chromaffin cells, sympathetic nerves, and ganglia. The enzyme dopamine -hydroxylase (DBH) converts DA to NE,

and as is the case for DA synthesis, tyrosine hydroxylase is the rate-limiting enzyme for NE synthesis (Figure 1–5B). The dietary depletion of tyrosine and -methyl-p-tyrosine (a TH inhibitor) has played an important part in efforts aimed at delineating the role of catecholamines in the pathophysiology and treatment of mood and anxiety disorders (Coupland et al. 2001; McCann et al. 1995). FIGURE 1–5. The noradrenergic system.

This figure depicts the noradrenergic projections throughout the brain (A) and the various regulatory processes involved in norepinephrine (NE) neurotransmission (B). NE neurons innervate nearly all parts of the neuroaxis, with neurons in the locus coeruleus being responsible for most of the NE in the brain (90% of NE in the forebrain and 70% of total NE in the brain). The amino acid L-tyrosine is actively transported into presynaptic NE nerve terminals, where it is ultimately converted into NE. The rate-limiting step is conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa) by the enzyme tyrosine hydroxylase (TH).

-Methyl-p-tyrosine (AMPT) is a competitive inhibitor of tyrosine

hydroxylase and has been used to assess the impact of reduced catecholaminergic function in clinical studies. Aromatic amino acid decarboxylase (AADC) converts L-dopa to dopamine (DA). L-dopa then becomes decarboxylated by decarboxylase to form dopamine (DA). DA is then taken up from the cytoplasm into vesicles, by vesicle monoamine transporters (VMATs), and hydroxylated by dopamine

-hydroxylase (DBH) in the presence of O2 and ascorbate to form NE. Normetanephrine (NM), which is formed by the

action of COMT (catechol-O-methyltransferase) on NE, can be further metabolized by monoamine oxidase (MAO) and aldehyde reductase to 3-methoxy4-hydroxyphenylglycol (MHPG). Reserpine causes a depletion of NE in vesicles by interfering with uptake and storage mechanisms (depressive-like symptoms have been reported with this hypertension). Once released from the presynaptic terminal, NE can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic regulation of NE neuron firing activity and release occurs through somatodendritic (not shown) and nerve-terminal

2

adrenoreceptors, respectively. Yohimbine potentiates

NE neuronal firing and NE release by blocking these

2

adrenoreceptors, thereby disinhibiting these neurons from a negative feedback influence. Conversely, clonidine

attenuates NE neuron firing and release by activating these receptors. Idazoxan is a relatively selective 2 adrenoreceptor antagonist primarily used for pharmacological purposes. The binding of NE to G protein receptors (Go , Gi, etc.) that are coupled to adenylyl cyclase (AC) and phospholipase C– (PLC-b) produces a cascade of secondmessenger and cellular effects (see diagram and later sections of the text). NE has its action terminated in the synapse by rapidly being taken back into the presynaptic neuron via NE transporters (NETs). Once inside the neuron, it can either be repackaged into vesicles for reuse or undergo enzymatic degradation. The selective NE reuptake inhibitor and antidepressant reboxetine and older-generation tricyclic antidepressant desipramine are able to interfere/block the reuptake of NE. On the other hand, amphetamine is able to facilitate NE release by altering NET function. Green spheres represent DA neurotransmitters; blue spheres represent NE neurotransmitters. DAG = diacylglycerol; IP3 = inositol-1,4,5-triphosphate. Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nestler et al. 2001. There are seven NE cell groups in the mammalian CNS, designated A1 through A7. In the brain stem, these are the lateral tegmental neurons (A5 and A7) and the locus coeruleus (A6) (Dahlstrom 1971) (see Figure 1–5B). In general, the projections from A5 and A7 are more restricted to brain stem areas and do not interact with those of A6. The term locus coeruleus (LC) was derived from the Greek because of its saddle shape and its "bluish color" (caeruleum). The LC is the most widely projecting CNS nucleus known (Foote et al. 1983), responsible for approximately 90% of the NE innervation of the forebrain and 70% of the total NE in the brain (Figure 1–5A). Indeed, the LC NE neurons, although small in number, constitute a diffuse system of projections to widespread brain areas via highly branched axons. The extensive efferent innervation suggests that the LC plays a modulatory and integrative role, rather than a role in specific sensory or motor processing (Foote et al. 1983). A number of physiological roles have been ascribed to the LC, notably in the control of vigilance and the initiation of adaptive behavioral responses (Foote et al. 1983). Considerable data support the hypothesis that NE neurons in the LC constitute a CNS response or defense system, since the neurons are activated by "challenges" in both the behavioral/environmental and the physiological domains (Jacobs et al. 1991). Thus, while a variety of sensory stimuli are capable of increasing LC activity, noxious or stressful stimuli are particularly potent in this regard. Moreover, considerable evidence also supports a role for LC NE neurons in the learning of aversively motivated tasks and in the conditioned response to stressful stimuli (Rasmussen et al. 1986a, 1986b), with obvious implications for a variety of psychiatric conditions (see Gould et al. 2003; Szabo and Blier 2001). Indeed, tonic activation of the LC appears to occur preferentially in the response to stressful stimuli, in contrast to stimuli limited to simply evoking activation or arousal (Rasmussen et al. 1986a, 1986b).

Norepinephrine Transporter The norepinephrine transporter (NET), the first of the monoamine transporters to be cloned in humans, transports NE from the synaptic cleft back into the neuron (Pacholczyk et al. 1991). Like other monoamine transporters, NET comprises 12 putative transmembrane domains, and autoradiography with various NE reuptake inhibitors has been used to determine the brain distribution of NET. A high level of NET is found in the LC, with moderate to high levels found in the dentate gyrus, raphe nuclei, and hippocampus (Tejani-Butt and Ordway 1992; Tejani-Butt et al. 1990). This pattern of expression is consistent with the NE innervation to these structures. The NET is expressed mainly on NE terminals, as demonstrated by a drastic reduction in labeling following NE destruction with the neurotoxin 6-hydroxydopamine or DSP-4 (Tejani-Butt and Ordway 1992; Tejani-Butt et al. 1990). The NET is dependent on extracellular Na+ to mediate NE reuptake and the effectiveness of NE reuptake inhibitors in inhibiting NE reuptake (Bruss et al. 1997, 1999; Harder and Bonisch 1985). The uptake of NE is Cl– dependent, meaning that the electrogenic process of NE transport is Na+ and Cl– driven (Harder and Bonisch 1985). In addition to the electrogenic process, the NET demonstrates properties of a channel-like pore, in that it can transport NE showing an infinite stoichiometry that can be blocked by cocaine and desipramine (Galli et al. 1995, 1996). A number of studies suggest that NET can be regulated by diverse stimuli, neuronal activity, and peptide hormones, as well as protein kinases. Indeed, studies have shown that all monoaminergic transporters (5-HTT, DAT, and NET) are rapidly regulated by direct or receptor-mediated activation of cellular kinases, particularly PKC (Bauman et al. 2000). PKC activation results in an activity-dependent transporter phosphorylation and sequestration. Protein phosphatase–1/2A (PP-1/PP-2A) inhibitors, such as okadaic acid and calyculin A, also promote monoaminergic transporter phosphorylation and functional downregulation (Bauman et al. 2000). These phenomena that occur beyond the receptor level may well be important in the long-term actions of psychotropic drugs known to regulate protein kinases (G. Chen et al. 1999; Manji and Lenox 1999).

Adrenergic Receptors The 3

and

catecholamine receptors were first discovered more than 50 years ago (Alhquist 1948) and later subdivided further into 1,

2,

and

1,

2,

and

adrenoreceptors—all of which are GPCRs—on the basis of molecular cloning and pharmacological and biochemical studies (see Figure 1–5B).

receptors There are three subtypes of

1

receptors, denoted 1A, 1B, and 1D; they are all positively coupled to PLC and possibly phospholipase A2 (see Figure 1–5B).

The 2 family comprises the 2A/D, 2B, and 2C subtypes, which couple negatively to adenylyl cyclase and regulate K+ and Ca2+ channels (see Figure 1–5B). The 2A, 2B, and 2C adrenoceptors correspond to the human genes 2-C10, 2-C2, and 2-C4, respectively (see Bylund et al. 1994). The bovine, guinea pig, rat, and mouse a2D adrenoreceptor is thought to be a species homolog or variant of the human to as

2A

adrenoreceptor (Bylund et al. 1994) and is often referred

2A/D.

The 2 receptors represent autoreceptors for NE neurons, and blockade of these autoreceptors results in increased NE release—a biochemical effect that has been postulated to play a role in the mechanisms of action of selected antidepressants (e.g., mianserin, mirtazapine) and antipsychotics (e.g., clozapine). In the LC,

2-adrenergic

receptors converge onto similar K+ channels as

represent a mechanism for the efficacy of clonidine (an

opioid receptors, and this convergence has been postulated to

agonist) in attenuating some of the physical symptoms of opioid withdrawal. The 2 antagonist yohimbine, which robustly increases NE neuron firing and NE release, has been used as a provocative challenge in clinical studies of anxiety disorders and 2

as an antidepressant-potentiating agent. Given that NE neurons colocalize and release orexins, it is of interest that this neuropeptide has been implicated in sleep disorders and hypoglycemia through its glucose-sensing tandem-pore K+ (K2P) effects in coordinating arousal (M. M. Scott et al. 2006).

receptors The

receptor family comprises

1,

2,

and

3

adrenoreceptors, which are all positively coupled to adenylyl cyclase (Bylund et al. 1994) (see Figure 1–5B).

As is discussed in greater detail in the chapters on antidepressants and anxiolytics (see Chapters 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26), most effective antidepressants produce a downregulation/desensitization of may play a role in their therapeutic efficacy. Interestingly, proposal that

1

receptors in rat forebrain, leading to the suggestion that these effects

receptors have also been shown to play a role in regulating emotional memories, leading to the

antagonists may have utility in the treatment of posttraumatic stress disorder (PTSD) (Cahill et al. 1994; Przybyslawski et al. 1999).

3

receptors are not believed to be present in the CNS but are abundantly expressed on brown fat, where they exert lipolytic and thermogenic effects. Not surprisingly, there is active research attempting to develop selective 3 agonists for the treatment of obesity.

Cholinergic System ACh is the only major low-molecular-weight neurotransmitter substance that is not derived from an amino acid (Kandel et al. 2000). ACh is synthesized from acetyl coenzyme A and choline in nerve terminals via the enzyme choline acetyltransferase (ChAT). Choline is transported into the brain by uptake from the bloodstream and enters the neuron via both high-affinity and low-affinity transport processes (Cooper et al. 2001). In addition to the "standard"

ChAT pathway, there are several additional possible mechanisms by which ACh can be synthesized; the precise roles of these additional pathways and their physiological relevance in the CNS remain to be fully elucidated (Cooper et al. 2001). The highest activity of ChAT is observed in the interpeduncular nucleus, caudate nucleus, corneal epithelium, retina, and central spinal roots. In contrast to the other transmitters discussed thus far (which are most dependent on reuptake mechanisms), ACh has its signal terminated primarily by the enzyme acetylcholine esterase, which degrades ACh (Figure 1–6B). Not surprisingly, therapeutic strategies to increase synaptic ACh levels (e.g., for the treatment of Alzheimer's disease) have focused on inhibiting the activity of cholinesterases. FIGURE 1–6. The cholinergic system.

This figure depicts the cholinergic pathways in the brain (A) and various regulatory processes involved in cholinergic neurotransmission (B). Choline crosses the blood–brain barrier to enter the brain and is actively transported into cholinergic presynaptic terminals by an active uptake mechanism (requiring ATP). This neurotransmitter is produced by a single enzymatic reaction in which acetyl coenzyme A (AcCoA) donates its acetyl group to choline by means of the enzyme choline acetyltransferase (ChAT). AcCoA is primarily synthesized in the mitochondria of neurons. Upon its formation, acetylcholine (ACh) is sequestered into secretory vesicles by vesicle ACh transporters (VATs), where it is stored. Vesamicol effectively blocks the transport of ACh into vesicles. An agent such as -bungarotoxin or AF64 A is capable of increasing synaptic concentration of ACh by acting as a releaser and a noncompetitive reuptake inhibitor, respectively. In turn, agents such as botulinum toxin are able to attenuate ACh release from nerve terminals. Once released from the presynaptic terminals, ACh can interact with a variety of presynaptic and postsynaptic receptors. In contrast to many other monoaminergic neurotransmitters, the ACh signal is terminated primarily by degradation by the enzyme acetylcholinesterase (AChE) rather than by reuptake. Interestingly, AChE is present on both presynaptic and postsynaptic membranes and can be inhibited by physostigmine (reversible) and soman (irreversible). Currently, AChE inhibitors such as donepezil and galantamine are the only classes of agents that are FDA approved for the treatment of Alzheimer's disease. ACh receptors are of two types: muscarinic (G protein– coupled) and nicotinic (ionotropic). Presynaptic regulation of ACh neuron firing activity and release occurs through somatodendritic (not shown) and nerve terminal M2 autoreceptors, respectively. The binding of ACh to G protein–coupled muscarinic receptors that are negatively coupled to adenylyl cyclase (AC) or coupled to phosphoinositol hydrolysis produces a cascade of second-messenger and cellular effects (see diagram). ACh also activates ionotropic nicotinic receptors (nAChRs). ACh has it action terminated in the synapse through rapid degradation by AChE, which liberates free choline to be taken back into the presynaptic neuron through choline transporters (CTs). Once inside the neuron, it can be reused for the synthesis of ACh, can be repackaged into vesicles for reuse, or undergoes enzymatic degradation. There are some relatively new agents that selectively antagonize the muscarinic receptors, such as CI-1017 for M1, methoctramine for M2, 4-DAMP for M3, PD-102807 for M4, and scopolamine (hardly a new agent) for M5 (although it also has affinity for M3 receptor). nAChR or nicotine receptors are activated by nicotine and the specific alpha(4)beta(2*) agonist metanicotine. Mecamylamine is an AChR antagonist. DAG = diacylglycerol; IP3 = inositol-1,4,5-triphosphate. Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nestler et al. 2001. Several cholinergic pathways have been proposed, but until recently the circuits had not been worked out in the brain because of the lack of appropriate techniques. The development of tract tracing and histochemical techniques has provided a clearer picture of the cholinergic pathways. In brief, cholinergic neurons can act as local circuit neurons (interneurons) and are found in the caudate putamen, nucleus accumbens, olfactory tubercle, and islands of Calleja complex (Cooper et al. 2001). They do, however, also serve to function as projection neurons that connect different brain regions; one fairly

well-characterized pathway runs from the septum to the hippocampus (Figure 1–6A). The basal forebrain cholinergic complex is composed of cholinergic neurons originating from the medial septal nucleus, diagonal band nuclei, substantia innominata, magnocellular preoptic field, and nucleus basalis. These nuclei project cholinergic neurons to the entire nonstriatal telencephalon, pontomesencephalotegmental cholinergic complex, thalamus, and other diencephalic loci (see Figure 1–6A). Descending cholinergic projections from these nuclei also innervate pontine and medullary reticular formations, deep cerebellar and vestibular nuclei, and cranial nerve nuclei (Cooper et al. 2001).

Cholinergic Receptors There are two major distinct classes of cholinergic receptors, the muscarinic and nicotinic receptors. Five muscarinic receptors (M1 through M5) have been cloned (Kandel et al. 2000). These receptors are G protein–coupled and act either by regulating ion channels (in particular, K+ or Ca2+) or through being linked to second-messenger systems. Generally speaking, M1, M3, and M5 are coupled to phosphoinositol hydrolysis, whereas M2 and M4 are coupled to inhibition of adenylyl cyclase and regulation of K+ and Ca2+ channels (Cooper et al. 2001) (see Figure 1–6B). By contrast, the nicotinic receptors are ionotropic receptors, and at least seven different functional receptors (based on different subunit composition) have been identified. Biochemical and biophysical data indicate that the nicotinic receptors in the muscle are formed from five protein subunits, with the stoichiometry of

2

(Kandel et al. 2000). The binding of ACh molecules on the

nicotinic receptors contain only two types of subunits (

and

), with the

subunit is necessary for channel activation. By contrast, neuronal

occurring in at least seven different forms and the

in three (Cooper et al.

2001). Nicotinic receptors may be the targets of considerable cross-talk, as a variety of kinases (including PKA, PKC, and tyrosine kinases) are able to regulate the sensitivity of this receptor. A number of regulatory mechanisms exist. For example, the mammalian prototoxin lynx1 acts as an allosteric modulator of nicotinic acetylcholine receptors (Miwa et al. 2006). From a clinical standpoint, Freedman et al. (1997) demonstrated that in a cohort of patients with schizophrenia, abnormal P50 auditory evoked potentials were linked to a susceptibility locus for this disease on chromosome 15. Notably, this is where a nicotinic receptor subunit is found, providing indirect support for the long-standing contention that the high rates of cigarette smoking in patients with schizophrenia may represent (at least in part) an attempt to correct an underlying nicotinic receptor defect.

Glutamatergic System Glutamate and aspartate are the two major excitatory amino acids in the CNS and are present in high concentrations (Nestler et al. 2001; Squire et al. 2003). As the principal mediators of excitatory synaptic transmission in the mammalian brain, they participate in wide-ranging aspects of both normal and abnormal CNS function. Physiologically, glutamate appears to play a prominent role in synaptic plasticity, learning, and memory. However, glutamate can also be a potent neuronal excitotoxin under a variety of experimental conditions, triggering either rapid or delayed neuronal death. Unlike the monoamines, which require transport of amino acids through the blood–brain barrier, glutamate and aspartate cannot adequately penetrate into the brain from the periphery and are produced locally by specialized brain machinery. The metabolic and synthetic enzymes responsible for the formation of these nonessential amino acids are located in glial cells as well as neurons (Squire et al. 2003). The major metabolic pathway in the production of glutamate is derived from glucose and the transamination of

-ketoglutarate; however, a small proportion

of glutamate is formed directly from glutamine. The latter is actually synthesized in glia, via an active process (requiring adenosine triphosphate [ATP]), and is then transported to neurons where glutaminase is able to convert this precursor to glutamate (Figure 1–7). Following release, the concentration of glutamate in the extracellular space is highly regulated and controlled, primarily by a Na+-dependent reuptake mechanism involving several transporter proteins. FIGURE 1–7. The glutamatergic system.

This figure depicts the various regulatory processes involved in glutamatergic neurotransmission. The biosynthetic pathway for glutamate involves synthesis from glucose and the transamination of -ketoglutarate; however, a small proportion of glutamate is formed more directly from glutamine by glutamine synthetase. The latter is actually synthesized in glia and, via an active process (requiring ATP), is transported to neurons, where in the mitochondria glutaminase is able to convert this precursor to glutamate. Furthermore, in astrocytes glutamine can undergo oxidation to yield -ketoglutarate, which can also be transported to neurons and participate in glutamate synthesis. Glutamate is either metabolized or sequestered and stored in secretory vesicles by vesicle glutamate transporters (VGluTs). Glutamate can then be released by a calciumdependent excitotoxic process. Once released from the presynaptic terminal, glutamate is able to bind to numerous excitatory amino acid (EAA) receptors, including both ionotropic (e.g., NMDA [N-methyl-D-aspartate]) and metabotropic (mGluR) receptors. Presynaptic regulation of glutamate release occurs through metabotropic glutamate receptors (mGluR2 and mGluR3), which subserve the function of autoreceptors; however, these receptors are also located on the postsynaptic element. Glutamate has its action terminated in the synapse by reuptake mechanisms utilizing distinct glutamate transporters (labeled VGT in figure) that exist on not only presynaptic nerve terminals but also astrocytes; indeed, current data suggest that astrocytic glutamate uptake may be more important for clearing excess glutamate, raising the possibility that astrocytic loss (as has been documented in mood disorders) may contribute to deleterious glutamate signaling, but more so by astrocytes. It is now known that a number of important intracellular proteins are able to alter the function of glutamate receptors (see diagram). Also, growth factors such as glial-derived neurotrophic factor (GDNF) and S100 secreted from glia have been demonstrated to exert a tremendous influence on glutamatergic neurons and synapse formation. Of note, serotonin1A (5-HT1A) receptors have been documented to be regulated by antidepressant agents; this receptor is also able to modulate the release of S100 . AKAP = A kinase anchoring protein; CaMKII = Ca2+/calmodulin–dependent protein kinase II; ERK = extracellular response kinase; GKAP = guanylate kinase–associated protein; Glu = glutamate; Gly = glycine; GTg = glutamate transporter glial; GTn = glutamate transporter neuronal; Hsp70 = heat shock protein 70; MEK = mitogen-activated protein kinase/ERK; mGluR = metabotropic glutamate receptor; MyoV = myosin V; NMDAR = NMDA receptor; nNOS = neuronal nitric oxide synthase; PKA = phosphokinase A; PKC = phosphokinase C; PP-1, PP-2A, PP-2B = protein phosphatases; RSK = ribosomal S6 kinase; SHP2 = src homology 2 domain–containing tyrosine phosphatase. Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nicholls 1994. The major glutamate transporter proteins found in the CNS include the excitatory amino acid transporters (EAATs) EAAT1 (or GLAST-1), EAAT2 (or GLT-1), and EAAT3 (or EAAC1), with EAAT2 being the most predominantly expressed form in the forebrain. Additionally, these transporters are differentially expressed in specific cell types, with EAAT1 and EAAT2 being found primarily in glial cells and EAAT3 being localized in neurons. EAAT4 is mainly localized in cerebellum. The physiological events regulating the activity of the glutamate transporters are not well understood, although there is evidence that phosphorylation of the transporters by protein kinases may differentially regulate glutamate transporters and therefore glutamate reuptake (Casado et al.

1993; Conradt and Stoffel 1997; Pisano et al. 1996). Glutamate concentrations have been shown to rise to excitotoxic levels within minutes following traumatic or ischemic injury, and there is evidence that the function of the glutamate transporters becomes impaired under these excitotoxic conditions (Faden et al. 1989). It is surprising that the glutamatergic system has only recently undergone extensive investigation with regard to its possible involvement in the pathophysiology of mood disorders, since it is the major excitatory neurotransmitter in the CNS and known to play a role in regulating the threshold for excitation of most other neurotransmitter systems. Although direct evidence for glutamatergic excitotoxicity in bipolar disorder is lacking and the precise mechanisms underlying the cell atrophy and death that occur in recurrent mood disorders are unknown, considerable data have shown that impairments of the glutamatergic system play a major role in the morphometric changes observed with severe stresses (McEwen 1999; Sapolsky 2000). It is now clear that modification of the levels of synaptic AMPA-type glutamate receptors—in particular by receptor subunit trafficking, insertion, and internalization—is a critically important mechanism for regulating various forms of synaptic plasticity and behavior. Recent studies have identified regionspecific alterations in expression levels of AMPA and NMDA glutamate receptor subunits in subjects with mood disorders (Beneyto et al. 2007). Supporting the suggestion that abnormalities in glutamate signaling may be involved in mood pathophysiology, AMPA receptors have been shown to regulate affective-like behaviors in rodents. AMPA antagonists have been demonstrated to attenuate amphetamine- and cocaine-induced hyperactivity and psychostimulant-induced sensitization and hedonic behavior (Goodwin and Jamison 2007).

Glutamatergic Receptors The many subtypes of glutamatergic receptors in the CNS can be classified into two major subtypes: ionotropic and metabotropic receptors (see Figure 1–7).

Ionotropic glutamate receptors The ionotropic glutamate receptor ion channels are assemblies of homo- or hetero-oligomeric subunits integrated into the neuron's membrane. Every channel is assembled of (most likely) four subunits associated into a dimer of dimers as has been observed in crystallographic studies (Ayalon and Stern-Bach 2001; Madden 2002). Every subunit consists of an extracellular amino-terminal and ligand binding domain, three transmembrane domains, a reentrant pore loop (located between the first and second transmembrane domains), and an intracellular carboxyl-terminal domain (Hollmann et al. 1994). The subunits associate through interactions between their amino-terminal domains, forming a dimer that undergoes a second dimerization mediated by interactions between the ligand binding domains and/or between transmembrane domains (Ayalon and Stern-Bach 2001; Madden 2002). Three different subgroups of glutamatergic ion channels have been identified on the basis of their pharmacological ability to bind different synthetic ligands, each of which is composed of a different set of subunits. The three subgroups are the NMDA receptors, the AMPA ( -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, and the kainate receptor. The latter two groups are often referred to together as the "non-NMDA" receptors, but they undoubtedly subserve unique functions (see Figure 1–7). In the adult mammalian brain, NMDA and AMPA glutamatergic receptors are collocated in approximately 70% of the synapses (Bekkers and Stevens 1989). By contrast, at early stages of development, synapses are more likely to contain only NMDA receptors. Radioligand binding studies have shown that NMDA and AMPA receptors are found in high density in the cerebral cortex, hippocampus, striatum, septum, and amygdala.

NMDA receptors The NMDA receptor is activated by glutamate and requires the presence of a co-agonist, namely glycine or D-serine, to be activated, a process that likely varies in importance according to brain region (Panatier et al. 2006). However, the binding of both glutamate and glycine is still not sufficient for the NMDA receptor channel to open, since at resting membrane potential, the NMDA ion channel is blocked by Mg2+ ions. Only when the membrane is depolarized (e.g., by the activation of AMPA or kainate receptors on the same postsynaptic neuron) is the Mg2+ blockade relieved. Under these conditions, the NMDA receptor channel will open and permit the entry of both Na+ and Ca2+ (see Figure 1–7). The NMDA receptor channel is composed of a combination of NR1, NR2A, NR2B, NR2C, NR2D, NR3A, and NR3B subunits (see Figure 1–7). The binding site for glutamate has been localized to the NR2 subunit, and the site for the co-agonist glycine has been localized to the NR1 subunit, which is required for receptor function. Two molecules of glutamate and two of glycine are thought to be necessary to activate the ion channel. Within the ion channel, two other sites have been identified—the sigma ( ) site and the phencyclidine (PCP) site. The hallucinogenic drug PCP, ketamine, and the experimental drug dizocilpine (MK-801) all bind at the latter site and are considered noncompetitive receptor antagonists that inhibit NMDA receptor channel function. In clinical psychiatric studies, ketamine has been shown to transiently induce psychotic symptoms in schizophrenic patients and to produce antidepressant effects in some depressed patients (Krystal et al. 2002). Building on these preclinical and preliminary clinical data, recent clinical trials have investigated the clinical effects of glutamatergic agents in subjects with mood disorders. Recent clinical studies have demonstrated effective and rapid antidepressant action of glutamatergic agents, including ketamine, an NMDA receptor antagonist, and riluzole, a glutamate release inhibitor (Sanacora et al. 2007; Zarate et al. 2006a). These and other data have led to the hypothesis that alterations in neural plasticity in critical limbic and reward circuits, mediated by increasing the postsynaptic AMPA-to-NMDA throughput, may represent a convergent mechanism for antidepressant action (Zarate et al. 2006b). This line of research holds considerable promise for developing new treatments for depression and bipolar disorder. The NMDA receptor agonists glycine, D-serine, and D-cycloserine

have been shown to improve cognition and decrease negative symptoms in patients with schizophrenia who are receiving antipsychotics

(Coyle et al. 2002). NMDA receptors in the amygdala may also be of critical importance in the process of transforming a fixed and consolidated fear memory to a labile state (Ben Mamou et al. 2006). NMDA receptors play a critical role in regulating synaptic plasticity (Malenka and Nicoll 1999). The best-studied forms of synaptic plasticity in the CNS are long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission. The molecular mechanisms of LTP and LTD have been extensively characterized and have been proposed to represent cellular models of learning and memory (Malenka and Nicoll 1999). Induction of LTP and LTD in the CA1 region of the hippocampus and in many regions of the brain has now clearly been demonstrated to be dependent on NMDA receptor activation. During NMDA receptor–dependent synaptic plasticity, Ca2+ influx through NMDA receptors can activate a wide variety of kinases and/or phosphatases that in turn modulate synaptic strength. An important development was the finding that two of the primary molecules involved—CaMKII and the NMDA subtype of glutamate receptor—form a tight complex with each other at the synapse (Lisman and McIntyre 2001). Interestingly, this binding appears to enhance both the autophosphorylation of the kinase and the ability of the entire holoenzyme, which has 12 subunits, to become hyperphosphorylated (Lisman and McIntyre 2001). This hyperphosphorylated state has been postulated to represent a "memory switch" that can lead to long-term strengthening of the synapse by multiple mechanisms. One important mechanism involves direct phosphorylation of the glutamate-activated AMPA receptors, which increases their conductance. Furthermore, CaMKII, once bound to the NMDA receptor, may organize additional anchoring sites for AMPA receptors at the synapse. Switching of synaptic NMDA receptor subunits, which bind CaMKII, for other NMDA receptor subunits having no affinity for this enzyme dramatically reduces LTP, demonstrating that glutamate and calcium signaling interactions are critical for learning and memory (Barria and Malinow 2005). While the NMDA receptor clearly plays important roles in plasticity, abundant evidence has shown that excessive glutamatergic signaling is also involved in neuronal toxicity. With anoxia or hypoglycemia, the highly energy-dependent uptake mechanisms that keep glutamate compartmentalized in presynaptic terminals fail. Within minutes, glutamate is massively released into the synaptic space, resulting in activation of excitatory amino acid receptors. This leads to depolarization of target neurons via AMPA and kainate receptors and then to inappropriate and excessive activation of NMDA receptors. Considerable data suggest that the large excess of Ca2+ entering cells via the NMDA receptor channel may represent an important step in the rapid cell death that occurs

via excitotoxicity.

AMPA receptors The AMPA receptor is stimulated by the presence of glutamate and characteristically produces a fast excitatory synaptic signal that is responsible for the initial reaction to glutamate in the synapse. In fact, as discussed above, it is generally believed that it is the activation of the AMPA receptor that results in neuronal depolarization sufficient to liberate the Mg2+ cation from the NMDA receptor, thereby permitting its activation. The AMPA receptor channel is composed of the combination of the GluR1, GluR2, GluR3, and GluR4 subunits and requires two molecules of glutamate to be activated (see Figure 1–7). AMPA receptors have a lower affinity for glutamate than does the NMDA receptor, thereby allowing for more rapid dissociation of glutamate and, therefore, a rapid deactivation of the AMPA receptor (for a review, see Dingledine et al. 1999). Studies have indicated that AMPA receptor subunits are direct substrates of protein kinases and phosphatases. Phosphorylation of the receptor subunits regulates not only the intrinsic channel properties of the receptor but also the interaction of the receptor with associated proteins that modulate the membrane trafficking and synaptic targeting of the receptors (discussed in Malinow and Malenka 2002). Additionally, protein phosphorylation of other synaptic proteins has been proposed to indirectly modulate AMPA receptor function by affecting the macromolecular complexes that are important for the presence of AMPA receptors at the synaptic plasma membrane (Malinow and Malenka 2002; Nestler et al. 2001). Studies have been elucidating the cellular mechanisms by which AMPA receptor subunit insertion and trafficking occur and have revealed two major mechanisms (Malinow and Malenka 2002; Nestler et al. 2001). The first mechanism is used for GluR1-containing AMPA receptor insertion and is regulated by activity. The second mechanism is governed by constitutive receptor recycling, mainly through GluR2/3 heteromers in response to activity-dependent signals. Data suggest that AMPA receptor subunit trafficking may play an important role in neuropsychiatric disorders. Thus, Nestler and associates have shown that the ability of drugs of abuse to elevate levels of the GluR1 subunit of AMPA glutamate receptors in the VTA of the midbrain is crucial for the development of sensitization (Carlezon and Nestler 2002). They have demonstrated that even transient increases in GluR1 levels within VTA neurons can trigger complex cascades of other molecular adaptations in these neurons and, within larger neural circuits, can cause enduring changes in the responses of the brain to drugs of abuse. Chronic lithium and valproate have been shown to reduce GluR1 expression in hippocampal synaptosomes, effects that may play a role in the delayed therapeutic effects of these agents (Du et al. 2003; Szabo et al. 2002). Recent studies have sought to test the hypothesis that "antidepressant anticonvulsants," like traditional antidepressants, can enhance surface AMPA receptors (Du et al. 2007). It was found that the predominantly antidepressant anticonvulsants lamotrigine and riluzole significantly enhanced the surface expression of GluR1 and GluR2 in a time- and dose-dependent manner in cultured hippocampal neurons. By contrast, the predominantly antimanic anticonvulsant valproate significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine- and riluzole-treated neurons, supporting the surface receptor changes. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment. Recent clinical research has demonstrated a robust and rapid antidepressant effect of ketamine; studies were therefore undertaken to test the hypothesis that ketamine brings about its rapid antidepressant effect by enhancing AMPA relative to NMDA throughput (Maeng et al. 2008). Although the AMPA antagonist NBQX was without behavioral effects alone, it blocked the antidepressant-like effects of ketamine. AMPA antagonists also blocked ketamineinduced changes in hippocampal GluR1 AMPA receptor phosphorylation. Together, these results suggest that regulating AMPA relative to NMDA throughput in critical neuronal circuits may play an important role in antidepressant action.

Kainate receptors The kainate receptor has pre- and postsynaptic roles, sharing some properties with AMPA receptors. It is composed of the combination of the GluR5, GluR6, GluR7, KA1, and KA2 subunits (see Figure 1–7). The precise role of kainate receptors in the mature CNS remains to be fully elucidated, although the activity of the receptors clearly plays a role in synaptic function in many brain areas. Increasing data suggest the involvement of aberrant synaptic plasticity in the pathophysiology of bipolar disorder. Kainate receptors contribute to synaptic plasticity in different brain regions involved in mood regulation, including the prefrontal cortex, hippocampus, and amygdala. GluR6 (GRIK2) is a subtype of kainate receptor whose chromosomal loci of 6q16.3–q21 have been identified as potentially harboring genetic polymorphism(s) contributing to an increased risk of mood disorders. The role of GluR6 in modulating animal behaviors correlated with mood symptoms was investigated using GluR6 knockout and wild-type mice (Shaltiel et al. 2008). GluR6 knockout mice appeared to attain normal growth and showed no neurological abnormalities. GluR6 mice showed increased basal- or amphetamine-induced activity, were extremely aggressive, took more risks, and consumed more saccharin (a measure of hedonic drive). Notably, most of these aberrant behaviors responded to chronic lithium administration. These results suggest that abnormalities in kainate receptor throughput generated by GluR6 gene disruption may lead to the concurrent appearance of a constellation of behaviors related to manic symptoms, including persistent hyperactivity; escalated irritability, aggression, and risk taking; and hyperhedonia.

Metabotropic glutamate receptors The metabotropic glutamate receptors (mGluRs) are G protein–coupled receptors. The eight types of receptors that currently have been cloned can be organized into three different subgroups (groups I, II, and III) based largely on the signaling transduction pathways that they activate (see Figure 1–7). These receptors have a large extracellular N-terminal consisting of two lobes forming a "venus flytrap" binding pocket involved in glutamate recognition and a cysteine-rich extracellular domain that connects with seven transmembrane domains separated by short intra- and extracellular loops (see Figure 1–7). The intracellular loop plays an important role in the coupling with and selectivity of the G protein. The cytoplasmic carboxyl-terminal domain is variable in length and is involved with G protein activation and coupling efficacy (Bruno et al. 2001; Conn and Pin 1997). The mGluR group I includes the mGluR1 (a, b, c, d), and mGluR5 (a, b) receptors (see Figure 1–7). They preferentially interact with the G q/11 subunit of G proteins, leading to activation of the IP3/calcium and DAG/PKC cascades. The receptors are located on both pre- and postsynaptic neurons. Group II metabotropic receptors include mGluR2 and mGluR3, which have been best characterized as inhibiting adenylyl cyclase but, like many receptors coupled to Gi/Go, may also regulate ion channels. Group III receptors, which include mGluR4 (a, b), mGluR6, mGluR7 (a, b), and mGluR8 (a, b), are reported to produce inhibition of adenylyl cyclase as well, but also to interact with the phosphodiesterase enzyme regulating guanosine monophosphate (cGMP) levels (Cooper et al. 2001; Squire et al. 2003). The group II and III receptors are located in the presynaptic membrane and, because of their coupling with Gi/Go proteins, appear to negatively modulate glutamate and GABA neurotransmission output when activated (i.e., they serve as inhibitory auto- and heteroreceptors). Preclinical studies suggest that mGlu group II and III receptors are "extrasynaptic" in their localization; that is, they are located some distance from the synaptic cleft and are thus activated only under conditions of excessive (pathological?) glutamate release, when there is sufficient glutamate to diffuse out of the synapse to these receptors (Schoepp 2001). In preclinical studies, mGluR2/3 agonists have been demonstrated to exert anxiolytic, antipsychotic, and neuroprotective properties (Schoepp 2001).

Glycine Glycine is a nonessential amino acid that also functions as a neurotransmitter in the CNS. Although the exact metabolic pathway for glycine production has yet to be fully elucidated, evidence suggests that glycine may be produced in the CNS by two distinct pathways. First, glycine is produced from serine by the enzyme serine-trans-hydroxymethylase in a reversible folate-dependent reaction (Cooper et al. 2001; Squire et al. 2003). Additionally, glycine may be produced from glyoxylate by the enzyme D-glycerate dehydrogenase. This amino acid is found in higher concentrations in the spinal cord than in the rest of

the CNS. Glycine acts as an inhibitory neurotransmitter predominantly in the brain stem and spinal cord (Nestler et al. 2001). As discussed earlier, a very important role that glycine also plays is to augment the NMDA-mediated frequency of NMDA receptor channel opening. This effect is strychnine-insensitive and pharmacologically suggests that the actions of glycine on NMDA receptor function are different from its effect on the spinal cord, where glycine's inhibitory effect is blocked by strychnine (Cooper et al. 2001). The allosteric modulation of NMDA receptors via a glycine-insensitive site is further underscored by receptor binding experiments yielding an anatomic distribution similar to that of NMDA receptors. Functionally, it has been postulated that glycine is able to augment the NMDA-mediated responses by speeding up the recovery process of the receptor (Cooper et al. 2001). Given the ability of glycine to alter NMDA function, glycine may be beneficial in the treatment of schizophrenia (Coyle et al. 2002).

GABAergic System -Aminobutyric acid—the major inhibitory neurotransmitter system in the CNS—is one of the most abundant neurotransmitters, and GABA-containing neurons are located in virtually every area of the brain. Unlike the monoamines, GABA occurs in the brain in high concentrations in the order of micromoles per milligrams (about 1,000-fold higher than concentrations of monoamines) (Cooper et al. 2001; Nestler et al. 2001; Squire et al. 2003). GABA is produced when glucose is converted to -ketoglutarate, which is then transaminated to glutamate by GABA -oxoglutarate transaminase (GABA-T). Glutamic acid is decarboxylated by glutamic acid decarboxylase, which leads to the formation of GABA (Figure 1–8). Indeed, the neurotransmitter and the rate-limiting enzyme are localized together in the brain and at approximately the same concentration. Catabolism of GABA occurs via GABA-T, which is also important in the synthesis of this transmitter. FIGURE 1–8. The GABAergic system.

This figure depicts the various regulatory processes involved in GABAergic neurotransmission. The amino acid (and neurotransmitter) glutamate serves as the precursor for the biosynthesis of -aminobutyric acid (GABA). The rate-limiting enzyme for the process is glutamic acid decarboxylase (GAD), which utilizes pyridoxal phosphate as an important cofactor. Furthermore, agents such as L-glutamine- -hydrazide and allylglycine inhibit this enzyme and, thus, the production of GABA. Once released from the presynaptic terminal, GABA can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic regulation of GABA neuron firing activity and release occurs through somatodendritic (not shown) and nerve-terminal GABAB receptors, respectively. Baclofen is a GABAB receptor agonist. The binding of GABA to ionotropic GABAA receptors and metabotropic GABAB receptors mediates the effects of this receptor. The GABAB receptors are thought to mediate their actions by being coupled to Ca2+ or K+ channels via second-messenger systems. Many agents are able to modulate GABAA receptor function. Benzodiazepines, such as diazepam, increase Cl– permeability, and

there are numerous available antagonists directed against this site. There is also a distinctive barbiturate binding site on GABAA receptors, and many psychotropic agents are capable of influencing the function of this receptor (see blown-up diagram). GABA is taken back into presynaptic nerve endings by a high-affinity GABA uptake transporter (GABAT) similar to that of the monoamines. Once inside the neuron, GABA can be broken down by GABA transaminase (GABA-T), which is localized in the mitochondria; GABA that is not degraded is sequestered and stored into secretory vesicles by vesicle GABA transporters (VGTs), which differ from VMATs in their bioenergetic dependence. The metabolic pathway that produces GABA, mostly from glucose, is referred to as the GABA shunt. The conversion of -ketoglutarate into glutamate by the action of GABA-T and GAD catalyzes the decarboxylation of glutamic acid to produce GABA. GABA can undergo numerous transformations, of which the simplest is the reduction of succinic semialdehyde (SS) to -hydroxybutyrate (GHB). On the other hand, when SS is oxidized by succinic semialdehyde dehydrogenase (SSADH), the production of succinic acid (SA) occurs. GHB has received attention because it regulates narcoleptic episodes and may produce amnestic effects. The mood stabilizer and antiepileptic drug valproic acid is reported to inhibit SSADH and GABA-T. TBPS = t-butylbicyclophosphorothionate. Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. The function of this dual-role enzyme becomes apparent when placed in the context of its role in the metabolic process. GABA-T converts GABA to succinic acid, and subsequent removal of the amino group yields

-ketoglutarate. Thus,

-ketoglutarate is able to be used by GABA-T in GABA biosynthesis as

mentioned above (Cooper et al. 2001). This process, called the GABA shunt, maintains a steady GABA supply in the brain. As with the monoamines, the major mechanism by which the effects of GABA are terminated in the synaptic cleft is by reuptake through GABA transporters. The GABA transporters have a high affinity for GABA and mediate their reuptake via a Na+ and Cl– gradient (Squire et al. 2003). Detailed studies from the Rajkowska laboratory (Grazyna Rajkowska, The University of Mississippi Medical Center, Jackson, MS) have measured the density and size of calbindin-immunoreactive neurons (presumed to be GABAergic) in layers II and III of the dorsolateral prefrontal cortex, revealing a 43% reduction in the density of these neurons in patients with major depressive disorder compared with controls (discussed in Goodwin and Jamison 2007). Of particular note, in the rostral orbitofrontal cortex, there was a trend toward a negative correlation between the duration of depression and the size of neuronal cell bodies, suggesting changes associated with disease progression. Valproate has also been shown to have neurogenic effects in at least one study. In cultured embryonic rat cortical cells and striatal primordial stem cells, valproate markedly increased the number and percentage of primarily GABAergic neurons and promoted neurite outgrowth (Laeng et al. 2004).

GABA Receptors There are two major types of well-characterized GABA receptors, GABAA and GABAB, and most neurons in the CNS possess at least one of these types. The GABAA receptor is the more prevalent of the two in the mammalian CNS and as a result has been extensively studied and characterized. GABAA contains an integral transmembrane chloride channel, which is opened upon receptor activation, generally resulting in hyperpolarization of the neuron (i.e., suppressing excitability). The GABA receptor is a heteropentameric glycoprotein of approximately 275 kDa composed of a combination of multiple polypeptide subunits. GABAA displays enormous heterogeneity, being composed of a combination of five classes of polypeptide subunits ( ,

, ,

, ), of

which there are at least 18 total subtypes. The various receptors display variation in functional pharmacology, hinting at the multiple finely tuned roles that inhibitory neurotransmission plays in brain function. It is now well established that benzodiazepines (BZDs) function by binding to a potentiator site on the GABAA receptor, increasing the amplitude and duration of inhibitory postsynaptic currents in response to GABA binding. Coexpression of additional

subunits is believed to be necessary for the

potentiation of GABA-mediated responses by BZDs. In addition to BZDs, barbiturates and ethanol are also believed to exert many of their effects by potentiating the opening of the GABAA receptor chloride channel (see Figure 1–8). As noted earlier, GABAA receptors have a widespread distribution in the brain, and the majority of these receptors in the brain are targets of the currently available BZDs. For this reason, there has been considerable interest in determining if the desirable and undesirable effects of BZDs can be differentiated on the basis of the presence of different subunit composition. Much of the work has used gene knockout technology; thus, mutation of the BZD-binding site of the 1 subunit in mice blocks the sedative, anticonvulsive, and amnesic, but not the anxiolytic, effects of diazepam (see Gould et al. 2003; Mohler et al. 2002). In contrast, the 2 subunit (expressed highly in the cortex and hippocampus) is necessary for diazepam anxiolysis and myorelaxation. Thus, there is now optimism that an

2-selective

ligand will soon provide effective

acute treatment of anxiety disorders without the unfavorable side-effect profile of current BZDs. A compound with this preferential affinity has already been demonstrated to exert fewer sedative/depressant effects than diazepam in rat behavioral studies (see Gould et al. 2003; Mohler et al. 2002). The phosphorylation of GABAA receptors is another mechanism by which this receptor complex can be regulated in function and expression. In this context, it is noteworthy that studies have reported that knockout mice deficient in PKC

isoforms show reduced anxiety and alcohol consumption and an enhanced

response to the effects of BZDs (discussed in Gould et al. 2003). Furthermore, different GABAA receptor subunit partnerships, such as

1/

, mediate tonic

inhibitory currents in the hippocampus and are highly sensitive to low concentrations of ethanol (Glykys et al. 2007). The GABAB receptors are coupled to Gi and Go and thereby regulate adenylyl cyclase activity (generally inhibit), K+ channels (open), and Ca2+ channels (close). GABAB receptors can function as an autoreceptor but are also found abundantly postsynaptically on non-GABAergic neurons. Of interest, there is mounting evidence that receptor dimerization may be required for the activation of GABAB and possibly other G protein–coupled receptors; although receptor dimerization has long been known to occur for growth factor and JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) receptors (discussed later in this chapter), this was not expected for GPCRs. However, studies have reported that coexpression of two GABAB receptor subunits—subunit 1 (GABABR1) and subunit 2 (GABABR2)—is necessary for the formation of a functional GABAB receptor (Bouvier 2001). Some data suggest that GABABR2 may be necessary for proper protein folding of GABABR1 (acting as a molecular chaperone) in the endoplasmic reticulum, but this remains to be definitively established. Support for the physiological relevance of this dimerization comes from studies showing that the GABAB R1 and R2 subunits can be co-immunoprecipitated in rat cortical membrane preparations (Kaupmann et al. 1997); thus, the dimerization is not simply an in vitro phenomenon.

PURINERGIC NEUROTRANSMISSION: FOCUS ON ADENOSINE It has been known for quite some time that ATP is capable of exerting profound effects on the nervous system (Drury and Szent-Gyšrgyi 1929). However, adenosine and adenosine nucleotides have gained acceptance as neuroactive substances in the CNS only relatively recently (Cooper et al. 2001). Adenosine is released from neurons and glia, but many of the neurotransmitter criteria outlined in the beginning of this chapter are not met. Nonetheless, adenosine is able to activate many cellular functions that are able to produce changes in neuronal and behavioral states. For example, adenosine is able to stimulate cAMP in vitro in brain slices, and caffeine (which in addition to being a phosphodiesterase inhibitor is a well-known adenosine receptor antagonist) is able to block this response. Four adenosine receptors have been cloned (A1, A2A, A2B, and A3), each of which exhibits unique tissue distribution, ligand binding affinity (nanomolar range), and signal transduction mechanisms (Cooper et al. 2001). Currently available data suggest that the high-affinity adenosine receptors (A1 and A2A) may be activated under normal physiological conditions, whereas in pathological states such as hypoxia and inflammation (in which high adenosine concentrations [micromolar range] are present), low-affinity A2B and A3 receptors are also activated. A2B receptors are expressed in low levels in the brain but are ubiquitous in the rest of the body, whereas A2A receptors are found in high concentrations in areas of the brain that receive dopaminergic projections (i.e., striatum, nucleus accumbens, and olfactory tubercle) (Nestler et al. 2001). Given this receptor's distribution and the inverse relationship between DA and adenosine, it has been postulated that A2A antagonists may have some utility in the treatment of Parkinson's disease (Nestler et al. 2001).

The mood stabilizer and antiepileptic drug carbamazepine acts as an antagonist of the A1 subtype and also decreases protein levels of the receptor (for a review, see Gould et al. 2002). Adenosine is widely regarded as important in the homeostasis of blood flow and metabolic demands in peripheral tissue physiology. Adenosine is also able to alter the function (both pre- and postsynaptically) of numerous neurotransmitters and their receptors, including NMDA, metabotropic glutamate receptors, ionotropic nicotinic receptors, NE, 5-HT, DA, GABA, and various peptidergic receptors. Recent evidence implicates adenosine as a fatigue factor in the decrease of cholinergic activity-arousal via presynaptic inhibition of glutamate release (Brambilla et al. 2005). In addition, P2X (ligand-gated ion channels) and P2Y (G protein–coupled receptors) are purine receptors that can be activated by ATP. It has been demonstrated that ATP is released from astrocytes (through an unknown mechanism) and that the release is accompanied by glutamate release (Ca2+-dependent) (Innocenti et al. 2000). However, more data suggest that it may be adenosine (that is derived from ATP) that serves as the true ligand for these purinergic receptors (Fields and Stevens-Graham 2002). The ATP/adenosine is then able to activate purine receptors (P2Y receptors) on neighboring astrocytes, and this stimulates Ca2+ influx and subsequent release of glutamate and ATP to then impact other astrocytes and neurons. This may be a critical component in the communication process between glial cells, as well as representing a signaling molecule from glia to neurons (Fields and Stevens-Graham 2002).

PEPTIDERGIC NEUROTRANSMISSION Neuropeptides have garnered increasing attention as critical modulators of CNS function. In general, peptide transmitters are released from neurons when they are stimulated at higher frequencies from those required to facilitate release of traditional neurotransmitters, but they can also be colocalized and coreleased together with other neurotransmitters (Cooper et al. 2001; Nestler et al. 2001). Modulation of the firing rate pattern of neurons and subsequent release of neurotransmitters and peptides in a circumscribed fashion are likely important in the basal functioning of the brain as well as response to specific stimuli. For instance, cannabinoids, an example of a neuropeptide neurotransmitter, do not alter the firing rates of hippocampal neurons but instead change the temporal coordination of those neurons, an effect that correlates with memory deficits in individuals (Soltesz and Staley 2006). Virtually every known mammalian bioactive peptide is synthesized first as a precursor protein in which product peptides are flanked by cleavage sites. Neuropeptides are generally found in large dense-core vesicles, whereas other neurotransmitters, such as the monoamines, are packaged in small synaptic vesicles (approximately 50 nm) and are usually half the size of their peptidergic counterparts (Kandel et al. 2000; Squire et al. 2003). Space limitations preclude an extensive discussion of the diverse array of neuropeptides known to exist in the mammalian brain. Table 1–2 highlights some of the major neuropeptides that may be of particular psychiatric relevance. In the remainder of this section, the basic aspects of peptidergic transmission are highlighted vis-à-vis an overview of opioidergic neurotransmission. TABLE 1–2. Selected peptides and their presumed relevance to psychiatric disorders and treatment Group

Potential clinical reference

Opioid and related peptides Endorphin

All of these peptides may be involved in opiate dependence/drug abuse; possible antidepressant activity; chronic pain

Enkephalin Dynorphin Nociceptin Gut-derived peptides VIP

Sexual behavior

CCK

Anxiety/panic

Gastrin Secretin

Autism?

Somatostatin

Mood disorders and treatment

Tachykinin peptides Substance P

NK1 receptor antagonists may alleviate depression/anxiety

Substance K

Regulated by antipsychotics

Neuromedin N

Regulated by lithium

Pituitary peptides Oxytocin

Affiliative behavior

Vasopressin

Potential novel anxiolytics?

ACTH

Dysregulated in mood disorders

MSH Hypothalamic releasing factors CRF

Strongly implicated in depressive and anxiety symptoms; potential target for novel treatments

TRF

Potential antidepressant effects

GHRF LHRF Others Calcitonin gene–related peptide

Regulated by ECT and lithium

Angiotensin

Mood disorders, bipolar disorder

Neurotensin

Regulated by antipsychotics and stimulants

Leptin

Satiety signal; involved in diagnosis and in treatment-induced appetite/weight changes?

CART

Drug addiction, eating disorders

Galanin

Potentially relevant for Alzheimer's diagnosis and other cognitive disorders

Neuropeptide Y

Potential endogenous anxiolytic; regulated by antidepressants/lithium; reduced by early maternal separation

Group

Potential clinical reference

Orexin/hypocretin

Narcolepsy; sleep abnormalities in other disorders?

Note. This table summarizes selected peptides and their presumed relevance for psychiatric disorders and their treatment; it is not meant to be an exhaustive listing of findings. It should also be noted that in some cases—for example, CRF (mood/anxiety), NPY and neurotensin (regulation by medications), oxytocin (affiliative behavior), and orexin (narcolepsy)—the data are quite convincing. In many of the other examples noted, the evidence must be considered preliminary but is, in our opinion, quite noteworthy and warrants further investigation. ACTH = adrenocorticotropic hormone; CART = cocaine- and amphetamine-related transcript; CCK = cholecystokinin; CRF = corticotropinreleasing factor; ECT = electroconvulsive therapy; GHRF = growth hormone–releasing factor; LHRF = luteinizing hormone–releasing factor; MSH = melanocyte-stimulating hormone; NPY = neuropeptide Y; TRF = thyrotropin-releasing factor; VIP = vasoactive intestinal peptide. Opioids are a family of peptides that occur endogenously in the brain (endorphins), as botanicals, or as drugs. Pro-opiomelanocortin (POMC), proenkephalin-derived peptides, and prodynorphin-derived peptides yield opioid peptides upon cleavage. Three opioid peptide families currently exist: enkephalins, endorphins, and dynorphins. There are also three types of opioid receptors—namely, ,

, and —each of which is further subclassified. POMC

gene expression occurs in various areas of the brain as well as other tissues. POMC has tissue- and cell-specific regulatory factors at every step from gene transcription to its posttranslational processing. Opioid peptides are stored in large dense-core vesicles and are coreleased from neurons that usually contain a classical neurotransmitter agent (e.g., glutamate and norepinephrine). Opioids activate a variety of signal transduction processes, and different mechanisms in their regulation are in place for different cell types. The opioid receptors are G protein–coupled receptors and exert their cellular effects by inhibiting adenylyl cyclase and regulating K+ and Ca2+ channels, via activation of Gi/Go. Recently opiorphin, an endogenously derived enkephalin that inactivates zinc ectopeptidase, has been described as equal to morphine in the suppression of pain (Wisner et al. 2006). Although opiates are widely associated with and used therapeutically in pain modulation, recent evidence indicates that dynorphin can actually activate bradykinin receptors and contribute to neuropathic pain (Altier and Zamponi 2006). The continued study of the opioid system and the second-messenger changes brought about by the chronic administration of opioids has greatly facilitated our understanding of the molecular and cellular effects of drugs of abuse and the potential to develop novel therapeutics (Nestler et al. 2001).

NEUROTROPHINS Neurotrophins are a family of regulatory factors that mediate the differentiation and survival of neurons, as well as the modulation of synaptic transmission and synaptic plasticity (Patapoutian and Reichardt 2001; Poo 2001). The neurotrophin family now includes, among others, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin-4/5 (NT4/5), and neurotrophin-6 (NT6) (Patapoutian and Reichardt 2001). These various proteins are closely related in terms of sequence homology and receptor specificity. They bind to and activate specific tyrosine receptor kinases belonging to the Trk family of receptors, including TrkA, TrkB, and TrkC, and a pan-neurotrophin receptor p75 (Patapoutian and Reichardt 2001; Poo 2001). Additionally, there are two isoforms of TrkB receptors: the full-length TrkB and the truncated form of TrkB, which does not contain the intracellular tyrosine kinase domain (Fryer et al. 1996). The truncated form of TrkB can thus function as a dominant-negative inhibitor for the TrkB receptor tyrosine kinase, thereby providing another mechanism to regulate BDNF signaling in the CNS (Eide and Virshup 2001; Gonzalez et al. 1999). Neurotrophins can be secreted constitutively or transiently, and often in an activity-dependent manner. Observations support a model in which neurotrophins are generally secreted from the dendrite and act retrogradely at presynaptic terminals, where they act to induce long-lasting modifications (Poo 2001). Within the neurotrophin family, BDNF is a potent physiological survival factor that has also been implicated in a variety of pathophysiological conditions, such as Parkinson's disease, Alzheimer's disease, diabetic peripheral neuropathy, and psychiatric disorders (Malberg et al. 2000; Nagatsu et al. 2000; Pierce and Bari 2001; Salehi et al. 1998). In particular, a genetic variant of BDNF (Val66Met) has been associated with risk for development of mood disorders in humans, as well as with mood- and anxiety-related behaviors and response to antidepressant medications in animal models (Z. Y. Chen et al. 2006; Neves-Pereira et al. 2002; Sklar et al. 2002). Recent data also support a role for this polymorphism in human brain development and function (Frodl et al. 2007; Kleim et al. 2006). The cellular actions of BDNF are mediated through two types of receptors: a high-affinity tyrosine receptor kinase (TrkB) and a low-affinity pan-neurotrophin receptor (p75) (see Figure 1–1 for details). TrkB is preferentially activated by BDNF and NT4/5 and appears to mediate most of the cellular responses to these neurotrophins (Du et al. 2003; Poo 2001). Binding of BDNF initiates TrkB dimerization and transphosphorylation of tyrosine residues in its cytoplasmic domain (Patapoutian and Reichardt 2001), a process that involves cAMP activation (Ji et al. 2005). Binding of cytoplasmic src homology 2 (SH2) domain–containing scaffolding proteins—including Shc and Grb-2, which recognize specific phosphotyrosine residues on the receptor—can thus result in the recruitment of a variety of effector molecules. This recruitment of effector molecules generally occurs via interaction of proteins with modular binding domains SH2 and SH3 (named after homology to the src oncogenes—src homology domains). The ability of multiple effectors to interact with phosphotyrosines is undoubtedly one of the keys to the pleiotropic effects that neurotrophins can exert. The physiological effects of neurotrophins are mediated by varying degrees of activation of three major signaling pathways—the Ras/MAP kinase pathway, the phosphoinositide-3 kinase (PI3K) pathway, and the phospholipase C– 1 (PLC- 1) pathway (Figure 1–9). Among these pathways, the effects of the PI3K pathway and the MAP kinase pathway have traditionally been linked to the cell survival effects of neurotrophins (Patapoutian and Reichardt 2001) (see Figure 1–9). A series of studies by Duman (2002) have shown that BDNF and TrkB are upregulated by antidepressant treatment. The "neurotrophin hypothesis of depression" has enjoyed heuristic value in reconceptualizing mood disorders as arising from abnormalities in neural plasticity cascades. The demonstration that decreases in hippocampal BDNF levels are correlated with stress-induced depressive behaviors and that antidepressant treatment enhances BDNF expression has generated considerable interest. It is now accepted that the main function of BDNF in the adult brain is regulating synaptic plasticity rather than mediating neuronal survival. Exciting results show that BDNF is first synthesized as a precursor proBDNF, which is then proteolytically cleaved to mature BDNF (mBDNF). ProBDNF and mBDNF facilitate LTD and LTP, respectively, suggesting opposing cellular functions. Finally, BDNF plays different and perhaps opposing roles in the brain stress versus reward system (discussed in Martinowich et al. 2007). FIGURE 1–9. Neurotrophic cascades.

Cell survival is dependent on neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor, and the expression of these factors can be induced by synaptic activity. Phosphorylation of tyrosine receptor kinase (Trk) receptors activates a critical signaling pathway, the Ras/MAP kinase pathway (see Figure 1–15). Phosphorylated Trk receptors also recruit the phosphoinositide-3 kinase (PI3K) pathway through at least two distinct pathways, the relative importance of which differs between neuronal subpopulations. In many neurons, Ras-dependent activation of PI3K is the most important pathway through which neurotrophins promote cell survival (not shown; see text). In some cells, as shown in the figure, PI3K can also be directly activated through adaptor proteins (Shc, Grb-2, and Gab-1). PI3 K directly regulates certain cytoplasmic apoptotic pathways. Akt phosphorylates the pro-apoptotic Bcl-2 family member BAD (Bcl-xl/Bcl-2–associated death promoter), thereby inhibiting BAD's pro-apoptotic functions (Datta et al. 1997). Akt may also promote survival in an indirect fashion by regulating another major signaling enzyme: glycogen synthase kinase–3 (GSK-3) (Woodgett 2001). Interestingly, lithium is an inhibitor of GSK-3. Phosphorylated Trk receptors also recruit phospholipase C– 1 (PLC- 1). The Trk kinase then phosphorylates and activates PLC- 1, which acts to hydrolyze phosphatidylinositides to generate diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3 ). Antidepressant medication and mood stabilizers increase levels of BDNF and other neurotrophic factors, suggesting a therapeutic relevance.

Retrograde Transportation of Neurotrophin Receptors as Signal to the Cell Body Unlike most other internalized receptors, which are usually degraded after internalization, neurotrophin–Trk complexes in endocytotic vesicles function as signal transducers and provide a mechanism for long-range signaling in the neuronal cytoplasm. Several studies have provided support for the retrograde transportation model of neurotrophin–Trk complexes; these studies indicate that endocytotic vesicles containing neurotrophin–Trk complexes may be functionally active and should be viewed as activated signaling complexes that spread the cytosolic signaling of neurotrophin–Trk complexes to distant parts of the neuron via active transport mechanisms. Intriguingly, as has been shown with another tyrosine kinase (ErbB4 receptor tyrosine kinase), other hitherto unappreciated mechanisms, such as cleavage of receptor fragments, may also be operative in trafficking signals from extracellular receptors to intracellular and nuclear targets (Ni et al. 2001). Whether such novel signaling mechanisms are also utilized by neurotrophin receptors will undoubtedly be the focus of considerable future research.

Regulation of Neurotrophin Signaling by Neuronal Activity The neurotrophic functions of neurotrophins depend in large part on a cytoplasmic signal-transduction cascade, whose efficacy may be influenced by the presence of electrical activity in the neuron. Seizure activity, as well as nonseizure activity of a frequency or intensity capable of inducing LTP, has been shown to elevate BDNF mRNA levels and to facilitate the release of BDNF from hippocampal and cortical neurons (Poo 2001). Although BDNF was originally considered to be transported only retrogradely, evidence indicates that BDNF can also act anterogradely to modulate synaptic plasticity (Poo 2001). High-frequency neuronal activity and synaptic transmission have also been shown to elevate the number of TrkB receptors on the surface of cultured hippocampal neurons through activation of the CaMKII pathway and may therefore facilitate the synaptic action of BDNF (Du et al. 2000). Thus, electrically active nerve terminals may be more susceptible to synaptic potentiation by secreted neurotrophins than are inactive terminals. Neuronal or synaptic activity is also known to promote the effects of neurotrophins on the survival of cultured retinal ganglion cells; here, neuronal or synaptic activity elevates cAMP levels to enhance the responsiveness of the neuron to neurotrophins, apparently by recruiting extra TrkB receptors to the plasma membrane (Meyer-Franke et al. 1998). Moreover, the internalization of BDNF receptor TrkB is also upregulated by activity as a retrograde signal to the cell body in cultured hippocampal neurons (this regulation is discussed in some detail in Du et al. 2003). The activity-dependent regulation of BDNF signaling on BDNF synthesis and release, TrkB insertion onto neuronal surfaces, and activated TrkB tyrosine kinase internalization are crucial for its influence on synaptic plasticity and neuronal survival.

CYTOKINES AND JAK/STAT–COUPLED RECEPTORS There is mounting evidence that many psychiatric disorders may be associated with altered immune function. Even more convincing is the evidence that numerous medical disorders and treatments that regulate immune function are associated with psychiatric symptomatology (Evans et al. 2001). Thus, the mechanism by which the immune system is able to mediate its effects through specified signaling pathways in the CNS will undoubtedly be of increasing importance in our understanding of these complex disorders. Numerous cytokines and growth factors are able to activate the JAK/STAT pathway; here we focus on interferons as a prototype. Interferons are cytokines

that subserve important antiviral, antigrowth, and immunomodulatory activities (Larner and Keightley 2000). The interferon/cytokine receptor family is a group of receptors that, on binding to an extracellular site, produce dimerization or higher-order clustering. Unlike the tyrosine kinase type receptors (Trk), these receptors associate intrinsically in a noncovalent constitutive manner with proteins of the JAK (Janus tyrosine kinase) family to mediate their effects. Signal transducers and activators of transcription (STATs), which are SH2 domain–containing transcription factors, are required for the actions of many other cytokines and growth factors. There are two types of receptors for which interferons, on binding to the extracellular part of the receptor, are able to rapidly induce corresponding genes: interferon- / (IFN- / ), or type I receptors; and IFN- , or type II receptors. The interferon-stimulated gene factors, which are more commonly known as STATs, bind to enhancers in the promoter regions of type I and type II receptor genes to mediate transcription (Larner and Keightley 2000). It should be mentioned that in addition to interferon, interleukin-6 and prolactin are other cytokines whose effects have been documented to be mediated by STATs. STATs are modified through tyrosine kinases and are necessary for activation of early response genes on interferon binding to the receptor. Thus, the Janus tyrosine kinases (JAK1–3 and TYK2) are important in the regulation of interferon-mediated cellular effects. Evidence suggests that IFN- / cluster in receptor complexes, and upon ligand binding, these proteins are able to mediate some of the receptor–effector responses of interferons. Type I interferon receptors consist of two subunits (IFNAR1 and IFNAR2), of which the IFNAR2 subunit has three isoforms (IFNAR2a, IFNAR2b, and IFNAR2c). Upon binding of interferon to IFN- , the IFNAR2c subunit is necessary for the activation of the JAK/STAT pathway. Initially, interferons bind to two sites—IFNAR1 and IFNAR2—which heterodimerize, and then the activation of TYK2 and JAK ensues to phosphorylate the receptor (Larner and Keightley 2000). Other phosphatases and kinases are also able to interact with type I interferon receptors to produce a cascade of intercellular effects.

NUCLEAR HORMONES: FOCUS ON STEROIDS In contrast to the other neuroactive compounds we have discussed thus far, many hormones (including cortisol, gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane because of their lipophilic composition (Kandel et al. 2000). Retinoic acid (vitamin A) has recently been shown to be involved in sleep, as well as learning and memory formation (Drager 2006). Nuclear receptors are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Approximately 50 nuclear receptors are known to exist, and their structure is defined by a number of signature functional domains. Generally, nuclear receptors comprise an amino-terminal activation function, the DNA-binding domain, a hinge region, and a carboxy-terminal ligand-binding domain containing a second activation function (Kandel et al. 2000). Upon activation by a hormone, the steroid receptor–ligand complex translocates to the nucleus, where it binds to specific DNA sequences referred to as hormone responsive elements (HREs), which subsequently regulate gene transcription (Mangelsdorf et al. 1995; Truss and Beato 1993) (see Figure 1–1). It is now known that nuclear receptors are markedly regulated by additional "accessory proteins." Nuclear receptor coregulators are cellular factors that complement nuclear receptors' function as mediators of the cellular response to endocrine signals. They are generally divisible into coregulators that promote transcriptional activation when recruited (coactivators) and those that attenuate promoter activity (corepressors). In addition to the traditional view of steroid hormone action, it is now clear, however, that steroid hormones also have so-called nongenomic effects that include changes in neurotransmitter receptors, other membrane receptors, and second-messenger systems. These effects are less well characterized, but evidence for their existence includes modulation of neural activity in brain areas where there are few, if any, gonadal steroid receptors; there is also evidence showing that estrogen directly and rapidly inhibits calcium channels in neurons (McEwen 1999; Mermelstein et al. 1996). A growing body of data is also demonstrating bidirectional cross-talk between nuclear receptors and GPCRs. Thus, for example, gonadal steroids have long been known to modulate the activity of monoaminergic neurons and receptors. More recently, it has been shown that -adrenergic and dopamine D1 receptors are capable of transactivating glucocorticoid and progesterone receptors, respectively. Neuroactive steroid is the term used for a steroid that is able not only to bind to its respective intracellular receptor and become rapidly translocated to the nucleus but also to alter neuronal excitability via interactions with certain neurotransmitter receptors (Rupprecht 2003) (see Figure 1–1). Many of the above-mentioned neuroactive steroids are capable of altering neuronal excitability by interacting with GABAA receptors. Studies using chimeras of GABAA/glycine receptors suggest an allosteric action of neuroactive steroids at the N-terminal side of the middle of the second transmembrane domain of the GABA receptor

1

and/or 2 subunits (Rick et al. 1998). However, no direct

binding of the steroid to the receptor has been demonstrated. In addition to GABAA receptors, other members of the ligand-gated ion channel family (including 5-HT3, glycine, nicotinic, ACh, and glutamate receptors) have been postulated to represent targets for neuroactive steroids (Rupprecht 2003). In view of the GABAA-enhancing potential of 3 -reduced neuroactive steroids, these steroids have been suggested to possess sleep-modulating or -promoting (Mendels and Chernik 1973), anticonvulsant (Frye and Scalise 2000), anxiolytic (Crawley et al. 1986), and neuroprotective (Rupprecht 2003) properties. Finally, it has been postulated that neuroactive steroids may also contribute to psychiatric symptoms sometimes observed during pregnancy and in the postpartum period (Pearson Murphy et al. 2001).

UNCONVENTIONAL TRANSMITTERS: FOCUS ON GASES Many of the unconventional transmitters do not fit the well-accepted neurotransmitter criteria mentioned at the beginning of this chapter. A handful of unconventional transmitters have been characterized and may ultimately prove to have relevance for neuropsychiatric disorders; here, we limit ourselves to a discussion of the gases nitric oxide (NO) and carbon monoxide (CO), which have been demonstrated to exhibit neurotransmitter-like properties in the brain (Dawson and Snyder 1994). The gases, as a result of being small and uncharged, are able to permeate the lipid bilayer and enter the neuron and directly affect certain second-messenger generating systems directly. Synthesis of NO is derived from arginine via an enzymatic reaction involving NO synthase, flavin adenine dinucleotide, and flavin mononucleotide enzyme (Cooper et al. 2001). Currently, there are three different variations of NO synthase, which arise from different genes that share approximately 50% sequence homology. The neuronal NO synthase is activated by Ca2+ and calmodulin and is also regulated by phosphorylation, which decreases its function. NO is released from both neurons and glia and can activate the enzyme guanylate cyclase to augment cGMP concentrations, thereby regulating a variety of neurotransmitter systems (Cooper et al. 2001) (Figure 1–10). These effects likely occur via the activation of protein kinase G (termed G because it is activated by cGMP), but this remains to be definitely established. Notably, endocannabinoids, a class of fatty acid derivatives that bind to cannabinoid receptors, exert prominent effects on NO signaling (Alger 2005). FIGURE 1–10. Nitric oxide as a signaling molecule.

This figure depicts the various regulatory processes involved in nitric oxide (NO) signaling. Reactive oxygen species, in particular several gases, represent yet another means by which the brain is able to transmit messages. NO is formed via NO synthase (NOS), an enzyme that is generally activated by Ca2+-calmodulin. As such, Ca2+ entry into cells via NMDA (N-methyl-D-aspartate) receptor activation is an important means of activating NOS. NOS yields NO by converting arginine to citrulline using O2. NO then converts GTP to cGMP, which then is able to target soluble guanylyl cyclases (GCs) (enzymes that are similar to adenylyl cyclases but are activated by cGMP rather than cAMP). cGMP then activates the protein kinase (PKG) and, through the conversion of ATP to ADP, phosphorylates many proteins to bring about the physiological effects of NO. Once produced, NO is then able to diffuse out of the neuron and act on other cells as a signaling molecule. Interestingly, NO is able to also diffuse back to the presynaptic terminal, acting as a retrograde transmitter, and is thought to be important in reshaping synaptic connections (i.e., it has been linked to long-term potentiation). NO is labeled in yellow; glutamate is labeled in purple. GTg = glial transporter for glutamate; GTn = neuronal transporter for glutamate; 5-HT1A = serotonin1A receptor; S100 = calcium-binding protein expressed primarily by astrocytes. Source. Adapted from Girault J-A, Greengard P: "Principles of Signal Transduction," in Neurobiology of Mental Illness. Edited by Charney DS, Nestler EJ, Bunney BS. New York, Oxford University Press, 1999. Copyright 1999, Oxford University Press. Used with permission. CO appears to be formed in neurons exclusively by heme oxygenase–2 (HO-2), which cleaves the heme ring, releasing biliverdin, expelling iron from the heme ring, and releasing a one-carbon fragment as CO. HO-2 activity occurs in neuronal populations in numerous parts of the brain and is dynamically regulated by neuronal impulses through a kinase cascade in which PKC activates casein kinase–2, which in turn phosphorylates and activates HO-2. HO-2 activity generates low micromolar concentrations of CO in the brain. Similar to NO, CO augments cGMP levels to produce its effects in the brain. Additionally, protein carboxyl methylation and phospholipid methylation involve S-adenosylmethionine acting as the methyl donor. Protein carboxyl methylation and phospholipid methylation are able to impact certain aspects of brain function (i.e., calmodulin-linked enzymes), and indeed both NO and CO have been implicated in long-term neural alterations such as learning and memory. Thus, it has been presumed that these gases could influence events in the nucleus, such as transcription. When released from postsynaptic neurons, these gases have feedback potential that impacts neurotransmitter release, states of neuronal activity, and notably learning and memory.

SIGNAL TRANSDUCTION PATHWAYS Signal transduction refers to the processes by which extracellular stimuli are transferred to—and propagated as—intracellular signals (Figure 1–11). Multicomponent cellular-signaling pathways interact at various levels, thereby forming complex networks that allow the cell to receive, process, and respond to information (Bhalla and Iyengar 1999; Bourne and Nicoll 1993). These networks facilitate the integration of signals across multiple time scales, the generation of distinct outputs that depend on input strength and duration, and the regulation of intricate feed-forward and feedback loops (Bhalla and Iyengar 1999). These properties of signaling networks suggest that they play critical roles in cellular memory; thus, cells with different histories, and therefore expressing different repertoires of signaling molecules, interacting at different levels, may respond quite differently to the same signal over time. Given their widespread and crucial role in the integration, regulation, amplification, and fine-tuning of physiological processes, it is not surprising that abnormalities in signaling pathways have now been identified in a variety of human diseases (Simonds 2003; Spiegel 1998). Pertinent to the present discussion is the observation that a variety of diseases manifest a relatively circumscribed symptomatology, despite the widespread, often ubiquitous expression of the affected signaling proteins. FIGURE 1–11. Principles of signal transduction.

As described in the text, neurons regulate signaling pathways through multiple mechanisms and at multiple levels. Neuronal circuits possess a large number of extracellular neuroactive molecules (1; labeled A, B, and C) that can interact with multiple receptors (2). Binding of neuroactive molecules to receptors can result in stimulation and/or attenuation of multiple cellular signaling pathways (3), depending on the type of receptor, location in the central nervous system, and activity of other signaling pathways within the cell. Thus, the potential is there to greatly amplify the signals. This signaling can then converge on one signaling pathway (4) or diverge into many signaling pathways (5). Activation of signaling pathways alters gene transcription and activity of proteins such as ion channels and other signaling molecules (6). Additionally, activation of signaling pathways can both positively (7) and negatively (8) regulate the function of extracellular receptors. Bcl-2 = an anti-apoptotic protein; BDNF = brainderived neurotrophic factor; CREB = cAMP response element–binding protein. Although complex signaling networks are likely present in all eukaryotic cells and control various metabolic, humoral, and developmental functions, they may be especially important in the CNS, where they serve the critical roles of first amplifying and "weighting" numerous extracellularly generated neuronal signals and then transmitting these integrated signals to effectors, thereby forming the basis for a complex information-processing network (Bourne and Nicoll 1993; Manji 1992). The high degree of complexity generated by these signaling networks may be one mechanism by which neurons acquire the flexibility for generating the wide range of responses observed in the nervous system. These pathways are thus undoubtedly involved in regulating such diverse vegetative functions as mood, appetite, and wakefulness and are therefore likely to be involved in the pathophysiology of a variety of psychiatric disorders and their treatments.

G Proteins As mentioned already, G proteins were originally named because of their ability to bind the guanine nucleotides guanosine triphosphate and guanosine diphosphate. Receptors coupled to G proteins include those that respond to catecholamines, serotonin, ACh, various peptides, and even sensory signals such as light and odorants. Gs and Gi were among the first G proteins identified and received their names because of their ability to stimulate or inhibit adenylyl cyclase. Since that time, a multitude of G protein subunits have been identified by a combination of biochemical and molecular cloning techniques. Indeed, genes for 16 G

subunits are known and give rise via alternative splicing to at least 20 mature G

(Simonds 2003) (see Table 1–1). There are four homology-based subfamilies of G

subunits with differential tissue expression

subunits: the Gs subfamily, whose members stimulate adenylyl cyclase;

the Gi subfamily, which includes Gi1–3 and Gz, which inhibit adenylyl cyclase; the Gq subfamily, whose members activate PLC- ; and the G12 subfamily, whose members interact with regulators of G protein signaling (RGS) domain–containing Rho exchange factors (see Table 1–1 and Figure 1–2) (Simonds 2003). Genes encoding 5 G

isoforms and 12 different G subunits are known in humans; effectors of G

complexes include ion channels, isoforms of

adenylyl cyclase, isoforms of PLC- , and MAP kinase pathways (Simonds 2003) (see Table 1–1).

G Protein Function G proteins function in the context of two interrelated cycles: a cycle of subunit association and dissociation and a cycle of GTP binding and hydrolysis (discussed in detail in the legend to Figure 1–2). G protein heterotrimers consist of G , G , and G subunits at a 1:1:1 stoichiometry and are named according to decreasing mass, with the

subunits having an apparent mass of 40–52 kDa,

subunits having an apparent mass of 35–36 kDa, and

subunits having an apparent mass of 5–20 kDa. The different types of G protein have been named on the basis of the distinct

subunits they possess (i.e.,

Gs represents G proteins containing G s). This classification system arose from the erroneous assumption that it was only the subunits that were responsible for the proteins' specific functional activity; it is now known that the and subunits exert a number of functional effects on their own (see Table 1–1) and are not simply "anchoring proteins" for

subunits. Although the

and

noncovalent coiled-coil interactions; thus, they are generally assumed to function as effects on

subunits and effectors (e.g.,

2 2

subunits are not covalently bound, they are tightly linked by dimers. It is very likely that different

subunits exert different

behaves differently from 2 3), but the delineation of the differential effects of the different subunit

compositions is still in its infancy.

Mediation of neurotransmitter–neurotransmitter and receptor–receptor interactions

The CNS is remarkably complex, both anatomically and chemically, with a remarkable convergence of different receptors in common cortical layers and considerable convergence of neurotransmitter action. A single neuron in the brain receives thousands of synaptic inputs on the cell body and dendrites, and neuronal response is also modulated by a variety of hormonal and neurohormonal substances that are not dependent on synaptic organization (Kandel et al. 2000). The neuron needs to integrate all the synaptic and nonsynaptic inputs impinging on it; this integration of a multitude of signals determines the ultimate excitability, firing pattern, and response characteristics of the neuron, which are then conveyed to succeeding targets via synaptic transmission. How does the single neuron decipher and integrate the multitude of signals it receives and, additionally, generate unique responses to each of these signals or combinations of signals? Not only do G proteins amplify signals, but they also appear to form the basis of a complex information-processing network in the plasma membrane (Bhalla and Iyengar 1999; Manji 1992). Thus, the ability of G proteins to interact with multiple receptors provides an elegant mechanism to organize the signals from these multiple receptors and to transmit them to a relatively much smaller number of effectors. Signals from a variety of receptors can be "weighted" according to their intrinsic ability to activate a given G protein and integrated to stimulate a single second-messenger pathway (see Figure 1–11). Similarly, the dual (positive and negative) regulation of adenylyl cyclase by G proteins allows for stimulatory and inhibitory signals for these pathways to be "balanced" at the G protein level, yielding an integrated output. Thus, G proteins provide the first opportunity for signals from different receptors to be integrated. This complex web of interactions linking receptors, G proteins, and their effectors with signals converging to shared detectors appears to be crucial for the integrative functions performed by the CNS. Abnormalities in a variety of human diseases have now been clearly shown to arise from primary abnormalities in G protein signaling cascades and in the G protein subunits themselves (for an excellent discussion, see Simonds 2003; Spiegel 1998). To date, the direct evidence for the involvement of G proteins in psychiatric disorders is more limited. Thus, although elevations in the levels of G s have been found in postmortem brain and peripheral tissue in bipolar disorder, a mutation in the G s gene has not yet been identified (discussed in Manji and Lenox 1999). There is, however, convincing evidence that chronic lithium administration attenuates the functioning of both Gs and Gi, resulting in an elevation of basal cAMP levels but dampened receptor-mediated effects. The allosteric modulation of G proteins has been proposed to play a role in lithium's long-term prophylactic efficacy in protecting susceptible individuals from cyclic affective episodes induced spontaneously or by stress or drugs (e.g., antidepressant, stimulant) (G. Chen et al. 1999; Gould and Manji 2002).

The cAMP signaling cascade G proteins control intracellular cAMP levels by mediating the ability of neurotransmitters to activate or inhibit adenylyl cyclase (Figure 1–12; see also Figure 1–2). The mechanism by which neurotransmitters stimulate adenylyl cyclase is well established. Activation of those neurotransmitter receptors that couple to Gs results in the generation of free G s subunits that bind to and directly activate adenylyl cyclase. A similar mechanism appears to be the case for G olf, a type of G protein (structurally related to G s) that is enriched in olfactory epithelium and dopamine-rich areas of the brain and mediates the ability of odorant receptors and D1 receptors to stimulate adenylyl cyclase. The mechanism by which neurotransmitters inhibit adenylyl cyclase and decrease neuronal levels of cAMP is somewhat less clear, and more than one mechanism may be operative. By analogy with the action of Gs, it was originally proposed that activation of neurotransmitter receptors that couple to Gi results in the generation of free G i subunits, which could bind to, and thereby directly inhibit, adenylyl cyclase. While this mechanism may be operative, there are also data to suggest that subunit complexes, generated by the release of G i, might directly inhibit certain forms of adenylyl cyclase or might bind and "tie up" free G s subunits in the membrane. FIGURE 1–12. cAMP signaling pathway.

Receptors can be positively (e.g.,

-adrenergic, D1) or negatively (e.g., 5-HT1A, D2) coupled to adenylyl cyclase (AC) to regulate cAMP levels. The effects of cAMP are

mediated largely by activation of protein kinase A (PKA). One major downstream target of PKA is CREB (cAMP response element–binding protein). After activation, the phosphorylated CREB binds to the cAMP response element (CRE), a gene sequence found in the promoter of certain genes; data suggest that antidepressants may activate CREB, thereby bringing about increased expression of a major target gene, BDNF. Phosphodiesterase is an enzyme that breaks down cAMP to AMP. Some antidepressant treatments have been found to upregulate phosphodiesterase. Drugs like rolipram, which inhibit phosphodiesterase, may be useful as adjunct treatments for depression. Forskolin is an agent used in preclinical research to stimulate adenylyl cyclase. It is now clear that there are several forms of adenylyl cyclase that make up a distinct enzyme family; these various forms are differentially regulated and display distinct distributions in nervous and nonnervous tissues. For example, type I is found predominantly in brain, whereas types II and IV, although abundantly expressed in the brain, have a more widespread distribution. The topographical structure of the adenylyl cyclase proteins resembles that of

membrane transporters and ion channels. However, there is currently no convincing evidence of a transporter or channel function for mammalian adenylyl cyclases. As would be predicted, the different forms of adenylyl cyclase are regulated by distinct mechanisms. Type I through IV enzymes differ in their ability to be regulated by Ca2+ and calmodulin. Types I and III are stimulated by Ca2+-calmodulin complexes, whereas types II and IV are insensitive. Perhaps the most intriguing regulation is that by the G protein stimulatory receptor (e.g.,

and

-adrenergic receptor), the

subunits. Thus, it is now clear that when type II adenylyl cyclase is concurrently stimulated by a subunits released from an "inhibitory receptor" (e.g., 5-HT1A,

2,

GABAB) can, in fact, robustly

potentiate the cAMP response (Bourne and Nicoll 1993). Type II adenylyl cyclase thus serves as a "coincidence detector" in the CNS, capable of temporally and spatially integrating signals to bring about dramatically different effects. An additional important mechanism by which adenylyl cyclase can be regulated is by cross-talk with protein kinase C, thereby linking receptors linked to stimulation of adenylyl cyclase and those linked to the turnover of membrane phosphoinositides. The physiological effects of cAMP are mediated primarily by activation of protein kinase A, an enzyme that phosphorylates and regulates many proteins, including ion channels, cytoskeletal elements, transcription factors, and other enzymes. Indeed, one major CNS target for the actions of PKA is the transcription factor CREB (cAMP response element–binding protein), which plays a major role in long-term neuroplasticity and is an indirect target of antidepressants (Duman 2002) (see Figure 1–12). As we discuss in greater detail below, phosphorylation and dephosphorylation reactions play a major role in regulating a variety of long-term neuroplastic events in the CNS.

Phosphoinositide/Protein Kinase C Phosphoinositide Although inositol phospholipids are relatively minor components of cell membranes, they play a major role in receptor-mediated signal transduction pathways. They are involved in a diverse range of responses, such as cell division, secretion, and neuronal excitability and responsiveness. In many cases, subunits Gq/11 is involved, and it is believed that G q/11 directly binds to and activates phospholipase C (Figure 1–13). In other cases, however, it is the released upon activation of receptors coupled to Gi/Go that bring about activation of the enzyme PLC to produce the intracellular second messengers sn-1,2diacylglycerol (DAG; an endogenous activator of PKC) and inositol-1,4,5-triphosphate (IP3). IP3 binds to the IP3 receptor and facilitates the release of calcium from intracellular stores, in particular the endoplasmic reticulum (see Figure 1–13). The released calcium then interacts with various proteins in the cell, including the important family of calmodulins (Ca2+-receptor protein calmodulin, or CaM) (discussed later in this chapter; Figure 1–14). Calmodulins then activate calmodulin-dependent protein kinases (CaMKs), which affect the activity of diverse proteins, including ion channels, signaling molecules, proteins that regulate apoptosis, scaffolding proteins, and transcription factors (Miller 1991; Soderling 2000). FIGURE 1–13. Phosphoinositide (PI) signaling pathway.

A number of receptors in the CNS (including M1, M3, M5 , 5-HT2C) are coupled, via G q/11 , to activation of PI hydrolysis. Activation of these receptors induces phospholipase C (PLC) hydrolysis of phosphoinositide-4,5-bisphosphate (PIP2) to sn-1,2-diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). DAG activates protein kinase C (PKC), an enzyme that has many effects, including the activation of phospholipase A2 (PLA2), an activator of arachidonic acid signaling pathways. IP3 binds to the IP3 receptor, which results in the release of intracellular calcium from intracellular stores, most notably the endoplasmic reticulum. Calcium is an important signaling molecule and initiates a number of downstream effects such as activation of calmodulins and calmodulin-dependent protein kinases (see Figure 1–15). IP3 is recycled back to PIP2 by the enzymes inositol monophosphatase (IMPase) and inositol polyphosphatase (IPPase; not shown), both of which are targets of lithium. Thus, lithium may initiate many of its therapeutic effects by inhibiting these enzymes, thereby bringing about a cascade of downstream effects involving PKC and gene expression changes. Source. Adapted from Gould TD, Chen G, Manji HK: "Mood Stabilizer Pharmacology." Clinical Neuroscience Research 2:193–212, 2003. Copyright 2003, Elsevier. Used with permission. FIGURE 1–14. Calcium-mediated signaling.

In neurons, Ca2+-dependent processes represent an intrinsic nonsynaptic feedback system that provides competence for adaptation to different functional tasks. Ca2+ is generally mobilized in one of two ways in the cells: either by mobilization from intracellular stores (e.g., from the endoplasmic reticulum) or from outside of the cell via plasma membrane ion channels and certain receptors (e.g., NMDA [N-methyl-D-aspartate]). The external concentration of Ca2+ is approximately 2 mM, yet resting intracellular Ca2+ concentrations are in the range of 100 nM (2 x 104 lower). Local high levels of calcium result in activation of enzymes, signaling cascades, and, at extremes, cell death. Release of intracellular stores of calcium is primarily regulated by inositol-1,4,5-triphosphate (IP3 ) receptors that are activated upon generation of IP3 by phospholipase C (PLC) activity, and the ryanodine receptor that is activated by the drug ryanodine. Many proteins bind Ca2+ and are classified as either "buffering" or "triggering." These include calcium pumps, calbindin, calsequestrin, calmodulin, PKC, phospholipase A2, and calcineurin. Once stability of intracellular calcium is accomplished, transient low-magnitude changes can serve an important signaling function. Calcium action is local. Because of the high concentration of calcium-binding proteins, it is estimated that the free Ca2+ ion diffuses only approximately 0.5 M and is free for about 50 sec before encountering a Ca2+-binding protein. Ca2+ is sequestered in the endoplasmic reticulum (which serves as a vast web and framework for Ca2+-binding proteins to capture and sequester Ca2+). Ca2+ buffering/triggering proteins are nonuniformly distributed, so there is considerable subcellular variation of Ca2+ concentrations (e.g., near a Ca2+ channel). The primary mechanism for Ca2+ calcium exit from the cell is either via sodium-calcium exchange or by means of a calcium pump. IP3 can be metabolized both by dephosphorylation to form inositol-1,4-P2 and by phosphorylation to form inositol-1,3,4,5-P4 (IP4), which has been proposed to be involved in the entry of Ca2+ into cells from extracellular sources. Recycling of IP3 is important for continuation of phosphoinositide hydrolysis in response to extracellular signals. This is achieved by the enzyme inositol monophosphatase (IMPase), which is the rate-limiting enzyme that converts IP3 back to phosphoinositide-4,5-bisphosphate (PIP2). Without this enzyme, PIP2 cannot be recycled adequately, potentially leading to low levels of PIP2 and inhibition of the signaling cascades involving DAG and IP3. Lithium, at therapeutically relevant concentrations, is a noncompetitive inhibitor of IMPase (for a review, see Gould et al. 2003). This has led to the "inositol depletion hypothesis," which posits that lithium brings about a reduction in the levels of inositol by inhibiting the activity of this "recycling enzyme." Although lithium does reduce inositol levels in the areas of the brain in bipolar patients (Moore et al. 1999), this likely represents an upstream "initiating event," which brings about downstream changes in PKC and regulates gene expression, which may be ultimately responsible for some of its therapeutic effects (see Figure 1–13) (Brandish et al. 2005; Gould et al. 2003; Manji and Lenox 1999).

Protein Kinase C Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C, or PKC) is a ubiquitous enzyme, highly enriched in brain, where it plays a major role in regulating both pre- and postsynaptic aspects of neurotransmission (Nishizuka 1992; Stabel and Parker 1991). PKC is one of the major intracellular mediators of signals generated upon external stimulation of cells via a variety of neurotransmitter receptors (including muscarinic [M1, M3, M5], noradrenergic [ 1], and serotonergic [5-HT2] receptors) that induce the hydrolysis of various membrane phospholipids. Activation of PKC by DAG appears to involve the binding of the lipid to a specific regulatory site on the enzyme, resulting in an increase in the Ca2+ affinity, and thus its stimulation at physiological ionic concentrations. Ca2+ is also believed to contribute to PKC activation by facilitating the interaction of the enzyme with the lipid bilayer and hence with acidic phospholipids and DAG. PKC is now known to exist as a family of closely related subspecies, has a heterogeneous distribution in brain (with particularly high levels in presynaptic nerve terminals), and, together with other kinases, appears to play a crucial role in the regulation of synaptic plasticity and various forms of learning and memory. The multiple closely related PKC isoforms are all activated by

phospholipids and DAG, albeit with slightly different kinetics. The isoforms can be subclassified according to Ca2+ dependence: the "conventional" PKCs ( , I,

II, ) are dependent on Ca2+ for activity, whereas several others, termed "novel" ( , ,

, ) and "atypical" ( ,

,

), are calcium independent

(Nishizuka 1992). The conventional, novel, and atypical isozymes all share activation by phospholipids or DAG and an autoinhibitory pseudosubstrate region, which maintains the enzyme in an inactive state until activated. However, the subgroups are activated by different activators. The conventional PKCs require calcium, acidic phospholipids, and DAG for activation; the novel PKCs do not require calcium, and the atypical PKCs do not require calcium or DAG. PKC isozymes that do not share the pseudosubstrate region ( /PKD and

) have been described, which suggests a possible different mode of action.

The differential tissue distribution of PKC isozymes, as well as the fact that several isoforms are expressed within a single cell type, suggests that each isozyme may exert distinct cellular functions. At present, it is unclear whether such putative functional specificity arises from differential in vivo activation, differential substrate specificity, or a combination thereof. PKC has many growth-regulating properties in immature cells and has additional cell-specific responses in individual mature cells (Kanashiro and Khalil 1998). One protein whose activity is modulated by PKC is myristoylated alanine-rich C kinase substrate (MARCKS). This protein functions as a regulated crossbridge between actin and the plasma membrane, contributing to the cytoskeleton of the cell and subsequently to neuronal plasticity (Aderem 1992) (see Figure 1–13). PKC is also an important activator of phospholipase A2, thus linking the phosphoinositide cycle with arachidonic acid pathways (see Figure 1–13). Arachidonic acid functions as an important mediator of second-messenger pathways within the brain and is regulated by chronic lithium (Axelrod et al. 1988; Rapoport 2001). The activation of phospholipase A2 by PKC (and other pathways) results in arachidonic acid release from membrane phospholipids (Axelrod 1995). This release of arachidonic acid from cellular membrane allows for the subsequent formation of a number of eicosanoid metabolites such as prostaglandins and thromboxanes. These metabolites mediate numerous subsequent intracellular responses and, because of their lipid permeable nature, transsynaptic responses. PKC also has been demonstrated to be active in many other cellular processes, including stimulation of transmembrane glucose transport, secretion, exocytosis, smooth muscle contraction, gene expression, modulation of ion conductance, cell proliferation, and desensitization of extracellular receptors (Nishizuka 1992). One of the best-characterized effects of PKC activation in the CNS is the facilitation of neurotransmitter release. Studies have suggested that PKC activation may facilitate neurotransmitter release via a variety of mechanisms, including modulating several ionic conductances regulating Ca2+ influx, upstream steps regulating release of Ca2+ from intracellular stores, recruitment of vesicles to at least two distinct vesicle pools, and the Ca2+ sensitivity of the release process itself (discussed in Bown et al. 2002). Abundant data also suggest that the PKC signaling pathway may play an important role in the pathophysiology and treatment of bipolar disorder (Manji and Lenox 1999). Thus, elevations in PKC isozymes have been reported in postmortem brain and platelets in bipolar patients; more importantly, in animal and cell-based models, lithium and valproate exert strikingly similar effects on PKC isozymes and substrates in a time frame mimicking their therapeutic actions. A recent whole-genome association study of bipolar disorder has further implicated this pathway. Of the risk genes identified, the one demonstrating by far the strongest association with bipolar disorder was diacylglycerol kinase, an immediate regulator of PKC (Baum et al. 2008). In animal models of mania, several studies have demonstrated that both acute and chronic amphetamine exposure produces an alteration in PKC activity and its relative cytosolto-membrane distribution, as well as the phosphorylation of a major PKC substrate, GAP-43, which has been implicated in long-term alterations of neurotransmitter release. Increased hedonistic drive and increased tendency to abuse drugs are well-known facets of manic behavior; notably, PKC inhibitors attenuate these important aspects of the manic-like syndrome in rodents (Einat and Manji 2006; Einat et al. 2007). Recent preclinical studies have specifically investigated the antimanic effects of tamoxifen (since this is the only CNS-penetrant PKC inhibitor available for humans). These studies showed that tamoxifen significantly reduced amphetamine-induced hyperactivity and risk-taking behavior (Einat et al. 2007). Finally, with respect to cognitive dysfunction associated with mania, Birnbaum et al. (2004) demonstrated that excessive activation of PKC dramatically impaired the cognitive functions of the prefrontal cortex and that inhibition of PKC protected cognitive function. In summary, preclinical biochemical and behavioral data support the notion that PKC activation may result in manic-like behaviors, whereas PKC inhibition may be antimanic. These preclinical data, along with animal studies discussed above, have prompted clinical studies of PKC inhibitors and mood dysregulation. A number of small studies have found that tamoxifen, a nonsteroidal antiestrogen and a PKC inhibitor at high concentrations, possesses antimanic efficacy (Bebchuk et al. 2000; Kulkarni et al. 2006). Most recently, a double-blind, placebo-controlled trial of tamoxifen in the treatment of acute mania was undertaken (Zarate et al. 2007). Subjects showed significant improvement in mania on tamoxifen compared with placebo as early as 5 days, and the effect size for the drug difference was very large after 3 weeks.

Calcium Calcium is a very common signaling element and plays a critical role in the CNS by regulating the activity of diverse enzymes and facilitating neurotransmitter release (see Figure 1–14). Importantly, excessively high levels of calcium are also a critical mediator of cell death cascades within neurons, necessitating diverse homeostatic mechanisms to regulate intracellular calcium levels very precisely. Thus, although the external level of Ca2+ is approximately 2 mM, the resting intracellular Ca2+ concentrations (Ca2+i) are in the range of 100 nM (that is, 2 x 104 lower) (Rasmussen 1989). Neuronal stimulation by depolarization or receptor activation activates phosphoinositol turnover and increases Ca2+i by one to two orders of magnitude as a result of release of Ca2+ from intracellular stores and/or influx of Ca2+ through ion channels (Rink 1988). Acting via intracellular proteins such as calmodulin and enzymes such as PKC, calcium ions influence synthesis and release of neurotransmitters (Parnas and Segel 1989), receptor signaling (Rasmussen 1986), and neuronal periodicity (Matthews 1986). Many proteins bind Ca2+; these are classified as either "buffering" or "triggering" and include calcium pumps, calbindin, calsequestrin, calmodulin, PKC, phospholipase A2, and calcineurin (see Figure 1–14). Once stability of intracellular calcium is accomplished, transient low-magnitude changes can serve an important signaling function. Importantly, calcium action is locally mediated; that is, because of the high concentration of calcium-binding proteins, it is estimated that the free Ca2+ ion diffuses only approximately 0.5 M and is free for around 50 sec before encountering a Ca2+-binding protein. Ca2+ is sequestered in the endoplasmic reticulum (which serves as a vast web and framework for Ca2+-binding proteins to capture and sequester Ca2+). Ca2+ buffering/triggering proteins are nonuniformly distributed, and thus there is considerable subcellular variation of Ca2+ concentrations (e.g., near a Ca2+ channel). Calcium is generally mobilized in one of two ways in the cell, either by mobilization from intracellular stores or by selective diffusion across plasma membrane ion channels (see Figure 1–14). Ca2+ ions pass the membrane through more or less specific channels regulated by changes of membrane potential or transmitter binding. This Ca2+ influx lasts until Ca2+ levels reach a critical level in the submembranal compartment; a potassium current is then activated that repolarizes the membrane. This Ca2+-dependent potassium current represents a strong inhibitory mechanism of the single neuron itself without synaptic input. Its attractiveness for psychiatry lies in its sensitivity to modulatory influences: many amines, peptides, or drugs with relevance in the etiology and/or treatment of these disorders (e.g., norepinephrine, dopamine, corticotrophin-releasing factor [CRF], caffeine, neuroleptics) modify (i.e., increase or decrease) this potassium current. When activation of the potassium pump is decreased, the capacity for negative feedback after excitation becomes impaired and the neuron switches to a state of higher activation, coincidentally with increased calcium influx. Such an overdrive in calcium currents and discharge activity could be a functional prerequisite for states of pathological activity, possibly underlying neuropsychiatric symptoms such as epilepsy, mania, or depression. Ca2+ released intracellularly is regulated both positively and negatively, resulting in the generation of dynamic Ca2+ waves. Once intracellular Ca2+ levels are increased, this triggers/activates a number of proteins (e.g., adenylyl cyclase type I, CaMKs, PKC, calpain [a protease], calcineurin [a protein phosphatase]). In neurons, Ca2+-dependent processes represent an intrinsic nonsynaptic feedback system that provides the competence for adaptation to

different functional tasks (see Figure 1–14). Regulation of intracellular Ca2+ could be of particular relevance to the study of psychiatric disorders, because the same elevation of intracellular Ca2+ may facilitate or inhibit a given function, depending on the target enzyme, the phase of the cell cycle, the intracellular effector protein, and the Ca2+-dependent process. In addition, higher or more sustained increases of intracellular Ca2+ may inhibit the same function that smaller elevations facilitate (Wolff et al. 1977), so that elevated intracellular Ca2+ can produce excessive activation of some systems and inhibition of others. A polymorphism in PPP3CC, a component of the calcium-dependent protein phosphatase calcineurin, has been associated with risk of developing schizophrenia in at least two patient populations (Gerber et al. 2003; Y. L. Liu et al. 2007).

Signaling Cascades Generally Utilized by Neurotrophic Receptors in the CNS The pleiotropic and often profound effects (e.g., neuronal growth, differentiation, survival) of neurotrophins and growth factors in the CNS are generally mediated by varying degrees of activation of three major signaling pathways: MAP kinase (extracellular response kinase [ERK]) pathway, the phosphoinositol-3 kinase pathway, and the phospholipase C– 1 pathway (see Figure 1–9). Among these pathways, the effects of the PI3K pathway and the MAP kinase pathway have been most directly linked to the cell survival effects of neurotrophins (Patapoutian and Reichardt 2001).

MAP Kinase Cascade MAP kinases are abundantly present in brain and have been postulated to play a major role in a variety of long-term CNS functions, in both the developing and the mature CNS (Fukunaga and Miyamoto 1998; Kornhauser and Greenberg 1997; Matsubara et al. 1996; Robinson et al. 1998). With respect to their actions in the mature CNS, MAP kinases have been implicated in mediating neurochemical processes associated with long-term facilitation (Martin et al. 1997), long-term potentiation (English and Sweatt 1996, 1997), associative learning (Atkins et al. 1998), one-trial and multitrial classical conditioning (Crow et al. 1998), long-term spatial memory (Blum et al. 1999), and modulation of the addictive effects of abused drugs (Lu et al. 2005). They have also been postulated to integrate information from multiple infrequent bursts of synaptic activity (Murphy et al. 1994). Importantly for the present discussion, MAP kinase pathways have been demonstrated to regulate the responses to environmental stimuli and stressors in rodents (Xu et al. 1997) and to couple PKA and PKC to CREB protein phosphorylation in area CA1 of the hippocampus (Roberson et al. 1996, 1999). These studies suggest the possibility of a broad role for the MAP kinase cascade in regulating gene expression in long-term forms of synaptic plasticity (Roberson et al. 1999). For example, it has recently been shown that CREB modulates excitability of neurons of the nucleus accumbens, which helps to limit behavioral sensitivity to cocaine in rodent models (Dong et al. 2006). Thus, overall, the data suggest that MAP kinases play important physiological roles in the mature CNS and, furthermore, may be important targets for the actions of CNS-active agents (Nestler 1998). Growth factors acting through specific receptors (e.g., BDNF acting on TrkB) activate the Ras/MAP kinase signaling cascade (Figure 1–15). Among the targets of the MAP kinase pathway is ribosomal S6 kinase (RSK). RSK phosphorylates CREB and other transcription factors. Studies have demonstrated that the activation of the MAP kinase pathway can inhibit apoptosis by inducing the phosphorylation and inactivation of the pro-apoptotic protein BAD (Bcl-xl/Bcl-2–associated death promoter) and increasing the expression of the anti-apoptotic protein Bcl-2 (the latter effect likely involves CREB) (Bonni et al. 1999; Riccio et al. 1997). Phosphorylation of BAD occurs via activation of RSK. RSK phosphorylates BAD and thereby promotes its inactivation. Activation of RSK also mediates the actions of the MAP kinase cascade and neurotrophic factors on the expression of Bcl-2. RSK can phosphorylate CREB, leading to the expression of genes with neurotrophic functions, such as Bcl-2 and BDNF (see Figure 1–15). Treatment with mood-stabilizing drugs activates the ERK (extracellular signal–related kinase) pathway in brain regions involved in mood regulation (reviewed in G. Chen and Manji 2006). Earlier work showed that lithium and valproate induce AP-1 and CREB transcription factors and enhance expression of the bcl-2 gene. Later, it was found that chronic lithium or valproate treatment promotes neurogenesis in the hippocampus, an effect mediated at least in part by activation of the ERK pathway (see G. Chen and Manji 2006). FIGURE 1–15. MAP (mitogen-activated protein) kinase signaling pathway.

The influence of neurotrophic factors on cell survival is mediated by activation of the MAP kinase cascade and other neurotrophic cascades. Activation of neurotrophic factor receptors referred to as tyrosine receptor kinases (Trks) results in activation of the MAP kinase cascade via several intermediate steps, including phosphorylation of the adaptor protein Shc and recruitment of the guanine nucleotide exchange factor Sos. This results in activation of the small guanosine triphosphate–binding protein Ras, which leads to activation of a cascade of serine/threonine kinases. This includes Raf, MAP kinase kinase (MEK), and MAP kinase (also referred to as extracellular response kinase, or ERK). One target of the MAP kinase cascade is the ribosomal S6 kinases, known as RSK, which influences cell survival in at least two ways. RSK phosphorylates and inactivates the pro-apoptotic factor BAD (Bcl-xl/Bcl-2–associated death promoter). RSK also phosphorylates cAMP response element–binding protein (CREB) and thereby increases the expression of the anti-apoptotic factor Bcl-2 and brain-derived neurotrophic factor (BDNF). Ras also activates the phosphoinositol–3 kinase (PI3K) pathway, a primary target of which is the enzyme glycogen synthase kinase (GSK-3). Activation of the PI3 kinase pathway deactivates GSK-3. GSK-3 has multiple targets in cells, including transcription factors ( -catenin and c-Jun) and cytoskeletal elements such as tau. Many of the targets of GSK-3 are pro-apoptotic when activated. Thus, deactivation of GSK-3 via activation of the PI3K pathway results in neurotrophic effects. Lithium inhibits GSK-3, an effect that may be, at least in part, responsible for lithium's therapeutic effects. These mechanisms underlie many of the long-term effects of neurotrophins, including neurite outgrowth, cytoskeletal remodeling, and cell survival. Source. Adapted from Gould TD, Chen G, Manji HK: "Mood Stabilizer Psychopharmacology." Clinical Neuroscience Research 2:193–212, 2002. Copyright 2002, Elsevier. Used with permission. Inactivation of the ERK pathway in the CNS induces animal behavioral alterations reminiscent of manic symptoms, which are likely to depend on ERK's effect on distinct brain regions and the presence of interacting molecules (Shaltiel et al. 2007). Moreover, ERK knockout mice display behavioral abnormalities related to manic symptoms. These data support a clinical role for the ERK pathway in therapeutic action of mood stabilizers. Nevertheless, the possible role of this pathway in the pathophysiology of bipolar disorder has yet to be elucidated.

PI3 Kinase–Akt Pathway The PI3K–Akt pathway is also particularly important for mediating neuronal survival in a wide variety of circumstances. Trk receptors can activate PI3K through at least two distinct pathways, the relative importance of which differs between neuronal subpopulations. In many neurons, Ras-dependent activation of PI3K is the most important pathway through which neurotrophins promote cell survival (see Figure 1–15). In some cells, however, PI3K can also be activated through three adaptor proteins: Shc, Grb-2, and Gab-1. Binding to phosphorylated tyrosine 490 of Shc results in recruitment of Grb-2 (see Figure 1–9). Phosphorylated Grb-2 provides a docking site for Gab-1, which in turn is bound by PI3K (Brunet et al. 2001). PI3K directly regulates certain cytoplasmic apoptotic pathways. Akt has been proposed to act both prior to the release of cytochrome c by pro-apoptotic Bcl-2 family members and subsequent to the release of cytochrome c by regulating components of the apoptosome. Akt phosphorylates the pro-apoptotic Bcl-2 family member BAD, thereby inhibiting BAD's pro-apoptotic functions (see Figure 1–15) (Datta et al. 1997). Another important target of Akt is the enzyme glycogen synthase kinase–3 (GSK-3) (see Figures 1–11 and 1–15). GSK-3 is a serine/threonine kinase that is, in general, constitutively active in cells. It is found in two forms— and

—and currently appears to be the only kinase significantly directly inhibited by

lithium (Davies et al. 2000; Klein and Melton 1996; Stambolic et al. 1996). It may thus represent a target of the development of novel medications for the treatment of bipolar disorder (Gould and Manji 2005). While most research has focused on the

isoform, available evidence suggests that the two forms

may have very similar—though not absolutely identical—biological properties (Ali et al. 2001; Plyte et al. 1992). GSK-3 was named on the basis of its originally described function as a kinase that inactivates glycogen synthase. Following insulin receptor stimulation, PI3K and Akt are activated, and this results in the phosphorylation and concomitant inactivation of GSK-3. Inactivated GSK-3 no longer phosphorylates glycogen synthase, allowing the formation of glycogen from glucose (Cohen and Frame 2001; Woodgett 2001).

In addition to regulation by Akt, other kinases, including p70 S6 kinase, RSK, and cAMP-dependent protein kinase (PKA), appear to deactivate GSK-3 by phosphorylation (Cohen and Frame 2001; Grimes and Jope 2001). The effect of GSK-3 on transcription factors such as c-Jun, heat shock factor–1 (HSF-1), nuclear factor of activated T-cells (NFAT), and

-catenin (see below) has drawn considerable interest and is particularly noteworthy (Frame and Cohen

2001; Grimes and Jope 2001) (see Figure 1–15). Generally, GSK-3 activity results in suppression of the activity of transcription. Conversely, inactivation of GSK-3 appears to activate these transcription factors (Grimes and Jope 2001). Thus, GSK-3 is well positioned to receive signals from multiple diverse signal pathways, a function that is undoubtedly critical in the CNS. GSK-3 is also a critical regulator of the Wnt pathway. Wnt is a family of secreted glycoproteins that are well known to have important roles in development. Signaling through Wnt glycoproteins results in inactivation of GSK-3 and a subsequent increase in the transcription factor -catenin. Furthermore, some studies suggest a role for -catenin (and Wnt) in synaptic plasticity (Salinas 1999; Salinas and Hall 1999). Additional studies have suggested that -catenin itself may play an important role for this protein in the function of the brain. Indeed, upregulation of this protein is sufficient to cause the formation of gyri and sulci in the mouse brain, a finding observed only in higher mammals, and is suggestive of an important role in higher mammalian cognitive functions (Chenn and Walsh 2002).

PLC- 1 Pathway Phosphorylated Trk receptors also recruit PLC- 1 (see Figure 1–9). The Trk kinase then phosphorylates and activates PLC- 1, which acts to hydrolyze phosphatidylinositides to generate DAG and IP3. IP3 induces the release of Ca2+ stores, increasing levels of cytoplasmic Ca2+ and thereby activating many pathways controlled by Ca2+. It has been shown that neurotrophins activate protein kinase C

, which is required for activation of the ERK cascade and for

neurite outgrowth (Patapoutian and Reichardt 2001). As discussed previously, emerging data suggest that the regulation of hippocampal LTP by TrkB receptors is mediated primarily through the PLC- cascade (for details, see Minichiello et al. 2002).

Phosphorylation/Dephosphorylation For many proteins, a change in charge and conformation due to the addition or removal of phosphate groups results in alterations in their intrinsic functional activity. Although proteins are covalently modified in many other ways—for example, by ADP ribosylation, acylation (acetylation, myristoylation), carboxymethylation, and glycosylation—none of these mechanisms appear to be as widespread and readily subject to regulation by physiological stimuli as phosphorylation. Indeed, protein phosphorylation/dephosphorylation represents a pathway of fundamental importance in the chemistry of biological regulation (see Nestler et al. 2001). Virtually all types of extracellular signals are known to produce many of their diverse physiological effects by regulating the state of phosphorylation of specific proteins in the cells that they target. The phosphate group provides an unwieldy negative charge that often interacts with the catalytic and other regions of enzymes. The addition of a phosphate often results in conformational changes in proteins. In the case of enzymes, this change may increase (more commonly) or decrease the affinity of an enzyme for its substrate. Thus, phosphorylation may result in a change in kinase activity, a change in phosphatase activity, or the marking of a protein for cleavage by proteases. The catalytic activity of an enzyme can be switched on or off, or an ion channel can be opened or closed. For many other proteins, phosphorylation-induced changes in charge and conformation result in alterations in the affinity of the proteins for other molecules. For example, phosphorylation alters the affinity of numerous enzymes for their cofactors and end-product inhibitors, phosphorylation of receptors can alter their affinity for G proteins, and phosphorylation of some nuclear transcription factors alters their DNA-binding properties. Therefore, phosphorylation can produce varied effects on cellular physiology and ultimately can have major behavioral manifestations. Protein kinases are classified by the residues that they phosphorylate, with the two major classes being serine/threonine kinases and tyrosine kinases. Most phosphorylation (>95%) of proteins occurs on serine residues, a small amount (about 3%–4%) on threonine residues, and very little (0.1%) on tyrosine residues (but, as discussed earlier, the tyrosine kinases can be very important for neurotrophic signaling). In all cases, the kinases catalyze the transfer of the terminal ( ) phosphate group of ATP to the hydroxyl moiety in the respective amino acid residue, a process that requires Mg2+. Within cells, protein kinases often form sequential pathways, whereby one kinase phosphorylates/activates another, which phosphorylates/activates another kinase, and so forth. In this manner, signals can be propagated within cells, allowing ample opportunity (see below) for the signal to be altered by other intracellular signals, often in a cell type–specific manner, allowing for considerable "fine-tuning." Although clearly playing critical roles in modulating the function of proteins by catalyzing the cleavage of the phosphoester bond, protein phosphatases have not been as extensively studied as kinases. In the CNS, phosphatases often function as a molecular "off switch," thereby decreasing the activity of enzymes and the intracellular signaling pathways they control. However, it is clear that protein phosphatases are much more than simple off switches. Thus, in an elegant series of studies, Greengard and associates demonstrated that a major CNS phosphoprotein, known by the acronym DARPP-32 (dopamine and cAMP-regulated phosphoprotein, 32 kDa), brings about many of its long-term neuroplastic effects by regulating the activity of a protein phosphatase (protein phosphatase–1; PP-1) (for a review, see Greengard 2001a). Thus, they demonstrated that the DARPP-32/PP-1 pathway integrates information from a variety of neurotransmitters and produces a coordinated response involving numerous downstream physiological effectors. DARPP-32 phosphorylation by PKA is regulated by the actions of various neurotransmitters, principally dopamine acting at D1 receptors but also a variety of other neurotransmitters (Greengard 2001b; Nestler et al. 2001). Phospho-DARPP-32, by inhibiting the activity of PP-1, acts in a synergistic manner with different protein kinases (primarily PKA and PKC) to increase the level of phosphorylation of various downstream effector proteins and thereby long-term neuronal adaptations that have also been implicated in the actions of drugs of abuse and antidepressants (Greengard 2001b; Nestler et al. 2001). While propagation of signals may be very immediate, even short-term phosphorylation of many types of proteins can have long-term effects, resulting in "molecular and cellular memory." Indeed, various forms of learning and memory are known to be regulated, in large part, by phosphorylation events. Short-term memory may involve the phosphorylation of presynaptic or postsynaptic proteins in response to synaptic activity, a process that results in transient facilitation or inhibition of synaptic transmission. Long-term memory may involve phosphorylation of proteins that play a role in the regulation of gene expression, which would result in more permanent modifications of synaptic transmission, potentially via structural brain changes (Malenka and Nicoll 1999). As discussed, long-term potentiation, one of the most extensively studied models of learning and memory, is believed to be initiated through short-term changes in Ca2+-dependent protein phosphorylation and maintained by long-term changes in gene expression. There is also growing appreciation that protein phosphatases play a critical role in the extinction of memory. Thus, abundant data now suggest that rather than representing a passive process, "forgetting" is more an active process of memory erasure (discussed in Genoux et al. 2002). In an elegant series of behavioral studies using transgenic mice, Genoux et al. (2002) provided strong evidence that PP-1 is involved in forgetting rather than in preventing the encoding of memory. Although the precise mechanisms by which PP-1 brings about these effects remain to be fully elucidated, these investigators postulate that CaMKII and the GluR1 subunit of the AMPA receptor play important roles. These findings may have major implications for the ultimate development of agents that could be used to facilitate the erasure of traumatic memories—for example, in PTSD.

CONCLUSION In this chapter, we have attempted to provide an overview of some fundamental aspects of neurotransmitters, signal transduction pathways, and second messengers. For most psychiatrists, molecular and cellular biology have not traditionally played a major role in day-to-day clinical practice. However, new insights into the molecular and cellular basis of disease and drug action are being generated at an ever-increasing rate and will ultimately result in a transformation of our understanding and management of diseases. Indeed, the last decade of the twentieth century was truly a remarkable one for biomedical research. The "molecular medicine revolution" has utilized the power of sophisticated cellular and molecular biological methodologies to tackle

many of society's most devastating illnesses. The rate of progress has been exciting indeed, and hundreds of G protein–coupled receptors and dozens of G proteins and effectors have now been identified and characterized at the molecular and cellular levels. These efforts have allowed the study of a variety of human diseases that are caused by abnormalities in cell-to-cell communication; studies of such diseases are offering unique insights into the physiological and pathophysiological functioning of many cellular transmembrane signaling pathways. Psychiatry, like much of the rest of medicine, has entered a new and exciting age demarcated by the rapid advances and the promise of molecular and cellular biology and neuroimaging. There is a growing appreciation that severe psychiatric disorders arise from abnormalities in cellular plasticity cascades, leading to aberrant information processing in synapses and circuits mediating affective, cognitive, motoric, and neurovegetative functions. Thus, these illnesses can be best conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters (Carlson et al. 2006). Furthermore, many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes. Targeting these cascades in treatment may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality. The role of cellular signaling cascades offers much explanatory power for understanding the complex neurobiology of bipolar illness (Goodwin and Jamison 2007). Signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in psychiatric disorders and are targets for the most effective treatments. The highly integrated monoamine and prominent neuropeptide pathways are known to originate in and project heavily to limbic-related regions, such as the hippocampus, hypothalamus, and brain stem, which are likely associated with neurovegetative symptoms. Abnormalities in cellular signaling cascades that regulate diverse physiological functions likely explain the tremendous medical comorbidity associated with psychiatric disorders.

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Jiang-Zhou Yu, Mark M. Rasenick: Chapter 2. Basic Principles of Molecular Biology and Genomics, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.416279. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 2. Basic Principles of Molecular Biology and Genomics BASIC PRINCIPLES OF MOLECULAR BIOLOGY AND GENOMICS: INTRODUCTION In June 2000, it was announced that both a corporate effort and a government consortium had succeeded in sequencing all of the human genome. This was followed by the publication of that sequence in February 2001 (Lander et al. 2001; Venter et al. 2001). For anyone involved in biology or medicine, these events represented a revolution in the technical and conceptual approach to both research and therapy. It seems that humans are far less complex than most scientists had previously thought. Rather than having 100,000–150,000 genes, as was once the belief, humans may have only about 30,000 genes. At this point, not all of those genes have an identified function, and it is becoming clear that many gene products have more than one function. Perhaps more importantly, genes that have been identified in a single cell type may have an entirely different function in other cell types. Some other genes may enjoy a brief and transient expression during the process of embryonic development only to play an entirely different role in the adult. Truly understanding those genes and gene products will revolutionize all of science, and this may be especially true for psychiatry. Consider that prior to identification of the genome, psychiatric genomics has been limited to studies of chromosomal linkage wherein a putative gene for a disorder could be roughly localized to a given region of a chromosome. The burgeoning understanding of the human genome now occurring has led to a rudimentary understanding of genetic variation among humans. In many humans, a single base or single nucleotide is modified, and it is a combination of knowing the entire genetic code and determining aberrations in individuals with disease that will allow the pinpointing of specific genes associated with psychiatric diseases. New advances and technology are also furthering our understanding of the genome. Microarrays, which permit one to put several genes on a chip, show the ability of a given cell or tissue to activate given genes. Sometimes, during a disease process, inappropriate genes are activated or inactivated. Identification of these genes also helps to shed light on the disease process and on possible therapy. At the same time that rapid advances are being made in understanding the genome, rapid advances in molecular biology are allowing the manipulation of genes and proteins in individual nerve cells. The development of molecular and cellular models for neuropsychiatric disease has also permitted tremendous advancement in our understanding of both biochemical defects and possible new approaches toward ameliorating those defects. In this chapter, we present information about genetics, genomics, and the genome and explain modern molecular biology and the investigative methods used in that field. We also discuss pathophysiology, as related to neuropsychiatry and molecular strategy, and introduce findings from studies on the cell biology of the neuron that help us to understand both psychopharmacology and the biology of the brain and mind.

CELL BIOLOGY OF THE NEURON To appreciate the molecular biology presented in this chapter, it is necessary to describe the components of the neuron that process signals that directly or indirectly modify the aspects of the genome described below. Neurons —specialized cells that function to transmit signals to other neurons, muscles, and secretory cells—contain four basic domains (Figure 2–1), and these domains serve to receive signals, process and integrate signals, conduct impulses, and release transmitter. FIGURE 2–1. Diagram of a typical neuron.

As described in the text, this neuron is divided into zones for the reception of signals (input = dendrites), integration of signals (regulation = nucleus and soma), conduction of signals (axon), and transmission of signals (axon terminal). The nucleus resides in the cell body (the signal processing domain) and contains the DNA that codes for the genes expressed by neurons. Activation of a given gene results in the generation of a messenger RNA (mRNA), which is then translated into a protein (see below). Although such events are common to all cells, neural cells are unique in some aspects of molecular signaling. Of importance, the variety of gene expression is far greater in the brain than in any other organ or tissue. Some estimates are that in aggregate, the brain expresses as much as 10 times the number of genes expressed in any other tissue. This does not mean that individual neurons undergo a much greater gene expression. Rather, it suggests an extraordinary heterogeneity among neurons and glia, which allows for a rich regulation when those neurons and glia assemble into the elaborate network of the human brain. mRNA molecules exported from the nucleus are translated into proteins by ribosomes in the endoplasmic reticulum. Note that most of the protein production occurs in the cell body, although there is also some mRNA in the dendrites (Steward and Wallace 1995). This means that newly made proteins must be transported from that cell body to the axon terminal, a distance as great as 1 m. These proteins are often packaged in vesicles, and specialized "motor" molecules transport packaged proteins down microtubule "tracks" at the cost of adenosine triphosphate (ATP) hydrolysis (Setou et al. 2000).

ESSENTIAL PRINCIPLES OF GENE EXPRESSION Genes and DNA The DNA double helix transmits genetic information from generation to generation and is the repository of information required to guide an organism's development and interaction with the environment. The role of DNA in storing and transferring hereditary information depends on the innate properties of its four constituent bases. There are two purine bases, adenine (A) and guanine (G), and two pyrimidine bases, cytosine (C) and thymine (T). Within the DNA double helix, A is complementary to T, and G is complementary to C. Each block of DNA that codes for a single RNA or protein is called a gene, and the entire set of genes in a cell, organelle, or virus forms its genome. Cells and organelles may contain more than one copy of their genome. There are 46 chromosomes in a typical human cell; when "unraveled," the total DNA of a single cell is approximately 1 m in length. The 46 human chromosomes consist of 22 pairs of autosomes and 2 sex chromosomes, either XX for females or XY for males. Such a large amount of genetic material is effectively packaged into a cell nucleus, which is also the site of DNA replication and transcription. Only a small percentage of chromosomal DNA in the human genome is responsible for encoding the genes that act as a template for RNA strands; there are approximately 20,000–25,000 genes total, of which about 10,000–15,000 genes are expressed in any individual cell. Among RNA strands, only ribosomal RNA (rRNA), transfer RNA (tRNA), and small nuclear RNA (snRNA) have independent cellular functions. Most cellular RNA, mRNA, serves as a template for protein synthesis. RNA, like DNA, is also composed of four nucleotide building blocks. However, in RNA, the nucleotide uracil (U) takes the

place of thymine (T), and RNA is a flexible single strand that is free to fold into a variety of conformations. Thus, the functional versatility of RNA greatly exceeds that of DNA. Chromosomal DNA contains both genes and more extensive intergenic regions. Some regions of DNA in genes act as the template for RNA, but some regions are responsible for regulatory functions. The distribution of genes on chromosomes is not uniform: some chromosomal regions, and indeed whole chromosomes, are richly endowed with genes, whereas other regions are more amply supplied with noncoding DNA. Regulation of gene expression conferred by the nucleotide sequence of a DNA molecule is referred to as cis-regulation, because the regulatory and transcribed regions occur on the same DNA molecule. cis-Regulatory elements that determine the transcription start site of a gene are called basal (or core) promoters; other cis-regulatory elements are responsible for tethering different activators and repressor proteins to DNA. There are specific regions of DNA that bind to regulatory proteins. These regulatory proteins may be encoded at any regions in the genome, and because they are not coded by the stretch of DNA to which they bind, they are sometimes called trans-acting factors. Trans-acting factors that regulate the transcription of DNA are also called transcription factors.

DNA Replication Chromosomal DNA must be replicated to coordinate with cell division. Replication begins at a sequence called the origin of replication. It involves the separation of the double helix DNA strands over a short length and the binding of enzymes, including DNA and RNA polymerases. During DNA replication, each existing strand of DNA serves as a template for the synthesis of a new double helix that contains one old strand and one strand that is newly synthesized but complementary. This process is known as semiconservative replication. In the process of cell division, each of the 46 double helices is replicated and folded into chromosomes.

Transcription Only a fraction of all the genes in a genome are expressed in a given cell or at a given time. These genes undergo the process of transcription, in which an RNA molecule complementary to one of the gene's DNA strands is synthesized in a 5' to 3' direction, using nucleotide triphosphates. Transcription can be classified into three discrete steps: initiation, mRNA chain elongation, and chain termination. Transcriptional regulation may occur at any step in the process; however, initiation appears to be the primary control point because, in a sense, it is the rate-limiting step. Localization of the transcription start site and regulation of the rate of transcription are essential to initiation. The cis- and trans-acting factors described above all regulate the initiation of transcription.

Translation Each mRNA in a cell can code for the primary amino acid sequence of a protein, using a triplet of nucleotides (codon) to represent each of the amino acids. Some amino acids are represented by more than one codon, because there are more triplet codons than there are amino acids. The codons in mRNA do not interact directly with the amino acids they specify. The translation of the individual codons of mRNA into protein depends on the presence of another RNA molecule, tRNA, which has a cloverleaf structure. On the top leaf of the tRNA structure, three nucleotides form a complementary codon (an anticodon) to each mRNA nucleotide triplet. Thus, each mRNA nucleotide triplet can code for a specific amino acid. Each tRNA carries an amino acid corresponding to its anticodon, and when thus "charged," the complex is termed aminoacyl-tRNA. Anticodons of aminoacyl-tRNA bind with mRNA codons in ribosomes. Ribosomes, a complex of rRNA and enzymes needed for translation, provide the structure on which tRNA can bind with the codons of mRNA in sequential order. Initiation of protein synthesis involves the assembly of the components of the translation system. These components include the two ribosomal subunits, the mRNA to be translated, the aminoacyl-tRNA specified by the first codon in the message, guanosine triphosphate (GTP), and initiation factors that facilitate the assembly of this initiation complex. In eukaryotes, there are at least 12 distinct translation initiation factors (Roll-Mecak et al. 2000). After the ribosome recognizes the specific start site on the mRNA sequence, which is always the codon AUG coding for methionine, it slides along the mRNA molecule strand and translates the nucleotide sequence one codon at a time, adding amino acids to the growing end of the polypeptide chain (the elongation process). During elongation, the ribosome moves from the 5'-end to the 3'-end of the mRNA that is being translated. The binding of GTP to the elongation factor tu (EFtu) promotes the binding of aminoacyl-tRNA to the ribosome (Wieden et al. 2002). When the ribosome finds a stop codon (UAA, UGA, or UAG) in the message RNA, the mRNA, the tRNA, and the newly synthesized protein are released from the ribosomes, with the help of release factors that also bind GTP. The translation process is stopped, and a nascent protein exists.

It is noteworthy that initiation, elongation, and release factors undergo a conformational change upon the binding of GTP. In this regard, they are similar to the G proteins (both heterotrimeric G proteins and small "ras-like" G proteins) involved in cellular signaling (Halliday et al. 1984; Kaziro et al. 1991).

REGULATION OF GENE EXPRESSION Chromatin and DNA Methylation Biophysics and molecular biology have revealed that chromatin consists of a repetitive nucleoprotein complex, the nucleosome. This particle consists of a histone octamer, with two copies of each of the histones (H2A, H2B, H3, and H4), wrapped by 147 base pairs of DNA. In the octamer, histones H3 and H4 are assembled in a tetramer, which is flanked by two H2A–H2B dimers. A variable length of DNA completes the second turn around the histone octamer and interacts with a fifth histone, H1. H2A, H2B, H3, and H4 are variously modified at their amino- and carboxyl-terminal tails to influence the dynamics of chromatin structure and function (Ballestar and Esteller 2002; Keshet et al. 1986; Kornberg and Lorch 1999; Strahl and Allis 2000). Although chromatin provides structure to chromosomes, it also plays a critical role in transcriptional regulation in eukaryotes because it can repress gene expression by inhibiting the ability of transcription factors to access DNA. In fact, chromatin ensures that genes are inactive until their expression is commanded. In the activation process, cells must attenuate nucleosomemediated repression of an appropriate subset of genes by means of activator proteins that modify chromatin structure. An activator protein displaces nucleosomes, which permits a complex of proteins (general transcription factors) to bind DNA at a promoter and to recruit RNA polymerase. Cytosine methylation at CpG dinucleotides is the most common modification of the eukaryotic genome. In vertebrates, methylation occurs globally throughout the genome, with the exception of CpG islands. These are CG-rich regions of DNA that stretch for an average of ~1 kilobase (kb), coincident with the promoters of 60% of human RNA polymerase II–transcribed genes. Methylation of cytosines at CpG represses transcription (Ballestar and Esteller 2002). Genetic imprinting, a process by which particular paternal or maternal genes are inactivated throughout a species, is at least partly controlled by DNA methylation. Specific proteins binding to methylated DNA may establish a bridge between chromatin and DNA methylation. They recruit histone deacetylases (HDACs) to activate a methylated promoter, which in turn deacetylates histones, leading to a repressed state (Ballestar and Esteller 2002; Keshet et al. 1986).

RNA Polymerases There are three distinct classes of RNA polymerase—RNA polymerase I, RNA polymerase II, and RNA polymerase III—in the nucleus of eukaryotic cells, and they are designed to carry out transcription. RNA polymerase I synthesizes large rRNA molecules. RNA polymerase II is mainly used to yield mRNA and, subsequently, proteins. RNA polymerase III produces snRNA, small rRNA, and tRNA molecules. Each class of RNA polymerase recognizes particular types of genes. However, RNA polymerases do not bind to DNA directly. Rather, they are recruited to DNA by other proteins that bind to promoters (Figure 2–2). FIGURE 2–2. Transcription factors and RNA polymerase II complex.

Typical transcription factors contain DNA-binding domains, protein dimerization domains, and transcription activation domains. Some transcription factors (e.g., cAMP response element–binding protein [CREB]) may be modified by phosphorylation. The transcription activation domain interacts with an RNA polymerase II (Pol II) complex to induce transcription. TATA binding protein (TBP) binds to the TATA box element and associates with general transcription factors (TFII). This gene transcription apparatus recruits Pol II to the appropriate gene. mRNA is transcribed from DNA by RNA polymerase II with heterogeneous nuclear RNA (hnRNA), an intermediate product. The core promoter recognized by RNA polymerase II is the TATA box (Hogness box), a sequence rich in nucleotides A and T, which is usually located 25–30 bases upstream of the transcription start site. The TATA box determines the start site of transcription and orients the basal transcription complex that binds to DNA and recruits RNA polymerase II to the TATA box; thus, it establishes the 5' to 3' direction in which RNA polymerase II synthesizes RNA. The formation of the basal transcription complex is promoted by a TATA binding protein (TBP) that binds to a core promoter, together with multiple TBP-associated factors and other general transcription factors. Enhancers are DNA sequences that increase the rate of initiation of transcription by RNA polymerase II through its interaction with transcription factors, which can be located "upstream" or "downstream" of the transcription start site. Enhancer elements are important to cell-specific and stimulus-dependent expression of hnRNA. Some RNA polymerase II species, including those for many genes that are expressed in neurons, lack a TATA box and possess instead an initiator, a poorly conserved genetic promoter element.

Transcription Factors Transcription factors act as the key regulators of gene expression. Sequence-specific transcription factors typically contain physically distinct functional domains (see Figure 2–2). Numerous transcription factors have been found. Some of them translocate to the nucleus to bind their cis-regulatory elements in response to activation reaction, such as nuclear factor B (NF- B). However, some transcription factors are already bound to their cognate cis-regulatory elements in the nucleus under basal conditions and are converted into transcriptional activators by phosphorylation. cAMP (cyclic 3'-5'-adenosine monophosphate) response element–binding protein (CREB), for example, is bound to regions of DNA, called cAMP response elements (CREs), before cell stimulation. CREB can promote transcription when it is phosphorylated on a serine residue (ser133), because phosphorylated CREB can interact with a coactivator, CREB-binding protein, which in turn contacts and activates the basal transcription complex. Of interest, CREB-binding protein possesses intrinsic histone acetyltransferase (HAT) activity. The activity of most transcription factors is regulated through second-messenger pathways. CREB can be activated via phosphorylation at ser133 by second messengers, such as cAMP, Ca++, and growth factors (Figure 2–3). FIGURE 2–3. Activation of cAMP response element–binding protein (CREB) via different signal transduction pathways.

Signal cascades are activated by external stimuli, such as hormones or neurotransmitters and growth factors. Arrows indicate the interaction between pathways. AC = adenylyl cyclase; C = catalytic subunits of PKA; Ca++ = calcium; CaMK IV = calmodulin-dependent kinase IV; cAMP = cyclic 3'-5'-adenosine monophosphate; CBP = CREB-binding protein; Epac = exchange protein activated by cAMP; ERK = extracellular-regulated kinase; G s = subunit of the stimulatory G protein; P = phosphorylation; PKA = cAMP–dependent protein kinase; R = regulatory subunits of PKA; Rap and Ras = small GTPases (small proteins that bind to guanosine triphosphate [GTP]); RSK2 = ribosomal S6 kinase 2. CREB is a molecule that is widely implicated in learning and memory in many species. Mice expressing mutant CREB isoforms show impaired memory, but this is dependent on the genetic background of the mice (Graves et al. 2002). CREB-binding protein (CBP) is a transcriptional coactivator with CREB. A partial-knockout mouse model, in which CBP activity is lost, exhibits learning deficiencies (Oike et al. 1999). Further, Rubinstein-Taybi syndrome (RTS) is an autosomal-dominant dysmorphic syndrome that results in severe impairment of learning and memory. The RTS gene has been mapped to chromosome 16 and identified as CBP. The loss of function of CBP is likely one important contributing factor to the learning and memory defects seen in RTS (Murata et al. 2001; Oike et al. 1999; Petrij et al. 1995).

Posttranscriptional Modification of RNA The mRNA of prokaryotes can be used without any modification to direct protein synthesis, but posttranscription processing of mRNA is needed in eukaryotes. The DNA sequences that code for mRNA (exons) are frequently interrupted by intervening DNA sequences (introns). When a protein-coding gene is first transcribed, the hnRNA contains both exons and introns. Before the transcript exits the nucleus, its introns are removed and its exons are spliced to form mature mRNA (Figure 2–4). The hnRNA that is synthesized by RNA polymerase has a 7-methylguanosine "cap" added at the 5' end. The cap appears to facilitate the initiation of translation and to help stabilize the mRNA. In addition, most eukaryotic mRNA has a chain of 40–200 adenine nucleotides attached to the 3' end of the mRNA. The poly (A) tail is not transcribed from DNA; rather, it is added after transcription by the nuclear enzyme poly (A) polymerase. The poly (A) tail may help stabilize the mRNA and facilitate mRNA exit from the nucleus. After the mRNA enters the cytoplasm, the poly (A) tail is gradually shortened. FIGURE 2–4. Transcription and RNA splicing.

The horizontal black line between exons indicates an intron. The region before the first exon is the 5' regulatory region of the gene, such as a TATA box. There also are cis-regulatory elements in introns and downstream of the last exon. The heterogeneous nuclear RNA (hnRNA), containing both exons and introns, is spliced to form mRNA. mRNAs are then exported from the nucleus to the cytoplasm, where they will direct the synthesis of distinct proteins.

RNA Editing RNA editing has been detected in eukaryotes ranging from single-celled protozoa to mammals and plants and is now recognized as a type of RNA process (posttranscriptional modification of RNA) that differs from the established processes of RNA splicing, 5' end formation, and 3' endonucleolytic cleavage and polyadenylation (DeCerbo and Carmichael 2005; Kable et al. 1997). The conversion of adenosine to inosine was observed first in yeast tRNA (Grosjean et al. 1996) but has since been detected in viral RNA transcripts and mammalian cellular RNA (Bass 1997; Simpson and Emeson 1996). The inosine residues generated from adenosines can alter the coding information of the transcripts, as inosine is synonymous for guanosine during transcript translation. For example, upon A-to-I editing, the CAC codon for histamine is transformed to CIC, coding for arginine. RNA editing can have dramatic consequences for the expression of genetic information, and in a number of cases it has been shown to lead to the expression of proteins not only with altered amino acid sequences from those predicted from the DNA sequence but also with altered biological functions (Bass 2002; Burns et al. 1997). The enzymes for RNA editing are referred to as adenosine deaminases that act on RNA (ADARs). ADARs target RNA that is double-stranded and convert adenosines to inosines by catalyzing a hydrolytic deamination at the adenine base (Bass 2002). Mammals have several ADARs, of which two (ADAR1 andADAR2) are expressed in most tissues of the body (Seeburg and Hartner 2003). RNA editing may also catalyze the conversion of one or a few adenosines in a transcript to inosines (Maas et al. 1997; Stuart and Panigrahi 2002). On the other hand, RNA editing can convert numerous adenosines to inosines in RNA. This type of editing is thought to be the result of aberrant production of dsRNA (DeCerbo and Carmichael 2005) and has been suggested to lead to RNA degradation (Scadden and Smith 2001), nuclear retention (Zhang and Carmichael 2001), or even gene silencing (Wang et al. 2005). The 5-HT2C receptor is a G protein–coupled receptor that is well known to have variants generated by A-to-I editing (Burns et al. 1997). 5-HT2C receptor transcripts can be edited at up to five sites, potentially generating 24 different receptor versions, and hence a diverse receptor population. The RNA-edited 5-HT2C receptor affects ligand affinity and the efficacy of G protein coupling (Berg et al. 2001; Wang et al. 2000; Yang et al. 2004). The unedited form of the 5-HT2C receptor has the highest affinity to serotonin and exhibits constitutive activity independent of serotonin levels. When RNA is edited, the basal activity of the 5-HT2C receptor is suppressed, and agonist potency and efficacy are modified.

Modification of the Nascent Polypeptide Chain

The posttranslational modifications described above occur after translation is initiated. They may include removal of part of the translated sequence or the covalent addition of one or more chemical groups that are required for protein activity. Some of these modifications, such as glycosylation or prenylation, represent an obligatory step in the synthesis of the "finished" protein product. In addition, many proteins may be activated or inactivated by the covalent attachment of a variety of chemical groups. Phosphorylation, glycosylation, hydroxylation, and prenylation are common types of covalent alterations in posttranslational modifications. A number of different enzymes coordinate these processes, and they represent a major portion of the events of cellular signaling.

APPROACHES TO DETERMINING AND MANIPULATING GENE EXPRESSION Changes in gene expression within the central nervous system (CNS) have profound effects on all other aspects of the organism. Changes in gene expression are causally associated not only with the development of the CNS but also with the complex phenomena of brain function, such as memory formation, learning, cognition, and affective state. Changes in gene expression likely underlie the pathogenesis of many sporadic or inherited CNS-related disorders, such as Alzheimer's disease, Huntington's disease, depression, and schizophrenia. Thus, insight into and characterization of gene expression profiles are necessary steps for understanding how the brain functions at the molecular level and how malfunction will result in disease. Molecular biological and genomic technologies such as gene mapping and cloning, DNA libraries, gene transfection and expression, and gene knockout and gene targeting have provided numerous benefits to neuropsychopharmacology. Genomic methods applied to pedigree and population samples of patients with psychiatric disorders may soon make it possible to identify genes contributing to the etiology and pathogenesis of these diseases and to provide a potential basis for new therapies.

Cloning of DNA The cloning of DNA confers the ability to replicate and amplify individual pieces of genes. Cloning can be performed with genomic DNA or complementary DNA (cDNA). cDNA is synthesized artificially from mRNA in vitro with the aid of reverse transcriptase. Cloned genomic DNA may contain any stretch of DNA, either introns or exons, whereas cloned cDNA consists only of exons. For cloning (see Figure 2–5 for outline of the process), the desired pieces of DNA (often called "inserts") are connected with the DNA of genetically engineered vectors or plasmids, and the vectors are introduced into hosts, such as bacteria or mammalian cells. A DNA library is a collection of cloned restriction fragments of the DNA of an organism that consists of random pieces of genomic DNA (i.e., genomic library) or cDNA (i.e., cDNA library). Complete cDNA libraries contain all of the mRNA molecules expressed in a certain tissue. Sometimes cDNA libraries can be made from a specific tissue in a distinct circumstance. For example, a cDNA library could be made from cerebral cortex in rats undergoing transient forebrain ischemia (Abe et al. 1993). FIGURE 2–5. Outline of gene cloning.

See text for details. The cloning of disease-related genes is an important step toward insight into the pathogenesis of diseases and development of new drugs against these diseases. If a protein is suspected of involvement in pathogenesis, a nucleic acid sequence can be deduced from the partial amino acid sequence. cDNA libraries are screened with the partial sequence in order to fish out a complete clone of interest. The isolated cDNA molecules are used to infect bacteria, which amplify the cloned cDNA. Bacteria expressing these cDNA molecules will often make the protein of interest, which can be detected with antibody. A variation on the above technique uses antibodies against the purified proteins to screen a DNA library transfected into bacteriophages. The bacteriophages containing the "right" cDNA can be retrieved, and the sequence of cDNA can be analyzed.

Polymerase Chain Reaction Polymerase chain reaction (PCR) is a rapid procedure for in vitro enzymatic amplification of specific segments of DNA. Amplification of the genes of interest occurs by selecting and synthesizing "primers"—stretches of DNA that span the region of interest to be "filled in"—and by heating DNA to make it single stranded, allowing polymerase and primers to bind. The polymerase then reads the "blank" stretch of DNA between the primers and synthesizes DNA corresponding to the region of interest. This is usually done in "thermal cyclers" that heat the DNA at regular intervals and allow "cycles" of PCR to amplify the genes repetitively. To avoid continual addition of polymerase, the DNA polymerase used is often from bacteria that inhabit hot springs or hot ocean vents. This polymerase is not denatured by heating and can therefore support several cycles of PCR. A variation on PCR is reverse transcriptase PCR (or RT-PCR), in which the RNA is the template. Reverse

transcriptase (the "RT" of RT-PCR) is employed to synthesize cDNA from the RNA. Enzymatic amplification of this cDNA is then accomplished with PCR. Real-time PCR is based on the method of RT-PCR, following the reverse transcription of RNA into cDNA. Real-time PCR requires suitable detection chemistries to report the presence of PCR products, as well as an instrument to monitor the amplification in real time through recording of the change in fluorescence (Wittwer et al. 1997). Generally, chemistries in PCR consist of fluorescent probes. Several probes exist, including DNA-binding dyes like EtBr or SYBR green I, hydrolysis probes (5'-nuclease probes), and hybridization probes (Valasek and Repa 2005). Each type of probe has its own unique characteristics, but the strategy for each is to link a change in fluorescence to amplification of DNA (Kubista et al. 2006; Lind et al. 2006). The instrumentation to detect the production of PCR must be able to input energy for excitation of fluorescent chemistries at the desired wavelength and simultaneously detect a particular emission wavelength. Many instrument platforms are available for real-time PCR. The major differences among them are the excitation and emission wavelengths that are available, speed, and the number of reactions that can be run in parallel (Kubista 2004).

Positional Cloning Disease genes can sometimes be isolated with the aid of positional cloning, a process also known as reverse genetics (Collins 1995). Positional cloning is the process used to identify a disease gene, based only on knowledge of its chromosomal location, without any knowledge of the biological function of the gene. Positional cloning requires a genetic map of unique DNA segments or genes (genetic markers), with known chromosomal location, that exist in several alternative forms (alleles). These allelic variations (polymorphisms) allow comparisons of the wild type as the "diseased" genotype. Linkage analysis is a method of localizing one or more genes influencing a trait to specific chromosomal regions. This is performed by examining the cosegregation of the phenotype of interest with genetic markers. Relatives who are phenotypically alike will share common alleles at markers surrounding the genes influencing the phenotype, whereas other relatives (i.e., those who are phenotypically dissimilar) will not carry these alleles. To carry out linkage analyses, investigators need, minimally, a set of families in which phenotyped individuals have known relationships to one another and the genotypes of these individuals, including one or more genetic markers. Once the chromosomal location of the disease gene has been ascertained, the area of chromosomal DNA can be cloned. Until recently, the process of positional cloning involved laborious efforts to build a physical map and to sequence the region. (The sequencing of the human genome has obviated this step.) Physical maps can be produced by isolating and linking together yeast and/or bacterial artificial chromosomes containing segments of human DNA from the region. These fragments are then sequenced and ordered, and from these data, the genomic DNA sequence for the region of the candidate gene region is determined.

Differential Display The technique of differential display is designed to determine the complement of genes being expressed (mRNAs) by a tissue or an organ at a given point in time. The establishment of differential display is dependent on the random amplification and subsequent size separation of cDNA molecules (Liang et al. 1992). With RT-PCR amplification with specific oligo-T primers (one- or two-base anchored oligo-dT primers, such as oligo-T-XC, oligo-T-XG, oligo-T-XT, and oligo-T-XA; X = G/A/C), four separate cDNA synthesis reactions are performed. These cDNA synthesis reactions form the four pools of cDNA for one original mRNA population. The resulting cDNA molecules from each RT-PCR reaction are amplified, using the same primer of the reverse transcription step plus randomly chosen primers. Because the randomly chosen primers will anneal at various locations upstream of the oligo-T site, many individual cDNA fragments of different sizes are amplified in each PCR reaction. cDNA fragments derived from different original mRNA populations are sized and then separated on parallel gels to analyze the presence of unique bands. The differentially expressed cDNA fragments can be excised from gels, cloned, and further characterized by a variety of technologies based on different purposes, such as in situ hybridization, sequences, and Northern blot analysis. Differential display is a useful tool in identifying region-specific mRNA transcripts in brain. The molecular markers for these regions can be found by screening for gene expression in specific brain regions or nuclei (Mizushima et al. 2000; Tochitani et al. 2001). In addition, under different stimulation or behavioral conditions, the changes in gene expression can be explored by differential display (Hong et al. 2002; Q. R. Liu et al. 2002; Mello et al. 1997; Tsai et al. 2002). This technique has even been adapted to indicate the RNA expression profile of an individual

neuron (Eberwine et al. 1992). Many genes related to ischemia or Alzheimer's disease in the CNS were also isolated by means of differential display (Doyu et al. 2001; Imaizumi et al. 1997; Tanaka et al. 2002). Genes that are activated in response to chronic drug treatment (e.g., opiates or antidepressants) can also be identified this way. Furthermore, as described later in this chapter (see "Microarray Technology"), streamlined technologies (gene arrays) are now available for this purpose.

Gene Delivery Into Mammalian Cells The introduction of recombinant DNA (including desired genes) into cells is becoming an increasingly important strategy for understanding certain gene functions in neurons or glia. These advances in gene function studies have benefited the diagnosis of, and therapy for, a variety of disorders that affect the CNS. The delivery of desired genes into cells may also provide the technological base for insight into molecular mechanisms of brain function and, ultimately, for gene therapy in the CNS.

Vectors and Delivery For gene transfer, it is necessary to incorporate the desired cDNA into various vectors, such as appropriate plasmids or replication-deficient viruses. Vectors used for transfection generally possess two essentially independent functions: 1) carrying genes to the target cell and 2) expressing the genes properly in the target cell. There are currently many commercial vectors with different features from which to choose, and the choice is dependent on the purpose of the experiments and on the characterizations of exogenous desired genes. In one form of transfection, stable transfection, cells expressing the gene of interest can be actively selected by a marker (e.g., neomycin resistance genes, Neo), and the cDNA or other type of foreign DNA is stably integrated into the DNA of a chromosome. In transient transfection, however, cells express the gene of interest for a few days. Cells for hosting the foreign DNA can be either established cell lines or primary cultured neuronal cells. The desired cDNA delivered into cells may be native genes, fragments of the genes, mutant genes, or chimeric genes. The main barrier to the delivery of DNA into cells is getting the foreign DNA through the cellular membrane. Over the past decades, various methods have been developed to convey the foreign DNA molecules into mammalian cells. These include chemical or physical techniques, such as calcium phosphate coprecipitation of DNA, liposome fusion, electroporation, microinjection, ballistic injection, and viral infection. At present, methods dependent on incorporation of DNA into cationic liposomes (e.g., lipofectin) are used most widely. These methods of transfection are accessible to both cell lines and cultured primary neuronal cells. The ratio of DNA to liposomal suspension, cell density, and time duration of exposure to the DNA–liposomal complex must be optimized for each cell type in culture.

Viral Vectors Over the past few years, several viral vectors with low toxicity, high infection rate, and persistent expression have extended the methodology of delivery of genes to mammalian cells. These viruses include DNA viruses, such as adenoviruses and adeno-associated viruses, herpes simplex viruses, and RNA retroviruses. Recently, as a result of advances in genetic manipulation, adenoviruses and adeno-associated viruses have been more widely applied to gene transfer. The advantages of adenoviruses are 1) the ability to carry large sequences of foreign DNA, 2) the ability to infect a broad range of cell types, and 3) an almost 100% expression of the foreign gene in cells. Human adenovirus is a large DNA virus (36 kb of DNA) composed of early genes (from E1 to E4) and later genes (L1 to L5). Wild-type adenovirus cannot be applied to gene transfer, because it causes a lytic infection. Thus, recombinant adenoviruses with defects of some essential viral genes are used for gene delivery. These recently developed adenoviral expression systems are safe; such systems have the capacity for large DNA inserts and allow for relatively simple adenoviral production (Harding et al. 1997; He et al. 1998). The process of gene transfer into cells (cell lines and primary cells) via recombinant adenoviruses is simple, but the optimal viral titer, the time of exposure to virus, and the multiplicity of infection should be optimized for each cell type. Cell lines and a variety of primary neuronal cells have been infected by adenoviruses (Barkats et al. 1996; Chen and Lambert 2000; Hughes et al. 2002; Koshimizu et al. 2002; Slack et al. 1996). In addition, recombinant adenoviruses containing the desired genes can be delivered to neurons in vivo via intracerebral injection into particular brain areas (Bemelmans et al. 1999; Benraiss et al. 2001; Berry et al. 2001; Neve 1993).

Identification of Ectopic Gene Expression After delivery of the desired genes into cells, identification of their proper expression is necessary. The general

strategies for identification (Chalfie et al. 1994; Kohara et al. 2001; Yu and Rasenick 2002; Yu et al. 2002b) include 1. The measurement of some functional changes elicited by gene expression in targeted cells. If an enzyme is expressed, this would involve measuring the activity of that enzyme. 2. The detection of the proteins coded by the desired genes by techniques relying on antibodies, such as western blot, immunoprecipitation, and immunocytochemistry. Expression of the desired genes tagged with some epitopes, such as HA, GST, and His-tag, can also be determined with antibodies directed against these epitopes. 3. The use of green fluorescent protein (GFP) as an indicator. GFP, a protein from the jellyfish Aequorea victoria, can be either cotransfected with the desired genes or fused with the desired genes before incorporation into cells. The fluorescence from GFP is easy to detect using fluorescent microscopy, and this allows the monitoring of gene expression in living cells. Furthermore, if GFP is fused with the gene of interest, its fluorescence provides a useful tool for studying the function and cellular localization of proteins coded by the genes of interest. At this point, several different "colors" have been developed through mutation of the initial GFP gene (Shaner et al. 2005). Depending on the wavelengths of excitation, they can be used to localize multiple protein species, or fluorescence resonance energy transfer (FRET) can be used to demonstrate that two target proteins are in close (0.8

N in meta-analysis

References

Schizophrenia

0.81 (0.73–0.9)

Bipolar disorder

0.79–0.85

Major depression

0.37 (0.31–0.42)

5 studies (UK, Sweden, US), N >21,000

Sullivan et al. 2000 (meta-analysis)

Panic disorder

0.43 (0.32–0.53)

3 studies, N >9,000

Hettema et al. 2001 (meta-analysis)

Generalized anxiety disorder

0.32 (0.24–0.39)

2 studies, N >12,000

Hettema et al. 2001 (meta-analysis)

Specific phobias

0.25–0.35

Kendler et al. 1992, 2001b

Social phobias

0.20–0.30

Kendler et al. 1992, 2001b

Agoraphobia

0.37–0.39

Kendler et al. 1992, 2001b

Bailey et al. 1995; Rutter 2000 12 studies (Sweden, US, England, Norway, Denmark, Finland, Germany) Sullivan et al. 2003 (meta-analysis) Kendler et al. 1995b; McGuffin et al. 2003

Obsessive-compulsive disorder 0.45–0.65 (children)

van Grootheest et al. 2005 (review)

0.27–0.47 (adults) Anorexia nervosa

0.56 (0.00–0.86)

Bulimia nervosa

0.28–0.83

Swedish twin registry, N >30,000

Bulik et al. 2000 (review)

Bulik et al. 2006

Alcohol dependence

0.48–0.73 (men)

Tyndale 2003 (review)

0.51–0.65 (women) Nicotine addiction

0.4–0.7

Antisocial personality disorder

0.32

Li 2003; Tyndale 2003 (reviews) 51 studies

Rhee and Waldman 2002 (meta-analysis)

Genetic epidemiology can also contribute to the exploration of more complex questions, such as whether genetic risk factors are shared among different psychiatric disorders and gender and whether they can moderate the effects of environmental risk factors (Kendler 2001) and can thus lead the design of follow-up molecular genetic studies. For example, a twin study has suggested that genetic risk factors for major depression could in part act by increasing vulnerability to stressful life events (Kendler 1995). This finding has been corroborated in recent years by the now well-replicated interaction of functional alleles of the locus encoding the serotonin transporter protein with stressful life events to predict depression (Caspi et al. 2003; Kaufman et al. 2004; Kendler et al. 2005; Sjoberg et al. 2006; Surtees et al. 2006; Wilhelm et al. 2006). Genetic epidemiological and more specifically twin studies have therefore been an important foundation of psychiatric genetics and are likely to continue to contribute more elaborate disease models for future molecular genetic analysis. The major limitation of these studies, however, is that the estimated heritability using twin studies is only an estimate of the aggregate genetic effect. Heritability does not give information on the contributions of specific genes to risk for a disorder. These questions, the answers to which ultimately will shed light on the underlying developmental neurobiology underlying psychiatric illness, require molecular genetic methods.

Psychiatric Disorders Are Complex Genetic Disorders Genetic epidemiological studies have also established that psychiatric disorders are likely not single-gene disorders inherited in a Mendelian fashion (i.e., in a clear recessive, dominant, or X-linked fashion), although rare families in which psychiatric phenotypes are inherited this way have been reported (Brunner et al. 1993). A genetic disorder can be complex for several reasons: Incomplete penetrance. Not everybody carrying the disease allele(s) becomes ill. Phenocopy. Individuals, even within the same families, can exhibit similar or identical traits because of environmental factors. Locus heterogeneity. Variants in different genes can lead to similar or identical disease phenotypes. Allelic heterogeneity. Different patterns of variation within the same gene or genes can lead to similar or identical disease phenotypes. Polygenic inheritance. Additive or interactive effects of variation at multiple genes (i.e., epistatic effects) are necessary for an illness to manifest. Gene–environment interaction. A disorder manifests in response to environmental factors only in the context of predisposing genetic variants. An extreme example of such interaction is phenylketonuria, where exposure to dietary phenylalanine causes severe neurobehavioral impairment in individuals carrying two mutant copies of the locus encoding phenylalanine hydroxylase; limitation of dietary phenylalanine prevents the neurobehavioral disorder. High frequency of the disorder and the predisposing alleles. It appears increasingly likely that common disorders such as schizophrenia, diabetes mellitus, stroke, or hypertension represent final common outcomes to a variety of combinations of environmental and genetic predisposing factors. Thus, two individuals, even within the same family, might manifest clinically indistinguishable disorders for different reasons. Other genetic mechanisms of inheritance. Alternative genetic mechanisms—for example, mitochondrial inheritance or alteration of the genome across generations, such as occurs in trinucleotide-repeat-expansion disorders (e.g., Huntington's disease, fragile X syndrome) or in epigenetic disorders—may be operable in producing a disorder. Epigenetic disorders result from alterations in the genetic material that do not involve changes in the base pair sequence of DNA. Examples of epigenetic disease include the imprinted disorders Angelman syndrome and Prader-Willi syndrome, in which parent-of-origin–dependent chemical modification of DNA produces different phenotypic outcomes from the same chromosomal deletion. Newton and Duman recently reviewed possible roles of epigenetic mechanisms in the action of psychotropic drugs (Newton and Duman 2006) and in neuronal plasticity (Duman and Newton 2007). From the cumulative evidence of psychiatric genetic studies so far, one can conclude that psychiatric disorders best fit a polygenic mode of inheritance, with two or more polymorphic loci contributing to these disorders, including unipolar depression (Johansson et al. 2001; Kendler et al. 2006), bipolar disorder (Blackwood and Muir 2001), schizophrenia (Sobell et al. 2002), and autism (Folstein and Rosen-Sheidley 2001). However, it is still relatively unclear how many loci contribute to each disorder. The inheritance of schizophrenia, for example, fits models including only a few loci as well as very large numbers of loci (Risch 1990a, 1990b; Sullivan et al. 2003). Data from gene-mapping studies suggest that different loci are indeed likely to contribute to schizophrenia and bipolar disorder in different individuals or families (meta-analyses [Levinson et al. 2003; Lewis et al. 2003; Segurado et al. 2003]), strongly supporting the hypothesis that locus heterogeneity is an important factor in schizophrenia. Thus, Bleuler (1951) appears to have been correct when he referred to dementia praecox as "the group of schizophrenias." As already noted, susceptibility genes are likely to interact with environment, gender, and other genes, making the search for genes for psychiatric disorders even more complex (Kendler and Greenspan 2006). Twin studies have produced evidence of genetic interactions with stressful life events predicting major depression (Kendler et al. 1995a) and with early rearing environment to predict schizophrenia, conduct disorder, and drug abuse (Cadoret et al. 1995a, 1995b; Tienari et al. 2004). These gene–environment interactions have now been substantiated by several molecular genetic studies (e.g., Binder et al. 2008; Bradley et al. 2008; Caspi et al. 2002, 2003, 2005), suggesting that future genetic and genomic studies will need to include analysis of both sets of factors. Furthermore, it is likely that there are gender-specific predisposing genes for psychiatric disorders. Data from twin studies suggest that the combined genetic factors predisposing to major depression, phobias, and alcoholism may differ in some respects for men and women (Kendler and Prescott 1999; Kendler and Walsh 1995; Kendler et al. 2001a, 2002, 2006; Prescott and Kendler 2000; Prescott et al. 2000), and this has been supported in molecular genetic studies by the identification of gender-specific loci for major depression (e.g., Abkevich et al. 2003; Zubenko et al. 2002). Finally, gene–gene interactions may be relevant for these disorders (Risch 1990b).

Response to Drug Treatment In contrast to disease susceptibility, genetic epidemiological studies on responses to psychotropic drugs are rare. There is some evidence from family studies that suggests an important contribution of genetic factors in antidepressant response. Already in the early 1960s, studies on the effects of tricyclic antidepressants (TCAs) in relatives suggested that response to these drugs was similar among family members (Angst 1961; Pare et al. 1962). O'Reilly et al. (1994) reported a

familial aggregation of response to tranylcypromine, a monoamine oxidase inhibitor, in a large family with major depression. These initial reports were followed by only a few systematic studies. Franchini et al. (1998) indicated a possible genetic basis of response to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in 45 pairs of relatives. In light of these data, some groups have used or proposed to use response to certain antidepressant drugs or mood stabilizers as an additional phenotype in classical linkage analyses for mood disorders in the hope of identifying genetically more homogeneous families (Serretti et al. 1998; Turecki et al. 2001). Nonetheless, family studies supporting a genetic basis of response to psychotropic drugs are sparse, certainly reflecting the extreme difficulties inherent in conducting well-controlled family studies of therapeutic responses to medications. It has been proposed that genetic modifiers for response to treatment to psychotropic drugs may be easier to detect than associations with disease susceptibility, as the genetic contribution to these traits may be less complex (Weinshilboum 2003). So far, the data are insufficient to support or refute that contention.

HUMAN GENETIC VARIATION As mentioned above, genetic epidemiological studies can only indicate the presence of an aggregate genetic effect but not which type and how many variations contribute to the effect. This next section will give an overview of the types of variation that occur in the human genome and will provide examples for implications of each of them for psychiatric disorders (see also Figure 3–2). FIGURE 3–2. Chromosomes, genes, and genetic variation.

Panel A shows a representation of chromosome 6 (Chr6), which spans 170 megabases of DNA. Panel B shows a zoomed-in representation of the area highlighted in red in panel A. This region contains 31 genes within 2 megabases. Genes can be transcribed from both strands of the DNA. The arrows indicate the direction of transcription and translation of the respective genes. In the region shown, three copy number variants (CNVs) have been identified. All three span several genes. Panel C shows a zoomed-in representation of the gene for FK506 binding protein 5 (FKBP5) highlighted with a red frame in panel B. The gene spans 115 kilobases and is composed of 11 exons (translated into protein). The intervening introns are transcribed into RNA but are spliced out to form the mature mRNA that serves as the template for translation. The transcription start is at exon 1. In this gene, more than 60 SNPs have been genotyped within the HapMap Project. Their positions are indicated by the triangles. Panel D shows sequence examples for three common polymorphisms. Source. Representations from www.hapmap.org.

Variation on a Chromosomal Scale Variation in Chromosomal Number The human genome has approximately 3 billion bases that are distributed over 23 chromosome pairs, with 22 pairs of autosomes and 1 pair of sex chromosomes, X and Y. The most obvious genetic variations can be observed at the light microscope level in the karyotype. This approach visualizes metaphase chromosomes using histological procedures, allowing identification of each specific pair of chromosomes and variations in the total number of chromosomes, such as unisomies and trisomies. Several of the known variations of total chromosome number have an associated psychiatric phenotype. For example, Down syndrome is a complex neurodevelopmental disorder that results in variable levels of mental retardation, and in old age, dementia strikingly similar to Alzheimer's disease (Visootsak and Sherman 2007). Down syndrome results from trisomy 21 (i.e., inheritance of three copies of chromosome 21, due to meiotic nondysjunction during oogenesis. Turner syndrome, in which there is only a single X chromosome (i.e., an XO karyotype), is associated with nonverbal learning disabilities, particularly in arithmetic, select visuospatial skills, and processing speed (Sybert and McCauley 2004).

Translocations Karyotypic examination and other cytogenetic techniques such as fluorescent in situ hybridization (FISH) can reveal additional large-scale chromosomal

abnormalities, such as translocations, deletions, or duplications of large regions of chromosomes. In a large Scottish pedigree, a balanced translocation between chromosomes 1 and 11 appears causally linked to a series of major psychiatric disorders, including schizophrenia, bipolar disorder, recurrent major depression, and conduct disorder (St. Clair et al. 1990). This balanced translocation (which exchanged parts of chromosome 1 with parts of chromosome 11 to produce two abnormal chromosomes, but no net loss of chromosomal material) disrupts two genes at the translocation breakpoint on chromosome 1, termed "disrupted in schizophrenia" (DISC) 1 and 2 (Millar et al. 2000, 2001). Subsequent molecular analysis has provided strong evidence that variation in DISC1 can alter the risk for schizophrenia; the locus is presently considered by most a "confirmed" schizophrenia locus (Porteous et al. 2006).

Deletions Microdeletions occurring on the long arm of chromosome 22 have received considerable attention as cytogenetic risk factors for the development of schizophrenia (Karayiorgou and Gogos 2004). The 22q11 deletion syndrome (DS), in which 1.5–3 million base pairs of DNA are missing on one copy of 22q, includes a spectrum of disorders affecting structures associated with development of the fourth branchial arch and migration of neural crest cells (e.g., the great vessels of the heart, the oropharynx, facial midline, and thymus and parathyroid glands). Originally described as distinct disease syndromes prior to the elucidation of their common molecular etiology, 22q11DS includes velocardiofacial syndrome (VCFS), DiGeorge syndrome, and conotruncal anomaly face syndrome. Following an initial report of early-onset psychosis in patients with VCFS (Shprintzen et al. 1992), Pulver and colleagues examined psychiatric symptoms in adults with VCFS (Pulver et al. 1994) and in a cohort of patients ascertained for schizophrenia (Karayiorgou et al. 1995). The latter study identified two previously undiagnosed cases in 200 patients, verified by fluorescent in situ hybridization to carry 22q11 deletions. These findings, together with earlier reports of suggestive linkage of 22q11–22q12 (Gill et al. 1996; Pulver et al. 2000), strongly suggested that a gene or genes in the 22q11DS region could contribute to risk for schizophrenia.

Duplications Duplications of the long arm of chromosome 15 (15q11–13) are the most frequent cytogenetic anomalies in autism spectrum disorders, occurring in approximately 1%–2% of cases (Cook 2001). This duplication syndrome cannot be clinically differentiated from idiopathic autism spectrum disorders (Veenstra-VanderWeele and Cook 2004), indicating that a complete workup of autism should include testing for this cytogenetic abnormality, as well as for several others (Martin and Ledbetter 2007). Interestingly, deletion of this same region of 15q is associated with Angelman syndrome when the deletion occurs on the maternal copy of chromosome 15, and with Prader-Willi syndrome when the deletion occurs on the paternal chromosome (or more rarely, when two maternal copies of chromosome 15 are present, and the paternal chromosome is missing entirely, a condition known as maternal disomy). Both syndromes manifest as quite distinct but dramatic neurobehavioral disorders (Nicholls and Knepper 2001; Vogels and Fryns 2002).

Molecular Variation in the Genome The majority of genetic and genomic studies in neuropsychiatry conducted to date have examined variation at the molecular level, which would be undetectable with methods appropriate for the kinds of variation described above. To introduce this section, we provide basic definitions of terms.

Definition of Alleles, Genotypes, Haplotypes The definition of alleles, genotypes, and haplotypes is common to all the types of polymorphisms discussed below. An allele is a variation in DNA sequence that occurs at a particular polymorphic site on one chromosome. Every individual with a normal set of chromosomes has two alleles for each polymorphism on the autosomes (nonsex chromosomes, numbers 1–22). On the sex chromosomes, men have only one allele each for all polymorphisms located on the X and Y chromosomes, whereas women carry two copies of each X-linked allele. A genotype is the combined description for the variation at a particular corresponding point on homologous chromosomes and is expressed as two alleles. When the alleles on both chromosomes are the same, it is a homozygous genotype. When the alleles differ, it is a heterozygous genotype. A haplotype, a term derived from abbreviation of "haploid genotype," is the sequence of alleles along an adjacent series of polymorphic sites on a single chromosome. When genotypic data are available from three generations, haplotypes in the third generation can be unambiguously deduced. In the absence of sufficient family-based data (e.g., in case–control studies of unrelated individuals), some haplotypes are ambiguous because the combination of genotypes at the polymorphic sites under study can be explained by more than one set of possible chromosomal arrangements of the component alleles. In such cases, methods such as estimation maximization (EM) can be used to infer the most likely haplotype (Hawley and Kidd 1995; Long et al. 1995).

Copy Number Variation Genome-scale investigations enabled by the sequencing of the human genome and the advent of microarray-based comparative genomic hybridization have recently revealed a previously unappreciated form of polymorphic variation in the human genome: chromosomal regions containing one or more genes can sometimes be deleted or, alternatively, occur in multiple copies, with the number of copies differing among individuals (Nadeau and Lee 2006; Sebat et al. 2004). Such copy number variants (CNVs) occur normally in human populations, and a preliminary map of such variants is now available (Redon et al. 2006). They have recently been associated with marked differences in gene expression (Stranger et al. 2007). CNVs can also be associated with predisposition to disease, including neurobehavioral disorders such as autism and schizophrenia (International Schizophrenia Consortium 2008; Sebat et al. 2007; Stefansson et al. 2008). Research in this exciting new area is in its infancy but has already contributed importantly to the genetics of psychiatric disorders (Cook and Scherer 2008). Copy number variation of the cytochrome P450 gene CYP2D6, which is important for the metabolism of many antidepressants, neuroleptics, and mood stabilizers (Kirchheiner et al. 2004), provides a prominent example of the importance of CNVs to pharmacogenetics. The presence in the genome of copy-number variation at this locus was inferred through biochemical–genetic studies predating the molecular era and was subsequently confirmed by molecular studies. The reported range of copy numbers of CYP2D6 is from 0 to 13. The number of functional CYP2D6 gene copies directly correlates with plasma levels of metabolized drugs, such as the TCA nortriptyline (Bertilsson et al. 2002). Patients with 0 or 1 functional copy of the gene attain therapeutic plasma levels of nortriptyline with very low doses and can easily reach potentially toxic concentrations with typical or high doses. Patients with 2–4 copies, on the other hand, would require high-normal doses to even reach therapeutic plasma levels (Kirchheiner et al. 2001). In the case of the one reported patient with 13 gene copies, even high-normal doses did not produce therapeutic plasma concentrations (Dalen et al. 1998).

Insertion/Deletion Polymorphisms Microscopic insertions and deletions (much smaller than CNVs—on the order of one to hundreds of base pairs [bp]) are another important type of genetic variation. The most famous insertion/deletion polymorphism in psychiatric genetics is a common functional polymorphism in the promoter region of the serotonin transporter gene SLC6A4, referred to as the 5-HT transporter gene–linked polymorphic region (5-HTTLPR). It consists of a repetitive region containing 16 imperfect repeat units of 22 bp, located approximately 1,000 bp upstream of the transcriptional start site (Heils et al. 1996; Lesch et al. 1996). The 5-HTTLPR is polymorphic because of the insertion/deletion of the repeat units 6–8 (of the 16 repeats), which produces a short (S) allele that is 44 bp shorter than the long (L) allele. Although the 5-HTTLPR was originally described as biallelic, rare (

Chapter 7. Psychoneuroendocrinology PSYCHONEUROENDOCRINOLOGY: INTRODUCTION An association between hormones and psychiatric disorders has been long recognized, but it is only in the past few decades that we have reached an understanding of the mechanisms underlying this association. A full account of the myriad ways in which the various endocrine systems influence neurobehavioral function would be beyond the scope of a single chapter. We will therefore focus on examples of promising research directions in this area: namely, how the stress and reproductive hormone axes contribute to the pathoetiology of psychiatric conditions, in particular mood and anxiety disorders. Major depression is considered to be a maladaptive, exaggerated response to stress, and although it is accompanied by abnormalities in multiple endocrine systems, it is the hypothalamic-pituitary-adrenal (HPA) axis that is the main component of the physiological stress response that plays the key role. Stressful life events, particularly those related to loss, have a strong causal relationship with depressive episodes. However, not all people who experience such events develop depression, and an individual's vulnerability to depression depends on the interaction of genetic, developmental, and environmental factors. In addition to the role of the HPA axis in depression, there is growing evidence of HPA axis abnormalities in anxiety disorders and posttraumatic stress disorder (PTSD).

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS The HPA axis transforms stressful stimuli into hormonal messages that enable the organism to adapt to environmental change and to maintain the body's homeostasis. Corticotropin-releasing hormone (CRH) is synthesized in the hypothalamus and is stimulated by stressors, which can be either "physical" (e.g., exercise, starvation) or "psychological" (e.g., perceived danger, stressful life events). The HPA axis is closely linked to the autonomic nervous system, and brain stem catecholamine systems can also "activate" CRH release (Herman et al. 1990; Plotsky 1987; Plotsky et al. 1989). CRH stimulates secretion of pituitary adrenocorticotropic hormone (ACTH), resulting in the secretion of glucocorticoids by the adrenal cortex in a feedforward cascade. Cortisol is the main glucocorticoid, and its secretion is tightly controlled by negative feedback effects of glucocorticoids at both pituitary and brain sites. These comprise very rapid real-time inhibition of the stress response that prevents oversecretion of glucocorticoids (Keller-Wood and Dallman 1984) and results in a slower effect on messenger ribonucleic acid (mRNA) and subsequent protein stores for both CRH and the ACTH precursor, pro-opiomelanocortin (Roberts et al. 1979) (Figure 7–1). FIGURE 7–1. The hypothalamic-pituitary-adrenal axis.

ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone. Stressful stimuli activate all levels of the HPA axis, causing increases in CRH, ACTH, and cortisol secretion. However, these increases are superimposed on an intrinsic circadian pattern of HPA activity driven by the suprachiasmatic nucleus (SCN) (Krieger 1979). HPA axis hormone secretion is pulsatile in nature, with the trough of integrated secretion occurring in the evening and early night and the peak of secretion occurring just before awakening; active secretion continues throughout the morning and early afternoon. This rhythm persists even in the absence of corticosteroid feedback (e.g., adrenalectomy [Jacobson et al. 1989]), and there is evidence that there are intrinsic neural elements responsible for both initiation and inhibition of the CRH/ACTH/cortisol circadian rhythm and that glucocorticoids merely act to dampen the overall amount of secretion (Kwak et al. 1993).

HPA Axis in Depression and Anxiety Disorders Depression Overactivity of the HPA axis as manifested by an increase in cortisol secretion is now a well-established phenomenon in depression (Carroll et al. 1976; Sachar et al. 1973). The first studies (Sachar et al. 1973) showed that up to 50% of depressed patients have higher mean plasma cortisol concentrations and an increased number and duration of cortisol secretory episodes, suggesting increased cortisol secretory activity. Numerous studies have subsequently validated these findings (Carroll et al. 1976; Halbreich et al. 1985; Krishnan et al. 1990a; Pfohl et al. 1985; Rubin et al. 1987). As many as two-thirds of endogenously depressed patients fail to suppress cortisol, or show an early

escape of cortisol, following overnight administration of 1 mg of dexamethasone (using a cortisol cutoff of 5 g/dL to define "escape") (Carroll et al. 1981). While nonsuppression of cortisol in response to dexamethasone is strongly associated with endogenous depression, this finding is less robust in outpatients with depression. Although both hypercortisolemia and feedback abnormalities in response to dexamethasone are present in depressed patients, they do not necessarily occur in the same individuals (Carroll et al. 1981; Halbreich et al. 1985). Other abnormalities, such as reduced glucocorticoid fast feedback (Young et al. 1991) and a blunted ACTH response to exogenous CRH, have also been reported in depressed patients (Gold et al. 1986; Holsboer et al. 1984; Young et al. 1990). The blunted response to CRH appears to be dependent on increased baseline cortisol, since blockade of cortisol production with metyrapone normalizes the ACTH response (Von Bardeleben et al. 1988; Young et al. 1995). It was expected that the increased cortisol would be accompanied by an increased level of ACTH in plasma, but this has been difficult to validate, although several studies (Linkowski et al. 1985; Pfohl et al. 1985; Young et al. 2001) have demonstrated small differences in mean 24-hour plasma ACTH levels between healthy control subjects and depressed subjects. The demonstration of enhanced sensitivity to ACTH 1–24 in depressed patients suggests that increased ACTH secretion is not necessarily the cause of increased cortisol secretion (Amsterdam et al. 1983). However, other studies using very low "threshold" doses of ACTH 1–24 have not been able to demonstrate increased sensitivity to ACTH in depressed patients (Krishnan et al. 1990b), which suggests that increased cortisol secretion is secondary to increased ACTH secretion. Our 24-hour studies of ACTH and cortisol secretion demonstrated that subjects with increased mean cortisol also demonstrated increased mean ACTH, supporting a central origin of the HPA axis overactivity (Young et al. 2001). Further studies with metyrapone in major depression also support the presence of increased central nervous system (CNS) drive, at least in the evening (Young et al. 1994, 1997). It appears likely that there is increased CRH/ACTH secretion, which is then probably amplified by the adrenal, leading to increased cortisol secretion. These changes in cortisol secretion are commonly considered to be "state" changes that resolve when the depression resolves. However, almost all studies examining the HPA axis in major depression in euthymic subjects have examined patients on tricyclic antidepressants, which exert direct effects on the HPA axis. Three of our recent studies in epidemiological samples and a recent British study (Bhagwagar et al. 2003) found that salivary cortisol is increased in subjects with lifetime major depression, most of whom had no current mood symptoms (Bhagwagar et al. 2003; Young et al. 2000a). The overall picture suggests that depression generally shows both an increase in activity of circadian activational elements of the system and reduced feedback inhibition.

Anxiety Disorders The HPA axis has also been studied in patients with anxiety disorders, particularly panic disorder, with and without comorbid major depression. Both the cortisol response to dexamethasone and the response to CRH have been examined in pure panic disorder without comorbid depression. The earliest study with dexamethasone demonstrated a 15% nonsuppression rate in panic disorder (Curtis et al. 1982). A number of other studies have since been conducted, and the overall incidence of cortisol nonsuppression is 17% in panic disorder (13 studies), while the incidence for major depression is 50% (Heninger 1990). Grunhaus et al. (1987) compared patients with major depression to those with major depression with panic disorder and found a similar rate of cortisol nonsuppression following dexamethasone administration (approximately 50%) in the two populations, suggesting that the presence of comorbid panic disorder had little impact beyond that of depression on dexamethasone nonsuppression. In CRH challenge tests, panic disorder patients have demonstrated a decreased integrated ACTH response relative to control subjects in some studies (Holsboer et al. 1987; Roy-Byrne et al. 1986) but a normal response in others (Brambilla et al. 1992). Similar to findings in

depression, "baseline" plasma cortisol was increased in panic patients who showed blunted CRH responses. A study of CRH challenge in panic disorder patients (Curtis et al. 1997) demonstrated a normal response to CRH challenge. Studies of the HPA axis in social phobia have not found evidence of baseline hyperactivity by urinary free cortisol (Uhde et al. 1994), although few challenges other than a social speaking task have been used. Public speaking challenges in anxiety disorders do not support an exaggerated ACTH or cortisol response to this stressor (Gerra et al. 2000; Levin et al. 1993; Martel et al. 1999). A few studies in children with anxiety disorders have also examined the HPA axis. Children with anxiety disorders coming in for a CO2 challenge demonstrated elevated "basal" cortisol in those who panicked in response to CO2, suggesting that increased reactivity to a threatening situation (i.e., anticipation of a procedure that would cause discomfort) was linked to activation of the HPA axis (Coplan et al. 2002). This interpretation is further supported by an extremely large study of basal 24-hour cortisol in normal children and children with either anxiety disorders or major depression, which found lower nighttime cortisol and a sluggish morning rise in cortisol in children with an anxiety disorder. This suggests that anxiety disorders lead to stress hyperreactivity (in the case of anxious children, in the context of a threatening experimental procedure of CO2) with compensatory decreased basal cortisol secretion (24-hour study) (Feder et al. 2004). Overall, the studies to date do not suggest HPA axis hyperactivity in anxiety disorders to the same extent as shown in depression (Abelson and Curtis 1996). Feedback elements are generally normal, and the abnormalities that do exist may reflect "extrinsic" factors that contribute to heightened reactivity within activational elements of the system. The question of whether stress-activated HPA axis elements are abnormal in comorbid major depression and anxiety has not yet been well studied.

Posttraumatic Stress Disorder Given the stress-related etiology of PTSD, it was expected that PTSD patients would show HPA axis abnormalities similar to those seen in depressed patients or chronically stressed animals, but this has not always been the case. An initial study (Mason et al. 1986) found that urinary free cortisol (UFC) excretion was lower in PTSD than in major depression. However, another study (Pitman and Orr 1990) found increased UFC excretion in outpatient PTSD veterans compared with combat-exposed control subjects without PTSD. Since then, there have been various findings, but the most comprehensive studies of PTSD, those by Yehuda and colleagues (for a review, see Yehuda 2002), continue to show low cortisol and enhanced cortisol suppression in response to dexamethasone in combat veterans with PTSD. Interestingly, the presence of comorbid major depression does not change the neuroendocrine picture. The main criticism of this body of work is that the sample comprised only male combat veterans and therefore is not representative, given that in the community, it is women who are most likely to experience PTSD (Breslau et al. 1991, 1995; Kessler et al. 1995). Furthermore, significant confounds with current and past alcohol and substance abuse occur in the veteran population. Several studies have sought to address this problem, with the majority examining women with a history of childhood sexual abuse. While some studies have demonstrated increased UFC in women with PTSD or a history of abuse compared with control subjects (Lemieux and Coe 1995), others have demonstrated similar plasma cortisol (Rasmusson et al. 2001), and still others have found lower cortisol and enhanced cortisol suppression in response to dexamethasone (Stein et al. 1997). Yehuda (2002) examined Holocaust survivors, who were also predominantly exposed early in life, and observed lower UFC and enhanced cortisol suppression following dexamethasone administration in this population. The issue of comorbid depression in the PTSD population has not been well addressed, with most studies including comorbid individuals and few analyzing the data by the presence or absence of comorbid depression. The exception is the studies of Heim et al. (2001), which focused on childhood abuse and major depression and examined multiple HPA axis challenges in the same subjects. These studies found an effect of early abuse (with comorbid PTSD in 11 of 13 subjects) and

major depression on stress reactivity, with both increased ACTH and cortisol response to the stressor compared with either healthy control subjects or depressed patients without childhood abuse. In this same cohort, there was a blunted response to CRH challenge in patients who had major depression with or without childhood abuse, but an increased response to CRH in those with early abuse but without major depression. The abused subjects also showed a blunted cortisol response to ACTH 1–24. Thus, childhood abuse produced an increased pituitary response with adaptive adrenal compensation, a change compatible with low or normal basal cortisol. Furthermore, lower cortisol and enhanced feedback to low-dose dexamethasone were found in the same subjects (Newport et al. 2004) regardless of the presence or absence of PTSD as the primary diagnosis, thus indicating enhanced feedback. Epidemiologically based samples in adults have focused on natural disasters and have generally examined exposure with high and low PTSD symptoms (Anisman et al. 2001; Davidson and Baum 1986; Fukuda et al. 2000) but without diagnostic information. However, one study (Maes et al. 1998) that examined PTSD subjects recruited from community disasters demonstrated increased UFC in PTSD. In general, community-based studies suggest that exposure to disaster increases plasma (Fukuda et al. 2000) and saliva cortisol (Anisman et al. 2001) and UFC (Davidson and Baum 1986). Studies examining motor vehicle accident survivors (Hawk et al. 2000) found no difference in cortisol between those with and without PTSD 6 months later. Studies of male and female adults with exposure to mixed traumas have found either no effect of PTSD on basal cortisol (Kellner et al. 2002, 2003) or elevated basal cortisol (Atmaca et al. 2002; Lindley et al. 2004). Our analysis of recent trauma exposure in two community samples (Young and Breslau 2004a, 2004b; Young et al. 2004) found increased cortisol in those with past-year exposure to trauma, but no effect of greater than 1 year past trauma exposure and no effect of childhood abuse on basal saliva cortisol or UFC. To add further complexity, the majority of studies of trauma and PTSD included subjects with comorbid depression, and in most studies, the majority of subjects had both PTSD and major depression. The PTSD studies generally report comorbid depression in their subjects; however, studies of depression often fail to measure and report trauma histories. As a result, documented depression confounds much of the PTSD HPA axis literature, and undocumented trauma and abuse may confound some of the depression HPA axis literature. In addition to the issue of exposure to trauma, the persistence of the neuroendocrine changes following recovery from PTSD is unclear. In an early study, Yehuda et al. (1995) reported that Holocaust survivors with past but not current PTSD demonstrated normal UFC, while later studies of offspring of Holocaust survivors (Yehuda et al. 2002) suggested that changes in cortisol may persist beyond the duration of the symptoms and thus may represent a marker of underlying vulnerability to PTSD. The large analysis by Boscarino (1996) of cortisol data from several thousand combat veterans showed a very small effect of PTSD on basal cortisol, but a very clear effect of combat exposure, with increasing levels of severity of combat exposure associated with increasingly lower cortisol. Our recent studies of cortisol in PTSD from two epidemiological samples (Young and Breslau 2004a, 2004b; Young et al. 2004) demonstrated normal UFC and saliva cortisol in community-based individuals with "pure" and comorbid PTSD. The studies also demonstrated a clear effect of lifetime comorbid major depression on cortisol, showing increased HPA axis activation in the late afternoon/evening in patients with both major depression and PTSD. Furthermore, the elevated HPA drive demonstrated by increased evening cortisol levels was greater in the comorbid group than the elevation already documented in pure major depression. Studies examining the response to low-dose dexamethasone in PTSD veterans found enhanced feedback to dexamethasone in veterans who met criteria for PTSD, regardless of the presence of comorbid major depression (Yehuda et al. 2002). Similar enhanced cortisol suppression in response to dexamethasone administration has been found in Holocaust survivors with PTSD and their offspring.

In the studies of Yehuda (2002) as well as the report by Stein et al. (1997), the enhanced suppression was also paired with low baseline cortisol, although other studies did not replicate this finding (Kellner et al. 2004a, 2004b). In a CRH challenge study in combat-related PTSD, there was a normal to increased plasma cortisol at the time of challenge (Smith et al. 1989) and a decreased ACTH response in subjects with high baseline cortisol. Another study of women with PTSD and a history of childhood abuse (Rasmusson et al. 2001) showed enhanced cortisol response to CRH and to exogenous ACTH infusion, as well as a trend toward higher 24-hour UFC. Interestingly, all the women with PTSD had either past or current major depression, so comorbidity was the rule. In the study by Heim et al. (2001) examining response to CRH in women with major depression with and without childhood abuse, 14 of 15 major depressive disorder patients with childhood abuse also met criteria for PTSD. This group with comorbid major depression and PTSD demonstrated a blunted ACTH response to CRH challenge similar to that observed in major depression without PTSD. The abused groups also demonstrated lower baseline and stimulated cortisol both in response to CRH challenge and following ACTH infusion. These same groups of women showed a significantly greater HPA response to the Trier Stress Test, despite smaller responses to CRH challenge (Heim et al. 2000). Several additional studies have evaluated response to stressors. Our early study (Liberzon et al. 1999) using combat noise versus white noise in male veterans with PTSD showed elevated basal and postprovocation cortisol compared with combat controls but no real evidence of a difference between the combat and white-noise days. A study by Bremner et al. (2003) of PTSD subjects of both sexes used a stressful cognitive challenge and found elevated basal saliva cortisol and continued higher cortisol for 60 minutes postchallenge. Eventually the saliva cortisol of the PTSD group returned to the same level as that of controls, raising the issue of whether the "basal" samples were truly basal or were influenced by the anticipatory challenge. Similar data were found in a study (Elzinga et al. 2003), using trauma scripts, in women with childhood abuse and PTSD compared with abused women with no PTSD. In that study, salivary cortisol was again significantly elevated at baseline, increased in response to the challenge (whereas controls showed no response), and then greatly decreased following the stressor, compatible with "basal" levels already reflecting exaggerated stress sensitivity in this group. Using a 1-minute cold pressor test, a recent study (Santa Ana et al. 2006) compared the ACTH and cortisol response in PTSD subjects with either childhood trauma or adult trauma with that of control subjects and found lower basal cortisol in the childhood abuse group. However, their data do not support an actual change in ACTH or cortisol in response to the stressor in any group, so it is difficult to interpret their findings as reflecting differences in stress response. In addition, sampling was very infrequent and therefore inadequate to characterize the time course to a very brief stressor. Overall, the existing stress data suggest an exaggerated stress response in PTSD. Furthermore, the challenge studies certainly suggest that the picture is complicated in PTSD with comorbid depression; the findings of some studies look like depression while others look quite different—for example, showing a smaller response to ACTH infusion whereas patients with major depression show an augmented response. Age of trauma exposure may be one reason for contradictory data. Finally, one study by Yehuda (2002) of combat veterans with PTSD demonstrated greater rebound ACTH secretion compared with controls following administration of metyrapone in the morning, indicating that increased CRH drive is present in the morning but is normally restrained by cortisol feedback. The other two studies examining metyrapone challenge in PTSD found a normal ACTH response to afternoon or overnight metyrapone as well as a normal response to cortisol infusion in PTSD subjects and panic disorder subjects (Kanter et al. 2001; Kellner et al. 2004a, 2004b). In summary, these data suggest that there may be no simple relationship between diagnostic categories and specific HPA axis abnormalities. Timing of trauma or of onset of depression or anxiety disorders may differentially affect the HPA axis profile, although definitive studies have not been done.

DEPRESSION AND REPRODUCTIVE HORMONE CHANGES In women with a previous episode of depression, times of rapidly changing gonadal steroid concentrations, such as those occurring premenstrually or postpartum, mark particularly vulnerable times for the occurrence of depressive symptoms. Several studies have shown that in women, a history of depression increases the risk of both postpartum "blues" and postpartum major depression (O'Hara 1986; O'Hara et al. 1991; Reich and Winokur 1970) and that hormonal changes occurring premenstrually may affect mood (Halbreich et al. 1984, 1986). When they were euthymic, 62% of women with a history of major depressive episodes reported the occurrence of premenstrual mood changes and biological symptoms typical of major depressive disorder. Other studies found a relationship between the rise in estrogen and testosterone levels and the rising incidence of depression in girls during adolescence (Angold et al. 1999). More recently in two epidemiological cohorts (Cohen et al. 2006; Freeman et al. 2006), there was an increased incidence of depressive symptoms and major depression during the menopausal transition. Both high and low estrogen were associated with depression (Freeman et al. 2004, 2006), and the variability in estrogen levels may drive depression—that is, those women who show rapid changes from high to low estrogen and vice versa are those who develop depressive symptoms during the perimenopause transition. This suggests that examining the reproductive axis in depression may be a fruitful area of psychoneuroendocrine research.

HYPOTHALAMIC-PITUITARY-GONADAL AXIS The secretion of the principal gonadal steroids, estrogen and progesterone, is governed by cyclic changes in ovarian follicular and corpus luteum development over the course of the menstrual cycle. Critical to the proper functioning and timing of the monthly hormonal cycle is the pulsatile secretion of gonadotropin-releasing hormone (GnRH). GnRH secretion from the hypothalamus drives the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotropes (Midgley and Jaffe 1971). During the early follicular phase, FSH plays the major role in maturing the follicle (diZerega and Hodgen 1981), and the developing follicle secretes increasing amounts of estradiol as it matures. Maturation-induced increases in estradiol exert a negative feedback on FSH secretion and both negative and delayed positive feedback effects on LH secretion (Karsch et al. 1983). The change in estradiol feedback from negative to positive late in the follicular phase is complemented by rising progesterone and results in the midcycle surge in LH necessary for ovulation. Following ovulation, progesterone levels continue to rise as a result of active secretion from the corpus luteum. LH secretion is necessary for the maintenance of the corpus luteum and subsequent estrogen and progesterone secretion and also facilitates estradiol production by the follicle and controls the secretion of hormones by the corpus luteum but is inhibited by progesterone (Chabbert et al. 1998). In the absence of fertilization, regression of the corpus luteum occurs, with the subsequent fall in estrogen and progesterone leading to the onset of menses. The pulsatile secretion of GnRH is driven by a pulse generator in the arcuate nucleus of the hypothalamus (Knobil 1990). This pulsatile pattern of GnRH secretion is critical for the control of serum LH, FSH, and ovulation. Indeed, continuous administration of the GnRH agonist leuprolide in a nonpulsatile pattern suppresses ovulation as effectively as does inadequate secretion of GnRH. Studies in primates with arcuate lesions have demonstrated that administration of GnRH pulses in frequencies that are too fast or too slow results in low serum concentrations of LH (Belchetz et al. 1978). LH secretory pulses in the peripheral circulation are used as the marker of GnRH secretory pulses. In humans, the follicular phase of the menstrual cycle is characterized by reasonably constant amplitude LH pulses every 1–2 hours (Reame et al. 1984). During the luteal phase, pulse amplitude becomes much more variable and pulse frequency decreases. The slowing of the LH pulses during the luteal phase is due to the actions of progesterone on the GnRH pulse generator (Goodman and Karsch 1980;

Soules et al. 1984; Steele and Judd 1986). Gonadal steroids exert negative feedback effects on the amplitude and frequency of GnRH pulses and through this mechanism (in addition to direct actions on the pituitary) inhibit the secretion of LH and FSH. Likewise, central opioids, particularly

-endorphin,

exert a tonic inhibition on GnRH secretion (Ferin and Vande 1984). Circadian changes in LH secretion are not as prominent as those of the HPA axis (Jaffe et al. 1990). During puberty and following recovery from anorexia- or exercise-induced amenorrhea, nighttime secretion of LH becomes particularly prominent. Furthermore, nighttime slowing of LH pulses during the early follicular phase also occurs in normal women (Soules et al. 1985).

Effect of HPA Axis on the Reproductive Axis Stress has long been known to inhibit the reproductive axis, and the work of Christian (1971) demonstrating infertility secondary to high population density is often cited as a seminal report. Shortly after the isolation and sequencing of CRH, it was demonstrated in rats that CRH inhibited LH secretion (Rivier and Vale 1984) and GnRH secretion (Petraglia et al. 1987), and further primate studies showed inhibition of LH secretion by injection of CRH (Olster and Ferin 1987). While early studies used peripheral administration of high doses of CRH, subsequent studies demonstrated that intracerebrovascular administration of CRH demonstrated much greater potency and confirmed a central site of action of the inhibition, pointing to direct inhibition of GnRH by CRH (Gambacciani et al. 1986; Nikolarakis et al. 1986a, 1986b; Olster and Ferin 1987; Petraglia et al. 1987). However, the peripheral administration of CRH also demonstrated an opioid-mediated inhibition by CRH that could be abolished by dexamethasone pretreatment, suggesting a role for pituitary-derived opioids, most probably

-endorphin from anterior pituitary corticotropes. Anatomical

studies demonstrate that CRH neurons synapse with GnRH neurons (MacLusky et al. 1988); in vitro studies demonstrate that CRH can function as a secretagogue for arcuate

-endorphin secretion from the

-endorphin system (Nikolarakis et al. 1986a). Studies in primates by the Knobil laboratory

(Williams et al. 1990) recording multiunit activity from the arcuate nucleus (i.e., the GnRH pulse generator) demonstrated that CRH administration induced inhibition of the rhythmic firing of the arcuate nucleus accompanying LH secretory pulses, as well as abolishing LH pulses. Studies with a CRH antagonist,

-helical CRH9–41, demonstrated the antagonist's ability to reverse stress-induced LH

suppression in rats, confirming a central CRH-based mechanism by which stress inhibits LH secretion (Rivier et al. 1986). While the primate and rat studies have clearly pointed to CRH as the primary mechanism by which stress inhibits GnRH release, this is not true in all species (e.g., central CRH has no effect on GnRH or LH secretion in sheep [Tilbrook et al. 1999]), and some stressors act through cortisol (Debus et al. 2002). The demonstration of a central CRH effect on GnRH release does not preclude an effect of cortisol in both rats and primates, including humans. So is there evidence that cortisol may also be involved in the inhibition of reproductive function? Several studies have demonstrated that ACTH administration reduces the increase in serum LH concentrations following ovariectomy or orchidectomy in rats (Mann et al. 1982; Schwartz and Justo 1977). This effect is dependent on the presence of the adrenal but could also involve adrenal production of gonadal steroids, which is regulated by ACTH (Putnam et al. 1991). Glucocorticoids also exert inhibitory effects on GnRH secretion or LH responsiveness to GnRH, including direct effects of cortisol on the gonadotrope (Suter and Schwartz 1985). Radovick et al. (1990) demonstrated a glucocorticoid-responsive element (GRE) on the GnRH gene, providing the potential for glucocorticoids to modulate GnRH gene expression. Diminished LH response to GnRH following long-term prednisolone treatment has been found in women (Sakakura et al. 1975). Patients with Cushing's disease, in which cortisol is increased but central CRH is likely to be low because of excessive glucocorticoid feedback on paraventricular nucleus of the hypothalamus CRH, show inhibition of LH secretion. Recent studies in ewes have found that 1) LH secretory amplitude is clearly inhibited by stress; 2) the effects of stress or endotoxin are reversed by metyrapone inhibition of cortisol

synthesis; and 3) infusion of stress levels of cortisol can produce inhibition of LH pulse amplitude but not frequency, which is blocked by RU486, a glucocorticoid receptor antagonist (Breen et al. 2004; Debus et al. 2002). Finally, a recent study of exercise-induced reproductive abnormalities in adolescent girls concluded that "in active adolescents, increased cortisol concentration may. . . precede gonadotropin changes seen with higher levels of fitness" (Kasa-Vubu et al. 2004, p. 1). These data suggest that cortisol, in addition to central CRH, may also play a role in LH disruption. Other studies in humans have linked hypothalamic-pituitary-gonadal (HPG) axis abnormalities to HPA axis activation. These include exercise-induced amenorrhea, anorexia nervosa, and hypothalamic amenorrhea. In all three syndromes, hypercortisolemia has been observed, indicating overactivity of the HPA axis (Berga et al. 1989; Casanueva et al. 1987; Hohtari et al. 1988; Loucks et al. 1989; Suh et al. 1988; Villanueva et al. 1986). In all three syndromes, CRH has been used as a challenge to evaluate pituitary and adrenal function. The response to exogenous CRH challenge demonstrates diminished ACTH or cortisol responses, suggesting that high baseline cortisol exerts negativefeedback effects on the hormonal responses to CRH (Berger et al. 1983; Biller et al. 1990; Gold et al. 1986; Hohtari et al. 1991). In anorexia nervosa, the hormonal abnormalities in both HPA and HPG axes are secondary to weight loss. Weight restriction and low body weight are also observed in exerciseinduced amenorrhea, and low body weight has been reported in hypothalamic amenorrhea. Even relatively mild degrees of weight loss in normal-weight or obese subjects can lead to disturbances in both axes, as manifested by resistance to dexamethasone and by disturbances in menstrual regularity or amenorrhea (Berger et al. 1983; Edelstein et al. 1983; Pirke et al. 1985). Consequently, these three syndromes present with evidence of increased HPA axis activation and disrupted HPG functioning and amenorrhea. The disturbances in LH secretion in anorexia nervosa and hypothalamic amenorrhea have been evaluated primarily by examining the characteristics of LH pulsatile activity. In anorexia nervosa, LH secretory patterns may revert to prepubertal levels of low nonpulsatile secretion or to a pubertal pattern of entrainment of LH secretion to the sleep cycle. Studies by Reame et al. (1985) in women with hypothalamic amenorrhea demonstrated that LH secretion in the follicular phase is slowed to the rate normally observed during the luteal phase. In these individuals, LH and FSH responses to GnRH appear normal, indicating that the reduced pulse frequency is not secondary to pituitary changes but presumably due to changes in the GnRH pulse generator. Figure 7–2 summarizes the various levels at which hormones of the HPA axis may impinge on the reproductive axis. Despite suggestions that reproductive hormones may play a role in mood disorders, the HPG axis has received little examination in depression. FIGURE 7–2. Effects of the hypothalamic-pituitary-adrenal axis on the hypothalamic-pituitarygonadal axis.

GH = growth hormone; GHIH = growth hormone–inhibiting hormone; GHRH = growth hormone–releasing hormone; IGF-1 = insulin-like growth factor 1.

Reproductive Abnormalities in Depression In depression, response to GnRH has been assessed by several groups. Some studies have reported a normal LH and FSH response to GnRH in pre- and postmenopausal women (Unden et al. 1988; Winokur et al. 1982). However, given the major differences in LH pulse amplitude and mean LH levels between follicular and luteal phases, it would be extremely difficult to observe a difference in basal LH secretion between major depression and control women without strict control of menstrual cycle phase. However, Brambilla et al. (1990) noted a decreased LH response to GnRH in both premenopausal and postmenopausal women, with lower baseline LH concentrations in postmenopausal depressed women. It may be that the increased secretion of LH following removal of the negative feedback of gonadal steroids in postmenopausal women unmasks a decrease in LH secretion that is not as easily observed in women with intact estrogen and progesterone feedback. Other studies examining depressed patients of both sexes, which were not analyzed separately, observed no change in baseline or GnRH-stimulated LH and FSH secretion (Unden et al. 1988). Only recently have studies begun to focus on the pulsatile rhythm of LH secretion in women with major depression. Thus far, there have been only four published studies examining pulsatile LH secretion in depressed women: two by Meller et al. (1997, 2001), a third by us (Young et al. 2000b), and a fourth looking at the data from both Meller and Young with spectral analysis (Grambsch et al. 2004). The data from the Meller studies showed slower LH frequency in the follicular phase. Our data revealed significantly lower estradiol in the follicular phase in a small sample of depressed women. Since our publication in December 2000, a large-scale epidemiological study by Harlow et al. (2003) has found that earlier menopause is accompanied by lower estradiol in perimenopausal depressed women. Thus, three recent carefully done studies using modern techniques with sophisticated analyses have found evidence of reproductive axis abnormalities in depressed women. One study of the reproductive axis in men with major depression (Schweiger et al. 1999) also revealed decreased testosterone and a trend for slower LH pulses, suggesting that abnormalities in the reproductive axis are also found in men. Consequently, further studies on the reproductive axis in depression are indicated.

Estrogen and Depression Because of increased incidence of depression at critical hormonal transition phases such as postpartum and perimenopause, much speculation has taken place about estrogen's role as a precipitant. Recent studies have found increased incidence of depressive symptoms and major depression during the menopause transition (Cohen et al. 2006; Freeman et al. 2006). The initial findings of Freeman et al. (2004) in regard to estrogen were that both high and low estrogen levels were associated with depression. More recently, the data suggest that variability in estrogen levels may drive depression. A model of differential sensitivity to estrogen has been proposed for premenstrual dysphoric disorder (PMDD) and also by Cohen et al. (2006) to explain the findings of increased depression during the menopause transition. Increased FSH, suggesting ovarian aging, and overall low or variable estrogen were also found to be strongly associated with depression (Freeman et al. 2006). And in the Freeman et al. study, PMDD was associated with depression during the menopause transition. Furthermore, the central effects of estrogen are intriguing and lend credence to a possible role of estrogen in modulating critical neuronal systems involved in depression. Studies in nonhuman primates have confirmed that estrogen increases tryptophan hydroxylase, the rate-limiting step in serotonin synthesis (Bethea et al. 2002). Estrogen also decreases serotonin1A (5-HT1A) autoreceptor binding, which would serve to increase serotonin levels at the synapse (Bethea et al. 2002). Estrogen modulates the serotonin transporter, leading to decreases in the transporter mRNA but increases in the transporter expression in the hypothalamus (Bethea et al. 2002). Estrogen also decreases monoamine oxidase A activity, which would potentiate actions of norepinephrine in the synapse, and increases tyrosine hydroxylase, the critical first enzyme for synthesis of norepinephrine (Bethea et al. 2002). However, use of estrogen as a treatment has produced mixed results, perhaps because not all studies have targeted women with changing estrogen levels. Early studies found an effect of high-dose estrogen augmentation on response to antidepressants (Klaiber et al. 1979; Shapira et al. 1985). In situations of recent-onset estrogen deficiency such as postpartum and perimenopause, estrogen has been demonstrated to be an effective treatment for depression in randomized, controlled trials (Gregoire et al. 1996; Schmidt et al. 2000; Soares et al. 2001). However, randomized, controlled trials examining the effects of estrogen on mood in postmenopausal women have been negative (Hlatky et al. 2002; Morrison et al. 2004), suggesting a loss of beneficial mood response to estrogen following prolonged periods without estrogen. Finally, if data on estrogen's role in inhibiting the HPA axis in normal women are correct, then lower estradiol in depressed women would result in exacerbation of the HPA axis abnormalities seen in major depression, and these may need to be corrected along with changing the ovarian hormone milieu.

Premenstrual Dysphoric Disorder One of the most well-studied mood disorders, with respect to the influence of ovarian steroids on mood, is PMDD. In any studies of this disorder, it is necessary to define carefully the study population and limit both endocrine investigations and treatment to women with clear luteal phase depressive symptoms who are well during the follicular phase; many more women report significant variations in mood premenstrually in retrospective reports than are found to have symptoms with prospective studies. In a study that used optimal sampling frequency to investigate LH and FSH, pulse frequency, and amplitude in follicular, midluteal, and late luteal phases of the menstrual cycle and examined estradiol and progesterone levels at these three time points, there was no difference between estradiol and progesterone at any time point between women with PMDD and control women (Reame et al. 1992). LH pulse frequency was also similar in both groups, with parallel changes across the menstrual cycle. Thus, these and earlier data (Rubinow et al. 1988) do not suggest an alteration in GnRH secretion or ovarian steroids in women with PMDD. Nevertheless, several studies have suggested that hormone manipulations can improve the symptoms. One of the best-documented effective treatments is elimination of menstrual cycling with leuprolide, a

GnRH agonist that improves mood. A number of studies found that leuprolide was highly effective in reducing symptom severity and cyclicity in PMDD patients (Mortola et al. 1991; Rosenbaum et al. 1996; Schmidt et al. 1998), although an increased rate of depressive-like symptoms has also been reported during leuprolide treatment (Steingold et al. 1987; Zorn et al. 1990). Leuprolide also leads to hypoestrogenism, which affects both bone density and cardiovascular disease; thus, it is necessary to add both steroid hormones. In the study by Mortola et al. (1991), just the addition of a placebo, with the suggestion that it might make mood symptoms worse, caused a significant worsening in mood symptoms. However, addition of conjugated equine estrogen with or without medroxyprogesterone acetate (MPA) while patients were still on leuprolide did not lead to a relapse in depressive symptoms. Not all studies have agreed that progesterone can be added back without significant worsening of symptoms. Schmidt and colleagues studied a group of women with PMDD whose symptoms were significantly improved by leuprolide, as well as a group of control women with no previous mood symptoms who were also taking leuprolide. They demonstrated a return of symptoms following administration of estradiol or progesterone but not with placebo. In the control women, none of the hormone replacements altered mood (Rubinow and Schmidt 2006). Finally, progesterone itself has been used for the treatment of PMDD despite its documented lack of effectiveness. The results of a recent Cochrane Database review of 17 randomized, placebo-controlled trials were equivocal, and the authors were unable to determine whether progesterone was useful or ineffective in the treatment of PMDD. They concluded that there was not enough evidence to say whether progesterone was helpful or ineffective (Ford et al. 2006). Since it is generally believed that the symptoms of PMDD are related to delayed effects of progesterone on mood, several studies have investigated the effects of RU486, a progesterone antagonist, on mood symptoms. In the studies of Schmidt et al. (1991), creation of an artificial follicular phase during the second half of the menstrual cycle by the use of RU486 plus human chorionic gonadotropin did not result in a reduction of mood symptoms. Likewise, blockade of progesterone's action led to early menses, with depressive symptoms still occurring. The study by Chan et al. (1994), using a randomized, double-blind, placebo-controlled crossover design for 6 months, showed no effectiveness of RU486 on mood symptoms. Thus, although it is generally believed that PMDD is related to changes in CNS neurotransmitter systems caused by progesterone, the data do not support the conclusion that progesterone blockade affects these mood symptoms. Rubinow and Schmidt (2006) have proposed that PMDD represents an abnormal response to normal hormone changes or levels that occurs in a small proportion of genetically susceptible women and is most likely associated with gene polymorphisms involved in the gonadal steroid signaling pathway. Another period of increased vulnerability to depression in women is the postpartum period. Although it is known that this period is accompanied by a sudden drop in progesterone and estradiol levels, there is limited information available on how this relates to the onset of depression. Postpartum depression is associated with a history of depression (O'Hara 1986; O'Hara et al. 1991), marital disharmony, and a higher number of stressful life events in the previous year (Cox et al. 1982). Gregoire et al. (1996) reported that transdermal estrogen is an effective treatment for depression. However, the group of women studied was small, heterogeneous, and ill-defined, and no information was available on whether these women had a new onset of depression or a prior psychiatric history. Furthermore, some of the patients were being concurrently treated with antidepressants.

GROWTH HORMONE AND THE HYPOTHALAMIC-PITUITARY-SOMATOTROPHIC AXIS Growth hormone (GH) or somatotropin is another stress-sensitive neuroendocrine system. GH is synthesized by the anterior pituitary, and although it can be used as an endpoint in itself for neuroendocrine research in psychiatry, its predominant use is as a marker of the integrity of the noradrenergic system following challenge. The hypothalamic-pituitary-somatotrophic (HPS) axis is under complex regulatory control that is not yet fully understood since cross-species variations in GH

regulation make it difficult to extrapolate to humans from animal studies. It is well established, however, that the final common pathways for control of GH release from the pituitary are hypothalamic growth hormone–releasing hormone (GHRH) (stimulation) and somatostatin (inhibition). The wide variety of metabolic, endocrine, and neural influences that alter GH secretion do so primarily through effects on GHRH and/or somatostatin. Neural influences may be mediated by noradrenergic, cholinergic, dopaminergic,

aminobutyric acid (GABA)–ergic, and serotonergic

neurotransmission. Clear physiological regulatory roles, however, have only been well documented in humans for noradrenergic and cholinergic inputs. Dopamine, serotonin, and GABAergic drugs can alter GH release but do so in contradictory ways, depending on the experimental paradigm, leaving their roles as GH regulatory agents uncertain at present (Devesa et al. 1992; Muller 1987). In humans, GH is released by acute stress, but is suppressed by chronic stress. Chronic psychosocial stress in children can result in growth arrest and even short stature and delayed puberty. A variety of other endocrine, metabolic, and physiological factors can influence GH release, although the mechanisms by which they do so are not clear. Factors that can inhibit GH release include free fatty acids (Penalva et al. 1990) and, most importantly for this review, CRH (Corsello et al. 1992) and glucocorticoids (del Balzo et al. 1990; Giustina and Wehrenberg 1992). Studies by Wiedemann et al. (1991) examined GH secretion in healthy control subjects given hourly pulses of ACTH (1 g) or h-CRH (10 g) between 9 A.M.

and 6 P.M. to induce hypercortisolemia. They found an increase in the number of GH pulses and

amount of GH secreted during the daytime but did not find an increase in the total 8 A.M. to 3 A.M. GH secretion because of blunted nighttime secretion. This pattern is similar to that seen in depressed patients (Mendlewicz et al. 1985) who have increased daytime GH secretion and reduced sleeprelated GH secretion, suggesting a similar mechanism may occur in depressed patients. However, our own studies of 26 premenopausal women with major depression and 26 age- and menstrual-cycleday-matched control women examining 10-minute secretion of GH for 24 hours found no changes in GH secretion (Amsterdam et al. 1989). Current evidence suggests that the normal episodic GH secretory pattern is shaped by an alternating rhythm of GHRH and somatostatin release (Plotsky and Vale 1985), which has been called the hypothalamic-somatotroph rhythm (HSR) (Devesa et al. 1992). This is not a regular alternation but consists rather of four to eight short pulses of GH secretion distributed irregularly over a 24-hour period, the largest one occurring shortly after the onset of sleep. The significant role of somatostatin in shaping the HSR is evidenced by its persistence in the face of a constant GHRH infusion (Hulse et al. 1986; Vance et al. 1985). The intrinsic HSR, in turn, appears to shape the response to exogenous GHRH (Devesa et al. 1989, 1990, 1991a, 1992; Tannenbaum and Ling 1984). The response is greatest if GHRH is given while plasma GH is rising or near the peak of a pulse, presumably indicating that somatostatin is suppressed. The GH response is minimal if GHRH is given while plasma GH is low and stable, presumably indicating predominance of the somatostatin effect. Currently available human data therefore suggest that clonidine exerts a major effect on GH release via suppression of somatostatin-mediated inhibition. It appears that cholinergically mediated suppression of somatostatin plays a significant role in regulating nocturnal GH release (Ghigo et al. 1990; Mendelson et al. 1978; Peters et al. 1986). Factors that can enhance GH release include estrogen (Devesa et al. 1991b; Ho et al. 1987), thyroid-releasing hormone, vasoactive intestinal peptide, hypoglycemia, sleep, exercise, and stress (Devesa et al. 1992; Muller 1987; Uhde et al. 1992). Finally, GH exerts a negative feedback inhibition of its own secretion (Devesa et al. 1992; Muller 1987). It appears to act at the level of the hypothalamus and/or median eminence to stimulate somatostatin release (Devesa et al. 1992). It may also inhibit GHRH release (Devesa et al. 1992). GH also stimulates the production of somatomedin-C/insulin-like growth factor 1 (IGF-1) in peripheral tissues, including liver. Somatomedin-C in turn has a dual inhibitory feedback effect. It directly suppresses GH secretion at the pituitary level and stimulates somatostatin release at the hypothalamic level (Devesa et al. 1992). Levels of somatomedin-C correlate positively with, and

can be used to infer, systemic GH levels during the past 8–12 hours (Copeland et al. 1980; Ross et al. 1987; Vance et al. 1985). Measurement of somatomedin-C levels thus can provide another means of evaluating the overall functional status of the HPS axis.

Growth Hormone Studies in Psychiatric Disorders Adrenergic input to the HPS axis is mediated primarily by the

2-adrenergic

receptor.

2-Adrenergic

agonism is a potent stimulus for GH secretion, the effect being blocked by corresponding antagonists (Devesa et al. 1992; Muller 1987).

-Adrenergic stimulation of GH release may also be antagonized by

-adrenergic agonism (Devesa et al. 1992), but the

-adrenergic-receptor-mediated influences are

less well researched. In humans, the evidence suggests that the GH-releasing effect of

2-adrenergic

agonism may be due primarily to inhibition of somatostatin release, with perhaps a secondary stimulation of GHRH. This is based on two main types of evidence. First, for at least 2 hours after a supramaximal dose of GHRH (200 g), the pituitary is refractory to a repeated dose of GHRH, but the 2-adrenergic

agonist clonidine (Valcavi et al. 1988) or insulin-induced hypoglycemia (Shibasaki et al.

1985) will still evoke a vigorous GH response. Presumably, if the GH-releasing cells are unresponsive to GHRH, clonidine must stimulate GH release through a non-GHRH mechanism, the most likely alternative being inhibition of somatostatin release. Similarly, insulin-induced hypoglycemia is thought to stimulate noradrenergic outflow, which then suppresses somatostatin secretion (Shibasaki et al. 1985). Whereas the GH response to GHRH depends on the point in the HSR rhythm at which the GHRH is given, the response to clonidine does not (Devesa et al. 1990, 1991a, 1992), again suggesting that clonidine acts through a non-GHRH mechanism, again presumably somatostatin. Downregulation of GH release in response to clonidine presumably occurs in response to chronic, excessive noradrenergic outflow from the locus coeruleus, which is thought to play a role in anxiety states (Uhde et al. 1992). The blunted GH response to clonidine in panic disorder has been replicated in 8 of 10 studies from 6 of 7 different clinical research groups (Abelson et al. 1991, 1992; Amsterdam et al. 1989; Charney and Heninger 1986; Coplan et al. 1993; Nutt 1989; Schittecatte et al. 1988, 1992; Uhde et al. 1986, 1991). Both failures to replicate (Schittecatte et al. 1988, 1992) were by the same group. One of those studies (Schittecatte et al. 1988) involved only seven subjects, and blunting was absent only in the female subjects, in whom birth control pills or menstrual cycle phase can obscure blunting. Blunted GH response to clonidine is seen in generalized anxiety disorder (Abelson et al. 1991) and social anxiety disorder (Uhde et al. 1991) but not in obsessive-compulsive disorder (OCD) (Hollander et al. 1991; Lee et al. 1990). It has also recently been reported in patients with PTSD (Morris et al. 2004). It is unlikely that the GH blunting seen in anxiety disorders is an artifact of tricyclic exposure, given that in our own work, 10 of 12 anxiety patients with blunted responses had no significant prior exposure to tricyclic antidepressants (Abelson et al. 1992) and our recent findings demonstrate a blunted response in subjects with anxiety (predominantly social phobia) with no tricyclic exposure (Cameron et al. 2004). The nonspecificity of the GH response to clonidine suggests that it could be a secondary response to the presence of a psychiatric disorder. However, the absence of blunting in patients with OCD (Lee et al. 1990), schizophrenia (Lal et al. 1983), or heroin abuse (Facchinetti et al. 1985) argues against this interpretation. Although the replicability of the blunted GH response to clonidine in panic disorder is well established, the mechanism remains less certain. It has been thought to reflect subsensitivity (downregulation) of postsynaptic

2-adrenergic

receptors

(Siever et al. 1982). Our own data support the presence of blunted GH response to clonidine in social anxiety disorder, suggesting that excessive noradrenergic tone is also present in this form of anxiety (Cameron et al. 2004). These data are consistent with the hypothesis that excessive noradrenergic outflow from the locus coeruleus plays a pivotal role in anxiety states (Charney and Heninger 1986). Numerous studies have also demonstrated reduced GH responses to clonidine in patients with major and melancholic depression (Amsterdam and Maislin 1990; Amsterdam et al. 1989; Charney et al. 1982; Checkley et al. 1981; Corn et al. 1984; Lesch et al. 1988; Siever and Uhde 1984), but not all

studies have replicated these findings (Gann et al. 1995; Katona et al. 1993; Mitchell et al. 1991; Schittecatte et al. 1989, 1994). In particular, more recent studies have not found a blunted GH response to clonidine. It is unclear whether diagnostic changes and subject selection have affected these failures to replicate, given that several investigators found differences between endogenous and nonendogenous depression, with more severe blunting in the endogenous groups (Amsterdam et al. 1989; Checkley et al. 1984; Matussek and Laakmann 1981; Matussek et al. 1980). Furthermore, most of the studies in depression were done before it was realized that menstrual status (i.e., pre- vs. postmenopausal), menstrual cycle phase, and prior tricyclic exposure affected the GH response to clonidine. In particular, patients with endogenous depression are more likely to have been older and postmenopausal, both factors that decrease the GH response. The altered GH response to clonidine is thought to result from 2-noradrenergic receptor downregulation, since studies using either GHRH, which acts directly at the pituitary, or apomorphine, which acts via dopamine input to the GH system, demonstrate normal GH response in depressed patients (Amsterdam and Maislin 1990; Corn et al. 1984; Krishnan et al. 1988; Lesch et al. 1988; Thomas et al. 1959). Again, this is consistent with increased central noradrenergic activation in depression, similar to that hypothesized in panic disorder. Our own recent studies (Cameron et al. 2004) found a normal GH response to clonidine in patients with "pure" depression (i.e., patients who did not meet criteria for any anxiety disorders). All of our patients had been off any psychotropic drugs for at least 6 months. Furthermore, there was no relationship between dimensional measures of anxiety or dimensional measures of depression and GH response. Patients with melancholic depression did not differ from nonmelancholic patients or control subjects. Subjects with a high Hamilton Anxiety Scale (Ham-A) score ( 20, n = 13) did not differ from their matched controls. Thus, our data suggest that blunted GH response to clonidine challenge is specific to anxiety disorders and is not seen with less severe forms of anxiety or with depression in the absence of an anxiety disorder.

CONCLUSION In this chapter we have reviewed ways in which hormonal systems may be altered in psychiatric disorders that may be linked to the pathoetiology of the disorders. The evidence is strongest for the HPA system, which has been implicated in at least two disorders, depression and PTSD, both disorders clearly linked to stress-based etiologies. The evidence for abnormalities in reproductive hormones is still small, but this is a subject of continued investigation. Most notably, abnormalities of reproductive hormones have not been found in PMDD, the disorder most responsive to changing reproductive hormone milieu. Finally, hormones can be used as markers of the functioning of CNS neurotransmitters or receptors, as is the case for GH. As neuroimaging ligands are developed to directly measure these receptors, the latter role of neuroendocrinology may be useful. Many of the critical hormones, like cortisol and estradiol, regulate many other critical neurotransmitter systems, such as serotonin, as well as regulating gene transcription. The area of psychoneuroendocrinology continues to expand, and in combination with the major advances occurring throughout the field of psychiatry, it will become possible to identify the genetic and molecular mechanisms involved in psychiatric disorders, thereby leading to the development of better treatments.

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C. Lindsay DeVane: Chapter 8. Principles of Pharmacokinetics and Pharmacodynamics, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.408715. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 8. Principles of Pharmacokinetics and Pharmacodynamics PRINCIPLES OF PHARMACOKINETICS AND PHARMACODYNAMICS: INTRODUCTION Pharmacokinetics is defined as the study of the time course of drugs and their metabolites through the body. Pharmacodynamics is defined as the study of the time course and intensity of pharmacological effects of drugs. A convenient lay description of these terms is that pharmacokinetics describes what the body's physiology does to a drug, and pharmacodynamics describes what a drug does to the body. Although clinicians are more interested in drug effects than drug concentrations, these disciplines are closely connected. Pharmacokinetic and pharmacodynamic variability is a major determinant of the dose–effect relationship in patients (Figure 8–1). There is increasing recognition that genetic variability—in the form of polymorphic genes controlling the transcription of proteins involved in drug-metabolizing enzymes, drug transporters, and drug targets—is a substantial determinant of pharmacokinetic and pharmacodynamic variability. An integrated knowledge of these areas is essential in the drug development process and can be instrumental in individualizing dosage regimens for specific patients. FIGURE 8–1. Pharmacokinetic and pharmacodynamic variability as determinants of the dose–effect relationship.

The dose and the frequency of dosing necessary to produce the desired pharmacological response from psychoactive drugs differ widely among patients. This variability in the drug dose–effect relationship is not surprising, given the large differences in patients' physiology, ages, range of severity of illness, activity of drug metabolizing enzymes and transporters, renal function, and other variables. Thus, a rational approach to drug dosage regimens, based on scientific principles, is needed to reach therapeutic objectives without either underdosing (and obtaining an unsatisfactory response) or overdosing (and risking intolerability or toxicity). The interface between pharmacokinetics and pharmacodynamics, where drugs interact with molecular targets at an effect site (see Figure 8–1), is increasingly becoming the focus of research. The ability to link drug concentrations with pharmacodynamic effects using mathematical models has improved greatly in recent years with the availability of new computer software. Population pharmacokinetic/pharmacodynamic modeling enables definition of the relationship between drug concentration and effect in individuals from vulnerable populations such as children, pregnant women, and the elderly where only sparse data may be available (Bies et al. 2004). Covariants such as age, gender, genotype of drug-metabolizing enzymes, and concomitant treatment with other drugs can be easily incorporated into these models and tested for their significance in influencing drug concentration and effects

(DeVane et al. 2006). Measurements of plasma drug concentration are easily performed with sensitive analytical methods including gas and liquid chromatography and mass spectrometry. In recent years, our understanding of the role of drug transporters and of gene expression of intestinal and hepatic enzymes in influencing drug movement within the body has increased considerably. Extensive contributions to our understanding of the sources of variability in pharmacokinetic/pharmacodynamic response have come from the field of pharmacogenetics. Genetic polymorphisms in drug-metabolizing enzymes enhance or diminish the body's ability to biotransform a variety of substrate drugs. A large number of defective alleles have been discovered, some of which have functional significance. On the pharmacodynamic side of the dose–effect relationship, the significance of polymorphisms in drug targets is an intense area of investigation. One of the most studied polymorphisms is in the promoter region of the gene encoding the serotonin transporter (5-HTT) and consists of the insertion or deletion of a 44–base pair sequence, giving rise to two variants: long (l) and short (s). A meta-analysis of 15 studies representing 1,435 patients concluded that patients with the ss genotype are less likely to reach remission during selective serotonin reuptake inhibitor (SSRI) therapy and require a longer treatment period for 50% symptom improvement (Serretti et al. 2007). Although the discipline of pharmacokinetics relies heavily on mathematical description and prediction of the time course of drugs in the body, the purpose of this chapter is to explain basic principles of pharmacokinetics and how they interface with pharmacodynamics to provide insight into observed dose–effect relationships that can aid in developing drug dosage regimens. The fundamental concepts of pharmacokinetics have not changed since the initial publication of this chapter. These principles are reviewed here, and the interface of pharmacokinetics with the discipline of pharmacogenetics—the study of the genetic basis for differences in drug effects—is discussed as a essential component of variability in drug dose–effect relationships in psychopharmacology (see Figure 8–1).

PHARMACOKINETICS A human pharmacokinetic study typically results in a mathematical description of drug concentration changes in plasma over time. The value of these data and of their use varies according to patient circumstances. During drug development, this knowledge is essential to develop guidelines for ensuring safe and effective dosage regimens in clinical trials. In clinical practice, plasma concentration measurements are useful to guide dosage adjustments to reach targeted steady-state concentrations of lithium, some anticonvulsant mood stabilizers, and clozapine. In the United States, the low utilization of tricyclic antidepressants and conventional antipsychotics has narrowed the scope of plasma drug concentration monitoring in psychiatry. However, a resurgence of interest is occurring as the search for biomarkers of drug efficacy and tolerability is increasing in drug development (Sunderland et al. 2005). Even without patient-specific drug concentration data, some knowledge of population pharmacokinetic parameters is clinically useful. Population estimates of drug and metabolite half-life can predict the time required for washout from the body once drug dosing is discontinued. This is useful for predicting the overlap of drug in the body when switching among antidepressants or antipsychotics, the presence of drug in the body during anesthesia for surgical procedures, and the probability of a drug–drug interaction when initiating new pharmacotherapy. Such information is useful when prescribing fluoxetine, for example, which produces an active metabolite, norfluoxetine, with an elimination half-life estimated between 4 and 16 days. Thus, an interval as long as 1 month may be necessary after discontinuing fluoxetine before initiating treatment with a monoamine oxidase (MAO) inhibitor to minimize the possibility of developing a serotonin syndrome. The use of slow-release microspheres for injection of risperidone results in an extended drug half-life that predicts continual accumulation to a steady state over four injections given every 2 weeks and sustained drug concentration in plasma for 4–6 weeks after the last injection (Gefvert et al. 2005). The fundamental description of drug disposition begins with studies of single drug doses.

Single-Dose Drug Disposition Absorption The route of administration is a major determinant of the onset and duration of a drug's pharmacological effects. Intravenous injection ensures that all of the administered drug is available to the circulation. The rate of drug injection or infusion can be used to control completely the rate of drug availability. However, few psychopharmacological drugs are administered intravenously. Intramuscular administration is commonly thought to produce a rapid onset of effect, but exceptions have been documented. For example, drug absorption by this route was slow and erratic with chlordiazepoxide (Greenblatt et al. 1974). The recent availability of intramuscular forms of some atypical antipsychotics will be advantageous for treating psychotic states when rapid tranquilization is desired and oral administration is impractical. For drugs that are equally well absorbed by the intramuscular and oral routes of administration, the total systemic exposure (as reflected in the area under the plasma concentration–time curve

[AUC]) from the two routes should be similar, as should the elimination half-life. A major difference is that the rate of absorption from the intramuscular route may be more rapid. Intramuscular administration of olanzapine 5 mg produced a maximum plasma concentration five times higher than the maximum plasma concentration produced by a 5-mg oral dose with a similar AUC from both routes of administrations (Bergstrom et al. 1999). Most psychoactive drugs are highly lipophilic compounds, which are well absorbed when taken orally. More than 60% of the drugs available on the market are for oral use because of the ease of administration and efficiency of absorption, together with greater patient compliance. Drug absorption is usually a passive process occurring in the small intestine. The efficiency of oral absorption is influenced by the physiological state of the patient, by formulation factors, and by the timing of administration around meals. Most drugs are best absorbed on an empty stomach. The presence of food or antacids in the stomach usually decreases the rate of drug absorption. Exceptions are sometimes noted. Coadministration of sertraline with food increased peak plasma concentration by approximately 25% and decreased time to peak concentration from 8 hours to 5 hours, with a negligible effect on the AUC (Ronfeld et al. 1997). A partial explanation for this finding is that a food-induced increase in hepatic blood flow could allow more unabsorbed drug to escape first-pass hepatic uptake and metabolism. The significance of this food–drug interaction is doubtful, given that sertraline's therapeutic benefits are reported in association with chronic daily administration. The rate of drug absorption is important when a rapid onset of effect is needed. Normally, the presence of food can be expected to reduce the peak drug concentration achieved in blood or plasma and prolong the time following an oral dose to reach the maximum plasma concentration. The absolute amount of drug absorbed may or may not be affected. Acute drug effects are facilitated by administration apart from meals. Sedative-hypnotic drugs are examples of drugs for which the rate of absorption is clinically meaningful (Greenblatt et al. 1978). Formulation factors are especially meaningful when a drug effect is associated with achieving a minimal effective concentration (MEC) in plasma. Figure 8–2 shows the predicted plasma concentration–time curves of a drug following a rapid intravenous injection (I), an oral formulation that is completely absorbed with no presystemic elimination (II), an incompletely absorbed oral formulation (III), and an extended-release formulation that results in slow absorption of drug (IV). A formulation with poor bioavailability (III) may not result in a plasma concentration above the MEC, whereas a drug whose absorption is delayed (IV) may retard the onset of effect but maintain an effective concentration for a period similar to the more rapidly available formulations (I, II). The principle of an MEC may apply in antipsychotic therapy, where minimal occupancy of dopamine D2 receptors during a dosage interval may be needed for optimal therapeutic benefit. FIGURE 8–2. Predicted plasma concentration curves following single doses of a drug by rapid intravenous injection (I), a dosage form with complete bioavailability (II), a dosage form with reduced bioavailability (III), and an extended-release dosage form that reduces the rate but not the completeness of absorption (IV).

MEC = minimal effective concentration. Recent research in pharmaceutical science has resulted in a variety of systems for controlling the release of oral drugs. These include coated systems, with a core of active drug surrounded by a slow-releasing film; matrix systems, with active drug distributed in erodible gel matrices, and other hydrophilic, swellable, or erodible polymers to slowly dissolve and release drug at predictable rates to produce one or more peak concentrations during a dosage interval. Bupropion, paroxetine, venlafaxine, and the psychostimulants used to treat attention-deficit/hyperactivity disorder (ADHD) are examples of drugs whose clinical utility has been improved by reformulation as sustained- or extended-release dosage forms. Among the immediate-release dosage formulations, a general rank order of products providing the most rapid to the slowest rate of drug release for oral absorption is solutions, suspensions, tablets, enteric- or film-coated tablets, and capsules. Regardless of the dosage formulation selected, the last several hours of declining drug concentration in plasma occur in parallel, because drug elimination rate is unaffected by its rate or extent of absorption (see Figure 8–2). The time at which a terminal elimination phase is clearly observable following a single dose may be delayed, but the terminal elimination half-life is unchanged. Formulation into sustained- or slow-release tablets or capsules may allow drugs with short elimination half-lives, which must be given multiple times per day to maintain an effective concentration, to be effective when administered once or twice daily.

Presystemic Elimination Many drugs undergo extensive metabolism as they move from the gastrointestinal tract to the systemic circulation (i.e., as they pass through the gastrointestinal membranes and hepatic circulation during absorption). This process is known as the first-pass effect or presystemic elimination and is an important determinant of drug bioavailability after oral administration. Several factors are potentially important in influencing the degree of first-pass effect. A first-pass effect is usually indicated by either a decreased amount of parent drug reaching the systemic circulation or an increased quantity of metabolites after oral administration compared with parenteral dosing. This process is important in the formation of active metabolites for psychoactive drugs and is a major source of pharmacokinetic variability (George et al. 1982). Presystemic metabolism of drugs is extensively accomplished by cytochrome P450 (CYP) enzymes in the luminal epithelium of the small intestine (Kolars et al. 1992). CYP3A4 represents approximately 70% of total cytochrome P450 in the human intestine. Many useful psychopharmacological drugs are CYP3A4 substrates. Examples of these drugs are listed in Table 8–1 along with substrates, inhibitors, and inducers of other major human CYP isoforms. The liver contains about two- to fivefold greater amounts of CYP3A protein (nmol/mg protein) compared with the intestine (de Waziers et al. 1990). Nevertheless, intestinal CYP3A4 has a profound effect on presystemic drug metabolism. Up to 43% of orally administered midazolam, for example, is metabolized as it passes through the

intestinal mucosa (Paine et al. 1996). The exposure of drugs to gut CYP3A4 is not limited by binding to plasma proteins, as can occur with hepatic metabolism. Slower blood flow may also contribute to intestinal metabolism, thereby compensating for the lower quantity of CYP3A4 in the gut compared with the liver. TABLE 8–1. Substrates, inhibitors, and inducers of the major human liver cytochrome P450 (CYP) enzymes involved in drug metabolism CYP

Inhibitorsa

Substrates

Inducers

enzyme CYP1A2

Caffeine,b clozapine, duloxetine, haloperidol,b imipramine,b b

b

b

phenacetin, tacrine, theophylline, verapamil, warfarin

Cimetidine,

Charcoal-broiled beef,

fluoroquinolines

cigarette smoke,

(ciprofloxacin,

cruciferous vegetables,

norfloxacin), fluvoxamine

marijuana smoke, omeprazole

CYP2A6

Coumarin, nicotine

Tranylcypromine

CYP2B6

Bupropion, cyclophosphamide, diazepam,b nicotine, tamoxifen

Barbiturates Phenobarbital, cyclophosphamide (in vitro)

CYP2C9

b

Amitriptyline, diclofenac, metoclopramide, phenytoin, b

b

b

propranolol, tetrahydrocannabinol, tolbutamide, warfarin

Disulfiram, fluconazole,

Rifampin, phenytoin,

fluvoxamine, d

secobarbital

propoxyphene, sulfaphenazole CYP2C19 Amitriptyline,b clomipramine,b desmethyldiazepam,b diazepam,b

Omeprazole

Rifampin

ibuprofen, imipramine,b S-mephenytoin, moclobemide, naproxen, omeprazole,b piroxicam, tenoxicam CYP2D6

Amitriptyline,b codeine,b debrisoquin, desipramine,

Cimetidine, fluoxetine,

None documented in

dextromethorphan, duloxetine, haloperidol,b imipramine,b

paroxetine, quinidine,

vivo

metoclopramide, metoprolol, mexiletine, nortriptyline,

sertraline

b

ondansetron, orphenadrine, paroxetine, pindolol, propafenone, propranolol,b risperidone, sparteine, thioridazine, timolol, venlafaxineb CYP2E1

Caffeine,b dapsone,b ethanol

CYP3A4

Alprazolam, amiodarone, amitriptyline,b astemizole, bupropion,

Disulfiram

b

Ethanol

Cimetidine, erythromycin, Barbiturates, fluoxetine, fluvoxamine,

carbamazepine,

b

indinavir, ketoconazole,

dexamethasone,

diazepam, diltiazem, erythromycin, estradiol, ethinylestradiol,

naringenin, nefazodone,

phenytoin, rifampin, St.

ritonavir, saquinavir,

John's wort

caffeine, carbamazepine, cisapride, clarithromycin, clonazepam, b

b

codeine, cortisol, cyclosporin, dapsone, desmethyldiazepam, b

b

b

fluoxetine, haloperidol, imipramine, lidocaine, loratadine, lovastatin, midazolam, nefazodone, nicardipine, nifedipine,

sertraline (weak)

omeprazole,b ondansetron, orphenadrine, progesterone, quinidine, rifampin, sertraline, tamoxifen, terfenadine, testosterone, trazodone, triazolam, venlafaxine,b verapamil,b zolpidem a

Inhibitory potency varies greatly (see text).

b

More than one CYP enzyme is known to be involved in the metabolism of these drugs.

Source. Ketter et al. 1995; Nemeroff et al. 1996; Schmider et al. 1996. Certain foods, such as grapefruit juice, can substantially alter the bioavailability of some drugs. Components in grapefruit juice—which contains a variety of suspect candidates, including naringin, other flavonoids, bergamottin, and other furanocoumarins—inhibit intestinal CYP3A4-mediated first-pass metabolism (Paine et al. 2005). The maximal effect can occur within 30 minutes of ingestion of juice. Grapefruit juice may also inhibit the efflux transport of drugs by P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), which are efflux transporters expressed in the human small intestine. The more completely studied of these drug transporters is the transmembrane pump P-gp (also known as the multidrug resistance protein), which causes the adenosine triphosphate (ATP)–dependent efflux of a diverse range of drugs from cells. The distribution of P-gp includes the

epithelial cells lining the luminal surface of enterocytes in the small intestine and kidney, making P-gp a critical determinant of oral drug bioavailability and biliary and renal excretion for many drugs (Benet et al. 1999; Silverman 1999). P-gp is also expressed on the luminal surface of the endothelial cells making up the blood–brain barrier and other critical organs. In the gut, P-gp works in concert with CYP3A4 to limit the intestinal absorption of drugs that are common substrates for both proteins. Changing the route of administration to avoid presystemic metabolism can have a therapeutic advantage. When given orally, selegiline, an irreversible inhibitor of MAO, is substantially converted to several metabolites through extensive first-pass metabolism. Transdermal dosing with drug contained in a removable patch adhering to the skin results in higher systemic exposure to selegiline and lower exposure to metabolites. This allows greater central nervous system (CNS) exposure to selegiline from a given dose to inhibit MAO relative to the required dose from oral administration (Azzaro et al. 2007). Buccal or sublingual administration can also avoid some presystemic drug elimination (Markowitz et al. 2006). In summary, an important pharmacokinetic principle is that the choice of drug formulation and the route of administration can determine the rate at which the drug and metabolites appear in the systemic circulation. This rate may be manipulated to retard the magnitude of the peak plasma drug concentration when a high peak concentration is related to the occurrence of adverse effects. For example, slow-release formulations of lithium and paroxetine reduce gastrointestinal side effects (DeVane 2003). Alternatively, rapid absorption may be desirable to achieve immediate pharmacological effects.

Distribution Drug distribution to tissues begins almost simultaneously with absorption into the systemic circulation. The rate at which distribution occurs will partially influence the onset of pharmacological response. Access to effect sites depends on membrane permeability, the patient's state of hydration, regional blood flow, and other physiological variables. There is increasing evidence that drug transporters in the blood–brain barrier influence drug passage to and accumulation in the brain. Sadeque et al. (2000) demonstrated that loperamide, a potent opiate used to reduce gut motility and not normally distributed to the CNS, produced typical opiate depressant effects on respiratory drive when coadministered with quinidine, a P-gp inhibitor. Physicochemical properties influencing the rate of drug distribution to effect sites include lipid solubility, ionizability, and affinity for plasma proteins and tissue components. Diazepam is highly lipophilic, and its onset of effect is rapid as a result of its entry into the brain within minutes after oral administration (Greenblatt et al. 1980). The concentration of diazepam at its effect site may fall so precipitously as a result of redistribution that its duration of action after an initial dose is shorter than would be expected based on its elimination half-life. Frequently, the intensity and duration of the pharmacological effect of a second drug dose, taken immediately after cessation of the effect of the first dose, are greater and longer, respectively, than the intensity and duration of the effect of the first dose. This is known as the second-dose effect in pharmacokinetics (DeVane and Liston 2001). When dosing is repeated before the previous dose has been eliminated from the body, the second and subsequent doses produce a greater effect than the initial dose, but the relative intensity of subsequent doses diminishes. This second-dose effect occurs, regardless of the half-life of the drug, when dosing is repeated in response to the observed effect. Common examples of this phenomenon include the self-administration of caffeine and the administration of certain anesthetics. The predicted time course of drug concentration in plasma and in tissue following a single intravenous drug injection is shown in Figure 8–3. Drug concentration in plasma rapidly declines in a manner consistent with the extensive distribution of the compound out of the systemic circulation. Drug concentration in tissue rapidly increases during this time. Pharmacological effects may not occur immediately but may be delayed until the tissue concentration at the effect site rises above an MEC. An equilibrium eventually occurs between drug in plasma and in tissue. Concentrations from this time forth decline in parallel during a terminal elimination phase. FIGURE 8–3. Predicted concentration of a drug in plasma and tissue following a rapid intravenous injection.

MEC = minimal effective concentration. The observed time course of drug concentration changes in plasma has frequently been considered in the pharmacokinetic literature to confer the characteristics on the body of a two-compartment mathematical model (Gibaldi and Perrier 1975). Many drugs appear to be absorbed into a central compartment composed of the circulation and rapidly equilibrating tissues and then distributed to less accessible tissues, which collectively form a peripheral compartment. This compartmentalization of drug concentration greatly aids mathematical analysis of pharmacokinetic data but is clearly an oversimplification, because drug concentrations determined in animal studies can vary over orders of magnitude among different tissues (DeVane and Simpkins 1985). Even though the drug concentration can vary widely among tissues, equilibrium eventually occurs between drug concentration in plasma and in tissue (see Figure 8–3). The concentration of drug in brain tissue may be substantially different—higher or lower—from that in plasma, but renal and hepatic elimination of drug from the central compartment reducing the plasma drug concentration should be mirrored by a proportional reduction of drug concentration from the brain or other tissues. For this reason, an MEC determined from plasma data may reflect an MEC at the effect site. The distribution of a drug in the body largely depends on the drug's relative binding affinity to plasma proteins and tissue components and the capacity of tissues for drug binding. This pharmacokinetic principle is illustrated in Figure 8–4. Only unbound drug is capable of distributing between plasma and tissues. Different degrees of plasma protein binding among antidepressants, for example, cannot be used to draw valid conclusions about the availability of drug to exert pharmacological effects at the site of action (DeVane 1994). The nonspecific binding of drugs to tissue components complicates the interpretation of the significance of plasma protein–binding differences among drugs. Drug binding in tissues cannot be measured directly in vivo and must be inferred using mathematical models and/or in vitro methods. FIGURE 8–4. Effect of protein binding on distribution of drug between plasma and tissue.

Most drugs circulate in the blood bound to plasma proteins, principally albumin or alpha-1-acid glycoprotein. Many psychotropic drugs are highly protein bound, frequently to a degree greater than 90%. Displacement of drug from plasma protein–binding sites may result from drug–drug interactions. This situation should lead to more unbound drug being available for distribution to peripheral tissues and interaction with receptor sites (see Figure 8–4). As a result, potentially greater pharmacological effects, either beneficial or detrimental, may be expected. However, there are few documented examples in which the above events occurred with psychoactive drugs and led to significant clinical consequences. Compensatory changes occur in the body to buffer the impact of drug-binding interactions (DeVane 2002). When plasma protein binding is restrictive regarding the drug's hepatic and/or renal elimination, the increased free drug concentration in plasma will be a transient effect as more free (non-proteinbound) drug becomes available to routes of elimination. Total (bound plus free) drug concentration in plasma will eventually return to a predisplacement value. The conclusion of several authoritative reviews is that plasma protein– binding displacement interactions are rarely a major source of variability in psychopharmacology (DeVane 2002; Greenblatt et al. 1982; Rolan 1994; Sellers 1979).

Elimination Drugs are eliminated or cleared from the body through renal excretion in an unchanged or conjugated form; through biotransformation, primarily in the liver, to polar metabolites; or through both of these mechanisms (see Figure 8–1). Clearance is defined as the volume of blood or other fluid from which drug is irreversibly removed per unit of time. Thus, clearance units are volume per time. Drug clearance is analogous to creatinine clearance by the kidney. From the blood that delivers drug to the liver, or any other eliminating organ, an extraction occurs as blood travels through the organ. Because drug extraction by the liver and other organs is rarely 100%, the portion that escapes presystemic elimination reaches the systemic circulation intact. Plasma protein binding, as mentioned above, can restrict the organ extraction process, depending on the specific drug. If a drug were to be completely extracted, then clearance would equal the blood flow to the organ. An average hepatic blood flow is 1,500 mL/minute. When drug is eliminated by additional organs, the total clearance is an additive function of all the individual organ clearances. Clearance values reported in excess of 1,500 mL/minute for many psychopharmacological drugs are reflective of presystemic elimination (DeVane 1994). When the drug dose and bioavailability are constant, then clearance is the pharmacokinetic parameter that determines the extent of drug accumulation in the body to a steady state. In contrast, elimination half-life is useful to reflect the rate, but not the extent, of drug accumulation. Elimination half-life is defined as the time required for the amount of drug in the body, or drug concentration, to decline by 50%. This parameter is commonly determined after a single-dose pharmacokinetic study or after drug discontinuation in a multiple-dose study. In either situation, drug concentration decline in plasma can be followed by multiple blood sampling. Half-life is easily determined by graphical means or by inspection, as long as data are used from the terminal log-linear portion of the elimination curve (see Figures 8–2 and 8–3). Knowledge of a drug's elimination half-life is particularly useful for designing multiple-dosing regimens.

Multiple Dosing to Steady State Multiple drug doses usually are required in the pharmacotherapy of mental illness. During a multiple-dosing regimen, second and subsequent drug doses are usually administered before sufficient time has elapsed for the initial dose to be completely eliminated from the body. This process results in drug accumulation, as illustrated in Figure 8–5. When drug elimination follows a linear or first-order process, the amount of drug eliminated over time is proportional to the amount of drug available for elimination (Gibaldi and Perrier 1975). Accumulation does not occur indefinitely; rather, it reaches a steady state. A steady state exists when the amount of drug entering the body is equal to the amount leaving the body. From a practical standpoint, this definition means that after a period of

continuous dosing, the body retains a pool of drug molecules from several doses, and the drug eliminated each day is replaced by an equivalent amount of newly administered drug. The time required from the first administered dose to the point at which an approximate steady state occurs is equivalent to the total of four to five elimination half-lives. The same amount of time is required for a new steady state to be achieved after an increase or decrease in the daily dosing rate or for a drug to wash out of the body after dosing is discontinued (see Figure 8–5). FIGURE 8–5. Accumulation of drug during multiple dosing.

It takes four to five half-lives (4–5 t1/2 ) to achieve initial steady state (Cpss) on a constant dosage regimen, to achieve a new steady state after an increase in dosage, or to wash out drug from the body after discontinuation. The average steady-state concentration lies somewhere between the peaks and troughs of drug concentration during a dosage interval. The term steady state is a misnomer in that a true drug steady state occurs only with a constant-rate intravenous infusion. Because of the concurrent processes of drug absorption, distribution, and elimination, drug concentration is constantly changing in plasma and tissues during an oral dosing regimen. A peak and a trough concentration occur within each dosage interval. The average steady-state concentration occurs somewhere between these extremes and is determined by the daily dose and the drug's total body clearance for that individual. On reaching a steady-state concentration, the average concentration and the magnitude of the peaks and troughs may be manipulated according to established pharmacokinetic principles. Figure 8–6 shows the predicted plasma concentration changes based on drug doses given every 24 hours. The selected dose does not produce a high enough average steady-state concentration to reach the desired concentration range between an MEC and a concentration threshold associated with an increased risk of toxicity. By doubling the dose and keeping the dosage interval constant, the average steady-state concentration increases, but the magnitude of the peak and trough concentration difference also increases. These changes are consistent with the pharmacokinetic principles of superposition and linearity (Gibaldi and Perrier 1975). FIGURE 8–6. Predicted plasma concentration changes from administering either a selected dose (D) every 24 hours (D q24h), twice the dose every 24 hours (2D q24h), or the original dose every 12 hours (D q12h).

MEC = minimal effective concentration. Linearity refers to maintaining a stable clearance across the usual dosage range. Within the linear dose range, the magnitude of a dosage increase results in a proportional change in steady-state concentration (see Figure 8–6). The magnitude of the dose change theoretically superimposes on the new peak and trough concentration. In Figure 8–6, doubling the daily dose results in an adequate average steady-state concentration, but the new peak and trough concentration values cause both an increased risk of toxicity and an inadequate concentration declining below the MEC for a portion of each dosage interval. An alternative is to increase the total daily dose and divide it into more frequent administrations. This is accomplished by administering the original dose every 12 hours instead of every 24 hours. The new average steady-state concentration remains within the desired range, and the differences between the peak and trough concentrations are reduced to an acceptable fluctuation. Selection of a proper drug dosage regimen must consider both the amount of drug administered and the frequency of administration. Some drugs with half-lives long enough to be administered once daily may not be suitable for administration every 24 hours because toxicity may be precipitated by an excessive peak concentration in a single dose. Examples include lithium and clozapine. Once-daily dosing with lithium may produce gastrointestinal intolerance, and clozapine is dosed two or more times each day to avoid peak concentrations that might predispose to seizure activity. Bupropion was initially formulated to be dosed multiple times a day to avoid high peak concentrations in plasma for this same reason but reformulation into an extended-release tablet allows once-daily administration. When high peak concentration is tolerable, then the dosage interval can theoretically be extended beyond 1 day by giving larger amounts of drug in single doses less frequently. This principle applies to fluoxetine, which is available as a 90-mg capsule for once-weekly administration.

PHARMACODYNAMICS Pharmacodynamic variability may exceed pharmacokinetic variability (see Figure 8–1). The drug dose or concentration that produces a pharmacological effect differs widely among patients. Similarly, pharmacological effects can vary widely among patients with a comparable plasma concentration of drug. The principles of dosage regimen design discussed above rely heavily on the existence of a functional relationship between the concentration at an effect site and the intensity of the response produced. Many observed processes in nature behave according to the sigmoid relationship shown in Figure 8–7. At a low dose or concentration, only a marginal effect is produced. As drug dose or concentration increases, the intensity of effect (E) increases until a maximum effect (Emax) is achieved. This response is observed as a plateau in the sigmoid dose–effect curve (see Figure 8–7). Further dosage increases do not produce a greater effect. FIGURE 8–7. The sigmoid maximum effect (Emax) pharmacodynamic model relates concentration (C) to intensity of

effect (E).

EC50 is the concentration that produces half of the Emax, and n is an exponent that relates to the shape of the curve. The sigmoid dose–effect relationship in Figure 8–7 has practical applications to psychopharmacology. The increase in drug response that results from an increase in dosage depends on the shape and steepness of the theoretical dose–response curve for each patient and the starting point on the curve when a dosage is changed. At low doses or concentrations, a substantial dose increase may be necessary to achieve an effect. In a linear part of the relationship, dosage increases should result in proportional increases in effect. In the higher dose or concentration range, a further increase will not produce a significant increase in effect because of diminishing returns. This phenomenon is likely caused by the saturation of enzyme-binding sites or receptors by drug molecules above a critical concentration. The general equation shown in Figure 8–7 describes the sigmoid relationship between concentration and response (i.e., intensity of effect). The response is usually measured as a percentage change or the difference from the baseline effect. C is the drug concentration, and EC50 is the effective concentration that produces half of the Emax. Theoretically, n is an integer reflecting the number of molecules that bind to a specific drug receptor. Practically, it is a parameter that determines the sigmoid shape of the concentration–effect relationship. Pharmacokinetic– pharmacodynamic models have found wide application in psychopharmacology—for example, relating concentration to electroencephalogram parameters, psychomotor reaction times, and subjective effects from drugs of abuse (Dingemanse et al. 1988). Drugs rarely have a single pharmacological effect or interact with only a single receptor population or molecular target. Drugs generally have affinity for multiple receptors; therefore, several theoretical concentration–effect relationships can exist for a given drug. Dose–response curves are shown in Figure 8–8 for a drug that produces a therapeutic effect and mild and severe toxicity. The greater the separation between the curves for therapeutic and toxic effects, the more safely the drug can be administered in increasing doses to achieve therapeutic goals. Estimates of these interrelationships are made in preclinical animal studies and Phase I human studies for drugs in development. In clinical practice, the degree of separation between these curves and their steepness will show both inter- and intraindividual variability. Concurrent medical illness may predispose patients to side effects by effectively causing a shift to the left in one or both of the concentration–toxicity curves. This narrows the range over which doses can be safely administered without incurring adverse effects. The EC50 in Figure 8–8 produces

negligible toxicity. Increasing the concentration with a dosage increase to gain an increased response can only be accomplished at the expense of mild toxicity. As the dosage and concentration increase, therapeutic effects approach a plateau, and small increments in concentration result in a disproportionate change in toxicity. FIGURE 8–8. Concentration–effect curves for a drug that produces a therapeutic effect and mild (A) and severe (B) toxicity.

The concentration is shown for a therapeutic effect that produces 50% of the maximum effect (EC50 ). The pharmacodynamic relationships considered above are most reproducible when pharmacological effects are direct and closely related to plasma concentration. In Figure 8–9, the concentration–effect relationship is shown as a function of drug concentration changes over time. In Figure 8–9A, the changes in effect are almost superimposable with the increase and decrease in concentration. This type of relationship often reflects a direct action of the drug with a single receptor. This straightforward relationship is generally not observed in psychopharmacology. FIGURE 8–9. Theoretical relationships of drug concentration versus intensity of effect.

Drug concentration changes occur in the direction of the arrow. Effects superimposable on concentration changes (A) suggest a direct and reversible interaction between drug and receptor, a clockwise hysteresis curve (B) suggests the development of tolerance, and a counterclockwise curve (C) suggests an indirect effect or the presence of an active metabolite. In Figure 8–9B, the response has begun to diminish with time before concentration begins to decline. This type of plot is known as a clockwise hysteresis curve. The observed effect may be explained by the development of tolerance. The time course of tolerance to psychoactive drug effects varies from minutes to weeks. Acute tolerance to some euphoric effects of cocaine can occur following a single dose (Foltin and Fischman 1991). Tolerance to the sedative effects of various drugs may take weeks. The mechanisms operative in the development of tolerance include acute depletion of a neurotransmitter or cofactor, homeostatic changes in receptor sensitivity from blockade of various transporters, or receptor agonist or antagonist effects. Ultimately, cellular responses to chronic treatment with drugs can alter gene transcription factors as mediators of physical and psychological aspects of tolerance (Nestler 1993). A time delay in response occurs when effects are increasing and are maintained despite decreasing plasma drug concentration (see Figure 8–9C). This results in a counterclockwise hysteresis curve. A pharmacokinetic explanation of this lag in response may involve a delay in reaching the critical drug MEC at the effect site until the plasma concentration has already begun to decline. Alternatively, response may depend on multiple "downstream" receptor effects. This theory likely accounts for the counterclockwise hysteresis curve observed between plasma drug concentration and growth hormone response in plasma after an intravenous alprazolam challenge (Osman et al. 1991). Response may increase despite a decreasing drug concentration when a metabolite contributes to the observed effects. To overcome these complications, kinetic dynamic models can incorporate an "effect"

compartment (see Figure 8–1). The effect site equilibrates with plasma after a finite time, which can be assigned a half-life. Models can also incorporate the presence of metabolites (Dingemanse et al. 1988).

VARIABILITY IN THE DOSE–EFFECT RELATIONSHIP A major challenge of treating mental illness with drugs is that both pharmacokinetic and pharmacodynamic variability complicate the dose–effect relationship. The presence of active metabolites, the influence of pharmacogenetics, and the effects of combining two or more drugs contribute to variability. Noncompliance with the prescribed treatment plan on the part of the patient can seriously undermine reliability in the expected effects from pharmacotherapy. Physiological differences between patients are another source of variability. The effects of age, weight, and hepatic and other disease states are major factors in pharmacokinetics and pharmacodynamics that indicate the need for individualization of therapy.

Active Metabolites With the exceptions of lithium and gabapentin, which are renally excreted, drugs used in clinical psychopharmacology are cleared partially or completely by metabolism, primarily in the liver. Many psychoactive drugs produce pharmacologically active metabolites that distribute to the effect sites (see Figure 8–1) to produce pharmacological effects. Like their precursors, metabolites may have multiple pharmacological effects that may be similar to or different from those of the parent drug. Sertraline's metabolite, desmethylsertraline, has about 10% of the activity of sertraline in inhibiting the serotonin (5-HT) transporter, but the metabolite is equipotent with sertraline in its affinity for the hepatic isoenzyme CYP2D6 (Fuller et al. 1995). The major metabolite of risperidone, 9-hydroxyrisperidone, has pharmacological effects similar to its precursor as a dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonist but differs in its affinity for and inhibition of the drug transporter P-gp (Zhu et al. 2007). When switching therapy from one drug or drug class to another, the presence of any active metabolites should be considered (Garattini 1985). Norfluoxetine, for example, has an average half-life of 8–9 days, much longer than the average of 2–3 days for fluoxetine, its parent drug (DeVane 1994), and is an equipotent serotonin reuptake inhibitor. It may take several weeks for this metabolite to clear the body after discontinuation of fluoxetine (Pato et al. 1991). A similar situation applies to aripiprazole and its active metabolite, dehydro-aripiprazole, which have elimination half-lives of 75 hours and 94 hours, respectively. Metabolites will accumulate to a steady state in the body in relation to their elimination half-lives and not those of their parent drugs. For a drug that is nearly completely metabolized in the liver, a characteristic of numerous psychoactive drugs, the produced metabolites will always have an elimination half-life that is equal to or longer than the half-life of the parent drug. This is a logical conclusion of considering that a metabolite cannot be eliminated faster than it is formed. Of course, administration of the metabolite as a separate molecular entity apart from the parent drug would produce a drug concentration–time curve independent of any influence of the metabolite being formed from a precursor in vivo. For some drugs, the full expression of direct pharmacological effects may not be expected until both the drug and any important active metabolites have all attained their steady-state concentration. For drugs producing indirect effects when the response depends on second messengers or a cascade of receptor actions, the waiting period for fully expressed effects may be even longer.

Stereochemistry Stereochemistry or chirality of drug molecules is an increasingly important consideration in pharmacokinetics. Many psychoactive drugs exist as two or more stereoisomers or enantiomers with distinctly different biological properties and are marketed as the racemic (i.e., 50:50) mixtures of both isomers. Although enantiomers have identical physicochemical properties, they are often recognized as distinct entities by biological systems and may bind to transport proteins, drug-metabolizing enzymes, and pharmacological effect sites with different affinities. As a result, one enantiomer may possess a significant pharmacological effect, while the other stereoisomer may lack similar effects or produce different effects. Enantiomers may also differ in their absorption, metabolism, protein binding, and excretion, leading to substantial differences in pharmacokinetic properties (DeVane and Boulton 2002). Furthermore, one isomer may modify the effects of the other. The development of single-isomer drugs may offer advantages over use of the racemic mixture. Potential advantages include a less complex and more selective pharmacological profile, a potential for an improved therapeutic index, a more simplified pharmacokinetic profile, a reduced potential for complex drug interactions, and a more definable relationship between plasma drug concentration and effect. Examples of racemic mixtures in current use include methadone, methylphenidate, bupropion, venlafaxine, fluoxetine, and citalopram. Clearly, each drug needs to be considered individually with regard to its development as a single stereoisomer formulation. Recent examples of successful switches to single isomers are escitalopram and dexmethylphenidate.

Pharmacogenetics Inheritance accounts for a large part of the variations observed in the ability to eliminate drugs (see Figure 8–1) among individuals. This forms the basis of pharmacogenetics, which is defined as the study of the genetic contribution to the variability in drug response (Kalow et al. 1986; Price Evans 1993). This term was originally applied to the effect on pharmacokinetics, while pharmacogenomics dealt specifically with genes mediating drug response. More recently, the terms have been used interchangeably. Numerous association studies have been performed of genetic polymorphisms of molecular targets as predictors of disease susceptibility, specific drug response, and tolerability. This topic is covered in the chapter addressing pharmacogenomics (see Chapter 3, "Genetics and Genomics"). The genetic differences in pharmacokinetics that have been detected apply mostly to drug metabolism. The renal clearance of drugs appears to be similar in age- and weight-matched healthy subjects with no defined genetic polymorphisms. Genetic polymorphisms have been identified and defined for some drug transporters, primarily P-gp, and several hepatic enzymes important for the cellular transport and metabolism of many drugs used in psychopharmacology. These genetic polymorphisms are summarized in Table 8–2. TABLE 8–2. Some genetically determined variations influencing drug pharmacokinetics Protein (major

Frequency of poor

polymorphisms)

metabolizers or

Clinical consequences

Example substrates

Increased drug

Digoxin, fexofenadine, methadone, olanzapine,

bioavailability

aripiprazole, risperidone, paliperidone, citalopram,

dysfunctional phenotypes P-glycoprotein

Unknown

(T1236C, G2677T,

sertraline, amitriptyline, buspirone, clozapine,

C3435T)

fluvoxamine, haloperidol, nortriptyline, venlafaxine CYP2D6

5%–10% Caucasians 3% Blacks

High drug

Desipramine, nortriptyline, codeine,

concentrations; possible

dextromethorphan

toxicity

1% Asians 1% Arabs CYP2C9

10% Caucasians 1%–3% Blacks

Reduced substrate

Tolbutamide, S-warfarin, phenytoin

clearance

0%–2% Asians CYP2C19

3%–5% Caucasians 15%–20% Asians

High drug

Diazepam, S-mephenytoin

concentrations; increased sedation and possible toxicity

NAT-2

40%–60% Caucasians 10%–20% Asians and Eskimos

Plasma cholinesterase

150a

Secondary tricyclics

Tetracyclics

a

Total concentration of the parent compound and the desmethyl metabolite.

Source. Adapted from Nelson JC: "Tricyclic and Tetracyclic Drugs," in Comprehensive Textbook of Psychiatry/VII, 7th Edition. Edited by Kaplan HI, Sadock BJ. Baltimore, MD, Lippincott Williams & Wilkins, 2000, p. 2494. Copyright 2000, Lippincott Williams & Wilkins. Used with permission. Hepatic metabolism of the tricyclics and tetracyclics occurs along two principal metabolic pathways. Demethylation of the side chain converts the tertiary amines to secondary amines—for example, amitriptyline is converted to nortriptyline—and the characteristics of the compound are altered. The tertiary amines are relatively more serotonergic, whereas the demethylated amines are relatively more noradrenergic. The other pathway in hepatic metabolism is hydroxylation of the ring structure. Hydroxylation results in the formation of hydroxy metabolites. In some cases, the levels of the metabolite are substantial. The concentration of 10-hydroxynortriptyline usually exceeds that of the parent compound (Bertilsson et al. 1979). Usually 2-hydroxydesipramine is present at levels approximately 40%–50% of those present in the parent compound, but these ratios are quite variable, depending on the rate of hydroxylation (Bock et al. 1983; Potter et al. 1979). Thus, in extensive metabolizers, the ratio of hydroxy metabolite to parent compound can be quite high, but total drug levels are low. Hydroxyimipramine and hydroxyamitriptyline are present at very low concentrations and are clinically unimportant. The hydroxy metabolites are then conjugated and excreted. The conjugated metabolites are not active. Hydroxynortriptyline and hydroxydesipramine both block the norepinephrine transporter (Bertilsson et al. 1979; Potter et al. 1979). Both have been shown to have antidepressant activity (Nelson et al. 1988b; Nordin et al. 1987). The potency of hydroxydesipramine is comparable to that of the parent compound in terms of norepinephrine reuptake blockade. There are two isomers of hydroxynortriptyline, E- and Z-10-hydroxynortriptyline. E-10-hydroxynortriptyline is present at levels four times higher than those of the Z isomer and is about 50% as potent as nortriptyline in blocking norepinephrine uptake. The clinical significance of high levels of less potent hydroxynortriptyline is not entirely clear. In particular, it is not clear whether high levels of less potent hydroxynortriptyline

might interfere with the action of nortriptyline—a question of interest because such an effect might explain the therapeutic window described for this drug. Both hydroxynortriptyline and hydroxydesipramine are less anticholinergic than their parent compounds. The hydroxy metabolites may have other effects. Early studies suggested that hydroxynortriptyline concentrations were disproportionately associated with cardiac conduction abnormalities (Schneider et al. 1988; Young et al. 1985), but later studies indicated that the E enantiomer of 10-hydroxynortriptyline was less cardiotoxic (Pollock et al. 1992). The principal metabolic pathway for amoxapine is hydroxylation, during which 7-hydroxyamoxapine and 8-hydroxyamoxapine are produced (Coupet et al. 1979). These compounds differ: 7-hydroxyamoxapine has high-potency neuroleptic properties but a short half-life; 8-hydroxyamoxapine is metabolized more slowly and appears to contribute to the drug's antidepressant action. In recent years, identification of the specific isoenzyme pathways involved in the metabolism of a variety of drugs, including the tricyclics, has been the focus of intensive study. The CYP2D6 pathway appears responsible for hydroxylation of desipramine and nortriptyline (Brosen et al. 1991). In fact, desipramine has been considered the prototypic substrate for CYP2D6 because it has no other major metabolic pathways. Demethylation of the tertiary-amine compounds appears to involve a number of CYP isoenzymes, including 1A2, 3A4, and 2C19. These hepatic isoenzymes are under the control of specific genes, and the gene loci have been identified for several of these isoenzymes, including CYP2D6. Approximately 5%–10% of Caucasians are homozygous for the recessive autosomal 2D6 trait, resulting in deficient hydroxylation of desipramine and nortriptyline (Brosen et al. 1985; Evans et al. 1980). These individuals are termed poor metabolizers, while those with adequate 2D6 enzyme are referred to as extensive metabolizers. Approximately 20% of individuals of Asian descent have a genetic polymorphism resulting in deficient CYP2C19 metabolism. This pathway is involved in the metabolism of the tertiary tricyclic compounds. The variability in plasma concentrations that results from these metabolic differences is substantial. For example, in a sample of 83 inpatients who were given a fixed dose of 2.5 mg/kg of desipramine, we observed steady-state plasma concentrations ranging from 20 ng/mL to 934 ng/mL (Nelson 1984). Even among extensive metabolizers, there can be variability in the rates of metabolism, resulting in the term ultrarapid metabolizers. Various methods have been used to phenotype the individuals who are slow or fast metabolizers. For example, formation of the debrisoquine metabolite in the urine has been used to characterize the metabolic rate of CYP2D6 (Brosen et al. 1991; Evans et al. 1980). Recent work in this area has shifted to genotyping the involved isoenzymes. In clinical practice, blood levels of the compounds themselves are more often used as a crude index of the rate of metabolism. As noted above, desipramine has often been used as a substrate for 2D6 because 2D6 is the only major metabolic pathway for this compound. While desipramine may be useful for examination of 2D6 inhibition, it may overestimate the magnitude of drug interactive effects for those agents that have multiple pathways.

Steady-State Concentrations Steady state is an important pharmacological concept for clinicians to understand if drug monitoring is employed. Steady state is that point, on a fixed dose, at which plasma concentrations of the drug reach a plateau. Steady state is achieved after five half-lives. At this point, the concentration of the drug should be 97% of the maximal concentration achieved for that dose. In fact, after three half-lives, the drug will have achieved about 87% of the steady-state concentration. If blood level monitoring is employed, a sample is drawn before the next dose is given, usually in the morning after the patient's level has reached a steady state. Steady-state drug concentrations should remain

relatively stable as long as the dose is constant, the patient is compliant, and no interactive drugs are added. The day-to-day biological variability of drug concentrations at steady state is not frequently described. In inpatients at steady state, the coefficient of variation (SD/mean) of desipramine is approximately 10%–15% (J. C. Nelson, unpublished data, 1985). In outpatients, this variability may increase. This means that if the average plasma concentration is 150 ng/mL, two-thirds of samples obtained will be ±10%, or between 135 ng/mL and 165 ng/mL. Research studies of drug concentrations usually employ an average of two or three plasma samples to reduce the effect of this variability. If only one sample is drawn, the clinician needs to remember that even if the laboratory error is low, there will be moderate biological variability. Single blood levels are better viewed as estimates than as precise measures. When the drug concentration is measured, the total of both the free and bound drug is reported. Few laboratories are prepared to measure free levels, yet drug concentrations in the cerebrospinal fluid are proportional to the free levels. The free concentration is dependent on dose and hepatic clearance but is not affected by plasma protein binding (Greenblatt et al. 1998). The latter is often misunderstood. Factors that affect plasma proteins—malnutrition, inflammation—may lead to changes in the bound fraction, but the absolute free concentration is unaffected. If another drug affects binding, the absolute free concentration remains unaffected. In these instances, the free fraction may change because the bound portion declines, not because there is a change in the free concentration.

Linear Kinetics Most of the tricyclics have linear kinetics; that is, concentration increases in proportion to dose within the therapeutic range. There are exceptions. Desipramine, for example, appears to have nonlinear kinetics in the usual dose range (Nelson and Jatlow 1987). Rapid metabolizers of desipramine are most likely to display nonlinear changes during the time when the dose is increasing. In these patients, a disproportionate rise in the drug concentration occurs when the dose is increased. In cases of overdose, nonlinear changes are more likely to occur, and the clinician cannot assume that usual rates of drug elimination will be maintained.

Effects of Aging Many changes in the pharmacodynamics and pharmacokinetics of drug treatment occur with aging, yet some may be relatively unimportant (Greenblatt et al. 1998). The ratio of fat to lean body mass increases, and cardiac output and hepatic blood flow decrease. There may be further changes associated with medical illness. But the clinical importance of these changes is usually relatively minor because of the dramatic variability of hepatic metabolism. Age-related changes in metabolism vary with the isoenzymes involved. The activity of the CYP3A4 pathway does slow with age (von Moltke et al. 1995). Most studies of the tertiary amines, such as imipramine, suggest that concentrations of these drugs are increased somewhat in older individuals (Abernathy et al. 1985; Benetello et al. 1990; Furlanut and Benetello 1990). Alternatively, most studies of nortriptyline (Bertilsson 1979; Katz et al. 1989; Smith et al. 1980; Young et al. 1984; Ziegler and Biggs 1977) and desipramine (Abernathy et al. 1985; Nelson et al. 1985, 1995) indicate that ratios of blood level to dosage of these drugs are relatively unaffected by aging, suggesting that the 2D6 isoenzyme is not similarly affected. In addition, the relationship of nortriptyline and desipramine plasma concentrations to therapeutic effects appears to be relatively similar in younger and older adults (Katz et al. 1989; Nelson et al. 1985, 1995; Young et al. 1988). Renal clearance of the hydroxy metabolites does decrease with age (Nelson et al. 1988a; Young et al. 1984). As a result, concentrations of hydroxynortriptyline may be substantially elevated in older patients. In children, the clearance of tricyclic compounds is increased. Half-lives of imipramine are shorter and ratios of desmethylimipramine to imipramine are higher, consistent with more rapid metabolism

(Geller 1991; Rapoport and Potter 1981). Alternatively, a study of desipramine in children found that the clearance of both desipramine and hydroxydesipramine was increased so that hydroxy metabolite–parent compound ratios were not elevated (Wilens et al. 1992).

Relationship of Plasma Concentration to Clinical Action Plasma Concentration and Response Marked interindividual variability of tricyclic plasma concentrations was described by Hammer and Sjöqvist in 1967. This finding suggested that drug level monitoring might ensure that therapeutic blood levels are achieved and might help to avoid toxic levels. In carefully selected inpatients with endogenous or melancholic major depression, treatment with adequate levels of imipramine or desipramine resulted in robust response rates of about 85% (Glassman et al. 1977; Nelson et al. 1982). For several years, the relationship of tricyclic blood levels to response and the utility of monitoring blood levels were the focus of considerable attention and debate. A task force of the American Psychiatric Association (1985) that reviewed these studies concluded that relationships between plasma level and response had been demonstrated for imipramine, desipramine, and nortriptyline (see Table 12–2). For imipramine, drug levels above 200 ng/mL were more effective than lower levels (Glassman et al. 1977; Reisby et al. 1977). For desipramine, levels above 125 ng/mL were more effective (Nelson et al. 1982). For both desipramine and imipramine, blood levels in excess of 300 ng/mL were more likely to be associated with serious side effects. Effective plasma concentrations were also established for nortriptyline, but the relationship appeared to be curvilinear. For this drug, plasma levels between 50 ng/mL and 150 ng/mL were more effective than lower or higher levels (Åsberg et al. 1971; Kragh-Sørenson et al. 1973, 1976). For amitriptyline, it has been more difficult to establish a therapeutic relationship between plasma levels and response (American Psychiatric Association 1985). In part, this difficulty may be related to the fact that during amitriptyline administration, three active compounds are present (amitriptyline, nortriptyline, and hydroxynortriptyline), and it is unclear if their effects are additive or if there is a more complicated relationship (Breyer-Pfaff et al. 1982). During amitriptyline administration, responders usually have total amitriptyline and nortriptyline levels in the neighborhood of 150–250 ng/mL (Kupfer et al. 1977), but there is not good agreement between studies. For clomipramine, blood levels of 150–300 ng/mL (total of clomipramine and desmethylclomipramine) have been suggested for antidepressant effectiveness. Higher levels are usually employed in the treatment of OCD. The data relating blood levels and response are limited for the other tricyclic and tetracyclic compounds. The therapeutic utility of blood level monitoring has been the subject of controversy. Blood level– response relationships have been demonstrated in melancholic inpatients. But similar relationships have proven difficult to demonstrate in depressed outpatients. In outpatients, drug–placebo differences are often small, and the effect of drug treatment is harder to detect. Depressed outpatients may be more heterogeneous and include individuals who are not responsive to any drug treatment. Finally, many studies are not designed to detect blood level–response relationships. Fixed dosing is required, and the plasma concentrations achieved must fall above and below the suspected threshold. If all patients achieve adequate drug concentrations, no relationship with response will be found. It is logical to conclude that blood level relationships determined in severely depressed inpatients might be used as a guide for treatment of outpatients, but this assumption has not been empirically validated.

Plasma Concentration and Toxicity The alternative question is whether blood level monitoring might help to avoid toxicity. A variety of data support this view. The risk of delirium is substantially increased at amitriptyline plasma

concentrations above 450 ng/mL and is moderately increased at concentrations above 300 ng/mL (Livingston et al. 1983; Preskorn and Simpson 1982). But amitriptyline is the most anticholinergic tricyclic and is most likely to produce delirium. The risk of first-degree atrioventricular block is also increased with plasma concentrations of imipramine greater than 350 ng/mL (Preskorn and Irwin 1982). The risk of seizures also increases at higher doses and, presumably, higher blood levels, although a clear plasma-level threshold for seizures has not been demonstrated. Following overdose, tricyclic blood levels greater than 1,000 ng/mL can be achieved, and the risks of delirium, stupor, cardiac abnormalities, and seizures are all substantially increased (Preskorn and Irwin 1982; Rudorfer and Young 1980; Spiker et al. 1975). The value of blood level monitoring to avoid serious adverse effects has been hard to demonstrate because rates of serious toxicity are low so that large samples are required to demonstrate any increase in risk at higher blood levels. For some adverse reactions (e.g., delirium), early warning signs may prompt dose reduction. Alternatively, there may be no warning for seizures or cardiac arrhythmia, and blood level monitoring might be most useful for reducing the risk of those adverse events. If blood level monitoring is undertaken, the clinician needs to remember that the patient needs to be at steady state, the blood sample should be drawn before the next dose (a trough level), and the sample should be sent to the laboratory promptly. For a quantitative estimate the laboratory will usually employ high-performance liquid chromatography (HPLC). In a competent laboratory, the coefficient of variation for an HPLC assay is usually less than 10%. This assay is relatively specific; however, other drugs can interfere. Because there are many modifications of the HPLC technique, the interfering drugs will vary by site. Under the best of circumstances, there will still be biological variability of the compound (discussed earlier in subsection "Steady-State Concentrations"). Add to this occasional missed doses or laboratory problems, and there will be considerable sample-to-sample variability. For these reasons, the clinician should not view the concentration reported as a precise measure. Yet, because concentrations vary across such a wide range, it may be very helpful to know if the level is low (e.g., 25–75 ng/mL), moderate (e.g., 100–300 ng/mL), or high (e.g., 300–1,000 ng/mL).

Prospective Dosing Techniques Conventional dosing requires administration of a given dose for a long enough period of time to determine whether that dose is effective. Sometimes two or three trials are needed to determine the effective dose. The possibility of rapid dosage adjustment using plasma levels was suggested when several investigators demonstrated a relationship between an initial timed blood sample and the final steady-state level (Alexanderson 1972; Brunswick et al. 1979; Cooper and Simpson 1978; Potter et al. 1980). This method appeared most applicable for nortriptyline, which has linear kinetics, but was also useful for desipramine, because the targeted level was within a broad range. Clinical studies using blood levels to adjust dose were reported for amitriptyline (Dawling et al. 1984; Madakasira and Khazanie 1985), but sedation and anticholinergic side effects limited the rate at which the dose could be adjusted. Alternatively, a clinical study using rapid dosing of desipramine found that treatment could be initiated at full dose once the dose needed to reach a therapeutic level was determined from a 24-hour blood level following a test dose (Nelson et al. 1987). Sixteen of the 18 patients who completed treatment had plasma levels within the targeted range, and side effects appeared to be no greater than those experienced with more gradual dosing. The practical application of these methods was limited by laboratory issues. The laboratory performing the assay had to be prepared to determine drug concentrations accurately at very low levels (below the therapeutic range) and had to be able to report results quickly. Most labs were not prepared to do either. A more practical and clinically feasible method is to start the drug at a low or moderate fixed dose, obtain a blood sample after 5–7 days on that dose, and then make further adjustments based on

that level. There are exceptions. Elderly depressed patients often require gradual dosing in order to assess tolerance. In panic patients, lower starting doses are employed to avoid exacerbation of panic attacks.

MECHANISM OF ACTION Early biochemical theories of depression were in large part based on the knowledge of drug action. The observation that the tricyclic agents increased the availability of norepinephrine and serotonin suggested that depression resulted from a deficit in these neurotransmitters (Bunney and Davis 1965; Prange 1965; Schildkraut 1965). This work stimulated interest in the role of these neurotransmitters in the etiology of depression, and several abnormalities were identified. Yet, it remains unclear which, if any, of these abnormalities play a central role in causing depression or are responsible for the vulnerability to becoming depressed. Recent challenge studies in depressed patients do confirm that the actions of antidepressant drugs are mediated by serotonin and norepinephrine. For example, administration of a tryptophan-free diet rapidly depletes serotonin and, in depressed patients who have been successfully treated, causes relapse (Delgado et al. 1990). In addition, tryptophan depletion caused relapse in patients who were treated with serotonergic agents, whereas those who were treated with norepinephrine reuptake inhibitors were relatively unaffected. Alternatively, administration of AMPT, which interrupts the synthesis of catecholamines, caused relapse in patients who were being successfully treated with noradrenergic agents but not those receiving serotonergic drugs (Delgado et al. 1993). Tryptophan depletion in untreated depressed patients, however, had no effect on the patients' depression. These studies provide supporting evidence that serotonin and norepinephrine mediate antidepressant effects, but they do not necessarily imply that alterations in these neurotransmitter systems are central to the pathophysiology of depression. The synaptic effects of tricyclic and tetracyclic agents on norepinephrine and serotonin transporters and receptors were described in detail earlier (see section "Pharmacological Profile" earlier in this chapter). The early theories of depression that focused on depletion of norepinephrine or serotonin suggested that it might be possible to identify "serotonergic" and "noradrenergic" depressions and that such identification would help the clinician select the appropriate type of antidepressant (Beckmann and Goodwin 1975; Maas et al. 1972). A number of studies investigated the predictive value of urinary MHPG, a metabolite of norepinephrine, but a definite predictive link with a noradrenergic antidepressant was not established. Some of these studies were, in part, hampered by the use of agents such as amitriptyline and imipramine, which are not very selective. However, even those studies that examined the ability of MHPG to predict response to more selective agents, such as zimelidine, fluoxetine, and desipramine, failed to demonstrate clear predictive utility (Bowden et al. 1993; Potter 1984). The data, taken together, suggest that urinary MHPG is not a clinically useful predictor. Nevertheless, these studies do not rule out the possibility that there are depressions in which serotonin or norepinephrine plays a relatively more prominent role. More recently, research into the mechanism of action of the tricyclics and other antidepressant drugs has shifted to include consideration of factors affecting postsynaptic signal transduction (Manji et al. 1995). These factors include coupling of G proteins to the adrenergic receptor or to adenylyl cyclase and the activity of membrane phospholipases and protein kinases. Other novel targets, including glucocorticoid receptors (Barden 1996), neurotrophic factors (Duman et al. 1997), and gene expression (Lesch and Manji 1992; Nibuya et al. 1996; Schwaninger et al. 1995), have been explored.

INDICATIONS AND EFFICACY Major Depression

The efficacy of the tricyclic and tetracyclic compounds in major depression is well established. The evidence for their effectiveness has been reviewed previously (Agency for Health Care Policy and Research 1993; Davis and Glassman 1989). Imipramine is the most extensively studied tricyclic antidepressant, in part because for many years it was the standard agent against which other new drugs were compared. In 30 of 44 placebo-controlled studies, imipramine was more effective than placebo. If data from these studies are combined, 65% of 1,334 patients completing treatment with imipramine were substantially improved, whereas 30% of those on placebo improved. Intentionto-treat response rates for placebo-controlled studies of imipramine in outpatients were 51% for imipramine and 30% for placebo (Agency for Health Care Policy and Research 1993). In most comparison studies, the other tricyclic and tetracyclic antidepressants have been found to be comparable to imipramine in efficacy. The tricyclic compounds are also effective when used for maintenance treatment. Early studies demonstrated that maintenance treatment with a tricyclic would reduce the relapse rate associated with placebo by about 50% (Davis 1976). These studies, however, usually employed low doses. Subsequently, the Pittsburgh group found that imipramine, at full dose, effectively maintained nearly 80% of the depressed patients for a 3-year period compared with 10% of those on placebo (Frank et al. 1990). In this study, maintenance psychotherapy had an intermediate effect, with about 30% of the patients remaining well. Although this seminal study demonstrated the impressive value of maintenance treatment with full-dose imipramine, the magnitude of the findings may reflect characteristics of the sample treated. The sample comprised patients with recurrent depression who might have been expected to do poorly on placebo. In addition, the patients selected for the study had a history of symptom-free periods between prior episodes, suggesting that these patients might be more likely (than patients with a history of residual symptoms) to have a complete response to treatment. In practice, clinicians may encounter patients with chronic depression, patients with residual symptoms, or patients with comorbid medical and psychiatric disorders. For such patients, drug treatment may be more effective than placebo, but the actual number of patients whose depression remains in remission may be lower. The U.S. Food and Drug Administration (FDA) has approved all of the tricyclic and tetracyclic compounds discussed in this chapter for the treatment of depression with the exception of clomipramine. In Europe, clomipramine is also used for depression; in fact, it is regarded by many as the most potent antidepressant.

Melancholia or Severe Depression The efficacy of the tricyclic compounds appears to vary in different subtypes of depression. Four decades ago, when Kuhn studied imipramine, the prevailing view was that it was essential to establish efficacy of an antidepressant in patients with endogenous depression or at least in those with severe depression (Kuhn 1970). The early studies of imipramine and the other tricyclic compounds were frequently conducted in hospitalized patients with severe or endogenous depression, and in these patients the tricyclics were found to be effective. In fact, these agents may be especially effective in this group. Two studies of imipramine and desipramine found rates of response of about 85% in severely depressed hospitalized patients who did not have a refractory history, did not have prominent personality disorder, received an adequate plasma concentration of the drug, and completed treatment (Glassman et al. 1977; Nelson et al. 1982). When the SSRIs were introduced, it was suggested that they might be less effective than the tricyclic antidepressants in treating severe or melancholic depression. In a large meta-analysis of more than 100 studies comparing tricyclic antidepressants and SSRIs, Anderson (2000) found that in general, these agents had comparable efficacy. When individual agents and patient characteristics were considered, the only tricyclic agent that appeared to be more effective than the SSRIs was amitriptyline, and the only patient characteristic was inpatient status. In a separate meta-analysis of

25 inpatient studies (Anderson 1998), the advantage of the tricyclics appeared limited to those with dual action, namely amitriptyline and clomipramine. Two of the most frequently cited studies in this regard were the two Danish University Antidepressant Group (1986, 1990) studies that found clomipramine to be more effective than paroxetine or citalopram in severely depressed inpatients. Recent clinical trials of antidepressants were usually conducted in outpatients with depression of moderate severity. In outpatients, the designation of melancholia does not appear to predict an advantage for tricyclic antidepressants versus SSRIs (Anderson and Tomenson 1994; Montgomery 1989). Although the question of the best treatment for severely melancholic inpatients lingers, the expense of these studies, and the shift in practice to treatment of depression in outpatient settings, has substantially decreased interest in this question.

Anxious Depression Anxious depression is not recognized in DSM-IV-TR (American Psychiatric Association 2000) as a subtype of depression; nevertheless, it has been frequently studied. Three of the tricyclic and tetracyclic compounds—doxepin, amoxapine, and maprotiline—have received FDA approval for use in patients with depression and symptoms of anxiety. For many years, clinical lore suggested that amitriptyline was most effective for anxious depression. Direct comparison studies, however, have found little indication that one of these compounds is better than another for treatment of anxious depression. Depressed patients who are anxious may respond less well than less anxious patients. This has been observed with amitriptyline (Kupfer and Spiker 1981), imipramine (Roose et al. 1986), and desipramine (Nelson et al. 1994). Yet these drugs are still more effective than placebo in anxious depressed patients, and it is not established that other classes of antidepressants are more effective in these patients.

Atypical Depression A series of studies by the Columbia University Group examined the efficacy of imipramine in depressed patients with atypical features (Liebowitz et al. 1984, 1988). These depressed patients had reactive mood and reversed vegetative symptoms, severe fatigue, or rejection sensitivity. Imipramine was more effective than placebo but significantly less effective than the monoamine oxidase inhibitor (MAOI) phenelzine. Other investigators have reported the value of switching from a tricyclic to an MAOI in tricyclic-refractory depressed patients, especially those with atypical features (McGrath et al. 1987; Thase et al. 1992). In fact, the validity and utility of the atypical subtype of depression were in large part supported by this observed difference. However, this subtype has not been shown to be preferentially responsive to SSRIs (Fava et al. 1997), nor has any second-generation antidepressant been shown to be superior to any other in treating atypical depression.

Psychotic Depression In 1975, Glassman et al. observed that imipramine was less effective in patients with major depression who had delusions. Later, Chan et al. (1987), in reviewing several studies addressing this question and involving more than 1,000 patients, found that antidepressants—usually tricyclics—given alone were effective in approximately two-thirds of the nonpsychotic patients but only about one-third of those with psychotic features. Although the definition of psychosis has undergone several changes, currently it is defined in DSM-IV-TR as major depression with delusions or hallucinations. Several open studies reviewed elsewhere (Nelson 1987) and one prospective study (Spiker et al. 1985) found that the tricyclics, when combined with an antipsychotic, are effective in psychotic depression. Anton and Burch (1990) suggested that because of its antipsychotic effects, amoxapine might be effective for psychotic depression. In a double-blind study, these researchers demonstrated that amoxapine was comparable in efficacy to the combination of perphenazine and amitriptyline in treating psychotic depression (Anton and Burch 1990).

Bipolar Depression Thirty years ago, it was suggested that the MAOI antidepressants might be more effective than the tricyclics in treating bipolar depression (Himmelhoch et al. 1972). Later, Himmelhoch et al. (1991) demonstrated in a double-blind study that tranylcypromine was more effective than imipramine for bipolar depression. In addition, tricyclics are more likely than other agents to induce mania (Weir and Goodwin 1987). As a result, the tricyclics are not recommended for monotherapy of bipolar depression.

Chronic Major Depression and Dysthymia Imipramine appears to be effective in treating chronic depression and dysthymia and to be relatively comparable to sertraline in efficacy (Keller et al. 1998; Kocsis et al. 1988; Thase et al. 1996). Imipramine and desipramine have both been studied in controlled trials and have been found to be more effective than placebo both for acute treatment and for maintenance treatment (N. L. Miller et al. 2001).

Late-Life Depression Gerson et al. (1988) reviewed the studies of tricyclic antidepressants reported prior to 1986. They found 13 placebo-controlled trials but noted several problems, such as lack of diagnostic criteria, inclusion of younger patients, and dosing issues. Although tricyclics were effective, overall drug and placebo response rates in these older patients appeared to be lower than rates in nonelderly patients (Agency for Health Care Policy and Research 1993). Katz et al. (1990) performed one of the first placebo-controlled trials of nortriptyline in the treatment of patients older than 80 years living in a residential care facility. Nortriptyline was more effective than placebo. The doses employed and levels achieved were similar to those in younger subjects. This study remains the only study to date showing an advantage for an antidepressant over placebo in depressed patients older than 75 years.

Depression in Children In children and adolescents, the tricyclic antidepressants have not demonstrated superiority over placebo (Ryan 1992).

Obsessive-Compulsive Disorder Unlike depression, which responds to a variety of antidepressant agents, OCD appears to require treatment with a serotonergic agent. Clomipramine, the most serotonergic of the tricyclics, is approved by the FDA for use in OCD, and its efficacy in this disorder is well established (Greist et al. 1995). Studies comparing its effectiveness with noradrenergic agents such as desipramine found that clomipramine was substantially superior (Leonard et al. 1989). Although the SSRIs are effective in treating OCD, there is a suggestion that clomipramine may be superior (Greist et al. 1995). Whether this putative superiority is due to the dual mechanism of clomipramine or to other factors is unclear.

Panic Disorder None of the tricyclic or tetracyclic drugs are approved for use in panic disorder. Yet imipramine was the first drug described for use in this disorder (Klein 1964). In fact, observation of the effects of imipramine helped to establish the diagnostic utility of panic disorder. The efficacy of both tertiary and secondary tricyclics has been demonstrated in controlled trials (Jobson et al. 1978; Munjack et al. 1988; Zitrin et al. 1980). In treating this disorder, the drug is initiated at a low dose to avoid exacerbation of panic symptoms.

Attention-Deficit/Hyperactivity Disorder The efficacy of the stimulant drugs in treating attention-deficit/hyperactivity disorder (ADHD) is well established. The tricyclics, especially desipramine, also appear to be of value. In one study,

desipramine, given at doses greater than 4 mg/kg for 3–4 weeks, was effective in two-thirds of the children, whereas placebo was effective in only 10% (Biederman et al. 1989). Desipramine was also found to be more effective than placebo in adults with ADHD (Wilens et al. 1996). One of the advantages of desipramine is its low potential for abuse. Unfortunately, five cases of sudden death were reported in the early 1990s in children being treated with desipramine (Riddle et al. 1991, 1993). All were under the age of 12 years. As a result, desipramine is now contraindicated in children younger than 12 years (discussed in greater detail below; see section "Side Effects and Toxicology"). Given that tricyclics as a group share the same adverse cardiac effects, there is reason to be concerned that other tricyclics might also have safety issues in young children.

Pain Syndromes The tricyclics and maprotiline have been widely used in various chronic pain syndromes. In a review of the literature, O'Malley et al. (1999) identified 56 controlled studies involving tricyclic antidepressant therapy for various pain syndromes, including headache (21 studies), fibromyalgia (18 studies), functional gastrointestinal syndromes (11 studies), idiopathic pain (8 studies), and tinnitus (2 studies), and Salerno et al. (2002) identified 7 more placebo-controlled trials of tricyclics or maprotiline used for chronic back pain. These agents were quite effective; in fact, the mean effect size (0.87) and the drug–placebo difference in response rates (32%) observed in pain syndromes are more robust than those usually observed in placebo-controlled studies in depression. In studies in which depression was also assessed, improvement in pain appeared to be independent of improvement in depression. Thus, the analgesic effects of these compounds were not simply the result of their antidepressant effects. The mechanism of these agents' analgesic effects appears to differ from that of their antidepressant effects. The antinociceptive actions of the antidepressants result from actions on descending norepinephrine and serotonin pathways in the spinal cord (Yoshimura and Furue 2006). In animals, norepinephrine reuptake inhibitors and combined norepinephrine–serotonin reuptake inhibitors appear to be more potent than SSRIs (Mochizucki 2004). In humans, there is some evidence that the combined-action agents amitriptyline and clomipramine are more effective than the SSRI fluoxetine (Max et al. 1992) or the norepinephrine-selective agents maprotiline (Eberhard et al. 1988) and nortriptyline (Panerai et al. 1990). In humans, antidepressant dosing and timing of effects for pain differ from those observed in depression. For example, usual dosages of amitriptyline required for pain management ( 75 mg/day) are lower than those required to treat depression (15–300 mg/day), and response occurs more quickly, usually within the first 1 or 2 weeks.

Other Indications Imipramine has been used for treatment of nocturnal enuresis in children with FDA approval, and controlled trials indicate that it is clearly effective (Rapoport et al. 1980). The dose of imipramine is usually 25–50 mg at bedtime. Amitriptyline and nortriptyline also appear to be useful, although they are not approved for use in this disorder. The mechanism of action is unclear but may in part be anticholinergic. It is not clear, however, that the risk of cardiac problems would be substantially less with tricyclics other than desipramine in children younger than 12 years, although the low doses required may reduce this risk. Tricyclic antidepressant drugs have been extensively studied in patients with schizophrenia. However, in the absence of a major depressive syndrome, these agents appear to be of limited value (Siris et al. 1978).

SIDE EFFECTS AND TOXICOLOGY The delineation of side effects during the treatment of depressed patients is complicated because depression itself is accompanied by a variety of somatic symptoms. For example, headache,

constipation, and drowsiness—symptoms usually considered as "side effects"—have been observed in more than 50% of untreated inpatients with major depression if these symptoms were each directly assessed (Nelson et al. 1984). During treatment, patients may be quick to label these somatic symptoms as side effects even if the symptoms were preexisting. Another manifestation of this issue is the rate of spontaneously reported "side effects" on placebo in clinical trials. One of the best examples is headache. Clinical trial data for recently marketed antidepressants indicate that the rate of headaches on placebo in depressed outpatients ranges from 17% to 24% (Physicians' Desk Reference 2002). For fluoxetine, sertraline, paroxetine, and bupropion, the rate for drug was only 1%–2% higher than that for placebo. For venlafaxine XR and citalopram, the rate of headaches was higher for placebo than for drug. A strong argument can be made that headache is usually a symptom of depression. Of course, these mean values conceal the possibility that a symptom may worsen or emerge during treatment in some patients and improve with treatment in others. In groups of patients, however, the strongest predictor of overall somatic symptom severity is the severity of the depression at the time of assessment (Nelson et al. 1984), and the best intervention may be more aggressive treatment. Another general factor contributing to side effects is the patient's vulnerability. For example, one of the best predictors of orthostatic hypotension during treatment is the presence of orthostatic hypotension prior to treatment (Glassman et al. 1979). Seizures are most likely in a patient with a history of seizures (Rosenstein et al. 1993). Cardiac conduction problems are most likely to occur in patients with preexisting conduction delay (Roose et al. 1987a). The final manifestation of somatic symptoms during treatment is the net result of the interaction of direct effects of the medication on specific organs, the indirect effects of the medication on depression and its associated somatic symptoms, and the patient's vulnerability to certain symptoms. The attribution of cause—that is, whether a physical symptom is a "side effect" of a drug or a symptom of depression—involves a judgment about whether the symptom is new or has worsened during drug treatment. Antidepressant drugs do, of course, have direct effects on a variety of organs and can produce adverse effects. The in vitro potency or affinity of antidepressant compounds for various receptor sites (see Table 12–1) is one method for comparing the likelihood that various agents will produce specific side effects. A related issue is how the in vitro potency of a secondary effect relates to the potency of the primary action of the drug. If the secondary effect is more potent, it will occur at concentrations below the therapeutic level of the drug. An example for the tricyclics is orthostatic hypotension, which often manifests at plasma concentrations below the usual antidepressant threshold. Alternatively, in patients without preexisting medical illness, the proarrhythmic and proconvulsant effects of the tricyclic antidepressants are uncommon at therapeutic concentrations but become more frequent at levels encountered in overdose.

Central Nervous System Effects The principal action of the tricyclic and tetracyclic agents in the central nervous system is to alleviate depression. In particular, they reduce the symptoms of depression rather than simply elevating mood. Nondepressed subjects given imipramine may feel sleepy, quieter, light-headed, clumsy, and tired. These effects are generally unpleasant (DiMascio et al. 1964). The anticholinergic and antihistaminic effects of the tricyclics and tetracyclics can produce confusion or delirium. The incidence of delirium is dose-dependent and increases at blood levels above 300 ng/mL. One study reported that 67% of patients with blood levels above 450 ng/mL developed delirium when receiving the tertiary amines, particularly amitriptyline (Livingston et al. 1983; Preskorn and Simpson 1982). The clinician should be alert to the possibility of delirium in a patient whose depression is worsening during treatment. This can be especially problematic in patients with

psychotic depression. Patients with concurrent dementia are particularly vulnerable to the development of delirium, and the more anticholinergic tricyclics should be avoided in these patients. Intramuscular or intravenous physostigmine can be used to reverse or reduce the symptoms of delirium. Although physostigmine may represent a useful diagnostic test, its short duration of action makes the continued use of this agent difficult. Seizures can occur with all of the tricyclic and tetracyclic agents and are dosage- and blood level– related (Rosenstein et al. 1993). For clomipramine, the risk for seizures is reported to be 0.5% at dosages up to 250 mg/day. At dosages above 250 mg/day, the seizure risk increases to 1.67% (new drug application data on file with the FDA). For maprotiline, the overall risk of seizures is reported to be 0.4%, but, again, this risk increases at dosages above the maximum recommended dose of 225 mg/day (Dessain et al. 1986). The seizure risk for some of the older compounds was not as well established at the time of marketing. A retrospective meta-analysis of imipramine found an estimated seizure rate of 1 per 1,000 patients receiving less than 200 mg/day (Peck et al. 1983). At dosages above 200 mg/day, the rate was 0.6%. Another large review (Jick et al. 1983) found similar dose-dependent rates for amitriptyline and doxepin. Rates of 1%–4% have been reported at doses between 250 mg/day and 450 mg/day, but the samples in these studies were often small, and the confidence intervals for these rates were large. Consistent with a dose-dependent effect, the risk of seizures is substantially increased following overdose (Spiker et al. 1975). Seizure rates for the secondary amines have not been well described. Because the risk of convulsions is clearly increased in patients with predisposing factors such as a prior history of seizures, brain injury, or presence of neuroleptics; because the rates are low (e.g., 1/100); and because sample size in drug trials is often on the order of 200 patients, inclusion of a few patients who have a significant vulnerability to seizures can have a marked effect on the rate of seizures reported. The mechanism by which tricyclics produce seizures is not well understood. It has been suggested that antidepressant drugs induce convulsions by acting at the -aminobutyric acid (GABA) receptor chloride–ionophore complex, where they inhibit chloride conductance (Escorihuela et al. 1989; Malatynska et al. 1988). A fine, rapid tremor can occur with use of tricyclic agents. Because this tremor is dose dependent, tends to occur at higher levels, and is not a typical depressive symptom, development of a tremor may be a clinical indicator of an elevated blood level (Nelson et al. 1984). Dose reduction will often lead to improvement in the tremor. Because the 7-hydroxy metabolite of amoxapine has neuroleptic properties, administration of amoxapine carries the potential risk of neuroleptic malignant syndrome, which has been reported (Lesaca 1987; Madakasira 1989; Taylor and Schwartz 1988; Washington et al. 1989), and tardive dyskinesia. The occurrence of these adverse events is rare; however, the seriousness of the risk and the availability of many alternatives suggest that use of amoxapine should be reserved for patients whose clinical condition warrants the use of an agent with antipsychotic properties.

Anticholinergic Effects The tricyclics block muscarinic receptors and can cause a variety of anticholinergic side effects, such as dry mouth, constipation, blurred vision, and urinary hesitancy. These effects can precipitate an ocular crisis in patients with narrow-angle glaucoma. The tricyclic and tetracyclic compounds vary substantially in their muscarinic potency (see Table 12–1). Amitriptyline is the most potent, followed by clomipramine. Of the tricyclics, desipramine is the least anticholinergic. Amoxapine and maprotiline also have minimal anticholinergic effects. Anticholinergic effects can contribute to tachycardia, but tachycardia also occurs as a result of stimulation of

-adrenergic receptors in the heart. Thus,

tachycardia regularly occurs in patients receiving desipramine, which is minimally anticholinergic (Rosenstein and Nelson 1991). Although anticholinergic effects may be annoying, they are usually not serious. They can, however,

become severe. An ocular crisis in patients with narrow-angle glaucoma is an acute condition associated with severe pain. Urinary retention can be associated with stretch injuries to the bladder. Constipation can progress to severe obstipation. (Paralytic ileus has been described but is rare.) In these conditions, medication must be discontinued and appropriate supportive measures instituted. Elderly patients are at greatest risk for severe adverse consequences. The frequency of severe anticholinergic adverse reactions is increased by concomitant neuroleptic administration. Use of nortriptyline or desipramine, either of which is less anticholinergic, can help to reduce the likelihood of these problems. Anticholinergic effects may benefit from other interventions. Bethanechol (Urecholine) at a dosage of 25 mg three or four times a day may be helpful in patients with urinary hesitancy. The regular use of stool softeners helps to manage constipation. Patients with narrow-angle glaucoma who are receiving pilocarpine eyedrops regularly can be treated with a tricyclic, as can those who have had an iridectomy. Tricyclic agents do not affect patients with chronic open-angle glaucoma.

Antihistaminic Effects Several of the tricyclic compounds and maprotiline have clinically significant antihistaminic effects. Doxepin is the most potent H1 receptor blocker in this group. It is more potent than the commonly administered antihistamine diphenhydramine. More recently, however, it has been surpassed by mirtazapine and olanzapine, which are even more potent antihistamines. Central H1 receptor blockade can contribute to sedation and delirium and also appears to be related to the increased appetite and associated weight gain that patients may develop with chronic treatment. Because of their sedating effects, the tricyclic antidepressants, especially amitriptyline, have been used as hypnotics. Given their cardiac effects and the frequency of lethal overdose, this practice should be discouraged.

Cardiovascular Effects Orthostatic hypotension is one of the most common reasons for discontinuation of tricyclic antidepressant treatment (Glassman et al. 1979). It can occur with all of the tricyclics but appears to be less pronounced with nortriptyline (Roose et al. 1981; Thayssen et al. 1981). The

1-adrenergic

blockade associated with the tricyclics contributes to orthostatic hypotension; however, it is the postural reflex that is primarily affected. Resting supine blood pressure may be unaffected or can even be elevated (Walsh et al. 1992). Orthostatic hypotension is most likely to occur or is most severe in patients who have preexisting orthostatic hypotension (Glassman et al. 1979). It is also aggravated by concurrent antihypertensive medications, especially volume-depleting diuretic agents. The elderly are more likely to have preexisting hypotension and are also more vulnerable to the consequences of orthostatic hypotension, such as falls and hip fractures. Often, orthostatic hypotension occurs at low blood levels, so that dosage reduction is not a helpful management strategy. Gradual dose adjustment may allow accommodation to the subjective experience of light-headedness, but the actual orthostatic blood pressure changes do not accommodate within a reasonable period of time (e.g., 4 weeks) (Roose et al. 1998). Thus, unless the plasma level is elevated and the dose can be reduced, patients who experience serious symptomatic orthostatic hypotension may not be treatable with a tricyclic antidepressant. Fludrocortisone (Florinef) has been used to raise blood pressure, but in this author's experience it is not very effective. If patients are receiving antihypertensives, it may be possible and helpful to reduce the dose of these agents. Desipramine has been reported to raise supine blood pressure in younger patients, although it is not clear this effect is limited to that age group (Walsh et al. 1992). This effect may be similar to that reported for venlafaxine. Tachycardia occurs with all the tricyclics, not just the more anticholinergic agents. Both supine and

postural pulse changes can occur, and the standing pulse can be markedly elevated. A relatively recent study of nortriptyline, dosed to a therapeutic plasma concentration, found a mean pulse rise of 11% (8 beats per minute) (Roose et al. 1998). Patients do not accommodate to the pulse rise, which can persist for months. Tachycardia is more prominent in younger patients, who appear more sensitive to sympathomimetic effects, and is one of the most common reasons for drug discontinuation in adolescents. A persistent pulse rise in older patients, however, increases cardiac work and may be clinically significant in patients with ischemic heart disease. The effect of tricyclic antidepressants on cardiac conduction has been a subject of great interest. Cardiac arrhythmia is the principal cause of death following overdose (Biggs et al. 1977; Pimentel and Trommer 1994; Spiker et al. 1975). As a result of this observation, for many years there was great concern about the use of tricyclic antidepressants in patients with and without heart disease. The effect of these agents has now been well described. Apparently, through inhibition of Na+/K+-ATPase, the tricyclics stabilize electrically excitable membranes and delay conduction, particularly His ventricular conduction. Consequently, the tricyclics have type I antiarrhythmic qualities or quinidine-like effects. At therapeutic blood levels, the tricyclics can have beneficial effects on ventricular excitability. In patients with preexisting conduction delay, however, the tricyclic antidepressants can further delay conduction and cause heart block (Glassman and Bigger 1981; Roose et al. 1987b). A pretreatment QTc interval of 450 milliseconds or greater indicates that conduction is already delayed, that a tricyclic may aggravate this condition, and that the patient is not a candidate for tricyclic antidepressant treatment. High drug plasma levels further increase the risk of cardiac toxicity. For example, firstdegree atrioventricular heart block is increased with imipramine plasma concentrations above 350 ng/mL (Preskorn and Irwin 1982). The tricyclic antidepressants do not reduce cardiac contractility or cardiac output (Hartling et al. 1987; Roose et al. 1987a). Studies using radionuclide angiography indicate no adverse effect of imipramine or doxepin on cardiac output, even in patients with diminished left ventricular ejection fractions. But orthostatic hypotension was common in these studies and could be severe in these patients. Glassman et al. (1993), noting that the type I antiarrhythmic drugs given following myocardial infarction actually increased the risk of sudden death, suggested that the tricyclics may pose similar risks. The risk of sudden death is also increased when heart rate variability is reduced, and the tricyclics reduce heart rate variability (Roose et al. 1998). As mentioned earlier (see subsection "Attention-Deficit/Hyperactivity Disorder"), sudden death has been reported in five children under the age of 12 years who were receiving desipramine (Riddle et al. 1991, 1993). It was suggested that the immature conduction system in some children might render them more vulnerable to the cardiac effects of desipramine. Subsequently, a study was conducted in 71 children with 24-hour cardiac monitoring (Biederman et al. 1993). No cardiac abnormalities were observed. Wilens et al. (1992) examined the possibility that hydroxydesipramine might reach unusually high levels in children and adolescents, but such levels were not found. A study of electrocardiographic parameters in that sample failed to show a relationship between those parameters and concentrations of desipramine or hydroxydesipramine (Wilens et al. 1993). Although these studies failed to reveal a mechanism for the sudden deaths reported, they do suggest that these events are not predictable, that they are not dose-dependent cardiac effects, and that usual blood level or electrocardiogram monitoring is not likely to identify those at risk. To summarize the clinical implications of these cardiac effects, the clinician may wish to consider the following. In adults without cardiac disease, orthostatic hypotension may occur with tricyclic use, but conduction problems are not likely. In patients with preexisting conduction delay, the tricyclics may cause heart block. In patients with ischemic heart disease, continued use of tricyclics will increase

cardiac work and reduce heart rate variability, possibly increasing the risk of sudden death. Children younger than 12 years also appear vulnerable to the risk of sudden death during tricyclic administration, possibly because of cardiac conduction effects or reduced heart rate variability. Cardiac arrhythmia is the most common cause of death with tricyclic overdose. These cardiac safety issues, coupled with the recently reported safety of the SSRI sertraline when administered for depression following myocardial infarction (Glassman et al. 2002), indicate that the tricyclics are relatively contraindicated in patients with ischemic heart disease and that their use should be reserved for patients whose illnesses are refractory to other treatments.

Hepatic Effects Acute hepatitis has been associated with administration of imipramine (Horst et al. 1980; Moskovitz et al. 1982; Weaver et al. 1977) and desipramine (Powell et al. 1968; Price and Nelson 1983). Mild increases of liver enzymes (less than three times normal) are not uncommon and usually can be monitored safely over a period of days or weeks without apparent harmful consequences. These changes in liver enzymes do not appear to be related to drug concentrations (Price et al. 1984). Acute hepatitis is relatively uncommon but can occur. The etiology is not well established but in some cases appears to be a hypersensitivity reaction. It is characterized by very high enzyme levels (e.g., aspartate aminotransferase [AST] levels >800), which develop within days. The enzyme pattern can be either hepatocellular or cholestatic. Enzyme changes may precede clinical symptoms, especially in the hepatocellular form. If a random blood test indicates mildly elevated liver enzymes, enzyme levels can be followed for a few days. Because of the rapid rise in liver enzyme levels in acute hepatitis, that condition will become evident quickly and will be easily distinguished from mild, persistent enzyme level elevations. Acute hepatitis is a dangerous and potentially fatal condition. The antidepressant must be discontinued and should not be introduced again because the next reaction may be more severe. Unfortunately, it is not uncommon for the patient to be receiving several medications, so that the offending agent may be hard to identify. The risk of severe drug-induced hepatitis is not well established. This author has observed four cases associated with desipramine in the course of treating approximately 500 patients.

Other Side Effects Increased sweating can occur with the tricyclic compounds and occasionally can be marked. The mechanism for this symptom is unclear but may be associated with noradrenergic effects. Another side effect for which the mechanism is unclear is carbohydrate craving. This effect, when coupled with antihistaminic effects, can lead to significant weight gain. One report of outpatients treated with amitriptyline found an average gain of 7 kg during a 6-month period (Berken et al. 1984). Weight gain appears to be greater with the tertiary compounds (Fernstrom et al. 1986) and is less common with nortriptyline, desipramine, and protriptyline. Sexual dysfunction has been described with the tricyclics but generally is less common with this group than during treatment with the SSRIs. This side effect appears to be associated with the more serotonergic compounds and does occur with clomipramine. Tricyclic antidepressants can cause allergic skin rashes, which are sometimes associated with photosensitivity reactions. Various blood dyscrasias also have been reported; fortunately, these are very rare.

Overdose Because antidepressants are used for depressed patients who are at risk for overdose, the lethality of antidepressant drugs in overdose is of great concern. A tricyclic overdose of 10 times the total daily dose can be fatal (Gram 1990; Rudorfer and Robins 1982). Death most commonly occurs as a result of cardiac arrhythmia. However, seizures and central nervous system depression can occur. Although the use of tricyclics for the treatment of depression has declined, amitriptyline remains widely used for

other disorders, such as pain. The total number of deaths associated with amitriptyline is comparable to that for all other tricyclics and tetracyclics combined. Overdoses often include multiple drugs. In 2006, the American Association of Poison Control Centers (Bronstein et al. 2007) began reporting deaths based on single substance ingestions, which gives a more accurate estimate of lethality. There were 2,730 ingestions of amitriptyline, with 6 deaths, and 1,938 ingestions of all other tricyclic and tetracyclic antidepressants, with 6 deaths. By comparison, there were 19,598 ingestions of various SSRIs, with 3 deaths. The mortality rate for the cyclic antidepressants was 257 per 100,000, while the rate for the SSRIs was 15.3 per 100,000, a 17-fold difference. All of the tricyclic and tetracyclic compounds are dangerous in overdose. Desipramine appears to have a particularly high fatality rate. Amoxapine has been reported to produce high rates of seizure in overdose. But the differences among these drugs are relatively minor in comparison with the improved safety of the second-generation antidepressant agents.

Teratogenicity Although it would be ideal to discontinue all drugs during pregnancy, the patient and physician are faced with a dilemma. The risk of relapse is a serious concern in patients with recurrent depression because the risk may be increased during pregnancy or the postpartum period. This risk is particularly high for patients with a prior history of depression during or following pregnancy. The long history of tricyclic use without observation of birth defects argues for the safety of these agents. Of course, the patient must be informed of the possible risks and benefits of taking the drug and of discontinuing treatment before making a decision. If tricyclics are continued during pregnancy, dosage adjustment may be required because of metabolic changes related to the pregnancy (Altshuler and Hendrick 1996). Drug withdrawal following delivery can occur in the infant and is characterized by tachypnea, cyanosis, irritability, and poor sucking reflex. The drugs in this class should be discontinued 1 week prior to delivery if possible. The tricyclics are excreted in breast milk at concentrations similar to those in plasma. The actual quantity delivered, however, is very small, so that drug levels in the infant are usually undetectable (Rudorfer and Potter 1997).

DRUG–DRUG INTERACTIONS Pharmacodynamic Interactions Pharmacodynamic interactions are those in which the action of one drug affects the action of the other. More commonly, the effects of the two drugs are additive and result in an adverse event. Perhaps the best example is the interaction of the tricyclics with MAOI drugs. The most dangerous sequence is to give a large dose of a tricyclic to a patient who is already taking an MAOI. This can result in a sudden increase in catecholamines and a potentially fatal hypertensive reaction. These two compounds have been used together to treat patients with refractory depression (Goldberg and Thornton 1978; Schuckit et al. 1971). Treatment is begun with lower doses, and either the two compounds are started together or the tricyclic is started first. Once begun, coadministration may actually reduce the risk of tyramine reactions (Pare et al. 1985); however, because the protective effect is variable and unpredictable, the usual MAOI diet is maintained. Perhaps the most common pharmacodynamic interaction is when two psychotropic drugs are added together, resulting in increased sedation. This interaction might occur when tricyclics are combined with antipsychotic agents or with benzodiazepines. Other pharmacodynamic interactions can occur. By blocking the transporters, the tricyclics block the uptake and thus interfere with the action of guanethidine. Desipramine and the other tricyclics reduce the effect of clonidine. Quinidine is an example of a drug with a potential dynamic and kinetic interaction with tricyclics. Because the tricyclics have quinidine-like effects, the effects of tricyclics and quinidine on cardiac

conduction are potentially additive. In addition, quinidine is a potent CYP2D6 isoenzyme inhibitor that can raise tricyclic levels, further adding to the problem.

Pharmacokinetic Interactions Recently, pharmacokinetic interactions have received considerable attention. One type of pharmacokinetic interaction is enzyme inhibition. A number of drugs can block the metabolic pathways of the tricyclics, resulting in higher and potentially toxic levels. Desipramine has been of particular interest because its metabolism is fairly simple, occurring via the CYP2D6 isoenzyme. Because there are no major alternative pathways, inhibition of CYP2D6 can result in very high desipramine plasma levels, and toxicity can occur (Preskorn et al. 1990). A number of drugs inhibit 2D6. Quinidine, mentioned above, is a very potent 2D6 inhibitor. Other drugs commonly used in psychiatry that inhibit CYP2D6 include the SSRIs fluoxetine and paroxetine, duloxetine, bupropion, and some antipsychotics. Fluoxetine and paroxetine at usual doses raise desipramine levels, on average, three- to fourfold in extensive metabolizers (Preskorn et al. 1994). In slow metabolizers, enzyme inhibitors have less of an effect, because the patients are already deficient in the enzyme and the drug level is already high. In ultrarapid metabolizers, fluoxetine and paroxetine may cause a greater increase in desipramine levels, but these patients are likely to have very low initial desipramine levels. Sertraline 50 mg/day increases desipramine levels, on average, about 30%–40%, which is not a clinically meaningful difference (Preskorn et al. 1994). At higher doses, there is proportionally greater inhibition, but the increase is still substantially less than the 300%–400% increase that occurs with fluoxetine or paroxetine. The magnitude of the effect of bupropion on CYP2D6 has not been reported but appears to be clinically significant. Venlafaxine, nefazodone, mirtazapine, and citalopram appear to have minimal effects on 2D6. 2D6 inhibitors would be expected to block nortriptyline metabolism, but the magnitude of this interaction has not been well studied. Antipsychotic agents such as chlorpromazine and perphenazine also inhibit 2D6 (Gram et al. 1974; Nelson and Jatlow 1980). At usual doses, perphenazine raises desipramine levels, on average, twofold, but this effect varies with dose and with the neuroleptic employed. Haloperidol can also inhibit the CYP2D6 pathway, but in this author's experience, this effect is not likely to be clinically meaningful at low dosages (e.g.,

Chapter 14. Sertraline HISTORY AND DISCOVERY Research has implicated dysregulation of serotonin (5-HT) in mood and anxiety disorders. Despite the effectiveness of the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), which exert their effects by inhibiting the enzymatic degradation and reuptake of monoamines, respectively, side effects and potential serious adverse events limited their utility. Researchers thus identified compounds that are selective in blocking neurotransmitter reuptake and yet have little agonist and antagonist activity at receptors thought to be associated with adverse effects. Sertraline [(+)-cis-(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine], a naphthylamino compound that is structurally different from MAOIs and TCAs (Figure 14–1), is one of this class of drugs (Guthrie 1991; Heym and Koe 1988). FIGURE 14–1. Chemical structure of sertraline.

For the 12 months ending June 2006, it has been estimated that sales of sertraline (under the brand name Zoloft) in the United States exceeded $3 billion (Rancourt 2006). In August 2006, a generic formulation of sertraline became available in the United States, and within the first 2 weeks of its availability, the substitution rate exceeded 77% (Block 2006).

STRUCTURE–ACTIVITY RELATIONS Sertraline hydrochloride specifically blocks the reuptake of 5-HT in the soma and terminal regions of serotonergic neurons. The ability of sertraline to inhibit 5-HT reuptake is approximately 20-fold higher than its capacity to inhibit uptake of either norepinephrine or dopamine (DA) (Heym and Koe 1988). However, sertraline is more potent at blocking DA receptor uptake than are other selective serotonin reuptake inhibitors (SSRIs) and TCAs (Hiemke and Härtter 2000; Richelson 1994). Serotonin neurons in the midbrain raphe nuclei have inhibitory autoreceptors in both the soma (serotonin1A [5-HT1A] receptors) and terminal area (serotonin1B [5-HT1B] receptors) that are stimulated by the acute increase in 5-HT. Thus, the immediate effect of serotonin transporter (5-HTT) blockade is to increase the amount of 5-HT in axosomatic synapses and to decrease neuronal firing

(Blier 2001; Blier et al. 1990; Heym and Koe 1988). Over several weeks, these autoreceptors are desensitized and firing rates increase. Unlike the older TCAs, sertraline has little appreciable antagonistic effect on histamine1 (H1), muscarinic, or dopamine2 (D2) receptors and thus is associated with few difficulties with severe constipation, drowsiness, and dry mouth (Hiemke and Härtter 2000; Richelson 1994). The antagonism of

1-adrenoreceptors

by sertraline is at least 10-fold more than that of other SSRIs (Hiemke and

Härtter 2000), although this antagonism does not translate into clinically meaningful hypotension or reflex tachycardia. However, there is a report suggesting that sertraline decreases sympathetic nervous system activity, a property consistent with

receptor blockade (Shores et al. 2001). It is also

possible that the decrease in sympathetic response is related to stimulation of the 5-HT1A receptors noted above. Given that sertraline and other medications in its class exhibit anxiolytic effects, it is possible that the decrease in sympathetic activity is related to these effects. Sertraline is metabolized to desmethylsertraline (see section "Pharmacokinetics and Distribution" below). This compound is approximately one-tenth as active in blocking the reuptake of 5-HT; it also lacks antidepressant activity in animal models (Heym and Koe 1988).

PHARMACOLOGICAL PROFILE Among the various antidepressant agents that block the 5-HTT, sertraline is second only to paroxetine in potency for 5-HT reuptake blockade, as demonstrated in animal models (Hiemke and Härtter 2000; Owens et al. 2001; Richelson 1994). The selectivity of sertraline over norepinephrine follows that of escitalopram (Hiemke and Härtter 2000; Owens et al. 2001), although other work suggests greater selectivity for fluvoxamine than for sertraline (Richelson 1994). The relative selectivity for the 5-HTT, compared with the dopamine transporter (DAT), is lowest for sertraline (Owens et al. 2001). Sertraline exhibits inhibitory activity on several cytochrome P450 (CYP) enzymes. The ability of the compound to slightly elevate dextromethorphan and desipramine supports modest inhibition of CYP2D6 (Hiemke and Härtter 2000; Ozdemir et al. 1998; Preskorn 1996). It has little appreciable inhibition of CYP1A2, even when used at higher doses (Ozdemir et al. 1998). A very mild elevation of CYP2C9/10 substrates has been found in several studies (Preskorn 1996). Sertraline has complex effects on the CYP3A3/4 enzyme system: it initially shows slight inhibition, but it also induces this system, albeit modestly, over time (Preskorn 1996).

PHARMACOKINETICS AND DISTRIBUTION Sertraline is absorbed slowly via the gastrointestinal tract, with peak plasma levels occurring between 6 and 8 hours after ingestion (Warrington 1991). The delay in achieving peak levels may be the result of enterohepatic circulation (Hiemke and Härtter 2000; van Harten 1993). When sertraline is taken with food, the peak level decreases to about 5.5 hours ("Zoloft" 2001). The medication is more than 95% protein bound; however, because it binds weakly to 1-glycoproteins, it does not cause substantial displacement of other protein-bound drugs (Preskorn 1996). The volume of distribution (Vd) of sertraline is large in that it exceeds 20 L/kg. The distribution is larger in young females than in young males (Warrington 1991). In animal models, the concentration of sertraline is 40 times higher in brain than in plasma (Hiemke and Härtter 2000). The elimination half-life of sertraline is 26–32 hours, and steady-state levels are achieved after 7 days. Sertraline shows linear pharmacokinetics within a range of 50–200 mg/day (Warrington 1991) and does not appear to inhibit or induce its own metabolism. Peak plasma levels are somewhat lower in young males, compared with females and older males (Ronfeld et al. 1997; Warrington 1991; "Zoloft" 2001), and the elimination rate constant is higher in young males than in females or older males (0.031/hour in young males; 0.022/hour in young females and 0.019/hour in older males and females).

In children between the ages of 6 and 17 years, weight-corrected metabolism is more rapid. The maximum concentration and area under the curve (AUC) are 22% lower than in adults. Despite the greater efficiency, the smaller body mass found in children suggests that lower dosages should be used ("Zoloft" 2001). Sertraline is metabolized in the liver via oxidative metabolism; the concentration of the primary metabolite, desmethylsertraline, is up to threefold higher than that of the parent compound (Hiemke et al. 1991; Ronfeld et al. 1997; Warrington 1991). Desmethylsertraline levels are also lower in young males than in females and elderly males. The peak concentration (tmax) of desmethylsertraline is attained more quickly in young females than in young males (6 hours in young females vs. 9 hours in young males, 8 hours in older females, and 14 hours in older males) (Warrington 1991). The half-life of desmethylsertraline is 1.6–2.0 times that of the parent compound (Warrington 1991). As mentioned above, desmethylsertraline is the major metabolite of sertraline; minor metabolites include a ketone and an alcohol compound (Warrington 1991). Less than 0.2% of an oral dose of sertraline is excreted unchanged in urine, whereas approximately 50% is found in feces. The enzymes involved in metabolism of sertraline to desmethylsertraline remain unclear (Greenblatt et al. 1999). Although six different CYP enzymes have the capacity to catalyze this reaction, none accounts for more than 25% of sertraline's clearance. The contribution of each CYP enzyme is dependent on not only the protein's activity on the substrate, as evidenced through in vitro models, but also the abundance of the enzyme. Given these properties, one computer model found that the greatest contribution to the demethylation of sertraline is from 2C9 (~23%), with 3A4 and 2C19 each contributing about 15%, 2D6 adding 5%, and 2B6 contributing 2% to the process (Greenblatt et al. 1999; Lee et al. 1999). The percentages could vary in a particular individual, depending on the amount of enzyme available or enzyme inhibition that occurs. However, given that multiple CYP enzymes are involved in this metabolic process, concurrent medications with specific CYP inhibition are not likely to impair metabolism of sertraline (Greenblatt et al. 1999). Patients with liver disease experience decreased sertraline metabolism (Hiemke and Härtter 2000). For individuals with mild liver impairment, the half-life of drug may be increased threefold ("Zoloft" 2001). It is likely to be greater in patients with severe impairment, such as in those with cirrhosis. On the other hand, renal impairment does not appreciably influence the metabolism of sertraline (Hiemke and Härtter 2000).

MECHANISM OF ACTION The means by which antidepressants exert their therapeutic action is still unknown, although some of the properties noted above have been related to hypothetical mechanisms (Blier 2001; Blier et al. 1990). As previously noted, the immediate effect of sertraline is to decrease neuronal firing rates. This is followed by normalization and an increase in firing rates, as autoreceptors are desensitized. Normalization in firing coincides with the time course of patient improvement in depressive symptoms and has been theoretically linked to the mechanism of action. It has been suggested that the downregulation of autoreceptors is important in correcting the depressive disorder (Blier 2001; Blier et al. 1990). However, the activity of noradrenergic neurons is also affected. As activity in the presynaptic neuron increases, noradrenergic neurons are stimulated by postsynaptic 5-HT receptors located on noradrenergic nerve terminals. This leads to eventual downregulation of

-adrenergic

receptors, a property caused by many, but not all, antidepressant agents (Frazer and Scott 1994; Guthrie 1991). Not inconsistent with the above are more recent results suggesting that SSRI treatment decreases production of 5-HT1B messenger RNA (mRNA), the message for a regulatory autoreceptor on dorsal raphe neurons that controls the amount of 5-HT released with each impulse (Anthony et al. 2000). Again, the decrease in mRNA production coincides temporally with the time frame for SSRI therapeutic

effects.

INDICATIONS AND EFFICACY Sertraline is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder (OCD) and pediatric OCD, posttraumatic stress disorder (PTSD), panic disorder, premenstrual dysphoric disorder (PMDD), and, most recently, social anxiety disorder. Some of the pivotal studies using this compound for these indications are reviewed below.

Major Depressive Disorder The efficacy of sertraline in the treatment of MDD was established by a number of placebo-controlled trials for acute-phase therapy (Fabre et al. 1995; Opie et al. 1997; Reimherr et al. 1990). In a multicenter trial, 369 patients were randomly assigned to a fixed dose of sertraline (50 mg, 100 mg, or 200 mg daily) or placebo for 6 weeks (Fabre et al. 1995). Patients at all doses of sertraline showed approximately equivalent improvement, which was greater than placebo for most measures, including the total Hamilton Rating Scale for Depression (Ham-D) score, Beck subscale of the Ham-D, and the Clinical Global Impressions (CGI) Scale score. The combined effect size for sertraline, compared with placebo, was 0.31 (Davidson et al. 2002). Sertraline was compared with amitriptyline and placebo in a multicenter trial of 448 patients (Reimherr et al. 1990). Sertraline was dosed flexibly up to 200 mg daily, and amitriptyline was administered at dosages as high as 150 mg/day. Both active treatments were superior to placebo, as indicated by Ham-D and CGI scores; similarly, response rates (rates at which patients attained a 50% decrease in the Ham-D or a CGI score of 1 or 2) were higher with the active treatment compared with placebo. Comparisons of sertraline and amitriptyline showed superiority on the Ham-D for amitriptyline until about week 3, after which both treatments were equivalent; response rates were nonsignificantly higher in the amitriptyline group. The effect size for sertraline, compared with placebo, in this study was 0.45 (Davidson et al. 2002). A recent study sponsored by the National Institute of Mental Health (NIMH) that compared the acute-phase efficacy of Hypericum perforatum (St. John's wort), sertraline, and placebo in the acute-phase treatment of MDD had more equivocal results (Davidson et al. 2002). The study enrolled 340 patients with MDD for 8 weeks of treatment. Average patient age ranged from 40 to 43 years, and 37%–40% were male. The dosage of sertraline was flexibly titrated to 50–150 mg daily, although patients were at the highest dose for no more than 2 weeks. At study endpoint, there were no statistically significant differences in full response, defined as a CGI Scale score of score of

8. However, more patients had a partial response (CGI

2 and a Ham-D

2, 50% improvement on the Ham-D,

but not full response) in the sertraline group (26%), compared with the placebo (13%) and Hypericum (16%) groups. Sertraline was also statistically superior to both placebo and Hypericum when the CGI Scale was used as a continuous measure. The effect size for sertraline, compared with placebo, was 0.24 with the Ham-D and 0.41 with the CGI Scale (Davidson et al. 2002). The difference between sertraline and placebo may have failed to achieve significance in some tests because the sample size may have been inadequate given the effect size. In a multicenter study of 235 men and 400 women with either chronic MDD (enduring at least 2 years) or MDD superimposed on dysthymic disorder, probands were randomly assigned to 12 weeks of either sertraline or imipramine in a 2:1 ratio (Kornstein et al. 2000). Treatment was double-blind, and participants had their medication titrated to a maximum total daily dose of 200 mg of sertraline or 300 mg of imipramine. Full remission was defined as a CGI–Improvement (CGI-I) score of

2 and a

24-item Ham-D (Ham-D24) score of 17) who entered 8 weeks of acute-phase treatment with sertraline, dosed flexibly between 50 and 200 mg daily; 68% of those patients responded, and 300 patients entered double-blind, placebo-controlled maintenance therapy. After 44 weeks of maintenance treatment, 13% of sertraline-treated patients, compared with 46% of placebo-treated patients, experienced a relapse. The utility of sertraline in preventing illness recurrence has been explored using data from the chronic depression maintenance trial discussed above (Keller et al. 1999). Fifty-five percent of the acute-phase responders (378 of the total 426 patients who received sertraline) began continuation-phase treatment, and 169 patients continued to meet the criteria for remission (CGI-I score of 1 or 2 and a Ham-D score of

Chapter 15. Paroxetine PAROXETINE: INTRODUCTION Paroxetine (Paxil) is classified as one of the serotonin reuptake inhibitors (SRIs) because of its potent inhibition of presynaptic serotonin (5-HT) uptake. It is also a relatively potent norepinephrine (NE) reuptake inhibitor, particularly at higher doses, leading some to argue for its inclusion in the growing class of acknowledged dual serotonin–norepinephrine reuptake inhibitors (SNRIs). Since its approval for the treatment of depression, paroxetine has been demonstrated to be effective and has been approved for a broad spectrum of anxiety disorders, including panic disorder, obsessive-compulsive disorder (OCD), social anxiety disorder, generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD). Moreover, studies have demonstrated the efficacy of paroxetine in premenstrual dysphoric disorder (PMDD), postmenopausal hot flashes, and child and adolescent OCD and social anxiety disorder. Paroxetine is still one of the most prescribed antidepressant medications in the United States because of its proven efficacy, as demonstrated in randomized, double-blind clinical trials, and its much improved tolerability compared with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Although paroxetine shares many characteristics with other members of the SRI class, its unique pharmacological characteristics and clinical database are reviewed, with particular attention to the clinical setting.

HISTORY AND DISCOVERY The synthesis of the first SRI, fluoxetine, in 1972 marked the inception of an exciting new era of scientific and clinical innovation in the field of psychiatry (Wong et al. 1995). Prior to this discovery, psychiatrists had only a few classes of pharmacological treatments for managing depression and anxiety. These medications, including TCAs, MAOIs, and benzodiazepines, were indeed efficacious; however, they were poorly tolerated and, therefore, quite limited in usefulness. Shortly after the introduction of fluoxetine into the U.S. market in 1988, a marked increase in research led to the development of other SRIs, which ultimately proved effective in a wide array of psychiatric disorders. Paroxetine was the third SRI approved by the U.S. Food and Drug Administration (FDA) for the treatment of depression. Since then, it has also attained approval by the FDA for the treatment of all five DSM-IV-TR (American Psychiatric Association 2000) anxiety disorders: panic disorder, OCD, PTSD, social anxiety disorder, and GAD. Paroxetine is available in 10-, 20-, 30-, and 40-mg tablets and in suspension form. A controlled-release (CR) formulation is available in 12.5-, 25-, and 37.5-mg tablets. It exhibits equal or better efficacy than the paroxetine immediate-release (IR) formulation, as well as clear advantages in tolerability (Golden et al. 2002).

STRUCTURE–ACTIVITY RELATIONS AND PHARMACOLOGICAL PROFILE Paroxetine is a phenylpiperidine derivative chemically unrelated to any other antidepressant (Bourin et al. 2001) (Figure 15–1). As noted above, it has been traditionally codified with the SRI class of drugs and is indeed the most potent inhibitor of the serotonin transporter (5-HTT) within this group of compounds (Frazer 2001). By comparison, sertraline has about one-half and fluoxetine has only one-tenth the affinity of paroxetine for the human 5 HTT (Owens et al. 1997). Positron emission tomography (PET) reveals that 85%–100% of 5-HTT binding sites are occupied in the amygdala and midbrain following 20- to 40-mg daily doses of paroxetine in human subjects (Kent et al. 2002; Meyer

et al. 2001). Paroxetine-induced antagonism of the 5-HTT is prolonged following single-dose administration, and transporter binding is maintained for up to 14 days after 4 weeks of treatment in rodents, suggesting that it dissociates slowly from the 5-HTT binding site (Magnussen et al. 1982; Thomas et al. 1987). FIGURE 15–1. Chemical structure of paroxetine.

Data from both humans and rodents, using the transfected human norepinephrine transporter (NET), have revealed that paroxetine is the most potent inhibitor of the NET among drugs classified as SRIs. Despite its relatively high affinity for the NET, paroxetine has a higher affinity for the 5-HTT (Finley 1994). Ex vivo experiments in rats demonstrated a 21% and 34% inhibition of the NET within the central nervous system (CNS) at serum concentrations of 100–500 ng/mL and >500 ng/mL, respectively (Owens et al. 2000). Results from an ex vivo study of patients with depression demonstrated substantial NET antagonism at serum concentrations attained with paroxetine IR dosages of 40 mg/day and higher (Gilmor et al. 2002) (Figure 15–2). These results have recently been replicated in depressed patients in a high-dose, forced-titration protocol comparing paroxetine CR dosages of 12.5 and 75 mg/day with venlafaxine XR dosages of 75–375 mg/day. Both medications produced dose-dependent inhibition of the 5-HTT and NET. Maximal 5-HTT inhibition for paroxetine and venlafaxine was 90% and 85%, respectively, whereas maximal NET inhibition for the two drugs was 33% and 61% (Owens et al. 2008). Such data reflect the inhibitory activity of both medications at the NET and 5-HTT within the CNS. The utility of ex vivo studies is best understood with respect to bioavailability. Paroxetine, which is highly protein bound, must pass through the blood–brain barrier in order to interact with the NET and thereby contribute to the antidepressant effect of the drug (Frazer 2001). Because the ex vivo studies utilize transfected cells in tissue culture exposed to patient sera, only free drug that is not protein bound is available to interact in the NE uptake assay. These results can therefore be extrapolated to pharmacological effects in the CNS. Whether the NET antagonism observed in these ex vivo studies has clinical significance in terms of additional efficacy in comparison with drugs that solely block 5-HT reuptake will need to be further studied. FIGURE 15–2. Norepinephrine and serotonin uptake inhibition versus serum paroxetine concentration.

Standard curves for paroxetine inhibition of NE (A) and 5-HT (B) resulting from NET and 5-HTT antagonism, respectively. Note that at 100 ng/mL of paroxetine, which represents a typical therapeutic dose, there is a 15% decrease in NE uptake and a 90% decrease in 5-HT uptake. Transporter inhibition occurs in a dose-dependent manner. 5-HT = serotonin; 5-HTT = serotonin transporter; NE = norepinephrine; NET = norepinephrine transporter. Source.Gilmor et al. 2002. Paroxetine's role as a norepinephrine reuptake inhibitor (NRI) has implications for interpreting the results of head-to-head comparisons with other antidepressants. The minimal NET activity observed at more conventional doses of paroxetine necessitates that clinical trials comparing it with established SNRIs (Goldstein et al. 2004; Shelton et al. 2005) would have to employ doses much higher than 20 mg in order to be considered a valid comparison. It currently remains somewhat controversial whether the combination of 5-HTT and NET inhibition is associated with greater antidepressant efficacy (J. C. Nelson 1998; J. C. Nelson et al. 1991, 2004; Seth et al. 1992; Thase et al. 2001). Additionally, it remains to be discovered what magnitude of NE reuptake inhibition would result in increased efficacy and/or decreased latency of antidepressant effect. Paroxetine has no appreciable affinity for the dopamine transporter (DAT) or for dopamine1 (D1), dopamine2 (D2), serotonin1A (5-HT1A), serotonin2A (5-HT2A),

1-

and

2-adrenergic,

and histamine1

(H1) receptors, indicating that it is a relatively "clean" drug, particularly when compared with the older generation of antidepressants, such as TCAs and MAOIs (Hyttel 1994; Owens et al. 1997). It is distinguished from sertraline by its high affinity for the NET and low affinity for the DAT. Sertraline, in contrast, has a very high affinity for the DAT but no affinity for the NET (Tulloch and Johnson 1992). The affinity of paroxetine for the muscarinic cholinergic receptor is approximately 22 nmol, which is

similar to that of desipramine, though paroxetine is used in lower doses than desipramine and is therefore less anticholinergic than this TCA. However, this property may account for its mild anticholinergic side effects, including dry mouth, blurry vision, and constipation (Owens et al. 1997). However, compared with nortriptyline, paroxetine has virtually no measurable anticholinergic activity in geriatric patients treated for depression (Pollock et al. 1998). Table 15–1 shows a comparison of paroxetine and other available antidepressants in terms of their affinity for various neurotransmitter receptors and monoamine transporters. TABLE 15–1. Inhibition constants (Ki, nmol/L) of various antidepressants for various transporters and receptors in human and animal cells Compound

5-HTTa

NETa

H1b

Paroxetine

0.07

85

>10,000

1,000

4,000

42

Sertraline

0.15

800

5,000

36

470

230

Fluoxetine

1

800

1,000

1,300

3,000

500

Venlafaxine

7.5

2,300

>10,000

>10,000

>100,000

>10,000

Desipramine

22

0.63

30

23

1,400

37

Nefazodone

450

600

30

6

85

4,500

Citalopram

16.2

>10,000

300

>10,000

>10,000

>10,000

Escitalopram

6.6

>10,000

1,500

>10,000

>10,000

>10,000

1

a

2

a

Muscarinicc

Note. 5-HTT = serotonin transporter; NET = norepinephrine transporter. a

Human cortex.

b

Guinea pig brain.

c

Rat cortex.

PHARMACOKINETICS AND DISPOSITION Paroxetine is well absorbed from the alimentary tract, and absorption is not affected by the presence or absence of food (Kaye et al. 1989). Being a highly lipophilic compound, paroxetine is readily distributed into peripheral tissues and exhibits a high volume of distribution, ranging from 3.1 to 28 L/kg (Kaye et al. 1989). Once absorbed, paroxetine is reportedly 95% bound to serum proteins (Kaye et al. 1989), though we have observed protein binding of 85% in our studies (M. J. Owens and C. B. Nemeroff, unpublished observations, June 1997). Oral bioavailability is affected by extensive first-pass metabolism, which is carried out by a high-affinity, low-capacity hepatic enzyme system (Lane 1996). With serial dosing, bioavailability increases as this metabolic system becomes saturated and a larger proportion of parent compound enters the systemic circulation (Kaye et al. 1989). Steady-state concentrations of paroxetine, following oral dosing, exhibit wide intersubject variability (Sindrup et al. 1992a). Following 30 days of daily administration of 30 mg of paroxetine, steady-state plasma concentrations ranged from 8.6 to 105 ng/mL (Kaye et al. 1989). Such variability has been considered inconsequential because a consistent relationship between paroxetine levels and clinical response or adverse outcome has not been found (see Tasker et al. 1989). However, higher plasma concentrations are associated with a greater magnitude of both 5 HTT and NET inhibition (Gilmor et al. 2002). Strong in vivo and in vitro evidence points to the hepatic cytochrome P450 (CYP) 2D6 enzyme system as the rate-limiting mechanism in the metabolism of paroxetine (Crewe et al. 1992; Sindrup et al. 1992a). Genetic studies have demonstrated up to 40 polymorphisms of the 2D6 enzyme, which likely explain, at least in part, the wide-ranging differences in pharmacokinetic parameters observed among individuals (Lane 1996). Phenotypically, individual probands can be categorized as poor, extensive, or

ultrarapid metabolizers and will have very high, low, or very low serum paroxetine concentrations, respectively (Charlier et al. 2003). Patients with negligible or diminished 2D6 activity are poor metabolizers of paroxetine and other 2D6-dependent substrates and are thought to use alternative enzyme systems (Gunasekara et al. 1998; Lane 1996). The 2D6 enzyme system is believed to be primarily responsible for the initial step in the metabolism of paroxetine in extensive and ultrarapid metabolizers, carrying out oxidation of the methylenedioxy bridge. The resulting unstable catechol intermediate is methylated and subsequently conjugated into polar compounds by the addition of a glucuronide or sulfate moiety and is then excreted into urine and feces (Haddock et al. 1989). These conjugated entities are the major circulating metabolites of paroxetine; however, unlike the metabolites of other SRIs, such as fluoxetine or sertraline, they exhibit minimal in vitro monoamine uptake inhibition and likely do not contribute any therapeutic activity (DeVane 1992; Haddock et al. 1989). Paroxetine is the most potent inhibitor of the 2D6 enzyme system of all of the SRIs (Ki = 0.15 M) (Crewe et al. 1992; Nemeroff et al. 1996). Studies in healthy volunteers show that the drug continues to cause meaningful inhibition of 2D6 up to 5 days postdiscontinuation (Liston et al. 2002). As both a substrate for and an inhibitor of its own metabolism, paroxetine has a nonlinear pharmacokinetic profile, such that higher doses produce disproportionately greater plasma drug concentrations as the enzyme becomes saturated and, therefore, less available for metabolic activity (Preskorn 1993). Peak plasma concentration is attained in approximately 5 hours, and plasma steady-state concentration is achieved within 4–14 days, following oral administration of paroxetine IR (Kaye et al. 1989). The terminal half-life (t½) of the parent compound is approximately 1 day and increases at higher doses, consequent to autoinhibition of 2D6 (Preskorn 1993). The pharmacokinetic properties of paroxetine appear to be affected by age. Bayer et al. (1989) reported a threefold increase in maximum plasma concentration in elderly subjects, compared with younger subjects, following a single dose of paroxetine. Furthermore, t½ in the elderly subgroup was extended by nearly 100%. Although there was significant overlap in both pharmacokinetic parameters between the age groups studied, the clinical principle of "start low and go slow" regarding medication treatment in older patients applies to paroxetine. Patients with renal and hepatic insufficiency are often subject to alterations in metabolism and clearance of drugs, compared with healthy subjects. In individuals with renal impairment, both half-life and maximum plasma levels of paroxetine have been shown to increase relative to the extent of renal disease (Doyle et al. 1989). In a single-dose study, no significant difference was observed in pharmacokinetic outcomes in patients with cirrhosis of the liver, compared with healthy volunteers (Krastev et al. 1989); however, subsequent data revealed considerable elevations in steady-state concentration and t½ of paroxetine following 14 days of administration of paroxetine in individuals with severe liver disease (Dalhoff et al. 1991). Accordingly, patients with substantial renal or hepatic dysfunction should initially be treated with a lower dose of paroxetine than is generally recommended to avoid potential side effects associated with unusually high plasma paroxetine levels. Paroxetine CR was designed to slow absorption and delay the release of paroxetine until after the tablet has passed the stomach. The dissolution rate of paroxetine CR after single dosing is about 4–5 hours. It is completely absorbed and otherwise exhibits the same pharmacokinetic parameters with regard to t½ and nonlinearity as the IR formulation. Following absorption, paroxetine CR is extensively distributed and highly protein bound. Paroxetine CR causes increased plasma concentrations of paroxetine in patients with renal and hepatic dysfunction, and lower doses are therefore recommended for these patients (Paxil CR 2002). Paroxetine mesylate is a generic formulation of the compound in which a methanesulfonic acid moiety is attached to the compound during the salification process instead of the hydrochloric acid used in paroxetine hydrochloride. It is currently available in some European countries including Holland and

Denmark. Although currently there are no studies available comparing its efficacy or bioequivalence to paroxetine hydrochloride, there are several published case reports indicating problems of efficacy and tolerability in patients switched from paroxetine hydrochloride to paroxetine mesylate (Borgherini 2003) and this warrants further investigation.

PHARMACOGENOMICS The subject of pharmacogenomics has been of increasing interest to researchers and clinicians in all branches of contemporary medicine, including psychiatry. Inquiries into this field have been undertaken to gain a better understanding of the mechanisms by which variation between individuals occurs in clinical response to psychopharmacological treatment. Although pharmacogenetic principles are covered more thoroughly elsewhere in this text (see Chapter 3, "Genetics and Genomics"), here we will briefly focus on some of the recent work as applied to paroxetine. Specific attention will be paid to aspects of drug–gene interactions that affect tolerance and efficacy. As previously described in this chapter, paroxetine's primary mode of action is likely mediated by its binding to the serotonin transporter (5-HTT). A well-known polymorphism (5-HT transporter gene–linked polymorphic region [5-HTTLPR]) has been located in the promoter region of the gene (SLC6A4) that encodes 5-HTT, resulting in two alleles referred to as "long" and "short." It has been proposed that this polymorphism might be a pharmacogenetic marker for antidepressant efficacy with some evidence that the short form, or S allele, results in reduced efficacy to SRI medications, including paroxetine (Zanardi et al. 2000). This finding was replicated in a study that included severity of drug-induced adverse events, dosing compliance indices, and discontinuations due to adverse events as main outcome measures in elderly depressed patients treated with paroxetine. The data revealed that subjects carrying the S allele experienced more severe adverse events, achieved lower final daily doses, and had more discontinuations during the course of the study. When, however, these subjects reached doses comparable with those of the homozygous L/L sample, efficacy measures were quite similar, albeit slower to exert maximal benefit, indicating that the main effect of the S allele was on the tolerability of paroxetine rather than its efficacy (G. M. Murphy et al. 2004). In the only known head-to-head comparison of paroxetine and another SRI, in regard to the 5-HTTLPR polymorphism, a sample of 81 depressed Japanese patients were treated with either paroxetine or fluvoxamine. The results showed that although both drugs had similar efficacy in L-carrying probands, S/S homozygotes responded significantly better to paroxetine (Kato et al. 2005). Another intriguing locus that has been studied as a possible genetic marker for antidepressant efficacy is the 102 T/C single-nucleotide polymorphism (SNP) in the serotonin2A (5-HT2A) gene (5HTR2A). A second study, using the same patient sample and the same outcome measures as those of G. M. Murphy et al. (2004), was used to evaluate the role of the 102 T/C SNP in medication intolerance. Survival analysis showed a more or less linear relationship between the number of C alleles and the odds of patients discontinuing paroxetine therapy due to untoward effects (G. M. Murphy et al. 2003). Of note, when these investigators similarly studied the effect of genetic polymorphisms at the hepatic CYP2D6 gene, of which there are 40 known alleles, no signal could be detected with regard to tolerance or efficacy of paroxetine. The authors conclude that pharmacodynamic differences among patients, particularly at the 5HTR2A site, appear to have a greater impact on paroxetine tolerability than pharmacokinetic variables.

MECHANISM OF ACTION Despite almost four decades of intensive investigation directed at understanding the pathogenesis and pathophysiology of depression and related psychiatric disorders and the precise mechanism(s) of the therapeutic action of antidepressants, the answers to these questions remain elusive. Early theorists suggested a causal association between an aberration in synaptic monoamine neurotransmitter concentrations and depression, based largely on the precipitation of depressive

symptoms in a significant number of individuals treated with the antihypertensive agent reserpine, a monoamine-depleting drug (Goodwin and Bunney 1971). The once-celebrated "monoamine hypothesis of depression" provided the theoretical framework for the development and investigation of successive generations of antidepressants. This hypothesis, although seminal, has since been challenged as being too simplistic to explain either the pathophysiological underpinnings of depression or the mechanisms of action of antidepressants (Duman et al. 1997; Ressler and Nemeroff 2000). Antidepressants that effectively increase monoamine neurotransmitter concentrations in the synapse, such as MAOIs, TCAs, SRIs, and SNRIs, clearly implicate the serotonergic and noradrenergic neuronal systems as targets of action of these drugs; however, drug binding to a specific receptor or transporter and consequent manipulation of its affiliated neural circuitry do not necessarily equate to the ultimate mechanism of action of a pharmacological agent (Dubovsky 1994). Although our understanding of antidepressant pharmacology and the biology of depression has grown exponentially, the relationship between the evident pharmacodynamic actions of antidepressants and their well-documented therapeutic effects remains relatively obscure. Paroxetine and all of the other SRIs cause immediate elevations in extracellular fluid 5-HT concentrations in serotonergic synapses, resulting from the decreased 5-HT clearance associated with 5-HTT inhibition (Wagstaff et al. 2002). Blier et al. (1990) demonstrated that administration of paroxetine initially causes a paradoxical decrease in 5-HT neurotransmission, likely caused by activation of a negative feedback system mediated by increased 5-HT binding to the 5-HT1A autoreceptor and subsequent diminution in serotonergic neural activity. After 2 weeks of paroxetine treatment, a desensitization of the 5-HT1A autoreceptors occurs and is associated with an increase in serotonergic neurotransmission (Chaput et al. 1991). The delayed changes in 5-HT1A receptor sensitivity and 5-HT neurotransmission seen after long-term paroxetine administration are temporally associated with clinical improvement, hinting at a possible mechanistic link. These and related findings led to the study of pindolol, a nonselective

-adrenergic receptor

antagonist/5-HT1A antagonist, as a novel approach to accelerate the therapeutic response to SRIs, as well as to convert SRI nonresponders to responders. Preclinical studies revealed greater and more persistent increases in extracellular 5-HT concentrations after treatment with pindolol and an SRI than after treatment with an SRI alone (Dreshfield et al. 1996; Hjorth 1993; Sharp et al. 1997). This observation, coupled with the hypothesis that blockade of the presynaptic 5-HT1A autoreceptor might serve to avert the initial reduction in serotonergic transmission induced by SRI treatment, suggested that the combination of pindolol and paroxetine might produce a more rapid and more robust clinical response (Perez et al. 1999). Results from open studies supported both hypotheses (Artigas et al. 1994; Blier and Bergeron 1995). Double-blind, placebo-controlled trials also indicated that the addition of pindolol (2.5–5 mg three times a day) to paroxetine in the early phase of treatment for major depression might decrease latency to clinical improvement. However, the augmentation of clinical efficacy with pindolol was not compelling, especially in individuals refractory to monotherapy with paroxetine (Bordet et al. 1998; Perez et al. 1999; Tome et al. 1997; Zanardi et al. 1997). Currently, the available data do not support the use of pindolol to accelerate or augment the efficacy of paroxetine or other SRIs. To be fair, at the doses of pindolol used, PET imaging revealed that only a relatively low percentage of 5-HT1A binding sites were occupied; therefore, the studies should be repeated with adequate doses of pindolol or another 5-HT1A autoreceptor antagonist (Martinez et al. 2000). Consistent with the potency of paroxetine in blocking NE reuptake are reports that it increases NE concentrations in extracellular fluid, as demonstrated by microdialysis techniques (Hajos-Korcsok et al. 2000). Although not studied extensively, chronic treatment with paroxetine, unlike TCAs such as desipramine, does not produce downregulation of postsynaptic cerebral cortex and hippocampus (Duman et al. 1997).

-adrenergic receptor binding sites in

While 5-HT and

-adrenergic receptor adaptation remains an attractive area of research, attention has

increasingly been focused on postreceptor intracellular signal transduction changes observed after long-term antidepressant treatment. Chronic administration of antidepressants has been shown to activate second-messenger systems, such as cyclic adenosine monophosphate (cAMP) and tyrosine kinase B, associated with hippocampal neurons (Duman 1998). Data derived from postmortem human brain tissue studies suggest increased levels of brain-derived neurotrophic factor (BDNF) within the hippocampus of subjects with depression who had been treated with antidepressants, compared with control subjects with depression who had been nonmedicated (Chen et al. 2001). It has been suggested that neuronal injury mediated by stress-related illnesses, such as depression and anxiety, may be reversed by antidepressant-induced increases in BDNF expression in the CNS posited to contribute to clinical response (Duman 1998). Antidepressants from diverse classes, including SRIs, have all been shown to increase the rate of neurogenesis in the hippocampus of adult animals (Duman et al. 2001). A recent boon to the study of antidepressant effect has been the development and fine-tuning of techniques in the field of functional brain imaging. One study compared the modulation of corticallimbic systems in depressed patients who were treated with either paroxetine or cognitive-behavioral therapy (CBT) (Mayberg et al. 2004). PET was used to obtain images serially during the course of treatment and revealed interesting distinctions in brain activity in response to the two treatment modalities. Paroxetine responders experienced significant increases in prefrontal cortical activity in the setting of decreases in hippocampal and subgenual cingulate processing. This is in marked contrast to treatment-emergent changes seen in the CBT group in which patients developed increases in hippocampal and dorsal cingulate metabolism subsequent to subtle decreases in dorsal, ventral, and medial frontal cortical processing. The implication is that antidepressant therapy seems to entail a "bottom up" approach distinguishable from the "top down" effect seen with CBT. These results may help explain why combination treatment with antidepressants and various psychotherapies consistently outperforms monotherapy, particularly in moderate to severe depression. Another major advance in the study of antidepressant action has been the link between paroxetine and the corticotropin-releasing factor (CRF)/hypothalamic-pituitary-adrenal (HPA) axis. It is well established that a sizeable percentage of patients with depression exhibit HPA axis hyperactivity and hypersecretion of CRF from hypothalamic and extrahypothalamic circuits (Heim and Nemeroff 1999). Early life stress, as exemplified by maternal separation, is associated with profound hyperactivity of the HPA axis and increased CRF messenger RNA (mRNA) expression (Nemeroff 1996; Newport et al. 2002). In adult animals, these effects are reversed by chronic, but not acute, paroxetine treatment. Thus, paroxetine exerts multiple effects on neurotransmitter systems implicated in the pathophysiology of mood and anxiety disorders, including 5-HT, NE, and CRF.

INDICATIONS AND EFFICACY Depression Comparison With Other Agents Tricyclic and tetracyclic antidepressants The efficacy of paroxetine in major depression has been established in several randomized, placebocontrolled studies, as well as in studies comparing the effects of paroxetine with those of active comparators, including fluoxetine, TCAs, and other agents. The preponderance of early data with paroxetine in establishing efficacy in depression was in comparison trials with TCAs, particularly imipramine and amitriptyline, and placebo. The earliest placebo-controlled trials used 10–50 mg of paroxetine and were 6 weeks in duration. Outcome variables typically used were the Hamilton Rating Scale for Depression (Ham-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the

Clinical Global Impressions (CGI) Scale. These trials demonstrated the clear superiority of paroxetine over placebo in the treatment of major depression (Claghorn et al. 1992; Kiev 1992; Rickels et al. 1989; Smith and Glaudin 1992). A meta-analysis by Montgomery (2001) compared the efficacy and tolerability of paroxetine with those of TCAs, including amitriptyline, imipramine, clomipramine, doxepin, and nortriptyline, and the tetracyclic antidepressants mianserin and maprotiline. Studies included in the meta-analysis were randomized, double-blind, and parallel-group in design; were 6 weeks or less in duration; and employed the Ham-D as the primary outcome measure. Results from the pooled data of 3,758 hospitalized and ambulatory patients from 39 studies showed no overall significant difference in antidepressant response rates between paroxetine and TCAs or tetracyclics, based on a 50% reduction in the Ham-D total score or in remission rates, defined as an endpoint Ham-D score of

8.

Clearly, paroxetine is better tolerated than the TCAs and related heterocyclic antidepressants in terms of lower rates of discontinuation attributed to adverse events. In addition, paroxetine had a greater effect on concomitant anxiety associated with depression, compared with all other studied medications, except clomipramine, which was equally efficacious with regard to anxiolysis. Despite the overwhelming evidence supporting the equivalent antidepressant efficacy of paroxetine and TCAs, one notable exception exists. The Danish University Antidepressant Group (1990) conducted a multicenter double-blind, placebo-controlled, fixed-dose investigation comparing efficacy and tolerability of paroxetine (30 mg/day) with clomipramine (150 mg/day) and found nonresponder rates to be significantly greater in the paroxetine group. Whereas most of the data supporting the clinical superiority of paroxetine are derived from outpatient studies, the Danish University Antidepressant Group (1990) study comprised only inpatients. These data appear to argue for relative greater efficacy of clomipramine in severe depression; however, two notable confounds exist here. First, higher dosages of paroxetine (e.g., 50–60 mg/day) might well show equivalent efficacy with clomipramine, especially in view of the NET findings described above. Second, Ham-D scores reported in this study were no more severe than those in the outpatient trials, making it difficult to draw any conclusions regarding relative superiority of clomipramine based on severity of depression. All other published studies comparing paroxetine with clomipramine have shown no difference in efficacy in outpatients with depression; paroxetine is, of course, uniformly better tolerated (Guillibert et al. 1989; Pelicier and Schaeffer 1993; Ravindran et al. 1997).

Other SRIs Because the SRIs, as a class, have become the first-line pharmacological agents in the treatment of depression and a number of anxiety disorders, the results of a large number of studies, mostly sponsored by the pharmaceutical industry, are available. To date, fluoxetine, fluvoxamine, and sertraline have been compared with paroxetine in the treatment of major depression. In addition, given the favorable response of SRIs in several anxiety disorders, clinical trials have compared the clinical ameliorative effects of paroxetine with those of other SRIs on anxiety symptoms associated with depression. De Wilde et al. (1993) found, at various time points during the trial, statistically significant advantages of paroxetine (20–40 mg/day) over fluoxetine (20–60 mg/day) in total Ham-D score and anxiety subscore. However, by the end of the 6-week study, there was no difference noted in any outcome variable. Geretsegger et al. (1994) studied a group of geriatric patients with severe depression (n = 106) and found a significantly greater proportion of patients treated with paroxetine (20–40 mg/day) than fluoxetine (20–60 mg/day) to have a 50% reduction in total Ham-D and MADRS scores by the end of the study; however, no difference was observed in terms of response based on the CGI Scale or between-group differences in MADRS or Ham-D at the termination of the study. Other studies have found paroxetine and fluoxetine to be equally effective in the treatment of major depression and associated anxiety (Chouinard et al. 1999; Fava et al. 1998, 2000; Tignol 1993).

Similar results have been observed in trials comparing paroxetine and sertraline. Zanardi et al. (1996) studied a small group (n = 46) of hospitalized patients with psychotic depression and found rates of response to both medications among study completers to be comparable. The intent-to-treat analysis in this trial revealed sertraline (150 mg/day) to be more effective than paroxetine (50 mg/day). The authors suggested that the difference might be attributable to the disproportionately high dropout rate (41%) in the paroxetine group, likely caused by the rapid paroxetine dose titration, compared with the dropout rate in the sertraline group. In the only published study comparing paroxetine and sertraline in a 6-month trial, the two medications had similar antidepressant efficacy and similar ratings on quality-of-life measures (Aberg-Wistedt et al. 2000). Kiev and Feiger (1997) reported that paroxetine (20–50 mg/day) and fluvoxamine (50–150 mg/day) had equivalent efficacy in the treatment of depression.

Other agents Paroxetine has also been compared with nefazodone, mirtazapine, bupropion, moclobemide, duloxetine, venlafaxine, and investigational agents such as substance P (neurokinin 1 [NK1]) antagonists in the treatment of depression. Nefazodone (200–600 mg/day) and paroxetine (20–40 mg/day) were shown to possess similar efficacy and tolerability in an 8-week randomized, double-blind trial of 206 outpatients with moderate to severe depression (Baldwin et al. 1996). In this study, 42.3% of patients in the paroxetine-treated group and 39.7% of patients in the nefazodonetreated group achieved 50% reduction in the Ham-D intent-to-treat analysis. Furthermore, both groups had similar significant reductions in associated anxiety. In a study comparing paroxetine (20–40 mg/day) and mirtazapine (15–45 mg/day) in 275 outpatients with major depression, both medications fared equally well in terms of efficacy and tolerability (Benkert et al. 2000). There was evidence of a slightly faster onset of action with mirtazapine, as determined by significant reductions in the 17-item Ham-D and Hamilton Anxiety Scale (Ham-A) scores by week 1 of the study, compared with paroxetine. A recent randomized open trial was conducted in Italy comparing paroxetine with moclobemide, a reversible MAOI widely prescribed in Europe for the treatment of depression (Pini et al. 2003). The results suggested greater efficacy for paroxetine in the treatment of major depressive disorder with comorbid panic disorder; however, these data are limited by lack of double-blinding. The SNRI venlafaxine was compared with paroxetine in a population of hospitalized and ambulatory patients with treatment resistance to two or more antidepressants (Poirier and Boyer 1999). Venlafaxine (200–300 mg/day) was superior to paroxetine (30–40 mg/day) in bringing treatmentrefractory patients into remission, defined as total Ham-D score of

10 at study end (37% vs. 18%,

respectively). It should be noted that this definition of remission departs from the customary criterion of Ham-D total score

7 and that the study period was rather short (4 weeks), limiting comparison

with data from longer-term parallel-group studies with a more standard definition of remission. In the meta-analysis of the venlafaxine worldwide database, in which venlafaxine showed a slight statistically significant advantage in efficacy over SRIs as a class, there was no such difference demonstrated between venlafaxine and paroxetine (Nemeroff et al. 2003). A more recent comparison between venlafaxine XR and paroxetine demonstrated higher rates of remission with venlafaxine in the maintenance treatment of depression (Shelton et al. 2005). An important caveat in interpreting these results is that the doses of paroxetine used never exceeded 20 mg/day and are therefore indicative of only minimal NE reuptake antagonism. Similarly, a study comparing paroxetine with the SNRI duloxetine (40–80 mg/day) revealed higher probability of remission with duloxetine 80 mg/day than with paroxetine (57% and 34%, respectively) (Goldstein et al. 2004). Again, paroxetine was administered to test subjects at the "selective" serotonergic dose of 20 mg/day, too low to exhibit true SNRI activity.

Paroxetine has also been compared with investigational agents such as substance P (NK1) receptor antagonists. In the Merck-sponsored NK1 receptor antagonist trials in major depression, paroxetine 20 mg/day was superior to both placebo and the putative novel agent (Cutler et al. 2000).

Depression in the Elderly Geriatric depression deserves special attention because it is a particularly common, debilitating, and potentially life-threatening disorder (see Weihs et al. 2000). A large number of studies have been conducted with a variety of medications, particularly TCAs and SRIs, in geriatric patients with depression. SRIs are currently the treatment of choice in this population because of their demonstrated efficacy and their relative safety over TCAs and MAOIs. Paroxetine has been shown to be effective in treating individuals with late-life depression in a number of parallel-group trials. Hutchinson et al. (1992) reported that paroxetine (20–30 mg/day) and amitriptyline (50–100 mg/day) were equally effective in a 6-week trial, as determined by similar rates of response and a somewhat faster onset of action for paroxetine. Another study comparing paroxetine (20–30 mg/day) and amitriptyline (50–150 mg/day) yielded similar results, although the time to response was identical between the two agents (Geretsegger et al. 1995). Clomipramine (75 mg/day) and paroxetine (30 mg/day) were equally effective in patients (ages 60 years) with depression, as determined by a change in Ham-D and Widlocher Scale scores (Guillibert et al. 1989). Although dropout rates secondary to adverse events were similar, CNS and anticholinergic side effects, not surprisingly, were more frequent in the clomipramine group (41% vs. 18%). Mulsant et al. (1999) reported similar response rates for nortriptyline (mean dosage = 51.4 mg/day) and paroxetine (mean dosage = 23 mg/day) in 80 geriatric patients with depression. The two drug groups had comparable dropout rates. In view of evidence that elderly patients with depression are more likely to experience earlier relapses than nonelderly depressed patients following successful treatment (Zis et al. 1980), Bump et al. (2001) conducted a study, funded by the National Institute of Mental Health (NIMH), that compared paroxetine (10–40 mg/day) and nortriptyline (20–125 mg/day) in an 18-month, open-label continuation and maintenance trial. No significant differences in rates of relapse (15% for paroxetine and 9.5% for nortriptyline) or time to relapse (60.3 weeks for paroxetine and 58.8 weeks for nortriptyline) were noted. Maintenance efficacy was likewise investigated by Reynolds et al. (2006) using monthly interpersonal psychotherapy (IPT) as a comparator. Patients 70 years or older with major depression who responded to combined treatment with paroxetine and IPT were significantly less likely to have recurrent depression if they received 2 years of maintenance paroxetine compared with placebo. Conversely, maintenance psychotherapy in the absence of drug was ineffective in preventing recurrence. The researchers concluded that the number needed to treat with paroxetine to prevent 1 recurrence was 4 (95% confidence interval [CI] = 2.3–10.9). In a study by Schöne and Ludwig (1993), paroxetine (20–40 mg/day) was superior in efficacy to fluoxetine (20–60 mg/day) in elderly patients using response rates ( 50% reduction in Ham-D score) as the measure of improvement. Improvements in cognitive function, as measured by the Sandoz Clinical Assessment Geriatric (SCAG) Scale, were similar in both groups at the end of 6 weeks; however, there appeared to be a more rapid response with paroxetine (Gunasekara et al. 1998). A subsequent trial also found paroxetine to be more effective in improving cognitive function at early time points and by study end (Geretsegger et al. 1994). In both studies, paroxetine and fluoxetine were shown to be well tolerated. Weihs et al. (2000) compared paroxetine (10–40 mg/day) and bupropion sustained-release (SR) (100–300 mg/day) in 100 elderly patients with major depression and found similar improvements in all outcomes and comparably low discontinuation rates secondary to adverse events by study end. One element of concern in treating the frail elderly with paroxetine is the fear of possible anticholinergic side effects. This population is, of course, susceptible to cognitive decline caused by

muscarinic antagonist drugs, which can, in some cases, lead to frank delirium. This concern was formally tested in a study of paroxetine effects on mood and cognition in depressed elderly patients without dementia using fluoxetine as a comparator because of the latter drug's minimal anticholinergic activity (Cassano et al. 2002). The results revealed that paroxetine did not cause cognitive decline but rather produced marked improvement on neuropsychological test scores in depressed elderly patients.

Long-Term Treatment It is now well recognized that because unipolar depression is often a chronic and recurrent disorder, the prevention of recurrence should be a primary aim. Although there are considerable data supporting the efficacy of paroxetine in short-term trials, only a handful of studies have evaluated its effectiveness in maintaining remission following an acute episode of depression over an extended period. In a large multicenter open-label trial, Duboff (1993) treated 433 patients with paroxetine (mean dose = 32.9 mg) for 54 weeks. Subjects had moderate to severe depression (mean 17-item Ham-D baseline score = 27.9), and most subjects (81%) had a history of depressive episodes. Approximately two-thirds of the subjects were judged responders (Ham-D score

8) at 54 weeks. Nineteen percent

of the subjects suffered a relapse (Ham-D score 18 at some time point), and 30% withdrew from the study because of adverse events. A 3-year extension study of 110 patients demonstrated the continued antidepressant effects of paroxetine. Montgomery and Dunbar (1993) studied 172 patients with major depression who had had two or more previous depressive episodes in an 8-week open-label trial with paroxetine (20–40 mg/day), followed by a double-blind, placebo-controlled 1-year extension phase for the acute-treatment responders. The authors reported significantly higher rates of relapse in placebo recipients (43%), compared with paroxetine-treated patients (16%). Claghorn and Feighner (1993) compared paroxetine (10–50 mg/day), imipramine (65–275 mg/day), and placebo in 717 patients with major depression. Similar rates of response among all three groups were noted after 1 year, following a blinded 6-week acute course of therapy. However, more placebotreated patients withdrew from the long-term trial because of lack of efficacy (22%) than did those treated with paroxetine (12%) or imipramine (4%). Moreover, 25% of the placebo group relapsed, compared with 15% of the paroxetine group and 4% of the imipramine group. A substantially greater percentage of patients in the imipramine group (35%) withdrew from the study because of adverse events than in the group receiving paroxetine (15%) or placebo (9%). In all three studies cited above, the paroxetine doses used in the long-term phases were those typically used in the acute studies (20–40 mg). Thus, for maintenance therapy for depression, the recommended dose of paroxetine is the dose that was effective during the acute phase. In most patients with an acute major depressive episode, an initial daily dose of 20 mg is usually sufficient for the duration of the illness episode, at least using response as an endpoint (Dunner and Dunbar 1992). However, to improve the likelihood of remission, we recommend increasing the dosage in 10-mg increments per week—up to 50 mg/day or more of the IR form and up to 75 mg/day of the CR form (Nemeroff 1993). Elderly patients and those with renal and hepatic dysfunction should be initiated at a lower dose, with gradual dose titration to therapeutic effect, while monitoring for side effects.

Bipolar Depression Patients with bipolar disorder present significant clinical challenges, not the least of which are episodes of bipolar depression; nearly 50% of such patients are unresponsive to the antidepressant effects of lithium alone (Sachs 1996). This is a particularly difficult clinical problem because

antidepressants may precipitate manic episodes in patients with bipolar disorder. Two paroxetine studies have demonstrated the efficacy and safety of this SRI in treating patients with this often treatment-refractory disorder. In one study with lithium-treated patients, Bauer et al. (1999) found paroxetine (20–40 mg/day) to be superior to amitriptyline (75–150 mg/day), on the basis of the Ham-D and CGI–Severity of Illness (CGI-S) scores, although relatively low doses of amitriptyline were used in the 6-week study. In a multicenter double-blind, placebo-controlled comparison trial, Nemeroff et al. (2001) found no difference in response rates among paroxetine (20–50 mg/day), imipramine (150–300 mg/day), and placebo in patients stabilized on a regimen of lithium in a 10-week trial; however, both antidepressants were superior to placebo in treating patients with bipolar disorder with serum lithium concentrations

0.8 mEq/L. A study of 27 patients with

bipolar I and II disorders receiving a mood stabilizer (lithium or divalproex) at the time of the study evaluated the addition of a second mood stabilizer or paroxetine for the treatment of depression (Young et al. 2000). Both treatment conditions were found to be effective, although patients in the mood stabilizer plus paroxetine group experienced fewer side effects and were more likely to complete the study. Sachs et al. (2007) did not find any difference between paroxetine (10–40 mg/day), bupropion SR (150–375 mg/day), and placebo in a 26-week placebo-controlled study of antidepressant augmentation of mood stabilizer therapy in 366 patients with bipolar depression. Paroxetine was not associated with an increased rate of switch into mania or hypomania in any of these studies.

Depression Associated With Medical Illness It has been increasingly recognized that depression frequently occurs as a "co-traveler" with a number of medical conditions, and paroxetine has been studied and found to be efficacious in several of these disorders, including rheumatoid arthritis, irritable bowel syndrome, and, most recently, interferon- -induced depression in malignant melanoma patients (Bird and Broggini 2000; Masand et al. 2001; Musselman et al. 2001). The Musselman et al. (2001) study is a true landmark in the field, because it demonstrated, for the first time, the prevention of an induced depression by pretreatment with paroxetine (Figure 15–3). The association between ischemic heart disease (IHD) and depression has also been extensively studied. Individuals with IHD have a greater risk than the general population for developing depression, and patients with depression are more likely to develop IHD and cerebrovascular disease than are individuals without depression (Anda et al. 1993; Frasure-Smith et al. 1993; J. M. Murphy et al. 1987; Musselman et al. 2007; Simonsick et al. 1995). FIGURE 15–3. Paroxetine effect on interferon-

(IFN- )–induced depression.

Kaplan-Meier analysis of the percentage of patients in the placebo and paroxetine groups who were free of major depression (A) and of severe depression, requiring the discontinuation of IFN- (B). Source.Musselman et al. 2000. Increased platelet reactivity has been observed in individuals with depression, which may explain the increased vulnerability to IHD in this population (Musselman et al. 1996). One study demonstrated normalization of platelet activity in patients with depression, following 6 weeks of treatment with paroxetine 20 mg/day (Musselman et al. 2000). It is unclear whether the antidepressant action of paroxetine or a direct pharmacological effect of the drug on platelet activity resulted in the observed outcome, but the preponderance of evidence with other SRIs supports the latter hypothesis (Serebruany et al. 2003). Although the physiological association between depression and IHD is still obscure, there is ample evidence that the treatment of depression and comorbid IHD with SRIs is safe and effective and that it reduces the risk of adverse cardiac events (Roose and Spatz 1999). In a landmark study, Roose et al. (1998) reported that paroxetine and nortriptyline were both effective in treating depression in elderly patients with severe heart disease but that paroxetine had a superior safety and tolerability profile. It is currently unknown whether early recognition and treatment of depression will reduce the risk of future cardiac disease.

Childhood and Adolescent Depression The subject of the role of paroxetine in the treatment of depression in children and adolescents has been one of great controversy and media attention. On June 19, 2003, the FDA released a statement regarding a possible increased risk of suicidal thinking and suicide attempts in children and

adolescents 18 years of age and younger treated with paroxetine for major depressive disorder (U.S. Food and Drug Administration 2003). The statement was based on data from three well-controlled unpublished studies, each showing no benefit for paroxetine above placebo in the treatment of pediatric depression. In addition to the lack of demonstrable efficacy for paroxetine, the data were troubling in that they revealed a two- to threefold increase in suicidal ideation and suicide attempts for paroxetine compared with placebo (3.4% and 1.2%, respectively). These data contrasted with those of an earlier study supporting the efficacy of paroxetine in the treatment of depression in this population. Keller et al. (2001) conducted a randomized, double-blind study of adolescents (ages 12–18 years) that compared paroxetine with placebo. Paroxetine demonstrated a significant advantage over placebo in most, but not all, outcome variables. It is, however, notable that they reported a rate of suicidal behavior/ideation in the paroxetine group of 5.4%; the rate of the placebo arm was not contained in the report. More recently, Emslie et al. (2006) reported that paroxetine was no more efficacious than placebo in the treatment of pediatric depression. Using the Children's Depression Rating Scale—Revised, they found that at week 8 of treatment, the total adjusted mean changes in score from baseline for patients receiving paroxetine and placebo were –22.58 and 23.38 points, respectively. In this trial, rates of suicidal ideation and behavior were comparable between the paroxetine (1.92%) and placebo (0.98%) groups. An important distinction between the above-mentioned studies was that Emslie et al. (2006) used lower doses of paroxetine than did Keller et al. (2001); mean dosages were 20.4 and 28 mg/day, respectively. This difference is highly relevant, given that paroxetine has been shown to exhibit marked nonlinear kinetics in children. Findling et al. (1999) showed that an increase in dosage from 10 to 20 mg results in a sixfold increase in child serum paroxetine levels. The FDA's black box warning concerning antidepressant use and suicidality risk in children and adolescents has already had a major adverse impact on SRI prescribing in the under-18 age group (Nemeroff et al. 2007). For the first time in a decade, an increase in teenage suicide rates has been noted, perhaps due to the decrease in antidepressant prescribing.

Obsessive-Compulsive Disorder Prior to the introduction of SRIs, the most effective pharmacological treatment for OCD was clomipramine. Early studies showed that patients with both OCD and depressive symptoms fared better on clomipramine than patients treated with other available TCAs (Pigott and Seay 1999). Later work revealed that clomipramine was effective in treating OCD, independent of the presence or severity of comorbid depressive symptoms (Fineberg et al. 1992). The notable efficacy of clomipramine in OCD was attributed to its remarkable potency as a 5-HT reuptake inhibitor (Benfield et al. 1980). The 5-HTT-specific action of clomipramine, coupled with its specificity in targeting obsessive-compulsive symptoms, led to the formulation of the "serotonin hypothesis of OCD," which posited disturbed 5-HT neurotransmission in OCD (see D. L. Murphy et al. 1989; Zohar and Insel 1987). Consequently, researchers focused their efforts on identifying and developing other agents that were effective in treating OCD, without the unfavorable side effects of TCAs, including their anticholinergic, antihistaminergic, and antiadrenergic properties. Currently, among the SRIs, fluvoxamine, fluoxetine, sertraline, citalopram, and paroxetine have been shown to be effective, in comparisons with placebo, in the treatment of OCD in randomized, double-blind trials (Greist et al. 1995; Montgomery et al. 2001). Although two meta-analyses assessing the efficacy and tolerability of clomipramine and SRIs in OCD seemed to favor clomipramine in terms of overall effectiveness (Greist et al. 1995; Piccinelli et al. 1995), the only placebo-controlled multicenter study to compare clomipramine (50–250 mg/day) directly with an SRI, paroxetine (20–60 mg/day), revealed equal efficacy (Zohar and Judge 1996). Moreover, significantly more patients receiving clomipramine dropped out of the study because of side effects compared with patients

receiving either paroxetine or placebo. These results suggest that paroxetine is a safe and effective treatment for OCD and is preferable to clomipramine as a first-line agent. More recent work in the field of functional brain imaging has elucidated paroxetine's effect on neural processing in patients suffering from OCD. Saxena et al. (2002) demonstrated that paroxetine treatment led to significant decreases in metabolic activity in the right caudate, bilateral orbitofrontal thalamus, and bilateral striatum. This group later published a study (Saxena et al. 2003) indicating that pretreatment hyperintensities in the right caudate were the imaging findings most predictive of response to paroxetine. Such findings, which implicate striatal far more than limbic structures, have lent credence to speculation that OCD is more nosologically similar to tic disorders such as Tourette's syndrome than to anxiety disorders (Grados et al. 2001). In addition to paroxetine's proven efficacy in adult OCD, the drug has also been shown to be of benefit in pediatric OCD. A randomized multicenter, double-blind, placebo-controlled trial revealed paroxetine to be an effective and generally well-tolerated treatment for OCD in children and adolescents (Geller et al. 2004). Patients with comorbid major depressive disorder were excluded from the study, and the authors reported only one incident of treatment-emergent suicidal behavior or ideation. However, because the onset of suicidality in this case occurred 4 days after the patient was asked to leave his guardian's house and forced to move into a youth shelter, the incident was surmised to be situational rather than an untoward response to paroxetine. In adults, daily doses of 60 mg of paroxetine are usually required to optimally treat OCD. Although patients characteristically respond to treatment within 3–4 weeks, clinical improvement may not be discernible until 10–12 weeks; therefore, a standard drug trial of up to 12 weeks should be conducted before an alternative medication is considered (Rasmussen et al. 1993). Why patients with OCD require higher mean doses of paroxetine than patients with unipolar depression is unclear.

Panic Disorder Estimates from the National Comorbidity Study indicate that the lifetime prevalence rate of panic disorder in the general population is approximately 3.5% (Kessler et al. 1994). Nearly 30% of patients with panic disorder have comorbid depression, and 15% of patients with panic disorder display substance or alcohol abuse. Considerable evidence suggests that patients with panic disorder who have comorbid depression have higher suicide attempt rates than patients with major depression alone (Weissman et al. 1989). These statistics underscore the serious morbidity and mortality of this condition and the need for effective treatment. Paroxetine was the first SRI granted FDA approval for the treatment of panic disorder. In a 12-week trial of patients with panic disorder that compared paroxetine (20–60 mg/day) and clomipramine (50–150 mg/day) with placebo, Lecrubier et al. (1997) reported that paroxetine was as efficacious as clomipramine in all efficacy measures. Indeed, paroxetine showed significant improvements in the mean change in full panic attacks and in the proportion of subjects who became panic free. In addition, a faster onset of action was noted with paroxetine. Study completers were offered the opportunity to continue in their respective treatment arms for an additional 9 months (Lecrubier and Judge 1997). The results demonstrated the enduring efficacy of both medications; however, 19% of clomipramine-treated patients dropped out, because of adverse events, compared with 7.4% for the paroxetine-treated patients and 6.7% of the subjects receiving placebo. Paroxetine is clearly as effective as clomipramine in the treatment of panic disorder, and it is better tolerated. The psychotherapeutic treatment of panic disorder has been studied extensively, and evidence for the effectiveness of CBT in this disorder is considerable. Direct comparison of paroxetine (20–60 mg/day) with CBT, clomipramine (50–150 mg/day), and placebo, in a study involving 131 patients, revealed paroxetine to be more effective than both CBT and placebo in all outcomes, except for panic frequency (Bakker et al. 1999). Surprisingly, patients treated with CBT alone in this study fared no differently

than patients given placebo. The authors suggested that the apparent lack of effect of CBT as monotherapy, a finding that contrasts with results from previous studies supporting its efficacy, was due to the inclusion in the study of an unusually high proportion of severely agoraphobic individuals. Thus, patients with more severe pathology may require initial treatment with paroxetine (or possibly another SRI) before CBT is employed in order to diminish anxiety to a degree that renders psychotherapy more tolerable; however, these data should be replicated before conclusions are drawn. In a study comparing paroxetine (20–60 mg/day) with placebo in patients receiving concomitant CBT for panic disorder, paroxetine was better at reducing both the total number of panic attacks by 50% from baseline and the number of panic attacks to one or zero by the end of the 12-week study (Oehrberg et al. 1995). Therefore, the combination of CBT and paroxetine is more effective in the treatment of panic disorder than CBT alone. In general, patients with panic disorder should initially be treated with a low dose of paroxetine (e.g., 10 mg/day), with gradual increases in dose, as clinically indicated. The data that led to FDA approval indicated that 40 mg/day is the minimum effective dosage for this condition; however, clinical experience indicates that lower dosages may be sufficient in some patients and higher dosages may be required in other patients (Ballenger et al. 1998). The standard duration of treatment ranges from 6 to 12 months; however, rates of relapse appear to be greater than those for major depressive disorder, indicating that panic disorder may require an indefinite course of treatment (Hirschfeld 1996).

Social Anxiety Disorder Paroxetine, sertraline, fluvoxamine CR, and venlafaxine XR are the only medications with FDA approval for the treatment of social anxiety disorder, which is also known as social phobia. The efficacy of paroxetine in the treatment of social anxiety disorder was first suggested by the results of open clinical trials conducted in the mid-1990s (Mancini and van Amerigen 1996; M. B. Stein et al. 1996). These studies were initiated following the appearance of several case reports, as well as openand placebo-controlled trials involving other SRIs, that documented the effectiveness of this class of drugs in treating social anxiety disorder (Czepowicz et al.1995; Katzelnick and Kobak 1995; van Amerigen et al. 1993; van Vliet et al. 1994). Shortly thereafter, a number of double-blind, placebo-controlled paroxetine studies were conducted that supported these early positive findings (Baldwin 2000; Lydiard and Bobes 2000; M. B. Stein et al. 1998). In the first such trial, 187 patients with social anxiety disorder were randomized to treatment with a flexible-dosing regimen of paroxetine (20–50 mg/day) or placebo (M. B. Stein et al. 1998). Fifty-five percent of patients in the paroxetine group, versus 24% of patients in the placebo group, were assessed as either "much improved" or "very much improved" on the CGI–Improvement (CGI-I) scale by the end of the 12-week study. Improvement in the primary outcome measures in the paroxetine group, compared with the placebo group, was significant as early as 2 weeks after initiation of the treatment. These findings were confirmed in a second large placebo-controlled multicenter trial that reported significant improvements in primary efficacy variables by week 4 (Baldwin et al. 1999). Lydiard and Bobes (2000) reported that the optimal daily dose of paroxetine for the treatment of social anxiety disorder is 20–40 mg, adding that there is no additional efficacy observed at a dose of 60 mg. Because nearly 80% of social anxiety disorder patients have comorbid depressive or anxiety disorders, such individuals were excluded from the three studies described above to ensure that the treatment response observed was specific for social phobia (Baldwin 2000). To date, there are no published data comparing paroxetine with other SRIs, benzodiazepines, or MAOIs; however, there is a head-to-head comparison with venlafaxine XR in the treatment of social anxiety disorder. Liebowitz et al. (2005) found that response rates were similar between the paroxetine and venlafaxine XR samples (62.5% and 58.6%, respectively) and that both agents were superior to placebo (36.1% response rate). D. J. Stein et al. (2002) evaluated whether paroxetine's

efficacy in social anxiety disorder could be maintained after treatment discontinuation. A single-blind acute-treatment phase (12 weeks) was used to identify paroxetine responders, who then continued into the maintenance phase, with 162 receiving paroxetine and 161 receiving placebo. Both groups were followed for 24 weeks. At the end of the study, significantly fewer patients relapsed in the paroxetine arm than in the placebo arm (14% vs. 39%). These data indicate that long-term maintenance treatment of social anxiety disorder may be necessary, although more research is needed in this disorder to guide clinical decision making. In a double-blind, randomized study of children and adolescents (ages 8–17 years) with social anxiety disorder, paroxetine (10–50 mg/day) was found to be superior to placebo on the basis of the number of treatment responders who had a CGI-I score of 1 (very much improved) or 2 (much improved) at the end of 16 weeks (Wagner et al. 2004). In the intent-to-treat population (n = 319), treatment responders were seven times more likely to have received paroxetine than placebo. It is important to note that a total of 5 patients in the paroxetine group, versus none in the placebo group, exhibited suicidal threats or gestures. The authors noted that none of these 5 cases was considered serious, none involved clear evidence of a suicide attempt, and none was attributed to the study medication by the investigator.

Generalized Anxiety Disorder GAD is characterized by persistent and uncontrollable worry associated with somatic and psychic symptoms of anxiety, such as muscle tension, difficulty concentrating, and sleep disturbance. GAD is a relatively common disorder, with a lifetime prevalence rate of around 3% in the general population (Judd et al. 1998). Although the classification of this disorder has undergone considerable revision since its introduction in DSM-III (American Psychiatric Association 1980), its negative impact on quality of life and high medical resource utilization are well documented (Roy-Byrne 1996; Wittchen et al. 1994). Currently, a number of treatments for GAD are available; however, concerns over dependence and abuse potential with benzodiazepines, efficacy of and patient satisfaction with buspirone, and the side effects associated with the TCAs have led to a growing interest in the development and investigation of newer agents (see Pollack et al. 2001). Extended-release venlafaxine, escitalopram, duloxetine, and paroxetine have all been approved by the FDA for the treatment of GAD. It has been estimated that nearly 70% of GAD patients have comorbid depression (Judd et al. 1998). To assess the specificity of paroxetine in the treatment of GAD, investigators have excluded subjects with depression and other Axis I disorders. The first such published study supporting the use of paroxetine in GAD compared it with both imipramine and 2'-chlorodesmethyldiazepam, a benzodiazepine (Rocca et al. 1997). Not surprisingly, patients receiving the benzodiazepine showed the earliest improvement in symptoms, based on reduction in Ham-A total scores; however, both paroxetine and imipramine showed significant reductions in Ham-A total score, exceeding that of 2'-chlorodesmethyldiazepam by week 4 of the 8-week trial. Pollack et al. (2001) studied 326 nondepressed subjects who had moderate to severe GAD in an 8-week placebo-controlled study. Paroxetine produced a significant improvement in the Ham-A score, compared with placebo, as well as significant improvements in social impairment, as measured by the Sheehan Disability Scale (SDS). These results were replicated by a group that demonstrated SDS-measured response rates of 62% and 68%, respectively, with daily paroxetine doses of 20 mg and 40 mg, compared with a 46% response rate with placebo (Rickels et al. 2003). Because paroxetine is effective in the treatment of major depression and several anxiety disorders, it should be effective in patients with comorbid GAD and depression; however, no such clinical trials have been conducted. Like other anxiety disorders, GAD is a chronic condition with a characteristic relapsing and remitting natural course. Long-term treatment of GAD with paroxetine (20–50 mg/day) was studied in a randomized, placebo-controlled trial (Stocchi et al. 2003). Following an 8-week single-blind treatment

phase involving 652 moderately to extremely ill patients (CGI-S score = 4–7), 566 treatment responders were randomized in a double-blind fashion to paroxetine (20–50 mg/day) or placebo for 24 weeks. At the end of the study, 39.9% of the placebo-treated patients had experienced a relapse, compared with only 10.9% of the paroxetine-treated patients. These findings demonstrate that the efficacy of paroxetine in the treatment of GAD persists for up to 6 months. Even longer-term data are needed to assess the continued efficacy of paroxetine beyond this time period. Head-to-head comparisons between paroxetine and other medications in the treatment of GAD are sparse. One such study compared paroxetine 20–50 mg/day with escitalopram 10–20 mg/day (Bielski et al. 2005). Although there was no significant difference in efficacy between the two medications, as measured by the Ham-A, the authors noted considerably higher rates of adverse events, leading to withdrawal from the trial, in patients treated with paroxetine compared with those treated with escitalopram (22.6% vs. 6.6%). Treatment-emergent side effects recorded more frequently with paroxetine therapy included insomnia, constipation, ejaculation disorder, anorgasmia, and decreased libido. Conversely, diarrhea and upper respiratory tract infection were more common with escitalopram than with paroxetine. One possible explanation for the divergence in dropout rates may be the seeming disparity in dose ranges between the two medications. Paroxetine was titrated to high-normal doses (between 30 and 50 mg/day) in 63% of subjects, whereas escitalopram was raised only to a dose representing its high-normal range (20 mg/day) in 54% of subjects and never above that. It is important to note that specific adverse events were not stratified by medication dose in the published results. Given the high prevalence rate and morbidity associated with GAD, the addition of paroxetine to the armamentarium of effective pharmacological agents for this disorder represents a significant clinical advance. In addition to improvement in the disabling symptoms of anxiety and coexistent depression, patients can expect to achieve an improved quality of life. In summary, paroxetine is an effective and well-tolerated treatment choice for patients with GAD. Clinical experience and investigative research indicate that the usual effective dosage for treating GAD is 20 mg/day (Paxil 2001).

Posttraumatic Stress Disorder The lifetime prevalence of PTSD, an illness causing marked impairment in individual daily functioning and a considerable burden to society as a whole, has been estimated to be as high as 10.5% for women and 5% for men. In addition, PTSD tends to be a chronic disabling condition with an 80% comorbidity rate with other psychiatric disorders (Kessler et al. 1995). As a class, the SRIs are the most studied medications for this disorder. Fluoxetine, sertraline, and paroxetine have all been shown to be effective in treating PTSD in placebo-controlled trials (Brady et al. 2000; van der Kolk et al. 1994). Paroxetine, with its established efficacy in a wide range of mood and anxiety disorders, has been studied in considerable detail in PTSD. Indeed, paroxetine first fared well in a small open-label trial of patients with chronic (greater than 3 months' duration), non-combat-related PTSD (Marshall et al. 1998). In a subsequent study, Marshall et al. (2001) conducted a large randomized, placebo-controlled trial in patients with chronic PTSD (n = 551 intentto-treat group). The authors found significant improvements in all efficacy measures in paroxetinetreated (20 mg/day and 40 mg/day) patients, compared with placebo-treated patients. Paroxetine was effective in treating the three main cluster groups of reexperiencing, avoidance/numbing, and hyperarousal, with significant separation from placebo at all measured time points, beginning at week 4. In addition, there were significant reductions in disability and depression, compared with placebo, in both paroxetine treatment groups. Patients with comorbid major depression (40%) responded just as favorably as subjects without depression. Tucker et al. (2001) demonstrated, in a 12-week double-blind trial, that 20–50 mg of paroxetine was superior to placebo in the intent-to-treat population (n = 307), as assessed by improvement on the Clinician-Administered PTSD Scale—Part 2 (CAPS-2) and on all secondary measures by week 4. Male and female subjects responded equally well

to paroxetine. Tucker's group went on to show, in an open-label trial, that paroxetine treatment led not only to improvement in subjective symptoms but also to normalization of elevated heart rate and blood pressure reactivity in PTSD patients with comorbid depression (Tucker et al. 2004). Additionally, Bremner et al. (2003) reported that yearlong treatment of PTSD patients with paroxetine (10–50 mg/day) was associated with significant improvements in verbal declarative memory, along with increases in hippocampal volume. These findings, when taken together, suggest that paroxetine (20–50 mg/day) is an effective treatment for chronic PTSD. Long-term studies are important to assess the efficacy of paroxetine during maintenance treatment. Furthermore, the potential synergy of the combination of paroxetine and psychotherapy for optimal treatment response in PTSD has emerged as an area of interest for clinical investigators.

Premenstrual Dysphoric Disorder Premenstrual syndrome and the more severe PMDD together affect up to 8% of women of reproductive age and are characterized by disabling psychological and physical symptoms (Steiner and Pearlstein 2000). Features of both conditions typically include bloating, weight gain, breast tenderness, poor concentration, and disturbed sleep and appetite, which manifest in the luteal phase of ovulation and disappear upon menstruation. These symptoms are cyclical, predictably appearing prior to each menses (Dimmock et al. 2000). The psychological symptoms of PMDD are more severe and prominent and include irritability, dysphoria, tension, and mood lability. The pathophysiology of PMDD remains obscure; however, it may involve altered sensitivity to circulating ovarian hormones. There is also ample evidence that alterations of serotonergic systems play an important role in the production of these premenstrual symptoms, partly because serotonergic agents such as SRIs and clomipramine are effective in the treatment of these disorders but noradrenergic antidepressants are not (Steiner and Pearlstein 2000). The classification of PMDD as a biologically determined disorder is partly grounded both on twin studies, suggesting a strong genetic component, and on the elimination of symptoms with surgical or medical suppression of ovarian hormonal activity (Condon 1993). Although conservative treatment, such as diet restrictions and exercise, may be somewhat helpful, women with PMDD often do not respond adequately to these nonpharmacological measures and require medication for remission of symptoms (Steiner and Born 2000). The benefit of paroxetine in PMDD has been shown in a number of clinical studies. It was shown to be significantly more effective than maprotiline, an NE reuptake inhibitor, in reducing both psychological and somatic symptoms of PMDD in a double-blind, placebo-controlled study of 65 women (Eriksson et al. 1995). Two smaller open trials revealed positive findings with paroxetine treatment (Sunblad et al. 1997; Yonkers et al. 1996). A more recent double-blind, placebo-controlled study demonstrated that paroxetine CR (25 mg/day) was both well tolerated and effective in the treatment of PMDD (Cohen et al. 2004). Steiner et al. (2005) further clarified that the disorder could be successfully managed with paroxetine CR by using an intermittent luteal phase dosing schedule. Patients were instructed to begin drug therapy 14 days prior to their estimated time of next menses and to continue only until the onset of menstruation. They then stayed off the medication during the intervening follicular phases of their cycle. The patients in the paroxetine CR arm did significantly better than those in the placebo group; however, this intermittent-dosing regimen was not tested against standard fixed-dosing schedules. It is likewise unknown whether such "drug holidays" lead to better adherence or outcomes.

Menopausal Vasomotor Symptoms In addition to its proven efficacy in PMDD, paroxetine (20 mg/day) was shown to be effective in the treatment of postmenopausal hot flashes in breast cancer survivors with chemotherapy-induced ovarian failure in two open trials (Stearns et al. 2000; Weitzner et al. 2002); for a review, see

Bordeleau et al. 2007) and in a double-blind study (Stearns et al. 2005). Paroxetine CR (25 mg/day) was subsequently found to be efficacious in treating perimenopausal hot flashes in a placebocontrolled trial (Stearns et al. 2003). The drug's usefulness in this setting is underscored by recent concerns about the safety of hormone replacement therapy (HRT), hitherto the treatment of choice (H. D. Nelson et al. 2002). For clinicians and patients concerned about the long-term consequences of estrogen replacement in treating hot flashes, paroxetine provides a reasonable alternative.

SIDE EFFECTS AND TOXICOLOGY The popularity of SRIs, as a class, in the treatment of psychiatric disorders is owed not to their superiority in efficacy over their predecessors but rather to their overall tolerability and safety. In general, SRIs share a common profile in terms of severity and frequency of side effects. The side-effect profile of paroxetine has been studied extensively in comparison studies with other psychotropic medications and placebo. The most commonly cited adverse experiences in patients treated with paroxetine are, in order of frequency, nausea, headache, somnolence, dry mouth, asthenia, sweating, constipation, dizziness, and tremor (Boyer and Blumhardt 1992). According to the worldwide preregistration clinical trial database, anticholinergic side effects, tremor, dizziness, postural hypotension, and somnolence were more common in comparison drugs—generally TCAs—in mostly short-term studies (Jenner 1992). Nausea and abnormal ejaculation were more frequently reported with paroxetine than with active controls. In these early trials, a greater proportion of patients in the antidepressant comparison and placebo groups withdrew because of adverse events than did patients in the paroxetine group. According to preregistration data, 13% of patients taking paroxetine dropped out prior to study's end because of side effects, compared with 19% for other agents and 5% for placebo. The most common side effect associated with early termination for paroxetine was nausea. Clinical experience demonstrates that this significant complaint can be mitigated with a conservative starting dose and administration with food, as well as with the use of the CR form of the compound. Furthermore, patients reported that nausea diminishes markedly with prolonged administration, a phenomenon also noted in long-term trials (Jenner 1992). According to the limited data available comparing paroxetine directly with other newer-generation antidepressants, notably venlafaxine, sertraline, and fluoxetine, tolerability was similar and early termination rates were also comparable (Aberg-Wistedt et al. 2000; Ballus et al. 2000; Poirier and Boyer 1999; Schöne and Ludwig 1993; Tignol 1993). A possible exception to this might be mirtazapine. As described earlier in this chapter (see "Pharmacogenomics" section), the presence of the S allele in the 5-HTT gene and the C allele in the 5-HT2A receptor gene both confer lower tolerability and earlier discontinuation in patients taking paroxetine. Neither of these polymorphisms had any effect on tolerability of mirtazapine, which demonstrated lower rates of adverse events and discontinuation in comparison with paroxetine (G. M. Murphy et al. 2003, 2004). As noted earlier, elderly patients do not appear to be more susceptible to the side effects of paroxetine, and cognitive function remains intact or improves during treatment (Cassano et al. 2002; Nebes et al. 1999). The paroxetine CR formulation has been compared with paroxetine IR in a placebo-controlled, randomized trial (Golden et al. 2002). Although the frequency of reported side effects was similar between the two active agents, paroxetine CR was significantly less likely to induce nausea (14%), compared with paroxetine IR (23%), in the first week of treatment. A later comparison that used time to discontinuation and economic costs as primary outcome measures found that patients on the CR formulation remained on therapy longer, resulting in better outcomes and lower health care costs (Sheehan et al. 2004). Because nausea is the most frequently reported side effect associated with paroxetine treatment and because it often results in medication discontinuation, paroxetine CR may offer a clinical advantage over the IR formulation in terms of improved treatment compliance and overall clinical effectiveness.

Sexual Side Effects

Sexual dysfunction is a liability associated with many psychotropic medications, and the full scope of this problem is only recently gaining its deserved recognition. When assessing emergence of side effects, most clinical studies rely on spontaneous reporting of adverse experiences. Because most patients do not feel comfortable reporting sexual side effects, it is not surprising that treatmentemergent sexual dysfunction is often underreported in these trials. In one prospective study, specific inquiry about sexual dysfunction with treatment of fluoxetine, paroxetine, sertraline, or fluvoxamine resulted in nearly a threefold increase in reporting of sexual problems, compared with only spontaneous communication (Montejo-Gonzalez et al. 1997). Typically, data derived from clinical studies estimate sexual disability attributed to SRIs to be less than 20%, whereas in clinical practice the incidence appears to be significantly higher, perhaps as high as 40%. This side effect clearly has an adverse effect on medication adherence, partly because discussion of sexual issues is difficult for patients and clinicians alike. Although all SRIs and venlafaxine have been associated with male and female sexual dysfunction, there is a prevailing view among clinicians that this side effect might be more problematic with paroxetine, although few controlled data are available to address this issue. In a comparison study of 200 subjects treated with paroxetine, fluoxetine, fluvoxamine, or sertraline, paroxetine treatment was associated with higher rates of anorgasmia or difficulty with ejaculation and impotence in both men and women (MontejoGonzalez et al. 1997). Significant differences among the four drugs were not noted with respect to decrease in libido, delay in orgasm, or patient attitude toward treatment-induced sexual disability. In a large cross-sectional observational study (N = 6,297) conducted by Clayton et al. (2002), paroxetine was associated with the highest prevalence of overall sexual dysfunction, compared with a wide range of novel antidepressants, including mirtazapine, venlafaxine, sertraline, citalopram, fluoxetine, nefazodone, and bupropion. However, a significant difference between paroxetine and the other agents was observed with only fluoxetine, bupropion, and nefazodone. Waldinger et al. (1998) studied 51 men without depression who had premature ejaculation and noted greater delay in time to ejaculation during paroxetine treatment, compared with treatment with fluoxetine, fluvoxamine, and sertraline. The above findings have led to the use of paroxetine and other SRIs in the treatment of premature ejaculation (PE) in men (Balon 1996). Head-to-head comparisons between paroxetine and other antidepressants in the treatment of PE currently exist only for dapoxetine and mirtazapine. Safarinejad (2006) used a measure called the Intravaginal Ejaculatory Latency Time (IELT) to test paroxetine's effectiveness in slowing down male climax versus dapoxetine, a short-acting SRI that is currently awaiting FDA approval for the treatment of PE. Male patients taking paroxetine in a randomized, double-blind fashion showed IELT increases from a mean of 31 seconds at baseline to 370 seconds with treatment, whereas subjects taking dapoxetine (38 seconds to 179 seconds) or placebo (34 seconds to 55 seconds) did not fare as well. Ejaculatory latency was likewise compared, using the IELT measure, between paroxetine and mirtazapine. In a 6-week double-blind study, treatment with paroxetine (20 mg/day), but not mirtazapine (30 mg/day), resulted in significant delays in orgasm and ejaculation in men with PE (Waldinger et al. 2003). Sexual side effects emerge in a dose-dependent fashion and do not appear to diminish with prolonged administration. Strategies to lessen the impact of psychotropic medications on sexual function include using dosage reduction, changing to a different antidepressant with lesser sexual side-effect liability, and adding an agent, such as sildenafil, yohimbine, buspirone, cyproheptadine, amantadine, methylphenidate, or bupropion, to reverse the sexual side effects (Rosen et al. 1999). Controlled studies demonstrating the efficacy of these agents are largely lacking, with one exception. Ephedrine, an

- and

-adrenergic agonist previously shown to enhance genital blood flow in women, was

evaluated in 19 women experiencing SRI-induced sexual dysfunction from paroxetine, sertraline, or fluoxetine (Meston 2004). Although ephedrine (50 mg taken within 1 hour of sexual activity onset)

significantly improved self-reported scores of desire and orgasm intensity compared with baseline, these measures, in addition to sexual arousal and satisfaction, were also similarly enhanced by placebo.

Suicidality Apprehension surrounding the alleged relationship between SRIs and suicide first gained media attention in the late 1980s, largely due to incidental reports of supposed SRI-induced suicide and homicide circulated in the lay press. The issue once again gained international attention in October 2004, when the FDA ordered drug companies to place a black box warning on all antidepressants, stating that suicidal behavior might increase in children and adolescents taking these drugs. The FDA based this decision on a pooled analysis of 24 antidepressant trials involving more than 4,400 children and adolescents. Paroxetine was not singled out in this analysis, and, indeed, the warning applies to all antidepressants. Data on paroxetine and suicidal behavior in pediatric depression are covered more specifically in the "Childhood and Adolescent Depression" subsection earlier in this chapter. Concerns about a link between antidepressant usage and suicidal ideation led FDA regulators to request that antidepressant manufacturers examine their databases for a similar link in adult patients. GlaxoSmithKline (Paxil/Seroxat) responded by supporting a meta-analysis of its clinical data comparing suicidality between paroxetine and placebo. The researchers found that 0.32% (11 of 3,455) of people taking paroxetine for depression attempted suicide, compared with 0.05% (1 of 1,978) of depressed patients taking placebo, an odds ratio of 6.7 (see GlaxoSmithKline 2006). Incidences of completed suicide in both samples were exceedingly rare, with one reported in the paroxetine sample versus none reported with placebo. Such data need to be considered cautiously for several reasons. First, it should be noted that neither suicidal ideation nor self-harming behaviors were among the main outcome measures in any of the pooled studies. Procedures to assess suicidality are not standardized and are based largely on unsolicited and unstructured reports and observations. Second, transient suicidal thinking must be viewed in the context of the overall risk–benefit analysis of paroxetine in the treatment of adults with major depressive disorder, an illness for which there is robust evidence supporting its efficacy. In late 2006, an FDA advisory panel used the above data, along with findings from a total of 372 randomized, placebo-controlled antidepressant trials (involving close to 100,000 adult patients), in their decision to recommend that the black box warning be extended to cover young adults up to their mid-20s (U.S. Food and Drug Administration 2007). They reported that in patients 18–24 years of age, antidepressant use was associated with four cases of suicidal ideation per 1,000 patients treated, whereas drug therapy for patients older than 30 years was unequivocally protective against suicidality. The decision to extend the warning was made despite evidence that the initial warning might have had dangerous, unintended consequences for children and adolescents suffering from depression in the United States. Nemeroff et al. (2007) analyzed prescription data and physician surveys detailing prescription practices to identify trends in antidepressant use among children and adolescents. They found that from April 2002 to February 2004, antidepressant prescriptions among children and teens increased by an average of 0.79% a month. Between February 2004 and July 2004, prescriptions declined by an average of 4% a month. The latter period corresponds with the time that the initial FDA advisory committee was holding highly publicized hearings regarding a link between antidepressant treatment and suicide attempts in depressed children. The Centers for Disease Control and Prevention (2007) recently reported that suicide rates in American children and adolescents increased by a staggering 18% in 2004 after 10 straight years of steady decline. Suicide and attempted suicide were the main outcome measures in a recently published highly powered cohort study in which 15,390 patients, representing all subjects hospitalized in Finland for a confirmed suicide attempt between January 1997 and December 2003, were followed prospectively to ascertain whether active antidepressant treatment was associated with change in risk compared with

patients taking no medication (Tiihonen et al. 2006). The investigators concluded that current SRI treatment across age groups was associated with a substantial decrease in overall mortality (relative risk of 0.59). Paroxetine was noted to confer increased risk of death in the population of patients between the ages of 10 and 19 years (relative risk: 5.44) compared with subjects who were not taking an antidepressant during the follow-up period. This was a naturalistic study, and it should be emphasized that patients are most likely to opt for antidepressant treatment when they are most depressed and that severe depression is a risk factor for suicide attempts. Still, it should also be noted that patients 10–19 years of age had higher risks of suicidal ideation with paroxetine than with other SRIs studied in the trial. Theories attempting to explain the possible association between antidepressants and the onset of suicidality have been a part of psychiatric folklore since these medicines became available decades ago. Paroxetine in particular has several characteristics that may explain its implication in suicidal adverse events in children and adolescents with major depressive disorder. As previously noted, it has nonlinear kinetics, such that small dosage increases produce dramatic increases in child serum levels. Such high levels could lead to activation, akathisia, or disinhibition, any of which might explain suicidal thoughts or acts (Brent 2004). This effect is even more dramatic in those children who are slow metabolizers of the CYP2D6 isoenzyme (roughly 10% of the Caucasian population) (Riddle 2004). Additionally, paroxetine has a relatively short half-life (11 hours vs. 5 days with fluoxetine), and limited dosing adherence, not uncommon in children and teens, could lead to SRI discontinuation syndrome and dysphoria (Brent 2004). Another possibility is that paroxetine, along with venlafaxine and other NE-acting antidepressants that have similar links to suicidal risk in depressed children, might lead to manic or mixed-episode switching in children or adolescents who have undiagnosed bipolar disorder (Rihmer and Akiskal 2006). These possibilities require further study to elucidate. Regardless of whether the association between antidepressants and transient suicidal activation in young people is causal, clinicians should inform their patients about the possible risks and should monitor depressed patients closely once paroxetine or any other antidepressants are prescribed, particularly during the early phase of treatment. The FDA advisory committee has made it clear that the black box warning should not dissuade physicians from prescribing antidepressants to patients in need (U.S. Food and Drug Administration 2007).

Medical Safety Paroxetine treatment in clinical trials has not been associated with any significant abnormalities in standard laboratory tests, including hematological indices and chemistry panels, electroencephalogram (EEG), or electrocardiogram (ECG). One possible concern regarding paroxetine had been the potential for decreased heart rate variability (HRV), because depressed patients have been shown to exhibit lower HRV than nondepressed persons and this decrease represents a significant risk factor for myocardial infarction (Gorman and Sloan 2000). Moreover, NE reuptake– inhibiting antidepressant drugs have been shown to cause further decreases in this electrophysiological variable (Rechlin 1994). Decreases in HRV have been implicated in increased cardiovascular mortality (Carney et al. 2005), and depression itself has been conclusively shown to be a risk factor in the development of heart disease (Musselman et al. 1998). Davidson et al. (2005) demonstrated that paroxetine (doses up to 40 mg/day) resulted in lower NET occupancy compared with venlafaxine XR (doses up to 225 mg/day). In contrast to venlafaxine, paroxetine had no effect on HRV, as measured by changes in R-R interval during forced 10-second breaths and respiratory sinus arrhythmia (RSA) during paced breathing. Further comparisons of the effects of antidepressant medications on HRV are warranted. Paroxetine and other SRIs have been implicated in precipitation of the syndrome of inappropriate antidiuretic hormone (SIADH), particularly in elderly individuals, which resolves on discontinuation of the medication (Strachan and Shepherd 1998). The potential for paroxetine-induced hyponatremia

was prospectively evaluated in a 12-week open trial involving depressed male and female subjects between the ages of 63 and 90 years (Fabian et al. 2004). Hyponatremia, defined as plasma sodium levels lower than 135 mEq per liter, developed in 9 of the 75 total subjects (12%), in most cases within 10 days of initiation. Risk factors for developing hyponatremia were low body mass index (BMI) and low starting plasma sodium levels. These results underscore the importance of monitoring electrolytes closely in geriatric patients treated with paroxetine and other antidepressants.

Discontinuation Syndrome Following closely on the heels of the widespread use of SRIs came the realization that abrupt discontinuation of these drugs often precipitates the emergence of unpleasant symptoms. This constellation of psychological and physical symptoms, which may appear upon treatment interruption, is referred to as the "SRI discontinuation syndrome." Postmarketing data gathered in the United Kingdom reported the occurrence of withdrawal-related events to be greater in paroxetine-treated patients (5.1% of total adverse drug events) than in patients treated with sertraline (0.9%), fluvoxamine (0.4%), or fluoxetine (0.2%), with a mean duration of 10.2 days (Price et al. 1996). Rosenbaum et al. (1998) compared paroxetine with fluoxetine and sertraline, following, on average, nearly 12 months of open-label treatment in 242 patients with major depression to assess the emergence of withdrawal symptoms in a double-blind, placebo-substitution fashion. The authors found paroxetine to be associated with a significantly greater mean score on the discontinuationemergent signs and symptoms (DESS) checklist than both sertraline and fluoxetine. Both paroxetine and sertraline were associated with significant deterioration in depressive symptoms, as rated by the 28-item Ham-D and MADRS, during the 5- to 7-day placebo substitution. The most common symptoms attributed to paroxetine discontinuation were nausea, dizziness, insomnia, headache, and nervousness. Withdrawal in all groups was resolved upon subsequent reintroduction of medication. These findings were confirmed in another blinded, placebo-substitution study, which reported a significantly greater total number of adverse events in paroxetine-treated patients with depression versus either fluoxetine or sertraline, as early as day 2 of active drug withdrawal (see Michelson et al. 2000). Similar liability was associated with paroxetine in terms of the 21-item Ham-D and State Anxiety Inventory scores, as well as changes in standing and orthostatic heart rate. Discontinuation was more recently compared between paroxetine and agomelatine, a mixed melatonergic and serotonergic agonist currently under FDA evaluation for the treatment of depression. In a doubleblind, placebo-controlled discontinuation study, 192 depressed patients who had experienced sustained remission on either drug were randomly assigned to continue active treatment or to receive placebo for a 2-week follow-up period (Montgomery et al. 2004). During the first week postrandomization, placebo substitution resulted in considerable discontinuation symptoms in the paroxetine group (active dosage = 20 mg/day) but none in patients taking agomelatine (active dosage = 25 mg/day). These effects were not observed into the second week of discontinuation for either drug. The studies noted above tested treatment discontinuation effects over a minimum of 5–8 days. Newer trials have evaluated the effects of shorter-term interruptions (3–5 days) similar to what a patient would experience if he or she were to inadvertently miss just a few doses. Following brief treatment interruption with placebo, Judge et al. (2002) found that paroxetine cessation led to significant discontinuation-emergent events, whereas fluoxetine-treated patients were not symptomatic. It was surmised that fluoxetine's long half-life conferred a protective effect during interruption. Paroxetine fared better during brief discontinuation in comparison with escitalopram. Measurements on the DESS checklist indicated that there were no significant differences between the two drugs when randomly replaced with placebo for 3- to 5-day periods (Baldwin et al. 2006), as both medications showed similar degrees of SRI withdrawal. The researchers did note that paroxetine (mean dosage = 26.3 mg/day) was significantly more likely to cause discontinuation side effects in comparison with

escitalopram (mean dosage = 13.9 mg/day) during a taper period at the end of the trial in which higher-dosed subjects in either group were switched to lower doses for a week and lower-dosed subjects were switched to alternate-day dosing for a week prior to complete cessation. Results from these studies suggest that the abrupt cessation of paroxetine is associated with the SRI discontinuation syndrome in approximately one-third of patients. This syndrome has been attributed to the short half-life of paroxetine, relative to that of other SRIs, as well as to the lack of any active metabolites (Michelson et al. 2000). Symptoms occur as early as the second day after a missed dose and may persist for several days. To mitigate the emergence of withdrawal symptoms, practitioners are advised to gradually taper the dose of paroxetine when discontinuing this medication in their patients. Despite the potential for "withdrawal" reactions after abrupt discontinuation of paroxetine, venlafaxine, duloxetine, and other antidepressants, there is no clinical evidence for dose escalation, craving, or drug-seeking behavior associated with dependence liability or "addiction" (Inman et al. 1993; Johnson et al. 1998; Sharma et al. 2000). Overdoses with paroxetine are rarely associated with morbidity or mortality, which stands in stark contrast to the situation with the TCAs, with their low therapeutic index, or venlafaxine (Buckley et al. 2003; Cheeta et al. 2004). In the clinical trials program prior to FDA registration of paroxetine, 16 patients had ingested an overdose (doses of up to 850 mg of paroxetine); all patients recovered uneventfully (Jenner 1992). A review examining the American Association of Poison Control Centers (AAPCC) and FDA adverse events databases, as well as a MEDLINE literature search, revealed a total of 28 fatalities involving paroxetine overdoses; however, in nearly all cases, either coingestants were involved or causality could not be ascertained (Barbey and Roose 1998). In the overwhelming majority of intentional overdoses of paroxetine, individuals recovered without incident. Consequently, paroxetine can be safely prescribed in patients in whom impulsivity and suicidality are present.

Pregnancy and Lactation One of the most challenging questions faced by patients and health care practitioners in family planning is whether to initiate or continue antidepressant therapy during conception, pregnancy, and the postpartum period. In exploring the risk–benefit analysis, one needs to consider the potential teratogenic risk of exposure of the antidepressant to the infants against the risks to the unborn children of women with untreated depression during pregnancy. Newborns of women with depression have been shown to have a disproportionately higher risk of lower birth weight, preterm delivery, and small size for gestational age (Steer et al. 1992). Additionally, women with depression have higher rates of smoking and alcohol consumption, which represent further risks to pregnancy outcome (Zuckerman et al. 1989). Laboratory animal studies have demonstrated no significant effects of paroxetine in offspring of exposed pregnant mice in terms of early developmental tasks, locomotor and exploratory behavior, or cognition (Christensen et al. 2000; Coleman et al. 1999). In human studies, placental passage of paroxetine from mothers to developing infants was assessed by comparing maternal serum SRI concentrations with those found in cord blood at the time of delivery (Hendrick et al. 2003b). Paroxetine and sertraline had lower ratios of umbilical cord–maternal serum drug concentrations compared with citalopram and fluoxetine. Furthermore, unlike fluoxetine and sertraline, paroxetine cord blood concentrations did not correlate with maternal dosing, suggesting that an increase in maternal medication dose during pregnancy will not necessarily be accompanied by a comparable increase in fetal paroxetine exposure. Clinical studies of paroxetine in the setting of pregnancy suggest that gestational exposure might have transient negative effects on newborn infants, particularly if the mother is treated during the third trimester. A prospective cohort study compared perinatal outcomes of 55 pregnant mothers treated with paroxetine, at various doses, during the third trimester with those of 27 mothers treated with paroxetine during one or both of the first two trimesters. A third sample was a control group of 27

expectant females treated with other medications classified as nonteratogenic. In this trial, Costei et al. (2002) found that third-trimester paroxetine exposure was associated with significant increases in neonatal distress (odds ratio = 9.53) compared with the other two groups. The most commonly observed forms of distress were characterized as respiratory distress and hypoglycemia. Results like these have stirred debate among neonatologists as to whether newborn distress attributed to SRIs is a manifestation of toxicity or of withdrawal (Stiskal 2005). Numerous case reports and case series have described transient neonatal symptoms following in utero exposure to SRI antidepressants, and these include (but are not limited to) tremor, hypertonicity, irritability, and poor feeding (Knoppert et al. 2006). Large trials correlating neonatal distress symptoms with infant serum drug levels, however, have not been performed thus far with paroxetine. Reduced or absent CYP2D6 isoenzyme activity associated with high paroxetine concentrations and hyperserotonergic states has been suggested as a putative mechanism for infant distress in many cases (Laine et al. 2004). Conversely, it has also been argued that in view of paroxetine's short half-life, neonatal distress is more likely to be caused by an SRI discontinuation effect (Stiskal 2006). The question is somewhat muddied by the fact that both hyper- and hyposerotonergic states can result in similar symptoms in newborns, such as restlessness and rigidity (Einarson and Koren 2006). The differential diagnosis between SRI neonatal withdrawal and serotonergic symptoms has important ramifications, given that withdrawal would be optimally treated with an SRI. In contrast, such treatment may endanger babies exhibiting serotonin toxicity. Another significant clinical question is whether paroxetine is associated with teratogenicity. The results of an unpublished study conducted by GlaxoSmithKline (Paxil) led the FDA to warn that paroxetine may increase the risk of major congenital malformations. In a retrospective analysis of data from two U.S. managed-care insurance databases, pregnancy outcomes from a sample of 3,581 gravid mothers (ages 12–49 years) who were taking antidepressants were studied (see GlaxoSmithKline 2005). Of the 18 total medications compared, including other SRIs, SNRIs, TCAs, and newer drugs, only paroxetine had an increased risk of malformations that was significantly greater than that of other antidepressants (odds ratio = 2.20). Several organ systems, including the gastrointestinal, genitourinary, and central nervous systems, were affected in similar proportions. The most common cardiovascular anomalies were ventricular septal defects. The study did not include pregnant women without antidepressant exposure; however, the accepted prevalence of major congenital malformations for all births in the United States is roughly 3%, while the absolute rate observed among first-trimester paroxetine-exposed infants in this study was 4%. A 1% increase in absolute risk over baseline translates to a need for 100 pregnant women to take paroxetine during the first trimester before additional harm would come to 1 infant. Limitations of this study include its retrospective design, lack of controls, lack of clinical details about individual cases, and the fact that it represents a post hoc secondary analysis. These data are contradicted by several other trials that might be considered more scientifically valid, given their prospective nature. In a cohort study, Kulin et al. (1998) compared rates of major congenital malformations in 237 pregnant women treated with paroxetine, fluvoxamine, or sertraline and found no significant differences among the medication groups compared with control groups. More recently, Hendrick et al. (2003a) followed a total of 138 pregnant females treated with paroxetine, fluoxetine, or sertraline and found that rates of neonatal complications and congenital malformations were lower (1.4%) than rates in the general population. There were no significant differences among individual antidepressants when compared with each other. In a postmarketing surveillance report, 137 pregnancies involving maternal exposure to paroxetine were cited, with no infant abnormalities noted (Inman et al. 1993). In spite of these more reassuring data, the American College of Obstetricians and Gynecologists Committee on Obstetric Practice (2006) has recommended that paroxetine be avoided in women who are pregnant or planning to become pregnant. Whether a woman decides to begin or continue paroxetine for the treatment of depression during pregnancy, the clinician is advised to monitor for relapse because one study demonstrated that higher

doses are often needed, especially in the early third trimester, to effect or maintain disease remission (Hostetter et al. 2000). Another time of increased risk is the postpartum period, when women are at a threefold higher relative risk for depression compared with non-child-bearing women (Cox et al. 1993). It is estimated that 13% of women develop depression following childbirth (O'Hara and Swain 1996). Furthermore, children of women with postpartum depression suffer from a number of social and intellectual impairments thought to be associated with compromised mother–infant bonding (A. Stein et al. 1991). Consequently, postpartum depression represents a significant health risk to both mother and child, and treatment with antidepressants during this period is often necessary. Balanced against the established hazards associated with postpartum depression is the potential risk of exposure to antidepressants by the nursing infant. Breast feeding has long been advocated by health care providers for improved mother–child interaction and for infant health. In women with postpartum depression, the decision to breast feed, therefore, presents a dilemma. The emerging data appear to allay the concern of the exposure of SRIs, including paroxetine, to infants through breast milk. Like other antidepressants, paroxetine is secreted into breast milk, with greater concentrations found in hindmilk than foremilk (Ohman et al. 1999; Stowe et al. 2000). In a prospective study involving 16 women with postpartum depression treated with paroxetine, the sera of nursing infants were analyzed for the presence of paroxetine at several time points following maternal administration of paroxetine. Paroxetine was undetectable in all infants (Stowe et al. 2000). The authors cautioned against interpreting the findings to suggest that there is no infant exposure to paroxetine through breast milk because it is indeed found in breast milk, albeit in very low concentrations. Nevertheless, in view of the undetectable concentrations in infant blood, the exposure appears to be minimal. Furthermore, no obvious alterations in infant behavior or temperament have been observed in the breast-fed children of women treated with paroxetine in the short term. These data suggest that the benefits of breast-feeding can be maintained in women treated with paroxetine with minimal apparent risk of exposure to the infant. This issue is described in considerable detail elsewhere in this textbook (see Chapter 64, "Psychopharmacology During Pregnancy and Lactation").

DRUG–DRUG INTERACTIONS Many medications rely on common metabolic processes for biotransformation into an active agent or inactive metabolite. As such, the likelihood that pharmacokinetic interactions among prescription and over-the-counter medications may lead to adverse outcomes becomes greater as medications with shared metabolic pathways are administered concurrently. As noted previously, paroxetine is primarily dependent on the CYP2D6 enzyme for conversion into its inactive metabolites (Hiemke and Härtter 2000). Paroxetine is not only a substrate for this system but also an inhibitor; therefore, other drugs that use this hepatic enzyme are potentially subject to decreased clearance and subsequent increased plasma concentrations (Sindrup et al. 1992b). Concern is greatest for potential drug–drug interactions when the affected medication has a low therapeutic index. Medications that are CYP2D6 dependent include many antipsychotics, TCAs, type IC antiarrhythmics, -adrenergic agents, trazodone, and dextromethorphan (Nemeroff et al. 1996). Most reports of interactions between these medications and paroxetine are published as case reports from which firm conclusions regarding causality cannot be drawn (Lane 1996). In regard to the TCAs, Brøsen et al. (1993) and Alderman et al. (1997) demonstrated, in prospective studies, that desipramine concentrations increased by 364% and 358%, respectively, when coadministered with paroxetine. Imipramine levels are also increased with the coadministration of paroxetine (Albers et al. 1996). Antipsychotics are often prescribed with paroxetine in the treatment of psychotic depression and in the treatment of negative symptoms in schizophrenia or as augmentation therapy in patients with primary mood disorders. Paroxetine does not appear to potentiate the sedative effects of haloperidol (Cooper et al. 1989). Dystonia resulting from the combination of paroxetine and haloperidol has been reported (Budman et al. 1995). In one prospective study, clozapine levels increased by an average of

40% over controls when coadministered with SRIs, including paroxetine, at a mean dose of 31.2 mg (Centorrino et al. 1996). In another study using a lower dose of paroxetine (20 mg), no significant increases in clozapine concentrations were noted (Wetzel et al. 1998). These findings indicate that caution should be exercised when paroxetine and clozapine are prescribed together, particularly at higher doses of paroxetine. Case reports have demonstrated possible exaggerated extrapyramidal side effects when paroxetine was administered with perphenazine, molindone, and pimozide (Horrigan and Barnhill 1994; Malek-Ahmadi and Allen 1995; Ozdemir et al. 1997). A number of medications that are bound to plasma proteins are capable of displacing or being displaced by highly protein-bound drugs, such as paroxetine, resulting in a potentially significant increase in the free concentration of the drug, although this mechanism rarely, if ever, is clinically meaningful (Preskorn 1993). In a prospective study with 27 patients, 5 patients developed mild bleeding when paroxetine was added to ongoing treatment with warfarin, although concentrations of warfarin and paroxetine, as well as prothrombin time, did not change significantly (Bannister et al. 1989). Although an explanation for an increased propensity for bleeding is unclear, it is recommended that anticoagulation parameters be carefully monitored when warfarin and paroxetine are coprescribed. Digoxin levels are unaffected by paroxetine treatment (Bannister et al. 1989), and lithium concentrations are also unchanged by paroxetine administration (Haenen et al. 1995). In prospective studies involving the antiepileptic/mood stabilizers valproate and carbamazepine, as well as the anticonvulsant phenytoin, coadministration with paroxetine did not cause any significant changes in plasma levels of these drugs (Andersen et al. 1991; Kaye et al. 1989). In contrast, both phenytoin and carbamazepine have been shown to decrease plasma paroxetine concentrations by 28% (Kaye et al. 1989) and 55% (Hiemke and Härtter 2000), respectively. Valproate may increase plasma paroxetine concentrations (Andersen et al. 1991). Cimetidine, which is a potent inhibitor of the CYP2D6 isoenzyme, has been shown to result in a 50% elevation of paroxetine concentrations (Bannister et al. 1989). The clinical significance of the overall deviations in serum paroxetine concentration at steady state caused by these agents is minor because of wide interindividual pharmacokinetic variability, high therapeutic index, and lack of a concentration–efficacy relationship with paroxetine (Gunasekara et al. 1998). Sedation is a possible side effect associated with barbiturates, benzodiazepines, and ethanol. Paroxetine does not potentiate the psychomotor effects of amobarbital, oxazepam, or alcohol (Cooper et al. 1989). No clinical or pharmacokinetic interaction was noted when paroxetine and diazepam were coadministered in a prospective study (Bannister et al. 1989). Combination of medications that enhance serotonergic activity may result in the so-called serotonin syndrome, which may manifest as agitation, myoclonus, hyperreflexia, diarrhea, sweating, delirium, fever, elevated blood pressure, and possibly death (Weiner et al. 1997). Following case reports describing the emergence of this syndrome with the combination use of fluoxetine and MAOIs, the concomitant use of MAOIs with any of the SRIs is absolutely contraindicated, and a washout period of 14 days is recommended when switching from one agent to another (Gunasekara et al. 1998; Weiner et al. 1997). Evidence for the serotonin syndrome with paroxetine, in combination with other drugs, has been documented in case reports for moclobemide (Hawley et al. 1996), nefazodone (John et al. 1997), dextromethorphan (Skop et al. 1994), imipramine (Weiner et al. 1997), trazodone (Reeves and Bullen 1995), and others. The combination of SRIs and sumatriptan, a serotonin1D (5-HT1D) receptor agonist used in the treatment of migraine, was previously discouraged because of the theoretical risk of precipitation of the serotonin syndrome; however, a series of six cases, one involving paroxetine, of concurrent sumatriptan and SRI administration demonstrated no adverse events (Leung and Ong 1995). This lack of interaction has been confirmed in a prospective trial (Franklin et al. 1996). Overall, paroxetine may be safely administered with other medications, as clinically indicated. Coadministration with an MAOI is absolutely contraindicated, and careful monitoring is advised when

TCAs, warfarin, and clozapine are used in conjunction with paroxetine. As with any medication, clinicians are advised to minimize polypharmacy and remain vigilant to the possibility of drug–drug interactions (see Table 15–2 for the important drug–drug interactions with paroxetine). TABLE 15–2. Potential drug–drug interactions involving paroxetine Monoamine oxidase inhibitors

Clinically significant

Tricyclic antidepressants

Clinically significant

Type IC antiarrhythmics

Probably significant

-Adrenergic antagonists

Probably significant

Antiepileptic agents

Probably significant

Cimetidine

Probably significant

Typical antipsychotics

Possibly significant

Warfarin

Possibly significant

Clozapine

Inconclusive

Lithium

Not clinically significant

Digoxin

Not clinically significant

CONCLUSION Paroxetine has been demonstrated to be an effective treatment for several psychiatric disorders, including major depression and virtually all of the anxiety disorders. It is well tolerated with convenient once-daily dosing and is available in both IR and CR formulations. Most patients can expect symptomatic relief within 4 weeks, and some patients as early as 2 weeks. Concern for pharmacokinetic interactions with other drugs is minimal, although concomitant MAOI use is contraindicated. Overdosage rarely results in significant toxicity, rendering paroxetine a judicious choice among available psychotropics for the impulsive or suicidal patient. Paroxetine should be used cautiously in the treatment of pediatric anxiety disorders and sparingly in child and adolescent patients with depression. Its use in pregnancy remains controversial and requires more data to resolve safety concerns. In the postpartum setting, however, nursing very likely poses a negligible exposure risk to infants of mothers receiving treatment with paroxetine. Paroxetine, with its wide application and favorable safety profile, represents an important member of the SRI class of drugs, although it appears to behave as an SNRI at higher doses. It continues to be evaluated for efficacy in the treatment of other psychiatric and nonpsychiatric disorders.

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Elias Aboujaoude, Lorrin M. Koran: Chapter 16. Fluvoxamine, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.417768. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 16. Fluvoxamine FLUVOXAMINE: INTRODUCTION Fluvoxamine is a member of the selective serotonin reuptake inhibitor (SSRI) family of drugs. Initially manufactured by Duphar Laboratories in the United Kingdom in 1971, fluvoxamine was registered as an antidepressant in Switzerland in 1983, becoming the first drug in the now hugely popular SSRI class to reach the market (Freeman 1991). Since its introduction, fluvoxamine has undergone a wide range of trials to assess its therapeutic potential in depression and across several anxiety disorders, including obsessive-compulsive disorder (OCD). Fluvoxamine has been available in the United States since 1994, when it received U.S. Food and Drug Administration (FDA) approval for the treatment of OCD (Ware 1997). More than 28 million people worldwide have been treated with fluvoxamine (Buchberger and Wagner 2002).

STRUCTURE–ACTIVITY RELATIONS Fluvoxamine belongs to the 2-aminoethyl oxime ethers of the aralkyl ketones, a unique chemical series unrelated to tricyclic antidepressants or other SSRIs. Fluvoxamine maleate is chemically identified as 5-methoxy-4'-(trifluoromethyl) valerophenone-(E)-O-(2-aminoethyl) oxime maleate (1:1). Its empirical formula is C15H21O2N2F3.C4H4O4, and its molecular weight is 434.4. Unlike the other SSRIs, fluvoxamine does not have an asymmetric carbon and hence does not have a chiral center or exist in stereoisomers. It is a whitish, odorless crystalline powder that is only sparingly soluble in water. It possesses local irritant properties that preclude its parenteral use ("Fluvoxamine" 2002). Figure 16–1 shows the molecular structure of fluvoxamine. FIGURE 16–1. Chemical structure of fluvoxamine.

MECHANISM OF ACTION Like other SSRIs, fluvoxamine binds to the presynaptic serotonin transporter (SERT) and prevents it from absorbing serotonin back into the presynaptic terminals, where it is metabolized by monoamine oxidases or stored in secretory vesicles. This has the net effect of increasing serotonin in the synaptic cleft. How these actions translate into efficacy for depression or anxiety remains the subject of investigation, especially because clinical improvement typically takes several weeks, whereas the drug's effect in enhancing monoamine neurotransmission is almost immediate. As a result, downstream mechanisms have been hypothesized to explain the therapeutic effects of SSRIs. These

mechanisms include 5-HT1A autoreceptor desensitization (Stahl 1998), increased sensitivity of the D2-like receptors in the nucleus accumbens (Gershon et al. 2007), enhanced neurogenesis in the hippocampus (Dranovsky and Hen 2006), cyclic adenosine monophosphate (cAMP)–mediated activation of the pathway for cAMP response element–binding protein brain-derived neurotrophic factor (CREB-BDNF) (Gershon et al. 2007), and individual pharmacogenomic factors that determine how SSRIs interact with specific gene variants of the serotonin transporter (Mancama and Kerwin 2003). Recent research has examined the putative role of the sigma-1 receptor in the mechanism of action of SSRIs and the pathophysiology of various psychiatric illnesses, including major depression. Sigma-1 receptors are thought to exert potent modulatory effects on several neurotransmitter systems, including the serotonergic, glutamatergic, noradrenergic, and dopaminergic pathways. Studies using positron emission tomography have demonstrated that fluvoxamine's affinity for the sigma-1 receptor in the human brain is higher than that of any of the other SSRIs (Ishikawa et al. 2007).

PHARMACOLOGICAL PROFILE Although the data are somewhat inconsistent, in vitro and in vivo studies suggest that fluvoxamine is a more potent inhibitor of serotonin reuptake than the tricyclic antidepressants, including clomipramine, but less potent than the other SSRIs. Fluvoxamine also is very selective for the human serotonin transporter (Ki = 2.3 nmol/L) and has only minimal affinity for the human norepinephrine and dopamine transporters (Ki = 1,427 and 16,790 nmol/L, respectively) (Owens et al. 2001). Fluvoxamine also has minimal affinity for the muscarinic, 1-adrenergic, histaminic, and 5-HT2C receptors and possesses no monoamine oxidase–inhibiting properties (Lapierre et al. 1983; Owens et al. 2001; Palmer and Benfield 1994; Ware 1997; Westenberg and Sadner 2006).

PHARMACOKINETICS AND DISPOSITION After oral administration, fluvoxamine is almost entirely absorbed from the gastrointestinal tract, regardless of the presence of food (Van Harten 1995). However, despite complete absorption, oral bioavailability (i.e., the amount available in systemic circulation in intact form) is only 53% (DeVane 2003; DeVane and Gill 1997) due to first-pass hepatic metabolism. Following single-dose administration, peak plasma concentrations are reached within 2–8 hours, and steady-state concentration is achieved within 10 days (Van Harten 1995). At steady state, fluvoxamine appears to display nonlinear pharmacokinetics over its therapeutic dosage range, with disproportionately higher plasma concentrations at higher dosages. Plasma concentration, however, shows no consistent correlation with efficacy or severity of side effects, suggesting that plasma concentration monitoring is of limited value. The mean half-life of fluvoxamine is 15 hours (range: 8–28 hours). This relatively short half-life makes twice-daily dosing preferable. Although psychoactive medications with relatively short half-lives are more likely to cause discontinuation syndromes if stopped abruptly, this effect appears to be rare with fluvoxamine (Buchberger and Wagner 2002), especially in comparison with paroxetine, an SSRI with a somewhat longer half-life but worse discontinuation problems (Pae and Patkar 2007). A possible explanation for this difference is provided from fluorine-19 magnetic resonance spectroscopy (19F MRS) data showing that fluvoxamine is more slowly eliminated from the brain than from plasma (mean ratio of brain elimination half-life to plasma half-life = 2.4) (Strauss et al. 1998). Because of its lipophilicity, fluvoxamine is widely distributed and is found in higher concentrations in the brain and other major organs than in plasma (Benfield and Ward 1986). For this reason, it is unnecessary to give replacement doses of fluvoxamine to patients receiving hemodialysis for severe renal dysfunction: re-equilibration should occur, with drug being recruited from tissues to plasma (DeVane and Gill 1997). Compared with other SSRIs, fluvoxamine's rate of protein binding is relatively low, at 77% (DeVane

and Gill 1997). Only escitalopram has a lower protein-binding rate (56%) (Rao 2007). Low protein binding can be advantageous, because interactions through drug displacement are less likely to occur when multiple medications that are bound to the same proteins are coadministered. Protein binding is also important in determining the hemodialyzability of drugs. At least 11 products of fluvoxamine hepatic metabolism have been identified, but none are thought to be pharmacologically active (DeVane and Gill 1997; Palmer and Benfield 1994; Ruijten et al. 1984). Metabolism is thought to occur primarily through oxidative demethylation, although the exact enzyme systems involved in fluvoxamine breakdown have not been fully elucidated. Only minimal amounts of fluvoxamine (3%) are excreted unchanged by the kidneys, suggesting that renal impairment should not significantly alter fluvoxamine's pharmacokinetics (Van Harten 1995). Because hepatic clearance is decreased in patients with liver disease and in elderly patients, dosage adjustments are sometimes necessary in these populations (DeVane and Gill 1997; Van Harten et al. 1993). No gender-based differences in fluvoxamine concentration seem to exist in adults, although most pharmacokinetic data were obtained from male subjects (DeVane and Gill 1997). Studies examining the pharmacokinetics of fluvoxamine among children and adolescents have found a higher area under the curve (AUC) in children compared with adolescents, with the difference being more pronounced among female children, suggesting that lower drug dosages may be sufficient in this group. No appreciable pharmacokinetic differences were observed between the adolescent and adult groups ("Fluvoxamine" 2002).

INDICATIONS AND EFFICACY Depression The first trial to assess the role of fluvoxamine in the treatment of depression dates back to 1976. We identified 38 randomized, single- or double-blind studies conducted since then to test the antidepressant efficacy of fluvoxamine against placebo, SSRIs (sertraline, fluoxetine, citalopram, and paroxetine), serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine and milnacipran), tricyclic antidepressants (clomipramine, imipramine, desipramine, amitriptyline, and nortriptyline), tetracyclic antidepressants (mianserin and maprotiline), and a reversible inhibitor of monoamine oxidase (moclobemide). These trials varied widely in design, including the diagnostic and inclusion criteria utilized, the requirement for a washout period before initiation of study drug, and the way treatment response was defined. However, taken together, these studies support the efficacy and safety of fluvoxamine in the treatment of mild, moderate, and severe depression—including psychotic depression—across all age groups and in both inpatient and outpatient settings (Fukuchi and Kanemoto 2002; Haffmans et al. 1996; Kiev and Feiger 1997; Otsubo et al. 2005; Rapaport et al. 1996; Rossini et al. 2005; Ware 1997; Zanardi et al. 2000; Zohar et al. 2003). Among all studies, none showed fluvoxamine to be inferior in efficacy to another active comparator when a priori response criteria were applied. Study durations ranged from 4 to 7 weeks, and dosages ranged from 50 to 300 mg/day. Furthermore, the benefits from fluvoxamine seem to be sustained over the long term. In a double-blind, placebo-controlled study assessing the efficacy of fluvoxamine continuation treatment, fluvoxamine at 100 mg/day was significantly superior to placebo in preventing symptom recurrence over the 1-year maintenance period (Terra and Montgomery 1998).

Obsessive-Compulsive Disorder in Adults Clomipramine is the only tricyclic antidepressant with established efficacy in OCD. Given that clomipramine is also the most serotonergic drug in its class, its efficacy supported the hypothesis that serotonin pathways are implicated in the pathophysiology of OCD. When fluvoxamine, a drug that is more potent and selective for the serotonin transporter than clomipramine, became available in the early 1980s, researchers quickly became interested in exploring its potential efficacy in the treatment of OCD. The first formal testing took place in 1987: a positive single-blind trial of 10 subjects with OCD

(Price et al. 1987). Since then, multiple randomized studies have established fluvoxamine's efficacy and safety in the treatment of OCD, regardless of the presence or severity of comorbid depression. These trials have compared fluvoxamine with placebo, clomipramine, and other SSRIs. In randomized, double-blind comparisons with placebo, subjects were given fluvoxamine 100–300 mg/day for 6–10 weeks. Significant improvements in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and other primary and secondary outcome measures were observed after a 3- to 4-week delay. Overall, response rates ranged from 38% to 52% (vs. 0% to 18% for placebo) (Figgitt and McClellan 2000). We identified five published double-blind comparisons of fluvoxamine and clomipramine, both dosed at 300 mg/day, involving a total of 531 subjects and lasting 9–10 weeks (Figgitt and McClellan 2000; Freeman et al. 1994; Koran et al. 1996; Milanfranchi et al. 1997; Mundo et al. 2000, 2001). All of these studies demonstrated equal efficacy for the two agents (range of response rates: 56%–85% for fluvoxamine and 53%–83% for clomipramine). In the largest of these comparisons, 227 subjects meeting DSM-III-R (American Psychiatric Association 1987) criteria for OCD were randomly assigned to either fluvoxamine or clomipramine (both at 150–300 mg/day) for 10 weeks. At study end, rates of response (defined as

35% improvement in Y-BOCS score) were similar for the two drugs (62% for

fluvoxamine vs. 65% for clomipramine, P = NS). However, fluvoxamine was better tolerated than clomipramine, as evidenced by its much lower rate of premature withdrawal due to side effects (8% for fluvoxamine vs. 16% for clomipramine) (Mundo et al. 2001). Only one published study has compared fluvoxamine with other SSRIs. This small 10-week single-blind study of 30 subjects randomly assigned to fluvoxamine, paroxetine, or citalopram suggested similar efficacy among the three agents (Mundo et al. 1997). Data also suggest that long-term maintenance treatment with fluvoxamine following acute response is protective against OCD relapse. A 2-year open-label follow-up study in 130 subjects who had responded to a 6-month course of fluvoxamine 300 mg/day, clomipramine 150 mg/day, or fluoxetine 40 mg/day showed that for all three agents, maintenance treatment at full or half dosages was significantly superior to treatment discontinuation in preventing OCD relapse (Ravizza et al. 1996). Use of fluvoxamine in the short term has been reported to enhance the efficacy of behavioral therapy in patients with OCD. In a 9-week study that compared 58 evaluable subjects who received exposure therapy in combination with fluvoxamine ( 300 mg/day) or placebo, the response rate ( 35% reduction in Y-BOCS score) was higher in the fluvoxamine group than in the placebo group (87.5% vs. 60%, P 0.05) (Hohagen et al. 1998). In another study in 60 subjects with OCD, fluvoxamine ( 300 mg/day) combined with either antiexposure or exposure therapy significantly reduced daily rituals, compared with placebo combined with exposure therapy (P = 0.02), in the first 2 months of treatment, although this superior response did not persist at subsequent follow-up points (Cottraux et al. 1993). The long-term benefit of fluvoxamine relative to behavioral treatment was explored in a study of 102 subjects recruited 5 years after completing two 16-week studies that tested the effectiveness of cognitive therapy alone, exposure response prevention alone, or cognitive-behavioral therapy in combination with fluvoxamine (Van Oppen et al. 2005). The original sample included 122 subjects. At the 5-year follow-up point, the clinical benefits to patients who had received cognitive therapy alone, exposure response prevention alone, or cognitive-behavioral therapy with fluvoxamine were maintained. Significantly more subjects who were still on antidepressants had received fluvoxamine in the controlled trials, suggesting that subjects who were randomized to the fluvoxamine group in the original trials tended to stay on the drug. However, more than 63% of subjects had received some form of additional psychological or pharmacological treatment in the intervening 5 years, making the results difficult to interpret. More than half (53.5%) of subjects no longer met DSM-III-R criteria for OCD at follow-up, and only 5% showed signs of deterioration.

Obsessive-Compulsive Disorder in Children and Adolescents OCD often manifests in childhood or adolescence. Early intervention could potentially alter what is often a chronic waxing and waning course, but few pharmacological options for OCD have been adequately studied in this patient population. The safety and efficacy of fluvoxamine 50–200 mg/day were assessed in a 10-week double-blind, placebo-controlled multisite study involving 120 subjects ages 8–17 years with DSM-III-R–defined OCD. Response was defined as a reduction of at least 25% in the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score. Mean CY-BOCS scores were significantly lower in the fluvoxamine group than in the placebo group as early as week 1 and remained lower at weeks 2, 3, 4, 6, and 10 (P 10% rate than placebo) were insomnia and asthenia (Riddle et al. 2001).

Panic Disorder SSRIs are considered a first-line treatment for panic disorder. Several small randomized, double-blind, placebo-controlled studies lasting 6–8 weeks were conducted in the 1990s to assess the efficacy of fluvoxamine 50–300 mg/day in the treatment of subjects with DSM-III-R–defined panic disorder. These studies generally showed favorable results compared with placebo, reporting reductions of 54%–100% in the weekly rate of panic attacks (Figgitt and McClellan 2000). More recently, a large multisite study was conducted in 188 subjects who met DSM-III-R criteria for panic disorder with or without agoraphobia, recruited from four centers in the United States. Subjects were randomly assigned to receive 8 weeks of fluvoxamine 100–300 mg/day or placebo. At study end, significantly more subjects in the fluvoxamine group were free from panic attacks (69% vs. 46%, P = 0.002). An early onset of action was also seen: between-group differences in the proportion of subjects free from panic attacks at week 1 were significant in favor of fluvoxamine (P

Chapter 18. Monoamine Oxidase Inhibitors HISTORY AND DISCOVERY Monoamine oxidase inhibitors (MAOIs) were first identified as effective antidepressants in the late 1950s. An early report suggested that iproniazid, an antitubercular agent, had mood-elevating properties in patients who had been treated for tuberculosis (Bloch et al. 1954). Following these observations, two studies confirmed that iproniazid did indeed have antidepressant properties (Crane 1957; Kline 1958). Zeller (1963) reported that iproniazid caused potent inhibition of monoamine oxidase (MAO) enzymes both in vivo and in vitro in the brain. He also reported that the medication reversed some of the actions of reserpine. Because reserpine produced significant depression as a side effect, it was suggested that iproniazid might have mood-elevating properties. The use of iproniazid soon fell into disfavor because of its significant hepatotoxicity. Other MAOIs, both hydrazine derivatives (e.g., isocarboxazid and phenylhydrazine) and nonhydrazine derivatives (e.g., tranylcypromine), were introduced. These MAOIs were not specific for any subtype of MAO enzyme, and they were irreversible inhibitors of MAO (see next section, "Monoamine Oxidase"). Their use has been rather limited because hypertensive crisis by the MAOIs may occur in some patients from potentiation of the pressor effects of amines (such as tyramine) in food (Blackwell et al. 1967). In the past few years, there has been a resurgence of interest in the development of new monoamine oxidase inhibitors—that is, in those MAOIs that are more selective for specific subtypes of MAO enzyme and in those that are reversible in nature. Newer MAOIs, such as L-deprenyl (selegiline hydrochloride), a monoamine oxidase B (MAO-B) inhibitor, have been introduced (Table 18–1). Reversible monoamine oxidase A (MAO-A) inhibitors, such as moclobemide, have been introduced in Europe but are not yet available in the United States. TABLE 18–1. Classification of monoamine oxidase inhibitor (MAOI) drugs by structure, selectivity, and reversibility Drug

Hydrazine

Selective

Reversible

Phenelzine

Yes

No

No

Isocarboxazid

Yes

No

No

Tranylcypromine

No

No

No

Selegiline

No

Yesa,b

No

Moclobemide

No

Yesc

Yes

Brofaromine

No

Yesc

Yes

a

Selective for MAO-B at lower doses.

b

Becomes nonselective at higher doses.

c

Selective for MAO-A.

MONOAMINE OXIDASE

A and B Isoenzymes MAO is widely distributed in mammals. Two isoenzymes, MAO-A and MAO-B, are of special interest in psychiatry (Cesura and Pletscher 1992). Both are present in the central nervous system (CNS) and in some peripheral organs. Both MAO-A and MAO-B are present in discrete cell populations within the CNS. MAO-A is present in both dopamine (DA) and norepinephrine (NE) neurons, whereas MAO-B is present to a greater extent in serotonin (5-HT)–containing neurons. They are also present in nonaminergic neurons in various subcortical regions of the brain. Glial cells also express MAO-A and MAO-B (Cesura and Pletscher 1992). The physiological functions of these two isoenzymes have not been fully elucidated. The main substrates for MAO-A are epinephrine, NE, and 5-HT. The main substrates for MAO-B are phenylethylamine, phenylethanolamine, tyramine, and benzylamine. DA and tryptamine are metabolized by both isoenzymes. The localization of the MAO subtypes does not fully correspond to the neurons containing the substrates. The reason for this discrepancy is unknown. The occurrence of the MAO-B form in 5-HT neurons may actually protect these neurons from amines (other than 5-HT) that could be toxic to them (Cesura and Pletscher 1992). The primary structures of MAO-A and MAO-B have been fully described. MAO-A has 527 amino acids, and MAO-B has 520 amino acids. About 70% of the amino acid sequence of the two forms is homologous. The genes for both isoenzymes are located on the short arm of the human X chromosome. MAO-A and MAO-B are linked and have been located in the XP11.23–P11 and XP22.1 regions, respectively. The genes are about 70 kilobases and consist of about 15 exons and 14 introns. MAO-A has two messenger RNA (mRNA) transcripts of 2.1 and 5.0 kilobytes in length. MAO-B has a 3-kb mRNA single transcript (Cesura and Pletscher 1992). A rare inherited disorder, Norrie's disease, is characterized by deletion of both genes; patients with this disorder have very severe mental retardation and blindness. The subunit composition of MAO is unknown. The enzyme is primarily found in the outer mitochondrial membrane; flavin adenine dinucleotide (FAD) is a cofactor for both MAO-A and MAO-B. Because the cofactor domain is the same for both of the MAO isoenzymes, the structural differences responsible for substrate specificity are believed to lie in regions of the protein that bind to the hydrophobic moiety of the substrate. Although DA is considered to be a mixed substrate for both MAO-A and MAO-B, the breakdown of DA in the striatal regions of the brain is preferentially by MAO-B. In other regions, MAO-A may be more important. There may be regional differences as to which isoenzyme is responsible for the metabolism of other biogenic amines that are substrates for both forms of MAO (Cesura and Pletscher 1992).

Enzyme Kinetics The enzyme kinetics of MAO-A have not been well studied. The enzyme kinetics for MAO-B, for which more information is available, depend on the nature of the substrate. Some substrates (e.g., tyramine) go through ping-pong mechanisms characterized by first oxidation of the amine to the imine form that is subsequently released from the reduced enzyme before reoxidation of the latter occurs. Other substrates (e.g., benzylamine) involve formation of a tertiary complex with the enzyme and oxygen (Husain et al. 1982; Pearce and Roth 1985; Ramsay and Singer 1991).

MECHANISM OF ACTION The target function of MAOIs is regulation of the monoamine content within the nervous system. Because MAO is bound to the outer surface of the plasma membrane of the mitochondria, in neurons MAO is unable to deaminate amines that are present inside stored vesicles and can metabolize only amines that are present in the cytoplasm. As a result, MAO maintains a low cytoplasmic concentration of amines within the cells. Inhibition of neuronal MAO produces an increase in the amine content in

the cytoplasm. Initially, it was believed that the therapeutic action of MAOIs was a result of this amine accumulation (Finberg and Youdim 1984; Murphy et al. 1984, 1987). More recently, it has been suggested that secondary adaptive mechanisms may be important for the antidepressant action of these agents. After several weeks of treatment, MAOIs produce effects, such as a reduction in the number of -adrenoreceptors,

1- and

2-adrenoreceptors, and serotonin1 (5-HT1) and serotonin2 (5-HT2)

receptors. These changes are similar to those produced by the chronic use of tricyclic antidepressants (TCAs) and other antidepressant treatment (DaPrada et al. 1984, 1989). MAOIs can be subdivided on the basis of not only the particular type of enzyme inhibition but also the type of inhibition they produce (reversible or irreversible). The reversible MAOIs are basically chemically inert substrate analogs. MAOIs are recognized as substrates by the enzyme and are converted into intermediates by the normal mechanism. These converted compounds react to the inactive site of the enzyme and form a stable bound enzyme. This effect occurs gradually, and there is usually a correlation between the plasma concentration of the reversible inhibitors and pharmacological action.

PHARMACOLOGICAL PROFILE The classic MAOIs inhibit both forms of the enzyme and are divided into two main subtypes: hydrazine and nonhydrazine derivatives. The hydrazine derivatives, two of which (phenelzine and isocarboxazid) are currently available, are related to iproniazid. The nonhydrazine irreversible MAOI is tranylcypromine, which is chemically similar to amphetamine. Clorgyline is an example of an irreversible inhibitor of MAO-A, whereas selegiline is an irreversible inhibitor of MAO-B. The only reversible inhibitor of MAO-A available anywhere is moclobemide. Three classic MAOIs (i.e., tranylcypromine, phenelzine, and isocarboxazid) are of clinical interest. Clinicians must recognize that these drugs not only inhibit MAO but also exert other actions that may be clinically relevant. Thus, these compounds can block MAO uptake—tranylcypromine more than isocarboxazid or phenelzine. In addition, because tranylcypromine is structurally similar to amphetamine, it is believed to exert stimulant-like actions in the brain. Many issues are common to all three of these MAOIs.

INDICATIONS AND EFFICACY Major and Atypical Depression Many studies have examined the efficacy of MAOIs in the treatment of different types of depression. MAOIs have been effective in the treatment of major depression or atypical depression (Davidson et al. 1987a; Himmelhoch et al. 1982, 1991; Johnstone 1975; Johnstone and Marsh 1973; McGrath et al. 1986; Paykel et al. 1982; Quitkin et al. 1979, 1990, 1991; Rowan et al. 1981; Thase et al. 1992; Vallejo et al. 1987; White et al. 1984); Zisook et al. 1985). Although early studies of relatively low-dose regimens suggested that the efficacy of MAOIs was lower than that of TCAs, more recent studies have documented that their efficacy is comparable (Table 18–2). TABLE 18–2. Indications for use of monoamine oxidase inhibitors (MAOIs) Definitely effective

Other possible uses

Atypical depression

OCD

Major depression

Narcolepsy

Dysthymia

Headache

Melancholia

Chronic pain syndrome

Panic disorder

GAD

Definitely effective

Other possible uses

Bulimia Atypical facial pain Anergic depression Treatment-resistant depression Parkinson's diseasea Note. GAD = generalized anxiety disorder; OCD = obsessive-compulsive disorder. a

Selegiline is the only MAOI that is useful in the treatment of Parkinson's disease.

Quitkin et al. (1979, 1991) reviewed both phenelzine and tranylcypromine studies in patients with either atypical neurotic depression or melancholic depression. The authors reported that phenelzine appeared to be effective for the treatment of atypical depression. Relatively few studies of endogenous depression in patients have been done. From the limited number of initial patient studies, it is difficult to conclude that phenelzine is effective in the treatment of these patients. In addition, very few well-controlled studies of tranylcypromine, compared with placebo, have been done. Three of the four studies that compared tranylcypromine with placebo showed that tranylcypromine was more effective. In one study, a nonsignificant trend was found favoring tranylcypromine. More recently, studies have documented the efficacy of tranylcypromine in treating anergic depression and, at high doses, treatment-resistant depression (Himmelhoch et al. 1982, 1991; Thase et al. 1992; White et al. 1984). In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, patients who had failed to respond to at least three treatment options were randomly assigned to tranylcypromine or a combination of venlafaxine and mirtazapine. Remission rates were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group, and the rates were not statistically different between groups (McGrath et al. 2006). The heterogeneity of acetylation rate may account for some of the variance in response to phenelzine (Johnstone 1975; Johnstone and Marsh 1973; Paykel et al. 1982; Rowan et al. 1981). One-half of the patients in a given population are often slow acetylators. An initial study by Johnstone and Marsh (1973) suggested that slow acetylators improve more with phenelzine than do fast acetylators. Other groups have been unable to confirm the relation between acetylation, acetylator type, and response to MAOIs. MAOIs are used in a wide range of psychiatric disorders. Early studies suggested that MAOIs are particularly effective in patients who have atypical depression, originally defined as depression with anxiety or chronic pain, reversed vegetative symptoms, and rejection sensitivity (Quitkin et al. 1990). The concept of atypical depression remains controversial and has not been completely validated. In general, patients with atypical depression have an earlier age at onset than do patients with melancholic depression, and the prevalence of dysthymia, alcohol abuse, sociopathy, and atypical depression is increased in the relatives of patients with atypical depression. The best differentiating criterion appears to be that phenelzine and other irreversible MAOIs are more effective than TCAs in treating these patients (Cesura and Pletscher 1992; Quitkin et al. 1990; Zisook et al. 1985). Some studies have also suggested that MAOIs are effective in treating typical major depression and melancholic depression (Davidson et al. 1987a; McGrath et al. 1986; Vallejo et al. 1987).

Panic Disorder Both single- and double-blind studies have found that phenelzine and iproniazid are effective in treating panic disorder (Lydiard et al. 1989; Quitkin et al. 1990; Tyrer et al. 1973). About 50%–60% of patients with panic disorder respond to MAOIs. In the early stages of treatment, patients may have

a worsening of symptoms. This is reduced in clinical practice by combining the MAOI with a benzodiazepine for the initial phase of the study. It has been suggested that in addition to its antipanic effect, phenelzine has an antiphobic action (Kelly et al. 1971). The time course of effect and the dose used are similar to those for major depression.

Social Phobia Liebowitz et al. (1992) reported that phenelzine is effective in treating social phobia. In an open-label study, Versiani et al. (1988) suggested that tranylcypromine is effective. Versiani et al. (1992) also demonstrated the efficacy of moclobemide in a double-blind study. In clinical experience, about 50% of patients respond to MAOIs, and the onset of response is gradual (usually about 2–3 weeks).

Obsessive-Compulsive Disorder Although initial case reports suggested that MAOIs may be effective in obsessive-compulsive disorder (Jenike 1981), no double-blind studies have indicated efficacy.

Posttraumatic Stress Disorder The classic MAOI phenelzine has been proven effective for the treatment of posttraumatic stress disorder (PTSD) in single-blind trials (Davidson et al. 1987b) and a double-blind crossover trial (Kosten et al. 1991).

Generalized Anxiety Disorder MAOIs are not usually used to treat generalized anxiety disorder (GAD) because the risk–benefit ratio favors the use of selective serotonin reuptake inhibitors (SSRIs), azaspirones, or benzodiazepines. When they are used, MAOIs are used primarily for treating treatment-resistant GAD.

Bulimia Nervosa Both phenelzine and isocarboxazid have been shown to be effective in treating some symptoms of bulimia nervosa (Kennedy et al. 1988; McElroy et al. 1989; Walsh et al. 1985, 1987).

Premenstrual Dysphoria Preliminary studies and clinical experience suggest that MAOIs may be effective in the treatment of premenstrual dysphoria (Glick et al. 1991).

Chronic Pain MAOIs are believed to be effective in the treatment of atypical facial pain and other chronic pain syndromes. However, only limited data on these conditions are available.

Neurological Diseases The classic MAOIs have not been found to be effective for treating neurological disorders such as Parkinson's disease and Alzheimer's dementia. However, the MAO-B inhibitor selegiline has been shown to be effective in slowing the progression of Parkinson's disease (Cesura and Pletscher 1992), but the mechanism underlying this effect is unknown.

SIDE EFFECTS AND TOXICOLOGY The side effects of MAOIs are generally more severe or frequent than those of other antidepressants (Zisook 1984). The most frequent side effects include dizziness, headache, dry mouth, insomnia, constipation, blurred vision, nausea, peripheral edema, forgetfulness, fainting spells, trauma, hesitancy of urination, weakness, and myoclonic jerks. Loss of weight and appetite may occur with isocarboxazid use (Davidson and Turnbull 1982). Hepatotoxicity is more rare with the currently available MAOIs, compared with iproniazid. However, liver enzymes, such as aspartate transaminase

(AST) and alanine transaminase (ALT), are elevated in 3%–5% of patients. Liver function tests must be done only when patients have symptoms like malaise, jaundice, and excessive fatigue. Some side effects first emerge during maintenance treatment (Evans et al. 1982). These side effects include weight gain (which occurs in almost one-half of patients), edema, muscle cramps, carbohydrate craving, sexual dysfunction (usually anorgasmia), pyridoxine deficiency (see Goodheart et al. 1991), hypoglycemia, hypomania, urinary retention, and disorientation. Peripheral neuropathy (Goodheart et al. 1991) and speech blockage (Goldstein and Goldberg 1986) are rare side effects of MAOIs. Weight gain is more of a problem with hydrazine compounds, such as phenelzine, than with tranylcypromine. Therefore, weight gain that is caused by hydrazine derivatives is an indication to switch to tranylcypromine. Edema is also more common with phenelzine than with tranylcypromine. The management of some of these side effects can be problematic. Orthostatic hypotension is common with MAOIs. Addition of salt and salt-retaining steroids, such as fluorohydrocortisone, is sometimes effective in treating orthostatic hypotension. Elastic support stockings are also helpful. Small amounts of coffee or tea taken during the day also keep the blood pressure elevated. The dose of fluorohydrocortisol should be adjusted carefully because in elderly patients it could provoke cardiac failure resulting from fluid retention. Sexual dysfunction that occurs with these compounds is also difficult to treat. Common problems include anorgasmia, decreased libido, impotence, and delayed ejaculation (Harrison et al. 1985; Jacobson 1987). Cyproheptadine is sometimes effective in treating sexual dysfunction like anorgasmia. Bethanechol may also be effective in some patients. Insomnia occasionally occurs as an intermediate or late side effect of these compounds. Changing the time of administration does not seem to help much, although dosage reduction may be helpful. Adding trazodone at bedtime is effective, but this should be done with caution. Myoclonic jerks, peripheral neuropathy, and paresthesia, when present, are also difficult to treat. When a patient has paresthesia, the clinician should evaluate for peripheral neuropathy and pyridoxine deficiency. In general, patients taking MAOIs should also take concomitant pyridoxine therapy. When myoclonic jerks occur, patients can be treated with cyproheptadine. MAOIs also have the potential to suppress anginal pain; therefore, coronary artery disease could be overlooked or underestimated. Patients with hyperthyroidism are more sensitive to MAOIs because of their overall sensitivity to pressor amines. MAOIs can also worsen hypoglycemia in patients taking hypoglycemic agents like insulin.

DIETARY INTERACTIONS After the introduction of MAOIs, several reports of severe headaches in patients who were taking these compounds were published ("Cheese and Tranylcypromine" 1970; Cronin 1965; Hedberg et al. 1966; Simpson and Gratz 1992). These headaches were caused by a drug–food interaction. The risk of such an interaction is highest for tranylcypromine and lower for phenelzine, provided that the dose of the latter remains low. The interaction of MAOIs with food has been attributed to increased tyramine levels. Tyramine, which has a pressor action, is present in a number of foodstuffs. It is normally broken down by the MAO enzymes and has both direct and indirect sympathomimetic actions. The classic explanation of this side effect may not be entirely accurate; in fact, it has been suggested that the potentiation of tyramine by an MAOI may be secondary to increased release of NE rather than to the MAOI. Adrenaline would increase the indirect sympathetic activity of tyramine. The spontaneous occurrence of hypertensive crises in a few patients lends support to this hypothesis (O'Brien et al. 1992; Zajecka and Fawcett 1991). The tyramine effect of food is potentiated by MAOIs 10- to 20-fold. A mild tyramine interaction occurs

with about 6 mg of tyramine; 10 mg can produce a moderate episode, and 25 mg can produce a severe episode that is characterized by hypertension, occipital headache, palpitations, nausea, vomiting, apprehension, occasional chills, sweating, and restlessness. On examination, neck stiffness, pallor, mild pyrexia, dilated pupils, and motor agitation may be seen. The reaction usually develops within 20–60 minutes after ingestion of food. Occasionally, the reaction can be very severe and may lead to alteration of consciousness, hyperpyrexia, cerebral hemorrhage, and death. Death is exceedingly rare and has been calculated to be about 0.01%–0.02% for all patients taking tranylcypromine. The classic treatment of the hypertensive reaction is phentolamine (5 mg) administered intravenously (Youdim et al. 1987; Zisook 1984). More recently, nifedipine, a calcium channel blocker, has been shown to be effective. Nifedipine has an onset of action of about 5 minutes, and it lasts approximately 3–5 hours; in fact, some clinicians have suggested that patients should carry nifedipine with them for immediate use in the event of a hypertensive crisis. Because of the drug interaction of the classic MAOIs with food, clinicians usually make several dietary recommendations (Table 18–3). These recommendations are quite varied. TABLE 18–3. Food restrictions for monoamine oxidase inhibitors (MAOIs) To be avoided

To be used in moderation

Cheese (except for cream cheese)

Coffee

Overripe (aged) fruit (e.g., banana peel)

Chocolate

Fava beans

Colas

Sausage, salami

Tea

Sherry, liqueurs

Soy sauce

Sauerkraut

Beer, other wines

Monosodium glutamate Pickled fish Brewer's yeast Beef and chicken liver Fermented products Red wine All of the MAOI diets recommend restriction of cheese (with the exception of cream cheese and cottage cheese), red wine, sherry, liqueurs, pickled fish, overripe (aged) fruit, brewer's yeast, fava beans, beef and chicken liver, and fermented products. Other diets also recommend restriction of all alcoholic beverages, coffee, chocolate, colas, tea, yogurt, soy sauce, avocados, and bananas. The more restrictive the diet, the greater the risk of patient noncompliance. Furthermore, many of the compounds—for example, avocados and bananas—rarely cause hypertensive crisis. For example, an interaction may occur only if overripe fruit is eaten or, in the case of bananas, if the skin is eaten (which is an uncommon practice in the United States). Similarly, unless a person ingests large amounts of caffeine, the interaction is usually not clinically significant. In evaluating patients who have had a drug–food reaction, it is also important to evaluate the hypertensive reaction and differentiate it from histamine headache, which can occur with an MAOI. Histamine headaches are usually accompanied by hypotension, colic, loose stools, salivation, and lacrimation (Cooper 1967). The clinician should provide oral instructions, as well as printed cards, outlining these instructions to patients who are taking classic MAOIs.

In addition to the food interaction, drug interactions are extremely important (see next section, "Drug–Drug Interactions"). Each patient should be given a card indicating that he or she is taking an MAOI and instructions that the card should be carried at all times. A medical bracelet indicating that the wearer takes an MAOI is also a good idea.

DRUG–DRUG INTERACTIONS The extensive inhibition of MAO enzymes by MAOIs raises the potential for a number of drug interactions (Table 18–4). Of particular importance, many over-the-counter medications can interact with MAOIs. These medications include cough syrups containing sympathomimetic agents, which in the presence of an MAOI can precipitate a hypertensive crisis. TABLE 18–4. Drug interactions with monoamine oxidase inhibitors (MAOIs) Drug

Interaction

Comment Allow at least 1 week before changing MAOI

Other MAOIs (e.g., furazolidone,

Potentiation of side effects;

pargyline, procarbazine)

convulsions possible

Tricyclic antidepressants (TCAs)

Severe side effects, such as

Allow at least 2 weeks before changing MAOI;

(e.g., maprotiline, bupropion)

hypertension and convulsions,

combinations have been used occasionally for

possible

refractory depression

Low possibility of interaction;

Same as for TCAs

Carbamazepine

similar to TCAs Cyclobenzaprine

Low possibility of interaction;

Same as for TCAs

similar to TCAs Selective serotonin reuptake

Serotonin syndrome

inhibitors (SSRIs)

Avoid combinations; allow at least 2 weeks before changing MAOI and 5 weeks if switching from fluoxetine to MAOI

Stimulants (e.g.,

Potential for increased blood

methylphenidate,

pressure (hypertension)

Avoid combination

dextroamphetamine) Buspirone

Potential for increased blood

Avoid use; if used, monitor blood pressure

pressure (hypertension) Meperidine

Severe, potentially fatal

Avoid combination

interaction possible (see text) Dextromethorphan

Reports of brief psychosis

Direct sympathomimetics (e.g.,

Increased blood pressure

L-dopa)

Indirect sympathomimetics

Avoid high doses Avoid use, if possible; if they need to be used, use with caution

Hypertensive crisis possible

Oral hypoglycemics (e.g., insulin) Worsening of hypoglycemia

Avoid use Monitor blood sugar levels and adjust

possible

medications

Fenfluramine

Serotonin syndrome possible

Avoid use

L-Tryptophan

Serotonin syndrome possible

Avoid use

Another area of caution is the use of MAOIs in patients who need surgery. In this situation, interactions include those with narcotic drugs, especially meperidine. Meperidine administered with MAOIs can produce a syndrome characterized by coma, hyperpyrexia, and hypertension. This syndrome has been reported primarily with phenelzine; however, it has also been reported with tranylcypromine (Mendelson 1979; Stack et al. 1988). Stack et al. (1988) noted that this syndrome is

most likely to occur with meperidine and that it may be related to that drug's serotonergic properties. Similar reactions have not been reported to any significant extent with other narcotic analgesics such as morphine and codeine. In fact, many patients probably receive these medications without problems. Only a small fraction of patients may have this interaction, and it could reflect an idiosyncratic effect. In general, current opinion favors the use of morphine or fentanyl when intra- or postoperative narcotics are needed in patients taking MAOIs. The issue of whether directly acting sympathomimetic amines interact with MAOIs is more controversial. Intravenous administration of sympathomimetic amines to patients receiving MAOIs does not provoke hypertension. When a bolus infusion of catecholamines is given to healthy volunteer subjects who have been taking phenelzine or tranylcypromine for 1 week, a potentiation of the pressor effect of phenylephrine occurs, but no clinically significant potentiation of cardiovascular effects of NE, epinephrine, or isoproterenol occurs (Wells 1989). In general, direct sympathomimetic amine–MAOI interactions do not appear to produce significant cardiovascular problems. However, there is a low incidence of hypertensive episodes in the presence of indirect sympathomimetics. Ideally, these compounds should not be used in those patients who are receiving MAOIs. A direct-acting compound is preferable to an indirect-acting compound. Caution should be exercised when using MAOIs in patients with pheochromocytoma and cardiovascular, cerebrovascular, and hepatic disease. Because phenelzine tablets contain gluten, they should not be given to patients with celiac disease.

SPECIFIC MONOAMINE OXIDASE INHIBITORS Phenelzine Phenelzine, a hydrazine derivative, is a potent MAOI and the best studied among the MAOIs.

Pharmacokinetics Phenelzine is a substrate as well as an inhibitor of MAO, and major identified metabolites of phenelzine include phenylacetic acid and p-hydroxyphenylacetic acid. Phenelzine undergoes acetylation, and therefore drug levels are lower in fast acetylators than in slow acetylators. However, because phenelzine is an irreversible inhibitor, plasma concentrations are not relevant. The antidepressant effect, the degree of inhibition of MAO, and the amount of free phenelzine excreted in the urine are all significantly greater in slow acetylators than in fast acetylators (Baker et al. 1999).

Efficacy Phenelzine is useful in the treatment of major depression, atypical depression, panic disorder, social phobia, and atypical facial pain (see section "Indications and Efficacy" presented earlier in this chapter).

Side Effects The primary side effects of phenelzine are similar to those of other MAOIs. Hepatitis secondary to phenelzine may occur. This effect is quite rare (

Chapter 19. Trazodone and Nefazodone TRAZODONE AND NEFAZODONE: INTRODUCTION Trazodone was among the earliest "second generation" antidepressants to become available for clinical use in the United States in the early 1980s. Its side-effect profile and potential toxicity were considerably different from and, in many instances preferable to, those of the original antidepressants (i.e., the monoamine oxidase inhibitors [MAOIs] and tricyclic antidepressants [TCAs]). Several years later, its pharmacological "cousin," nefazodone, joined the growing armamentarium of effective antidepressant medications.

TRAZODONE History and Discovery Trazodone was first synthesized in Italy about three decades ago, and clinical studies began in the United States in 1978. Trazodone was different from the conventional antidepressants that were available at that time in several ways. It was the first triazolopyridine derivative to be developed as an antidepressant. In addition, it was developed as an outgrowth of a specific hypothesis (i.e., that depression is caused by an imbalance in the brain mechanisms responsible for the emotional integration of adverse unpleasant experiences). For this reason, new animal models that measured the response to noxious stimuli or situations were used as screening tests for developing the drug. In fact, trazodone is inactive in classic antidepressant screening tests, such as the reserpine model, the potentiation of yohimbine toxicity, and the behavioral despair/forced swim paradigm, yet it inhibits painful and conditioned emotional responses (Silvestrini 1980). Trazodone shares with the phenothiazines the ability to suppress self-stimulation behavior and amphetamine effects, and it produces substantial blockade of

-adrenergic receptors. In sharp contrast to most other

antidepressants available at the time of its development, trazodone showed minimal effects on muscarinic cholinergic receptors. In 1982, trazodone was introduced for clinical use in the United States under the brand name Desyrel. It quickly became a widely prescribed medication, capturing up to one-third of the American market. More recently, the availability of the extremely popular selective serotonin reuptake inhibitors (SSRIs) has led to a decline in trazodone use. The medication is now available in generic formulation.

Structure–Activity Relations Trazodone is chemically unrelated to other antidepressant drugs, although it does resemble some of the side-chain components of TCAs and the phenothiazines. Its structure (Figure 19–1) includes a triazole moiety that may be linked to its antidepressant activity. FIGURE 19–1. Chemical structure of trazodone.

Pharmacological Profile The effects of trazodone on serotonergic systems are complex. Trazodone is a relatively weak SSRI, compared with the more potent SSRIs such as fluoxetine or paroxetine. However, it is relatively specific for serotonin (5-HT) uptake inhibition, with minimal effects on norepinephrine (NE) or dopamine reuptake (Hyttel 1982). In the rat, systemic administration of trazodone leads to fivefold increases in extracellular 5-HT concentrations in the frontal cortex, which can be blocked by pretreatment with fluoxetine. Direct administration into the frontal cortex via reverse dialysis also elicits increases in extracellular 5-HT levels that are reduced by local perfusion of ketanserin. Thus, trazodone appears to increase extracellular 5-HT concentrations through a combination of mechanisms involving the 5-HT transporter (5-HTT) and the serotonin2A/2C (5-HT2A/2C) receptors (Pazzagli et al. 1999). In addition, trazodone has some 5-HT receptor antagonist activity, particularly at serotonin1A (5-HT1A), serotonin1C (5-HT1C), and serotonin2 (5-HT2) receptor subtypes (Haria et al. 1994). Furthermore, its active metabolite, m-chlorophenylpiperazine (m-CPP), is a potent direct 5-HT agonist. Thus, trazodone can be viewed as a mixed serotonergic agonist–antagonist, with the relative amount of m-CPP accumulation affecting the relative degree of the predominant agonist activity. In vivo, trazodone is virtually devoid of anticholinergic activity, and in clinical studies, the incidence of anticholinergic side effects is similar to that seen with placebo. Trazodone is a relatively weak blocker of presynaptic

2-adrenergic

receptors and a relatively potent antagonist of postsynaptic

1-adrenergic receptors. The latter property probably accounts for its propensity to cause orthostatic

hypotension. Trazodone has moderate antihistaminergic (histamine1 [H1] receptor) activity.

Pharmacokinetics and Disposition Trazodone is well absorbed after oral administration, with peak blood levels occurring about 1 hour after dosing when the drug is taken on an empty stomach and about 2 hours after dosing when the drug is taken with food. Trazodone is 89%–95% bound to plasma protein. Elimination appears to be biphasic, consisting of an initial alpha phase followed by a slower beta phase, with half-lives of 3–6 and 5–9 hours, respectively. Bioavailability is not influenced by age or by food intake. Gender differences are inconsistent. Trazodone undergoes extensive hepatic metabolism, including hydroxylation, splitting at the pyridine ring, oxidation, and N-oxidation. Less than 1% of the drug is excreted unchanged in feces and urine. The active metabolite m-CPP is cleared more slowly than the parent compound (4- to 14-hour half-life) and reaches higher concentrations in the brain than in plasma (Caccia et al. 1981). The cytochrome P450 (CYP) 2D6 and 3A microsomal enzyme systems also appear to play a role in trazodone metabolism. CYP3A inhibitors (e.g., ketoconazole, ritonavir, indinavir) inhibit trazodone clearance (see Zalma et al. 2000), and ketoconazole inhibits m-CPP formation (Rotzinger et al. 1998). The relation between steady-state blood levels and clinical response to trazodone is unclear. In a study involving geriatric patients, plasma concentrations of trazodone were lower in responders compared with nonresponders (Spar 1987). However, this study was limited by the lack of a

fixed-dose design (increasing the chances that patients who were destined to be nonresponders would have continued dose increases, yielding relatively higher plasma levels) and a small sample size. Another study of geriatric patients found a positive relation between steady-state trazodone plasma concentrations and clinical response in a sample of 11 subjects (Monteleone and Gnocchi 1990).

Mechanism of Action The ultimate mechanism of action of trazodone remains unclear. Although the drug is often referred to as a 5-HT reuptake inhibitor, such labeling overlooks the complexity of its effects on this neurotransmitter system. Binding studies confirm that trazodone has relative selectivity for 5-HT reuptake sites (Hyttel 1982); however, in vivo, it blocks the head twitch response induced by classic 5-HT agonists in animals. The potent 5-HT agonist properties of trazodone's major metabolite, m-CPP, may play a role in the mechanism of action of the parent compound. Trazodone, unlike the vast majority of antidepressants, does not produce downregulation of

-adrenergic receptors in rat cortex

(Sulser 1983).

Indications and Efficacy The primary indication for trazodone is the treatment of major depression. In a review of the double-blind studies published after the release of trazodone in this country, Schatzberg (1987) found the therapeutic efficacy of trazodone to be similar to that of TCAs in patients with either endogenous or nonendogenous depression. A review of the European literature by Lader (1987) yielded similar findings: data from open and double-blind trials suggest that the antidepressant efficacy of trazodone is comparable to that of amitriptyline, doxepin, and mianserin. Also, trazodone showed anxiolytic properties, low cardiotoxicity, and relatively mild side effects in the European studies. Questions have been raised about the effectiveness of trazodone in treating severely ill patients, especially those with prominent psychomotor retardation (Klein and Muller 1985). Shopsin et al. (1981) pointed out that in several unpublished double-blind, controlled studies, the rates of clinical response to trazodone were low (i.e., 10%–20%). Lader (1987) acknowledged that the numbers of patients with psychomotor retardation in the reported studies are too small to resolve the controversy regarding the efficacy of trazodone in this population. The performance of trazodone, in direct comparisons with other second-generation antidepressants, has been mixed. In a double-blind, placebo-controlled comparison with venlafaxine, the final response rates were 55% for placebo, 60% for trazodone, and 72% for venlafaxine. Trazodone was more effective than venlafaxine in ameliorating sleep disturbances and was associated with the most dizziness and somnolence (Cunningham et al. 1994). In a double-blind comparison, response rates for trazodone and bupropion were 46% and 58%, respectively (see Weisler et al. 1994). In a double-blind study of 200 hospitalized patients with moderate to severe major depressive episode, mirtazapine yielded greater reductions in depression ratings than did trazodone (van Moffaert et al. 1995). Because trazodone has minimal anticholinergic activity, it was especially welcomed as a treatment for geriatric patients with depression when it first became available. Three double-blind studies reported that trazodone has antidepressant efficacy similar to that of other antidepressants in geriatric patients (Gerner 1987). However, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falls, can have devastating consequences in elderly patients; thus, this side effect, along with sedation, often makes trazodone less acceptable in this population, compared with newer compounds that share its lack of anticholinergic activity but not the rest of its side-effect profile. Still, trazodone is often helpful for geriatric patients with depression who have severe agitation and insomnia. A recent survey of British geropsychiatrists identified trazodone as one of their most popular adjuncts or alternatives to atypical antipsychotics in the management of

behavioral symptoms in the elderly (Condren and Cooney 2001). A randomized, controlled trial found that trazodone, haloperidol, behavioral management techniques, and placebo each produced comparable modest reductions in agitation associated with Alzheimer's disease (Teri et al. 2001). Another double-blind study reported comparable therapeutic effects for trazodone and haloperidol in the treatment of dementia-associated agitated behaviors, with more common adverse effects in the latter group (Sultzer et al. 1997). A recent Cochrane Database review found insufficient evidence to support trazodone as a treatment for the behavioral and psychological symptoms of dementia, although the review could not conclude that trazodone was ineffective, given the limited number of eligible studies (Martinon-Torres et al. 2004). Trazodone has also been reported to have antianxiety properties. In a randomized, double-blind, placebo-controlled trial, the anxiolytic efficacy of trazodone was comparable to that of diazepam in weeks 3–8 of treatment for generalized anxiety disorder, although patients treated with diazepam had greater improvement during the first 2 weeks of treatment (Rickels et al. 1993). Early case reports had indicated that trazodone is associated with improvement in obsessive-compulsive disorder, but a double-blind, placebo-controlled study found that trazodone lacked antiobsessional effects (Pigott et al. 1992). Many clinicians use low-dose trazodone as an alternative to benzodiazepines for the treatment of insomnia. Two recent reviews found that trazodone is the second most prescribed agent for insomnia, even though there is minimal evidence to support its use for this indication (Mendelson 2005; Rosenberg 2006). Mendelson (2005) noted that there are few data to support trazodone's use in primary insomnia, because most studies have been limited to patients with depression. In addition, the available literature is characterized by small sample sizes, limited control groups, and weak statistical analyses. Rosenberg (2006) arrived at very similar conclusions. Controlled trials have confirmed trazodone's efficacy (at doses of 50–100 mg) in treating insomnia that occurs as a side effect of some antidepressants (Nierenberg et al. 1994). A retrospective analysis at a Department of Veterans Affairs (VA) medical center found that approximately 24% of patients receiving trazodone were taking other primary antidepressants (Clark and Alexander 2000). Another VA study of patients with posttraumatic stress disorder (PTSD) found that of those patients who were able to tolerate trazodone (60 of 72 patients), 92% reported that it improved sleep onset and 78% reported that it improved sleep maintenance (Warner et al. 2001). Trazodone has been investigated as a treatment for adjustment disorders in medically ill populations. A randomized, double-blind study found a trend toward greater efficacy in trazodone, compared with clorazepate, in the management of adjustment disorders in patients with breast cancer (Razavi et al. 1999). A similar trend was noted in a study of adjustment disorders in patients who tested positive for HIV (DeWit et al. 1999). A handful of reports have described the use of trazodone in the treatment of bulimia nervosa, including a well-designed placebo-controlled trial that found trazodone to be superior to placebo in reducing the frequency of episodes of binge eating and vomiting (Hudson et al. 1989). In addition, trazodone has been found to be effective in the treatment of erectile dysfunction in some (e.g., Lance et al. 1995), but not all (e.g., Costabile and Spevak 1999), studies. Whether prescribed as an antidepressant or a hypnotic, trazodone should always be initiated at a low dose and increased gradually, based on clinical response and tolerance to side effects. For the treatment of a major depressive episode, the suggested initial dosage is 150 mg/day, with increases of 50-mg increments every 3–4 days. Doses may be divided, although many patients prefer bedtime dosing because of the sedating effects. The maximum dosage recommended for outpatients is 400 mg/day, although for inpatients with more severe depression, dosages up to 600 mg/day have been used. When trazodone is prescribed as a hypnotic agent, the usual dose is 50 mg at bedtime, although some patients may require as little as 25 mg or as much as 200–300 mg.

Side Effects and Toxicology Because of its lack of anticholinergic side effects, trazodone is especially useful in situations in which antimuscarinic effects are particularly problematic (e.g., in patients with prostatic hypertrophy, closed-angle glaucoma, or severe constipation). Trazodone's propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for other patients, including those individuals with considerable psychomotor retardation and feelings of low energy, therapeutic doses of trazodone may not be tolerable because of sedation. Trazodone elicits orthostatic hypotension in some patients, probably as a consequence of 1-adrenergic

receptor blockade. Trazodone-related syncope in the elderly has been described in the

literature (Nambudiri et al. 1989). A study of nursing home residents, however, found no increased rate of falls during the initiation of trazodone therapy, compared with tricyclic or SSRI therapy (Thapa et al. 1998). By contrast, trazodone was found to be among the top three medications associated with orthostatic hypotension in patients attending a VA geriatric clinic (Poon and Braun 2005). Case reports have noted cardiac arrhythmias emerging in relation to trazodone treatment, both in patients with preexisting mitral valve prolapse and in patients with negative personal and family histories of cardiac disease (see Janowsky et al. 1983; Lippman et al. 1983; Winkler et al. 2006). A relatively rare, but dramatic, side effect associated with trazodone is priapism. More than 200 cases have been reported (Thompson et al. 1990), and the manufacturer estimates that the incidence of any abnormal erectile function is approximately 1 in 6,000 male patients treated with trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e.,

Chapter 20. Bupropion HISTORY AND DISCOVERY Bupropion was discovered more than 40 years ago when investigators were searching for an antidepressant with a novel mechanism of action and safer side-effect profile. Synthesized in 1966, this unique compound, different from tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), was found to have antidepressant activity in animal models that are predictive of antidepressant activity in humans (Soroko and Maxwell 1983). Bupropion was discovered to have minimal sympathomimetic and anticholinergic side effects and a safer pharmacological and biochemical profile in comparison with other antidepressants. Although both bupropion and selective serotonin reuptake inhibitors (SSRIs) were developed with similar goals in mind, their mechanisms of action are unique (Hudziak and Rettew 2004; Soroko and Maxwell 1983). Bupropion is classified as an aminoketone antidepressant (Mehta 1983). Its mechanism of action is thought to be via dual inhibition of norepinephrine and dopamine reuptake (NDRI) without clinically significant serotonin reuptake inhibition (Horst and Preskorn 1998; Stahl et al. 2004). Both bupropion and SSRIs appear to be equally efficacious in the treatment of major depression (Feighner et al. 1991). The sustained-release (bupropion SR) formulation, approved in 1996, has also proved to be significantly better than placebo in preventing depression relapse (Weihs et al. 2002). Bupropion's tolerability is superior to that of SSRIs, with minimal effects on weight, less sedation, minimal withdrawal symptoms upon discontinuation, and fewer or no sexual side effects (Thase et al. 2005). Besides treatment of major depression, bupropion has proven effective across a wide range of depressive conditions, subtypes, and comorbidities (Clayton 2007). These include major depression with concomitant anxiety, depression in the elderly, smoking cessation, attention-deficit/hyperactivity disorder (ADHD), obesity, hypoactive sexual desire disorder, and seasonal affective disorder (SAD). It has also been effective in bipolar depression and as an augmentation agent in patients with partial response to SSRIs. Overall, bupropion is a unique antidepressant with a broad therapeutic spectrum and a superior tolerability profile. Bupropion first received U.S. Food and Drug Administration (FDA) approval in 1985. It was on the brink of release when a study by Horne et al. (1988) reported that 4 of 55 subjects with bulimia experienced seizures during treatment with the medication. Bupropion was withdrawn from the market pending additional investigation of its effects on seizure thresholds. Further research revealed that the risk of seizures increased from 0.3% to 0.4% at dosages of 450 mg/day to almost 2% at dosages of 600 mg/day. Bupropion was reintroduced in 1989 with a maximum recommended dosage of 450 mg/day (Davidson 1989). The original immediate-release (IR) formulation of bupropion was dosed three times daily. In an effort to improve tolerability and safety, a sustained-release (SR) formulation of bupropion, dosed twice daily, was subsequently introduced, and a once-daily extendedrelease (XL) formulation became available in 2003. Bupropion XL is now the most commonly prescribed formulation, as once-daily dosing is thought to optimize tolerability and adherence (McLaughlin et al. 2007). Among its many uses stated above, this medication was also FDA approved for the indication of smoking cessation under the name Zyban in 1997, and bupropion XL was FDA approved for

prophylaxis of seasonal depression in 2006. Over time, investigators continue to discover more uses and indications for this multifaceted medication.

STRUCTURE–ACTIVITY RELATIONS Bupropion, 2-(tert-butylamino)-1-(3'-chlorophenyl)propan-1-one, is a monocyclic antidepressant and member of the aminoketone group (Figure 20–1). It was designed as a simple chemical structure that would, in vivo, result in relatively innocuous metabolites (Mehta 1983). Bupropion works as an organic base with a high degree of both water and lipid solubility, resulting in good systemic absorption. Its benign side-effect profile in comparison with that of tricyclic and tetracyclic antidepressants is due to the absence of heterocyclic rings as well as other common functional groups (Mehta 1983). Bupropion has little potential for abuse (Griffith et al. 1983). Mehta (1983) discussed the many significant differences between the chemical structures of bupropion and psychostimulants and accounted for the varying pharmacological and clinical effects (Hudziak and Rettew 2004). FIGURE 20–1. Chemical structure of bupropion.

PHARMACOLOGICAL PROFILE Although similar to classical antidepressants such as TCAs and SSRIs in therapeutic efficacy, bupropion is considered to be an atypical antidepressant with a mixed neuropharmacological profile. Bupropion inhibits the reuptake of dopamine (DA) and norepinephrine (NE) by acting as a nonselective inhibitor of the dopamine transporter (DAT) and the norepinephrine transporter (NET). Studies show that bupropion also acts as an antagonist to nicotinic acetylcholine (nACh) receptors. Alternatively, bupropion does not act as an inhibitor of monoamine oxidase A or B, nor are the effects of bupropion mediated by serotonin (Ascher et al. 1995). Dwoskin et al. (2006) reported that bupropion inhibits DA reuptake into rat striatal synaptosomes, NE reuptake into rat hypothalamic synaptosomes, and, less potently, serotonergic reuptake into rat hypothalamic synaptosomes (Ascher et al. 1995; Dwoskin et al. 2006; Ferris and Beaman 1983; Ferris et al. 1982; Workman and Short 1993). In fact, Ferris et al. (1983) reported that bupropion is six times more potent than imipramine in blocking DA reuptake. Recent studies demonstrate that bupropion also raises DA concentrations by causing a rapid and reversible increase in vesicular DA reuptake via cellular redistribution of the vesicular monoamine transporter (VMAT2) protein. By increasing the presynaptic pool of DA available for release, the concentration of DA in the extracellular space is further augmented, adding to the therapeutic efficacy of this compound (Dwoskin et al. 2006; Rau et al. 2005). Although more is known about the dopaminergic effects of bupropion, interaction with the

noradrenergic system also plays an important role in the drug's antidepressant activity. Bupropion is a weak competitive inhibitor of NE; in comparison with imipramine, it is 65-fold less potent (Ferris and Beaman 1983). Along with inhibiting DA reuptake and NE function, bupropion has also been found to act as an nACh receptor antagonist. Research with various cellular expression systems has elucidated the ability of bupropion to interact with specific nACh receptors. Bupropion has been shown to work by noncompetitive inhibition of nACh receptors (Dwoskin et al. 2006). This action may partially contribute to the efficacy of bupropion not only as an antidepressant but also as an agent for tobacco cessation. It has been noted that bupropion shares some structural and neurochemical properties with sympathomimetics and has a phenylethylamine skeleton similar to that of amphetamine. Although it resembles amphetamine in certain structural aspects, bupropion does not increase the spontaneous release of catacholamines in rat striatum and hypothalamus. A study by Griffith et al. (1983) examining the effect of bupropion and amphetamine in previous amphetamine abusers concluded that bupropion had little abuse potential in humans. Although a great deal remains to be learned about the complete pharmacological profile of bupropion, what we do know is significant. In summary, bupropion is known to be an atypical antidepressant with a mixed pharmacological profile. It exerts its effect by blocking DA and NE reuptake as well as by antagonizing nACh receptors. It does not work through inhibition of monoamine oxidase and does not block serotonin reuptake. As Dwoskin et al. (2006) emphasized, in the future it will be important to elucidate which specific mechanism, or combination of mechanisms, is responsible for the clinical efficacy of bupropion.

PHARMACOKINETICS AND DISPOSITION Bupropion is rapidly absorbed in the gastrointestinal tract after oral administration (Findlay et al. 1981; Jefferson et al. 2005). Absorption has been found to be close to 100% (Schroeder 1983). After first-pass metabolism, systemic bioavailability of the drug is decreased (Jefferson et al. 2005; Schroeder 1983). Peak plasma levels occur within 2 hours for the IR preparation. As expected, absorption is prolonged for the SR and XL formulations, for which peak plasma concentrations occur at 3 and 5 hours, respectively (Jefferson et al. 2005). Although absorption times differ, the three forms are considered to be bioequivalent (Fava et al. 2005; Jefferson et al. 2005; Physicians' Desk Reference 2005). Food does not impair absorption, and protein binding ranges from 82% to 88%. Jefferson et al. (2005) noted that this level of protein binding is not high and is not likely to be of clinical importance. The elimination half-life for bupropion is 21(±9) hours, and the half-life for hydroxybupropion, the major metabolite of bupropion, is close to 20 (±5) hours (Clayton 2007; Jefferson et al. 2005). Steady state occurs in 7–10 days. Finally, excretion in the urine occurs with 0.5% of the drug unchanged (Findlay et al. 1981). Bupropion is extensively metabolized by the liver. The major metabolite, hydroxybupropion, is formed by cytochrome P450 (CYP) 2B6 (Hesse et al. 2000; Kirchheiner et al. 2003). The peak plasma concentration of hydroxybupropion at steady state is four- to sevenfold higher than that of bupropion. Although CYP2B6 is the primary isoenzyme involved in bupropion's metabolism, other isoforms, including 1A2, 2A6, 2CP, 2D6, 2E1, and 3A4, play a small role (Hesse et al. 2000; Kirchheiner et al. 2003). Bupropion inhibits CYP2B6 and therefore may interfere with drugs that are metabolized by this enzyme, such as desipramine and nortriptyline (Hesse et al. 2000; Jefferson et al. 2005). Besides hydroxybupropion, other active metabolites of bupropion are threohydrobupropion and erythrohydrobupropion. These two pharmacologically active metabolites have the capacity to accumulate at levels nearly five times greater than the parent compound and can have half-lives up to 43 hours (Golden et al. 1988; Jefferson et al. 2005; Posner et al. 1985; Preskorn et al. 1990). In examining the pharmacokinetics of bupropion in regard to gender, age, and smoking status, no

significant effect has been found and definitive results have been inconclusive (Daviss et al. 2006; Hsyu et al. 1997; Jefferson et al. 2005; Stewart et al. 2001; Sweet et al. 1995). Nevertheless, it is important to monitor elderly patients more closely as they often have greater clinical issues with tolerability. One study with the elderly found evidence for an extended half-life of bupropion and for accumulation of metabolites (Sweet et al. 1995). For patients with impaired renal function, dosing should be initiated at lower levels. Worrall et al. (2004) showed that accumulation of two of the metabolites of bupropion—hydroxybupropion and threohydrobupropion—was significantly elevated in patients with end-stage renal disease compared with historical controls. Moreover, the metabolism of bupropion is also negatively affected in hepatic disease. Two studies have found increased levels of both bupropion and hydroxybupropion or of bupropion alone in patients with hepatic dysfunction (DeVane et al. 1990; Jefferson et al. 2005; Physicians' Desk Reference 2005). These results prompted the manufacturer to recommend that bupropion be used with caution in patients with mild to moderate liver disease and with extreme caution in patients with severe liver disease (Physicians' Desk Reference 2005).

MECHANISM OF ACTION Despite considerable time and energy spent in elucidating bupropion's mechanism of action, what we know is limited. Preclinical data indicate that bupropion does not work by binding to postsynaptic histamine,

- or

-adrenergic, or serotonin receptors, nor does it inhibit monoamine oxidase (Ascher

et al. 1995; Baldessarini 2001; Fava et al. 2005; Stahl et al. 2004). Thus, it is the only newer antidepressant without substantial serotonergic activity (Ascher et al. 1995; Richelson 1996; Stahl et al. 2004). Most researchers believe, and there is strong evidence to support, that the neurochemical mechanisms mediating the antidepressant effects of bupropion are from DA and NE reuptake inhibition. As discussed earlier, evidence shows that bupropion is a nonselective inhibitor of the DAT and the NET and is also an antagonist at neuronal nACh receptors (Dwoskin et al. 2006). Bupropion's three major metabolites—hydroxybupropion, threohydrobupropion, and erythrohydrobupropion—play a crucial role in its antidepressant activity (Physicians' Desk Reference 2005). Together, bupropion and its active metabolites have been shown to decrease the reuptake of NE and DA into rat striatal and rat hypothalamic synaptosomes (Ascher et al. 1995; Ferris and Beaman 1983; Ferris et al. 1983; Miller et al. 2002). Moreover, in vitro studies have demonstrated that bupropion and its active metabolites inhibit both the NE and the DA human transporters (described in Fava et al. 2005). Although other antidepressants often produce their effects by downregulation of the postsynaptic noradrenergic receptors, bupropion differs in how it interacts with noradrenergic systems in that it decreases the firing rate of neurons in the locus coeruleus in a dose-dependent manner (B. R. Cooper et al. 1994; T. B. Cooper et al. 1984). Acute administration of bupropion not only decreases firing of brain stem NE and DA neurons but also increases extracellular NE and DA concentrations in the nucleus accumbens (Fava et al. 2005). Furthermore, the efficacy of bupropion and hydroxybupropion has been shown to decrease in animal models when NE- or DA-blocking drugs are administered (B. R. Cooper et al. 1980).

INDICATIONS AND EFFICACY Primary Indications Depression The efficacy of bupropion for the treatment of major depressive disorder is supported by many clinical trials. All three forms have proven to be equally useful in the treatment of depression. In 1983, Fabre et al. published results of a multicenter trial showing that bupropion IR at dosages of 300–600 mg/day was significantly better than placebo in reducing symptoms of depression. This was followed

by a 6-week double-blind, placebo-controlled five-center trial by Lineberry et al. (1990), which supported the conclusion that bupropion IR 300 mg/day was more efficacious than placebo in treating major depressive disorder. In evaluations against TCAs such as doxepin, amitriptyline, and imipramine in several clinical trials, bupropion was demonstrated to be equally efficacious (Branconnier et al. 1983; Feighner et al. 1986; Mendels et al. 1983). These studies also noted the more benign side-effect profile and improved tolerability of bupropion IR in comparison with TCAs. In 1991, Feighner et al. examined the efficacy of bupropion and fluoxetine in treating depressed outpatients and found it to be comparable. In addition, similar effectiveness in treating depression was also found between trazodone and bupropion IR (Weisler et al. 1994). After the development of bupropion SR, many studies followed comparing bupropion SR with SSRIs, including fluoxetine, sertraline, and paroxetine. In most studies, the effective daily dosage of bupropion SR was between 300 mg and 400 mg. All studies demonstrated that bupropion's effectiveness in treating symptoms of depression was equal to that of SSRIs (Coleman et al. 1999, 2001; Croft et al. 1999; Kavoussi et al. 1997; Weihs et al. 2000). In 2005, a meta-analysis of remission rates using all existing bupropion SR versus SSRI comparative trials was conducted by Thase et al. (2005). This analysis also found that remission rates with these two types of antidepressants were essentially the same. Although bupropion SR and SSRIs both were generally well tolerated, bupropion SR treatment was associated with less sexual dysfunction (Thase et al. 2005). Bupropion SR has also been shown to prevent relapse of depressive symptoms when given up to 1 year (Weihs et al. 2002). Like bupropion IR and bupropion SR, the third and most recently released formulation of this NDRI, bupropion XL, has also been studied in regard to its effectiveness in treating depressive symptoms. In two 8-week placebo-controlled comparative trials with bupropion XL and escitalopram, pooled analysis confirmed equivalent efficacy of the two agents based on mean change in Hamilton Rating Scale for Depression (Ham-D; Hamilton 1960) score. Both antidepressants produced remission rates greater than the rate with placebo alone (Clayton et al. 2006). Other studies comparing bupropion XL with the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine XR demonstrated clinical equivalence for the two drugs in the treatment of depression. However, a study that used higher dosages of bupropion XL (300–450 mg/day) found statistically significantly higher remission rates for bupropion XL relative to venlafaxine XR (Thase et al. 2006). It is also important to note that for patients who are unable to tolerate or fail to respond to SSRIs, bupropion may be added. Studies have shown bupropion to be efficacious for treatment of major depressive disorder not only as monotherapy but also as an augmenting agent with SSRIs or SNRIs (Bodkin et al. 1997; DeBattista et al. 2003; Fava et al. 2003; Ferguson et al. 1994; Lam et al. 2004; Rush et al. 2006; Spier 1998; Stern et al. 1983; Trivedi et al. 2006).

Depression in the elderly Depression in the elderly is often underdiagnosed and may go untreated. Elderly patients with depression frequently report less specific symptoms, such as insomnia, anorexia, and low energy, instead of admitting to depressed mood (Birrer and Vemuri 2004). Bupropion has been found to be an effective antidepressant in elderly patients (Birrer and Vemuri 2004; Branconnier et al. 1983; Weihs et al. 2000). An early study concluded that bupropion had therapeutic advantages over TCAs because it alleviated depressive symptoms without producing sedation or anticholinergic side effects, such as dry mouth, constipation, or confusion (Branconnier et al. 1983). A later study comparing bupropion SR and paroxetine noted that although both agents were effective in treating depression, bupropion SR had a more favorable side-effect profile (Weihs et al. 2000). Like bupropion SR, bupropion XL has proven efficacious for treatment of depression in the elderly (Clayton 2007). A recent study examining gender- and age-related differences in treatment of depressive symptoms, anxious and somatic symptoms, and insomnia found SSRIs and bupropion to be equally effective (Papakostas et al. 2007).

Depression with decreased energy, interest, and pleasure Bupropion XL has been studied specifically in patients with a retarded–anergic profile. Jefferson et al. (2006) showed that bupropion XL was more effective than placebo in treatment of patients with decreased energy, pleasure, and interest. This is the first study to look at those parameters exclusively. The unique NDRI mechanism of action of bupropion may play a role in its effectiveness in treating these symptoms (Jefferson et al. 2006).

Anxiety symptoms in depression Studies have demonstrated the effectiveness of bupropion dosages of 300–400 mg/day in reducing symptoms of anxiety (Fabre et al. 1983). Moreover, bupropion and SSRIs appear to be equally effective in this realm (Feighner et al. 1991; Weihs et al. 2000). In 2001, Trivedi et al. published results of a study examining the effects of bupropion SR versus sertraline on anxiety in depressed patients. This was a retrospective, pooled analysis of two 8-week double-blind, placebo-controlled trials that used the Hamilton Anxiety Scale (Ham-A) and the 21-item Hamilton Rating Scale for Depression (Ham-D-21) to measure symptoms. Results revealed that both bupropion SR and sertraline were superior to placebo in allaying depressive symptoms; however, treatment of anxious symptoms did not significantly differ from placebo for either active medication. The study concluded that bupropion and SSRIs were comparable in their antidepressant and anxiolytic effects in patients with major depressive disorder. Neither was favored for more specific management of anxiety (Trivedi et al. 2001). A more recent meta-analysis comparing efficacy of bupropion and selective serotonin reuptake inhibitors for treatment of anxious symptoms in major depressive disorder came to a similar conclusion. The study found that both classes of medication led to a similar degree of improvement in anxiety symptoms, with no significant difference in the severity of residual anxiety symptoms (Papakostas et al. 2008).

Bipolar depression A small number of studies have demonstrated the advantages of bupropion in the treatment of depression in bipolar disorder (Haykal and Akiskal 1990; Shopsin 1983; Wright et al. 1985). Although these investigations yielded positive results, they were limited by small numbers of subjects and were uncontrolled. A study by Sachs et al. (1994) comparing bupropion and desipramine in the treatment of bipolar depression suggested that bupropion may have a lower rate of precipitation of mania. Another study comparing the effect of bupropion SR versus topiramate, as an add-on agent for bipolar depression in patients already taking lithium or valproate, demonstrated no difference in response. Regarding change from baseline, a significant reduction in depressive symptoms occurred with both medications. This study reported no cases of affective switching in either arm (McIntyre et al. 2002).

Seasonal Affective Disorder Bupropion XL is the first, and currently the only, medication to have a labeled indication for the preventive treatment of SAD. A study published in 1992 initially suggested bupropion's efficacy as treatment for SAD (Dilsaver et al. 1992). In 2005, Modell et al. published results of three prospective randomized, placebo-controlled prevention trials involving 1,042 outpatients with a diagnosis of SAD. Patients received 150–300 mg/day of bupropion XL or placebo in autumn while they were still well. Bupropion XL reduced the frequency of emergence of SAD by 44% and protected against the recurrence of seasonal major depressive episodes. Furthermore, there was no noticeable increase in major depressive episodes following discontinuation of bupropion in the springtime (Modell et al. 2005).

Smoking Cessation The smoking cessation activity of bupropion was first noted after researchers observed unplanned suspension of smoking in depressed subjects who were being treated with bupropion (Hudziak and

Rettew 2004). In 1997, Hurt et al. published the results of a double-blind, placebo-controlled trial of bupropion SR therapy for smoking cessation. Six hundred and fifteen subjects received bupropion SR at dosages of 100, 150, or 300 mg/day for 7 weeks, with a target quit date of 1 week after beginning treatment. Brief counseling was also provided. Rates of smoking cessation at the end of 7 weeks were 29% for the 100-mg group, 39% for the 150-mg group, and 44% for the 300-mg group, versus 10% for placebo. At 1 year, rates for the three bupropion dosage groups were 20%, 23%, and 23%, respectively, compared with 12% for the placebo group. Cessation rates for the two higher dosages were significantly better than the rate for placebo. This trial concluded that bupropion SR is an effective agent for smoking cessation (Hurt et al. 1997). A later placebo-controlled study compared bupropion SR alone, nicotine patch alone, bupropion SR plus nicotine patch, and placebo. At 1 year, rates of smoking cessation were significantly higher in both the bupropion monotherapy group and the bupropion plus nicotine patch group than in the placebo group or the nicotine patch monotherapy group (Jorenby et al. 1999). In 2004, Killen et al. published results of the first study in adolescent smokers. In that study, 211 adolescent smokers (ages 15–18 years) were randomly assigned to two groups. One group received the nicotine patch plus placebo, and the other received the nicotine patch plus bupropion SR 150 mg/day. Both groups also received relapse prevention skills training. Results did not show a significant treatment effect but did reveal an overall reduction in cigarette consumption per day and maintenance of this reduction over time (Killen et al. 2004). Clinical trials have demonstrated that bupropion SR is effective in improving initial and long-term abstinence rates and may be helpful in preventing relapse. Hays et al. (2001) showed that subjects who had successfully stopped smoking for 7 weeks with bupropion treatment had a significant delay in smoking relapse with continued bupropion SR therapy compared with placebo. More recently, however, a trial looking specifically at extended treatment with bupropion SR for smoking cessation reported that bupropion SR did not surpass placebo (Killen et al. 2006). In the first study arm, 362 adult smokers received 11 weeks of open-label treatment consisting of bupropion SR, nicotine patch, and relapse prevention training. In the second arm of the study, subjects were randomly assigned to placebo or bupropion SR for 14 weeks of extended treatment. Whereas higher abstinence rates with bupropion SR than with placebo were found at week 25 (42% vs. 38%), abstinence rates were about the same at week 52 (33% vs. 34%). Another interesting finding this study uncovered was that men were more likely than women to abstain from smoking. Although more work needs to be done in areas of relapse prevention and long-term abstinence, it is clear that bupropion SR is helpful in smoking cessation. Many of theses studies were instrumental in the approval of bupropion SR for smoking cessation. Recommended dosages are 150 mg/day for 3 days, with an increase to 150 mg two times a day for 7–12 weeks. The patient should set a quit date of 1–2 weeks after treatment has been initiated. In 2003, Ferry and Johnston published a 5-year review of efficacy and safety data for bupropion SR in smoking cessation since its approval in 1997 for that indication. A risk–benefit analysis assuming a 30% 1-year quit rate found that 19 lives were saved out of 10,000 subjects and that 86 of the cases of smoking-attributed morbidity were avoided compared with a 0.22% chance of experiencing an adverse effect from bupropion SR (Ferry and Johnston 2003).

Other Uses Attention-Deficit/Hyperactivity Disorder Currently there is no FDA indication for this use, but studies have demonstrated that bupropion may also be helpful is treating symptoms of ADHD in both children and adults. Clinical trials in children with ADHD have shown bupropion to be a safe and effective alternative for treatment of this disorder (Conners et al. 1996; Simeon et al. 1986). A comparison trial of bupropion and methylphenidate

demonstrated that both drugs were effective in the treatment of ADHD and had similar efficacy (Barrickman et al. 1995). Bupropion has also been studied in adults with ADHD and has demonstrated statistically significant symptom improvement in this population (Wilens et al. 2001). In a meta-analysis by Peterson et al. (2008), long-acting forms of bupropion appeared to exhibit similar clinical effectiveness compared with long-acting stimulants in adults. An open trial by Riggs et al. (1998) suggested that bupropion may also be useful for treatment of ADHD in adolescents with both conduct disorder and substance abuse (Riggs et al. 1998). Currently, bupropion is thought of as a useful second-line agent in the treatment of ADHD and may be more favorable with comorbid conduct disorder or substance abuse (Riggs et al. 1998; Wilens et al. 2001). More studies are needed to further establish the efficacy of bupropion for use in this realm.

Obesity One of the well-known characteristics of bupropion is that it is usually not associated with weight gain as are many other classes of antidepressants. Alternatively, mild weight loss has been noted in many clinical trials. To further investigate this observation, Gadde et al. (2001) conducted a randomized, placebo-controlled trial investigating the tolerability and efficacy of bupropion for weight loss in 50 obese women using bupropion (100–400 mg/day) versus placebo. All subjects kept a food journal and were placed on a 1,600 kcal/day diet. Results revealed bupropion to be more effective than placebo in achieving weight loss at 8 weeks. At 24 weeks, responders to bupropion had lost an average of 13% of their baseline body weight (Gadde et al. 2001). Following this initial study for bupropion and weight loss, two larger studies confirmed these results (Anderson et al. 2002; Jain et al. 2002). A more recent randomized, open-label study found that combination treatment with zonisamide and bupropion resulted in more weight loss than treatment with zonisamide alone. Eighteen obese women were randomly assigned to receive either combination therapy or zonisamide monotherapy. For those who completed the study, women in the combination group lost an average of 8.1 kg, versus an average of 3.0 kg for women in the monotherapy group (Gadde et al. 2007). Although bupropion is not FDA approved for weight reduction, it may mitigate weight gain in patients being treated for depression.

Sexual Dysfunction Studies by Segraves et al. (2001) demonstrated that bupropion may be helpful in treatment of hypoactive sexual desire disorder (HSDD). More recently, a double-blind, placebo-controlled trial supported this finding and also revealed increases in sexual arousal, orgasm completion, and sexual satisfaction in women with HSDD receiving bupropion (Segraves et al. 2004). Another study of bupropion SR treatment of patients with SSRI-induced sexual dysfunction found that bupropion improved desire to engage in sexual activity and increased frequency of engaging in sexual activity (Clayton et al. 2004). Further studies have also demonstrated that bupropion may be helpful for treatment of sexual disorders in both men and women (Modell et al. 2000).

SIDE EFFECTS AND TOXICOLOGY Thousands of clinical trials and millions of patient exposures reveal bupropion to be a safe and generally well tolerated medication across populations. Because of its unique mechanism of action and structure, its reported side effects are somewhat different than with other antidepressants. In a series of large randomized, placebo-controlled multicenter trials evaluating the safety of bupropion SR in the treatment of depressed outpatients, Settle et al. (1999) found that the most commonly reported adverse events (occurring in >5% of subjects) were headache, dry mouth, nausea, insomnia, constipation, and dizziness. Only three of these—dry mouth, nausea, and insomnia —occurred at higher rates in patients taking bupropion SR than in those receiving placebo. The rate of discontinuation due to adverse events was low: 7% for bupropion SR, compared with 4% for placebo.

Rash, nausea, agitation, and migraine were the most common adverse effects leading to discontinuation (Settle et al. 1999). Similarly favorable safety and tolerability findings were reported for continuation-phase bupropion SR treatment in a longer-term (up to 44 weeks) relapse prevention trial (Weihs et al. 2002). Adverse events associated with bupropion XL are presented in Table 20–1. This table is based on combined results from four different studies previously discussed: the two escitalopram studies (Clayton et al. 2006); the venlafaxine XR study (Thase et al. 2006); and the reduced energy, pleasure, and interest study (Jefferson et al. 2006). These data indicate that the most common side effects of bupropion XL are similar to those of other formulations. Fatigue and somnolence were associated more with escitalopram, whereas bupropion XL caused more dry mouth. Compared with bupropion XL, venlafaxine XR was found to be associated with more dry mouth, nausea, diarrhea, somnolence, sedation, and yawning. These data indicate that bupropion XL does not appear to cause somnolence (Clayton et al. 2006). TABLE 20–1.. Frequency of adverse events: comparison studies of bupropion XL versus escitalopram, venlafaxine XR, and placebo in patients with MDD Comparison agent Adverse event

Bupropion XL

Escitalopram

Venlafaxine XR

Placebo

n

n (%)

n

n (%)

n

n (%)

n

n (%)

Dry mouth

579

120 (21)

281

37 (13)

174

51 (29)

412

38 (9)

Dizziness

135

14 (10)

—

—

—

—

139

3 (2)

Nausea

303

39 (13)

—

—

174

45 (26)

139

7 (5)

Insomnia

411

49 (12)

281

28 (10)

—

—

412

23 (6)

Anxiety

135

8 (6)

—

—

—

—

139

1 (90%) nearly equivalent to that of twice-daily dosing with the IR formulation (Troy et al. 1997a). The XR formulation may be taken in either the morning or evening, and bioavailability is not affected by coadministration with food (Troy et al. 1997a). The recommended starting dose of desvenlafaxine is 50 mg/day. A larger (100-mg) capsule is also available. The results of fixed-dose studies of venlafaxine suggest dose-dependent efficacy in MDD (Kelsey 1996; Khan et al. 1998; Rudolph et al. 1998c; Thase et al. 2006b). Perhaps most importantly, a large amount of data from RCTs suggests that patients who do not respond to lower dosages often benefit from dosage increases (Costa e Silva 1998; Diaz-Martinez et al. 1998; Dierick et al. 1996; Mehtonen et al. 2000; Thase et al. 2006b). As reviewed elsewhere (Thase 2006), there is relatively little evidence of a dose–response relationship in treatment of anxiety disorders. Whereas the original form of venlafaxine was approved for treatment at doses of up to 375 mg/day (divided bid or tid), the manufacturer "capped" the recommended maximum daily dosage of XR at 225 mg because of a lack of data on the safety and tolerability of once-daily therapy at higher doses. Although some clinicians disregard this arbitrary restriction, it is true that the incidence of elevated blood pressure during venlafaxine therapy is heavily dose dependent (Thase 1998), and if only for this reason, vigilance is warranted when higher-dose therapy is indicated. Less is known about the dose–response characteristics of desvenlafaxine. Early experiences with the compound in RCTs of MDD suggested that dosages above 200 mg/day may convey no additional efficacy and have a significantly higher incidence of side effects (DeMartinis et al. 2007; Septien-Velez et al. 2007). Although the full therapy development program has not yet been published, the minimum therapeutic dosage is 50 mg/day, and dosages above 100 mg/day are not recommended by the manufacturer. Whether patients who do not respond to 50 mg/day will benefit from upward titration to higher dosages has not yet been demonstrated. Clearance of venlafaxine and desvenlafaxine is reduced among patients with cirrhosis or severe renal disease (Troy et al. 1994); therefore, dosing should be adjusted downward accordingly. In the absence of formal studies to inform such decisions, a 50% reduction in dosage and slower titration (i.e., at least 7–10 days between adjustments) of both the parent drug and desvenlafaxine are generally recommended. In otherwise healthy elders, adjustments in dosing of venlafaxine do not appear to be necessary (Klamerus et al. 1996). However, initiation of treatment with a lower starting dose, and slower subsequent titration, is a sensible approach when treating frail elders or medically complicated patients. Specific studies of desvenlafaxine in older, medically complex patients have not yet been undertaken.

MECHANISM OF ACTION The mechanism of action of both venlafaxine and desvenlafaxine is believed to be inhibition of 5-HT and NE reuptake. From the beginning, comparisons with the first medication to be considered a "dual reuptake inhibitor," the TCA clomipramine, have been inevitable. Venlafaxine is also a weak inhibitor of dopamine reuptake in vitro (Muth et al. 1986), although this effect probably is not clinically significant at routine therapeutic doses. Consistent with this view are the results of one recent in vivo study of healthy volunteers, which found essentially no blockade of the dopamine transporter with venlafaxine dosages of 75 and 150 mg/day (Shang et al. 2007). There is good evidence that venlafaxine and desvenlafaxine are more potent inhibitors of 5-HT reuptake than of NE reuptake (BoldenWatson and Richelson 1993; Deecher et al. 2006; Vaishnavi et al. 2004). It has long been suggested that this relationship underpins the ascending dose–response relationship of venlafaxine (Kelsey 1996; Thase 1996). Moreover, some argue that venlafaxine is essentially an SSRI at the lowest therapeutic dosage (i.e., 75 mg/day) and that the noradrenergic effect is progressively recruited as the dose is increased (Kelsey 1996). There are both experimental (Harvey et al. 2000) and clinical (Davidson et al. 2005; R. Entsuah and Gao 2002; Rudolph et al. 1998a; Thase 1998; Thase et al. 2006b) data that are consistent with such a relationship. Nevertheless, significant effects on autonomic measures of noradrenergic function are evident at 37.5- and 75-mg/day dosages (Bitsios et al. 1999; Siepmann et al. 2007). Until it is possible to directly image NE transporter occupancy in vivo, this question cannot be definitively answered.

INDICATIONS AND EFFICACY Venlafaxine XR is approved by the FDA for the treatment of MDD, generalized anxiety disorder (GAD), social anxiety disorder, and panic disorder. Venlafaxine IR and desvenlafaxine are approved only for the treatment of MDD. Although venlafaxine has not been formally approved for treatment of other psychiatric disorders, there is evidence that it also has efficacy in other disorders that are responsive to SSRIs, including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and premenstrual dysphoric disorder (PMDD). Given that desvenlafaxine is the active metabolite of venlafaxine, it is likely to be effective in every disorder that is responsive to the parent drug.

Major Depressive Disorder The antidepressant efficacy of venlafaxine has been established in a large number of placebo-controlled, randomized trials (Cunningham 1997; Guelfi et al. 1995; Khan et al. 1991; Mendels et al. 1993; Rudolph et al. 1998c; Schweizer et al. 1991; Shrivastava et al. 1994; Thase 1997), including studies focusing on depressed patients with associated symptoms of anxiety (Feighner et al. 1998; Khan et al. 1998; Rudolph et al. 1998b). In published studies employing SSRIs as active comparators, venlafaxine therapy has been found to be comparable or superior to therapy with fluoxetine (Alves et al. 1999; Clerc et al. 1994; Costa e Silva 1998; De Nayer et al. 2002; Dierick et al. 1996; Keller et al. 2007a; Nemeroff and Thase 2007; Rudolph and Feiger 1999; Rudolph et al. 1998a; Schatzberg and Roose 2006; Silverstone and Ravindran 1999; Tylee et al. 1997; Tzanakaki et al. 2000), sertraline (Mehtonen et al. 2000; Rush et al. 2006; Shelton et al. 2006; Sir et al. 2005), paroxetine (Ballus et al. 2000; McPartlin et al. 1998; Poirier and Boyer 1999), and citalopram (Allard et al. 2004). Results of two studies comparing venlafaxine and escitalopram have yielded somewhat conflicting results (Bielski et al. 2004; Montgomery et al. 2004b), with comparability in the latter study and trends favoring the SSRI in the former study, which employed rapid titration to maximum FDA-approved doses (Bielski et al. 2004). A pooled analysis of these two trials also found a significant advantage for escitalopram among the subset of patients with higher pretreatment depression severity (Montgomery and Andersen 2006). Comparative studies of desvenlafaxine and SSRIs are under way, but results are not yet available.

Results from meta-analyses of early published and unpublished studies comparing venlafaxine and SSRIs provided some evidence that venlafaxine may produce a significantly greater antidepressant response than fluoxetine and perhaps than SSRIs as a class (T. R. Einarson et al. 1999; Smith et al. 2002; Stahl et al. 2002; Thase et al. 2001). In the meta-analysis by Thase et al. (2001), for example, the magnitude of this effect was a 10% higher rate of remission (as defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression), which was comparable to the magnitude of the effect favoring the SSRIs over placebo. The advantage versus fluoxetine was subsequently confirmed by an independent meta-analysis conducted by the Cochrane group (Cipriani et al. 2006), although this was not observed in the largest prospective head-to-head RCT (Keller et al. 2007a), which examined the outcomes of 1,096 patients with recurrent MDD across 10 weeks of double-blind therapy. Results of the most comprehensive meta-analysis of RCTs comparing venlafaxine and SSRIs undertaken to date are consistent with the hypothesis that venlafaxine therapy has significantly greater efficacy than fluoxetine alone and than the SSRIs as a class (Nemeroff et al. 2008). Working with individual patient data from all of the manufacturer-sponsored double-blind RCTs conducted worldwide (N = 34 studies), the antidepressant efficacy of venlafaxine, various SSRIs (fluoxetine, paroxetine, sertraline, citalopram, or fluvoxamine), and placebo (9 studies) across up to 8 weeks of therapy were compared in more than 8,500 adults with MDD. The absolute difference in remission rates was found to be 6%, favoring the SNRI (95% confidence interval = 3.8%–8.1%) (Figure 22–2). The difference was again statistically significant for the more numerous studies using fluoxetine as a comparator but not for the comparisons of the other SSRIs individually. A secondary analysis utilizing the funnel plot method, which also included results of all other known comparative studies of venlafaxine and SSRIs, yielded confirmatory results (Nemeroff et al. 2008). Although statistical significance was observed, the modest magnitude of the difference across studies falls below the standard for clinical significance suggested by the Cochrane group (e.g., Cipriani et al. 2006). FIGURE 22–2. Rate differences for remission and 95% confidence intervals for venlafaxine versus selective serotonin reuptake inhibitors (SSRIs).

Remission is defined as a 17-item Hamilton Rating Scale for Depression (Ham-D-17) score of 7 or less for 33 of the 34 studies. One study (4229; Allard et al. 2004) did not use the Ham-D, and remission was defined as a Montgomery-Åsberg Depression Rating Scale score of 10 or less. Remission rate differences for the individual studies ranged from –7% to 31%; differences numerically favored venlafaxine in 28 studies (although only 5 reached statistical significance), with 6 studies numerically favoring the SSRIs. Source. Reprinted from Nemeroff CB, Entsuah R, Benattia I, et al.: "Comprehensive Analysis of Remission (COMPARE) With Venlafaxine Versus SSRIs." Biological Psychiatry 63:424–434, 2008. Copyright 2008, Elsevier. Used with permission. With respect to other newer antidepressants, two studies comparing venlafaxine and mirtazapine therapies (Benkert et al. 2006; Guelfi et al. 2001) found trends favoring the latter compound early in the course of treatment but comparable efficacy at study endpoint. Mirtazapine, which is a potent blocker of histamine and 5-HT2 receptors, also had a significant advantage in relief of insomnia in both of these studies. One relatively large outpatient study contrasting bupropion, a norepinephrine–dopamine reuptake inhibitor (NDRI), and venlafaxine XR found a comparable overall pattern of efficacy, with the NDRI having a significant advantage in terms of a lower incidence of sexual side effects and a higher proportion of patients achieving remission at study endpoint (Thase et al. 2006a). The latter finding, which was discrepant from levels of symptom reduction and response rates, may be attributable to the special nature of the study population (i.e., relatively younger, sexually active patients). A pair of studies contrasting venlafaxine and the other widely available SNRI, duloxetine, found no differences in efficacy at either the primary or secondary study endpoints (Perahia et al. 2008). In the pooled data set of those two studies, several tolerability indices favored venlafaxine early in the course of therapy, whereas there were fewer discontinuation symptoms in the duloxetine group following cessation of study therapy. Several studies have evaluated the utility of venlafaxine therapy in bipolar depression. In the first, a double-blind, placebo-controlled study, the efficacy and safety of venlafaxine treatment were compared in 17 patients with bipolar II disorder and 31 patients with unipolar depression (Amsterdam 1998). Patients were randomly assigned to 6 weeks of double-blind treatment with once- versus twice-daily venlafaxine IR (up to 225 mg/day). Overall, similar efficacy was observed in unipolar and bipolar patients, although a more rapid reduction of symptoms was observed by week 2 of treatment among bipolar patients who completed the entire trial. No episodes of drug-induced hypomania or rapid cycling were observed. Vieta et al. (2002) compared therapy with venlafaxine or paroxetine in a double-blind study of 60 bipolar I patients taking concomitant mood stabilizers. Results suggested comparable efficacy and tolerability, although the patients treated with venlafaxine had a higher rate of treatment-induced mania (13%) than the group treated with paroxetine (3%). Venlafaxine was contrasted with bupropion and sertraline in 174 bipolar I and II patients taking concomitant mood stabilizers (Post et al. 2006). Again, there was no difference in efficacy, but the rate of treatment-emergent affective switches was significantly higher for the patients randomly assigned to the SNRI compared with those assigned to the other two antidepressants. Venlafaxine is one of the preferred choices for patients who have not responded to other first-line antidepressants (Thase et al. 2000). Two recent RCTs compared venlafaxine with other treatment options after nonresponse to an initial course of SSRI therapy (Baldomero et al. 2005; Rush et al. 2006). Despite a number of differences in design, these studies yielded almost identical results, with a modest numeric advantage in remission rates for the SNRI versus a second trial within the SSRI class. Results were statistically significant in a larger study (Baldomero et al. 2005), which was conducted in Spain, but did not reach significance in the smaller study, which was conducted in the United States as part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project (Rush et al. 2006). Another study within the STAR*D program contrasted the combination of venlafaxine and mirtazapine (n = 51) versus the monoamine oxidase inhibitor (MAOI) tranylcypromine (n = 58) among MDD patients who had not responded to three consecutive prospective medication trials (McGrath et al. 2006). Although the two strategies did not differ with respect to the primary outcome variable (remission rates were only 14% and 7% for the combination and MAOI strategies, respectively), patients treated with the combination strategy had significantly greater symptom reduction and a higher study completion rate than patients treated with the MAOI. Venlafaxine has not been studied in combination with antipsychotic medication for patients with psychotic depression. One study did, however, compare double-blind therapy with either venlafaxine IR (300 mg/day) or fluvoxamine (300 mg/day) as monotherapies in 28 psychotically depressed patients (Zanardi et al. 2000). Findings strongly favored the group receiving fluvoxamine (response rates: 79% vs. 50%), although such an apparently large difference was not statistically significant in this small study. Regardless, venlafaxine should not be thought of as a stand-alone therapy for patients with psychotic depression. Earlier longer-term open-label trials suggested that venlafaxine had sustained efficacy across 12 months of continued therapy (Magni and Hackett 1992; Tiller et al. 1992). Results of a pooled analysis of the extension phases of four randomized, double-blind, controlled studies in outpatients with major depression demonstrated that the rate of relapse at 6 months and 1 year was significantly lower in the venlafaxine-treated group than in the placebo-treated group (A. R. Entsuah et al. 1996). Double-blind, placebo-controlled studies subsequently confirmed the efficacy of venlafaxine treatment for prevention of relapse during 6 months of continuation treatment (Simon et al. 2004) and for prevention of recurrence during 12 months (Kocsis et al. 2007; Montgomery et al. 2004a) and 24 months (Keller et al. 2007b) of maintenance-phase therapy.

Generalized Anxiety Disorder Venlafaxine XR was approved by the FDA for treatment of GAD on the basis of a series of placebo-controlled RCTs (Allgulander et al. 2001; Davidson et al. 1999; Gelenberg et al. 2000; Nimatoudis et al. 2004; Rickels et al. 2000), including two trials that evaluated efficacy across 6 months of therapy (Allgulander et al. 2001; Gelenberg et al. 2000). Across studies, the efficacy of doses ranging from 75 mg/day to 225 mg/day was established versus placebo, with little evidence of dose–response relationships for both efficacy and tolerability. To date, there have been no studies of higher-dose venlafaxine therapy for GAD. Only a handful of studies have been completed comparing venlafaxine XR with other medications with established efficacy in GAD. Superiority to buspirone was found on some (but not all) measures in the one study that was undertaken (Davidson et al. 1999). In the single study that compared venlafaxine XR with the

benzodiazepine diazepam (Hackett et al. 2003), the two treatments were comparably effective, although neither active therapy was statistically more effective than placebo. Two comparative studies have contrasted venlafaxine XR with SSRIs in GAD. In the first, a randomized but open-label trial comparing venlafaxine XR and paroxetine in 60 outpatients, Kim et al. (2006) reported comparable efficacy and tolerability. In the second study (Bose et al. 2008), a relatively large (N = 392) RCT, venlafaxine XR and escitalopram were contrasted. Overall, there were no significant differences between the two therapies. However, venlafaxine XR was statistically significantly more effective than placebo on the primary outcome measure (whereas escitalopram was not), and attrition due to side effects was significantly greater in the venlafaxine arm than in the placebo arm (whereas the difference in attrition between the escitalopram and placebo arms was not statistically significant).

Social Anxiety Disorder Venlafaxine XR was approved for treatment of social anxiety disorder on the basis of a series of RCTs that confirmed its efficacy and safety relative to placebo across up to 6 months of double-blind therapy (Allgulander et al. 2004; Liebowitz et al. 2005a, 2005b; Rickels et al. 2004; Stein et al. 2005). As was the case in GAD, effective doses ranged from 75 mg/day to 225 mg/day, with little evidence of an ascending dose–response relationship. In the two studies that included paroxetine as an active comparator, venlafaxine therapy was at least as effective and as well tolerated as the SSRI (Allgulander et al. 2004; Liebowitz et al. 2005a).

Panic Disorder Although promising results in panic disorder were apparent in an early placebo-controlled study utilizing the IR formulation (Pollack et al. 1996), the research that ultimately led to a formal FDA indication was largely delayed until after studies of the XR formulation were completed in MDD, GAD, and social anxiety disorder. Antipanic efficacy was demonstrated in three placebo-controlled studies of acute-phase therapy, including one 10-week flexible-dose study (Bradwejn et al. 2005) and two 12-week fixed-dose studies investigating 75 mg/day and 150 mg/day (Pollack et al. 2007a) or 75 mg/day and 225 mg/day (Pollack et al. 2007b). These studies, which incorporated a 37.5-mg starting dose to minimize early side effects, established an effective dosage range of 75–225 mg/day. Two of the placebo-controlled studies also included paroxetine (40 mg/day) as an active comparator (Pollack et al. 2007a, 2007b). Overall, two fixed doses of venlafaxine XR (75 mg/day and 150 mg/day) were comparable to paroxetine in both efficacy and tolerability. In the single RCT that included a fixed-dose 225-mg/day arm, the higher dose of venlafaxine therapy was significantly more effective than paroxetine on several secondary outcome measures, including the proportion of patients who experienced complete relief from full symptom panic attacks (70% vs. 58%) (Pollack et al. 2007b). Sustained efficacy was demonstrated in one longer-term study using a classic relapse prevention design, in which patients who responded to 12 weeks of open-label therapy with venlafaxine XR (75–225 mg/day) were randomly allocated to 6 additional months of double-blind therapy with either the active drug or placebo (Ferguson et al. 2007).

Other Anxiety Disorders Early studies of venlafaxine therapy of PTSD have been reviewed by Pae et al. (2007). Results of two large RCTs demonstrated the efficacy of venlafaxine XR versus placebo (Davidson et al. 2006a, 2006b). The first trial, which enrolled 573 adults scoring at least 60 on the Clinician-Administered PTSD Scale (CAPS-SX17), compared venlafaxine XR (range = 37.5–300 mg/day; mean dosage = 225 mg/day), sertraline (range = 25–200 mg/day; mean dosage = 151 mg/day), and matching placebo across 12 weeks of double-blind treatment. Venlafaxine XR therapy was significantly more effective than placebo, as measured by change in CAPS-SX17 scores and remission rates at study endpoint, whereas sertraline was not. There were, however, no significant differences in efficacy between the two active therapies. Final remission rates were 30%, 24%, and 20% for the SNRI, SSRI, and placebo groups, respectively. In the second study, which enrolled 329 adults meeting the same entry criteria, venlafaxine XR (mean dosage = 222 mg/day) was compared with placebo across up to 6 months of double-blind therapy. The efficacy of the SNRI was documented by significant effects on all primary and secondary outcome measures, with final remission rates of 51% and 38% for the venlafaxine XR and placebo groups, respectively. The results of an initial open-label case series (Rauch et al. 1996) suggested that venlafaxine would also be a useful treatment of OCD. Indeed, results of a 12-week single-blind study indicated that venlafaxine might be at least as effective as clomipramine and significantly better tolerated (Albert et al. 2002). However, the manufacturer did not pursue a large-scale registration program for this indication, and the smaller-scale studies that have been performed do not reveal particular advantages as compared to approved SSRIs such as paroxetine (see the review by Thase 2006).

Premenstrual Dysphoric Disorder A randomized, double-blind, placebo-controlled study evaluated the efficacy of venlafaxine IR for the treatment of PMDD in 157 women treated across four menstrual cycles (Freeman et al. 2001). Dosages ranged from 50 mg/day to 200 mg/day, with adjustments for adverse events or lack of efficacy early in each cycle. Analysis of daily symptom rating scores revealed significantly greater improvement in the venlafaxine group compared with the placebo group at endpoint in the primary factors of emotion, function, physical symptoms, and pain. In a second small pilot study of intermittent (premenstrual) dosing, Cohen et al. (2004) treated 11 women with PMDD who had not responded to a single-blind placebo lead-in. Nine of the 11 responded to the two 14-day courses of venlafaxine XR 75–112.5 mg/day. The medication was well tolerated, and intermittent dosing was not associated with significant discontinuation symptoms. Further studies are needed to ascertain the longer-term efficacy of venlafaxine treatment for PMDD.

Treatment of Children and Adolescents Venlafaxine XR was being evaluated for treatment of MDD, GAD, and social anxiety disorder in pediatric populations at the time that concerns about the potential for antidepressants to induce suicidal ideation and behaviors in children began to surface in 2003–2004. Although the manufacturer chose not to pursue further formal indications in any pediatric disorder, results of the five completed studies have been published and include a pair of studies in MDD (Emslie et al. 2007), two RCTs in GAD (Rynn et al. 2007), and one study in social anxiety disorder (March et al. 2007). Results in the depression studies (pooled N = 334) were mixed: venlafaxine XR was significantly more effective than placebo among participants ages 12–17 years but not among children ages 7–11 years. In the pooled data set, venlafaxine XR therapy was associated with an increased risk of treatment-emergent suicidal and aggressive behaviors compared with

placebo (Emslie et al. 2007). In the pair of GAD studies (pooled N = 330), venlafaxine XR was significantly more effective than placebo in the pooled data set; one study was unequivocally positive, but the second study failed to separate between drug and placebo on the primary dependent measure (Rynn et al. 2007). In the social anxiety disorder study (N = 293), venlafaxine XR also was significantly more effective than placebo on both primary and secondary outcome measures (March et al. 2007).

SIDE EFFECTS AND TOXICOLOGY The side-effect profile of the IR formulation of venlafaxine was superior to the TCAs, although not quite as favorable as the SSRIs (Preskorn 1995). In the meta-analysis of Nemeroff et al. (2008), for example, 11% of the venlafaxine-treated patients withdrew from therapy because of adverse events, compared with 9% of patients treated with SSRIs. As an SNRI, the tolerability profile of venlafaxine includes all of the characteristic side effects associated with 5-HT uptake inhibition (i.e., nausea, insomnia, tremor, and sexual dysfunction) as well as side effects attributable to NE reuptake inhibition (i.e., sweating and dry mouth). The major advantage of the XR formulation, aside from permitting once-daily dosing, is a somewhat lower incidence of nausea during the first weeks of therapy (Cunningham 1997). To date, no comparative study of venlafaxine and an SSRI has included a detailed assessment of sexual dysfunction. The results of studies focused on detection of sexual dysfunction during antidepressant treatment suggest that venlafaxine and the SSRI are associated with similar risks (Clayton et al. 2002; Kennedy et al. 2000; Montejo et al. 2001). Like the SSRIs, venlafaxine does not affect cardiac conduction and does not lower the seizure threshold (at least at therapeutic doses). Unlike the SSRIs, however, venlafaxine is associated with a small increase in pulse rate and a dose-dependent increased risk of elevated blood pressure (Thase 1998). Experience with the IR formulation in studies of MDD indicated that the risk of sustained high blood pressure increased from 3% to 7% at dosages of 100–225 mg/day and to 13% at dosages above 300 mg/day (Thase 1998). In the studies of the XR formulation, which limited the maximum dosage to 225 mg/day, the increased risk was only 3% in patients with MDD and 0.5% in patients with GAD. Nevertheless, the manufacturer continues to recommend that all patients receiving venlafaxine have regular monitoring of blood pressure. In practice, it is prudent to record blood pressure prior to initiating venlafaxine therapy and to monitor serially if dosages above 225 mg/day are prescribed. More careful monitoring is warranted for patients with preexisting high blood pressure and for the elderly. Similar to most other antidepressants, venlafaxine is classified as pregnancy Category C, indicating that there are no adequate and well-controlled studies in pregnant women and that the drug should be used during pregnancy only if it is clearly needed. Results of a multicenter case–control study evaluating pregnancy outcome following gestational exposure to venlafaxine (n = 150), SSRIs (n = 150), or other drugs (n = 150) revealed no evidence that venlafaxine therapy increases the risk of major fetal malformations (A. Einarson et al. 2001). As with other psychotropic medications, venlafaxine and its metabolites are excreted in human breast milk. Reports by Ilett et al. (1998, 2002) of the distribution of venlafaxine in human milk and its effects in breast-fed infants demonstrated that the mean infant dose exposure was approximately 6%–7% of the maternal dose, which is below the 10% notional level of concern. No adverse effects were noted in any of the infants (Ilett et al. 2002). Although these data support the use of venlafaxine in pregnant or breast-feeding women, the findings are preliminary, and the available safety data remain limited. The decision to use venlafaxine in pregnancy or lactation should be made on the basis of an individual risk–benefit assessment. Precipitous withdrawal of venlafaxine can result in a characteristic "discontinuation" profile, including dizziness, dry mouth, insomnia, nausea, nervousness, sweating, anorexia, diarrhea, somnolence, and sensory disturbances (Haddad 2001). Venlafaxine therapy therefore should not be discontinued abruptly, and whenever possible, a taper schedule of no more than 75 mg/day/week is strongly recommended. It is important to note that the discontinuation schedule used in clinical trials was based on only 6- to 12-week durations of treatment. In practice, longer tapering schedules may be required, depending on the dose, the duration of therapy, and the individual patient. Clinicians should counsel patients about the possibility of adverse effects following abrupt discontinuation of treatment. In the 13-plus years since its initial introduction, there has been extensive experience with venlafaxine overdose. A number of fatal overdoses have been reported, primarily involving combinations of venlafaxine and other drugs and/or alcohol (Banham 1998; Kunsman et al. 2000; Long et al. 1997; Parsons et al. 1996). In nonfatal overdoses, electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), serotonin syndrome, and seizures have been reported (C. Howell et al. 2007; Whyte et al. 2003). In an analysis of fatal poisoning with antidepressants in the United Kingdom, Buckley and McManus (2002) used a statistic known as the fatal toxicity index (FTI), which was defined by the number of overdose deaths per million prescriptions, to compare the relative risks of different antidepressants. They found that venlafaxine had a significantly higher FTI than the SSRIs (13.2 vs. 0.7–3.0). The authors suggested that these data could mean that venlafaxine should not be used as a first-line treatment for patients with suicidal ideation. However, many nonpharmacological factors can contribute to the likelihood of a fatal overdose, particularly patient risk factors. In this regard, two studies have documented that the patients who are selected for treatment with venlafaxine are at greater inherent suicide risk than are patients selected for treatment with SSRIs (Mines et al. 2005; Rubino et al. 2007). Adjustment for these risk factors greatly reduced the difference in FTI between venlafaxine and the SSRIs (Rubino et al. 2007). Although the potential for lethality in overdose certainly warrants ongoing study, the current state of the evidence does not indicate that venlafaxine therapy should be avoided in patients at risk for suicidal behavior.

DRUG–DRUG INTERACTIONS Venlafaxine undergoes extensive metabolism in the liver by the cytochrome P450 (CYP) enzyme system, particularly by the CYP2D6 isoenzyme. Patients who are "poor CYP2D6 metabolizers," whether genetically or by taking drugs that inhibit this enzyme, thus have increased concentrations of the parent drug relative to ODV. Although it could be argued that this should not affect response, given that the parent drug and ODV are nearly pharmacologically equipotent, poor metabolizers of CYP2D6 may be at greater risk for side effects (McAlpine et al. 2007; Shams et al. 2006). Such patients thus could potentially be better candidates for therapy with desvenlafaxine than the parent drug. Despite being a substrate for CYP2D6, venlafaxine and ODV are among the weakest of inhibitors of this isoenzyme (Alfaro et al. 2000;

Amchin et al. 2001; Ball et al. 1997). In vitro and in vivo studies have shown that venlafaxine and ODV cause little or no inhibition of other CYP isoenzymes, including 1A2, 2C9, 2C19, and 3A4 (Ball et al. 1997; Owen and Nemeroff 1998). Although it does not appear to have significant affinity for CYP3A4, venlafaxine has been shown to decrease blood levels of the protease inhibitor indinavir, a substrate of CYP3A4 (Levin et al. 2001). Neither the mechanism nor the clinical significance of this interaction is known, but it is of concern given the critical nature of treatment with protease inhibitors. As SNRIs, both venlafaxine and desvenlafaxine are contraindicated in patients taking MAOIs, because of the risk of serotonin syndrome. This is as true for the newer transdermally delivered formulation of selegiline as it is with the older agents. As with cyclic antidepressants and SSRIs, venlafaxine or desvenlafaxine treatment should not be initiated until 2 weeks after discontinuation of an MAOI, and MAOI therapy should not be initiated until at least 7 days after discontinuation of venlafaxine or desvenlafaxine. Venlafaxine and desvenlafaxine appear to have no clinically significant interactions with lithium (Troy et al. 1996), diazepam (Troy et al. 1995a), or alcohol (Troy et al. 1997c).

CONCLUSION Venlafaxine, the first widely used member of the SNRI class, appears to be at least as effective as other first-line antidepressants and has an overall safety profile that is closer to the SSRIs than the TCA. There is evidence of a modest efficacy advantage compared with fluoxetine and perhaps to the SSRIs as a class, although to date a significant efficacy advantage has not been demonstrated against other specific members of the class, most particularly escitalopram. Venlafaxine also has established efficacy for treatment of GAD, social anxiety disorder, and panic disorder. Generic formulations of venlafaxine IR are now available, although the more heavily prescribed XR formulation, which is patent-protected for several more years, offers the advantages of once-daily dosing and a lower incidence of nausea during the first few weeks of therapy. ODV, the primary active metabolite of venlafaxine, was introduced as antidepressant (desvenlafaxine succinate) in 2008. Desvenlafaxine offers several advantages over venlafaxine XR in terms of simpler dosing (e.g., lower starting dose, lower minimum therapeutic dose, no active metabolite, and possibly less need for upward dosage titration); beyond this, however, the relative merits of the two drugs have not yet been assessed. Both drugs have a low potential for cytochrome P450–mediated drug–drug interactions and are associated with dose-dependent increases in blood pressure.

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Troy SM, DiLea C, Martin PT, et al: Pharmacokinetics of once-daily venlafaxine extended release (XR) in healthy volunteers. Curr Ther Res 58:504–514, 1997a Troy SM, Parker VP, Hicks DR, et al: Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine. J Clin Pharmacol 37:954–61, 1997b Troy SM, Turner MB, Unruh M, et al: Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and ethanol. J Clin Pharmacol 37:1073–1081, 1997c Tylee A, Beaumont G, Bowden MW, et al: A double-blind, randomized, 12-week comparison of the safety and efficacy of venlafaxine and fluoxetine in moderate to severe major depression in general practice. Prim Care Psychiatry 3:51–58, 1997 Tzanakaki M, Guazzelli M, Nimatoudis I, et al: Increased remission rates with venlafaxine compared with fluoxetine in hospitalized patients with major depression and melancholia. Int Clin Psychopharmacol 15:29–34, 2000 [PubMed] Vaishnavi SN, Nemeroff CB, Plott SJ, et al: Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity. Biol Psychiatry 55:320–322, 2004 [PubMed] Vieta E, Martinez-Aran A, Goikolea JM, et al: A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers. J Clin Psychiatry 63:508–512, 2002 [PubMed] Whyte IM, Dawson AH, Buckley NA: Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 96:369–374, 2003 [PubMed] Zanardi R, Franchini L, Serretti A, et al: Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. J Clin Psychiatry 61:26–29, 2000 [PubMed] Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.

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Sandhaya Norris, Pierre Blier: Chapter 23. Duloxetine and Milnacipran, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.427736. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 23. Duloxetine and Milnacipran DULOXETINE AND MILNACIPRAN: INTRODUCTION Duloxetine was first synthesized in the 1980s and subsequently patented in 1991. The U.S. Food and Drug Administration (FDA) did not approve this drug for the treatment of major depressive disorder and diabetic neuropathy, however, until the third quarter of 2004. This long delay occurred because the drug was initially tested in depressed patients at low dosages of 5–20 mg/day, which were not efficacious. Duloxetine has received approval in most countries worldwide since then but became available in Canada only in 2008. It is also approved in the United States for generalized anxiety disorder and fibromyalgia. Milnacipran was approved in France for the treatment of depression in 1996 but only recently was approved for use in North America for patients with fibromyalgia.

STRUCTURE–ACTIVITY RELATIONS Duloxetine and milnacipran (Figure 23–1), along with venlafaxine, are antidepressant medications that can act as serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine reuptake inhibitors. Whereas selective serotonin reuptake inhibitors (SSRIs) target only the 5-HT transporter (5-HTT), the dual-acting medications have the potential to inhibit both the 5-HTT and the norepinephrine transporter (NET). Collectively, these three medications are referred to as serotonin–norepinephrine reuptake inhibitors (SNRIs). Several lines of evidence have to be considered, however, to determine at which concentrations SNRIs are indeed effective dual reuptake inhibitors. This is of crucial importance in estimating their potency in clinical settings. FIGURE 23–1. Chemical structures of duloxetine and milnacipran.

PHARMACOLOGICAL PROFILES In Vitro Assessments The first data to consider in determining the biochemical profile of reuptake inhibitors are their affinity values for membranal carriers. These values can be calculated by determining the concentration of a medication necessary to displace 50% of the specific binding of a standard ligand for a given transporter subtype in a lyzed cell preparation (Ki). This technique generally provides rough estimates of the potential for drugs to inhibit reuptake. A somewhat more indicative approach consists of determining the concentrations of drugs necessary to inhibit the uptake of transmitters in intact cells from either animal brains or human cell lines. These physiological results are more reliable than mere binding data because of the integrity of the tissue. Indeed, recent data indicate that the binding of some norepinephrine reuptake blockers varies markedly when they are tested in membrane preparations versus intact cells, whereas with other agents, such as the tricyclic antidepressants (TCAs), it does not (Mason et al. 2007). As can be seen in Table 23–1, not only do the absolute potencies vary between the two preparations, their ratios vary as well. TABLE 23–1. In vitro affinity and inhibition values for milnacipran and duloxetine for human reuptake transporters Serotonin transporter Norepinephrine transporter Dopamine transporter Affinity values, Ki (nM) Milnacipran

8.4

22

ND

Serotonin transporter Norepinephrine transporter Dopamine transporter Duloxetine

0.1

1.2

230

Milnacipran

151

68

ND

Duloxetine

3.7

20

439

Inhibition values, Ki (nM)

Note. ND = Not detectable; values for duloxetine for the dopamine transporter are not physiologically significant. Source. Adapted from Vaishnavi et al. 2004.

In Vivo Assessments Ideally, the potency of reuptake inhibitors in animal experiments should be assessed in vivo with the medications administered systemically. One common technique is to conduct microdialysis studies whereby extracellular levels of neurotransmitters are estimated from the perfusion of an artificial cerebrospinal fluid. Data generated with duloxetine in rats indicate that it first enhances brain levels of 5-HT, and that with increasing doses it increases norepinephrine levels (Koch et al. 2003). In the case of milnacipran, the levels of 5-HT and norepinephrine are generally enhanced to the same extent (in guinea pigs; Moret and Briley 1997), although pronounced regional differences have been observed. For instance, milnacipran is six times more potent in the rat hypothalamus than in the midbrain raphe nuclei and the frontal cortex (Bel and Artigas 1999). These results suggest that milnacipran may not readily penetrate the blood–brain barrier. Potency can also be assessed in vivo using electrophysiological approaches. For instance, by determining the capacity of reuptake inhibitors to suppress the firing of 5-HT and norepinephrine neurons, reliable potency estimates can be obtained. As reuptake transporters are dose-dependently inhibited from their systemic injection, 5-HT and norepinephrine accumulate at the cell body level of such neurons that will activate their respective autoreceptors, thereby decreasing firing activity. Using this approach, duloxetine suppresses the firing rate of 5-HT neurons by 50% with an intravenous dose of 0.1 mg/kg and suppresses the firing rate of norepinephrine neurons to the same level with a dose of 0.5 mg/kg (Kasamo et al. 1996). This in vivo ratio of 1:5 is quite different from the in vitro affinity ratio of 1:12 (Vaishnavi et al. 2004; see Table 23–1). In contrast, using the same in vivo technique, the dose of milnacipran necessary to inhibit the firing rate of 5-HT neurons by 50% is 5.7 mg/kg (Mongeau et al. 1998). The latter results therefore suggest that milnacipran is much less potent in inhibiting 5-HT reuptake than duloxetine.

Assessments of 5-HT and Norepinephrine Reuptake in Humans Reuptake of neurotransmitters in humans cannot be assessed as directly as it can in the brains of laboratory animals. Several approaches can, however, provide useful estimates. For instance, 5-HT reuptake inhibition can be estimated using blood platelet uptake of radioactive 5-HT because platelets do not synthesize 5-HT and they have a 5-HTT that is nearly identical to the one present on 5-HT neurons in the brain. And because more than 90% of the 5-HT in blood is in platelets, whole blood can be used to measure 5-HT depletion by a reuptake inhibitor, making assessment simpler. Using this peripheral assay, duloxetine produces a dose-dependent depletion of the 5-HT level that reaches only about 60% with a 60-mg dose, an effect that is significantly inferior to that seen with the TCA clomipramine at a dose of 100 mg (Turcotte et al. 2001). Likewise, milnacipran produces a 64% inhibition of 5-HT uptake with the usual recommended dose of 100 mg (Puozzo et al. 1985). Using a similar assay, SSRIs produce a greater than 80% inhibition with clinically effective doses (Gilmor et al. 2002). Occupancy of the 5-HTT in the human brain is possible to assess directly using carbon 11

(11C)–labeled ligands of these transporters and positron emission tomography (PET). The minimal effective doses of the SSRIs and venlafaxine for treating depression all result in at least 80% occupancy of the 5-HTT (Meyer et al. 2004). A daily dose of 60 mg, but not 40 mg, of duloxetine produces sustained 80% occupancy (Takano et al. 2006). To our knowledge, milnacipran has not been tested using this approach. Occupancy of the NET in the human brain is currently not possible because a PET ligand, validated with standard norepinephrine reuptake inhibitors (NRIs), is still lacking. A variety of peripheral measures can, however, be used. In particular, the intravenous tyramine pressor test has produced consistent results. Tyramine penetrates into peripheral norepinephrine terminals through the NET and releases norepinephrine in a calcium-independent manner, thereby transiently elevating the systolic blood pressure. Any drug effectively blocking the NET attenuates this pressor response in a dose-dependent manner. The SSRIs paroxetine and sertraline do not affect this response, whereas the TCAs desipramine, nortriptyline, and clomipramine attenuate it, as is also the case with the selective NRIs maprotiline, reboxetine, and atomoxetine (Blier et al. 2007; Gobbi et al. 2003; Harvey et al. 2000; Slater et al. 2000; Turcotte et al. 2001). Venlafaxine significantly attenuates the tyramine response only at dosages in the 225–375 mg/day range in depressed patients (Aldosary et al. 2007; Debonnel et al. 2007). Duloxetine exerts a clear effect only at 120 mg/day (Vincent et al. 2004), whereas milnacipran, to our knowledge, has not been tested using this model. A variety of other peripheral measures suggest that duloxetine may begin to inhibit norepinephrine reuptake at 60 mg/day (Chalon et al. 2003; Turcotte et al. 2001; Vincent et al. 2004). Taken together, these results obtained in humans indicate that duloxetine is a potent 5-HT reuptake inhibitor at a dosage of 60 mg/day. The exact degree of norepinephrine reuptake inhibition occurring in humans at 60 mg/day remains uncertain, but at 120 mg/day it reaches a physiologically relevant level without any doubt. A definite answer to the degree of norepinephrine reuptake inhibition produced by duloxetine in the human brain awaits both the availability of a PET ligand for the NET and a comparison with clinically effective doses of selective NRIs such as desipramine. Such experiments will also serve to determine the NET reserve beyond which the overall function of the norepinephrine system is altered, as was determined for the 5-HTT (i.e., 80%; Meyer et al. 2004). With regard to milnacipran, it appears that it acts preferentially on the norepinephrine reuptake process because it has been easy to find evidence of this action in the brain of laboratory animals even with low doses, whereas 5-HT reuptake inhibition can only be documented with high doses. Robust 5-HT reuptake inhibition (>80%) in humans appears to be achieved only with supratherapeutic doses (i.e., 300–400 mg; Palmier et al. 1989).

MECHANISM OF ACTION Administration of SNRIs results in a rapid inhibition of reuptake transporters in the brain. However, their therapeutic effect on depression is delayed at least 2 weeks. Extensive electrophysiological and microdialysis studies in laboratory animals have provided consistent results showing a similar delay before SNRIs produce a net enhancement of 5-HT and/or norepinephrine transmission, thereby explaining their therapeutic lag in treating depression (see Blier 2006 for a review). In brief, SNRIs that are potent 5-HT reuptake inhibitors initially suppress the firing of 5-HT neurons through the activation of 5-HT1A autoreceptors on their cell bodies, as a result of 5-HTT inhibition. After 2–3 weeks of sustained administration, the firing rate returns to normal in the presence of sustained reuptake inhibition, due to 5-HT1A autoreceptor desensitization. At this time, there is a net enhancement of 5-HT transmission in the forebrain (Bel and Artigas 1993; Blier and de Montigny 1983; Rueter et al. 1998a, 1998b). Regarding SNRI inhibition of the NET, the firing rate of norepinephrine neurons is promptly diminished as a result of the activation of the

2-adrenergic

autoreceptors on their cell bodies. After 2–3 weeks of

sustained administration, the firing rate remains attenuated because the cell body autoreceptors do not become desensitized. In contrast,

2-adrenergic

2-adrenergic

autoreceptors on

norepinephrine terminals generally do become desensitized, leading to a net enhancement of norepinephrine transmission in the forebrain in the presence of sustained norepinephrine reuptake inhibition (Invernizzi and Garattini 2004; Rueter et al. 1998a, 1998b; Szabo and Blier 2001).

PHARMACOKINETICS AND DISPOSITION Absorption and Distribution Duloxetine is available in an enteric formulation. It is rapidly absorbed after oral administration, and its absorption is not altered by food. Plasma levels are proportional to doses, up to the maximum recommended dose of 60 mg twice daily. It is highly bound to plasma proteins, to an extent of about 90%. Its plasma elimination half-life is approximately 12 hours (Sharma et al. 2000). With repeated administration, duloxetine levels therefore reach a steady-state level after about 3 days. Milnacipran has low (13%) and nonsaturable plasma protein binding. It is rapidly absorbed after oral administration and has high bioavailability, and its absorption is not affected by food intake. It has no active metabolite, and its elimination half-life is 8 hours. Steady-state levels are thus achieved within 3 days, with no drug accumulation occurring during prolonged dosing, and the drug is cleared from the body within 3 days of treatment cessation. It is eliminated by the kidneys as essentially the parent compound and glucuronide, the inactive glucuronic acid conjugate (Puozzo and Leonard 1996).

Metabolism and Elimination Duloxetine is extensively metabolized through various pathways (Skinner et al. 2003). Numerous metabolites are found in circulation, none of which is believed to contribute to its therapeutic activity. Duloxetine is metabolized mainly by cytochrome P450 1A2 and 2D6 isoenzymes. The cytochrome P450 system is not involved in the metabolism of milnacipran (Briley 1998). Its metabolism is mediated mainly through phase II conjugation. Approximately 50%–60% of the drug is recovered in the urine as the parent compound and 20% as its glucuronic acid conjugate, the remainder being excreted mainly as an N-dealkyl metabolite and its glucuronic acid conjugate, and in negligible amounts as an N-didealkyl metabolite and a hydroxy metabolite (Puozzo et al. 2002).

INDICATIONS AND EFFICACY Duloxetine has been approved by the FDA for use in treating major depressive disorder, diabetic peripheral neuropathic pain, fibromyalgia, and generalized anxiety disorder; it is also approved in Europe for treating stress urinary incontinence. Additional common off-label uses include other neuropathic pain/chronic pain disorders. Milnacipran is used to treat major depressive disorder in various countries, although it has not yet received FDA approval for that indication. It was recently approved in the United States for the treatment of fibromyalgia.

Depression Duloxetine To date, 12 placebo-controlled studies have evaluated the antidepressant efficacy of duloxetine at dosages of 40–120 mg/day. Many of these had an active drug comparator group. Efficacy was measured by remission, the optimal outcome measure, or by response. Remission can be operationally defined as a score of less than or equal to 7 on the 17-item Hamilton Rating Scale for Depression (Ham-D) or a score of less than or equal to 10 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Response is often defined as a 50% reduction in the MADRS or Ham-D score from baseline to endpoint. These studies and non-placebo-controlled duloxetine trials are summarized in Tables

23–2 and 23–3. TABLE 23–2. Duloxetine versus placebo and/or active SSRI or SNRI comparator in acute studies ( 12 weeks) of depression Study

Duration Sample Duloxetine Comparator Comparator (weeks) size

dosage

used

(mg/day) Goldstein

8

173

120

Placebo? Results

dosage (mg/day)

Fluoxetine

20

Yes

et al. 2002

Duloxetine>placebo No difference with fluoxetine

Nemeroff

8

194

120

Fluoxetine

20

Yes

No difference in remission rates at endpoint

et al. 2002a Nemeroff

8

354

40, 80

Paroxetine

20

Yes

No difference in remission rates at endpoint

et al. 2002a Detke et

9

245

60

None

—

Yes

Duloxetine>placebo

9

267

60

None

—

Yes

Duloxetine>placebo

8

353

40, 80

Paroxetine

20

Yes

al. 2002b Detke et al. 2002a Goldstein et al. 2004

Duloxetine 80 (but not 40)>placebo No difference between duloxetine 80 and paroxetine

Detke et

8

354

80, 120

Paroxetine

20

Yes

al. 2004

Duloxetine (80 and 120)>placebo Paroxetine = placebo

Perahia et

8

392

80, 120

Paroxetine

20

Yes

al. 2006b

Duloxetine (80 and 120)>placebo Paroxetine = placebo

Raskin et

8

311

60

None

—

Yes

Duloxetine>placebo

Nierenberg 8

684

60

Escitalopram 10

Yes

No difference between

al. 2007

et al. 2007 Khan et al.

any groups at endpoint 8

278

60

Escitalopram 10–20

No

Escitalopram>duloxetine

8

327

60

None

—

Yes

Duloxetine>placebo

8

478

60

Paroxetine

20

No

Duloxetine = paroxetine

12

667

120

Venlafaxine

225

No

Duloxetine = venlafaxine

2007 Brecht et al. 2007 P. Lee et al. 2007 Perahia et al. 2008 Note. SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor. ">"

denotes significantly greater effect; "=" denotes no difference. a

These failed studies were reported in this review but were not conducted by Dr. Nemeroff.

TABLE 23–3. Duloxetine versus placebo and/or active SSRI comparator in continuation studies (>12 weeks) of depression Study

Duration

Sample Duloxetine

Comparator

Comparator

(weeks)

size

used

dosage

dosage (mg/day)

Pigott

32

684

60–120

Placebo? Results

(mg/day) Escitalopram

10–20

Yes

Duloxetine =

et al.

escitalopram; placebo

2007

group underpowered due to length of trial

Wade

24

295

60

Escitalopram

20

No

et al.

Duloxetine = escitalopram

2007 Note. SSRI = selective serotonin reuptake inhibitor. "=" denotes no difference. Head-to-head comparisons with SSRIs have yielded mixed results, which appear to be heavily influenced by dosing regimens (see Tables 23–2 and 23–3). In a recent 8-week, placebo-controlled comparison of duloxetine 60 mg/day and escitalopram 10 mg/day, the two drugs produced similar statistically significant improvement versus placebo on the primary efficacy measure of onset of efficacy and similar response and remission rates at endpoint (Nierenberg et al. 2007). In a recent meta-analysis of six Phase II/III studies that compared duloxetine with two SSRIs (fluoxetine or paroxetine) in outpatients with major depressive disorder, duloxetine 40–120 mg/day was reported to be an effective antidepressant, with an overall efficacy profile equal to that of fluoxetine and paroxetine at 20 mg/day (Thase et al. 2007). For patients stratified as having moderate to severe symptoms, the remission rates with duloxetine were statistically superior to those with the SSRIs (see Table 23–3). Another recent meta-analysis of nine randomized, controlled trials (RCTs) evaluating high doses of duloxetine in patients with severe depression concluded that duloxetine 120 mg/day produced significantly greater baseline-to-endpoint improvement than placebo on several of the 17 Ham-D items (Shelton et al. 2007).

Milnacipran A meta-analysis of three short-term (4- to 8-week), double-blind, acute efficacy multicenter trials in inpatients and outpatients with moderate to severe depression found that milnacipran exerts a superior antidepressant effect compared with placebo at dosages of 50 and 100 mg twice daily but not at a dosage of 25 mg twice a day (Lecrubier et al. 1996; Macher et al. 1989). Several studies have compared milnacipran with SSRIs or TCAs in the treatment of depression (Table 23–4). In comparison with the TCA imipramine, milnacipran has been noted to have equal efficacy, but superior tolerability (Puech et al. 1997). A recent meta-analysis concluded that there is insufficient evidence to suggest a difference in response rates between milnacipran and any SSRI: Pooling response rates of the agents revealed an overall response rate of 62.1% for milnacipran and 57.5% for the SSRIs (Papakostas and Fava 2007). To date, no continuation studies (>12 weeks' duration) have been published comparing the efficacy of milnacipran to that of any SSRI. There is no maximal recommended dose of milnacipran, but it is important to mention that the highest daily dose tested so far, 300 mg, was tested in only 41 patients and for only 2 weeks (Ansseau et al. 1991). TABLE 23–4. Milnacipran versus placebo and/or active SSRI comparator in acute studies ( 12 weeks) of depression

Study

Duration Sample Milnacipran

Comparator Comparator

(weeks) size

used

dosage (mg/day)

Macher et 4

Placebo? Results

dosage (mg/day)

58

100

None

—

127

150–300

Fluvoxamine 200

Yes

Milnacipran>placebo

No

Milnacipran =

al. 1989 Ansseau

4

et al.

fluvoxamine

1991 Ansseau

6

190

100a

Fluoxetine

20

No

Fluoxetine>milnacipran

644

50, 100, 200

None

—

Yes

Milnacipran 100 and 200

et al. 1994 Lecrubier 6–8 et al.

(but not 50)>placebo

b

1996

Guelfi et

12

289

100–200

Fluoxetine

6

113

100

6

302

70

20

No

Milnacipran = fluoxetine

Fluvoxamine 200

No

Milnacipran>fluvoxamine

100

Paroxetine

20

No

Milnacipran = paroxetine

100

Fluoxetine

20

No

Milnacipran = fluoxetine

al. 1998 Clerc 2001 Sechter et al. 2004 M. S. Lee 6 et al. 2005 Note. SSRI = selective serotonin reuptake inhibitor. ">" denotes significantly greater effect; "=" denotes no difference. a

Milnacipran was given once daily; this was in contrast to the other studies, in which it was administered on a

twice-daily basis. b

This is a composite of two positive controlled studies.

Generalized Anxiety Disorder Three placebo-controlled studies have had positive results showing a therapeutic action with duloxetine in patients with generalized anxiety disorder (Allgulander et al. 2007). Dosing strategies are similar to those used in major depression.

Neuropathic Pain/Chronic Pain TCAs and SNRIs clearly produce significant relief of physical symptoms such as pain in depression and in a variety of pain syndromes (Stahl et al. 2005). Potentiation of the activity of 5-HT and norepinephrine is believed to result in central pain inhibition through descending modulatory pathways (Sussman 2003).

Duloxetine Duloxetine exerts a prompt and substantial analgesic effect beyond its antidepressant action (Perahia et al. 2006a). Duloxetine has shown efficacy in the treatment of diabetic peripheral neuropathy in randomized, placebo-controlled trials (Fishbain et al. 2006; Wernicke et al. 2006). Response tends to occur early in therapy and has been associated with significant improvement in functional outcomes

(Armstrong et al. 2007; Pritchett et al. 2007b). In a recent 8-week study of patients with major depressive disorder and at least moderate pain of unknown etiology, a fixed dosage of duloxetine (60 mg/day) significantly reduced pain measures at endpoint from baseline compared with placebo (Brecht et al. 2007). The mean average pain score at 8 weeks was close to 3 on the Brief Pain Inventory—Short Form, which can be considered a mild level of pain compared with the moderate or higher levels of pain indicated by baseline scores (Brecht et al. 2007). Similarly, elderly patients with depression treated with duloxetine (60 mg/day) for 8 weeks reported significantly greater improvement in back pain scores and amount of time in pain compared with placebo recipients (Raskin et al. 2007). An RCT of duloxetine 60 mg/day demonstrated greater efficacy than placebo in reducing overall shoulder pain and back pain in depressed patients, as well as time spent with pain (Detke et al. 2002b). Overall pain severity and back pain improved the most. Improvements were assessed with the visual analog scales of pain severity, measuring overall pain, back pain, headaches, shoulder pain, interference with daily activities, and time in pain.

Milnacipran The capacity of milnacipran to relieve chronic pain has been reported in open trials, but no RCTs have been published to date.

Fibromyalgia A 12-week RCT of duloxetine 120 mg/day versus placebo in patients with fibromyalgia, some of whom were also diagnosed with depression, found significant improvement in pain scores in duloxetine recipients and greater improvement in tender points compared with placebo recipients (Arnold et al. 2005). Duloxetine 120 mg/day improved fibromyalgia symptoms and pain severity regardless of the extent of the accompanying depressive disorder. The drug has received FDA approval for this indication. A placebo-controlled study of milnacipran in fibromyalgia patients showed that 37% of the patients treated with 100 mg of milnacipran twice daily experienced a significant reduction in pain intensity of 50% or more compared with 14% of placebo recipients (Vitton et al. 2004). Here, too, milnacipran recently received FDA approval for this indication.

Stress Urinary Incontinence Duloxetine has been investigated in the treatment of stress urinary incontinence, with 40 mg twice daily being the recommended dosage (Norton et al. 2002). Serotonin and norepinephrine increase excitatory glutamate transmission in the Onuf nucleus in the sacral spinal cord, which facilitates urethral sphincter contraction (Thor 2003). This is presumably the mechanism for the beneficial effect of duloxetine in the treatment of this problem. The capacity of milnacipran to treat stress urinary incontinence has not been reported to date.

SIDE EFFECTS AND TOXICOLOGY Duloxetine In clinical trials to date, the safety and tolerability of duloxetine in the dosage range of 40–120 mg/day have been assessed. In an 8-month study, the most common treatment-emergent adverse events included nausea, dry mouth, vomiting, yawning, and night sweats (Pigott et al. 2007). Most of these emerged early, within the first 8 weeks. Other studies have reported insomnia, somnolence, headaches, ejaculation disorders, diarrhea, constipation, and dizziness as common adverse events with duloxetine (Detke et al. 2002a, 2002b; Khan et al. 2007; Nierenberg et al. 2007).

The rates of nausea with duloxetine appear to be comparable to those found with other SNRIs and with SSRIs. Nausea is transient and usually present at treatment initiation. A starting dosage of 60 mg/day appears to provide the best combination of clinical response and tolerability (Bech et al. 2006; Pritchett et al. 2007a). Clinicians may, however, consider starting at a lower dosage, 30 mg/day, for patients for whom tolerance is a concern. Duloxetine 30 mg/day offers the advantage of a lower rate of nausea as a treatment-emergent adverse event (in one study, 16% vs. 33% with duloxetine 60 mg/day; Dunner et al. 2005). A recent study indicates that the tolerability of duloxetine at an initial dosage of 60 mg/day can be improved if the drug is taken with food, to the point of being comparable to the tolerability at an initial dosage of 30 mg/day (Whitmyer et al. 2007). Duloxetine has not been associated with weight gain, and in one study it was in fact noted to be associated with a mean 1-kg weight loss (Nierenberg et al. 2007). This decrease was a statistically significant difference compared with the lack of effect that placebo and escitalopram had on weight. Changes in blood pressure and heart rate do not appear to be clinically significant. Pooled data on 735 patients treated with duloxetine 40–120 mg/day showed that 0.7% had a 10-mm Hg increase in systolic or diastolic blood pressure compared with 0.4% of patients receiving placebo. Heart rate was increased by less than 1 beat per minute (Schatzberg 2003). Rates of sexual dysfunction, including anorgasmia, erectile dysfunction, delayed ejaculation, and decreased libido, appear to be low with duloxetine. Researchers found that after 8 months, categorical outcomes shown on a questionnaire about changes in sexual functioning did not differ significantly between duloxetine and escitalopram groups (Pigott et al. 2007). In clinical practice, however, sexual dysfunction with any drug that potentially inhibits 5-HT reuptake does create some problems in a significant proportion of patients. Rates of discontinuation due to adverse events have not differed significantly in placebo and active comparator groups in acute or longer-term studies. However, it appears that study subjects who discontinue duloxetine due to adverse events often do so during the early study visits (Nierenberg et al. 2007; Perahia et al. 2008; Pigott et al. 2007), which may suggest poorer initial tolerability.

Milnacipran Analysis of a database of more than 3,300 patients concluded that the adverse-event profile of milnacipran is comparable to that of the SSRIs, except that with the SSRIs a higher frequency of nausea and anxiety is seen, whereas milnacipran is associated with a higher incidence of dysuria (Puech et al. 1997). Weight gain is uncommon, and sedation may be reported. Data on the occurrence of sexual dysfunction with milnacipran have not been reported, but its prevalence is estimated to be low compared with the prevalence of sexual dysfunction seen with venlafaxine and much lower than that seen with SSRIs (Stahl et al. 2005). The lower incidence of nausea and sexual dysfunction with milnacipran versus SSRIs may be taken as indirect evidence of its lower 5-HT reuptake inhibition potential, these two treatment-emergent adverse events being classically induced by potent 5-HT reuptake inhibitors. Blood pressure increases with milnacipran are minimal. A 12-week randomized, double-blind study comparing milnacipran dosages of 100 mg/day and 200 mg/day versus fluoxetine 20 mg/day in 289 depressed inpatients found no significant changes in blood pressure in any of the group (Guelfi et al. 1998). Tachycardia, a heart rate of greater than 100 beats per minute, was seen in 0% of patients receiving fluoxetine, 3% of patients receiving milnacipran 100 mg/day, and 6% of patients receiving milnacipran 200 mg/day. A review of more than 4,000 patients treated with milnacipran showed that the mean increase in blood pressure was less than 1 mm Hg and the mean increase in heart rate was 3.6 beats per minute (Puech et al. 1997). Given that an increase of heart rate is a thumbprint of potent norepinephrine reuptake inhibition, this increase is consistent with the capacity of milnacipran to effectively block norepinephrine reuptake. No cardiotoxicity has been reported with overdoses of up

to 2.8 g/day, which is 28 times the recommended daily dose (Montgomery et al. 1996). Analysis of the long-term safety of milnacipran (in 715 patients receiving milnacipran for >6 months, 189 for >12 months, as reported by Puech et al. 1997) has shown that most adverse events appear within the first 3 months of treatment and that the incidence decreases steadily thereafter. More important, no treatment-emergent adverse events developed during long-term treatment.

DRUG–DRUG INTERACTIONS Inhibitors of cytochrome P450 1A2, such as ciprofloxacin, increase plasma levels of duloxetine, and their use may require that duloxetine dosages be reduced or that duloxetine use be avoided. When duloxetine is coadministered with a cytochrome P450 2D6 inhibitor of moderate potency, such as bupropion or diphenhydramine, duloxetine levels may increase. Generally, however, such alterations of duloxetine levels are not clinically significant. Duloxetine does not inhibit or induce the activity of cytochrome P450 1A2, 2C9, or 3A4 systems. It does, however, moderately inhibit the activity of the 2D6 enzyme. If duloxetine is prescribed with an agent metabolized by 2D6, clinicians should use doses that are approximately half those usually recommended for the concomitant medication. Duloxetine does not potentiate the psychotropic effects of ethanol or benzodiazepines. Because milnacipran is not metabolized by the cytochrome P450 pathways, it does not produce pharmacokinetic drug–drug interactions. However, both milnacipran and duloxetine can have a serious, potentially lethal pharmacodynamic interaction if given concomitantly with a monoamine oxidase inhibitor (MAOI) due to the risk of serotonin syndrome. To avoid this catastrophic outcome, an MAOI must never be administered until at least 5 days after duloxetine or milnacipran has been discontinued. A longer washout period must be respected when switching from an MAOI to an SNRI. A washout period of at least 14 days should elapse before starting any SNRI.

CONCLUSION At their minimal effective dosages, duloxetine (60 mg/day) and milnacipran (100 mg/day) potently block the reuptake of 5-HT and norepinephrine, respectively. In the case of duloxetine, it is difficult to imagine that increasing the subtherapeutic dosage of 40 mg/day, at which it does not perform as an SSRI, to 60 mg/day would produce marked norepinephrine reuptake inhibition when the in vivo 5-HT–norepinephrine reuptake potency ratio is 1:5. In the case of milnacipran, a 100-mg dose produces suboptimal platelet 5-HT reuptake inhibition. Duloxetine at its maximal recommended dosage (120 mg/day) and milnacipran in its upper therapeutic range (200 mg/day) are dual reuptake inhibitors, but none of the three SNRIs currently available can be considered a balanced serotonin– norepinephrine reuptake inhibitor. Duloxetine and milnacipran have demonstrated efficacy for the treatment of depression and pain syndromes, with emerging evidence also suggesting a potential role for duloxetine in the treatment of stress urinary incontinence and some anxiety disorders. These medications are generally well tolerated, with most adverse events occurring early in treatment, being mild to moderate in severity, and having a tendency to decrease or disappear with continued treatment. Either of these two drugs may be used as a first-line treatment for depression because they are not toxic in overdosage and they can be used at therapeutic dosages from treatment initiation onward with minimal side effects. Furthermore, data suggest that treatment with a dual reuptake inhibitor is superior to treatment with an antidepressant with only one mechanism of action, such as an SSRI (Nemeroff et al. 2008; Poirier and Boyer 1999; Thase et al. 2007). Consequently, duloxetine and milnacipran may be useful in patients whose conditions have been resistant to treatment with SSRIs or NRIs, provided that they are used at dosages in the upper end of the therapeutic range.

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David V. Sheehan, B. Ashok Raj: Chapter 24. Benzodiazepines, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.417936. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 24. Benzodiazepines HISTORY AND DISCOVERY In spite of adverse publicity and a problematic public image, the most widely prescribed psychiatric medication in the United States over the past several years is not an antidepressant, an atypical antipsychotic, or a mood stabilizer but the benzodiazepine alprazolam, with 31 million prescriptions issued in 2001 (see Stahl 2002). The first benzodiazepine, chlordiazepoxide (Librium), was patented in 1959. Diazepam was introduced in 1963, and numerous derivatives of this drug have since been introduced into the market. The triazolobenzodiazepine alprazolam was introduced in 1981 and revolutionized the treatment of anxiety disorders when it was shown to be effective in the treatment of panic disorder (Chouinard et al. 1983; D. V. Sheehan et al. 1982). It was the first benzodiazepine to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of panic disorder. Since then, clonazepam, another high-potency benzodiazepine, has also received approval from the FDA for the treatment of panic disorder. Benzodiazepines were widely prescribed in the 1960s, 1970s, and 1980s for pathological anxiety by psychiatrists, family practitioners, and internists who knew they were effective and relatively safe when compared with prior anxiolytic medications such as the barbiturates and meprobamate. However, since the 1990s, benzodiazepines have increasingly been displaced by the selective serotonin reuptake inhibitors (SSRIs) as the clinician's first choice for the treatment of anxiety disorders (Kramer 1993). The SSRIs are safer and better tolerated than the tricyclic antidepressants and have been shown to be efficacious in a number of different anxiety disorders. In addition, they do not have the dependence, withdrawal, alcohol interaction, and abuse liability of the benzodiazepines. In the United States, benzodiazepine use between 1979 and 1990 decreased from 11.1% to 8.3%. At this time, 35 benzodiazepine products are available worldwide; of these, only 15 are marketed in the United States. Under the Controlled Substances Act (1970), benzodiazepines fall under Schedule IV and are classified as depressants. Despite these drawbacks, benzodiazepines are often used as an adjunctive treatment with an SSRI or as the primary treatment for the patient with no response or only a partial response to the SSRI. The net result is only a small decline in the recommendation for a benzodiazepine (Uhlenhuth et al. 1999). One user in four uses the benzodiazepine for a year or longer. Among those using it as a hypnotic, 14% reported long-term use (Balter 1991). Rates of use increase with age. Persons older than 65 years account for 27% of all benzodiazepine prescriptions and 38% of all benzodiazepine hypnotics (IMS America 1991). In recent years, there has been a shift to the use of short-half-life benzodiazepines. The use of benzodiazepine hypnotics has remained stable (Woods et al. 1992).

STRUCTURE–ACTIVITY RELATIONS Currently marketed benzodiazepines are similar in that they have the 1,4-benzodiazepine ring system (see, e.g., Figure 24–1). Modification of this ring system results in benzodiazepines with somewhat different properties. Increasing the electron-attracting ability of the attachment at the R1 position increases its potency. Alprazolam, a triazolobenzodiazepine, is formed by the addition of a

heterocyclic ring that joins the benzodiazepine ring at its 1 and 2 positions (see Figure 24–1) (Sternbach 1982). FIGURE 24–1. Chemical structures of diazepam and alprazolam.

PHARMACOKINETICS AND DISPOSITION Knowledge of benzodiazepine pharmacokinetics helps the clinician choose the most appropriate benzodiazepine for the patient and also guides in its correct use. Benzodiazepines differ in their pharmacokinetic properties, such as absorption, distribution, and elimination (Table 24–1). On the other hand, all benzodiazepines are similar in that to some degree they all exhibit anxiolytic, musclerelaxant, sedative-hypnotic, and anticonvulsant properties. The belief that one benzodiazepine is primarily anxiolytic while another is primarily hypnotic is not based on scientific evidence (Greenblatt et al. 1983a, 1983b). The preferential selection of a benzodiazepine for one market over another is usually dictated by its pharmacokinetic properties. This, however, is not true for the nonbenzodiazepine hypnotics zolpidem and zaleplon, as they are selective for the benzodiazepine1 ( 1)

receptor only.

TABLE 24–1. Pharmacokinetics of benzodiazepines Group

Medication

Metabolism

CYP enzyme(s) T½, hours Ki

Desmethyldiazepam

Diazepam

Oxidation

2C19, 3A4

26–50

9.6

Bromazepam

Oxidation

3A4

1–5

NA

Prazepam

Oxidation

>21

NA

>21

NA

Chlordiazepoxide Oxidation Desalkylflurazepam

3A4

Flurazepam

Oxidation

40–120

NA

Clonazepam

Oxidation

24–56

0.5

Triazolobenzodiazepine Triazolam

Oxidation

3A4

2–4

0.4

Alprazolam

Oxidation

3A4

10–15

4.8

Imidazobenzodiazepine Midazolam

Oxidation

3A4

1–3

0.4

Thienodiazepine

Brotizolam

Oxidation

3A4

4–8

0.9

Nitrazepam

Reduction

3A4, 2D6

20–50

11.5

Flunitrazepam

Reduction

10–25

3.8

Glucuronidation

5–15

17.2

Oxazolobenzodiazepine Oxazepam

Group

Medication

Metabolism

CYP enzyme(s) T½, hours Ki

Lorazepam

Glucuronidation

10–20

3.8

Temazepam

Glucuronidation

6–16

23.0

Note. CYP = cytochrome P450; Ki = kinetic inhibition constant value (nM); NA = not available.

Rate of Absorption Benzodiazepines that are rapidly absorbed from the gastrointestinal tract enter and peak in the circulation quickly and have a quicker onset of action than those that are absorbed more slowly. Diazepam and clorazepate are rapidly absorbed and act quickly, chlordiazepoxide and lorazepam have intermediate rates of absorption and onset of action, while prazepam is slowly absorbed and has a slower onset of action. Gastrointestinal absorption of benzodiazepines is dictated by intrinsic physiochemical properties of the drug and characteristics of the formulation such as particle size (Greenblatt et al. 1983a, 1983b). Benzodiazepine absorption when given intramuscularly is dictated by other factors. For example, chlordiazepoxide and lorazepam when given orally are absorbed at similar rates in the gastrointestinal tract. When given intramuscularly, lorazepam is more reliably, rapidly, and completely absorbed than chlordiazepoxide (Greenblatt et al. 1979, 1982b, 1983a, 1983b).

Lipophilicity The lipid solubility (lipophilicity) of a benzodiazepine at physiological pH influences the rate at which it crosses the blood–brain barrier by passive diffusion from the circulation, and this, in turn, determines the rapidity of onset of action and intensity of effect (Greenblatt et al. 1983a, 1983b). Highly lipophilic drugs cross the blood–brain barrier rapidly, and although all benzodiazepines are highly lipophilic, they differ in their degree of lipophilicity. As diazepam is more lipophilic than lorazepam or chlordiazepoxide, patients are more likely to experience rapid anxiety reduction and onset of side effects with the former.

Duration of Action With benzodiazepines, the duration of therapeutic action is determined mainly by the rate and extent of drug distribution rather than by the rate of elimination. Benzodiazepine distribution is largely determined by its lipophilicity. Diazepam, which has a longer half-life than lorazepam, has a shorter duration of clinical action after a single dose. The reason for this is that diazepam, because of its greater lipid solubility, is more extensively distributed to peripheral sites, particularly to fat tissue. Consequently, it is more rapidly moved out of the blood and brain into inactive storage sites and its central nervous system (CNS) effects are more rapidly ended. Conversely, less lipophilic benzodiazepines maintain their effective brain concentrations longer because they are less extensively distributed to the periphery (Greenblatt et al. 1983a, 1983b).

Rate of Elimination The rate of elimination (elimination half-life) influences the speed and extent of accumulation and the time to reach a steady state. It also influences the time for drug washout after termination of multiple doses. Accumulation is slow and extensive when the half-life is long. When the rate of metabolic removal equals the rate of ingestion, the drug is said to have reached steady state. A useful rule of thumb is that when treatment has been in progress for at least four to five times as long as the elimination half-life, then the accumulation process is more than 90% complete (Greenblatt et al. 1983a, 1983b). When drugs with long elimination half-lives are stopped, they are washed out slowly, and the symptoms recur gradually over a period of days, with less intense or sudden rebound phenomena (Greenblatt et al. 1981, 1982a; Kales et al. 1982). Side effects from long-term treatment

with long-half-life benzodiazepines last longer than with short-half-life benzodiazepines. Because of greater drug accumulation with long-half-life benzodiazepines, frequent drowsiness and sedation are a theoretical concern (Greenblatt et al. 1981). Tolerance to sedation occurs with long-term use, even though the plasma drug level remains the same. However, as a matter of caution, it is prudent to choose a benzodiazepine with a shorter or intermediate half-life for the elderly (Greenblatt et al. 1982c), individuals operating equipment, and those engaged in high-level intellectual tasks.

Biotransformation Pathway Benzodiazepines are metabolized in the liver by microsomal oxidation or by glucuronide conjugation. The oxidation pathway is influenced by hepatic disease, age, several medical illnesses, and a number of drugs that impair oxidizing capacity, such as cimetidine, estrogens, and the hydrazine monoamine oxidase inhibitors (MAOIs). These factors usually magnify the side effects of the benzodiazepine. Consequently, in the elderly and in individuals with liver disease, benzodiazepines that are conjugated (e.g., temazepam, oxazepam, and lorazepam) are safer than benzodiazepines that are metabolized by oxidation (e.g., diazepam and alprazolam). This is the reason why a patient who is taking alprazolam at a stable dose will report that sedation is potentiated more by the addition of a hydrazine MAOI than by a tricyclic antidepressant.

Dosing: Sustained-Release Formulations Dosing schedules of benzodiazepines should be dictated by knowledge about the rate of distribution rather than by information about elimination half-life. Patients who require several daily doses often feel as if they are on a roller coaster. They experience peaks of mild sedation followed by troughs of mild anxiety. This can lead to "clock watching" (Herman et al. 1987). Sustained-release formulations of several benzodiazepines have been introduced to correct this problem and are promoted as providing 24 hours of anxiolysis. In our experience, the sustained-release forms of alprazolam, clorazepate, diazepam, and adinazolam have a duration of therapeutic action of approximately 12 hours. Sustained-release alprazolam has recently been approved by the FDA for use in panic disorder and has been available in 51 countries for some time. The medication in sustained-release alprazolam is enmeshed in a hydroxypropyl–methylcellulose matrix that releases the compound slowly and consistently over several hours so that the patient receives a constant dose of medication for a more extended period than in the immediate-release formulation and a therapeutic benefit lasting 11±4 hours (D. V. Sheehan 1993; D. V. Sheehan et al. 1996). A number of clinical trials, with a total of 893 patients, have investigated the efficacy and safety of sustained-release alprazolam in the treatment of panic disorder (Alexander 1993; Pecknold et al. 1993, 1994; Schweizer 1993; Stahl 1993). The results of these studies suggest that sustained-release alprazolam, administered once in the morning, is superior to placebo and is equal to comparable doses of alprazolam in its compressed or immediate-release tablet form administered in four divided doses. When given in fixed doses twice daily, sustained-release alprazolam was found to be superior to placebo and also appeared to cause fewer CNS side effects than with single-dose administration. Given in a single dose at bedtime, it was not more effective than placebo. These studies do not answer practical clinical questions such as how to adjust dosing during a switch from the compressed-tablet to the extended-release formulation of a benzodiazepine. A methodology for switching patients from a stable maintenance dose of the compressed-tablet formulation of alprazolam to the extended-release formulation was described by D. V. Sheehan et al. (1996). This methodology, developed in connection with a 9-week open-label crossover study, relies on the use of a patient diary in which the patient records hourly anxiolytic benefit on a 0–10 scale as well as any side effects. During the first week, while patients were still taking the compressed-tablet formulation, they were instructed to keep hourly recordings of the degree of anxiolytic effect and any side effects

they experienced after the first morning dose. They were further instructed to wait until they saw a dip in efficacy (evidence of a loss of therapeutic action documented in their diary records) before taking a second dose. This made it possible to establish the average time it took for the first dose to lose therapeutic effect, which was labeled as the endpoint of duration of therapeutic action (DOA). Once the DOA of an effective dose was established, efforts were directed to adjusting the distribution of doses to provide optimal control. At the end of 3 weeks, all patients were switched to an equivalent dose of sustained-release alprazolam in 0.5- or 1.0-mg tablets. At the switch, the total number of milligrams of the compressed-tablet formulation of alprazolam taken before 5:00 P.M. was converted into the morning dose of sustained-release alprazolam, and the total number of milligrams of the compressed-tablet formulation taken after 5:00 P.M. was converted into the evening dose of sustainedrelease alprazolam. With this methodology, equivalent efficacy for the compressed-tablet and sustained-release formulations was found on weekly ratings of anxiety. At the end of the study (week 9), diary records provided evidence of the considerably longer mean duration of therapeutic action of the sustainedrelease formulation compared with the compressed-tablet formulation: 11.3±4.2 hours (range = 3–24 hours) versus 5.1±1.7 hours (range = 3–11 hours). The major advantage of the sustained-release form is the convenience of less frequent dosing. Since most (81%) of the patients in the described study (D. V. Sheehan et al. 1996) required only once- or twice-daily dosing, compliance is likely to be higher. When doses were adjusted with patient input to achieve a smooth therapeutic effect over 24 hours (as reflected in symptom scale scores), the majority reported the best effects with two-thirds of the total daily dose in the morning (8:00 A.M.) and one-third of the total daily dose in the evening (7:00 P.M.) (D. V. Sheehan et al. 1996, 2007). While this may seem odd, there are several explanations for this phenomenon. One explanation is "the second-dose effect in pharmacokinetics" (DeVane and Liston 2001). The effect of a second dose of a medication is always more intense and lasts longer than the effect of the first dose. However, this relative increase in effect diminishes with subsequent doses. When dosing is repeated in response to the observed effect, the second-dose effect occurs regardless of the half-life of the drug. Another explanation is that the individual sleeps during much of the time when the second dose of the day (taken in the evening) is active. During sleep, the individual is less aware of feedback indicating a need for full anxiolytic effect. Yet another explanation is that the anxious patient reports more anxiety in the morning. To better control this early-day anxiety, the patient feels a need for a slightly higher dose at that time. The study by D. V. Sheehan et al. (1996) reaffirms that the half-life of a benzodiazepine does not predict its duration of action. It also provides the clinician with a methodology for switching patients on a regular compressed-tablet formulation of a benzodiazepine to the extended-release formulation of that benzodiazepine (D. V. Sheehan et al. 1996, 2007).

MECHANISM OF ACTION Benzodiazepines produce anxiolysis by their effect on the -aminobutyric acid (GABA)–benzodiazepine receptor complex. GABA is synthesized from glutamic acid, which is also the most abundant free amino acid in the CNS. Like serotonin, norepinephrine, and dopamine neurons, the presynaptic GABA neuron has a reuptake pump that transports GABA from the synapse for storage or destruction by GABA transaminase. GABA has two target receptors, GABAA and GABAB. The chloride ion channel is controlled by GABAA. A number of nearby receptors have the ability to allosterically modulate the GABAA receptor. These include receptors for benzodiazepines, for nonbenzodiazepine sedatives like zolpidem and zaleplon, for barbiturates, for alcohol, for neuroactive steroids, and for the proconvulsant picrotoxin. The GABAB receptor has two dissimilar subunits that comprise the functional receptor (GABAB1 and GABAB2). Six GABAB1 isoforms (1a through 1f) have been reported (Dawson et al. 2005). The GABAB receptor is not allosterically modulated by benzodiazepines but is known to bind

to the muscle relaxant baclofen. Four distinct pharmacological properties have been described for the benzodiazepine receptor: anxiolytic, hypnotic, anticonvulsant, and muscle relaxation effects. Anxiolytic and sedative-hypnotic actions are mainly mediated by the 1 receptor and muscle relaxation through the benzodiazepine2 ( 2) receptor. Most benzodiazepines interact with both these receptor subtypes. The benzodiazepine3 ( 3)

receptor is found mostly outside the CNS, and its role is unclear at this time. Typically, when GABA

occupies the GABAA receptor site, the chloride channel is opened up a little, and this effect is inhibitory. If at the same time a benzodiazepine binds to the nearby benzodiazepine receptor, the GABAA receptor is allosterically modulated, and GABA exerts a greater effect on the chloride channel and conductance. Although GABA works alone at the GABA receptor, it works better in the presence of a benzodiazepine. The benzodiazepine, on the other hand, in the absence of GABA cannot influence the chloride channel by itself. The GABAA receptor–chloride ion channel complex has a transmembrane pentameric structure. There are five subunits selected from eight polypeptide classes: , , , , , , , and . Several of these classes have subunits that have been characterized (6

,3

, 3 , and 2

variants). As a

consequence, there is the potential for the existence of a large number of receptor isoforms. The coassembly of an

, a , and a

subunit produces a high-affinity benzodiazepine binding site.

Benzodiazepines also potentiate combinations of benzodiazepines do not potentiate combinations of GABAA receptors. The site. Combinations with

and , or and

and , subunits. On the other hand,

subunits even though they are functional

subunit seems to dictate the pharmacology of the benzodiazepine receptor 1

have different pharmacology compared with combinations with

2

or other

1 subunit and anxiolysis by the 2 subunit (Low et al. 2000; Mohler et al. 2002). It has been suggested that benzodiazepineinduced hyperphagia is mediated by the 2 and 3 subtypes (Cooper 2005).

alpha variants. Sedation and anticonvulsant activity are mediated by the

THERAPEUTIC USES Because of their multiple pharmacological actions, benzodiazepines have been found useful in many areas of medical practice, such as induction of anesthesia, use as a muscle relaxant, and control of seizures. It is beyond the scope of this chapter to elaborate on these uses. In psychiatry, benzodiazepines are used to control anxiety, to treat insomnia, and to acutely manage agitation and withdrawal syndromes. Surprisingly, in the treatment of anxiety disorders, benzodiazepines have a greater impact in some disorders than others. In panic disorder, they have a significant impact on all dimensions of the illness, with the exception of depression. Alprazolam, for example, has been shown to be effective in panic disorder at a mean dosage of 5.7 mg/day (range = 1–10 mg/day) (Ballenger et al. 1988; Chouinard et al. 1982; Cross National Collaborative Panic Study 1992; D. V. Sheehan et al. 1982, 1984, 1993). Rapid improvement can be observed within the first week in terms of decreased panic attacks, phobic fears and avoidance, anticipatory anxiety, and disability. These benefits have been shown to persist during a follow-up period of 8 months (Schweizer et al. 1993). Efficacy has also been shown for lorazepam (Rickels and Schweizer 1986) and clonazepam (Pollack et al. 1993; Tesar et al. 1991). In the latter study, clonazepam 2.5 mg/day was as effective and well tolerated as alprazolam 5.3 mg/day. Despite the well-documented efficacy of benzodiazepines in panic disorder, they have been displaced in clinical practice by the SSRIs. However, it is common practice to initiate treatment with both classes of drug simultaneously and then withdraw the benzodiazepine after 6 weeks. The benefits and practicality of this approach to treating panic disorder have been reinforced by the findings from a 12-week study (Goddard et al. 2001) in which patients with panic disorder were treated with open-label sertraline and double-blind clonazepam or placebo. After 4 weeks of combination treatment, the adjunct medication (clonazepam or placebo) was tapered over 3 weeks and then

discontinued. All patients received sertraline monotherapy for the last 4 weeks of the study. The group randomized to sertraline and clonazepam had fewer dropouts (25% vs. 38%) and separated as early as week 1 from the sertraline–placebo group on the Panic Disorder Severity Scale (PDSS). These findings have been further reaffirmed by a recent double-blind, placebo-controlled study (Goddard et al. 2008) in which patients were randomly assigned to flexible-dose treatment with either sertraline plus placebo or sertraline plus extended-release alprazolam for 4 weeks, followed by a 4-week taper from the benzodiazepine, followed by 4 weeks on sertraline alone. Onset of benefit was faster in the initial weeks on the SSRI–benzodiazepine combination, and the dropout rate was lower in this group, but withdrawal symptoms were significantly higher in the benzodiazepine–SSRI group. At the end of 12 weeks, there was no difference in efficacy between the two groups (Goddard et al. 2008). The American Psychiatric Association (1998) guidelines for the treatment of panic disorder recommending SSRI monotherapy as the treatment of first choice has failed to achieve traction, since more than two-thirds of the SSRI prescriptions were accompanied by a concomitant benzodiazepine. The above studies by Goddard et al. (2008) lend justification to the rationale for using the combination treatment more frequently and blessing it as a reasonable alternative first-line treatment for many patients with panic disorder. Three double-blind studies have shown efficacy for benzodiazepines in the treatment of social phobia. In the first study (Gelernter et al. 1991), alprazolam demonstrated only limited efficacy relative to other treatments. At week 12 (end of study), 69% of phenelzine-, 38% of alprazolam-, 24% of cognitive-behavioral-, and 20% of placebo-treated patients had responded. In the second study (Davidson et al. 1993), at the end of 10 weeks of treatment, 78% of social phobia patients treated with clonazepam, compared with only 20% of those treated with placebo, responded. The mean dosage of clonazepam at endpoint was 2.4 mg/day. Bromazepam, a benzodiazepine not available in the United States, was found to be effective in a 12-week double-blind, placebo-controlled study of social phobia at a mean dosage of 21 mg/day, but it took 8 weeks for bromazepam to separate from placebo (Versiani et al. 1997). In two parallel and concurrent studies (D. V. Sheehan et al. 1990a, 1990b), we demonstrated that the sustained-release formulation of the benzodiazepine adinazolam was effective in panic disorder and generalized anxiety disorder (GAD). However, the dose of adinazolam needed to treat GAD effectively was higher than the dose needed to treat panic disorder. Endpoint scores on the Hamilton Anxiety Scale (Ham-A) were lower (better) in the patients with panic disorder, even though the mean effective dose of adinazolam was lower than in the GAD patients. This suggests that, contrary to prior assumptions, benzodiazepines in general, and adinazolam in particular, are less effective in GAD than in panic disorder. This has some support from findings in a double-blind, placebo-controlled study (Rickels et al. 1993) showing that the tricyclic antidepressant imipramine was better than diazepam in the treatment of nondepressed GAD patients over 8 weeks. Imipramine showed a trend to be significantly better on the primary outcome measure scale (Ham-A) and was statistically superior to diazepam on the Psychic Anxiety factor of the Ham-A. Psychic anxiety includes the items of worry, anxious mood, tension, fears, and concentration problems. Diazepam and imipramine had identical endpoint Ham-A Somatic Anxiety factor scores, suggesting that they are equally effective against the somatic anxiety symptoms in GAD. This suggests that imipramine is a better "anti-worry" medication than the benzodiazepine. Patients treated with diazepam had an earlier response than those taking imipramine. Generally, benzodiazepines are thought to be ineffective in the treatment of obsessive-compulsive disorder (OCD). In a small crossover study, clonazepam was reported as effective in treating OCD (Hewlett et al. 1992). The strongest evidence for effective pharmacotherapy in posttraumatic stress disorder (PTSD) is with SSRIs. A meta-analysis of six studies showed a correlation between greater serotonergic activity and

higher effect size (Penava et al. 1996–1997). Another meta-analysis of medications in treating PTSD found effect sizes of 0.49 and 1.38 for benzodiazepines and SSRIs, respectively (Van Etten and Taylor 1998). In a study of 13 trauma survivors treated prophylactically within 2–18 days of their trauma with lorazepam or clonazepam for 6 months, the subjects did not do any better than a matched untreated group in terms of PTSD symptoms at the 6-month evaluation (Gelpin et al. 1996). Benzodiazepines have potential for benefit in the acute management of mania, as they can rapidly induce sleep with earlier resolution of the mania and allow for lower doses of antipsychotics in the acute phase (Nowlin-Finch et al. 1994). Antimanic effects have been described for clonazepam. In a double-blind, crossover study, clonazepam was more efficacious than lithium and also had a faster onset of action (Chouinard et al. 1983). It has been reported that clonazepam is more effective in acute mania than lorazepam (Bradwejn et al. 1990). Intramuscular clonazepam has been compared with intramuscular haloperidol in the management of acute psychotic agitation. Clonazepam use reduced agitation, but haloperidol use had a more rapid onset (Chouinard et al. 1993). Individuals with schizophrenia have high levels of anxiety and frequently experience panic attacks. High-potency benzodiazepines as adjunctive therapy have been shown to benefit schizophrenic patients, with or without panic attacks, in the short term. But long-term use is problematic given this population's poor adherence to therapeutic regimens, their propensity to substance abuse and dependence, and the dangers of benzodiazepine dependence and withdrawal syndromes with chronic use (Wolkowitz and Pickar 1991). Overall, it appears that benzodiazepines have a role in the acute management of agitation, and their use can reduce the need for or the dose of antipsychotics used.

SIDE EFFECTS AND TOXICOLOGY Benzodiazepines are among the safest of drugs, but unwanted effects do occur. The first 1,4-benzodiazepines, such as diazepam and flurazepam, had slow rates of elimination and low receptor-binding affinities. Their main side effect was excessive daytime sleepiness. The late 1970s saw the introduction of the 1,4-benzodiazepines flunitrazepam and lorazepam, which had shorter half-lives and were more potent. These drugs were associated with enhanced efficacy but also with more rapid development of tolerance and significant withdrawal problems. The triazolobenzodiazepines were introduced in the 1980s and were even more potent and had even shorter half-lives. They have also been found to be associated with amnesia, daytime anxiety, earlymorning insomnia, and withdrawal problems such as rebound insomnia, anxiety, and seizures (Noyes et al. 1986). Sedation and drowsiness are common, occurring in 4%–9% of patients taking benzodiazepines. Ataxia occurs in up to 2%. The drowsiness tends to disappear with time or a reduction in dose (Greenblatt et al. 1982b; R. R. Miller 1973; Svenson and Hamilton 1966). Several lines of investigation suggest that benzodiazepines may impair psychomotor performance. Most benzodiazepines, shortly after administration, at their peak concentration cause anterograde amnesia (Lister et al. 1988). These effects are dependent on potency and route of administration. For example, with a low-potency drug such as diazepam, the risk of amnesia is highest with intravenous, less with intramuscular, and rare with oral administration (Bixler et al. 1979). It has been shown that when given orally, lorazepam and flunitrazepam cause more amnesia than diazepam and flurazepam (Magbagbeola 1974). Triazolam, a very potent triazolobenzodiazepine, is reported to cause significantly more memory impairment than other hypnotics such as flurazepam and temazepam (Greenblatt et al. 1989; Ogura et al. 1980; Roth et al. 1980; Scharf et al. 1988). Overall, this memory impairment does appear to be independent of the degree of sedation produced by the drug (Scharf et al. 1988). Also of great significance is that benzodiazepine-treated subjects are often unaware or underestimate the extent of their memory impairment (Roach and Griffiths 1985, 1987).

Hyperexcitability phenomena such as early-morning awakening and rebound anxiety and nervousness are more likely with the short-half-life, high-potency benzodiazepines such as triazolam, alprazolam, lorazepam, and brotizolam (Kales et al. 1983, 1986, 1987; Vela-Bueno et al. 1983). Treatmentemergent hostility (Rosenbaum et al. 1984) may be seen in up to 10% of patients being treated with benzodiazepines. This is most likely to happen early in treatment, is unrelated to pretreatment impulsivity, and has been reported with all benzodiazepines with the exception of oxazepam. Treatment-emergent mania has been reported with alprazolam (Goodman and Charney 1987; Pecknold and Fleury 1986; Strahan et al. 1985). Depression may also emerge with treatment (Pollack et al. 1986). We have seen increased dreaming in some patients, and there are case reports of reversible hepatitis (Judd et al. 1986), ejaculatory inhibition (Munjack and Crocker 1986), and inhibition of female orgasm (Sangal 1985). Since the 1960s, benzodiazepines have been known to produce anterograde amnesia. Initially, it was believed that this effect happened only with intravenous use. But now the effect is well documented, even with oral dosing (Lister 1985). It is likely that the amnestic effects are produced by interference with the transfer of information from very-short-term memory to long-term memory storage areas. The deficit is therefore one of disrupted consolidation and not impairment of memory retrieval. The degree of amnesia can range from minimal inability to retain isolated pieces of information to total inability to recall any activities that occurred during a specific period. Whether some benzodiazepines are more likely than others to produce amnesia remains an unresolved question. Triazolam 0.5 mg has been compared to 30 mg of temazepam on immediate and delayed recall. In tests of delayed recall, triazolam consistently caused anterograde amnesia. No effects were found in immediate recall in both drugs (Scharf et al. 1988). Retrograde facilitation was better with triazolam than with temazepam. Triazolam, lorazepam, and alprazolam are the compounds that show the most amnestic potential. Compared with temazepam and clorazepate, they also tend to be those with the greater benzodiazepine receptor affinities, lower volumes of distribution, and less lipophilicity (Nutt et al. 1989). It is not clear if chronic dosing with benzodiazepines aggravates the problem. One study comparing lorazepam and alprazolam suggests memory impairment dissipates beyond the single-dose administration period (Kumar et al. 1987). Another area of concern is that the long-term use of benzodiazepines may lead to cognitive and other impairments that persist long after the drug has been discontinued. Abnormal computed tomography scans were reported in long-term users of benzodiazepines in one study (Lader et al. 1984) but not in others (Poser et al. 1983; Rickels 1985). Busto et al. (2000) found no difference in the computed tomography scans of brains of patients taking benzodiazepines compared with control subjects. Paulus et al. (2005) reported a dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. No other positron emission tomography or functional magnetic resonance imaging studies that might inform this question are yet available. Long-term benzodiazepine users have been compared with controls and found to have cognitive impairments that reversed on reexamination after taper (Golombok et al. 1988; Lucki et al. 1986; Rickels et al. 1999; Sakol and Power 1988). Another study found that after long-term use, if the benzodiazepine is stopped, there was only partial recovery even after 6 months (Tata et al. 1994).

DRUG–DRUG INTERACTIONS Antacids slow benzodiazepine absorption, as aluminum delays gastric emptying (Greenblatt et al. 1983a, 1983b). An acid medium is needed for conversion of clorazepate to desmethyldiazepam, the active metabolite, which is then absorbed (Shader et al. 1978). In the liver, benzodiazepines are metabolized by oxidation, reduction, or conjugation. Alprazolam, diazepam, clorazepate, prazepam, chlordiazepoxide, bromazepam, and halazepam are metabolized by oxidation; nitrazepam by reduction; and lorazepam, oxazepam, and temazepam by conjugation. Inhibitors of the oxidase system prolong the half-life of benzodiazepines that are metabolized by this

system. This accentuates the side effects, notably the sedation, ataxia, slurred speech, and imbalance. A decrease in dosage may solve this problem, or a switch to a benzodiazepine that is metabolized by conjugation may be needed. MAOIs, cimetidine (Greenblatt et al. 1984), and oral contraceptives inhibit the oxidative system. There is a decline in this system with age or liver disease. In the elderly, there is a 50% decrease in clearance, with a four- to ninefold increase in half-life and a two- to fourfold increase in the volume of distribution (Peppers 1996). Due to the decreased clearance of lorazepam, lower doses of the benzodiazepine are recommended in patients taking valproate or probenecid. Phenytoin and barbiturates (Scott et al. 1983) cause hepatic enzyme induction and reduce benzodiazepine half-life. Heparinized patients (Routledge et al. 1980) should have partial thromboplastin time (PTT) monitored more closely, as PTT is prolonged by benzodiazepines. Benzodiazepines increase digoxin levels (Castillo-Ferrando et al. 1980; Tollefson et al. 1984), increasing the chance of digoxin toxicity. As antidepressants like fluoxetine or nefazodone and protease inhibitors like indinavir sulfate inhibit the cytochrome P450 enzyme 3A4, they inhibit the metabolism of triazolobenzodiazepines such as midazolam, alprazolam, and triazolam. Inhibition of the gag reflex can occur with benzodiazepine administration (Nutt et al. 1989), increasing the risk for aspiration in patients with nausea and vomiting.

CLINICAL ISSUES Despite decades of research, the optimal extent and duration of appropriate benzodiazepine use in the treatment of anxiety and related disorders remain unresolved. This is primarily because of concerns expressed by prescribers, regulators, and the public about issues such as tolerance, dependence, and abuse liability of this class of medication.

Tolerance In a study of persistent users of alprazolam and lorazepam, Romach et al. (1995) found that most were not abusing these benzodiazepines, nor were they addicted to them; rather, they were using them appropriately for a chronic disorder and at a constant or a decreasing dose. Soumerai et al. (2003) found a lack of relationship between long-term use of benzodiazepines and escalation to high doses in 2,440 long-term (at least 2 years) users of benzodiazepines and that escalation to a high dose was very rare. Superior results with benzodiazepines are only achieved long term by careful attention to dose adjustment guidelines. The benefits are usually apparent within 2–3 weeks of starting the drug. At this stage, patients often report that the medication is no longer working as well as it did initially. Concurrently, the side effects have also subsided, because of tolerance. If the dose is adjusted up to the next level, the patient again usually gets benefit and continues to do well for another 4–6 weeks. At this stage, tolerance may yet again develop, with the patient losing some benefit and side effects. At this point, adjustment of the dose upward results in benefit again. Physicians may be concerned that there will be no end to this upward adjustment of the dose. However, with effective benzodiazepine therapy, there is a limit to the number of such plateaus that patients go through before reaching their final effective dose. Typically, this dose is reached by the second or third plateau, usually around week 10 or 12. Failure to identify and take appropriate action during these early troughs of partial tolerance in the initial weeks of treatment is common. Sometimes, patients will unilaterally increase the dosage to achieve benefit. The clinician should not take this to be evidence of addictive behavior. Benzodiazepines differ with regard to the degree and timeline for the development of tolerance. As a general rule, long-half-life benzodiazepines such as flurazepam, quazepam, diazepam, and clonazepam tend to be effective for a month or longer before tolerance is exhibited. On the other hand, short-half-life benzodiazepines such as triazolam, alprazolam, temazepam, and lorazepam lose some of their initial efficacy sooner, sometimes in just over a week (Bayer et al. 1986; Bixler et al. 1978; Kales et al. 1986, 1987). One milligram of alprazolam is approximately equivalent to 0.7 milligrams of clonazepam, to 10 milligrams of diazepam, and to 1 milligram of lorazepam. The cross-tolerance between the

benzodiazepines, although good, is not perfect, and it is preferable not to switch patients abruptly from one benzodiazepine to another.

Withdrawal A withdrawal syndrome is defined as a predictable constellation of signs and symptoms involving altered CNS activity (e.g., tremor, convulsions, or delirium) after the abrupt discontinuation of, or rapid decrease in, dosing of the drug (Rinaldi et al. 1988). Typically, a withdrawal syndrome from short-half-life benzodiazepines will intensify by the second day, will usually have peaked by day 5, and will begin to decrease and taper off by day 10. After 2 weeks, withdrawal symptoms have usually become minimal or absent. Drug factors associated with withdrawal symptoms include length of use, dose, potency, and rate of discontinuation. Psychic, physical, and perceptual symptoms can be observed during withdrawal. The most common are anxiety, restlessness, irritability, insomnia, agitation, muscle tension, weakness, aches and pains, blurred vision, and racing heart, in that order (O'Brien 2005). Nausea, sweating, runny nose, hypersensitivity to stimuli, and tremor are less frequent. Severe withdrawal symptoms, such as psychosis, seizures, hallucinations, paranoid delusions, and persistent tinnitus, are relatively rare and are more likely to occur in abrupt withdrawal from high doses of high-potency benzodiazepines and in the elderly (American Psychiatric Association 1990; Lader 1990; Petturson and Lader 1991). The minimum duration of use after which clinically significant withdrawal symptoms can be expected has not been definitively determined. At the end of any course of treatment with therapeutic doses and of duration greater than 3–6 weeks, withdrawal of the benzodiazepine should be done as a slow taper. This reduces the risk of unpleasant withdrawal symptoms and the danger of withdrawal seizures and minimizes rebound reactivation of the underlying anxiety disorder (Fontaine et al. 1984; Pecknold et al. 1988; Power et al. 1985). We recommend that alprazolam or clonazepam not be withdrawn at a rate faster than 0.5 mg every 2–3 weeks. If the drug is tapered at this rate, it is very unlikely that you will see a withdrawal seizure. In a patient taking either drug at a dosage of 6 mg/day, it may take a few months to complete taper on such a slow withdrawal schedule. However, there are no clinical reasons to taper more rapidly. All pharmaceutical companies manufacturing benzodiazepines and the FDA should encourage physicians to withdraw patients from all benzodiazepines at much slower rates than those currently recommended in order to prevent these complications. The recommended rate of withdrawal from alprazolam, for example, is not faster than 0.5 mg every 3 days. In our opinion this rate is too fast. All patients should be advised about the dangers of abruptly stopping the medication, and this should be documented. A systematic review of the literature on this topic in the Cochrane Database recommended slow withdrawal over 10 weeks (Denis et al. 2006). A number of factors are thought to influence the severity of the withdrawal syndrome. Withdrawal is more difficult with the use of short-half-life drugs, higher doses, long duration of use, rapid tapering, a diagnosis of panic disorder, and certain personality traits (Rickels et al. 1988, 1990; Schweizer et al. 1990). Eighteen percent of patients taking diazepam for 14–22 weeks had withdrawal symptoms, and 43% had withdrawal symptoms after 8 months of use (Rickels et al. 1983). Thirty-five percent of patients taking alprazolam (2–10 mg/day) for 8 weeks had withdrawal symptoms (Pecknold 1993; Pecknold et al. 1993). The first 50% of taper can be done fairly quickly over a 2- to 4-week period. It may be helpful to stay at this dose for several weeks or even a few months before proceeding with the remaining 50% taper at a very slow rate. Early dropouts from taper were found to score higher on the Dependence factor of the Minnesota Multiphasic Personality Inventory compared with late-taper dropouts and those who tapered successfully (Schweizer et al. 1998). In a 3-year follow-up of patients who had participated in a benzodiazepine taper program, it was found that of those who tapered successfully, 73% remained benzodiazepine free. Among those who were able to reduce intake by 50%, only 39% were benzodiazepine free at the end of 3 years. In the group that could not

tolerate taper at all, only 14% were benzodiazepine free (Rickels et al. 1991). A variety of medications have been tried as adjuncts to facilitate taper. Propranolol (Tyrer et al. 1981), progesterone (Schweizer et al. 1995), and dothiepin (Tyrer et al. 1996) were not better than placebo. Buspirone (Lader and Olajide 1987; Rickels 1988; Schweizer and Rickels 1986) was ineffective in patients who had used benzodiazepines for a year or longer but was of some benefit in those who had used lorazepam for a period of 3 months or less (Pancheri et al. 1995). Some benefit for carbamazepine at dosages of 200 to 600 mg/day has been reported (Klein et al. 1986; Neppe and Sindorf 1991; Schweizer et al. 1991; Swantek et al. 1991).

Addiction Potential In our zeal to heal an anxiety disorder, are we creating a population of addicts? There is much misinformation and concern generated because terms like addiction are used without precise definition and pejoratively. Terms such as addiction, physical dependency, and withdrawal syndrome are often used interchangeably. There is a presumption that a medicine's being associated with a withdrawal syndrome is evidence that the medicine is addicting. Some clinicians believe that benzodiazepines that require frequent dosing during the day are more addicting than those that require less frequent dosing. In fact, frequency of dosing is a function of the duration of therapeutic action of the drug rather than of any innate addiction potential of the drug. DSM-IV-TR (American Psychiatric Association 2000) defines substance (drug) dependence as a maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by three (or more) of the criteria shown in Table 24–2 occurring at any time in the same 12-month period. Addiction, in contrast, is defined as a chronic disorder associated with compulsive use of a drug, resulting in physical, psychological, or social harm to the user and continued use despite that harm (Rinaldi et al. 1988). Addiction involves both intense drug-seeking behavior and difficulty in stopping the drug use. If these criteria are used, benzodiazepines are not addictive drugs. Physical dependence is different from addiction and is defined as a physiological state of adaptation to a drug, with the development of tolerance to the drug's effects and the emergence of a withdrawal syndrome during prolonged abstinence. During withdrawal after chronic use, biochemical, physiological, or behavioral problems may be triggered. When used on a regular schedule, benzodiazepines are associated with physical dependence, as opposed to drug dependence or DSM-IV-TR "substance dependence," and have a withdrawal syndrome. In psychological dependence (Rinaldi et al. 1988), there is a state of emotional craving either to experience the drug's positive effect or to avoid the negative effects associated with its absence. This can lead to compulsive drug-seeking behavior. TABLE 24–2. DSM-IV-TR criteria for substance dependence A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period: (1) tolerance, as defined by either of the following: (a) a need for markedly increased amounts of the substance to achieve intoxication or desired effect (b) markedly diminished effect with continued use of the same amount of the substance (2) withdrawal, as manifested by either of the following: (a) the characteristic withdrawal syndrome for the substance (refer to criteria A and B of the criteria sets for withdrawal from the specific substances) (b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms (3) the substance is often taken in larger amounts or over a longer period than was intended

(4) there is a persistent desire or unsuccessful efforts to cut down or control substance use (5) a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chain-smoking), or recover from its effects (6) important social, occupational, or recreational activities are given up or reduced because of substance use (7) the substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer was made worse by alcohol consumption) Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. Copyright 2000, American Psychiatric Association. Used with permission.

Abuse Studies of abuse use four criteria for benzodiazepine abuse. A benzodiazepine is being abused if it is taken 1) to get high, 2) to promote psychological regression, 3) at doses higher than prescribed, and 4) after the medical indication has passed (Dietch 1983). On the basis of this definition, the data suggest that the incidence of benzodiazepine abuse in clinical practice is low. A U.S. national health survey in 1979 found that 1.6% of subjects studied used benzodiazepines regularly for at least 1 year (Mellinger et al. 1984). In another study of anxiolytic medication users in the United States, 15% used these drugs daily for more than 1 year (Balter et al. 1984). In a London general practice, 1.6% used benzodiazepines for more than 1 year (Salinsky and Dore 1987). In an Australian general practice study, 10% of first-time benzodiazepine users were still using them with no dose increase after 6 months (Mant et al. 1988). The incidence of benzodiazepine dependence in the therapeutic setting (among those for whom the drug is medically correctly prescribed) was estimated to be 1 case in 50 million patient-months (Marks 1978). Of these cases, 92% were associated with alcohol or other drugs of abuse. This estimate is probably on the low side since it is based on the number of published cases of dependence from 1961 to 1977. There is a positive correlation between benzodiazepine use and psychiatric morbidity (Fichter et al. 1989; Pakesch et al. 1989; Salinsky and Dore 1987; Schwartz and Blank 1991). "Benzodiazepine dependence" was diagnosed in only 150 cases (0.5%) of 33,000 consecutive admissions between 1974 and 1983 at a German psychiatric hospital. In contrast, 18.5% of admissions in 1984 ("quarterly incidence") were found to involve long-term users of benzodiazepines (Laux and Konig 1987). In Basel, Switzerland, with a catchment area of 300,000 people, physicians were surveyed on the prevalence of benzodiazepine abuse in their patients. Only 31 patients were identified—a prevalence of 0.01%, or 1 in 10,000. An additional 88 polysubstance abusers were identified (Ladewig and Grossenbacher 1988). In a small prospective study involving 71 outpatients treated with benzodiazepines for a diagnosis of major depression or an anxiety disorder, no evidence of benzodiazepine abuse was found. Five patients (7%) with a diagnosis of major depression misused benzodiazepines (Garvey and Tollefson 1986). Another study prospectively followed 99 anxiety disorder patients with a history of alcohol abuse and dependence and 244 without such a history. Over the 12 months of the study, only minor differences in the use of benzodiazepines were noted for the groups. The authors concluded that in patients with an anxiety disorder, the presence or absence of a history of alcohol use disorder was not a strong predictor of future abuse (Mueller et al. 1996). In a random sample of all psychiatric hospitalizations over 15 years (1967–1983) in Sweden (n = 32,679), Allgulander (1989) found only 38 admissions for substance dependence on sedative hypnotics. Twenty-one of the 38 had polysubstance abuse, and 17 had sedative-hypnotic abuse. In another study of all medical and psychiatric hospitalizations (n = 1.6 million) in Stockholm County, Allgulander

(1996) found that 0.04% of "prescribed medication" users (including benzodiazepines) were ever admitted for medical problems relating to their drug use. In a study of 5,426 physicians randomly selected from the U.S. physicians American Medical Association database, Hughes et al. (1992) found that although 11.9% had used benzodiazepines in the past year, only 0.6% met DSM-III-R (American Psychiatric Association 1987) criteria for benzodiazepine abuse and 0.5% met criteria for benzodiazepine dependence. In 1990, the American Psychiatric Association task force concluded that benzodiazepines were not normally drugs of abuse, but noted that people who abused alcohol, cocaine, and opiates were at increased risk for benzodiazepine abuse (Salzman 1991). Although some patients undergoing chronic therapy increase their benzodiazepine dose over time—39% in one study (Khan et al. 1981) and 50% in another (Maletzky and Klotter 1976)—the mean increase is only a small one. A number of studies have noted no increase in dosage with chronic therapy of duration from 1 to 2.5 years, even though many of the patients had residual symptoms that would have benefited from a dose increase or more intensive or additional treatment strategies (Pollack et al. 1986; D. V. Sheehan 1987). It has been reported that nonanxious subjects and those with low anxiety levels find benzodiazepines dysphoric (Reed et al. 1965), prefer placebo to diazepam (Johanson and Uhlenhuth 1978, 1980), or rate their mood as less happy and pleasant after they were given 10 mg of diazepam (Svenson et al. 1980). Although the data suggest that the prevalence of benzodiazepine abuse or dependence is generally low, this is not true among those who abuse alcohol and other drugs. In a study of chronic alcoholic individuals who were high consumers of benzodiazepines, 17% got their benzodiazepines from nonmedical sources (Busto et al. 1983). In a study of 1,000 admissions to an alcohol treatment unit, 35% of patients used benzodiazepines, but only 10% of the total sample were considered abusers or misusers (Ashley et al. 1978). A study of 427 patients seeking treatment in Toronto who met DSM-III (American Psychiatric Association 1980) criteria for alcohol abuse or dependence found that 40% were recent users and 20% had a lifetime history of benzodiazepine abuse or dependence. Women, unemployed individuals, and those with personality disorder were at higher risk for dependence. The current benzodiazepine users were more likely to endorse psychological distress and depression and have a lifetime history of an anxiety disorder (H. E. Ross 1993). On the other hand, only 5% of 108 alcoholic patients treated for a year with benzodiazepines for anxiety and tension showed evidence of abuse, and 94% felt it helped them function and remain out of hospital (Rothstein et al. 1976). Benzodiazepine abuse liability has been shown for abstinent alcoholic men (Ciraulo et al. 1988) and in the sons and daughters of alcoholic individuals (Ciraulo et al. 1989, 1996). Enhanced sensitivity to the effects of benzodiazepines on frontal electroencephalographic activity was found to correlate with euphoric subjective responses in abstinent alcoholic individuals (Ciraulo et al. 1997). Benzodiazepines were the primary drug of abuse in one-third of polydrug abusers (Busto et al. 1986), in 29% of 113 drug abusers admitting to the street purchase of diazepam in the previous month (Woody et al. 1975), and in 40% of patients at a methadone maintenance clinic (Woody et al. 1973). The principal reasons for benzodiazepine use among drug addicts are self-treatment of withdrawal symptoms, relief from rebound dysphoria, or potentiation of alcohol or street drug effects (Petera et al. 1987). In one study at an addictions treatment center, 100% of urine samples tested were positive for benzodiazepines and 44% were positive for multiple benzodiazepines, nonprescribed (Igochi et al. 1993). A survey of patients at three different methadone maintenance clinics found that 78%–94% admitted to a lifetime use of benzodiazepines and 44%–66% admitted to use in the prior 6 months. They also expressed a preference for diazepam, lorazepam, and alprazolam over chlordiazepoxide and oxazepam (Darke et al. 1995). Intravenous benzodiazepine use is more likely in polydrug users. In Australia, 48% of heroin users sampled injected benzodiazepines, with diazepam and temazepam being the most frequent. In the United Kingdom, the preference was for temazepam (Lader 1994; J. Ross et al. 1997). Snorting of benzodiazepines by cocaine addicts has been reported (M. F. Sheehan et al. 1991), primarily as a means of blunting the anxiogenic effect of cocaine and allowing for a more

pleasant and "less edgy" high from that drug. There is minimal evidence that sustained-release formulations may have less potential for abuse than do immediate-release formulations (Mumford et al. 1995). Flunitrazepam (Rohypnol), a benzodiazepine that is not legally available in the United States, has been popular as a party drug and is sold as "rophies," "roofies," and "roach." When mixed with alcohol, it has very strong sedating and amnestic properties and has been used as a "date rape" drug. Overall, the existing evidence suggests that the prevalence of benzodiazepine abuse is uncommon, except among those individuals who abuse alcohol and or other drugs. Despite extensive data and discussion on this topic, the issue remains and will continue to be controversial, with strong opinions held by opposing camps. Klerman characterized these camps as "pharmacological Calvinism" and "psychotropic hedonism," respectively (Klerman 1972; Rosenbaum 2005). The pharmacological Puritans or Stoics consider anxiety to be a lesser evil than the damage that may result from psychomotor impairment (including falls in the elderly) and the risks of abuse and dependence, especially in view of the fact that alternative treatments (antidepressants and cognitive-behavior therapy) are available (Geppert 2007). The psychotropic hedonists or the Epicureans consider anxiety disorder to be more hazardous than the aforementioned risks; they believe that an anxious patient has a right to seek a life free from anxiety and fear, and they trust the patient's ability to manage this controlled substance without abuse (Geppert 2007). The middle ground suggests that we should not hesitate to prescribe benzodiazepines when it is reasonable, but that we should exercise restraint in using them when we see any evidence of abuse (Pomeranz 2007). Attempts to restrict benzodiazepine prescription have had mixed results (Schwartz 1992; Schwartz and Blank 1991). For example, the triplicate prescription program instituted in 1989 by New York State with the intent to restrict benzodiazepine prescriptions resulted in increased use of older, more dangerous sedative-hypnotics such as barbiturates and meprobamate and an increase in prescriptions for benzodiazepines in the neighboring state of New Jersey (Hemmelgarn et al. 1997; Schwartz 1992; Schwartz and Blank 1991).

MEDICOLEGAL ISSUES In addition to issues of dependence and withdrawal described in the previous section, there are a number of potential medicolegal pitfalls in using benzodiazepines. These include issues of teratogenicity, injury, and interaction with substances.

Benzodiazepines and Pregnancy Since anxiety disorders have their highest incidence in women during their childbearing years, the clinician may have to advise patients who are planning a pregnancy or who become pregnant while taking a benzodiazepine.

First and Second Trimesters An important concern in the first and second trimesters is the possibility of teratogenic effects. Diazepam and desmethyldiazepam cross the placental barrier easily, and concentrations are higher in fetal blood than in maternal blood (Idanpaan-Heikkila et al. 1971). Early concern over benzodiazepine exposure in pregnancy arose because benzodiazepines act on GABA receptors and GABA is involved in palate shelf reorientation (Wee and Zimmerman 1983; Zimmerman and Wee 1984). Benzodiazepine receptors have been found in fetuses of 12–15 weeks (Aaltonen et al. 1983). The teratogenic effects of benzodiazepines, however, are a matter of controversy. Exposure to benzodiazepines has been associated with teratogenic effects, including facial clefts and skeletal anomalies in the newborn in some animal studies (R. P. Miller and Becker 1975; Walker and Patterson 1974; Wee and Zimmerman 1983; Zimmerman 1984; Zimmerman and Wee 1984) but not in others (Beall 1972; Chesley et al. 1991). Early human studies, including retrospective and case–control studies, reported an increased risk of oral clefts associated with diazepam (Aarskog 1975; Livezey et al. 1986; Safra and Oakley 1975; Saxen 1975; Saxen and Lahti 1974). These results, however, have been criticized on

methodological grounds and are contradicted by more recent prospective studies, case–control studies, and meta-analyses that show no increased risk of oral clefts related to benzodiazepine use in pregnancy (Altshuler et al. 1996; Bracken 1986; Czeizel 1988; Dolovich et al. 1998; Ornoy et al. 1998; Pastuszak et al. 1996; Rosenberg et al. 1983; Shiono and Mills 1984). Other anomalies, including inguinal hernia, pyloric stenosis, and congenital heart defects, have been reported with first-trimester use (Bracken and Holfred 1981); hemangiomas and cardiovascular defects have been associated with second-trimester use (Bracken and Holfred 1981). Isolated cases of skeletal defects such as spina bifida, absence of left forearm, syndactyly, and absence of both thumbs have also been reported following benzodiazepine use in pregnancy (Briggs et al. 1998; Istvan 1970; New Zealand Committee on Adverse Drug Reactions 1969; Ringrose 1972), and other malformations, including dysmorphic features, growth aberrations, and abnormalities of the CNS, have been attributed to benzodiazepines (Hartz et al. 1975; Laegreid et al. 1989; Milkovich and van den Berg 1974). Pooled data from seven cohort studies, however, do not support an association between fetal exposure to benzodiazepines and major malformations (Dolovich et al. 1998).

Third Trimester and Labor Two concerns associated with benzodiazepine use in the last trimester and through delivery are the possibilities of CNS depression and a withdrawal syndrome. Signs of CNS depression may include hypotonia, lethargy, sucking difficulties, decreased fetal movements, loss of cardiac beat-to-beat variability, respiratory depression, and thermogenesis. These symptoms in the neonate are more likely with higher doses and longer duration of benzodiazepine use by the mother. There have been numerous reports of "floppy infant syndrome" in babies born to women taking diazepam long term during pregnancy (Gillberg 1977; Haram 1977; Rowlatt 1978; Spreight 1977). Neonatal withdrawal symptoms may include hyperactivity and irritability. The occurrence of neonatal withdrawal symptoms is well documented (Barry and St. Clair 1987; Briggs et al. 1998; Cree et al. 1973; Fisher et al. 1985; Gillberg 1977; Haram 1977). Symptoms may be present at birth or appear weeks later and may continue for a period of time (Besunder and Blumer, in Schardein 1993). Elimination of benzodiazepines in the infant is slow, and it is believed that increased blood concentrations, together with an immature blood–brain barrier, contribute to newborns being more sensitive to these medications than are adults (Pastuszak et al. 1996). Diazepam in isolated doses is safe during labor (Briggs et al. 1998). There are conflicting reports on the effect of benzodiazepines on Apgar scores. Lowered Apgar scores have been reported with benzodiazepine use in some studies (Berdowitz et al. 1981; McElhatton 1994). One study found that diazepam reduced Apgar scores only when doses greater than 30 mg were administered during labor (Cree et al. 1973). Benzodiazepines do not appear to significantly affect fetal pH (Haram 1977). Diazepam contains a buffer, sodium benzoate, that displaces bilirubin from albumin in vitro (Haram 1977). Perhaps for this reason, parenteral diazepam given during labor has been associated with a dose-dependent elevation of neonatal serum bilirubin concentration secondary to delayed bilirubin metabolism (Haram 1977).

Evaluation of the Evidence on Benzodiazepine Teratogenicity Approximately 3% of all pregnancies end with the delivery of an abnormal live-born infant; only about 3% of these are associated with known teratogenic exposure (Coustan and Carpenter 1985). In the Collaborative Perinatal Project, the overall infant malformation rate was 6.5% (Heinonen et al. 1977). Several sources of bias must be considered in evaluating the data on benzodiazepine teratogenicity (Dolovich et al. 1998). Retrospective studies have been criticized for "recall bias" as well as confounding and ascertainment bias. Patients using benzodiazepines tend to be a little older, and their anxiety disorder may lead to increased use of cigarettes, alcohol, caffeine, or analgesics, all of which have been associated with complications in pregnancy. Because of their well-known muscle-relaxant

and catecholamine-reducing properties, it is conceivable, but not established, that benzodiazepines might prevent spontaneous abortions of an already malformed fetus. It is also possible that the underlying anxiety disorder itself may be associated with fetal complications (Cohen et al. 1989; Crandon 1979; Istvan 1986). Large population studies are needed in order to control for these confounding factors. In the meantime, the direction of the evidence would suggest that caution and conservative advice are prudent.

Advice to Patients Planning a Pregnancy If a patient taking a benzodiazepine plans a pregnancy, it is best to advise her to be off the medicine during her pregnancy. Benzodiazepines should always be discontinued very slowly. Some patients are unable to complete taper or tolerate the recurrence of their anxiety disorder and the consequent disability in work, social life, and family life. It is best in all cases to make an attempt to discontinue the benzodiazepine in the hope that the patient will manage without it before conceiving. Patients who are unable or unwilling to stop their benzodiazepine should be encouraged to use the lowest dose possible, preferably on an as-needed schedule. All patients are encouraged to have discontinued their benzodiazepine before the last 2 months of pregnancy. Withdrawal from benzodiazepines in a premature infant could tip the balance against healthy survival. It is common for panic disorder patients to experience a significant worsening of their panic disorder during the postpartum period. The benzodiazepine can be restarted immediately postpartum if they agree not to breast feed.

Management During an Unplanned Pregnancy It is estimated that almost half of all pregnancies in the United States are unplanned (Skrabanek 1992). It is not unusual for a patient who has been taking a benzodiazepine for months or years to come to a regular office visit and announce that she is pregnant. She now wonders whether she should abruptly stop the benzodiazepine or have a therapeutic abortion. The first recommendation is to ensure that the patient does not abruptly stop the benzodiazepine. Abrupt withdrawal could precipitate a withdrawal seizure and even a miscarriage. Typically, by the time she realizes that she is pregnant, the period for organogenesis (8–9 weeks) is past. The first step is to spend time discussing these issues with the pregnant patient and her family and then enter a detailed record of this discussion into the medical record. Consulting with a colleague on this issue for a second opinion may be helpful. The patient can be told that there is no compelling data to support the view that discontinuing the benzodiazepine will decrease the earlier-mentioned expected 3% risk of having a fetal complication (Coustan and Carpenter 1985). However, physicians prefer their pregnant patients to not be taking any medication, as the patients in these 3% of cases might blame the complication on the benzodiazepine, even if there is no association, and sue them. The next step is to plan carefully with her a very slow withdrawal of the benzodiazepine over weeks rather than over days. A therapeutic abortion is not indicated after routine use of a benzodiazepine in the first or second trimester, as the associated abnormalities are rarely life-threatening.

Breast Feeding Early on, neonates were found to have only limited capacity to metabolize diazepam (Morselli et al. 1973). Benzodiazepines are excreted in breast milk (Llewellyn and Stowe 1998). Because of the neonate's limited capacity to metabolize these drugs, they can potentially accumulate and cause sedation, lethargy, and loss of weight in the nursing infant. Although the extent to which benzodiazepines actually accumulate in the serum of breast-feeding infants is a matter of debate (Birnbaum et al. 1999), and three decades of studies support a low incidence of toxicity and adverse effects (Birnbaum et al. 1999; Llewellyn and Stowe 1998), caution taking benzodiazepines while breast-feeding is advised. Individualized risk–benefit assessments are recommended with the goal of minimizing, if not avoiding, infant exposure to benzodiazepines in breast milk.

Psychomotor Impairment

Another area of risk of benzodiazepine use relates to issues of psychomotor impairment resulting in injury. Examination of the medical records of a group of benzodiazepine users and nonusers who were part of a health maintenance organization found that the benzodiazepine users were more likely to experience at least one episode of accident-related health care and a greater number of accidentrelated inpatient days and also utilized significantly more non-accident-related health care services than did nonusers. Accident-related utilization of health care was more likely in the first month after the drug was prescribed (Oster et al. 1987). In the elderly, the issue of benzodiazepine use increasing the risk for falls and fractures is of great concern because hip fractures are associated with increased morbidity and mortality. A number of studies (Boston Collaborative Drug Surveillance Program 1973; Cummings et al. 1995; Greenblatt et al. 1977; Hemmelgarn et al. 1997; Ray et al. 1992; Roth et al. 1980) have found a greater risk for falls with the use of long-half-life benzodiazepines, and others (Cumming and Klineberg 1993; Herings et al. 1995; Leipzig et al. 1999) have found the risk to be greater with short-half-life drugs. A more recent study (Wang et al. 2001) found the risk for hip fracture in the elderly to be the same with the use of short- or long-half-life benzodiazepines. They did find that the risk increased when benzodiazepine dosages were >3 mg/day in diazepam equivalents. They also found the greatest risk to be shortly after initiation of therapy and after 1 month of continuous use. A 5-year prospective cohort study followed a large group of elderly people newly exposed to benzodiazepines (Tamblyn et al. 2005). The risk of injury varied by benzodiazepine, was independent of its half-life, and was highest for oxazepam, flurazepam, and chlordiazepoxide. The elderly using benzodiazepines are at greater risk of a motor vehicle accident (Hemmelgarn et al. 1997). On the other hand, a study of the effect of New York State requiring triplicate forms for prescribing benzodiazepines showed that despite a 50% drop in the number of prescriptions written, there was no significant change in age-adjusted risk for hip fractures (Wagner et al. 2007). Patients receiving benzodiazepines are nearly five times more likely than nonusers to experience a serious motor vehicle accident (Skegg et al. 1979). In the first 2 weeks of benzodiazepine use, there is a severalfold excess risk for hospitalization related to accidental injury compared with persons using antidepressants or antipsychotics (Neutel 1995). In a review of minor tranquilizers and psychomotor performance, the data overall support impairment by the few compounds studied—diazepam, lorazepam, and alprazolam. Generally, behavioral tolerance does not develop with chronic dosing (Smiley 1987). The problem with the psychomotor (driving) studies is that it is not clear how well these mirror real-life situations. In terms of utilization of medical services due to accidents, it is not yet resolved how much is due to the drug and how much is due to the illness itself, as there are no placebo-controlled studies. However, it is good practice to warn patients about the potential for sedation and psychomotor impairment with benzodiazepine use. They should be advised to be cautious when performing skilled tasks, driving, or working with machinery. Patients should be advised to avoid the use of alcohol or sedating antihistamines when taking benzodiazepines, as there are potentially serious additive effects (Van Steveninck et al. 1996). Ethanol has effects on the GABA–benzodiazepine receptor complex. Brain benzodiazepine levels are influenced by alcohol ingestion. Alcohol decreases triazolam levels, increases diazepam levels, and does not change chlordiazepoxide levels (Castaneda et al. 1996). The best protection is a discussion of these issues with the patient prior to prescribing a benzodiazepine. This discussion, including cautionary statements about driving or using dangerous appliances, should be documented in the chart at the start of therapy. The patient should be educated about potentiation by alcohol or other sedating drugs. He or she should be strongly advised never to abruptly discontinue the medicine because of a risk of seizures (Noyes et al. 1986), and this should be documented. Prescribing benzodiazepines for patients with a current or lifetime history of substance abuse or dependence should be done infrequently and only after documenting a risk–benefit discussion in the chart. It is good practice to routinely screen for substance abuse before prescribing

a benzodiazepine and to document that this was done. In one outpatient clinic, there was no information about alcohol use recorded in the charts of 57% of patients prescribed benzodiazepines (Graham et al. 1992).

CONCLUSION Benzodiazepines, if given in adequate doses, are effective in the treatment of anxiety. They have a lower mortality and morbidity per million prescriptions than some of the alternatives (Girdwood 1972). They are quicker in onset of action, easier for the clinician to use, associated with better compliance, and less subjectively disruptive for the patient than any of the other medication alternatives. Until they are replaced by another class of medicine that is safer, better tolerated, and as rapidly effective, it is likely that they will continue to be prescribed to a significant proportion of patients. It is also likely that we will see a shift toward the use of sustained-release formulations of benzodiazepines, since these formulations may have less abuse liability (Mumford et al. 1995) and blunt the peaks of toxicity and the troughs of symptom recurrence that are often problematic in the chronic management of such patients.

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Donald S. Robinson, Karl Rickels, Frank D. Yocca: Chapter 25. Buspirone and Gepirone, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.428442. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 25. Buspirone and Gepirone BUSPIRONE AND GEPIRONE: INTRODUCTION Evidence of altered central serotonergic function exists for several of the psychiatric disorders, especially the mood and anxiety disorders. Discovery of the serotonin1A (5-HT1A) receptor was instrumental in linking modulation of serotonin neurotransmission to anxiety symptoms. Similarly, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs) implicated serotonin in the pathophysiology and treatment of depression. The notion that serotonin (5-HT) plays a role in the treatment of anxiety initially arose from the discovery that both acute and chronic administration of benzodiazepines reduced turnover of 5-HT in rat brain and that administration of para-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, mimics the effects of benzodiazepines in behavioral models of anxiety utilizing a conflict paradigm (Wise et al. 1972). Subsequent characterization of subtypes of 5-HT receptor, especially the 5-HT1A and 5-HT2 receptors, and discovery of the 5-HT1A receptor partial agonist buspirone inferred that serotonin plays a key role in anxiolysis (Eison and Eison 1994). Because both the benzodiazepines and buspirone were found to pharmacologically reduce 5-HT impulse flow, albeit by different mechanisms, it was hypothesized that enhanced serotonergic tone might be an underlying factor in the etiology of anxiety disorders.

THE 5-HT1A RECEPTOR The development of specific pharmacological ligands in combination with molecular cloning and subsequent expression in heterologous systems has led to the unequivocal identification of 14 different 5-HT receptor subtypes (Hoyer et al. 2002). Except for the 5-HT3 receptor, all 5-HT receptor subtypes are members of the large family of seven transmembrane domain G protein–coupled receptors (Pierce et al. 2002). The 5-HT1A receptor is one of the most important receptors in this class and of the subfamily that couples negatively to adenylyl cyclase (De Vivo and Maayani 1986). It has been the most extensively studied 5-HT receptor because 1) identification of the selective agonists, including 8-OH-DPAT (Hamon et al. 1984) and the azapirones, and specific receptor antagonists (WAY-100635; Fletcher et al. 1996) have allowed for strict pharmacological classification; 2) it is the first 5-HT receptor to be cloned and sequenced (Fargin et al. 1988; Kobilka et al. 1987); 3) polyclonal antibodies have been generated for subcellular distribution studies in brain (Azmetia et al. 1996; El Mestikawy et al. 1990); and 4) human, rat, and mouse receptors have been cloned and sequenced (Albert et al. 1998; Charest et al. 1993; Fargin et al. 1988) in support of the translational studies. Furthermore, several studies have determined that the 5-HT1A receptor may play a role in neural development (del Olmo et al. 1998; Gross et al. 2002). Taken together with the recent implications of a salutary effect of chronic SSRI treatment on neurogenesis (Duman et al. 2001) and the fact that 5-HT1A agonists exhibit positive treatment effects in both anxiety and depressive states (Robinson et al. 1989a), the body of evidence suggests that this receptor plays a central role in neuropsychiatric disorders.

Distribution and Function The regional distribution of the 5-HT1A receptors was established using both selective agonist and

antagonist ligands with antibodies that were raised against unique peptide sequences within the receptor protein as well as mRNA densities. Studies utilizing the full agonist [3H]8-OH-DPAT (8-hydroxy-2-[N-dipropylamino]-tetralin) and the putative 5-HT1A receptor antagonist ligand [3H]WAY-100635 reveal high levels of specific binding in hippocampus, raphe nuclei, amygdala, hypothalamus, and cortex (Burnet et al. 1997; Palacios et al. 1990). The results with autoradiography were mirrored by the finding of localization of messenger RNA (mRNA) densities in these regions as well (Burnet et al. 1995; Chalmers and Watson 1991). At the subcellular level, the receptor was found to be localized on cell bodies and dendrites of 5-HT–containing neurons projecting to limbic brain regions. In limbic regions receiving input from 5-HT–containing neurons, particularly hippocampus and cortex, 5-HT1A receptors are located predominantly postsynaptically (Palacios et al. 1990; Riad et al. 2000).

Pharmacological and Clinical Implications The high regional density of 5-HT1A receptors in midbrain, hippocampus, and limbic areas of the brain is consistent with the notion that 5-HT neurotransmission modulates mood and anxiety. These brain regions of high density of 5-HT1A receptors play key roles in regulating diverse vital processes, including thermoregulation, endocrine function, appetite, aggressive and sexual behavior, and mood. Mice lacking the 5-HT1A receptor gene exhibit various manifestations of anxious behavior with stress (Parks et al. 1998) and exhibit increased autonomic hyperactivity when exposed to foot shock (Pattij et al. 2002). 5-HT1A receptors located on 5-HT–containing neurons in midbrain raphe regions modulate release of 5-HT at synapses in forebrain. These somatodendritic autoreceptors control impulse flow (Yocca 1990), synthesis (Yocca 1990), and release (Sharp et al. 1989) of neurotransmitter from ascending 5-HT–containing neurons. Postmortem study of suicide victims reveals enhanced radioligand binding of [3H]8-OH-DPAT to the inhibitory 5-HT1A autoreceptors located in the dorsal raphe, providing pharmacological evidence in support of the hypothesis that depressed suicide victims may have diminished activity of 5-HT neurons (Stockmeier et al. 1998). Blunted 5-HT1A receptor–mediated response of corticosteroids has been reported in patients with major depressive disorder (MDD), suggesting that there is desensitization of these receptors in patients with anxiety and depression (Lesch 1992; Rausch et al. 1990; Stahl 1992). In regions postsynaptic to ascending raphe neurons such as prefrontal cortex, altered levels of 5-HT1A receptor binding have been found in the prefrontal cortex of depressed suicide victims (Matsubara et al. 1991), although conflicting evidence exists (Arranz et al. 1994; Cheetham et al. 1990).

The 5-HT1A Receptor and Partial Agonists Given the large body of work implicating 5-HT in the etiology and treatment of affective disorders, and the role of the 5-HT1A receptor in the control of central 5-HT neurotransmission, it is not surprising to find that drugs targeting this receptor would have an impact in the treatment of mood disorders. It would seem logical to implicate this receptor because 5-HT–acting drugs, such as TCAs and monoamine oxidase inhibitors (MAOIs), increase synaptic concentrations of the neurotransmitter. Furthermore, there is a region-dependent difference in responses to 5-HT1A agonists at pre- and postsynaptic 5-HT1A receptors. This may be attributable to a difference in regional receptor reserve (Meller et al. 1990; Yocca et al. 1992). Therefore, the proper degree of agonism at both pre- and postsynaptic 5-HT1A receptors may be critical to achieving an optimal level of efficacy/tolerability using this pharmacological approach. Drugs acting as partial agonists represent an attractive strategy for discovery of new psychiatric agents, potentially offering therapeutic advantages (Yocca and Altar 2006). It is postulated that this emerging class of successful central nervous system drugs acts in part by signal attenuation at one or multiple target receptors. Partial agonist compounds, such as buspirone and aripiprazole, produce a

desired therapeutic response, with excellent safety and tolerability. Interestingly, among the first drugs in this category were selective partial agonists of 5-HT1A receptors. These agents have undergone extensive clinical development for treatment of both generalized anxiety disorder (GAD) and MDD. As yet, only buspirone has received marketing approval. Gepirone, a 5-HT1A agonist with greater intrinsic activity postsynaptically, has been extensively investigated as an anxiolytic and as an antidepressant agent. A new drug application (NDA) for gepirone extended-release (ER) for treatment of MDD recently failed to obtain U.S. Food and Drug Administration (FDA) approval. An NDA for GAD and hyposexual desire disorder by the drug sponsor is under consideration. Several other selective 5-HT1A agonists (ipsapirone, flesinoxan, tandospirone) have been unsuccessful in clinical development for a target clinical indication of either GAD or MDD.

BUSPIRONE History and Development Buspirone hydrochloride, an azaspirodecanedione derivative (Figure 25–1), was synthesized in 1968 in the laboratories of Mead Johnson by Wu et al. (1969). Based on positive findings in conditionedavoidance testing in rats, buspirone was originally studied clinically as a putative antipsychotic agent. It was projected to be largely devoid of the typical side effects of the antipsychotic class of drugs, but clinical trials failed to demonstrate usefulness in the treatment of schizophrenia (Sathananthan et al. 1975). Further study revealed that a single dose of buspirone had a marked taming effect in aggressive monkeys (Tompkins et al. 1980). In various behavioral models of anxiety in rodents, buspirone inhibited foot shock–induced fighting and prevented shock-induced suppression of drinking behavior, both screening tests predictive of anxiolytic effects (Riblet et al. 1982). At that time, minimal data were available on the molecular pharmacology of buspirone. However, Riblet et al. (1982) reported that buspirone displaced [3H]spiperone from dopamine D2 receptors in rat striatal membranes with an IC50 of 260 nM and demonstrated a right shift in binding activity in the presence of guanosine triphosphate (GTP), suggesting that it was a D2 agonist. Until the subsequent finding of high affinity binding to the newly discovered 5-HT1A receptor some 4 years later, the basis for the anxiolytic activity of buspirone was thought to be dopaminergic in origin. FIGURE 25–1. Chemical structure of buspirone.

A Phase II proof-of-concept study in patients with DSM-II (American Psychiatric Association 1968) anxiety disorder demonstrated significant anxiolytic treatment effects of buspirone compared with placebo (Goldberg and Finnerty 1979), leading to a full-scale clinical development as an antianxiety agent (Robinson 1991).

Pharmacological Profile Buspirone is relatively inactive in receptor binding studies in vitro at noradrenergic, cholinergic, and histaminergic sites. It does not displace [3H]diazepam or [3H]nitrazepam from the benzodiazepine receptor complex or affect -aminobutyric acid (GABA) modulation of the benzodiazepine binding site

(Riblet et al. 1982). Although buspirone does displace [3H]spiperone from rat striatal membranes at relatively high concentrations (Mennini et al. 1986, 1987), dopamine receptor binding is believed to play no role in either the therapeutic or side effects of buspirone (Eison et al. 1991). The discovery that nanomolar quantities of buspirone displaced [3H]5-HT from hippocampal membranes (Glaser and Traber 1983) led to elucidation of interactions of buspirone with specific central 5-HT receptors. Buspirone was found to inhibit [3H]5-HT binding to cortical and hippocampal membranes (Skolnick et al. 1985). Later, it was determined that buspirone selectively displaced [3H]8-OH-DPAT from 5-HT1A receptor binding sites in rat hippocampal membranes with high affinity (24 nM) (Yocca 1990). The antianxiety properties of buspirone appear to be exerted through its actions at both pre- and postsynaptic 5-HT1A receptors (Eison and Eison 1994; Yocca 1990). At presynaptic 5-HT1A receptors located in the dorsal raphe, buspirone acts as a full agonist, inhibiting neuronal 5-HT synthesis and firing, whereas at postsynaptic receptors in hippocampus and cortex, it functions as a partial agonist. It is postulated that the anxiolytic effect of buspirone is dependent on its serotonergic actions in the presence of a preexisting deficiency of this neurotransmitter. Buspirone does differ from benzodiazepines because of its lack of inhibition of spontaneous motor activity, effects on motor coordination, and induction of the serotonin syndrome in rats (Eison et al. 1991). Buspirone lacks abuse potential and does not impair psychomotor performance either alone or in combination with ethanol, unlike the benzodiazepines (Smiley 1987; Sussman and Chow 1988). The behavioral effects of buspirone and benzodiazepines differ in a number of animal models of anxiety (Barrett and Witkin 1991). Unlike benzodiazepines, buspirone does not uniformly increase punished or conflict responding in rats and monkeys, and when increased responding is observed, the magnitude of response tends to be less than that of a benzodiazepine. By contrast, in pigeons buspirone enhances punished response with a magnitude equivalent to benzodiazepines. This finding is characteristic of the 5-HT1A receptor agonists, including 8-OH-DPAT, gepirone, and agents of this class. Other classes of psychotropic drugs—for example, TCAs, SSRIs, opioids, antipsychotics, and psychomotor stimulants—do not increase responding in this behavioral model. Buspirone also enhances exploratory and social interaction behaviors in rodents, similar to the benzodiazepines. Of interest, 5-HT1A agonists also demonstrate activity in an animal model of depression. Similar to imipramine, desipramine, and fluoxetine, 5-HT1A agonists such as 8-OH-DPAT and the azapirones buspirone, gepirone, ipsapirone, and tandospirone produce antidepressant-like behavior in the forced-swim test in rats (Wieland and Lucki 1990). This occurs in the absence of changes in locomotor activity and is not diminished by pretreatment with the 5-HT synthesis inhibitor pCPA, suggesting that 5-HT1A agonists produce an antidepressant response through postsynaptic effects on 5-HT1A receptors. The major azapirone metabolite, 1-(2-pyrimidinyl) piperazine (1-PP), is devoid of behavioral activity in this test. The finding of activity in a preclinical model of depression comports with clinical studies of both buspirone and gepirone, which are indicative of antidepressant effects.

Pharmacokinetics and Disposition With oral administration, buspirone is subject to extensive first-pass metabolism, with an elimination half-life of 3 to 4 hours (mean) in normal subjects (Gammans and Johnston 1991). In the liver, buspirone undergoes extensive metabolic transformation by cytochrome P450 3A4 enzymes. Ingestion of food prolongs the elimination half-life of buspirone, as is also the case with significant hepatic and renal impairment. The pharmacokinetics of buspirone in elderly patients do not differ importantly from those in young adults (Gammans et al. 1989). It was known that buspirone had three major metabolites of varying pharmacological activities:

5-hydroxybuspirone (5-OH-Bu), 8-hydroxybuspirone (8-OH-Bu), and 1-PP. Because buspirone blocks 2-adrenergic

receptors, it is postulated that unwanted noradrenergic effects of 1-PP might be

deleterious in patients experiencing benzodiazepine withdrawal or panic attacks. The potential therapeutic advantage, if any, of 5-HT1A partial agonists lacking the 1-PP metabolite is presently unknown.

Identification of 6-Hydroxybuspirone as a Major Active Metabolite More recently, conversion of buspirone to the metabolite 6-hydroxybuspirone (6-OH-Bu) by means of biotransformation in human liver microsomes was identified as the predominant metabolic pathway involved in the hepatic clearance of buspirone (Zhu et al. 2005). Plasma levels of 6-OH-Bu were found to be 40-fold greater than those of buspirone following oral administration in humans (Dockens et al. 2006). In vitro, 6-OH-Bu demonstrates high affinity (25 nM) and partial agonist activity for the 5-HT1A receptor, whereas 6-OH-Bu in vivo exhibits anxiolytic activity in the fear-induced ultrasonic vocalization paradigm (F. D. Yocca, unpublished observations, June 1998). The plasma clearance, volume of distribution, and elimination half-life of 6-OH-Bu are similar to those of buspirone, but the bioavailability of 6-OH-Bu is significantly greater (19% vs. 1.4%; Wong et al. 2007). As with buspirone, 6-OH-Bu demonstrates in vivo occupancy of 5-HT1A receptors after intravenous administration in rats, with a fourfold greater potency exhibited in dorsal raphe than in the hippocampus (Wong et al. 2007). Taken together, these findings suggest that 6-OH-Bu contributes significantly to the therapeutic effect of buspirone.

Switching From Benzodiazepine Therapy to Buspirone A major pharmacodynamic interaction occurs in patients previously treated with benzodiazepines on switching to buspirone. Both tolerability and the therapeutic response to buspirone differ significantly in anxious patients naive to benzodiazepine treatment compared with patients previously treated with a benzodiazepine (DeMartinis et al. 2000; Schweizer and Rickels 1986). Meta-analysis of placebocontrolled efficacy trials of buspirone revealed that GAD patients with either no prior benzodiazepine treatment or temporally remote benzodiazepine treatment (>6 months previously) improved more with buspirone therapy than patients recently treated with a benzodiazepine. The mechanism of this pharmacodynamic interaction is not established, but it may reflect a subtle underlying benzodiazepine withdrawal syndrome (possibly exacerbated by 1-PP). It is also possible that previously treated patients might be preconditioned by benzodiazepine therapy and hold expectations involving the mildly euphoriant, sedating properties of a benzodiazepine. One wonders if successful past treatment with a benzodiazepine influences future attempts to treat anxiety with a nonbenzodiazepine such as buspirone. In the placebo-controlled trials, patients who had received recent prior benzodiazepine therapy and were randomly assigned to the benzodiazepine treatment group may have benefited from reinstitution of benzodiazepine treatment, with resultant amelioration of an unrecognized (subclinical) withdrawal syndrome.

Mechanism of Action While it has been clearly established that the anxiolytic effects of buspirone are mediated by its actions on 5-HT receptors in the limbic system (Eison and Eison 1994; Yocca 1990), buspirone also has unrelated neuroendocrine effects reflective of a complex pharmacology. Preclinical studies have shown buspirone possesses characteristics of both a D2 agonist and antagonist in addition to being a 5-HT1A agonist. These pharmacological attributes are important in understanding the neuroendocrine actions of buspirone, because it is well established that prolactin is regulated by the neurotransmitter dopamine acting via D2 receptors in the anterior pituitary gland. Furthermore, the evidence indicates that 5-HT1A receptors regulate neuroendocrine hormones, such as growth hormone, adrenocorticotropic hormone (ACTH) release, and corticosterone (Gilbert et al. 1988; Pan and Gilbert 1992; Van de Kar et al. 1985). This notion was further substantiated in a study by Vicentic et al.

(1998) in which increases in plasma levels of oxytocin, ACTH, and corticosterone induced by the selective 5-HT1A agonist 8-OH-DPAT were blocked by administration of the selective 5-HT1A antagonist WAY-100635. Meltzer and Fleming (1982) showed that buspirone produces a dose-dependent increase in rat plasma prolactin levels. Furthermore, buspirone has been shown to antagonize the inhibitory effects of dopamine on prolactin release from the rat pituitary gland in vitro, illustrative of its partial agonist activity at D2 receptors (Meltzer et al. 1991). Buspirone enhances secretion of corticosterone in rats, whereas in patients it increases prolactin, growth hormone, and corticosterone levels when administered orally (Meltzer et al. 1991). In healthy volunteers, buspirone, ipsapirone, and gepirone have been shown to increase plasma cortisol, prolactin, and growth hormone and to decrease body temperature (Cowen et al. 1990). Buspirone stimulation of prolactin and corticosterone secretion in the rat is enhanced by pretreatment with pCPA, whereas spiperone inhibits buspirone-induced increases in rat corticosterone secretion (Meltzer et al. 1991). Pindolol, a 5-HT1A antagonist, does not block the buspirone-induced increase in prolactin (Meltzer et al. 1991). Taken together, these results suggest that the neuroendocrine effects of buspirone in rat and man are complex, exhibiting pharmacological properties of both a dopamine antagonist and a 5-HT1A agonist.

Indications and Efficacy Generalized Anxiety Disorder The efficacy of buspirone was established in a series of well-controlled trials conducted in the 1970s and 1980s in a patient population with the DSM-II diagnosis of anxiety disorder (Robinson 1991). The clinical development program of buspirone as an anxiolytic agent was undertaken after positive findings in a placebo-controlled proof-of-concept study in anxious patients (Goldberg and Finnerty 1979). It is of interest that the study investigators commented on the possibility that buspirone possesses antidepressant as well as anxiolytic properties. In a series of Phase III placebo-controlled clinical trials comparing buspirone and diazepam, the efficacy of these two anxiolytics was comparable in patients fulfilling diagnostic criteria for DSM-II anxiety neurosis (Boehm et al. 1990a; Goldberg and Finnerty 1982; Rickels et al. 1982). In these double-blind dosage titration studies, buspirone and diazepam were prescribed on a thrice-daily schedule in dosages (mean) ranging from 20 to 25 mg/day during 4 weeks of treatment. By the time the FDA granted marketing approval of buspirone in 1986, the newest DSM classification system, DSM-III (American Psychiatric Association 1980), had replaced anxiety neurosis with the diagnostic category of GAD. As a result of this change, retrospective statistical analyses of the placebo-controlled efficacy trials were carried out. Analyses of Hamilton Anxiety Scale (Ham-A; Hamilton 1959) and other symptom ratings were found to be consistent with a diagnosis of DSM-III GAD, so buspirone received FDA-approved labeling for this clinical indication. In the controlled trials, buspirone was noted to have a slightly slower onset of therapeutic effect than the benzodiazepines (Enkelmann 1991; Pecknold et al. 1989; Rickels 1990). This perceived slower onset of effect was attributable to differences between buspirone and benzodiazepines in early relief of somatic anxiety symptoms but was not due to a difference in relief of psychic anxiety symptoms. It was postulated that absence of sedation with buspirone contributed to a perception of more gradual onset of anxiolytic effect, because relief of somatic anxiety, particularly insomnia, was only manifest with buspirone treatment after psychic anxiety symptoms had abated, whereas the immediate sedating properties of benzodiazepines accounted for a perception of faster onset of therapeutic benefit. A similar slower onset of effectiveness in anxiety disorders occurs with imipramine (Rickels et al. 1993) and SSRI treatment (Rickels et al. 2003). A longer-term 6-month double-blind comparative trial of buspirone and benzodiazepines found a

similar slow onset of anxiolytic effect with buspirone compared with clorazepate during the first 4 weeks of treatment (Rickels et al. 1988). However, with ongoing treatment the therapeutic response to the two drugs was thereafter similar. On double-blind termination of treatment after 6 months, patients who stopped clorazepate abruptly relapsed during a 4-week observation period, whereas the buspirone group experienced no symptom changes. These findings confirmed the observation of others (Fontaine et al. 1984; Noyes et al. 1988) that rapid return of symptoms on discontinuation of clorazepate is attributable to a benzodiazepine withdrawal syndrome and not to recrudescence of symptoms of the underlying anxiety disorder, because this did not occur with abrupt discontinuation of buspirone. Possible clinical benefit of buspirone therapy on the benzodiazepine withdrawal syndrome was assessed in 15 chronic anxiety patients representing 146 cumulative years of tranquilizer exposure who had previously failed in attempts at both abrupt and gradual withdrawal of benzodiazepine treatment (Schweizer and Rickels 1986). In this study, addition of buspirone overlapping with tapering of benzodiazepine dosage failed to ameliorate benzodiazepine withdrawal symptoms, and none of the patients could be maintained on buspirone alone after complete withdrawal of benzodiazepine treatment. In several other studies, buspirone appears to have only modest beneficial effect on the benzodiazepine withdrawal syndrome (DeMartinis et al. 2000; Shiaie et al. 1995; Udelman and Udelman 1990). Since the approval and availability of buspirone for clinical use, a limited number of well-controlled efficacy trials in GAD were conducted. One reason for this was its relatively short product life cycle and the fact that the drug sponsor was developing a successor to buspirone, the azapirone analog gepirone. After buspirone's approval, several placebo-controlled efficacy studies in anxiety disorders were conducted, and they reported that it had significant anxiolytic properties (Enkelmann 1991; Laakman et al. 1998; Lader and Scotto 1998; Murphy et al. 1989; Pecknold et al. 1989; Scheibe 1996). In a family practice setting, Boehm et al. (1990a) studied 60 patients with anxiety disorder in a placebo-controlled trial comparing the benzodiazepine clobazam and buspirone. In this 3-week treatment trial, treatment with clobazam and buspirone was equally effective and superior to placebo in relieving anxiety, as measured by the Ham-A and the Clinical Global Impressions–Improvement (CGI-I) scale. In a large placebo-controlled, fixed-dose multicenter study comparing buspirone and venlafaxine extended-release (XR) in GAD, neither venlafaxine XR nor buspirone differed significantly from placebo on the primary efficacy outcome measure, Ham-A total score (Davidson et al. 1999). On several secondary outcome measures, buspirone treatment appeared less effective than venlafaxine XR but did result in significant improvement in CGI-I scores compared with placebo treatment. One limitation of this trial was utilization of a fixed-dose study design, which underestimates treatment effects as compared with a flexible-dose study design in depression efficacy trials (Robinson and Khan 2004). Acute treatment of chronically anxious patients is often best managed initially with a benzodiazepine; however, longer-term use of a benzodiazepine can lead to physical dependence and symptom chronicity. For this reason, some patient populations are inappropriate for benzodiazepine therapy due to history of substance abuse or potential risk of cognitive impairment. When initiating therapy with buspirone, one should inform the patient that it is less sedating, with a more gradual onset of action, than benzodiazepine treatment. Patients can be reassured that if they require long-term drug therapy, buspirone will not lead to physical dependence or withdrawal symptoms on discontinuation. Patients also should be informed that acute or long-term treatment with buspirone does not impair cognition or ability to acquire new coping skills (Rickels and Schweizer 1990). Long-term follow-up at 40 months of patients who previously completed a prior 6-month controlled trial comparing buspirone and clorazepate revealed that none of the buspirone-treated patients was

taking either a regular or as-needed anxiolytic medication, whereas 30% of patients originally treated with clorazepate still required daily benzodiazepine therapy, and an additional 24% took benzodiazepines intermittently. Thus, more than 50% of patients treated for 6 months with clorazepate, but none of the buspirone-treated patients, were taking ongoing anxiolytic medication after 3 years (Rickels and Schweizer 1990). Scheibe (1996) reported similar observations in long-term follow-up of an acute efficacy controlled trial of patients with anxiety disorders. In this latter study, at 40 months 38% of buspirone-treated patients still required buspirone therapy, whereas 64% of patients treated with lorazepam required benzodiazepine medication. The therapeutic advantages of buspirone treatment in elderly anxious patients include the fact the drug both is nonsedating and spares cognitive and memory functions. Buspirone has been studied in elderly patients with anxiety symptoms in a double-blind, placebo-controlled trial and shown to be safe and effective (Boehm et al. 1990b). Meta-analyses of several multicenter trials of buspirone in elderly patients also indicated that the drug is very safe and well tolerated by older patients (Ritchie and Cox 1993; Robinson et al. 1988).

Panic Disorder Buspirone treatment has been evaluated in patients with panic disorder in placebo-controlled trials (Pohl et al. 1989; Sheehan et al. 1990). These trials did not find that buspirone diminished the number of panic attacks significantly. However, meta-analysis of the double-blind, three-arm multicenter trials comparing buspirone, imipramine, and placebo treatment found that both imipramine and buspirone had significant anxiolytic effects in panic disorder (Robinson et al. 1989b). Absence of buspirone effect on number of panic attacks is not surprising, given the findings of preclinical testing showing that buspirone causes increased firing rates of the locus coeruleus (Eison and Temple 1986) and noradrenergic hyperactivity (Charney and Heninger 1985), both manifestations of panic disorder.

Mixed Anxiety–Depression and Major Depressive Disorder It was observed in early trials of patients with anxiety disorder and subsyndromal depression that depressive symptoms also improved significantly during buspirone treatment (Feighner et al. 1982; Goldberg and Finnerty 1979). This generated interest in the potential antidepressant properties of buspirone because of the high comorbidity of GAD and MDD (T.A. Brown and Barlow 1992). It has been suggested that GAD and MDD may exhibit differing clinical manifestations of a single underlying diathesis. Genetic studies in patients with MDD and GAD suggest that the genetic vulnerability for both disorders is largely shared (Kendler et al. 1992). Wray et al. (2007) recently described a likely genetic association between variants of the gene PlexinA2 and anxiety disorders, providing potential evidence for the adult neurogenesis theory of depression. Several placebo-controlled trials of buspirone have been conducted in patients with MDD and significant associated anxiety symptoms (Rickels et al. 1991; Robinson et al. 1990). For inclusion, patients with MDD were eligible if their Hamilton Rating Scale for Depression (Ham-D; Hamilton 1960) and Ham-A scores were 18 or greater and 15 or greater, respectively. Following a starting dosage of 5 mg thrice daily for 3 days, the daily dosage in these dosage titration studies ranged up to a maximum of buspirone 90 mg/day (mean, ~50 mg/day). Buspirone treatment was found to be superior to placebo treatment, with a global response rate based on CGI-I score of 70% for buspirone and 35% for placebo (Rickels et al. 1991). In a subsequent placebo-controlled study involving 177 geriatric depressed outpatients, Schweizer et al. (1998) compared buspirone and imipramine treatment for 8 weeks. There was a statistically significant treatment effect for both buspirone (mean daily dose, ~50 mg) and imipramine (mean daily dose, ~90 mg) compared with placebo treatment. Global improvement (CGI-I) with buspirone and imipramine was 80% and 86%, respectively, compared with 49% with placebo treatment. Open-label augmentation of SSRI treatment of partially responding depressed patients leads to

further improvement (Dimitriou and Dimitriou 1998; Gonul et al. 1999; Jacobsen 1991; Landren et al. 1998). These findings were recently confirmed in a report of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) program. Patients who initially failed an adequate therapeutic trial with an SSRI responded when their medication was augmented with either buspirone or bupropion (Trivedi et al. 2006). We speculate that had the sponsor pursued an antidepressant clinical indication rather than a GAD indication, buspirone might well have become the first 5-HT1A partial antagonist to be developed as an antidepressant drug. Presently, buspirone lives in the shadows of the antidepressant drugs with high clinical exposure and promotion. The fact that the product life cycle of buspirone was relatively short (as mentioned earlier) while all of the SSRIs pursued a clinical indication for GAD served to limit clinical investigation of buspirone's full therapeutic profile.

Nonapproved Clinical Indications Potential clinical indications for buspirone treatment unapproved by the FDA were recently reviewed by Rickels et al. (2003). Only a few of these buspirone studies and potential clinical indications are mentioned here. Two small double-blind clinical trials indicated modest efficacy of buspirone over placebo in the symptomatic treatment of postmenopausal syndrome (C. S. Brown et al. 1990; Rickels et al. 1989). Several placebo-controlled trials showed that smoking cessation is facilitated by buspirone therapy (Hilleman et al. 1992; West et al. 1991); its main effect, however, is in smokers who are also highly anxious (Cinciripini et al. 1995). Buspirone has been assessed in a few doubleblind, placebo-controlled trials involving anxious outpatients with coexisting alcohol use disorders and found to be efficacious (Rickels et al. 2003). Because buspirone lacks abuse potential and has negligible additive effects on psychomotor and cognitive functions when coadministered with alcohol (Mattila et al. 1982), it has therapeutic benefit in the management of alcohol abuse and dependence. In a recent placebo-controlled trial, buspirone was found to be efficacious in ameliorating symptoms of opioid withdrawal (Buydens-Branchey et al. 2005). Recently, Lee et al. (2005) reported a placebo-controlled study showing beneficial effects of buspirone in migraine patients with anxiety symptoms. Buspirone has also been evaluated under double-blind conditions in patients with aggressive behavior and agitation. In a study of 26 patients Cantillon et al. (1996) demonstrated significantly greater decrease in tension with buspirone compared with haloperidol in patients with Alzheimer's disease.

Dosage and Administration The recommended dosage of buspirone for the treatment of GAD is 15–20 mg/day initially, prescribed in divided doses, with dosage increases to 30 mg/day if indicated. The maximal daily dosage recommended is 45 mg in the United Kingdom and 60 mg in the United States. It should be mentioned, however, that in the double-blind MDD trials (described earlier), the maximal dosage allowed was 90 mg/day. Thus, higher dosages of buspirone than those prescribed for anxiety disorders may be required in the treatment of MDD, either as monotherapy or as augmentation of an SSRI.

Side Effects and Toxicology Newton et al. (1986), summarizing data from 17 clinical trials, reported the incidence of frequently reported adverse events during buspirone treatment: dizziness (12%), drowsiness (10%), nausea (8%), headache (6%), nervousness (5%), fatigue (4%), insomnia (3%), light-headedness (3%), dry mouth (3%), and excitement (2%). No deaths by overdose of buspirone occurred during preapproval clinical development. Interestingly, patients given buspirone had similar incidences of drowsiness, insomnia, fatigue, and dry mouth as with placebo treatment, and no treatment-emergent sexual dysfunction was observed.

Extensive preclinical and clinical testing indicates that buspirone lacks abuse potential, unlike alcohol and benzodiazepines (Balster 1991). A large number of psychomotor function studies, including evaluation of complex motor driving skills and memory tasks, have documented absence of impairment with buspirone administration, unlike alcohol and the benzodiazepines (Boulenger et al. 1989; Greenblatt et al. 1994; Lucki et al. 1987; Smiley and Moskowitz 1986). Since buspirone's general availability in clinical practice, no deaths attributable to buspirone overdose alone have occurred to our knowledge. Buspirone remains an unusually safe and well-tolerated medication with no abuse liability and few drug–drug interactions except for those associated with concurrent use with MAOIs.

Drug–Drug Interactions Buspirone does not inhibit P450 enzymes, although it causes modest elevations of haloperidol and cyclosporin A levels. Buspirone has relatively few pharmacodynamic interactions with other psychotropic drugs. Because coadministration of buspirone with MAOIs carries the potential risk of serotonin syndrome, it is contraindicated in the buspirone labeling; however, cautious use of this combination has been regarded as being safe if clinically indicated (Ciraulo and Shader 1990).

GEPIRONE History and Development Gepirone, an azapirone analog of buspirone, is a substituted imide synthesized in 1986 by Bristol-Myers Squibb (refer to Figure 25–2 for chemical structure). The structural alteration (gem-dimethyl substitution) between buspirone and gepirone produces a major pharmacological difference—that is, negligible D2 receptor affinity. Gepirone exhibits a 30- to 50-fold reduction in affinity for D2 receptors (New 1990). The fact that gepirone has high affinity and greater intrinsic activity for postsynaptic 5-HT1A receptors yet lacks appreciable affinity for D2 receptors and has activity in a variety of preclinical anxiolytic and antidepressant models supports the notion that the antidepressant properties of azapirones reside in the agonist interaction at 5-HT1A receptors. Like buspirone, gepirone is chemically unrelated to the benzodiazepines and lacks sedative-hypnotic, anticonvulsant, and muscle-relaxant properties. FIGURE 25–2. Chemical structure of gepirone.

Given its preclinical pharmacological profile of selective action on serotonergic neurotransmission and its more complete agonist profile at postsynaptic 5-HT1A receptors, gepirone was initially developed as a dual antianxiety and antidepressant agent utilizing an immediate-release formulation. Because of its short elimination half-life and suboptimal tolerability, an extended-release formulation was deemed desirable, and clinical development was switched to gepirone ER. In 1993, gepirone was outlicensed to Fabre-Kramer, and in partnership with Organon, the clinical development of gepirone ER for MDD continued. The decision by Bristol-Myers Squibb to outlicense gepirone was based on competing

depression programs within the company at that time. Organon submitted an NDA for treatment of MDD in October 1999. In its review of the application, the FDA cited insufficient evidence of efficacy due to lack of the requisite two positive well-controlled (pivotal) efficacy trials. Fabre-Kramer reassumed responsibility for gepirone and undertook additional clinical development for treatment of depression. An NDA submitted in 2007 did not receive FDA approval. Further studies with gepirone ER in depression are planned, and clinical indications for GAD and hyposexual desire disorder are being considered by the drug sponsor.

Mechanism of Action A number of important in vitro and in vivo pharmacological studies have been undertaken with gepirone. At both pre- and postsynaptic 5-HT1A receptors in native tissue, gepirone displaces [3H]8OH-DPAT from bovine dorsal raphe rat hippocampal membranes with similar affinity, which is approximately fourfold less potent than buspirone (Yocca 1990). Presynaptically, gepirone exhibits potent agonist properties. This is evident in studies measuring markers of presynaptic 5-HT1A receptor stimulation (reduced accumulation of 5-HT [Yocca 1990]), reduction in hippocampal 5-HT levels measured through microdialysis (Sharp et al. 1989), and reduction in firing of 5-HT–containing dorsal raphe neurons (Blier and de Montigny 1987). At postsynaptic 5-HT1A receptors, gepirone displays partial agonist properties, albeit with less potency but greater intrinsic activity than buspirone (Yocca 1990). The partial agonist nature of gepirone was demonstrated in an elegant study by Andrade and Nicoll (1987). Microiontophoretic administration of gepirone, similar to 5-HT, hyperpolarizes rat hippocampal pyramidal neurons through an interaction with 5-HT1A receptors, only to a lesser degree. When gepirone and 5-HT are microiontophoretically applied simultaneously, gepirone antagonizes the full agonist effect of 5-HT. This study demonstrates the pharmacological versatility of a compound with partial agonist properties, which can function as either a receptor agonist or antagonist depending on ambient conditions. Gepirone lacks appreciable affinity for other monoamine or benzodiazepine receptors and does not bind to neurotransmitter transporter sites. Chronic treatment with gepirone produces downregulation of 5-HT2 receptors, a characteristic shared by mechanistically distinct agents with antidepressant properties (Yocca et al. 1991). Furthermore, similar to SSRIs, continuous treatment with gepirone desensitizes dorsal raphe 5-HT1A receptors, favoring enhanced serotonergic neuronal signaling (Blier and de Montigny 1987). Gepirone is similar to buspirone in demonstrating activity in a variety of animal models that predict clinical effect for anxiety and depression. In preclinical anxiety models, gepirone was active in the rat Vogel conflict and open-field test (Stefanski et al. 1992), the rat social stress test (Tomatzky and Miczek 1995), the rat ultrasonic vocalization test (Cullen and Rowan 1994), and the rat fear-potentiated startle paradigm (Kehne et al. 1988). In depression models, gepirone has activity in several behavioral models, including learned helplessness (Giral et al. 1988; Martin et al. 1990) and the forced-swim test (Detke et al. 1995) in rats. In a series of neuroendocrine studies in rodents and man (Anderson et al. 1990; Cowen et al. 1990), gepirone was observed to be similar to buspirone in that it significantly increases plasma levels of ACTH,

-endorphin, cortisol, prolactin, and growth hormone, accompanied by decreases in body

temperature. The fact that prolactin levels are increased by gepirone, which lacks appreciable affinity for dopamine D2 receptors, indicates that this prolactin effect of buspirone may result from multiple receptor interactions.

Pharmacokinetics and Disposition Gepirone is well absorbed orally, with time to peak plasma concentration (Tmax) approximately 1 hour. The Tmax of gepirone is significantly delayed by food ingestion. Gepirone is subject to extensive first-pass metabolism (15% bioavailability), undergoing rapid biotransformation with a short plasma elimination half-life. Gepirone ER formulations have been developed, yielding significantly lower

maximum plasma concentrations (Cmax) and longer Tmax than gepirone (Timmer and Sitsen 2003). Gepirone ER once daily has a similar area under the curve (AUC) as the gepirone immediate-release preparation administered twice daily. Cmax of the 1-PP metabolite of gepirone is significantly lower with gepirone ER administration, and the Tmax is longer. Fluctuations in plasma gepirone concentrations are considerably less with gepirone ER than with the immediate-release formulation. 1-PP, one of two major metabolites of gepirone, possesses activity as a presynaptic

2-adrenoreceptor

antagonist but is thought to lack intrinsic antidepressant effects. Plasma concentrations of 1-PP exceed gepirone plasma levels (Tay et al. 1993) with extended-release formulations, although 1-PP levels are lower than with the immediate-release formulations. The in vivo physiological effects exerted by gepirone may in part reside in 3-hydroxygepirone, which is an active metabolite of gepirone and has lower plasma concentrations with the ER preparation compared with the immediate-release formulation. It exhibits affinity and full agonist activity at the 5-HT1A receptor (Ki = 58 nM) and antidepressant activity in preclinical models (Ward et al. 2000). Furthermore, and like gepirone, 3-hydroxygepirone inhibits the firing of dorsal raphe neurons and produces a desensitization of rat somatodendritic 5-HT1A receptors after chronic exposure (Blier et al. 2000).

Indications and Efficacy The immediate-release formulation of gepirone was extensively studied for a clinical indication in both the anxiety and depressive disorders. In a placebo-controlled trial comparing gepirone with diazepam in GAD, Rickels et al. (1997) found gepirone somewhat less effective than diazepam, with inferior tolerability and excessive dropouts. These results were consistent with those of other trials with the gepirone immediate-release formulation. Studies in depressive disorders with immediate-release gepirone indicated that it possessed antidepressant properties (Jenkins et al. 1990; McGrath et al. 1994; Robinson et al. 1989a). Because of tolerability concerns with short-acting immediate-release formulations of gepirone, clinical development was switched to gepirone ER, with a major focus on treatment of MDD. Preliminary placebo-controlled studies provided evidence of the efficacy of gepirone ER in MDD (Feiger 1996; Wilcox et al. 1996). Feiger (1996) compared gepirone ER, imipramine, and placebo in an 8-week trial involving patients with DSM-III-R (American Psychiatric Association 1987) major depression. At dosages ranging from 10 to 60 mg/day, gepirone ER was significantly more effective than placebo treatment as measured by both the 17-item and 28-item versions of the Ham-D, with comparable efficacy to imipramine (150–300 mg/day). Gepirone ER was generally better tolerated than imipramine, with fewer anticholinergic and sexual side effects and with an adverse effect pattern typical of other azapirone agents, predominantly dizziness, light-headedness, and nausea. A well-controlled efficacy trial comparing gepirone ER and placebo in MDD has been reported that demonstrates therapeutic benefit in the treatment of major depression (Feiger et al. 2003). In this 8-week trial involving 204 patients (gepirone n = 101, placebo n = 103), treatment with gepirone ER was initiated at a dosage of 20 mg/day and increased to 40 mg/day after 3 days; further dosage increase to 60 mg/day at week 2 was permitted if clinically indicated. Remission rates at week 8 were 24.8% for gepirone ER and 14.9% for placebo treatment (P 35 inches) in women are indicative of the metabolic syndrome and are strong predictors of diabetes and other medical complications, including heart disease and sleep apnea (D. A. Wirshing et al. 2002a, 2002c). Deposition of weight in the abdomen, in excess of weight on the hips (highly correlated with the development of diabetes), can also be assessed with the WHR. Frankenburg et al. (1998) examined BMI and WHR in 42 patients treated with clozapine. The majority of patients experienced increases in both of these parameters. In females, the authors observed an average WHR of 0.8 after 37 months of clozapine therapy, with a

significant average increase in BMI from 23.2 to 29.1 kg/m2 (P = 0.001). Male subjects also gained weight and body mass. After 39 months of clozapine therapy, the average WHR in males was 0.93, with a significant average increase in BMI, from 26.4 to 29.7 kg/m2 (P

Chapter 29. Olanzapine HISTORY AND DISCOVERY The story of specific antipsychotic medications for patients with schizophrenia and other severe psychiatric illnesses began in the early 1950s, when chlorpromazine was first given to psychotic patients in France (Delay and Bernitzer 1952). The antipsychotic qualities of this compound, as well as its "tranquilizing" effect, were dramatic and substantial. Studies performed around the world during the 1950s showed the usefulness of this new compound and the others that followed. As is well known, multicenter trials of antipsychotic medications found that the approved medications were substantially and significantly better than placebo (Cole et al. 1964). Furthermore, despite the range of chemical structures, the clinical effects were similar. In addition, the need to investigate the new medications for psychiatric illness led to improved clinical trial methodology for the field. During the 1960s, randomized and placebo-controlled trials became the standard for assessing the new medications for schizophrenia. These trials led to the neuroleptic medications becoming the standard somatic treatment for schizophrenia. However, over time, the adverse effects of the neuroleptic medications began to be recognized as more troublesome (Table 29–1). For example, most patients complained of iatrogenic parkinsonism, dystonias, slowed thinking, blunted affect, akathisia, and tardive dyskinesia. These side effects were uncomfortable for patients taking the neuroleptic medications and, in many cases, led to poor adherence with treatment. TABLE 29–1. Shortcomings of traditional antipsychotic medications Significant response in only 60%–70% of patients Movement disorder side effects Dystonia Parkinsonism Tardive dyskinesia Akathisia Slowed thinking ("cognitive parkinsonism") Secondary negative symptoms In addition to the adverse effects of the neuroleptic medications, continued research of the neuroleptics indicated that a substantial number of patients were not fully treated (Angrist and Schulz 1990). Therefore, the field had the problem of an intervention that was not useful for all patients and was uncomfortable to take for many patients whose symptoms did respond. Studies with the first atypical antipsychotic medication, clozapine, began in the late 1960s, although the compound was initially discovered in 1961. This interesting agent led to decreases in symptoms of psychosis without causing movement disorder side effects. Trials were moving forward in Europe (Povlsen et al. 1985) and the United States (Shopsin et al. 1979) when reports of agranulocytosis

resulting in the death of some subjects first appeared (Amster et al. 1977). These unfortunate outcomes stopped research of clozapine essentially in its tracks. However, the hope for the development of an atypical antipsychotic medication did not die with these early studies of clozapine. Eventually, clozapine was approved as a treatment of last resort for schizophrenia, and its use must be accompanied by rigorous medical follow-up (Kane et al. 1988). Concurrent with this research, investigators at Eli Lilly were screening numerous compounds for psychotropic properties. In 1990, the company applied for and received a patent for the compound olanzapine. It is interesting to note that the new compound had many structural similarities to clozapine and was thought to have potential for schizophrenia, mania, and anxiety. Olanzapine was first given to patients with schizophrenia in 1995 (Baldwin and Montgomery 1995). The patients in the study had a substantial decrease in their symptoms while receiving 5–30 mg/day of the compound. The authors noted a low degree of extrapyramidal side effects (EPS), although concern was raised for elevation of liver enzymes, as one patient had to discontinue the study for that reason. The initial testing of olanzapine had useful results and led to a program of four pivotal trials of olanzapine. These first four controlled studies examined the differences between olanzapine (10 mg/day fixed dose) and placebo (Beasley et al. 1996a), olanzapine and haloperidol or placebo (Beasley et al. 1996b), olanzapine (low, medium, or high dose) and olanzapine 1.0 mg/day or haloperidol 15 mg/day (Beasley et al. 1997), and olanzapine and haloperidol in a large international study (Tollefson et al. 1997). The positive results for olanzapine led to U.S. Food and Drug Administration (FDA) approval in 1997 and then widespread use in the United States and around the world.

STRUCTURE–ACTIVITY RELATIONS Olanzapine is a thiobenzodiazepine derivative (Figure 29–1) that bears a close structural resemblance to clozapine. The formal chemical name of olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10Hthieno[2,3-b] [1,5]benzodiazepine. Structurally, it differs from clozapine by two additional methyl groups and the lack of a chloride moiety. This similarity leads to a relative similarity in the in vitro receptor binding profiles. According to the package insert, olanzapine is known to have a high affinity for selective dopaminergic, serotonergic (5-HT), histaminergic (H), and

-adrenergic receptors, with

weaker affinity for muscarinic (M) receptors and weak activity at benzodiazepine (BZD), -aminobutyric acid type A (GABAA), and

-adrenergic receptors (Eli Lilly 2006).

FIGURE 29–1. Chemical structure of olanzapine.

PHARMACOLOGICAL PROFILE In vitro and preclinical behavioral studies of olanzapine predicted significant antipsychotic activity

with a low propensity to induce EPS. Because clozapine is the prototype for second-generation antipsychotic action, similarity to its effects relative to those of classic antipsychotics is evidence for the "atypicality" of comparator compounds such as olanzapine. One possible mechanism for lowering risk for EPS is nonselective dopamine receptor binding. Classic antipsychotics selectively block D2-like (D2, D3, and D4) receptors over D1-like (D1 and D5) receptors—for example, haloperidol has a D2-to-D1 binding ratio of 25:1. Clozapine nonselectively binds all five dopamine receptor subtypes, with a D2-to-D1 ratio of 0.7:1, whereas olanzapine is only partially selective for the D2-like group, with a D2-to-D1 ratio of approximately 3:1, intermediate between those of haloperidol and clozapine. Antipsychotics have traditionally been most effective in treating the positive symptoms of schizophrenia, including delusions, hallucinations, and the agitation brought on by these symptoms. The hallmark of second-generation or atypical antipsychotics is a decreased propensity to cause EPS. "Atypicality" has generally been used to refer to agents with reduced risk of EPS. Olanzapine has a low tendency to induce catalepsy, once regarded as a marker of antipsychotic efficacy but now seen as an indicator of a drug's likelihood of producing EPS (Fu et al. 2000). In animal models predictive of antipsychotic efficacy, olanzapine produces effects indicating dopamine antagonism, with a low propensity to produce EPS. For example, in rats, olanzapine reduces climbing behavior induced by apomorphine and antagonizes stimulant-induced hyperactivity, both characteristic of antipsychotic effect. The ratio of the dose needed to produce catalepsy to the dose needed to inhibit conditioned avoidance, another model for atypical efficacy, is higher for olanzapine than for conventional agents, a circumstance that also denotes "atypicality" (Moore 1999). Another potential mechanism whereby dopamine antagonists may exert antipsychotic effects with minimal EPS is through selective activity in the A10 dopaminergic tracts from the ventral tegmentum to mesolimbic areas compared with effects antagonizing the A9 nigrostriatal projections that mediate EPS. Olanzapine in chronic administration, like clozapine, selectively inhibits firing of A10 neurons without significant inhibition of A9 tracts (Stockton and Rasmussen 1996a). The nigrostriatal tract has often been implicated in EPS, whereas the limbic system has been associated with the positive symptoms of schizophrenia. Olanzapine shows increased c-fos activity in the nucleus accumbens relative to the dorsolateral striatum, thus demonstrating selective blockade of the mesolimbic dopamine tract compared with the nigrostriatal tract (Robertson and Fibiger 1996). The current leading theory regarding atypicality relates to the fleeting effects of atypical antipsychotics at the D2 receptor, coupled with regional selectivity of these compounds (Seeman 2002).The 5-HT2A receptor in the nigrostriatal tract was once theorized to provide increased dopaminergic activity in that tract, thus sparing one from the parkinsonism frequently seen with conventional antipsychotics. However, this theory of atypicality is generally falling out of favor. Whereas olanzapine shows higher affinity for 5-HT2A receptors than for D2 receptors, the tight binding of serotonergic neurons does not show any influence on dopamine receptor blockade, and olanzapine still has a dopamine receptor saturation that is sufficient to produce antipsychotic activity and, at high enough doses, also strong enough to cause EPS (Kapur et al. 1998, 1999). Olanzapine has been shown to have a D2 receptor occupancy saturation that is between that of clozapine and haloperidol and may be responsible for a decreased risk of EPS (Tauscher et al. 1999). However, as the current secondgeneration antipsychotic medications have substantially differing effects at all of these targets thought to play a role in atypicality, consensus is not there regarding the true rationale for atypicality compared to the first-generation antipsychotics (Farah 2005). Amphetamine administration in rats is often used as a model for psychosis. The sympathomimetic activity and dopamine release provide a target for testing antipsychotic medications. Olanzapine disrupts the activity of amphetamines in rats (Gosselin et al. 1996). Olanzapine was shown in a rat

model to decrease dopamine release in the A10 dopaminergic neurons of the ventral tegmentum greater than the A9 dopaminergic neurons of the striatum after chronic administration and after an amphetamine challenge (Stockton and Rasmussen 1996a, 1996b). Olanzapine does not induce catalepsy in rats at doses needed for antipsychotic efficacy. Another model of psychosis in rats is the administration of the glutamatergic N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). Chronic PCP use in humans is associated with similar symptoms to schizophrenia, including negative symptoms, thus making it a putative model for schizophrenia (Krystal et al. 1994). Second-generation antipsychotics have been shown to enhance glutamatergic neurotransmission in pyramidal cells of the prefrontal cortex compared with firstgeneration antipsychotics (Ninan et al. 2003a). Olanzapine has been shown to decrease the hyperactivity of NMDA receptors under chronic PCP administration, which may have a bearing on the effect on negative symptoms (Ninan et al. 2003b). With chronic administration, glutamatergic activity continues to be affected by olanzapine (Jardemark et al. 2000). Despite these findings, olanzapine has no direct affinity for the NMDA receptor (Stephenson and Pilowsky 1999). Effects on other systems show that olanzapine has a broad range of neurotransmitter effects. Although olanzapine has potent muscarinic M1–5 receptor affinity in vitro (another contributor to putative anti-EPS effects), in practice few patients have anticholinergic side effects that are clinically and H1 histaminergic antagonism contribute to the adverse-effect profile of orthostatic hypotension ( 1), sedation (H1), and possibly weight gain (H1). Olanzapine has little or no

significant. effect on

2-

1-Adrenergic

and

-adrenergic, H2, nicotinic, GABA, opioid, sigma, or benzodiazepine receptors.

PHARMACOKINETICS AND DISPOSITION Olanzapine is well absorbed after oral administration, with peak concentrations in most people occurring 4–6 hours after ingestion (Kassahun et al. 1997). Approximately 40% of a given dose undergoes first-pass metabolism and therefore does not reach the systemic circulation, and food has little effect on olanzapine's bioavailability (Callaghan et al. 1999; Eli Lilly 2006; Kassahun et al. 1997). Two bioequivalent oral formulations of olanzapine are currently available: a standard oral tablet and an oral disintegrating tablet. The oral disintegrating tablets are intended for swallowing and absorption through the gut; however, sublingual administration has also been favored by some. Markowitz et al. (2006) discovered that while the oral disintegrating preparation of olanzapine is more quickly absorbed than a standard oral tablet, it is absorbed at an equal rate if taken sublingually or if swallowed conventionally. In either case, the onset of action with the oral dissolving tablet is faster than with the standard oral tablet. After a 12.5-mg oral dose of 14C-labeled olanzapine, approximately 57% of the radiocarbon was recovered in urine and 30% in feces. In vitro studies suggest that olanzapine is approximately 93% protein bound, binding primarily to albumin and

1-acid

glycoprotein

(Kassahun et al. 1997). Olanzapine is also available as an intramuscular preparation, intended for treatment of the acute agitation typically seen in schizophrenia or acute manic episodes of bipolar disorder. The peak plasma concentration is typically reached between 15 and 45 minutes after administration. The potency of intramuscular olanzapine is nearly five times greater than that of orally administered drug, based on plasma levels. Clinical antipsychotic onset with intramuscular olanzapine is evident within 2 hours of administration, with benefits lasting for at least 24 hours (Kapur et al. 2005). Olanzapine is currently being tested in a long-acting injectable preparation composed of a dihydrate form of olanzapine pamoate. As a dihydrate molecule, it is less soluble in water than a monohydrate and thus has the longer half-life required for a depot formulation. This formulation is currently being evaluated in studies with a dosage schedule of once every 4 weeks (Mamo et al. 2008). Finally, olanzapine is available in a combined preparation with fluoxetine. The olanzapine–fluoxetine

combination (OFC) tablet provides fixed doses of olanzapine and fluoxetine to enhance adherence to a regimen that includes both an antipsychotic agent and an antidepressant. Overall, there are few pharmacokinetic differences from adding fluoxetine to olanzapine, and those present are generally related to cytochrome P450 (CYP) 2D6 inhibition. There is no change in the overall half-life of olanzapine. While there are minor yet statistically significant differences in the concentration of olanzapine when taken in combination with fluoxetine, these changes are not clinically significant and do not change the side-effect profile of olanzapine (Gossen et al. 2002). Olanzapine is extensively metabolized to multiple metabolites but primarily to 10-N-glucuronide and 4'-N-desmethylolanzapine (Macias et al. 1998). After long-term administration, average plasma concentrations for these metabolites are 44% and 30% of olanzapine concentrations, respectively (Callaghan et al. 1999). Other metabolites include 4'-N-oxide olanzapine and 2-hydroxymethyl olanzapine (Kassahun et al. 1997). In vitro studies assessing the oxidative metabolism of olanzapine suggest that CYP1A2 is the enzyme primarily responsible for the formation of 4'-N-desmethylolanzapine, flavin-containing monooxygenase-3 (FM03) is responsible for the formation of 4'-N-oxide olanzapine, and CYP2D6 is the primary enzyme responsible for the formation of 2-hydroxymethyl olanzapine (Ring et al. 1996b). Although CYP1A2 appears to be a major route of metabolism, olanzapine clearance in one study was not significantly correlated with salivary paraxanthine-to-caffeine ratio (thought to be a measure of CYP1A2 activity) (Hagg et al. 2001). Another analysis, however, found that the 4'-N-desmethylolanzapine–to–olanzapine plasma metabolic ratio significantly correlated with olanzapine clearance (Callaghan et al. 1999). Olanzapine pharmacokinetic parameters do not differ significantly between extensive and poor metabolizers of CYP2D6 (see Hagg et al. 2001). Olanzapine shows linear pharmacokinetics within the recommended dosage range (Aravagiri et al. 1997; Bergstrom et al. 1995; Callaghan et al. 1999). Peak mean olanzapine concentrations after 8 days of olanzapine at 7.5 mg/day in 12 healthy males (11 smokers) were 18.3 ng/mL. Mean half-life was 36 hours, mean clearance was 29.4 L/hour, mean volume of distribution was 19.2 L/kg, and area under the concentration-time curve over 24 hours (AUC0–24) was 333 ng*hour/mL. The half-lives of the two major metabolites (4'-N-desmethylolanzapine and 10-N-glucuronide) were 92.6 and 39.6 hours, respectively, and their AUC0–24 were 57 ng*hour/mL and 112 ng*hour/mL (Macias et al. 1998). Other analyses also have found the mean half-life of olanzapine to be approximately 30 hours and the mean apparent clearance to be approximately 25 L/hour (Callaghan et al. 1999; Eli Lilly 2006; Kassahun et al. 1997). Once-daily administration of olanzapine produces steady-state concentrations in about a week that are approximately twofold higher than concentrations after single doses (Callaghan et al. 1999). An in vitro study suggested that olanzapine may be an intermediate substrate of P-glycoprotein (Boulton et al. 2002). In a recent study, Mitchell et al. (2006) compared the pharmacokinetics of a 10- to 20-mg olanzapine dosage with that of a 30- to 40-mg dosage. Both dosages showed similar pharmacokinetic profiles and general tolerability, although akathisia was noted to be slightly higher in the high-dose group. The clearance of olanzapine is generally decreased in women. Clearance of olanzapine is approximately 25%–30% lower in women than in men, based on results of population pharmacokinetic analyses (Callaghan et al. 1999; Patel et al. 1995, 1996). A study of 20 male and 7 female patients with schizophrenia receiving olanzapine also found that women had higher trough concentrations (29 ng/mL vs. 19 ng/mL) after receiving 1 week of olanzapine 12.5 mg/day; they continued to have higher plasma concentrations than men after the dosage was increased to 25 mg/day, with average week 8 plasma concentrations of 65 ng/mL and 35 ng/mL in women and men, respectively (Kelly et al. 1999). Despite the differences in clearance and plasma levels, there is no difference between sexes in incidence of EPS or other movement disorders (Aichhorn et al. 2006). Olanzapine's pharmacokinetics in the elderly and in children have been noted to differ from that in

adults. In the elderly, olanzapine clearance is approximately 30% lower than in younger individuals, and the half-life is approximately 50% longer (Callaghan et al. 1999; Patel et al. 1995). A study of eight children and adolescents (ages 10–18 years) found pharmacokinetic parameters similar to those reported in nonsmoking adults, with an average Tmax (time required to reach the maximal plasma concentration) of 4.7 hours, an average apparent oral clearance of 9.6 L/hour, and an average half-life of 37.2 hours (Grothe et al. 2000). In this study, patients could receive olanzapine dosages of up to 20 mg/day. The highest concentrations were seen when smaller-sized patients received dosages greater than 10 mg/day; therefore, dosing should take into consideration the size of the child. Impairment in either hepatic or renal function has not been associated with altered olanzapine disposition. In a study of four healthy individuals and eight patients with hepatic cirrhosis, no significant differences in olanzapine pharmacokinetics were found, although urinary concentrations of olanzapine 10-N-glucuronide were increased in patients with cirrhosis (Callaghan et al. 1999). A study comparing olanzapine pharmacokinetics in six subjects with normal renal function, six subjects with renal failure who received an olanzapine dose 1 hour before hemodialysis, and six subjects with renal failure who received an olanzapine dose during their 48-hour interdialytic interval did not find any significant differences. In subjects receiving olanzapine 1 hour before hemodialysis, olanzapine was not detected in the dialysis fluid, suggesting that hemodialysis does not remove significant quantities of olanzapine. These data suggest that olanzapine dosage does not need to be adjusted in patients with renal or hepatic disease (Callaghan et al. 1999).

MECHANISM OF ACTION In discussing the mechanism of action for olanzapine in the treatment of schizophrenia, it should be noted that there is no established molecular mechanism to unify the symptoms of schizophrenia. No precise animal or in vitro model for the illness exists, nor is there a consensus on the precise etiology or pathophysiology. Numerous neurochemical hypotheses exist, including abnormalities in dopaminergic, glutamatergic, serotonergic, and other systems such as neurotensin (Boules et al. 2007) and neuregulin (Benzel et al. 2007). Furthermore, other theories about the etiology and pathophysiology of schizophrenia include the possibility of abnormal development of the brain resulting in postulated changes in the relation of one part of the brain to the other (e.g., the prefrontal cortex to limbic areas) (Weinberger 1987). Further complicating these theories of pathophysiology of schizophrenia has been the understanding of the multiple different types of receptors for the same neurotransmitters that exist in the brain. Therefore, it is no longer possible to simply discuss hypotheses such as increased dopamine as a comprehensive theory for the etiology of schizophrenia. Despite the caveats noted above regarding the rudimentary knowledge of the nature of schizophrenia, it is important to note that all approved antipsychotic medications have an important effect on the dopaminergic system, largely through the blockade of D2 receptors (Kapur and Remington 2001). Even though there are substantial differences in affinities to the D2 receptor among the traditional antipsychotic medications and the atypical antipsychotics, they all are full antagonists or are partial agonists at the D2 receptor. Of interest is the evolving research indicating the importance for blockade of other receptors by the atypical antipsychotic medication class. As these systems have been investigated in the neuropsychopharmacology of schizophrenia, evidence is emerging that the action of second-generation antipsychotics, and olanzapine specifically, may improve different parts of the schizophrenia syndrome through effects on 5-HT receptors, by multiple-receptor binding, by regionspecific and more fleeting binding to dopamine receptors, by effects on glutamate neurotransmission, and perhaps by influence on neuroprotein neurotransmitters. Each of these specific ideas for the mechanism of action of olanzapine is discussed in order. As has been noted in the section on history of the development of olanzapine, innovations in the production of antipsychotic medications that cause fewer movement side effects have been a major advance clinically. One of the first theories about the mechanism of atypicality was the

5-HT–dopamine antagonist hypothesis (Meltzer et al. 1989). By comparing the ratio of 5-HT2A to dopamine receptor blockade, these groups showed that the agents with greater relative 5-HT receptor blockade were in the atypical group, whereas those with greater relative dopamine receptor blockade were more likely to be in the typical group. Both in vitro and in vivo studies have clearly reported that olanzapine has a substantially greater ability to block 5-HT2A receptors than dopamine receptors (Kapur et al. 1998). For several years, psychopharmacological research on schizophrenia focused on finding drugs that block specific receptors. In the area of schizophrenia, medications such as pimozide, which has very few nondopaminergic properties, were thought to focus on the specific etiology and pathophysiology of schizophrenia. Therefore, it was somewhat surprising that the first atypical antipsychotic medicine, clozapine, was a multiple-receptor blocker. As noted earlier in this chapter, olanzapine has many similarities to clozapine in its chemical structure as well as its receptor-blocking profile. Therefore, investigators have indicated that perhaps the multiple receptor–blocking properties of olanzapine are significant in its atypical antipsychotic effects. Blockade of dopamine receptors, 5-HT receptors, and histamine receptors, and perhaps other neurochemical properties as well, may be the result of the multiple receptor–blocking capabilities of the compound (Bymaster et al. 1999). In clinical investigations with positron emission tomography (PET) imaging, Kapur et al. (1998) showed that olanzapine at a wide range of doses blocks a high percentage (95% or greater) of 5-HT2A receptors and blocks dopamine receptors in a dose-dependent fashion—crossing the putative antipsychotic blockade line at doses commonly used to diminish psychotic symptoms of schizophrenia. This study indicated that olanzapine's primary mechanism was related to the blockade of dopamine receptors, and additionally noted that olanzapine showed stronger affinity for 5-HT2A receptors than for dopamine receptors at all dosage ranges. In addition to considering individual neurotransmitters, it has been noted that each neurotransmitter has multiple types of receptors. For dopamine, there are currently five different receptors that are grouped into two families (D1 and D5 vs. D2, D3, and D4). Work by Casey (1993) with nonhuman primates found that there may be regionally specific characteristics of the atypical antipsychotic medications compared with the typical compounds. These regionally specific characteristics of receptors and the observation that antipsychotic medications such as olanzapine have regionally specific activity may explain the ability of atypical compounds to decrease psychotic symptoms without causing movement disorders (Stockton and Rasmussen 1996a). Such regional selectivity is supported by molecular biology studies, such as those by Robertson and Fibiger (1996), which have reported increases of c-fos expression, which is regionally specific for the caudate area of the brain. A more compelling hypothesis regarding the atypicality of olanzapine has emerged from the in vivo PET scanning work being performed in a series of experiments at the University of Toronto and in Sweden. Results of the initial PET scanning studies of patients receiving clozapine indicated that there was atypical dopamine receptor binding (Farde and Nordstrom 1992; Farde et al. 1992; Kapur et al. 2000). The group subsequently found similar results for quetiapine and, to some degree, olanzapine (Kapur et al. 1998). The authors indicated that the successful reduction of psychotic symptoms in schizophrenic patients without movement disorder side effects may be the result of a "fast off" property of some of the atypical antipsychotic medications. They argued that for medicines that block the dopamine receptor but leave that receptor quickly, there may be an effect at the receptor to decrease psychosis but that a "physiological" dopamine activity at the receptor remains. Thus, for olanzapine, as likely also with clozapine and quetiapine, this may contribute to the treatment of schizophrenia while causing fewer EPS at standard doses. From a clinical view, it is important to note that at higher dosages of olanzapine (30 mg/day), higher dopamine receptor blockade is seen, and movement disorder side effects, such as akathisia, are more likely to occur. In recent years, there has been substantial interest in the role of glutamate, an excitatory

neurotransmitter, in the pathophysiology of schizophrenia (see, e.g., Javitt and Zukin 1991; Krystal et al. 1994; Lahti et al. 1995). This theory is supported by the psychotomimetic properties of glutamate antagonists such as phencyclidine and ketamine. These NMDA receptor antagonists lead to a group of behaviors that often have closer parallels to schizophrenia than do those of the dopamine sympathomimetic agents, in both mice and humans. Clinical trial evidence points to the usefulness of glutamatergic agonists (e.g., D-cycloserine) in treating schizophrenia (Goff et al. 1995). People with schizophrenia have been shown to have decreased glutamine synthetase and glutamate dehydrogenase in the prefrontal cortex, thus impacting the glutamate-to-glutamine conversion (Burbaeva et al. 2003). A current strategy under investigation involves administration of compounds such as D-cycloserine to patients. When glutamatergic agents have been given to patients with schizophrenia, there has generally been a measurable improvement in cognition and a decrease in negative symptoms, unless clozapine (a glutamatergic partial agonist) is present (Evins et al. 2000). However, no measurable decrease in the positive symptoms of the illness has occurred. Thus far, glutamatergic agonists have shown mixed results, although further research on the NMDA receptor, as well as on glycine transport antagonists, is in progress (Javitt 2006). Recent studies have also shown that LY2140023, a metabotropic glutamate receptor agonist, may be effective in treating schizophrenia. In a Phase II trial comparing LY2140023 with olanzapine and placebo, LY2140023 produced improvement in positive and negative symptoms, as measured by the Positive and Negative Syndrome Scale (PANSS), and had rates of EPS and weight gain similar to those of placebo (Patil et al. 2007). One way of examining the possible effect of olanzapine on glutamatergic measures was addressed in a study of rats with isolation-induced disruption of prepulse inhibition. Prepulse inhibition, a measure of sensory motor gating, is believed to be abnormal in patients with schizophrenia. In a study by Bakshi et al. (1998), both quetiapine and olanzapine reversed the isolation-induced prepulse inhibition deficit. Because there is a connection between NMDA antagonists and prepulse inhibition, this finding is evidence of olanzapine's effect on the glutamatergic system. Glutamine synthetase–like proteins (GSLP) and glutamate dehydrogenase have also been seen to be significantly higher in schizophrenia patients. Burbaeva et al. (2006) have shown that patients with a higher amount of GSLP in the platelets tend to respond more quickly to medication and specifically that olanzapine treatment alters the amounts of these peptides, further enhancing its antipsychotic properties. Utilizing magnetic resonance spectroscopy (MRS), Goff et al. (2002) have shown a more direct measure of olanzapine on patients' glutamate levels. They found that after a switch from conventional antipsychotic medications to olanzapine, serum glutamate levels increased appreciably. Brain glutamate levels, however, did not increase. Further examination indicated that in the patients whose negative symptoms improved, brain glutamate concentrations increased. The neuropeptide neurotensin also has been explored for its role in the pathophysiology of schizophrenia (Nemeroff et al. 1983), with several findings supporting an association of neurotensin with the symptoms of schizophrenia. Such findings include the close anatomical association between neurotensin and other neurotransmitter systems that have been implicated in schizophrenia, changes in neurotensin brain levels in animals when antipsychotic medications have been administered, and similarities between the effects of centrally administered neurotensin and the effects of antipsychotic medications. The effect of olanzapine and other antipsychotics on the neurotensin system has been investigated by using molecular biology techniques. After assessing neurotensin messenger RNA (mRNA) in the rat brain, the investigators reported increases in neurotensin mRNA when olanzapine was administered. The pattern of neurotensin changes seen with olanzapine was different from the pattern seen with haloperidol. These results are more similar to the results seen with the antipsychotic medication clozapine and show the effect of olanzapine on another system with importance in schizophrenia (Binder et al. 2001; Radke et al. 1998).

In summary, regarding the mechanism of action of olanzapine, a second-generation antipsychotic with well-demonstrated efficacy for psychosis in patients with schizophrenia, research indicates an effect on dopamine, acetylcholine, histamine, 5-HT (with greater affinity for 5-HT receptors than for dopamine receptors). glutamate, and neurotensin. Other effects are in the process of being evaluated. These effects have been measured by both biochemical assay and MRS and have been demonstrated in both human and animal models of the illness. At this time, dopamine receptor–blocking capabilities appear to be a necessary but not sufficient characteristic of an antipsychotic medication. The other studied mechanisms, when taken in total, may be the factors leading to olanzapine's broad efficacy and side-effect profile.

INDICATIONS AND EFFICACY To be prescribed in the United States, a medication must be approved by the FDA for a specific indication. This initial approval is based on an assessment of efficacy and safety requiring multiple tests of a medication compared with placebo and at least two studies demonstrating efficacy compared with placebo. In the case of olanzapine, its original indication was for psychosis. Currently, it has multiple indications, including schizophrenia, acute mania or mixed states in bipolar disorder, and as monotherapy or combination therapy in the maintenance treatment of bipolar disorder. The olanzapine–fluoxetine combination (OFC) has an FDA indication for bipolar depression. Intramuscular olanzapine carries an indication for acute agitation in schizophrenia and bipolar mania. Once a medication has received an FDA indication, physicians are able to use that medication off label for other theorized indications. Olanzapine has been studied, and at times used with limited evidence, in several other illnesses. In this section, we present the evidence base that supports the use of olanzapine for its FDA-indicated usages as well as for other off-label usages.

Schizophrenia As noted earlier, olanzapine was originally developed as a medication with potential for treating schizophrenia, mania, and anxiety. During the 1990s, significant energy was focused on the development of antipsychotic medications with new actions such that patients could have a reduction of psychosis with fewer side effects, especially neurological side effects. To gain FDA approval for the treatment of schizophrenia, olanzapine was tested in four pivotal studies to assess the compound for efficacy, safety, and dose ranging. The earliest testing of olanzapine was an assessment of olanzapine in doses of 5–30 mg following an initial starting dose of 10 mg. Brief Psychiatric Rating Scale (BPRS) scores were reduced substantially for the participants in the study, and EPS were low (Baldwin and Montgomery 1995). These encouraging results led to further studies and pointed to a dose range to be tested.

Efficacy Studies The first pivotal study examined a dose of 10 mg of olanzapine. The study showed that 10 mg of olanzapine was statistically significantly superior to placebo on objective rating scales (Beasley et al. 1996a). The next step was a dose-ranging study of olanzapine compared with haloperidol and placebo. The dosage ranges were 1) low (5±2.5 mg/day), 2) medium (10±2.5 mg/day), and 3) high (15±2.5 mg/day). Haloperidol was dosed to 15±2.5 mg/day. The medium and high doses of olanzapine and haloperidol led to significant improvements compared with placebo (Beasley et al. 1996b). Tollefson and Sanger (1997), after analysis of these early data, pointed out that the effect on negative symptoms by olanzapine was independent of movement disorders. Another large international multicenter trial used a flexible dosing strategy to show a statistical superiority of olanzapine over haloperidol. In this study, patients were started on olanzapine or haloperidol at dosages ranging from 5 to 20 mg/day. Ultimately, patients received olanzapine 13 mg/day compared with haloperidol 11.8 mg/day (Tollefson et al. 1997).

The third pivotal study included an interesting arm—olanzapine 1 mg/day—in comparison to low-, medium-, and high-dose olanzapine and haloperidol (15±5 mg/day). This study established the statistical efficacy of low- and high-dose olanzapine compared with 1 mg/day of olanzapine (Beasley et al. 1997). The group of studies described above led to the approval of olanzapine for psychosis (later changed to schizophrenia). Several other studies have reinforced olanzapine's efficacy for the treatment of schizophrenia. Coupled with its efficacy and substantially fewer movement disorder side effects, olanzapine has become an important addition to the armamentarium of the psychiatrist treating schizophrenia. Leucht et al. (1999) reported that olanzapine was statistically more effective than placebo (moderate effect) and also more effective than haloperidol (small effect) on global schizophrenia symptomatology. Olanzapine has shown superiority to haloperidol in several comparison studies. In a double-blind, placebo-controlled trial, it was shown to be modestly superior to haloperidol in improving cognitive functioning (Purdon et al. 2000). Its superiority was again demonstrated in a study of patients with prominent negative symptoms. Followed for 1 year, the olanzapine group and the risperidone group performed modestly better than the haloperidol group (Gurpegui et al. 2007). In a randomized, controlled trial versus haloperidol, 31.3% of olanzapine-treated patients showed an improvement in cognitive symptoms at study endpoint, compared with 12.5% for the haloperidol group (Lindenmayer et al. 2007). Despite these findings, other studies have shown no difference between olanzapine and haloperidol in effects on cognitive symptoms in schizophrenia patients with treatment-resistant illness (Buchanan et al. 2005). A large National Institute of Mental Health (NIMH)–funded trial was recently completed that sought to compare the atypical antipsychotics olanzapine, risperidone, quetiapine, and ziprasidone with perphenazine in order to understand the efficacy and side-effect profiles of the newer versus older antipsychotic medications (Lieberman et al. 2005). The study, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), was designed to provide a double-blind yet reasonably naturalistic way for clinicians to treat patients, using the time to discontinuation as a primary outcome variable. This outcome was intended to provide an estimate of overall efficacy and morbidity on a particular medication, as it was considered likely that patients would discontinue the medication if it was not working for any particular reason. Although the study design and its findings have at times been controversial, olanzapine demonstrated the longest time to discontinuation in the trial, based on all-cause discontinuation. Olanzapine had the highest rate of discontinuation due to metabolic complications such as weight gain, while perphenazine had the highest rate of discontinuation for EPS. Overall, however, the discontinuation rate was high for all medications, with nearly 75% of patients changing medications within the 18-month study duration. Much has been written since the initial findings were published, including analyses of cost-effectiveness (Rosenheck et al. 2006), psychosocial functioning (Swartz et al. 2007), and switching of medications (Essock et al. 2006), as well as numerous editorials about the treatment implications from the study and about the methodology of the study design. The pharmacoeconomics of using olanzapine in the treatment of schizophrenia are complicated. Rosenheck et al. (2003) have demonstrated that in pharmacoeconomic studies, olanzapine and haloperidol differentiate from each other. In these studies, haloperidol is accompanied by prophylactic benztropine to ward off EPS. When the cost-effectiveness of olanzapine and the other atypical antipsychotics was evaluated in the CATIE, perphenazine came out as the most cost-effective of the medications studied (Rosenheck et al. 2006). The general equality of efficacy among the medications, at least with respect to rehospitalization rates, as well as the decreased cost for the older medication, is partially responsible for this difference. Additionally, the metabolic consequences of olanzapine treatment become significant when one considers the overall total cost for the medication within the

entire health care system, as the increased rates of diabetes and associated medical conditions can cost thousands of dollars per year in associated medication, hospitalization, medical tests, and lost productivity. However, because the older antipsychotics carry a higher risk of neurological side effects, adherence to medications becomes relevant, and maintenance on medication is crucial to preventing relapse and expensive hospitalizations. Schizophrenia is not always responsive to traditional antipsychotic medication treatment. Clozapine was shown to be superior to chlorpromazine in treating schizophrenia that is refractory to other medications, and this led to its approval for traditional antipsychotic medication failures (Kane et al. 1988). However, clozapine has a unique and potentially more dangerous side-effect profile, with a rigorous associated treatment regimen, which can make it a difficult medication to use. Assessment of olanzapine for this difficult-to-treat patient group did not indicate usefulness for the treatmentrefractory group in a stringent nonresponder protocol (Conley et al. 1998). However, in an Eli Lilly– sponsored double-blind, noninferiority multicenter trial, olanzapine was shown to lower PANSS scores similarly to clozapine, although superiority of one agent over another was not addressed in this study design (Tollefson et al. 2001). A second phase of the CATIE examined the use of clozapine in patients with treatment-refractory illness and found that clozapine was a superior treatment for patients in which failure with other atypical medications had occurred, based on the time to discontinuation (McEvoy et al. 2006). Olanzapine has often been linked to improvements in the negative symptoms and cognitive symptoms of schizophrenia, although perhaps with less potency than for the positive symptoms. Negative and cognitive symptoms often do not respond to conventional antipsychotics and have even been shown to worsen, particularly if an adjunctive anticholinergic medication is used for treatment of EPS. The efficacy of olanzapine for negative symptoms was first reported by Tollefson et al. (1997), following completion of a large double-blind trial of olanzapine and haloperidol. A factor analytic model was used to determine the effect of olanzapine on negative symptoms, separate from the effect on positive symptoms. When all symptom improvements were taken into consideration, olanzapine-treated subjects had greater improvement in negative symptoms on both the Scale for the Assessment of Negative Symptoms (SANS) and the BPRS negative symptom subscore. In a flexible-dose comparison between risperidone and olanzapine in patients followed for 1 year, olanzapine-treated patients showed significantly greater improvement on SANS scores than did risperidone-treated patients (Alvarez et al. 2006). Interestingly, in a study by researchers from Eli Lilly that followed patients taking either quetiapine or olanzapine for 6 months, the two groups showed similar improvements on the SANS at study completion (Kinon et al. 2006). In a study comparing olanzapine and amisulpride, there was also no difference between the two medications, and only low-dose olanzapine outperformed placebo, with higher-dose olanzapine (20 mg) and amisulpride (150 mg) not showing a statistical benefit on the SANS (Lecrubier et al. 2006). Cognitive functioning is the most important prognostic indicator for schizophrenia (Green 2006). In a 1-year comparison of olanzapine with risperidone, both groups showed modest benefits on a cognitive function battery (Gurpegui et al. 2007). In a study conducted over a 1-year period by Eli Lilly researchers in Spain, olanzapine showed greater benefit on social functioning than did risperidone, as assessed by scores on the Social Functioning Scale (SFS). The greatest difference was in occupation/employment, but improvements were also seen in measures of independence, social engagement, and recreation (Ciudad et al. 2006). Olanzapine is indicated for the treatment of schizophrenia; however, studies leading to FDA approval are designed to include only patients between the ages of 18 and 65 years. Therefore, usefulness of olanzapine for young people with schizophrenia and patients older than 65 years was not addressed in the early studies. In a recent systematic review of the literature in children, second-generation antipsychotics were shown to be beneficial overall for targeting psychotic symptoms, although there

is still a need for research on the long-term safety profile of these agents (Jensen et al. 2007). To inform clinicians about the use of olanzapine in adolescents with schizophrenia, Findling et al. (2003) performed an open-label study of olanzapine using outcome measures from the PANSS and Clinical Global Impressions (CGI) Scale. In the 16 adolescent patients studied, there was a statistically significant reduction in PANSS-rated symptoms, and further exploration of the PANSS subscales found an effect on positive, negative, and general symptoms. The patients ended the study receiving an average olanzapine dosage of 12.4 mg/day, which was similar to the dosage used in many adult schizophrenic patients. A double-blind, flexible-dose study conducted in North Carolina demonstrated similar efficacy for risperidone, olanzapine, and haloperidol in psychotic young people (Sikich et al. 2004). In an NIMH-sponsored trial of adolescents with treatment-refractory schizophrenia, clozapine and olanzapine were compared. While clozapine showed a modestly more consistent pattern of symptom alleviation, particularly for negative symptoms, more side effects were noted in the clozapine group (Shaw et al. 2006). The use of olanzapine in a population considered to be at risk for schizophrenia but not yet meeting full symptom criteria was evaluated in a double-blind multicenter study. The olanzapine group demonstrated a decreased rate of conversion to psychosis compared with the placebo group, although the difference did not quite reach statistical significance. However, a number of factors, including high dropout rates in both groups, lack of a systematic method for diagnosing Axis I disorders, and the method of patient selection, limited the generalizability and reliability of the findings (McGlashan et al. 2006). The number needed to treat, a measure of effect size, was 4.5 in this study; thus, early medication treatment may benefit some patients. Nonetheless, given the long-term side-effect consequences of antipsychotics, much further refinement, including greater precision in identifying appropriate candidates for treatment, is required before presyndromal medication therapy can be considered to be evidence based. At the other end of the age spectrum, olanzapine has been tested in the treatment of several syndromes in the elderly. Further discussion of the use of olanzapine in dementia will follow in a separate subsection. Special challenges are involved in treating any disorder in elderly individuals, and schizophrenia or other psychosis is no exception. An early presentation of data reported a comparison of olanzapine with haloperidol in elderly psychotic patients. This report noted a decrease in symptoms for the olanzapine-treated patients, but the reduction was not statistically greater than in the haloperidol-treated patients. Notably, more movement disorder side effects were seen in the haloperidol group (Reams et al. 1998). The movement disorder results are important for the elderly, because they are at high risk for tardive dyskinesia. A more recent study of a group of older patients with chronic schizophrenia actually showed a statistical advantage for olanzapine (Barak et al. 2002). For a broad group of psychotic patients, Hwang et al. (2003) reported reduction in BPRS symptoms in 94 acutely ill patients, some with organic psychosis, thus illustrating the usefulness of olanzapine in this older patient group. As in any treatment with the elderly, special care must be taken for cardiovascular complications. With olanzapine, orthostatic hypotension, oversedation, and thus the risk of falls must be factored into the dosing decision (Gareri et al. 2006).

Treatment Approaches Early studies of olanzapine assessed dosages ranging from 5 to 30 mg/day. When olanzapine was initially released, it was recommended that it be started at a dosage of 10 mg/day—frequently as a bedtime dose. Subsequently, clinicians have used average dosages higher than 10 mg/day (e.g., approximately 13 mg/day). In the CATIE, the average daily dose in the flexible-dose segment (available doses were 7.5, 15.0, 22.5, and 30.0 mg) was 20.1 mg (Lieberman et al. 2005). For inpatient use, clinicians often will give patients 5 mg of olanzapine in the morning and 10 mg at bedtime (Schulz 1999). Some patients appear to have an inadequate response to olanzapine at the recommended doses, so clinicians have assessed the usefulness of olanzapine at dosages above the

recommended 20 mg/day. Many inpatient clinicians employ a loading strategy with olanzapine, particularly in patients presenting with agitation, using up to 40 mg/day for the first 2 days and gradually decreasing the dose to a goal of 20–30 mg/day (Baker et al. 2003; Brooks et al. 2008). While sedation and hypotension must be watched for in any individual patient, increased rates of those side effects were not seen in a study comparing the loading dose strategy with conventional 10-mg/day dosing (Baker et al. 2003). Typically, agitated patients are best treated with the rapid-dissolving preparation of olanzapine. Given their faster onset of action compared with the conventional pill form and their decreased risk for "cheeking" of the medication, rapid-dissolving tablets are preferable in the acute setting, particularly when some sedation is also needed. When patients are severely agitated, use of injectable olanzapine is often necessary. The intramuscular preparation also has a rapid onset of action, similar to that of dissolvable tablets, and a certainty of delivery that is imperative in an acute emergency. The injectable preparation has been shown to be superior to placebo at doses of 10 mg and as effective as haloperidol, with significantly fewer side effects (Breier et al. 2002). Case reports, however, caution against use of olanzapine in conjunction with intramuscular lorazepam because of hypotension (Zacher and Roche-Desilets 2005). Empirical studies of a "lowest effective dose" of olanzapine for long-term maintenance have not been performed, so clinical judgment regarding dose is needed at all stages of treatment. For schizophrenia, combinations of medications are sometimes helpful. As can be seen throughout this chapter, olanzapine has been tested in combination with antidepressant and mood-stabilizing compounds in patients with mood disorders. Therefore, these combinations in schizophrenic patients appear safe and appropriate when used judiciously.

Bipolar Disorder and Major Depressive Disorder In the past, before the introduction of atypical antipsychotic medications, it was well known that traditional antipsychotic medications were useful in the treatment of mania. Medications such as chlorpromazine and haloperidol could rapidly reduce agitation and excitement as well as diminish the psychotic symptoms of mania, when present. Early studies with clozapine indicated that this atypical agent was even useful in reducing symptoms of bipolar disorder refractory to previous mood stabilizer and traditional antipsychotic medication treatment (Calabrese et al. 1996). An assessment of the effect of olanzapine on symptoms of schizoaffective disorder provided a rationale for studying olanzapine in bipolar patients. The schizoaffective patients were identified as part of a larger study. When the results for the schizoaffective disorder patients were analyzed, those patients who received olanzapine had a superior outcome, compared with patients who received haloperidol, on many, but not all, measures (Tran et al. 1999). Therefore, a series of studies was conducted to assess the efficacy and safety of olanzapine in the treatment of bipolar disorder. The first controlled study was a comparison of olanzapine with placebo in a 21-day study that used objective rating scales (Tohen et al. 1999). The dosage of olanzapine could be adjusted between 5 and 20 mg/day. An analysis of the Young Mania Rating Scale (YMRS) showed a significant score reduction for patients taking olanzapine compared with those taking placebo. Of interest in treating bipolar patients, no difference was seen in the outcomes for depression; therefore, olanzapine did not lead to depression. It is also well known that bipolar patients are sensitive to the potential of movement disorders from antipsychotic medications. In this study, EPS were not more frequent in the olanzapine-treated patients than in the patients taking placebo (Tohen et al. 1999). These findings were confirmed by a second pivotal study showing an advantage of olanzapine over placebo (Tohen et al. 2000). An open-label follow-up (49 weeks) added valuable information, especially noting that decreases in YMRS scores continued. For the longer term, depression scores also improved. Importantly, for the patients who were exposed to olanzapine at a mean dosage of approximately 14 mg/day, no cases of tardive dyskinesia occurred (Sanger et al.

2001). An important question of practical interest is how olanzapine compares with conventional mood stabilizers such as lithium or valproic acid. The first study to approach this question, which was a small pilot study (N = 30 patients), compared olanzapine with lithium. No difference was found between BPRS and Mania Scale scores; patients in both groups showed significant improvement (Berk et al. 1999). In a larger double-blind trial conducted by Eli Lilly, olanzapine was compared with lithium in the maintenance treatment of bipolar disorder (mixed or manic) (Tohen et al. 2005). In the study, patients were stabilized on a combination of lithium and olanzapine and then randomly assigned to receive one or the other for 52 weeks. In the noninferiority analysis, olanzapine was shown to prevent depression relapse as well as lithium, and in fact it had a lower rate of mixed or manic relapse over the 52-week follow-up. Weight gain was higher in the olanzapine group (Tohen et al. 2005). Further studies confirmed the equivalent efficacy of olanzapine and the most widely used anticonvulsant mood stabilizer, divalproex (Tohen et al. 2002). In this 3-week study, olanzapine was found to be superior to placebo in reducing mania ratings (YMRS). More recently, another comparison of the two compounds confirmed no differences in treatment outcome but did note more sedation and weight gain in the olanzapine group (Zajecka et al. 2002). The group of studies focusing on olanzapine's use in treating mania that showed reduction of manic as well as psychotic symptoms led to the approval of olanzapine by the FDA for the treatment of manic symptoms. Mean dosages of olanzapine used in monotherapy appear similar to those used in schizophrenia: 13 mg/day. For acute mania, a recent study has shown the usefulness of intramuscular olanzapine in treating agitated bipolar patients (Meehan et al. 2001). Olanzapine has also been shown in several studies to be an effective adjunctive agent. In another study conducted by the group at Eli Lilly, olanzapine was found to reduce suicidal ideation in bipolar patients when added to a regimen that included lithium or valproic acid (Houston et al. 2006). The treatment of bipolar depression is often complicated. Monotherapy with antidepressants is associated with an increased risk of switching into mania. Olanzapine packaged with fluoxetine—the olanzapine–fluoxetine combination (OFC)—has been studied in the treatment of depression in bipolar disorder. In an 8-week double-blind trial conducted by Eli Lilly, OFC was compared against olanzapine monotherapy and placebo in patients with bipolar I disorder in a depressed phase. While both treatments were more effective than placebo, OFC was significantly more effective than either olanzapine or placebo in treating depressive symptoms. OFC-treated patients showed greater improvement in mood compared with olanzapine-treated patients by the fourth week of the study (Tohen et al. 2003). Benefits were also seen in the subjects' health-related quality of life (Shi et al. 2004). OFC was also recently compared with lamotrigine in a 7-week study (Brown et al. 2006). Although OFC demonstrated a statistical separation from lamotrigine by the first week, it is difficult to make a full comparison in such a short study. As lamotrigine requires slow titration to decrease the risk of serious rash, it was received at the target dose (200 mg/day) only for the last 2 weeks of the study, whereas the OFC dosage could be titrated to therapeutic levels much more quickly. Although the rapid titration of OFC is helpful when a more urgent approach is required, further study is needed to determine whether OFC's greater benefits persist once lamotrigine has had an opportunity to remain at a therapeutic dose for a longer period of time (Brown et al. 2006). Rates of treatmentemergent mania with OFC were low and did not significantly differ from rates with placebo or olanzapine monotherapy (Amsterdam and Shults 2005; Tohen et al. 2003). Patients with schizophrenia frequently have symptoms of depression, whereas others may appear to be depressed secondary to negative symptoms and the use of typical antipsychotic medications (Siris et al. 2000). This serious problem was addressed by Tollefson et al. (1998a, 1998b), who examined

the results of olanzapine pivotal trials in order to assess the effect of olanzapine on symptoms of depression in schizophrenic patients. In the Tollefson et al. (1998b) study, they used a path analysis to control for negative symptoms and EPS. They found a statistically significantly greater effect of olanzapine on depression compared with placebo, and at medium (102.5 mg/day) and high dosages, reductions in BPRS Anxiety/Depression scale scores were similar to those seen with haloperidol. For subjects with higher depression scores, olanzapine was statistically superior to haloperidol. These results demonstrate that olanzapine may have a useful effect in this patient group and suggest that further exploration of the potential for olanzapine in treating depressive mood disorders is warranted. The tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin– norepinephrine reuptake inhibitors (SNRIs) are all effective treatments for depression compared with placebo, but not all patients' symptoms respond to these agents. These patients with treatmentrefractory illness present a substantial challenge to clinicians and investigators alike. Augmentation strategies, including lithium, liothyronine, and other medications, have been tried with limited success and risks of side effects. OFC has been studied in treatment-refractory major depressive disorder. Thase et al. (2007) conducted a study comparing OFC against olanzapine or fluoxetine monotherapy in patients who had failed to respond to at least two prior trials with antidepressants. In the pooled analysis, which separated the subjects into two groups (group 1 had failed previous treatment with an SSRI; group 2 had failed previous treatment with an agent other than an SSRI), OFC showed improvement over olanzapine or fluoxetine monotherapy on the Montgomery-Åsberg Depression Rating Scale (MADRS). Although the difference was not significant for group 1 alone, it was significant for group 2 (Thase et al. 2007). In a double-blinded trial sponsored by Eli Lilly that compared olanzapine, fluoxetine, OFC, and venlafaxine, all treatments showed similar rates of efficacy (Corya et al. 2006). Another significant challenge in treating mood disorders is developing a strategy for patients who have major depression with psychotic features. Earlier work by Spiker et al. (1985) had indicated greater efficacy for a combination of antipsychotics and antidepressants over each administered alone. Because olanzapine has low levels of EPS compared with typical antipsychotics and has a positive effect on mood in schizophrenic patients (Tollefson et al. 1998a, 1998b), it would be a good candidate for depression with psychosis. In an open-label study, olanzapine monotherapy produced a significant reduction in symptoms of both depression and psychosis (measured by the Scale for the Assessment of Positive Symptoms). Again, it must be pointed out that this was an early pilot study, and no comparisons with other treatments were made (for an update on the overall significance of and approach to major depression with psychotic features, see Schatzberg 2003). In summary, the newer atypical antipsychotic medications have found a role in treating not only mania but also depression. Olanzapine has demonstrated efficacy in both acute and maintenance phases of bipolar disorder, and when combined in the OFC formulation has shown benefit in treating depression in bipolar I disorder. Particularly in cases where psychosis is prominent with mania, olanzapine is a reasonable first-line agent, although consideration must be given to the potential metabolic consequences. In depression, olanzapine has been studied primarily in treatment-refractory cases, and given its metabolic side-effect profile, it is most appropriate for use in such cases.

Dementia-Related Agitation and Psychosis Olanzapine is often used in an off-label manner for the treatment of dementia. Alzheimer's disease, the most prevalent form of dementia in the Western world, is characterized by progressive memory loss, decreased executive functioning, and deficits in language and visuospatial skills. However, Alzheimer's disease is also frequently accompanied by psychotic and mood symptoms, such as depression, paranoia, and hallucinations. In Lewy body dementia, visual hallucinations are a common manifestation, along with parkinsonism and autonomic instability. Frontotemporal dementia is characterized by disinhibition and euphoria, along with memory loss and changes in motor function

(Bird and Miller 2005). Olanzapine and other antipsychotic medications are typically used off-label for treatment of the neuropsychiatric manifestations of dementia. As elderly people are generally more sensitive to the EPS and tardive dyskinesia associated with first-generation antipsychotic medications, the second-generation medications are often preferred when antipsychotics are needed. A large placebo-controlled trial of olanzapine in Alzheimer's patients showed that the lower dosages of olanzapine (5–10 mg/day) were significantly better than placebo in treating target symptoms of agitation, hallucinations, and delusions (Street et al. 2000, 2001). However, the treatment of dementia-related psychosis is complicated. The FDA recently mandated placement of a black box warning on the prescribing information of antipsychotic medications calling attention to the increased risk of death, primarily from cardiovascular and infectious complications. According to the warning, second-generation antipsychotic use over a 10-week period carries a 1.6- to 1.7-fold increased risk of mortality based on data from 17 placebo-controlled trials of atypical antipsychotics in dementiarelated psychosis. The warning does not differentiate medications and has subsequently been extended to apply to first-generation antipsychotics as well. In a recent Cochrane review of atypical antipsychotic use in agitation associated with dementia, both risperidone and olanzapine were shown to effectively treat the agitation but were associated with an increased risk of stroke, even at olanzapine doses of less than 10 mg/day (Ballard and Waite 2006). However, the finding of increased stroke risk with antipsychotics, and the necessity of the black box warning, remains controversial, as several large population-based studies have reported conflicting results (Gill et al. 2005; Herrmann and Lanctot 2005; Herrmann et al. 2004; Layton et al. 2005; Schneider et al. 2006a). Ultimately, clinical judgment and thorough documentation are important, as in certain situations the hazards of untreated psychotic agitation may outweigh the potential risks of treatment. Several studies have examined olanzapine in the treatment of dementia without agitation (Brooks and Hoblyn 2007). A placebo-controlled multicenter trial conducted by researchers at Eli Lilly evaluated olanzapine at low fixed doses (1.0, 2.5, 5.0, and 7.5 mg/day) in the treatment of dementia-related psychosis (De Deyn et al. 2004). Although olanzapine did not separate from placebo on the primary outcome measure, Hallucinations and Delusions of the Neuropsychiatric Inventory—Nursing Home edition (NPI/NH), improvements were seen in each of the dosage groups studied. All patients who received dosages of 2.5 mg/day or greater were initially started on 2.5 mg/day, with the dosage titrated upward by 2.5 mg/week (as indicated based on their assigned study group), and there was an overall difference from placebo in the acute phase of the study, suggesting that a 2.5-mg dose was an effective starting dose in the more acute setting. On some secondary outcome measures, the greatest improvement was seen with the highest olanzapine dosage (7.5 mg/day), suggesting that for some patients, an increase to 7.5 mg/day is beneficial. Because no higher dosages were used in the study, it is unclear whether continuing to increase the dosage would lead to greater efficacy (De Deyn et al. 2004). In treatment of cognitive decline, acetylcholine has been the focus of treatments aimed at protecting people with dementia from undergoing as rapid a deterioration as they would naturally. Cholinesterase inhibitors have been used on that basis. Olanzapine may have beneficial effects on prefrontal cortex cholinergic and serotonergic neurons that may facilitate acetylcholine release to that region. However, in a double-blind study conducted by researchers at Eli Lilly, olanzapine was shown to worsen cognitive functioning, as assessed on the Alzheimer's Disease Assessment Scale for Cognition (ADAS-Cog), and there was no statistical difference between the olanzapine and placebo groups in scores on the Clinician's Interview-Based Impression of Change (CIBIC) scale (Kennedy et al. 2005). Patients in the olanzapine group also showed worsening on the Mini-Mental State Examination (MMSE). Previous studies have found little to no benefit on cognition from olanzapine treatment in nonagitated patients with dementia (De Deyn et al. 2004; Street et al. 2000). The CATIE studies described earlier also had an Alzheimer's disease component in which olanzapine,

risperidone, and quetiapine were compared with placebo for the treatment of psychosis and agitation in outpatients (Schneider et al. 2006b). Patients were included if they had psychotic symptoms and lived either in an assisted living facility or at home, but were excluded for skilled nursing needs or primary psychotic disorders. Patients who were to receive cholinesterase inhibitors or antidepressants were also excluded from the study. Like the schizophrenia portion of CATIE, the primary outcome variable was time to discontinuation. No difference was found among the groups in time to discontinuation, and no benefit was seen on the Clinical Global Impressions of Change (CGI-C). The average time to discontinuation ranged between 5 and 8 weeks among the treatments. Discontinuation because of lack of efficacy occurred sooner for placebo or quetiapine than for risperidone or olanzapine. Side effects such as parkinsonism, sedation, and higher body mass index were all increased with the study medications over placebo (Schneider et al. 2006b). Overall, there are limited data to support the effectiveness of atypical antipsychotics in the treatment of dementia. Risks for worsened cognitive function and metabolic concerns must be considered when use of antipsychotic medications is contemplated. Nonetheless, there are times when behavioral consequences and patient safety require more aggressive treatment, and antipsychotic medication may be warranted. Ultimately, a painstaking evaluation of the risk–benefit ratio of antipsychotic medications must precede any decision to prescribe these agents, in both the acute and the long-term time frames. Further study is needed, however, regarding the use of second-generation antipsychotic medications in this population (Schneider et al. 2006a).

Borderline Personality Disorder Borderline personality disorder is a severe psychiatric illness that afflicts nearly 1% of the population (Torgersen et al. 2001). It is well known to clinicians that symptoms of affective lability, self-injurious behavior, and impulse/aggression action patterns make this patient group difficult to treat. Patients with borderline personality disorder are often taking several medications of various classes, including mood stabilizers, antidepressants, and antipsychotics. Based on earlier studies indicating that low doses of traditional antipsychotic medications may be useful for borderline personality disorder (Goldberg et al. 1986; Soloff et al. 1986), Schulz et al. (1999) reported on an open-label study that found that olanzapine led to a substantial decrease in Symptom Checklist–90 symptoms, as well as on objective measures of impulsivity and aggression. Of the patients entered in the trial, 9 of 11 (82%) completed the study. The design of the trial allowed for early flexible dosing, and the subjects ended the 8-week trial taking olanzapine at an average dosage of approximately 7.5 mg/day, usually at bedtime. Zanarini and Frankenburg (2001) extended this open-label trial and showed superiority of olanzapine over placebo in a longer-term (26-week) study. This interesting study of only women indicated that lower dosages (5 mg/day) of olanzapine can be useful and are associated with only minimal weight gain. In a study comparing olanzapine, fluoxetine, and OFC in women with borderline personality disorder, olanzapine monotherapy was found to be more effective in treating the depressive symptoms of borderline personality disorder than either fluoxetine or OFC, as assessed on the MADRS. Additionally, olanzapine was superior to fluoxetine in treating symptoms of impulsivity and aggression, as measured by the Overt Aggression Scale (OAS). Weight gain was seen in a greater percentage of olanzapine-treated patients than of fluoxetine-treated patients (Zanarini et al. 2004). Dialectical behavioral therapy (DBT) is a mainstay of current treatment for borderline personality disorder. In a double-blind, placebo-controlled trial, olanzapine was studied as an adjunctive agent in patients receiving DBT. Impulsive and aggressive behaviors were found to be lower in the group that received olanzapine than in the placebo group. The average olanzapine dosage in the trial was 8.8 mg/day. Statistically significant levels of weight gain and dyslipidemia were observed in the olanzapine group compared with the placebo group (Soler et al. 2005). Therefore, with consideration for side effects, olanzapine may be helpful for a broader range of illnesses, particularly when used in

conjunction with psychotherapy.

Anorexia Nervosa Anorexia nervosa is a common and severe psychiatric illness that may well have the highest mortality of all mental disorders. Among the symptoms of this illness is severe restriction of food intake, leading to low weight; however, patients also have psychotic-like levels of self-perception of body size and appearance and unusual ideas about food and metabolism. Some investigators have begun to explore the possibility that olanzapine may help with this patient group. Initially, reports were largely from pilot studies, including case series, but data are now emerging from small controlled trials. In an open-label trial, 17 patients hospitalized for anorexia nervosa were given olanzapine in conjunction with concurrent cognitive-behavioral therapy (CBT) and DBT group treatment (Barbarich et al. 2004). Olanzapine was initiated at a dosage of 1.25–5.00 mg/day, with upward titration as needed, balancing sedation and side effects with efficacy. Although patients showed improvement in weight as well as in Beck Depression Inventory (BDI) and Spielberger State-Trait Anxiety Inventory (STAI) scores, the lack of a control group limits the validity of these results (Barbarich et al. 2004). Because olanzapine has weight gain as a significant side effect, the utility of that effect and the mechanism behind it have become a target for research. Ghrelin and leptin are hormones associated with satiety. In a double-blind, placebo-controlled trial, olanzapine was given concurrently with CBT in patients with anorexia, and ghrelin and leptin levels were assessed over 3 months. While both the olanzapine patients and the placebo patients gained weight, there was no statistical difference between groups in the amount of weight gained, nor in leptin or ghrelin levels, which remained unchanged over the course of the study (Brambilla et al. 2007). In addition to severe distortions of body image, people with anorexia nervosa often have ruminations and obsessions about their bodies and food intake that can lead to significant distress as well as morbidity and mortality in the illness. In a pilot study in Australia, olanzapine was compared with chlorpromazine in a flexible-dose trial. Based on assessments with self-report instruments, olanzapine demonstrated a benefit for the obsessive ruminations seen in anorexia (Mondraty et al. 2005). As the newer second-generation antipsychotic olanzapine continues to be tried in illnesses beyond psychosis, its potential benefit in anorexia will be followed up closely. Even though olanzapine has the side effects noted in other sections of this chapter, this illness is of such severity that further investigation of a possible role for olanzapine in its treatment is warranted.

Obsessive-Compulsive Disorder Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors that are often disabling and are difficult to treat. Affecting up to 2%–3% of the population, OCD has a very high prevalence and is the fourth most common psychiatric condition. Because nearly half of patients do not respond to conventional treatments with SSRIs, augmentation strategies are often sought. A significant portion of patients with OCD have comorbid psychosis. Second-generation antipsychotics had a number needed to treat of 4.5 to achieve a 35% reduction in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score, according to a systematic review (Bloch et al. 2006). Olanzapine was first evaluated as an adjunctive agent in several open-label trials and case series (Bogetto et al. 2000; D'Amico et al. 2003; Francobandiera 2001; Koran et al. 2000). In a small double-blind, placebocontrolled augmentation study (Bystritsky et al. 2004) in patients who had failed to respond to conventional treatment with serotonin reuptake inhibitors, the olanzapine-augmentation group showed a statistically significant decrease of 4 points on the Y-BOCS compared with the placebo group, which showed a slight gain in Y-BOCS score over the 6-week study duration. Subjects could be on any serotonin reuptake inhibitor, and the dosing of olanzapine was flexible (average dosage = 11 mg/day). In another double-blind, placebo-controlled augmentation trial, patients who were taking

fluoxetine 40 mg, generally considered a low dose for treatment of OCD, were randomly assigned to augmentation with either olanzapine (up to 10 mg/day) or placebo and followed for 6 weeks. In this study, there was no statistical difference between the groups; however, that could be attributed to the relatively low dose of fluoxetine used in the study and the high rate of response in the placebo group (Shapira et al. 2004). In an open-label study, subjects received olanzapine augmentation in addition to a serotonergic reuptake inhibitor and were followed for 1 year. Those who evidenced benefit at 12 weeks tended to continue to show a benefit when assessed at 1 year. Subjects with comorbid bipolar disorder showed the greatest response and demonstrated improvement in MADRS scores as well (Marazziti et al. 2005). Olanzapine has also been studied in Gilles de la Tourette syndrome (GTS), a disorder characterized by motor and vocal tics and frequently including obsessive and compulsive symptoms. Olanzapine has been noted in case reports to have benefit in treatment of the obsessive-compulsive features, as well as the tics (Van den Eynde et al. 2005). In a small (N = 4) double-blind, placebo-controlled crossover trial, olanzapine was compared with pimozide for the treatment of GTS. Olanzapine demonstrated positive effects at 5-mg and 10-mg doses, compared with pimozide doses of 2 mg or 4 mg, over 52 weeks (Onofrj et al. 2000). However, given the small sample size of this study, further research is needed to support a potential role for olanzapine in GTS. Overall, olanzapine has demonstrated benefit as an adjunctive agent in the treatment of several anxiety disorders. In OCD and GTS, there have been open-label studies that have shown benefit, and in small double-blind studies, there have been generally positive, although ultimately equivocal, results. Further research, including head-to-head trials and more long-term studies, is needed to fully evaluate the efficacy of olanzapine and other second-generation antipsychotic medications in OCD (Ballon et al. 2007).

Posttraumatic Stress Disorder Posttraumatic stress disorder (PTSD) is a clinically significant disorder with symptoms of reexperiencing a traumatic event, avoidance of situations associated with the trauma, and increased arousal. To qualify for the diagnosis, a patient must have experienced or witnessed a serious event that threatened injury or death or threatened physical integrity (American Psychiatric Association 2000). Clinical observations of such patients show that they have periods of insomnia, nightmares, perceptual disturbances, sensory illusions, and suspiciousness. Some clinicians have noted nonspecific psychotic comorbidities. To date, SSRIs have been frequently used for PTSD, but there is no sole pharmacological standard of treatment. Not surprisingly, olanzapine has been assessed for symptoms of PTSD. As in some of the other disorders discussed in this chapter, the early data are limited and in pilot form. The first study examined olanzapine in a double-blind, placebo-controlled study (2:1 randomization, olanzapine to placebo) at dosages ranging up to 20 mg/day. The research group reported no difference from placebo in this study but noted a high rate of placebo response (Butterfield et al. 2001). In the same year, a case series reported significant symptom reduction in the ClinicianAdministered PTSD Scale, as well as in depression and anxiety scale (Hamilton Rating Scale for Depression and Hamilton Anxiety Scale) scores. In this relatively short (8-week) study, olanzapine was found to be helpful in this group of patients with combat-related trauma. A third study examined the effect of olanzapine as an augmentation to SSRIs in patients not fully responsive to that treatment. This strategy is similar to that reported by Shelton et al. (2001) for refractory depression. Olanzapine or placebo was added to the patients' SSRI treatment. Active medication treatment led to statistically significantly greater reduction in PTSD symptoms, as assessed by PTSD scales, as well as in symptoms of anxiety and depression (Stein et al. 2002). These early studies have similarities to the others for borderline personality disorder and anorexia

nervosa in that some success is noted in difficult-to-treat patient groups. Further controlled trials are needed to determine whether olanzapine's use for these indications is supported by an evidence base beyond the theoretical and anecdotal rationales currently used. Again, in the clinical arena, the treating psychiatrist would need to weigh the evidence and alternative treatments before proceeding.

SIDE EFFECTS AND TOXICOLOGY The adverse effects of olanzapine in clinical use are consistent with the preclinical studies predicting few neurological effects. EPS, as manifested by dystonic reactions and parkinsonism, are uncommon, although these may be seen in patients who are sensitive to antipsychotics, such as patients with Parkinson's disease. In Phase II and III clinical trials, olanzapine-treated groups generally showed an improvement in EPS from baseline, reflecting the fact that most of the subjects had previously taken typical neuroleptics. In a large multinational comparison study (Tollefson et al. 1997), olanzapine produced fewer treatment-emergent neurological adverse effects than haloperidol for parkinsonism (14% vs. 38%) and akathisia (12% vs. 40%). In another study (Volavka et al. 2002), antiparkinsonian agents were prescribed to 13% of both clozapine- and olanzapine-treated subjects, compared with 32% of risperidone-treated patients. The reduction of EPS is predictive of decreased risk of tardive dyskinesia, the most problematic of the common adverse effects of classic neuroleptics. To date, the accumulated experience with atypical antipsychotics indicates that tardive dyskinesia is 10- to 15-fold less common, at an annual rate of 0.52% of olanzapine-treated patients compared with 7.45% of haloperidol-treated patients, based on pooled data from long-term comparison trials (Beasley et al. 1999). A major adverse effect found during treatment with olanzapine is weight gain. This is a serious concern because persons with schizophrenia are more likely than the general population to be obese, and weight gain may contribute to nonadherence to antipsychotic treatment, leading to increased risk for relapse. With the decrease in neurological side effects with second-generation antipsychotic agents, metabolic effects have emerged as a major risk for patients and a focus of consideration for clinicians. The relative degree of weight gain associated with first- and second-generation antipsychotics was studied in a comprehensive meta-analysis by Allison et al. (1999). Estimates of weight change associated with standardized doses over 10 weeks were calculated from published data from 81 studies. Clozapine produced the greatest weight gain (4.45 kg), followed by olanzapine (4.15 kg). By comparison, risperidone was associated with a gain of 2.1 kg, haloperidol was associated with a gain of 1.08 kg, and patients lost 0.74 kg while taking placebo. In long-term treatment, 30%–50% of patients may gain more than 7% of body weight, with low pretreatment weight and good clinical response associated with more weight gain. Efforts involving use of other pharmacotherapies to combat weight gain have largely been unsuccessful. Sibutramine, an SNRI, has been shown to be an effective weight-loss agent and has been tested as an adjunct to behavioral modification for management of olanzapine- and clozapineinduced weight gain in double-blind, placebo-controlled trials. In the olanzapine study (Henderson et al. 2005), there was an average 8-pound weight loss compared with placebo, while in the clozapine study (Henderson et al. 2007), there was no statistical difference from placebo. Unfortunately, there have been case reports of sibutramine-induced psychosis (Rosenbohm et al. 2007; Taflinski and Chojnacka 2000), so its use in the psychotic disorder population must be carefully monitored. Other agents, including H2 antagonists such as famotidine, have also been studied. In a double-blind trial in first-episode patients, famotidine given prophylactically had no benefit in preventing weight gain (Poyurovsky et al. 2004). Additionally, a trial of fluoxetine in first-episode schizophrenia patients yielded the same results (Poyurovsky et al. 2002). Small studies have shown modest positive results with the SNRI reboxetine (Poyurovsky et al. 2003) and the H2 antagonist nizatidine (Atmaca et al. 2003).

A recent post hoc analysis of first-episode patients in Spain indicated that use of the orally disintegrating formulation of olanzapine might result in decreased weight gain (Arranz et al. 2007). This hypothesis was first proposed by de Haan et al. (2004) in a report of a small nonrandomized study in which adolescents switched from conventional olanzapine to sublingual dissolvable olanzapine lost an average of 6.6 kg in 16 weeks. The authors suggested that differential effects on serotonergic receptors in the gut, particularly at the pylorus, might be responsible for their findings, but larger randomized studies are needed on this topic. Small studies using metformin, an agent known to decrease hepatic glucose output, have tested the possibility that it may help patients either lose weight or remain at the same weight while receiving olanzapine or other second-generation antipsychotics. In a double-blind, placebo-controlled trial (Baptista et al. 2006), patients were given 10 mg of olanzapine and randomly assigned to receive either metformin or placebo for 14 weeks. No differences between groups were seen in body mass index or waist circumference. There was a modest improvement in overall glucose levels and in measures of glucose homeostasis (homeostasis model assessment for insulin resistance [HOMA-IR]), but no change was seen in lipid levels. A follow-up study conducted by the same group (Baptista et al. 2007) demonstrated similar results, although in the second study, small differences in weight gain between the groups were found, with the metformin group losing an average of 1.5 kg and showing decreased leptin levels, while the placebo group maintained a consistent weight. In a double-blind, placebo-controlled trial in adolescents who had gained weight after 1 year of treatment with a secondgeneration antipsychotic (olanzapine, risperidone, or quetiapine), the addition of metformin resulted in statistical differences in waist circumference, body mass index, and overall weight gain (Klein et al. 2006). HOMA-IR scores were significantly decreased, and the number of subjects requiring referral for a glucose tolerance test was reduced, among the subjects who received metformin. These equivocal results suggest that further research is needed on adjunctive agents to help with the metabolic complications often seen with olanzapine. Weight gain is an even greater concern in the treatment of children and adolescents, who may be exposed to medication for a longer time and are concerned with body image. After 12 weeks of treatment with olanzapine, hospitalized adolescent patients gained 7.2±6.3 kg, approximately twice the weight gain experienced by those taking risperidone; 19 of 21 patients (90%) gained more than 7% of their body weight (Ratzoni et al. 2002). These findings in patients younger than 18 years have been confirmed by Findling et al. (2003), who reported an average 6.5-kg weight gain in their assessment of schizophrenic patients over 8 weeks. Concurrently with the attention to weight gain with second-generation antipsychotics, other metabolic effects have been noted. Reports of glucose intolerance, hyperglycemia, hyperlipidemia, diabetes, and diabetic ketoacidosis have surfaced, mostly associated with clozapine and olanzapine therapy. Cases reported to the FDA Drug Surveillance System and published cases of olanzapine-associated diabetes and hyperglycemia were reviewed by Koller and Doriswamy (2002). Two hundred eighty-nine cases were identified, of which 225 (78%) were new-onset diabetes, 100 (35%) involved ketosis or acidosis, and 23 (8%) patients died. Most cases developed within 6 months of initiation of olanzapine therapy. Many cases occurred in the first month of therapy, indicating that weight gain alone did not mediate the occurrence of diabetes-related problems. On the basis of the temporal relation between metabolic changes and the introduction and withdrawal of olanzapine, the young age of patients affected, and the number of reports, the authors concluded that the data suggested that olanzapine was causally related to the development or worsening of diabetes. A similar conclusion about clozapine and diabetes was reported earlier (Koller et al. 2001). Because case studies and reports by clinicians to regulatory agencies may reflect reporting bias, controlled studies comparing the development of metabolic disorders are needed to clarify whether these are related to the underlying psychosis, causally related to drug treatment in general, or specifically related to individual agents.

Studies that used large health system databases have been published linking use of antipsychotics with subsequent diagnoses of diabetes or use of hypoglycemic agents. These studies show increased risk of development of type 2 diabetes following the use of olanzapine and clozapine relative to the use of risperidone or typical antipsychotics or compared with matched untreated persons (Gianfrancesco et al. 2002; Koro et al. 2002a; Sernyak et al. 2002). While olanzapine has been associated with weight gain and type 2 diabetes, there have also been reports of diabetic ketoacidosis (DKA), a condition more often associated with type 1 diabetes mellitus. These reports first appeared in the literature in 1999 (Gatta et al. 1999; Goldstein et al. 1999; Lindenmayer and Patel 1999). In a review of 45 published cases of DKA associated with atypical antipsychotic medications, 42% of cases were related to olanzapine, 44% were related to clozapine, and 6% each were related to risperidone and quetiapine (Jin et al. 2004). The onset of DKA was not associated with weight gain, though 80% of the patients were overweight prior to initiating treatment. The overall incidence of DKA is unknown; however, given the potential morbidity and mortality associated with this acute condition, close monitoring is critical, as DKA was the first presenting sign of diabetes in 42% of reported cases and generally required an intensive care unit admission. In a review of California Medicaid data on cases of risperidone- and olanzapine-associated DKA, Ramaswamy et al. (2007) found a higher incidence of DKA for olanzapine than for risperidone and noted that the risk increased with duration of treatment with olanzapine. Another metabolic adverse effect seen with olanzapine is the development of dyslipidemia, often in association with weight gain. In a large British patient database, olanzapine conferred a fivefold increase in the rates of dyslipidemia over an untreated control condition and a threefold increase over conventional antipsychotics, whereas risperidone did not increase the risk (Koro et al. 2002b). Sedation is frequent at the start of therapy with olanzapine but diminishes as patients develop tolerance for this side effect. In long-term treatment, the incidence of sedation is about 15%, similar to that of haloperidol. Anticholinergic effects occur during treatment but at rates only slightly higher than those of placebo, and they rarely lead to treatment discontinuation. Mild elevations of liver enzymes may be seen in some patients, but these are stable or decline over time without progression to hepatic dysfunction. Prolactin elevations observed during olanzapine treatment occur early in the course of treatment, and levels are much lower than those seen with risperidone or classic antipsychotic treatment. However, prolactin concentrations may exceed normal levels in patients taking 30 mg/day or more of olanzapine. Leukopenia is rare and occurs at a rate similar to that seen with other typical and atypical antipsychotics, but olanzapine does not cause agranulocytosis, even in patients who developed this effect while taking clozapine. In animal toxicology studies and in clinical trials, no QTc prolongation was observed, and other cardiovascular effects are rarely of clinical importance. In summary, olanzapine is a well-tolerated antipsychotic agent with a low rate of EPS and diminished risk for tardive dyskinesia. Weight gain is common and can lead to discontinuation by choice or by clinician decision because of long-term health concerns. Patients should be monitored for the development of type II diabetes and dyslipidemia. Studies addressing weight gain are progressing, and new strategies may emerge in the near future.

DRUG–DRUG INTERACTIONS Olanzapine is metabolized primarily via glucuronidation and via oxidation by CYP1A2 (see section "Pharmacokinetics and Disposition" earlier in this chapter). Other drugs that affect the activity of these metabolic pathways would therefore be expected to affect olanzapine pharmacokinetics. Indeed, drugs that inhibit CYP1A2 activity have been shown to decrease olanzapine clearance, thereby increasing olanzapine plasma concentrations. Fluvoxamine, a known inhibitor of CYP1A2, has been shown to inhibit olanzapine metabolism in

several studies. A study of 10 healthy male smokers receiving 11 days of fluvoxamine administration (50–100 mg) resulted in an 84% increase in maximal olanzapine concentrations (Cmax) and a 119% increase in AUC0–24 compared with olanzapine administered with placebo. In this study, olanzapine clearance decreased 50%, and apparent volume of distribution decreased approximately 45%. The Cmax of olanzapine's metabolite 4'-N-desmethylolanzapine decreased 64%, and its AUC0–24 decreased 77%. No change in half-life was observed in either olanzapine or 4'-N-desmethylolanzapine, suggesting that fluvoxamine inhibited olanzapine's first-pass metabolism (Maenpaa et al. 1997). Another study found that in a population of patients receiving olanzapine, those also receiving fluvoxamine (n = 21) had, on average, a 2.3-fold higher concentration per dose ratio than did those not receiving fluvoxamine (n = 144) (Weigmann et al. 2001). A separate case report indicated that a patient who discontinued ciprofloxacin (also a CYP1A2 inhibitor) while receiving olanzapine experienced an approximately twofold decrease in olanzapine concentrations (Markowitz and DeVane 1999). Fluoxetine and imipramine, although not known to be significant inhibitors of CYP1A2, when coadministered with olanzapine have been associated with statistically significant but small changes in olanzapine pharmacokinetics. Coadministration of fluoxetine resulted in a 15% decrease in olanzapine clearance and an 18% increase in Cmax, with no significant difference in the half-life of olanzapine (Callaghan et al. 1999). Coadministration of imipramine resulted in an approximately 14% increase in olanzapine Cmax and a non–statistically significant increase in AUC of 19% (Callaghan et al. 1997). Inducers of the CYP1A2 enzyme increase olanzapine clearance, thereby decreasing olanzapine systemic exposure. Carbamazepine, an inducer of several CYP enzymes (including 1A2), affects olanzapine disposition. A study in healthy volunteers showed that 18 days of carbamazepine therapy (200 mg twice daily) resulted in significantly higher clearance (32.6 vs. 47.6 L/hour) and apparent volume of distribution (1,190 vs. 1,400 L/kg) but significantly lower Cmax (11.7 vs. 8.8 g/L), AUC (336 vs. 223 h* g/L), and half-life (26.0 vs. 20.8 hours) after a single 10-mg dose of olanzapine (Lucas et al. 1998). In one case report, the discontinuation of carbamazepine was associated with a 114% increase in olanzapine concentrations (Licht et al. 2000). Smoking, also known to induce CYP1A2, can affect olanzapine disposition. A study comparing 19 male smokers with 30 male nonsmokers found that olanzapine clearance in smokers was 23% higher than that in nonsmokers (Callaghan et al. 1999). A population pharmacokinetic analysis of 910 patients receiving olanzapine found that clearance among nonsmokers was 37% lower in men and 48% lower in women than it was in the corresponding group of smokers (Patel et al. 1996). A smaller analysis of healthy volunteers also found higher drug clearances among smokers (Patel et al. 1995). The polycyclic aromatic hydrocarbons in cigarette smoke are responsible for inducing the aryl hydrocarbon hydroxylases and thus lead to enzymatic induction (Desai et al. 2001). Thus, dosage adjustments might be needed when a patient who smokes is placed in a smoke-free inpatient unit, even if adequate nicotine replacement is provided. A recent study suggested that probenecid, a nonspecific inhibitor of uridine diphosphoglucuronateglucuronosyltransferase (UDPGT), can affect the disposition of a single 5-mg olanzapine dose. Following probenecid administration, a statistically significant increase of 19% occurred in olanzapine Cmax, an increase of 26% occurred in olanzapine AUC (P = 0.002), and an increase of 57% occurred in the absorption rate constant, indicating a faster rate of absorption. Clearance was not significantly altered by probenecid coadministration. Because probenecid may also inhibit the P-glycoprotein efflux transporter, this alternative mechanism may be contributing to this drug interaction (Markowitz et al. 2002). It is not known whether other UDPGT inhibitors also will affect olanzapine disposition, although in vitro testing with valproic acid did not show an interaction (Eli Lilly 2006). In vitro studies suggest that olanzapine does not significantly inhibit the activity of the CYP enzymes

1A2, 3A, 2D6, 2C9, or 2C19 (Ring et al. 1996a). In vivo studies suggest that olanzapine does not affect the disposition of aminophylline (Macias et al. 1998), diazepam, alcohol, imipramine (Callaghan et al. 1997), warfarin, biperiden, or lithium (Callaghan et al. 1999; Demolle et al. 1995).

CONCLUSION After review of the research focused on olanzapine, it is clear that this compound, which has been approved for use in the United States since 1997, has wide utility and is a step forward from the traditional antipsychotic medications. In addition to the positive effect on a broad group of symptoms of schizophrenia, olanzapine has now been approved for treatment of mania, both acute and long term, in bipolar disorder. Recent research has shown that there may be benefit to disorders beyond psychosis (e.g., borderline personality disorder, anorexia, PTSD, OCD, Tourette syndrome) with olanzapine. The extension of uses of olanzapine is in many ways allowed by the low rates of movement disorders. The lack of dystonia, parkinsonism, and tardive dyskinesia leads to greater acceptability in chronic schizophrenia and has encouraged clinicians and investigators to find patients earlier in the course of their illness, thus reducing the duration of untreated psychosis and perhaps decreasing the number of patients who develop psychosis (McGlashan et al. 2003). The low rate of movement disorders has been a major factor in moving forward with treatment of mood disorders and nonpsychotic illnesses. As noted in the section on side effects, olanzapine is not free of adverse effects, even though they are outside the movement disorder arena. Weight gain and metabolic disturbances are of significant concern and are the objects of intense research—in areas of both pathophysiology and prevention/treatment. In addition to providing better treatment for schizophrenia and other disorders, olanzapine's actions in the brain have provided new avenues of research in the exploration of pathophysiology of psychiatric disease. As noted earlier in this chapter, olanzapine's effects on glutamate measures and neurotensin may open new avenues of treatment. In conclusion, olanzapine is a psychotropic medication that was first approved for the treatment of psychosis related to schizophrenia. It has become a widely used medication for schizophrenia as well as other disorders. As noted, metabolic side effects are of concern and are the object of intense research. The future holds significant interest for understanding side effects, learning more about the effect of olanzapine on different syndromes, and gaining knowledge about the pathophysiology of psychiatric disease.

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Peter F. Buckley, Adriana E. Foster: Chapter 30. Quetiapine, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.430073. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 30. Quetiapine HISTORY AND DISCOVERY Quetiapine is a second-generation antipsychotic (SGA) developed and subsequently marketed by AstraZeneca. In preclinical trials, quetiapine showed both the features associated with antipsychotic efficacy and a low rate of motor effects (Goldstein 1999; Nemeroff et al. 2002). The Phase III placebo-controlled clinical trials necessary for product registration confirmed this preclinical impression and demonstrated that quetiapine was efficacious in treating the manifestations of psychosis (Arvanitis and Miller 1997; Small et al. 1997). Of note, these studies also reported a low rate of treatment-emergent extrapyramidal side effects (EPS) with quetiapine use across a wide range of dosages that was comparable to the rate among placebo recipients. Quetiapine was approved in 1997 by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia. Approval for use in Europe and in other countries worldwide has followed. Further clinical trials in patients with mania (McIntyre et al. 2005; Vieta et al. 2005) and patients with bipolar depression (Calabrese et al. 2005; Thase et al. 2006) led the FDA to approve additional indications for quetiapine's use in the acute and maintenance treatment of bipolar disorder. Most recently, the FDA has also approved a slow-release formulation of quetiapine for the treatment of schizophrenia (Kahn et al. 2007; Möller et al. 2007; Peuskens et al. 2007). Quetiapine is an established antipsychotic with broad efficacy and good tolerability, particularly with respect to EPS (Miodownik and Lerner 2006).

STRUCTURE–ACTIVITY RELATIONS Quetiapine is an SGA of the dibenzothiazepine class. It has a complex neuropharmacology, with binding at brain receptors of several classes (Goldstein 1999). Its binding profile, in comparison with that of several other antipsychotics, is shown in Table 30–1. Of considerable interest is the fact that quetiapine has a relatively low binding profile for dopamine type 2 (D2) receptors (Kapur et al. 2000a, 2000b; Kufferle et al. 1997; Seeman and Tallerico 1998; Stephenson et al. 2000). Indeed, considering the idea that an antipsychotic needs to occupy 60% or more of D2 receptors in order to be clinically efficacious (Kapur et al. 2000b), quetiapine's low D2 binding—typically approximately 30%—is noteworthy. TABLE 30–1. Comparative receptor binding profile of quetiapinea Quetiapinea Ziprasidonea Risperidonea Olanzapinea Clozapinea Aripiprazoleb D2

+

+++

+++

++

+

+++b

5-HT2A

+

++++

++++

+++

+++

+++

5-HT2C

–

++++

+++

+++

++

++

5-HT1A

+

+++b

+

–

+

+++b

5-HT1Dc

–

+++

+

+

–

–

++

++

+++

++

+++

++

++

–

–

+++

+++

–

1 -adrenergic

M1

Quetiapinea Ziprasidonea Risperidonea Olanzapinea Clozapinea Aripiprazoleb H1

+++

++

++

+++

+++

++

5-HT

–

++

–

–

–

++

NE

+

++

–

–

+

—

5-HT/NE reuptaked

Note. ++++ = Very high affinity; +++ = high affinity; ++ = moderate affinity; + = low affinity; – = negligible affinity; D2 = dopamine type 2 receptors; H1 = histaminergic type 1 receptors; 5-HT = 5-hydroxytryptamine (serotonin); 5-HT2A = serotonin type 2A receptors; M1 = muscarinic type 1 receptors; NE = norepinephrine. a

All information from human studies unless noted otherwise.

b

Partial agonist.

c

Bovine binding affinity.

d

In rat synaptosomes.

Source. Schmidt AW, Lebel LA, Howard HR Jr, et al: "Ziprasidone: A Novel Antipsychotic Agent With a Unique Human Receptor Binding Profile." European Journal of Pharmacology 425:197–201, 2001. Otsuka Pharmaceutical Co: Abilify (aripiprazole) full prescribing information. August 2008. In attempting to reconcile this apparently subtherapeutic D2 receptor antagonism with the well-recorded efficacy of quetiapine as an antipsychotic, Kapur and colleagues proposed an elegant kiss and run hypothesis for quetiapine's mechanisms of action (Kapur et al. 2000a). In a series of studies, they found that when D2 receptor occupancy with quetiapine was measured with positron emission tomography (PET) at shorter intervals (4 hours and 6 hours) than the conventional 12 hours after the last dose was taken, quetiapine did indeed show high D2 occupancy. They found that in contrast to other antipsychotics, quetiapine had a more rapid "run-off" from D2 receptors; that is, there was rapid dissociation of the D2 receptors (Kapur et al. 2000a). This was proposed to account for the discrepancy between observations of clinical potency and pharmacodynamic subthreshold receptor binding. This kiss-and-run theory is also put forward to explain the consistent observation of low rates of EPS and lack of increased prolactin levels during treatment with quetiapine (Nemeroff et al. 2002). Quetiapine also, like clozapine, has strong binding at 5-hydroxytryptamine (serotonin) type 2 receptors (5-HT2 receptors). This profile contrasts with its relatively weak affinity for other subclasses of the serotonin receptor family (Goldstein 1999). Quetiapine also has strong affinity for 1-noradrenergic

receptors. This antagonism may relate to its propensity to induce postural

hypotension—especially during rapid dose titration. Additionally, quetiapine has strong antagonism at histamine type 1 (H1) receptors. This most likely relates to its sedative effect. Weight gain during quetiapine therapy may also emanate from H1 receptor antagonism. However, this structure–activity relationship is less clear than the association between H1 antagonism and sedation. Relatively less is known about quetiapine's effects on other aspects of neurochemistry that are thought to be of relevance (but not central) to antipsychotic activity. Some studies have shown that SGAs can induce brain cell proliferation (neurogenesis) in experimental animals (Lieberman et al. 2006). The evidence for quetiapine in this regard is sparse. Also, little is known about the effect of quetiapine on brain neurotrophins. One study (Xu et al. 2002) reported that quetiapine could reverse reductions in levels of brain-derived neurotrophic factor in an animal model. There is accumulating evidence that other SGAs may also increase brain neurotrophins (Buckley et al. 2007).

PHARMACOKINETICS AND DISPOSITION Quetiapine is absorbed in the gastrointestinal tract, and its absorption is unaffected by food. Peak blood levels are achieved in about 2 hours, and effective plasma levels are sustained for

approximately 6 hours (DeVane and Nemeroff 2001). This provides the basis for the usual clinical regimen of twice-daily dosing. However, Chengappa et al. (2003b) conducted a short-term trial comparing once-daily dosing versus twice-daily dosing in patients with schizophrenia or schizoaffective disorder. The dosing profiles were equivalent in terms of efficacy and tolerability. Using PET, Mamo et al. (2008) found comparable plasma levels and D2 receptor occupancy between the immediate-release and the extended-release formulation. Quetiapine is metabolized by cytochrome P450 (CYP) 3A4 to inactive metabolites. Although genetic variations are not clearly described for the CYP3A4 enzyme, drug interactions with inhibitors and inducers of CYP3A4 are likely to be clinically significant. The anticonvulsants carbamazepine and phenytoin are common examples of CYP3A4 inducers, and in their presence quetiapine doses may need to be increased due to accelerated drug clearance (Potkin et al. 2002a, 2002b; Strakowski et al. 2002). Ritonavir, erythromycin, ketoconazole, and nefazodone are potent inhibitors of CYP3A4, and their use requires caution when they are coadministered with quetiapine; while they are used, doses of quetiapine should be lowered (de Leon et al. 2005; Wong et al. 2001). In 2007, the FDA approved an extended-release (XR) formulation of quetiapine for the treatment of schizophrenia on the basis of results from clinical trials (Kahn et al. 2007; Lindenmayer et al. 2008). These studies compared the efficacy and tolerability of XR and regular immediate-release (IR) formulations. Overall, the results of these studies indicate that quetiapine XR given once daily (at dosages of 400–800 mg/day) is effective for the treatment of schizophrenia. The XR formulation appears to have efficacy comparable to that of the IR formulation. The XR formulation was also similar in tolerability to the IR formulation in clinical trials, with perhaps some marginal benefit in causing less sedation. Quetiapine is excreted in the kidneys and is not affected by gender or smoking status (Thyrum et al. 2000). The metabolism of quetiapine is reduced by approximately 30% with advancing age (Goldstein 1999).

INDICATIONS AND EFFICACY Quetiapine currently has the following FDA-approved indications: Schizophrenia Bipolar disorder There are also reports of quetiapine's efficacy in treating other conditions, such as mood disorders in children and anxiety disorders, obsessive-compulsive disorder (OCD), and Parkinson's disease in adults. These uses have not been approved by the FDA. As a result of its use in the FDA indications and also in several unapproved circumstances, quetiapine is the most frequently prescribed antipsychotic in the United States at the time of writing. In this section of the chapter, we describe results of pivotal and recent studies of quetiapine for its FDA-approved indications. For completeness's sake and in recognition of quetiapine's use in nonapproved conditions, we also provide an account of some studies of subjects with other conditions. The use of any medication (in this case quetiapine) in situations that are not FDA-approved indications is not recommended for clinical practice.

Schizophrenia The pivotal product registration trials and early trials of quetiapine (Arvanitis and Miller 1997; Borison et al. 1996; Copolov et al. 2000; King et al. 1998; Peuskens and Link 1997; Small et al. 1997) demonstrated that quetiapine is an efficacious antipsychotic for the treatment of schizophrenia. In the United States, short-term (6-week) trials compared quetiapine and placebo using quetiapine dosages of either 250 mg/day or 750 mg/day (Small et al. 1997) or daily dosages of 75 mg, 150 mg, 300 mg, or 750 mg (Arvanitis and Miller 1997); the latter trial also compared quetiapine and haloperidol. Similar to registration trials of other antipsychotics, these studies established a range of effective dosages for quetiapine. However, they provided no clear evidence of a dose-dependent increase in

efficacy (although post hoc analyses have suggested that higher doses of quetiapine are more efficacious). Additionally, because of the wide range of dosages used in these studies, the initial dosing recommendations for quetiapine in schizophrenia patients were unclear and were further complicated by a slow titration pattern. As a result, clinicians tended to favor the lower end of the quetiapine dosing range. Subsequent studies helped refine quetiapine dosing strategies. Clinicians are also now using higher doses of quetiapine that are, on average, more consistent with those used in recent studies. Emsley et al. (2000) conducted a fixed-dose comparison trial of quetiapine at 600 mg/day versus haloperidol at 20 mg/day. The drugs had similar efficacy in this 8-week trial of patients who were a priori deemed "partial responders." More recent studies have shown that the titration of quetiapine can be quicker than heretofore considered. Pae et al. (2007) compared a rapid titration strategy (beginning at 200 mg/day, increasing to 800 mg/day by day 4) with a more conventional dosing strategy (50 mg/day on day 1, up to 400 mg/day by day 5). The two groups fared equally well in terms of tolerability during this 14-day study. The higher-dose, more rapid titration strategy had a marginal advantage in overall efficacy. Information on the use of high dosages (>800 mg/day) of quetiapine is very limited. Pierre et al. (2005) reported on quetiapine's efficacy in a sample of treatment-refractory schizophrenic patients at dosages of up to 1,200 mg/day. More fixed-dose comparison studies with quetiapine are needed to assist clinicians in further refining their dosing strategies with this agent. Although two meta-analyses cast doubt on quetiapine's efficacy with respect to first-generation antipsychotics (FGAs; Davis et al. 2003; Geddes et al. 2000), most studies comparing quetiapine with haloperidol or chlorpromazine report that the agents have similar efficacy in treating schizophrenia (Emsley et al. 2000; Peuskens and Link 1997; Small et al. 1997). Given that today most clinicians in the United States select one of the SGAs, comparisons between quetiapine and other SGAs are perhaps more meaningful. Several studies have been published that inform this consideration. A 4-month open-label trial of quetiapine and risperidone in a heterogeneous patient population —although predominantly subjects with schizophrenia and related psychotic disorders—showed overall comparability between the two agents (Mullen et al. 2001). Zhong et al. (2006) reported on an 8-week comparative trial of quetiapine and risperidone in a chronic schizophrenia patient population. The average quetiapine dosage was 525 mg/day and the average risperidone dosage was 5.2 mg/day. The drugs proved similar in efficacy. Quetiapine-treated patients had fewer EPS, lower prolactin levels, and fewer sexual side effects. Weight gain was similar in both treatment groups. Quetiapine was more sedating and was more frequently associated with dry mouth than was risperidone. Another study comparing quetiapine and risperidone, a 6-month study, reported better efficacy with risperidone (Potkin et al. 2006). Quetiapine was associated with more polypharmacy in that study. Kinon et al. (2006) reported on a 6-month double-blind comparative trial of quetiapine and olanzapine. Quetiapine-treated patients were less likely to complete the study. Relapse rates were comparable overall in the two treatment groups. More weight gain occurred in olanzapine recipients. As yet, no studies have directly compared quetiapine with either ziprasidone or aripiprazole in the treatment of schizophrenia. The most extensive comparative evaluation of quetiapine and other SGAs comes from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia studies. In the phase 1 study, in which the effectiveness of several antipsychotics was examined over 18 months, more quetiapinetreated patients than olanzapine-treated patients had discontinued treatment by 18 months (78% vs. 64%), and a similar (not statistically significant) trend was seen in comparisons of quetiapine versus risperidone, ziprasidone, or perphenazine (Lieberman et al. 2005). In the phase 2 study of efficacy pathways for patients with persistent symptoms, discontinuation rates favored clozapine and olanzapine over risperidone and quetiapine (McEvoy et al. 2006). The results from the tolerability pathways were more mixed, with similar efficacy observed between quetiapine and other agents (Stroup et al. 2007). The findings relating to quetiapine's relative adverse-effects profile in this

formative study are presented later in this chapter (see "Side Effects and Toxicology"). Another interesting analysis from the CATIE schizophrenia studies (Stroup et al. 2007) examined how those patients originally assigned to the perphenazine arm of the phase 1 study fared. In this analysis, switching to quetiapine was more efficacious than switching to any of the other agents. Much of the efficacy and tolerability differences among agents observed in the CATIE schizophrenia studies have been attributed to differential dosing profiles. An analogous comparative trial of quetiapine, risperidone, and olanzapine was conducted with patients experiencing their first episode of psychosis—the Comparison of Atypicals in First Episode Psychosis (CAFÉ) study. Here, discontinuation rates were similar with all three drugs over the course of the 1-year trial (McEvoy et al. 2007). The comparative dosing profiles for quetiapine, risperidone, and olanzapine in the CAFÉ study and the CATIE schizophrenia study, referenced against the FDA-approved dosages, are shown in Table 30–2. TABLE 30–2. Antipsychotic dosages used in CATIE and CAFÉ studies versus FDA-approved dosages: quetiapine, olanzapine, and risperidone CATIE (chronic) mean modal CAFÉ (first episode) mean

FDA-approved dosage

dosage (mg/day)

modal dosage (mg/day)

range (mg/day)

20.1

11.7

5–20

Risperidone 3.9

2.4

1–16

Quetiapine

506.0

25–800

Olanzapine

543.4

Higher dosages may be required to achieve efficacy in chronic versus first-episode schizophrenia. Note. CAFÉ = Comparison of Atypicals in First Episode Psychosis; CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness; FDA = U.S. Food and Drug Administration. Source. Data derived from McEvoy et al. 2007 (CAFÉ) and Lieberman et al. 2005 (CATIE). The use of quetiapine in patients with prodromal features of schizophrenia has not yet been studied. Little is known about quetiapine's efficacy in treatment-refractory patients. In a subanalysis of more severely ill patients in an 8-week comparative trial of quetiapine and haloperidol, quetiapine showed a small benefit over haloperidol (Buckley et al. 2004). The open-label observational study by Pierre et al. (2005) also showed some benefit for quetiapine at high doses in treatment-refractory patients. Sacchetti et al. (2004) reported a 50% response rate in a small sample of patients who had been refractory to prior treatment with FGAs. Information on the long-term efficacy of quetiapine is limited. Open-label follow-up in extension studies for up to 4 years has shown sustained efficacy, with the average dosage of quetiapine recorded at 450 mg/day (Buckley et al. 2004). A recently conducted 6-month placebo-controlled study of quetiapine (the new XR formulation) in schizophrenia patients showed a clinically beneficial effect on relapse prevention (Peuskens et al. 2007). Several studies have demonstrated improvements in cognitive performance during quetiapine therapy in patients with schizophrenia (Sax et al. 1998; Velligan et al. 2002, 2003).

Mood Disorders There is evidence that quetiapine is an effective and well-tolerated antipsychotic for treating patients with bipolar mania and bipolar depression. Initial evidence for mood effects were derived from observations on mood assessment items in the pivotal schizophrenia trials. In one of the pivotal product registration trials evaluating quetiapine (Small et al. 1997), both high and low doses of quetiapine were significantly better than placebo in improving Brief Psychiatric Rating Scale (BPRS) measures of mood disturbance in patients with schizophrenia (Goldstein 1999). In an analysis of another pivotal trial comparing five dosages of quetiapine in patients with schizophrenia (Arvanitis

and Miller 1997), patients receiving 150 mg/day showed significant improvement in BPRS-derived measures of mood. In the Quetiapine Experience with Safety and Tolerability (QUEST) study, quetiapine was compared with risperidone in a 4-month open-label, flexible-dose trial (Mullen et al. 2001). This study included patients with schizophrenia, schizoaffective disorder, bipolar disorder, and depression. At week 16 the mean dosage of quetiapine was 317 mg/day, and the mean dosage of risperidone was 4.5 mg/day. Mean improvement on the Hamilton Rating Scale for Depression was significantly greater in quetiapine recipients than in risperidone recipients. More recent studies have confirmed that quetiapine is efficacious for the acute treatment of mania and bipolar depression. In short-term placebo-controlled trials, quetiapine as a monotherapy reduced symptoms of mania. Quetiapine has also been assessed as an add-on agent with either lithium or valproic acid. Calabrese et al. (2005) and Thase et al. (2006) have studied quetiapine in patients with bipolar depression. In an 8-week trial, Calabrese et al. (2005) compared two dosages of quetiapine (300 mg/day and 600 mg/day) versus placebo. Both dosages were efficacious, with improvements observed across the full range of depressive and anxiety symptoms. Fifty-eight percent of patients met a priori criteria for treatment response. Additionally, this antidepressant effect was observed with a once-daily dosage regimen. In a subsequent similar study of the same two dosages (300 mg/day and 600 mg/day; Thase et al. 2006), quetiapine was again compared with placebo in an 8-week trial in patients with bipolar depression. Again, both dosages of quetiapine showed efficacy across a broad range of depressive symptoms. These two studies led to FDA approval of quetiapine for treating bipolar depression. Furthermore, Dorée et al. (2007) recently reported that in a pilot study (n = 20) quetiapine was an efficacious augmenting agent for major depression. There is also emerging information that quetiapine's metabolite may have mood-regulating effects (Goldstein et al. 2007).

Other Conditions and Patient Populations The two studies on bipolar depression cited above (Calabrese et al. 2005; Thase et al. 2006) also showed improvements in anxiety symptoms with quetiapine. Additionally, the sedative/calming effect of quetiapine is well described in a variety of product registration trials (Buckley et al. 2007; Chengappa et al. 2003a). Thus, there is interest in whether quetiapine may be helpful in treating anxiety states, and off-label use of quetiapine in patients with anxiety disorders has been reported. This is a complicated issue. A clinical trial of quetiapine to treat anxiety disorders is ongoing (www.clinicaltrials.gov). There is also published information from a small study showing that quetiapine reduces symptoms of both anxiety and posttraumatic stress disorder (Hamner et al. 2003). Information has also been published on the use of quetiapine as an augmenting agent with selective serotonin reuptake inhibitors in treating OCD (Dell'Osso et al. 2006; Denys et al. 2007). Dell'Osso et al. (2006) showed that quetiapine provided benefit in a small case series of patients with OCD. Denys et al. (2007) analyzed published augmentation studies in OCD patients and found that quetiapine augmentation was efficacious and, interestingly, was more efficacious in patients who were receiving lower doses of a selective serotonin reuptake inhibitor (SSRI) than in those receiving higher SSRI doses. Quetiapine appears to be an effective treatment for children with schizophrenia or bipolar disorder (Barzman et al. 2006; DelBello et al. 2007; McConville et al. 2000). DelBello et al. (2007) recently reported therapeutic effects of quetiapine in a cohort of children who showed subsyndromal symptoms and were at risk for bipolar disorder but who did not actually meet diagnostic threshold criteria for a bipolar diagnosis. Quetiapine is also used more broadly for treating agitation in children (Findling et al. 2007). Quetiapine has also been used in the elderly. McManus et al. (1999) reported baseline and 12-week data for 151 elderly patients (mean age, 76.8 years) who were treated in a 1-year open-label trial of quetiapine. Seventy percent of patients had some organic condition, predominantly Alzheimer's

disease, with the majority of remaining patients having a diagnosis of a functional psychosis such as schizophrenia, schizoaffective disorder, or delusional disorder. Fifty-two percent of all patients achieved a 20% or greater decline in BPRS total score. Quetiapine was well tolerated at a mean dosage of 100 mg/day. Zhong et al. (2007) reported a 10-week study comparing two dosages of quetiapine (100 mg/day and 200 mg/day) versus placebo in nursing home residents with dementia and agitation. Quetiapine at 100 mg/day was not efficacious, whereas quetiapine at 200 mg/day was efficacious for treating agitation. Quetiapine (100 mg/day) was also compared with risperidone (1.0 mg/day), olanzapine (5.5 mg/day), and placebo over 36 weeks in the CATIE Alzheimer's disease study (Schneider et al. 2006). This is the largest comparative study to date of the relative efficacy and tolerability of antipsychotics in elderly patients with Alzheimer's disease and related dementias. Overall, no effect was seen with any of the agents, and no differences were seen between the agents in terms of time to discontinuation of treatment for any reason. Several neuropsychiatric conditions, the most notable being Parkinson's disease, are associated with the emergence of transient or sometimes persistent psychotic symptoms (Juncos 1999). The management of Parkinson's disease is further complicated by hallucinations associated with levodopa therapy. Older antipsychotics were effective in relieving psychotic symptoms in these patients, but their use also aggravated the disease. Quetiapine may be a preferred treatment in patients with Parkinson's disease (Friedman 2003; Friedman et al. 1998; Juncos 1999; Targum and Abbott 2000). In a 24-week study of quetiapine in 29 patients with Parkinson's disease (mean age, 73 years), Juncos (1999) observed that treatment with quetiapine at a mean dosage of 62.5 mg/day improved psychosis without causing deterioration in motor function. Menza et al. (1999) reported similar results using quetiapine at dosages of 12.5–150 mg/day in three patients with Parkinson's disease whose medication was switched from clozapine to quetiapine. In another study, 25 patients with Parkinson's disease were switched from either clozapine or olanzapine to quetiapine; 17 (68%) of the patients were switched to quetiapine without a worsening of psychosis (Friedman et al. 1998). Targum and Abbott (2000) reported that quetiapine stopped visual hallucinations in 6 of 10 patients with Parkinson's disease, but delusions were less responsive to treatment. In a study by Merims et al. (2006), both clozapine and quetiapine showed efficacy in treating psychosis in Parkinson's disease patients. Clozapine was marginally more efficacious but was associated with a high adverse-effect burden. Agitation is a core aspect of several conditions. There is, of course, no FDA-approved drug for treating agitation, and use of antipsychotics for nonapproved clinical indications is strongly discouraged. Nevertheless, antipsychotics have been used to manage agitation in a variety of circumstances. Currier et al. (2006) reported an interesting study of quetiapine in agitated patients in the emergency room. Here, Currier and colleagues reported that quetiapine could be used as an acute antiagitation agent if the dose titration is judicious. Postural hypotension was observed in this study. Other studies of quetiapine and agitation reflect post hoc analyses of clinical trials and report benefits in treating hostility both in adults with schizophrenia (Chengappa et al. 2003a) or bipolar disorder (Buckley et al. 2007) and in children with conditions associated with disruptive, hostile behaviors (Barzman et al. 2006; Findling et al. 2007).

SIDE EFFECTS AND TOXICOLOGY To illustrate the profile of adverse effects that are typically seen with quetiapine, we have reproduced herein the results from a recent clinical trial of 8 weeks' duration (Zhong et al. 2006) in which schizophrenic patients received an average quetiapine dosage of 525 mg/day (Table 30–3). Overall, quetiapine was well tolerated in this study, and only 6% of patients discontinued treatment due to adverse effects. The most commonly recorded side effects of quetiapine treatment in this study were somnolence (26% of patients), headache (15%), weight gain (14%), dizziness (14%), and dry mouth (12%).

TABLE 30–3. Comparative side-effect profile of quetiapine versus risperidone: adverse effects present in 5% of patients in an 8-week study Quetiapine (n = 338; median dosage, Risperidone (n = 334; median dosage,

Adverse

525 mg/day)

= 5.2 mg/day)

n (%)

n (%)

P valuea

effect Somnolence

89 (26.3)

66 (19.7)

0.044

Headache

51 (15.1)

56 (16.7)

0.599

Weight gain

48 (14.2)

45 (13.4)

0.824

Dizziness

48 (14.2)

32 (9.6)

0.0737

Dry mouth

41 (12.1)

17 (5.1)

1,000

Note. SERT = serotonin reuptake site. Source. Adapted from McQuade RD, Burris KD, Jordan S, et al.: "Aripiprazole: A Dopamine–Serotonin System Stabilizer." International Journal of Neuropsychopharmacology 5 (Suppl 1): S176, 2002, with the following exceptions: a

Burris KD, Molski TF, Xu C, et al.: "Aripiprazole, A Novel Antipsychotic, Is a High Affinity Partial Agonist at Human

Dopamine D2 Receptors." Journal of Pharmacology and Experimental Therapeutics 302: 381–389, 2002. b

Jordan S, Koprivica V, Chen R, et al.: "The Antipsychotic Aripiprazole Is a Potent, Partial Agonist at the Human 5-HT1A

Receptor." European Journal of Pharmacology 441:137–140, 2002. c

"AbilifyTM (Aripiprazole) Tablets." Full Prescribing Information. Tokyo, Otsuka Pharmaceutical Co., Ltd., November

2006.

PHARMACOKINETICS AND DISPOSITION Aripiprazole is available for oral administration as tablets in strengths of 2, 5, 10, 15, 20, and 30 mg. The effective dose range is 10–30 mg/day for schizophrenia patients and 15–30 mg/day for bipolar I disorder patients. A rapidly disintegrating oral formulation of aripiprazole is available in 10-mg and 15-mg strengths. In addition, aripiprazole is available in a 1-mg/mL nonrefrigerated oral solution. Aripiprazole is taken once daily with or without food and is well absorbed after oral administration, with peak plasma concentrations occurring within 3–5 hours. Absolute oral bioavailability is 87%. An injectable form of aripiprazole for intramuscular (IM) use to provide rapid control of agitation in adults with schizophrenia or bipolar mania was approved by the U.S. Food and Drug Administration (FDA) in September 2006. Aripiprazole injection is available in single-dose, ready-to-use vials containing 9.75 mg aripiprazole in 1.3 mL of diluent (7.5 mg/mL); the recommended initial dose is 9.75 mg IM. Time to the peak plasma concentration is 1–3 hours after IM injection, and the absolute bioavailability of a 5-mg injection is 100%. The mean maximum concentration achieved after an IM dose is on average 19% higher than the maximum plasma concentration (Cmax) of the oral tablet. While the systemic exposure over 24 hours is generally similar for aripiprazole administered as an IM injection and as an oral tablet, the aripiprazole area under the curve (AUC) in the first 2 hours after an IM injection is 90% greater than the AUC after the same dose

in a tablet (Otsuka Pharmaceutical 2006). In plasma, aripiprazole and its major metabolite, dehydroaripiprazole, are both more than 99% bound to proteins, primarily albumin. Aripiprazole is extensively distributed outside the vascular system, and human studies demonstrating dose-dependent occupancy of D2 receptors have confirmed that aripiprazole penetrates the brain. Elimination half-lives for aripiprazole and dehydroaripiprazole are 75 hours and 94 hours, respectively. Aripiprazole is metabolized primarily in the liver. Two hepatic cytochrome P450 (CYP) enzymes, 2D6 and 3A4, catalyze dehydrogenation to dehydroaripiprazole. Therefore, coadministration with inducers or inhibitors of these CYP enzymes may require dosage adjustment of aripiprazole. The active metabolite accounts for 40% of drug exposure, but the predominant circulating moiety is the parent drug. Aripiprazole does not undergo direct glucuronidation and is not a substrate for the following CYP enzymes: 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2E1. Interactions with inhibitors or inducers of these enzymes, or with chemicals related to cigarette smoke, are therefore unlikely to occur. Patient demographic characteristics have not been shown to have any clinically significant impact on the pharmacokinetics of aripiprazole. In general, dosing does not need to be adjusted in respect of a patient's age, gender, race, smoking status, or hepatic or renal function. Following a single oral dose of 14C-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity were recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine, and approximately 18% of the oral dose was recovered unchanged in the feces.

MECHANISM OF ACTION Aripiprazole has partial agonist activity at D2 receptors, a feature that distinguishes it from all other currently available antipsychotics, which are full D2 antagonists. In vitro studies in D2 receptors in rat striatal membranes (A. Inoue et al. 1997) and rat anterior pituitary slices (T. Inoue et al. 1996) showed that aripiprazole acts as an antagonist when coadministered in the presence of a DA agonist. In other in vitro studies using cloned D2 receptors from either rat (Lawler et al. 1999) or human (Burris et al. 2002), aripiprazole dose-dependently inhibited isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) synthesis. In these studies, aripiprazole acted as an agonist in the absence of DA, although its maximal agonist activity was less than that of DA, a full agonist. The activity of aripiprazole at D2 receptors has also been studied in animal models of schizophrenia (Kikuchi et al. 1995). Aripiprazole exhibits DA antagonist activity in an animal model of hyperdopaminergic activity. In the intact rat with repetitive stereotyped behavior (stereotypy) induced by apomorphine, aripiprazole inhibits stereotypy and locomotion (Kikuchi et al. 1995). This agent may therefore be expected to inhibit hyperdopaminergic activity in the mesolimbic pathway of patients with schizophrenia and so, like other available agents, provide antipsychotic efficacy against the positive symptoms of schizophrenia. On the other hand, in animal models of hypodopaminergic activity, such as the reserpinized rat, aripiprazole has D2 receptor agonist activity. Because aripiprazole may display either D2 antagonist activity under hyperdopaminergic conditions or D2 agonist activity under hypodopaminergic conditions, this agent may be less likely than other antipsychotics to cause excessive D2 antagonism. Aripiprazole may offer further therapeutic benefits through modulation of central serotonergic pathways. Preclinical studies showed that aripiprazole has antagonist activity at 5-HT2A receptors (McQuade et al. 2002), a feature that has been associated with reductions in EPS (Meltzer 1999) and negative symptoms. In vitro studies also have shown that aripiprazole has partial agonist activity at 5-HT1A receptors (Jordan et al. 2002), a feature that has been associated with improvement in negative, cognitive, depressive, and anxiety symptoms (Millan 2000). Other receptor activity may explain some of the side effects of aripiprazole; for example, nausea/vomiting may be explained by its DA agonist effects, whereas orthostatic hypotension and mild sedation/weight gain are likely related to its antagonist activity at 1-adrenergic and H1 receptors, respectively.

INDICATIONS AND EFFICACY

In the United States, aripiprazole is approved by the FDA for: acute and maintenance treatment of schizophrenia in adults and in adolescents 13–17 years of age; for acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic features in adults and pediatric patients 10–17 years of age; as adjunctive therapy to either lithium or valproate for the acute treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic features in adults and pediatric patients 10–17 years of age; and as an adjunctive therapy to antidepressants for the acute treatment of major depressive disorder in adults. Additionally, aripiprazole injection is indicated for the acute treatment of agitation associated with schizophrenia or bipolar disorder (manic or mixed) in adults (Abilify [aripiprazole] U.S. Full Prescribing Information). The efficacy of aripiprazole as a treatment for acute relapse of schizophrenia was demonstrated in four short-term (4-week) double-blind, placebo-controlled studies. Among these was a pivotal Phase III parallel-group multicenter study with four treatment arms comparing aripiprazole (15 mg or 30 mg) with placebo (Kane et al. 2002). Haloperidol (10 mg/day) was used as an active control to confirm the study population's responsiveness to antipsychotic therapy. The total group of patients who were randomized to treatment (N = 414) comprised 282 patients with schizophrenia and 132 with schizoaffective disorder. Compared with placebo, aripiprazole at either dose produced statistically significant improvements from baseline in the following psychometric scores: Positive and Negative Syndrome Scale (PANSS)—Total, PANSS positive subscale, PANSS-derived Brief Psychiatric Rating Scale (BPRS)—Core, Clinical Global Impression (CGI)–Severity of Illness, and CGI–Improvement. Aripiprazole 15 mg also significantly improved PANSS negative score compared with placebo. Both doses of aripiprazole produced measurable improvement rapidly, with improvement from placebo detectable on psychometric scales by week 2. This trial suggests that at doses of 15 mg and 30 mg, aripiprazole provides effective symptom control in patients with acute relapse of schizophrenia. Similar findings emerged from another pivotal short-term multicenter Phase III study involving 404 inpatients with an acute relapse of schizophrenia or schizoaffective disorder (Potkin et al. 2003). Patients were randomly assigned to aripiprazole 20 mg, aripiprazole 30 mg, risperidone 6 mg, or placebo for 4 weeks. Compared with placebo, aripiprazole at both doses and risperidone treatment produced statistically significant improvements in scores on standard scales designed to measure antipsychotic efficacy. Likewise, responder rates (with response defined as a score of 1 or 2 on the CGI–Improvement) for both doses of aripiprazole and for risperidone were significantly higher than those for placebo. This study showed that aripiprazole at doses of 20 mg and 30 mg was significantly more effective than placebo. The antipsychotic efficacy of aripiprazole in acute relapse of schizophrenia was also demonstrated in two Phase II dose-ranging studies, both of which used haloperidol as an active control. In one study, 307 patients with an acute relapse of schizophrenia were randomized to aripiprazole 2 mg, 10 mg, or 30 mg daily or haloperidol 10 mg/day (Daniel et al. 2000). All three doses of aripiprazole produced improvements in efficacy measures from baseline, and the 30-mg dose produced statistically significant improvement compared with placebo on all illness scores, including CGI–Severity, BPRS–Total, BPRS–Core, PANSS–Total, and PANSS positive and negative subscales. Similarly, in a Phase II dose-titrating study, aripiprazole 5–30 mg was superior to placebo in improving BPRS–Total, BPRS–Core, CGI–Severity, and PANSS–Total scores (Petrie et al. 1997). Results from the three 4-week fixed-dose studies discussed above were pooled for analysis with those of an additional 6-week placebo-controlled, fixed-dose study of aripiprazole at doses of 10 mg, 15 mg, and 20 mg (Lieberman et al. 2002). The pooled analysis involving 898 patients randomized to aripiprazole showed that at all investigated doses greater than 2 mg, aripiprazole exhibited antipsychotic efficacy superior to placebo. Onset of efficacy was rapid, with improvement on psychometric scores detectable within 1 week of starting treatment. These pooled efficacy results demonstrate that doses of 10–30 mg represent an effective therapeutic range for aripiprazole treatment. The antipsychotic efficacy of aripiprazole in patients with schizophrenia has been further confirmed in two long-term double-blind, randomized, controlled multicenter trials. A 26-week placebo-controlled study in

310 patients with chronic stable schizophrenia investigated the efficacy of aripiprazole 15 mg in relapse prevention (Pigott et al. 2003). Patients who had been symptomatically stable on other antipsychotic medications for 3 months or longer were taken off these medications and randomly assigned to aripiprazole 15 mg or placebo for up to 26 weeks and observed for relapse (defined as a score of 5 [minimally worse] on the CGI–Improvement, a score of 5 [moderately severe] on the hostility or uncooperativeness items of the PANSS, or a 20% increase in the PANSS–Total score). Aripiprazole treatment significantly increased the time to relapse and resulted in significantly fewer relapses at endpoint compared with placebo (34% vs. 57%). From week 6 of therapy, PANSS–Total and PANSS positive subscale scores were significantly more improved with aripiprazole than with placebo. Another study evaluated the long-term efficacy of aripiprazole when treatment was maintained for up to 52 weeks (Kasper et al. 2003). Patients with acute relapse of schizophrenia (N = 1,294) were randomized to aripiprazole 30 mg/day (n = 861) or haloperidol 10 mg/day (n = 433). Significantly more aripiprazoletreated patients were still taking the medication and were responding to treatment at weeks 8, 26, and 52 than were haloperidol-treated patients. Both treatments produced sustained improvements in the PANSS–Total and PANSS positive subscale scores from baseline. However, aripiprazole produced significantly greater improvements in negative and depressive symptoms at weeks 26 and 52 and was associated with significantly lower scores on all EPS assessments compared with haloperidol. The efficacy of aripiprazole monotherapy in antipsychotic-resistant schizophrenia was evaluated in a 6-week double-blind, randomized trial in 300 patients who had failed to improve in a prospective 4- to 6-week open trial with olanzapine or risperidone (Kane et al. 2007). Subjects were randomly assigned to aripiprazole (15–30 mg/day) or perphenazine (8–64 mg/day). After 6 weeks, there was no statistical difference between the two groups on efficacy measures; 27% of aripiprazole-treated patients and 25% of perphenazine-treated patients were classified as responders (30% improvement from baseline or CGI–Improvement score of 1 or 2). Compared with aripiprazole, perphenazine was associated with a higher rate of EPS and elevated serum prolactin. The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (ages 13–17 years) was evaluated in a 6-week placebo-controlled trial of outpatients who met DSM-IV (American Psychiatric Association 1994) criteria for schizophrenia and had a PANSS score ≥70 at baseline (Findling et al. 2008). In this trial comparing two fixed doses of aripiprazole (10 mg/day or 30 mg/day) with placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Of 302 patients, 85% completed the 6-week study. Both aripiprazole doses showed statistically significant differences from placebo in reduction in PANSS–Total score; the 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. Adverse events occurring in more than 5% of either aripiprazole group and with a combined incidence at least twice the rate for placebo were extrapyramidal disorder, somnolence, and tremor. Mean body weight changes were –0.8, 0.0, and 0.2 kg for placebo, aripiprazole 10 mg, and aripiprazole 30 mg, respectively The efficacy of aripiprazole in the treatment of acute manic episodes was established in two 3-week placebo-controlled trials in hospitalized patients who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes (Keck et al. 2003; Sachs et al. 2006). These trials included patients with and without psychotic features and with and without a rapid-cycling course. The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology. A key secondary instrument included the Clinical Global Impression–Bipolar (CGI-BP) scale. In both trials (n = 268; n = 248), aripiprazole was started at 30 mg/day, but the dosage could be reduced to 15 mg/day on the basis of efficacy and tolerability. Aripiprazole was superior to placebo in the reduction of YMRS total score and CGI-BP Severity of Illness score (mania). In a third large randomized, double-blind trial involving 347 patients (Vieta et al. 2005), aripiprazole was compared with haloperidol in the treatment of acute bipolar mania over a 12-week period. Significantly more patients remained in treatment and were classified as responders (50% reduction in YMRS score from baseline) at week 12 for aripiprazole (49.7%) than for haloperidol (28.4%). EPS adverse events were more frequent with haloperidol than with aripiprazole (62.7% vs.

24.0%). The efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6-week placebo-controlled study (N = 384) with a 2-week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This study included patients with manic or mixed episodes and with or without psychotic features. Patients were initiated on open-label lithium or valproate at therapeutic serum levels and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response to lithium or valproate (YMRS total score 16 and

25% improvement on the YMRS total score) were randomized to receive either

aripiprazole (15 mg/day with an increase to 30 mg/day as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate. In the 6-week placebo-controlled phase, adjunctive aripiprazole starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0.6–1.0 mEq/L or 50–125 g/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the YMRS total score and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at the 6-week endpoint. Aripiprazole monotherapy was also evaluated in the treatment of nonpsychotic depressive episodes associated with bipolar I disorder. The results of two identically designed 8-week randomized, doubleblind, placebo-controlled multicenter studies were reported by Thase et al. (2008). Patients were randomly assigned to placebo or aripiprazole (initiated at 10 mg/day, then flexibly dosed at 5–30 mg/day based on clinical effect and tolerability). The primary endpoint was mean change from baseline to week 8 (last observation carried forward [LOCF]) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Although statistically significant differences were observed during weeks 1–6, aripiprazole did not achieve statistical significance versus placebo at week 8 in either study in the change in MADRS total score (primary endpoint). In addition, despite early statistical separation on the Clinical Global Impressions Bipolar Version Severity of Illness–Depression score (key secondary endpoint), aripiprazole was not superior to placebo at endpoint. Aripiprazole was associated with a higher incidence of akathisia, insomnia, nausea, fatigue, restlessness, and dry mouth versus placebo. More patients discontinued with aripiprazole versus placebo in both studies. Thus, aripiprazole monotherapy as dosed in this study design was not significantly more effective than placebo in the treatment of bipolar depression at endpoint (Thase et al. 2008). To evaluate the long-term effectiveness of aripiprazole in delaying relapse in bipolar I disorder patients, a trial was conducted in patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label aripiprazole and who had maintained a clinical response for at least 6 weeks (Keck et al. 2006). The first phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized (YMRS score 10 and MADRS score 13) and then maintained on open-label aripiprazole (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one outpatients were then randomized in a double-blind fashion to either the same dose of aripiprazole they were on at the end of the stabilization and maintenance period or a switch to placebo and were then monitored for manic or depressive relapse. During the randomization phase, aripiprazole was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study. The majority of these relapses were due to manic rather than depressive symptoms. Aripiprazole-treated patients had significantly fewer relapses than placebo-treated patients (25% vs. 43%). Aripiprazole was superior to placebo in delaying the time to manic relapse but did not differ from placebo in delaying time to depressive relapse. Significant weight gain (7% increase from baseline) was seen in 13% of the aripiprazole patients and none of the placebo patients. An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess intergroup differences. The efficacy of aripiprazole in the treatment of bipolar I disorder in pediatric patients (ages 10–17 years)

was evaluated in a 4-week placebo-controlled trial of outpatients (N = 296) who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a YMRS score 20 at baseline. This double-blind, placebo-controlled trial compared two fixed doses of aripiprazole (10 mg/day or 30 mg/day) against placebo. The aripiprazole dose was started at 2 mg/day, which was increased to 5 mg/day after 2 days and to the target dose in 5 days in the 10 mg/day treatment arm and in 13 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in change from baseline to week 4 on the YMRS total score. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients (Abilify [aripiprazole] U.S. Full Prescribing Information). Aripiprazole is also available in an injectable formulation for IM administration. The efficacy of aripiprazole injection in controlling acute agitation was evaluated in three short-term (24-hour) randomized, doubleblind, placebo-controlled studies in patients with schizophrenia (Andrezina et al. 2006; Tran-Johnson et al. 2007) and patients with bipolar disorder (manic or mixed) (Zimbroff et al. 2007), involving a total of 1,086 patients. The effectiveness of aripiprazole injection in controlling agitation was measured in these studies using several instruments, including the PANSS Excited Component (PANSS EC) and CGI–I scale. The primary efficacy measure used for assessing signs and symptoms of agitation was the change from baseline in the PANSS EC at 2 hours' postinjection. PANSS EC includes five items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Aripiprazole injection was statistically superior to placebo (P 0.05) in all three studies, as measured with the PANSS EC. In the two studies in agitated patients with schizophrenia, injectable aripiprazole and IM haloperidol were compared with placebo. The injectable formulations of aripiprazole and haloperidol were both superior to placebo. In the study in agitated bipolar I disorder (manic or mixed) patients, aripiprazole injection and lorazepam injection were compared with placebo. Both active agents were superior to placebo. FDA-approved dosage preparations are as follows: 5.25 mg/0.7 mL, 9.75 mg/1.3 mL, and 15 mg/2.0 mL. The recommended initial dose of aripiprazole injection is 9.75 mg. De Deyn et al. (2005) compared the efficacy, safety, and tolerability of aripiprazole against placebo in patients with psychosis associated with Alzheimer's disease (AD). This 10-week double-blind multicenter study randomized 208 outpatients (mean age = 81.5 years) with AD-associated psychosis to aripiprazole (n = 106) or placebo (n = 102). The initial aripiprazole dose of 2 mg/day was titrated upward (5, 10, or 15 mg/day) according to efficacy and tolerability. Evaluations included the Neuropsychiatric Inventory (NPI) Psychosis subscale and the BPRS, adverse event (AE) reports, EPS rating scales, and body weight measurement. Overall, 172 patients (83%) completed the study. The mean aripiprazole dose at study endpoint was 10.0 mg/day. The NPI Psychosis subscale score showed improvements in both groups (aripiprazole, –6.55; placebo, –5.52; P = 0.17 at endpoint). Aripiprazole-treated patients showed significantly greater improvements from baseline in BPRS Psychosis and BPRS–Core subscale scores at endpoint compared with placebo-treated patients. Somnolence was mild and was not associated with falls or accidental injury. There were no significant differences from placebo in EPS scores or in clinically significant electrocardiogram abnormalities, vital signs, or weight. In another double-blind, multicenter study (Mintzer et al. 2007), 487 institutionalized patients with psychosis associated with AD were randomized to placebo or aripiprazole, 2, 5 or 10 mg/day. Primary efficacy assessment was the mean change from baseline to week 10 on the Neuropsychiatric Inventory– Nursing Home (NPI-NH) version Psychosis Subscale score. Aripiprazole 10 mg/day showed significantly greater improvements than placebo on the NPI-NH Psychosis Subscale (–6.87 vs. –5.13; P = 0.013) by analysis of covariance; CGI-S (–0.72 vs. –0.46; P = 0.031); BPRS Total (–7.12 vs. –4.17; P = 0.030); and NPI-NH Psychosis response rate (65% vs. 50%; P = 0.019). Aripiprazole 5 mg/day showed significant improvements versus placebo on BPRS and Cohen-Mansfield Agitation Inventory (CMAI) scores. Aripiprazole 2 mg/day was not efficacious. Four cases of cerebrovascular adverse events were reported in the aripiprazole 10 mg/day group, two in the 5-mg group, and one in the 2-mg group. No cerebrovascular adverse events were reported in the placebo group.

In 2005, the FDA issued a black box warning for second-generation antipsychotics based on increased mortality rates (4.5% vs. 2.6%) observed in patients with dementia-related psychosis treated with second-generation antipsychotics as compared with placebo over a modal duration treatment period of 10 weeks. This warning was extended in June 2008 to include all older conventional antipsychotic agents. No antipsychotic is currently approved in the United States for treating the behavioral and psychotic symptoms that frequently accompany dementia. Nickel et al. (2006) conducted a double-blind, placebo-controlled study in 52 subjects (43 women and 9 men) meeting criteria for borderline personality disorder who were randomly assigned in a 1:1 ratio to 15 mg/day of aripiprazole (n = 26) or placebo (n = 26) for 8 weeks. Significant changes in scores on most scales of the Symptom Checklist (SCL-90-R), on the Hamilton Rating Scale for Depression (Ham-D), on the Hamilton Anxiety Scale (Ham-A), and on all scales of the State-Trait Anger Expression Inventory were observed in subjects treated with aripiprazole after 8 weeks. The improvements noted at 8 weeks of therapy were maintained at 18-month follow-up (Nickel et al. 2007). Because of aripiprazole's partial DA agonist activity, there has been substantial interest in evaluating the utility of aripiprazole in reducing cravings and drug use in cocaine-, alcohol-, and amphetamine-abusing patients and as an augmentation strategy in patients with treatment-resistant depression. Tiihonen et al. (2007) conducted a study in individuals meeting DSM-IV criteria for intravenous amphetamine dependence (N = 53) who were randomly assigned to receive aripiprazole (15 mg/day), slow-release methylphenidate (54 mg/day), or placebo for 20 weeks. The study was terminated prematurely because of unexpected results of interim analysis. Contrary to the hypothesized result, patients who received aripiprazole treatment had significantly more amphetamine-positive urine samples than did patients in the placebo group, whereas patients who received methylphenidate had significantly fewer amphetaminepositive urine samples than patients who had received placebo. Studies in cocaine-abusing subjects are ongoing. In a study in alcoholic patients (Anton et al. 2008) the efficacy and safety of aripiprazole was compared with placebo in a 12-week double-blind multicenter trial in 295 patients with alcohol dependence according to DSM-IV criteria. Patients were randomly assigned to treatment with aripiprazole (initiated at 2 mg/day and titrated to a maximum dose of 30 mg/day at day 28) or placebo after minimum 3 day abstinence during the screening period. The primary efficacy measure was percentage of days abstinent over 12 weeks. Discontinuations (40.3% vs. 26.7%) and treatment-related adverse events (82.8% vs. 63.6%) were higher with aripiprazole than with placebo. Mean percentage of days abstinent was similar between aripiprazole and placebo (58.7% vs. 63.3%; P = 0.227). Percentage of subjects without a heavy drinking day and the time to first drinking day were also comparable between groups, although the aripiprazole group had fewer drinks per drinking day (4.4 vs. 5.5 drinks; P10,000

4,400

33

Adrenergic

Source. Adapted from Leysen et al. 1993b. Several groups have studied the occupancy of D2 and 5-HT2 receptors in patients with schizophrenia, employing positron emission tomography (PET) or single-photon emission computed tomography (SPECT) ligand-binding techniques. Kapur et al. (1999) used PET to measure D2 occupancy with 11

C-labeled raclopride and 5-HT2 occupancy with 18F-labeled setoperone in patients with chronic

schizophrenia maintained on a stable clinician-determined dose of risperidone. The PET was performed 12–14 hours after the last dose of risperidone. Occupancy of D2 receptors ranged from 63% to 89%; 50% occupancy was calculated to occur with a daily risperidone dose of 0.8 mg. Patients treated with risperidone (6 mg/day) exhibited a mean D2 occupancy of 79%, which was consistent with the mean occupancy of 82% that was previously reported by Nyberg et al. (1999) and would be expected to exceed the putative threshold for EPS in some patients. A similar degree of D2 occupancy was calculated to occur with olanzapine at approximately 30 mg daily (Kapur et al. 1999). A maximal 5-HT2 occupancy of greater than 95% was achieved with risperidone at daily doses as low as 2–4 mg. In a small sample of patients treated biweekly for at least 10 weeks with risperidone microspheres (Consta), Remington et al. (2006) found that the 25-mg dose produced a mean D2 occupancy of 54% (preinjection) and 71% (postinjection), whereas the 50-mg dose produced occupancy levels of 65% (preinjection) and 74% (postinjection). Preclinical characterization of risperidone in rats revealed more potent antiserotonergic activity, compared with ritanserin, in all tests (Janssen et al. 1988). For example, in reversal of tryptophaninduced effects in rats, risperidone was 6.4 times more potent than ritanserin for reversal of peripheral 5-HT2-mediated effects and 2.4 times more potent for reversal of centrally mediated 5-HT2 effects (Janssen et al. 1988). Risperidone was also found to completely block discrimination of LSD, in contrast to the partial attenuation observed with ritanserin (Meert et al. 1989). Although risperidone demonstrated activity in all dopamine-mediated tests, the dose–response pattern differed from that of haloperidol (Janssen et al. 1988). The two drugs were roughly equipotent for inhibition of certain dopamine effects, such as amphetamine-induced oxygen hyperconsumption, whereas the dose of risperidone necessary to cause pronounced catalepsy in rats was 18-fold higher than that of haloperidol (Janssen et al. 1988). Risperidone depressed vertical and horizontal activity in rats at a dose 2–3 times greater than that of haloperidol but required doses more than 30 times greater than those of haloperidol to depress small motor movements (Megens et al. 1988).

PHARMACOKINETICS AND DISPOSITION Risperidone is rapidly absorbed after oral administration, with peak plasma levels achieved within 1 hour (Heykants et al. 1994). In early Phase I studies, risperidone demonstrated linear pharmacokinetics at dosages between 0.5 and 25 mg/day (Mesotten et al. 1989; Roose et al. 1988). After a single dose of the extended-release formulation of paliperidone (Invega), serum concentrations gradually increase until a maximum concentration is achieved approximately 24 hours after ingestion. Absorption of paliperidone is increased by approximately 50% when taken with a meal compared with the fasted state. Extended-release paliperidone also demonstrates dose-proportional pharmacokinetics within the recommended dosing range (3–12 mg/day). Risperidone microspheres do not begin to release appreciable amounts of drug until 3 weeks after injection and continue to

release drug for approximately 4 weeks, with maximal drug release occurring after about 5 weeks. Risperidone is 90% plasma protein bound, whereas 9-hydroxyrisperidone (paliperidone) is 74% plasma protein bound (Borison 1994). The absolute bioavailability of risperidone is about 100%; that of extended-release paliperidone is about 28%. Risperidone is metabolized by hydroxylation of the tetrahydropyridopyrimidinone ring at the seven and nine positions and by oxidative N-dealkylation (Mannens et al. 1993). The most important metabolite, 9-hydroxyrisperidone, accounts for up to 31% of the dose excreted in the urine and has a receptor affinity profile similar to that of the parent compound. Because hydroxylation of risperidone is catalyzed by cytochrome P450 (CYP) 2D6, the half-life of the parent compound varies according to the relative activity of this enzyme. In "extensive metabolizers," which include about 90% of Caucasians and as many as 99% of Asians, the half-life of risperidone is approximately 3 hours. In healthy subjects, approximately 60% of 9-hydroxyrisperidone is excreted unchanged in the urine, and the remainder is metabolized by at least four different pathways (dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission), none of which accounts for more than 10% of the total. The terminal half-life of 9-hydroxyrisperidone (and of extended-release paliperidone) is 23 hours. "Poor metabolizers" metabolize risperidone primarily via oxidative pathways; the half-life may exceed 20 hours. In extensive metabolizers, radioactivity from 14C-labeled risperidone is not detectable in plasma 24 hours after a single dose, whereas 9-hydroxyrisperidone accounts for 70%–80% of radioactivity. In poor metabolizers, risperidone is primarily responsible for radioactivity after 24 hours. In the U.S. multicenter registration trial, the correlations between risperidone dose and serum risperidone and 9-hydroxyrisperidone concentrations were 0.59 and 0.88, respectively (Anderson et al. 1993).

MECHANISM OF ACTION As previously discussed, risperidone was developed specifically to exploit the apparent pharmacological advantages of combining 5-HT2 antagonism with D2 blockade. Selective 5-HT2A antagonists administered alone have demonstrated activity in several animal models suggestive of antipsychotic effect, including blockade of both amphetamine- and phencyclidine (PCP)–induced locomotor activity (Schmidt et al. 1995). Dizocilpine-induced disruption of prepulse inhibition is also blocked by 5-HT2A antagonists, suggesting that sensory gating deficits characteristic of schizophrenia and perhaps resulting from glutamatergic dysregulation might also benefit from the 5-HT2 antagonism of risperidone (Varty et al. 1999). The disruption of prepulse inhibition by dizocilpine (MK-801, a noncompetitive N-methyl-D-aspartate [NMDA] antagonist) is attenuated by atypical antipsychotics, but not by conventional D2 blockers (Geyer et al. 1990). From a study in which the selective 5-HT2A antagonist M100907 was added to low-dose raclopride (a selective D2 blocker), Wadenberg et al. (1998) concluded that 5-HT2A antagonism facilitates D2 antagonist blockade of conditioned avoidance, another behavioral model associated with antipsychotic efficacy, but does not block conditioned avoidance when administered alone. One mechanism by which risperidone, paliperidone, and similar atypical agents might produce enhanced efficacy for negative symptoms and cognitive deficits and reduced risk for EPS is via 5-HT2A receptor modulation of dopamine neuronal firing and cortical dopamine release. Prefrontal dopaminergic hypoactivity has been postulated to underlie negative symptoms and cognitive deficits in schizophrenia (Goff and Evins 1998); both clozapine and ritanserin have been shown to increase dopamine release in prefrontal cortex, whereas haloperidol does not (Busatto and Kerwin 1997). Following 21 days of administration, risperidone, but not haloperidol, continued to increase dopamine turnover in the dorsal striatum and prefrontal cortex (Stathis et al. 1996). Ritanserin has been shown to enhance midbrain dopamine cell firing by blocking a tonic inhibitory serotonin input (Ugedo et al. 1989). Ritanserin also normalized ventral tegmental dopamine neuron firing patterns in rats after hypofrontality was induced by experimental cooling of the frontal cortex (Svensson et al. 1989).

Svensson et al. (1995) have performed a series of elegant studies examining the impact of atypical antipsychotics on ventral tegmental dopamine firing patterns disrupted by glutamatergic NMDA receptor antagonists. In healthy human subjects, administration of the NMDA antagonist ketamine is widely regarded as a promising model for several clinical aspects of schizophrenia, including psychosis, negative symptoms, and cognitive deficits (Goff and Coyle 2001; Krystal et al. 1994). In rats, administration of the NMDA channel blockers dizocilpine or PCP increased burst firing of ventral tegmental dopamine neurons predominately projecting to limbic structures but reduced firing of mesocortical tract dopamine neurons and disrupted firing patterns. Administration of ritanserin and clozapine preferentially enhanced firing of dopamine neurons with cortical projections, and when added to a D2 blocker, ritanserin increased dopamine release in prefrontal cortex. In addition to modulating ventral tegmental dopamine neuron firing, risperidone also blocks 5-HT2 receptors on inhibitory -aminobutyric acid (GABA)-ergic interneurons, which could also influence activity of cortical pyramidal neurons that are regulated by these local inhibitory circuits (Gellman and Aghajanian 1994). In placebo-controlled clinical trials, 5-HT2 antagonists have reduced antipsychotic-induced parkinsonism and akathisia (Duinkerke et al. 1993; Poyurovsky et al. 1999). This effect may reflect 5-HT2A antagonist effects upon nigrostriatal dopamine release. When combined with haloperidol, selective 5-HT2 antagonists increase dopamine metabolism in the striatum and prevent an increase in D2 receptor density, thereby possibly reducing the effects of D2 receptor blockade and dopamine supersensitivity (Saller et al. 1990). These agents do not affect dopamine metabolism in the absence of D2 blockade. The relative importance of 5-HT2 antagonist activity in producing atypical characteristics is the subject of debate. As argued by Kapur and Seeman (2001) and Seeman (2002), most atypical antipsychotic agents have dissociation constants for the D2 receptor that are larger than the dissociation constant of dopamine. This "loose binding" to the D2 receptor may allow displacement by endogenous dopamine and may contribute to a reduced liability for EPS and hyperprolactinemia. Unique among atypical agents, risperidone is "tightly bound" to the D2 receptor, with a dissociation constant smaller than that of dopamine (Seeman 2002). A model for atypical antipsychotic mechanisms that emphasizes D2 dissociation constants would predict that the apparent atypicality of risperidone, compared with that of haloperidol, reflects the reduced D2 occupancy achieved by more favorable dosing rather than the intrinsic pharmacological characteristics of risperidone. According to some binding data, a comparable clinical dosage of haloperidol would be approximately 4 mg/day, rather than 20 mg/day as used in the North American multicenter registration trial (Kapur et al. 1999). Consistent with this view, benefits of risperidone for negative symptoms and EPS were less apparent when compared with lower doses of haloperidol or with lower-potency conventional agents (see "Indications and Efficacy" section later in this chapter) than when compared with high-dose haloperidol (20 mg/day). An additional mechanism possibly contributing to the enhanced efficacy of risperidone and paliperidone is their considerable

-adrenergic antagonism. In a placebo-controlled augmentation

trial, Litman et al. (1996) demonstrated significant improvement in psychosis and negative symptoms with the

2-adrenergic

antagonist idazoxan when it was added to conventional antipsychotics.

Idazoxan has been shown to increase dopamine levels in the rat medial prefrontal cortex (Hertel et al. 1999). In aged rats (Haapalinna et al. 2000) and in patients with frontal dementias (Coull et al. 1996), 2-adrenergic

blockers have also been reported to improve cognitive functioning. Svensson et al.

(1995) found that prazosin, an

1

antagonist, inhibited both behavioral activation and the increase in

mesolimbic dopamine release produced by PCP or MK-801. In summary, risperidone and paliperidone possess at least two mechanisms that may confer atypical characteristics. 5-HT2A antagonism partially protects against D2 antagonist–induced neurological side effects and may improve negative symptoms and cognitive functioning via modulation of mesocortical

dopamine activity. In addition, blockade of adrenoceptors may further increase prefrontal cortical activity and could enhance antipsychotic efficacy by modulation of mesolimbic dopamine activity. Unlike other atypical agents, risperidone and paliperidone do not differ from conventional agents in their dissociation constant for the D2 receptor; this feature perhaps accounts for the risk of EPS at high doses, as well as their greater propensity to cause hyperprolactinemia.

INDICATIONS AND EFFICACY Risperidone is approved by the FDA for the treatment of schizophrenia, bipolar mania, and irritability associated with autism. In August 2007, the indication for schizophrenia was extended to include adolescents ages 13–17 years, and the bipolar mania indication was extended to include children 10–17 years of age. Risperidone microspheres (Consta long-acting injection) and extended-release paliperidone (Invega) are approved for the treatment of schizophrenia.

Schizophrenia Clinical Trial Results for Risperidone In the two North American registration trials (Chouinard et al. 1993; Marder and Meibach 1994), a total of 513 patients with chronic schizophrenia were randomly assigned to an 8-week double-blind, fixed-dose, placebo-controlled comparison of risperidone (2, 6, 10, or 16 mg/day) or haloperidol (20 mg/day). Risperidone dosages of 6, 10, and 16 mg/day produced significantly greater reductions, as compared with haloperidol, in each of the five domains of the Positive and Negative Syndrome Scale (PANSS), derived by principal-components analysis (Marder et al. 1997), and significantly higher response rates, defined as a 20% reduction in the PANSS total score. Effect sizes representing the difference in change scores between risperidone (6 mg/day) and haloperidol, although statistically significant, were uniformly small by Cohen's classification system (Cohen 1988): negative symptoms 0.31; positive symptoms 0.26; disorganized thoughts 0.22; uncontrolled hostility/excitement 0.29; and anxiety/depression 0.30 (Table 32–2). Severity of EPS was greater with haloperidol than with risperidone; further statistical analysis suggested that differences in EPS rates did not significantly influence the differences in PANSS subscale ratings (Marder et al. 1997). In fact, risperidone (10 and 16 mg/day) produced improvements in negative symptoms equivalent to those seen with risperidone (6 mg/day), despite increased EPS at the higher dosages of risperidone. TABLE 32–2. Effect sizes on Positive and Negative Syndrome Scale (PANSS) symptom dimensions: North American trials (N = 513) Adjusted mean change scores

Risperidone 6 mg/day

Placebo Risperidone 6

Effect size vs.

Effect size vs.

placebo

haloperidol

Haloperidol

mg/day PANSS total

–3.8

–18.6

–5.1

0.53

0.31

Negative

0.2

–3.4

–0.1

0.27

0.26

Positive

0.9

–5.7

–2.3

0.48

0.22

Disorganized

0.1

–4.6

–0.2

0.43

0.24

Hostility/excitement 0.2

–2.5

–0.1

0.47

0.29

–2.5

–0.6

0.36

0.30

thought

Anxiety/depression

–0.1

Source. Adapted from Marder et al. 1997. When risperidone (1, 4, 8, 12, and 16 mg/day) was compared with haloperidol (10 mg/day) in a large

8-week European trial involving 1,362 subjects with schizophrenia (Peuskens 1995), PANSS subscale change scores indicated preferential response to daily risperidone doses of 4 and 8 mg. However, neither the risperidone group taken as a whole nor individual risperidone doses achieved significantly better outcomes than haloperidol (10 mg/day) on any measure except for EPS, suggesting that the degree of the clinical superiority of risperidone, compared with haloperidol, may be dependent on the dosing of the comparator. In the National Institute of Mental Health–funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE; Stroup et al. 2003), 1,432 patients with chronic schizophrenia were randomly assigned to double-blind, flexibly dosed treatment for 18 months with risperidone, olanzapine, quetiapine, ziprasidone, or the conventional antipsychotic comparator perphenazine. Clinicians could adjust the dosage of each drug by prescribing 1–4 capsules daily; risperidone capsules contained 1.5 mg, and the mean daily dose administered in the study was 3.9 mg. Based on the primary outcome measure, time to all-cause discontinuation, risperidone was less effective than olanzapine (mean dosage = 20 mg/day) and comparable in effectiveness to perphenazine (mean dosage = 21 mg/day) and the other atypical agents (Lieberman et al. 2005). Although differences in rates of dropout due to intolerance did not reach statistical significance, risperidone consistently was the best-tolerated drug, particularly in subjects who had failed their first-assigned drug due to intolerance. Whereas the superior efficacy of risperidone for acute symptom reduction, compared with haloperidol, is quite broad (but of relatively small magnitude) and may be determined in part by the haloperidol dose, efficacy for prevention of relapse appears to be of a substantially greater relative magnitude. For example, Csernansky et al. (2002) randomly assigned 365 patients with stable schizophrenia or schizoaffective disorder to clinician-determined flexible dosing with risperidone or haloperidol for a minimum of 1 year. Kaplan-Meier estimates of the risk of relapse at the end of the study were 34% with risperidone, compared with 60% with haloperidol, a highly significant difference (P = 0.001). Several studies have indicated that risperidone may significantly enhance cognitive functioning, particularly verbal working memory, compared with haloperidol (Green et al. 1997). More recently, in a large double-blind, flexibly dosed 3-month trial in first-episode schizophrenia patients, risperidone (mean dosage = 3.2 mg/day) produced a modest, although statistically significant, improvement in the composite cognitive score compared with haloperidol (mean dosage = 2.9 mg/day) (Harvey et al. 2005). Another large double-blind trial examined cognitive effects in chronic schizophrenia patients treated for 52 weeks with risperidone (mean dosage = 5.2 mg/day), olanzapine (12.3 mg/day), and haloperidol (8.2 mg/day) (Keefe et al. 2006). No difference between treatments was found in improvement on the composite cognitive score, although risperidone and olanzapine were superior to haloperidol in a secondary analysis of completers (Keefe et al. 2006). No significant differences in cognitive effects were found among risperidone, perphenazine, or the other atypical antipsychotics in the CATIE (Keefe et al. 2007). Risperidone has been found to be well tolerated and effective in subgroups of patients with schizophrenia, including first-episode patients and elderly patients. In a 4 month double-blind trial comparing risperidone (mean dosage = 3.9 mg/day) and olanzapine (mean dosage = 11.8 mg/day) in 112 first-episode patients, both treatments were well tolerated, with an overall completion rate of 72% (Robinson et al. 2006). Response rates did not differ significantly between risperidone (54%) and olanzapine (44%), although patients who responded to risperidone were significantly more likely to retain their response. Experience with patients with treatment-resistant schizophrenia has been less consistent. In the U.S. multicenter registration study, Marder and Meibach (1994) found that patients who were presumed to have failed to respond to conventional agents, on the basis of a history of hospitalization for at least 6 months prior to study entry, did not respond to haloperidol (20 mg/day) but did display significant response to risperidone (6 and 16 mg/day), compared with placebo. Wirshing et al. (1999) reported significant improvement with risperidone (6 mg/day),

compared with haloperidol (15 mg/day), during a 4 week fixed-dose trial in 67 patients with schizophrenia and histories of treatment resistance. However, the difference between treatments was lost during a subsequent 4 week flexible-dose phase in which the mean risperidone dosage was increased to 7.5 mg/day and the mean haloperidol dosage was increased to 19.4 mg/day. Bondolfi et al. (1998) reported comparable significant improvement with risperidone (mean dosage = 6.4 mg/day) and clozapine (mean dosage = 292 mg/day) in a randomized, double-blind trial involving 86 patients with schizophrenia described as resistant or intolerant to conventional antipsychotics by history. In a large open trial, risperidone produced significantly higher response rates than did haloperidol in 184 patients with histories of poor response (Bouchard et al. 2000). The relative superiority of risperidone over haloperidol steadily increased over time, reaching a maximum at the conclusion of the 12-month study. In contrast, Volavka et al. (2002) found no difference between high-dose risperidone (8–16 mg/day) and haloperidol (10–20 mg/day) in patients established by history to be treatment resistant to conventional antipsychotics. In the CATIE, risperidone was more effective than quetiapine but did not differ from olanzapine and ziprasidone in patients who discontinued their first-assigned atypical antipsychotic medication due to lack of efficacy (Stroup et al. 2006). In contrast, patients who discontinued perphenazine (for any reason) subsequently did better on quetiapine or olanzapine than they did on risperidone (Stroup et al. 2007).

Clinical Trial Results for Paliperidone Extended-release paliperidone (Invega) at dosages of 6, 9, and 12 mg/day was more effective than placebo in a 6-week trial in acutely ill schizophrenia patients (Kane et al. 2007). In a flexibly dosed trial, extended-release paliperidone (9–15 mg/day) significantly reduced relapse compared with placebo (Kramer et al. 2007). The long-acting risperidone microsphere (Consta) formulation at fixed doses of 25 mg, 50 mg, and 75 mg administered biweekly was also superior in efficacy to placebo in a 12-week trial (Kane et al. 2003). In a 52-week study, treatment with risperidone microspheres was associated with low relapse rates; the incidence of relapse was 21.6% with the 25-mg dose and 14.9% with the 50-mg dose administered every 2 weeks (Simpson et al. 2006). In an open-label pilot trial of risperidone microspheres administered at a dose of 50 mg every 4 weeks, the 1-year relapse rate was estimated to be 22.4% (Gharabawi et al. 2007).

Affective Disorders Six controlled trials of 3–4 weeks' duration that included a total of 1,343 patients have examined the efficacy of risperidone as monotherapy or in combination with a mood stabilizer for the acute treatment of bipolar mania (Rendell et al. 2006). As monotherapy and in combination, risperidone was more effective than placebo and comparable to haloperidol (Rendell et al. 2006). Risperidone's comparative efficacy in long-term prevention of relapse in bipolar disorder has not been established (Rendell and Geddes 2006). Risperidone 1–2 mg/day was evaluated as an adjunct to antidepressant therapy in a 4-week placebocontrolled trial in 174 antidepressant-resistant patients with major depression recruited from 19 primary care and psychiatric centers (Mahmoud et al. 2007). Risperidone significantly lowered ratings of depressive symptoms compared with placebo. Remission rates were 25% with risperidone versus 11% with placebo (P = 0.004). Risperidone was well tolerated, with an 81% completion rate (vs. 88% with placebo).

Autism Risperidone was also studied in a large 8-week placebo-controlled trial in 101 children (ages 5–17 years) with autism accompanied by severe tantrums, aggression, or self-injurious behavior (McCracken et al. 2002). Flexible dosing with risperidone (range = 0.5–3.5 mg/day; mean dosage = 1.2 mg/day) resulted in a mean reduction of 57% in irritability, compared with a decrease of 14% in the placebo group, and the response rate was 69% with risperidone versus 12% with placebo. In a

study of 32 children (ages 5–17 years) treated for 4 months with open-label risperidone (mean dosage = 2 mg/day), those who continued treatment with risperidone during the second study arm, an 8-week double-blind substitution trial, had much lower relapse rates than patients switched to placebo (Research Units on Pediatric Psychopharmacology Autism Network 2005). Risperidone at a mean dosage of 2 mg/day was also found to be effective compared with placebo in a study of 31 adults with autism or pervasive developmental disorder (McDougle et al. 1998). In these studies, risperidone improved irritability and behavioral problems associated with autism but was not effective for social or language deficits. Risperidone at a dosage of 0.02–0.06 mg/kg was found to be well tolerated and effective for disruptive behaviors in children with low intelligence (intelligence quotient [IQ] between 36 and 84) in a 6-week placebo-controlled trial (Aman et al. 2002).

Other Disorders In a 4-week placebo-controlled trial in 417 patients with generalized anxiety disorder, anxiety symptoms improved to a similar degree in both the placebo and the risperidone groups (Pandina et al. 2007). Risperidone was highly effective for obsessive-compulsive disorder symptoms in a 6-week placebo-controlled trial in 36 adults prospectively confirmed to be refractory to treatment with a selective serotonin reuptake inhibitor (McDougle et al. 2000). Symptoms of anxiety and depression also responded to risperidone compared with placebo. Fifty percent of risperidone-treated patients responded (mean dosage = 2.2 mg/day), compared with 0% in the placebo group.

SIDE EFFECTS AND TOXICOLOGY Risperidone shares class warnings with other atypical antipsychotics in the United States, including the risks of tardive dyskinesia, neuroleptic malignant syndrome, and hyperglycemia and diabetes, as well as the risk of increased mortality in elderly patients with dementia-related psychosis. However, risperidone generally has been very well tolerated in clinical trials. In the U.S. multicenter trial reported by Marder and Meibach (1994), only headache and dizziness were significantly more frequent with risperidone (6 mg/day), compared with placebo, whereas the group receiving risperidone (16 mg/day) treatment also reported more EPS and dyspepsia than did the group receiving placebo (Table 32–3). Fatigue, sedation, accommodation disturbances, orthostatic dizziness, palpitations or tachycardia, weight gain, diminished sexual desire, and erectile dysfunction displayed a statistically significant relationship to risperidone dose, although most were not significantly elevated compared with placebo. In a flexible-dose relapse prevention study reported by Csernansky et al. (2002), no side effects were more frequent with risperidone, compared with haloperidol, although risperidone produced significantly greater weight gain. In a flexibly dosed, placebocontrolled trial of risperidone for children with disruptive behavior, risperidone (mean dosage = 1.2 mg/day) produced more somnolence, headache, vomiting, dyspepsia, weight gain, and prolactin elevation than did placebo; most side effects were rated mild to moderate and did not adversely affect compliance (Aman et al. 2002). TABLE 32–3. Side effects reported by patients with schizophrenia receiving placebo, risperidone, or haloperidol in the U.S. multicenter trial Percentage of patients Placebo (n =

Risperidone 6 mg (n

Risperidone 16 mg (n

Haloperidol (n =

66)

= 64)

= 64)

66)

Insomnia

9.1

12.5

9.4

12.1

Agitation

7.6

10.9

12.5

16.7

Anxiety

1.5

7.8

4.7

1.5

Nervousness

1.5

6.3

1.6

0

Percentage of patients Placebo (n =

Risperidone 6 mg (n

Risperidone 16 mg (n

Haloperidol (n =

66)

= 64)

= 64)

66)

Somnolence

0

3.1

9.4a

4.5

Extrapyramidal side

10.6

10.9

25.0a

25.8a

Headache

4.5

15.6a

9.4

7.6

Dizziness

0

9.4a

10.9b

0

Dyspepsia

4.5

9.4

6.3

4.5

Vomiting

1.5

6.3

6.3

3.0

Nausea

0

6.3

3.1

1.5

Constipation

0

1.6

6.3

1.5

Rhinitis

6.1

15.6

6.3

4.5

Coughing

1.5

9.4

3.1

3.0

Sinusitis

1.5

6.3

1.6

0

Fever

0

6.3

3.1

1.5

Tachycardia

0

4.7

6.3

1.5

effects

a

P 5,000

1,700

530

170

>5,100

2.0

68

5-HT2A receptors

120

8.9

3.3

0.29

220

0.39

3.4

5-HT2C receptors

4,700

17

10

10

1,400

1.72

15

5-HT uptake

1,800

3,900

>15,000

1,400

>18,000

53

98

5,500

390

2,000

28,000

680

48

2,090

transporters NE uptake transporters Binding affinities associated with potential adverse effects (mean pKi, nM) H1 receptors

440

1.8

2.8

19

8.7

47

61

M1 receptors

1,600

1.8

4.7

2,800

100

5,100

>10,000

1-adrenoceptors

4.7

4.0

54

1.4

15

13

57

2-adrenoceptors

1,200

33

170

5.1

1,000

310

74

Note. D2 = dopamine2 receptor; H1 = histamine1 receptor; 5-HT = 5-hydroxytryptamine (serotonin); M1 = muscarinic1 receptor; NE = norepinephrine. Source. DeLeon et al. 2004; Kroeze et al. 2003; Richelson and Souder 2000; Schmidt et al. 2001; Shapiro et al. 2003; Stahl and Shayegan 2003; Weiner et al. 2004. Ziprasidone is a potent antagonist at dopamine type 2 (D2) receptors but possesses inverse agonist activity at 5-hydroxytryptamine (serotonin) type 2A receptors (5-HT2A receptors). D2 receptor antagonism is thought to be a key mechanism underlying efficacy for the treatment of psychotic symptoms (Kapur and Remington 2001); positron emission tomography (PET) studies have shown that clinical antipsychotic response to ziprasidone is predicted by occupancy of at least 60% of striatal D2 receptors. D2 antagonism is also associated with potential liability for extrapyramidal side effects (EPS). However, ziprasidone's inverse agonist activity at 5-HT2A receptors disinhibits dopamine neurotransmission in the nigrostriatal, mesocortical, and tuberoinfundibular pathways (Kapur and Remington 1996; Schmidt et al. 2001); this reduces liability for EPS compared with antipsychotics with unopposed D2 antagonism and potentially contributes to therapeutic effects. Increased dopamine activity in the prefrontal cortex is putatively linked to efficacy in improving the negative and cognitive symptoms of schizophrenia (Stahl and Shayegan 2003). Enhanced dopaminergic transmission in the tuberoinfundibular pathway minimizes the potential effect of D2 receptor antagonism on prolactin

secretion. Ziprasidone's relatively high in vitro 5-HT2A/D2 receptor affinity ratio, compared with that of other second-generation antipsychotics, predicts both a low liability for EPS and potential therapeutic benefits for negative symptoms (Altar et al. 1986). Ziprasidone exhibits antagonist activity at 5-HT1D and 5-HT2C receptors, and unique (among secondgeneration antipsychotics) agonist activity at 5-HT1A receptors (see Table 33–1) (DeLeon et al. 2004; Schmidt et al. 2001). The 5-HT1A affinity is comparable to that of buspirone, an agent with antidepressant and anxiolytic properties (Mazei et al. 2002), suggesting a mechanism that may contribute to observed beneficial effects on affective, cognitive, and negative symptoms in schizophrenia and schizoaffective disorder (Diaz-Mataix et al. 2005; Ichikawa et al. 2001; Millan 2000; Rollema et al. 2000; Sumiyoshi et al. 2003; Tauscher et al. 2002). Blockade of 5-HT2C receptors disinhibits both dopamine and norepinephrine neurons in the cortex, an effect that could contribute to improvements in cognitive and affective abnormalities (Bremner et al. 2003; Bymaster et al. 2002; Mazei et al. 2002; Stahl 2003). Although 5-HT2C antagonist activity is potentially predictive of weight gain liability, based, for example, on a 5-HT2C knockout mouse model of obesity (Tecott et al. 1995), clinically significant predictive effects of 5-HT2C antagonist activity on the weight gain risk associated with antipsychotic drugs have not been reliably detected (Kroeze et al. 2003), and the weight gain risk associated with ziprasidone is among the lowest of any currently available antipsychotic (Allison et al. 1999b). Potent antagonism at 5-HT1D receptors has been proposed to potentially mediate antidepressant and anxiolytic effects (Briley and Moret 1993; Zorn et al. 1998). Another unique feature of ziprasidone is its relatively high affinity for serotonin and norepinephrine transporters (Seeger et al. 1995; Tatsumi et al. 1999). In vitro, ziprasidone demonstrates dose-dependent reuptake inhibition of serotonin and norepinephrine transport, with effects ranging up to those of imipramine and amitriptyline (Schmidt et al. 2001), suggesting potential antidepressant activity. In vivo, the clinical significance of ziprasidone's monoaminergic reuptake inhibition may be limited by plasma protein binding or be clinically relevant only at higher than currently recommended daily dosages. Monoaminergic reuptake inhibition is associated with hippocampal neurogenesis, suggesting potential value in countering the neuronal cell loss observed in both affective illness and schizophrenia (Arango et al. 2001; Duman 2004; Thome et al. 1998). Relevant to this activity, treatment with ziprasidone and risperidone has been associated with an increase in cortical gray matter volume (Garver et al. 2005). Ziprasidone has a low affinity for histaminergic1 (H1), muscarinic1 (M1), and

1-noradrenergic receptors.

Among the biogenic amine receptors, H1 antagonist activity is the largest predictor of weight gain liability (Figure 33–2) (Kroeze et al. 2003). H1 antagonist activity is also predictive of sedative effects, which are potentially undesirable for patients aiming to maximize cognitive performance and social, occupational, and community engagement. Low affinity for

1-adrenergic receptors predicts a lower likelihood of

orthostatic hypotension and sedation with ziprasidone than with commonly used antipsychotics with potent 1-adrenergic antagonist activity. Low affinity for M1 receptors predicts a low risk for anticholinergic side effects such as dry mouth, blurry vision, urinary retention, constipation, confusion, and memory impairment. FIGURE 33–2. Histamine1 (H1) receptor affinity predicts antipsychotic-induced weight gain.

ARI = aripiprazole; CLO = clozapine; HAL = haloperidol; K1 = binding affinity; OLA = olanzapine; QTP = quetiapine; RIS = risperidone; ZIP = ziprasidone. Source. Adapted from Kroeze et al. 2003. Ziprasidone's complex neuropharmacology provides explanatory support for observed treatment effects on psychotic and affective symptoms of schizophrenia, schizoaffective disorder, and bipolar disorder and for its favorable tolerability profile including minimal extrapyramidal and metabolic side effects (Stahl and Shayegan 2003).

Positron Emission Tomography Studies An in vivo PET study (Mamo et al. 2004) examining the affinity of ziprasidone for dopamine (D2) and serotonin (5-HT2) receptors observed that optimal D2 receptor occupancy occurs at the high end of the initially recommended dosage range. In this study, the ziprasidone plasma concentration associated with 50% of maximal D2 receptor occupancy was more than twice the plasma concentration associated with 50% of maximal 5-HT2 receptor occupancy. Using an imaging protocol where 60% or greater D2 dopamine receptor occupancy is generally predictive of antipsychotic activity, approximately 60% D2 occupancy was observed in relation to plasma concentrations equivalent to those attained with a dosage at or above 120 mg/day. These results, consistent with clinical trial results discussed later in this chapter (see "Indications and Efficacy"), strongly suggest that antipsychotic activity with ziprasidone is most commonly associated with dosages of 120 mg/day or greater (Figure 33–3). FIGURE 33–3. Relationship between dopamine2 (D2) and serotonin2 (5-HT2) receptor occupancy and ziprasidone plasma levels in 16 patients with schizophrenia or schizoaffective disorder receiving therapeutic dosages of ziprasidone.

Dotted straight lines represent minimal D2 receptor occupancy and plasma concentration that would be expected to be associated with a clinical antipsychotic response, corresponding to a ziprasidone dosage of approximately 120 mg/day. Source. Adapted from Mamo et al. 2004.

Dosing Recommendations In addition to the PET data, accumulating evidence from clinical trials (discussed below) suggests that ziprasidone dosing targets should be higher than initially recommended. In the United States, it was initially recommended that ziprasidone treatment in patients with schizophrenia be initiated at a dosage of 20 mg twice daily and then titrated at no less than 2-day intervals to a maximal dosage of 80 mg twice daily (Pfizer Inc. 2008). In contrast, more recent FDA approval of ziprasidone for the treatment of bipolar mania includes a recommendation that treatment be initiated at 40 mg twice daily with a more rapid titration; on the second day of treatment, the dosage should be increased to 60 or 80 mg twice daily and should subsequently be adjusted on the basis of toleration and efficacy within the 40- to 80-mg twice-daily range. A review of short-term trials of ziprasidone (Kane 2003) concluded that daily dosages of 120–160 mg are more effective than lower dosages in the treatment of acute schizophrenia and also are associated with lower rates of medication discontinuation. A more recent 6-month prospective, observational, naturalistic, uncontrolled study performed in Spain also found that dosages greater than 120 mg/day were associated with a lower risk of discontinuation for any cause (Arango et al. 2007). As a corollary, another European observational multicenter trial found that both initial and overall underdosing are associated with high discontinuation rates (Kudla et al. 2007). In a pooled analysis of both flexible-dose and fixed-dose studies (N = 2,174), greater efficacy was observed in patients who received an initial dosage of 80 mg/day than in patients who received an initial dosage of 40 mg/day (Murray et al. 2004). Reported clinical experience with ziprasidone has also suggested the need for dosages greater than 160 mg/day in selected patients (Harvey and Bowie 2005; Nemeroff et al. 2005). Finally, two large observational database analyses support the other lines of evidence suggesting that

higher dosages of ziprasidone are associated with better treatment outcomes than lower dosages (Joyce et al. 2006; Mullins et al. 2006). Both studies used prescription refills as an indicator of prescription adherence, a key measure of treatment continuation and overall effectiveness. Joyce et al. (2006) examined the files of more than 1,000 commercially insured patients with schizophrenia or schizoaffective disorder and concluded that an initial daily dosage of 120–160 mg was associated with a significantly lower risk of discontinuation at 6 months than an initial daily dosage of 60–80 mg. Mullins et al. (2006), evaluating a sample of more than 1,000 Medicaid recipients with schizophrenia, similarly concluded that patients receiving an initial dosage of 120–160 mg daily had lower rates of medication discontinuation than patients receiving an initial dosage of 20–60 mg daily. Taken together, results from receptor occupancy studies, clinical trials, and pharmacoepidemiological analyses provide support for the conclusion that initiation and treatment with ziprasidone dosages greater than 120 mg/day are more likely to be effective than lower dosages in the treatment of schizophrenia and schizoaffective disorder.

PHARMACOKINETICS AND DISPOSITION Absorption and Distribution Based on evidence of enhanced absorption in the presence of food, it is recommended that ziprasidone be taken with meals. Administration with food increases absorption by more than 50%, giving ziprasidone an oral bioavailability of approximately 60% (Pfizer Inc. 2008). Maximal plasma concentration (Cmax) is achieved in 3.7–4.7 hours and reaches 45–139 g/L in healthy volunteers receiving 20–60 mg twice daily, and steady-state serum concentrations occur within 1–3 days of twice-daily dosing (Hamelin et al. 1998; Miceli et al. 2000c). In contrast to oral administration, intramuscular administration of ziprasidone results in 100% bioavailability. A therapeutic plasma level is reached within 10 minutes, and Cmax is achieved within 30 minutes of administration of a 20-mg dose (Pfizer Inc. 2008). The mean apparent volume of distribution of ziprasidone is 1.5 L/kg (Pfizer Inc. 2008), which is lower than that of many other antipsychotic drugs. Given the wider potential for unwanted interactions with various intracellular targets that has been observed with lipophilic drugs having a high volume of distribution (Dwyer et al. 1999), this may be a favorable attribute for ziprasidone and other similar compounds. Ziprasidone is more than 99% bound to plasma proteins. However, in vitro binding studies indicate that it does not alter the protein binding of two highly protein-bound drugs, warfarin and propranolol, neither do these two drugs interfere with the protein binding of ziprasidone, suggesting that these types of drug interactions are unlikely.

Metabolism and Elimination Ziprasidone is extensively metabolized with a mean terminal elimination half-life of approximately 7 hours after oral administration within the recommended clinical dosage range (Pfizer Inc. 2008). The elimination half-life of intramuscular ziprasidone is less than 3 hours with a single dose (Brook et al. 2000). Ziprasidone is cleared primarily via three metabolic pathways to yield four major circulating metabolites (Figure 33–4). Elimination occurs primarily through hepatic metabolism, with less than one-third of metabolic clearance mediated via cytochrome P450 (CYP)–catalyzed oxidation and approximately two-thirds via reduction of the parent compound by aldehyde oxidase to dihydroziprasidone, which then undergoes S-methylation. The current published literature reports no commonly encountered clinically significant pharmacological inhibitors of aldehyde oxidase, suggesting limited real-world potential for drug–drug interactions that would alter the clinical activity of ziprasidone (Obach et al. 2004). FIGURE 33–4. Major metabolic pathways of ziprasidone.

BITP = benzisothiazole piperazine; CYP = cytochrome P450; M = metabolite; TMT = thiol methyltransferase. Source. Adapted from U.S. Food and Drug Administration Pharmacological Drugs Advisory Committee: Briefing Document for Ziprasidone Mesylate for Intramuscular Injection (Figure 2 [Metabolism of Ziprasidone in Humans: Proposed Metabolic Pathways to Major Circulating Metabolites], p. 5). February 15, 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3685b2_01_pfizer.pdf. Additional secondary metabolic pathways include N-dealkylation (via CYP enzymes 3A4 and 1A2) and direct S-oxidation (via CYP3A4) (Beedham et al. 2003; Prakash et al. 2000). S-methyl-dihydroziprasidone is the only active metabolite, with lower D2 receptor affinity and no significant binding to H1, M1, or and

1-

2-adrenergic receptors. A small amount of the parent compound is excreted unchanged in the urine

(60 msec) via either pharmacokinetic or pharmacodynamic interactions (Montanez et al. 2004). This has understandably led to regulatory interest in drug effects on the QTc interval. It should be noted that epidemiological studies in the general population suggest that modest prolongations of the QTc interval are not a risk factor for cardiovascular mortality or sudden death, so any risk in the general population of modest QTc prolongations is likely to be small and difficult to detect reliably (Montanez et al. 2004). Compared with risks like obesity, hypercholesterolemia, diabetes, hypertension, physical inactivity, or cigarette smoking, each with well-characterized effects in the general population, modest QTc prolongations are not a comparable risk factor for cardiovascular mortality or sudden death in the general population. Against this background, thioridazine was recently required to add to its prescribing information a black box warning related to its QTc interval–prolonging effects, following decades of use. Other conventional antipsychotics, including haloperidol, are also associated with some risk of QTc prolongation (Gury et al. 2000; O'Brien et al. 1999). Investigators (Glassman and Bigger 2001) have estimated the rate of occurrence of torsades de pointes with conventional antipsychotics as "10–15 such events in 10,000 person-years of observation" (p. 1774). Ziprasidone, like some other antipsychotic agents, can induce orthostatic hypotension, particularly early in treatment exposure, which can lead to transient tachycardia, dizziness, or syncope (Swainston Harrison and Scott 2006). However, tachycardia has been observed to be infrequent and as common in patients treated with ziprasidone as in those treated with placebo (Swainston Harrison and Scott 2006). Tachycardia and syncope related to hypotension are to be distinguished from ventricular arrhythmias that can rarely occur in relation to QTc prolongation.

Ziprasidone treatment has been demonstrated to result in a modestly increased risk of QTc prolongation (Pfizer Inc. 2008). This QTc prolongation at Cmax (mean increase, >15 msec) is 9–14 msec greater than that seen with risperidone, olanzapine, quetiapine, or haloperidol but approximately 14 msec less than that seen with thioridazine. Unlike the case with thioridazine, the modest effect of ziprasidone on the QTc interval is not worsened by the presence of commonly encountered inhibitors of drug metabolism. In clinical trials of ziprasidone monotherapy that report QTc changes as well as in case reports of ziprasidone overdosing (with doses up to 12,800 mg), there has been no evidence of any significant clinical sequelae such as torsades de pointes or sudden death (Arato et al. 2002; Arbuck 2005; Daniel 2003; Gomez-Criado et al. 2005; Harrigan et al. 2004; Insa Gómez and Gutiérrez Casares 2005; Levy et al. 2004; Lieberman 2007; Miceli et al. 2004; Montanez et al. 2004; Nemeroff et al. 2005; Taylor 2003; Weiden et al. 2002, 2003a). This is consistent with analyses of large population samples, which have failed to demonstrate any association between QTc duration and either cardiovascular or all-cause mortality (Goldberg et al. 1991). Rare cases of torsades de pointes have been reported in patients being treated with multiple medications including ziprasidone, but the incidence of these events appears to be below the known prevalence of torsades de pointes in community-based population samples (Heinrich et al. 2006). The USPI suggests that clinicians should nonetheless be cognizant of this potential risk and be aware of circumstances that may increase risk for the occurrence of torsades de pointes and/or sudden death in association with the use of any drugs that can prolong the QTc interval. Such circumstances include bradycardia, hypokalemia, or hypomagnesemia; concomitant use of other medications known to cause clinically significant QT prolongation (although an additive effect with ziprasidone has not been established); and presence of congenital long-QT syndrome. The USPI further states that ziprasidone should not be used in patients with significant cardiovascular conditions, such as uncompensated heart failure or a cardiac arrhythmia, or in those who have had a recent acute myocardial infarction or persistent QTc measurements of greater than 500 msec, and the prudent clinician might consider employing the same caution with many other antipsychotic and psychotropic medications currently in use.

CONCLUSION Ziprasidone is the fourth atypical antipsychotic following clozapine to become available in the United States. This agent has a unique pharmacological profile with the highest 5-HT2A/D2 affinity ratio of currently available agents, potent serotonin and norepinephrine reuptake inhibition activity, agonist activity at 5-HT1A receptors, and clinically relevant antagonist activity at various 5-HT2 receptor subtypes. Ziprasidone has demonstrated rapid-onset and sustained efficacy for the treatment of schizophrenia, schizoaffective disorder, and bipolar mania, with promising evidence of favorable mood, cognitive, and prosocial effects. It is now available in an intramuscular formulation for the treatment of acute agitated psychoses. Ziprasidone has a highly favorable safety and tolerability profile with limited potential for drug–drug and drug–disease interactions, critical issues for a patient population that generally has a high burden of medical comorbidity and is commonly exposed to complex polypharmacy. The adverse-effect profile of ziprasidone is particularly noteworthy in areas that are key to safety and tolerability in patients with major mental disorders such as schizophrenia and bipolar disorder, including low drug-related risk for EPS and minimal effects on cardiometabolic risk factors like obesity and dyslipidemia. As a fuller understanding of the cumulative risks associated with prolonged antipsychotic treatment develops, along with the risks and benefits of various commonly used adjunctive medications, it is likely that clinicians will increasingly appreciate individual medications with a wide spectrum of therapeutic activity and a favorable safety profile that support long-term use and optimize both medical and psychiatric outcomes.

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Joseph K. Stanilla, George M. Simpson: Chapter 34. Drugs to Treat Extrapyramidal Side Effects, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.430901. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 34. Drugs to Treat Extrapyramidal Side Effects EXTRAPYRAMIDAL SIDE EFFECTS History The discovery of the therapeutic properties of chlorpromazine (Delay and Deniker 1952; Laborit et al. 1952) was soon followed by the description of its tendency to produce extrapyramidal side effects (EPS) that were indistinguishable from classical Parkinson's syndrome. A debate soon arose regarding the relationship between EPS and therapeutic efficacy. Flügel (1953) suggested that a therapeutic response from chlorpromazine required the development of EPS. Haase (1954) postulated that the neuroleptic dose that produced minimal subclinical rigidity and hypokinesis (i.e., the "neuroleptic threshold") was the minimal neuroleptic dose necessary for therapeutic antipsychotic effect and that it was manifested by micrographic handwriting changes. Other investigators also reported that EPS were necessary for therapeutic efficacy (see Denham and Carrick 1960; Karn and Kasper 1959). Brooks (1956), on the other hand, suggested that "signs of parkinsonism heralded the particular effect being sought" (p. 1122) but that "the therapeutic effects were not dependent on extrapyramidal dysfunction. On the contrary, alleviation of such dysfunction, as soon as it occurred, sped the progress of recovery" (p. 1122). The need to develop EPS for therapeutic efficacy was also questioned by others. The differences in opinion regarding EPS and neuroleptic efficacy were partially attributable to differences in the definitions of EPS and in the methodologies of the studies (Chien and DiMascio 1967). Haase's concept—that mild subclinical EPS manifested by handwriting changes were indicative of a therapeutic dose—was demonstrated in studies that found no difference in therapeutic response at doses beyond the neuroleptic threshold (Angus and Simpson 1970a; G. M. Simpson et al. 1970). Patients treated with doses beyond the neuroleptic threshold received significantly larger doses of medication without further therapeutic benefit. This finding has been discussed more fully (Baldessarini et al. 1988) and has been replicated (McEvoy et al. 1991). When clozapine was first developed in 1960, it sparked little interest as a potential antipsychotic. Many investigators believed that EPS were necessary for antipsychotic effect, and clozapine appeared not to produce EPS. Even after studies showed that clozapine possessed antipsychotic activity, interest regarding commercial development was still limited. The hesitancy on the part of the pharmaceutical company was related to the belief held by many members of the psychiatric community—that is, that a drug could not have antipsychotic effect without producing EPS (Hippius 1989). In contrast, the current goal in the development of new antipsychotic medications is to replicate the EPS profile of clozapine and to develop antipsychotics that do not produce EPS. This situation essentially brings the story of EPS full circle. The terms used to name and characterize antipsychotic medications have also evolved. The term tranquilizer was initially introduced to characterize the psychic effects of reserpine. The term neuroleptic, derived from Greek and meaning "to clasp the neuron," was introduced to describe

chlorpromazine and the extrapyramidal effects that it produced (Delay et al. 1952). Until clozapine was approved for use, all commercially available drugs with antipsychotic properties possessed the following neuroleptic properties: blocking apomorphine and amphetamine-induced stereotypy; antagonizing the conditioned avoidance response; and producing catalepsy, elevated serum prolactin levels, and EPS. For that reason, all antipsychotic drugs were referred to as neuroleptics. With the subsequent development of clozapine and other antipsychotic drugs that possess reduced EPS profiles, the term neuroleptic no longer correctly categorizes all drugs with antipsychotic effects; therefore, the term antipsychotic is more accurate and more preferable. Severe EPS can have a significantly negative effect on treatment outcome by contributing to poor compliance and exacerbation of psychiatric symptoms (Van Putten et al. 1981). Akathisia, in particular, is associated with poor clinical outcome (Levinson et al. 1990; Van Putten et al. 1984), increased violence (Keckich 1978), and even suicide (Shear et al. 1983). The presence of EPS early in treatment may place a patient at increased risk of developing tardive dyskinesia (TD) (Saltz et al. 1991). Orofacial TD may have a negative effect on the social acceptability of patients, even though they are often unaware of the movements (Boumans et al. 1994). Laryngeal dystonia can adversely affect speech, breathing, and swallowing (Feve et al. 1995; Khan et al. 1994) and can be potentially life-threatening (Koek and Pi 1989). Clearly, EPS are significant, need to be assessed, and should be minimized so that the overall treatment and health of patients may be optimized.

Types Four types of EPS have been delineated, and the treatment of each type should be individualized. Acute dystonic reactions (ADRs) are generally the first EPS to appear and are often the most dramatic (Angus and Simpson 1970b). Dystonias are involuntary sustained or spasmodic muscle contractions that cause abnormal twisting or rhythmical movements and/or postures. ADRs tend to occur suddenly and generally involve muscles of the head and neck (as in torticollis, facial grimacing, or oculogyric crisis). Nearly 90% of all ADRs occur within 4 days of antipsychotic initiation or dosage increase, and virtually 100% of all ADRs occur by day 10 (Singh et al. 1990; Sramek et al. 1986). Although tardive dystonia can occur after this period, movements occurring beyond this time frame are much less likely to be ADRs. Instead, other conditions, including seizures, need to be considered. Akathisia is the second type of EPS to appear. Akathisia, meaning "inability to sit," consists of both an objective restless movement and a subjective feeling of restlessness that the patient experiences as the need to move. It may be difficult for a patient to explain the sensation of akathisia, and the diagnosis can be missed. At times, patients may display the classical movements of akathisia, but they may not have the subjective distress—a condition that has been termed pseudoakathisia, which may be a type of tardive syndrome (Barnes 1990). The third type of EPS, (pseudo)parkinsonism, is virtually indistinguishable from classical Parkinson's syndrome. The symptoms include a generalized slowing of movement (akinesia), masked facies, rigidity (including cogwheeling rigidity), resting tremor, and hypersalivation. Parkinsonism generally occurs after a few weeks or more of neuroleptic treatment. Akinesia needs to be differentiated from primary depression and the blunted affect of schizophrenia (Rifkin et al. 1975). Tardive syndromes make up the fourth group of EPS. TD, although clearly associated with the use of antipsychotic medications, was actually described prior to the advent of antipsychotics (G. M. Simpson 2000). TD consists of irregular stereotypical movements of the mouth, face, and tongue and choreoathetoid movements of the fingers, arms, legs, and trunk. It tends to occur after months to years of use of antipsychotic medications. Patients frequently have no awareness of the abnormal movements. The lack of awareness may be related to frontal lobe dysfunction (Sandyk et al. 1993). Tardive dystonia, a variant of TD, also generally emerges months to years after treatment with antipsychotics (Burke et al. 1982) Unlike in ADRs, the movements associated with tardive dystonia

tend to be persistent and more resistant to medical treatment (Kang et al. 1988).

Incidence Ayd (1961) was the first to report the incidence of EPS, noting an overall incidence of 39%, with 21% demonstrating akathisia, 15% demonstrating parkinsonism, and only 2% having ADRs. Varying rates of occurrence, including much higher incidences of ADRs, have been reported since that time. A prospective study found that the range of incidence of ADRs was between 17% and 38%, with the higher rate occurring with haloperidol (Sramek et al. 1986). In general, higher prevalence rates for all types of EPS occur at higher doses and with higher-potency antipsychotics. In a series of surveys of 721 patients with schizophrenia conducted over 10 years, McCreadie (1992) found that the point prevalence was 27% for parkinsonism, 23% for akathisia or pseudoakathisia, and 29% for TD. Forty-four percent of patients had no movement disorder. A 10-year prospective study found that the overall incidence of TD within a group remained fairly stable—30% at baseline, 37% at 5 years, and 32% at 10 years (Gardos et al. 1994). Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies found the presence of probable TD by Schooler-Kane criteria in 212 (15%) of 1,460 subjects (D. D. Miller et al. 2005). Tardive dystonia has been reported to occur in 1%–2% of patients taking antipsychotic medications (Yassa et al. 1986). Extrapyramidal movements have been reported to occur in 17%–29% of neuroleptic-naive patients with schizophrenia (Caligiuri et al. 1993; Chatterjee et al. 1995). This finding raises questions regarding the role of antipsychotics in the etiology of TD (see G. M. Simpson et al. 1981). These data refer to first-generation typical antipsychotics. Data from the CATIE trials include subjects treated with second-generation atypical antipsychotics as well as typical antipsychotics. The presence of probable TD by Schooler-Kane criteria was found in 212 of 1,460 subjects (15%), which is lower than rates noted above (D. D. Miller et al. 2005). The incidence for all types of EPS has been shown to be less with the second-generation atypical antipsychotics.

Etiology The exact mechanisms involved in the production of EPS are not known. Control of motor activity apparently involves an interaction between nigrostriatal dopaminergic, intrastriatal cholinergic, and -aminobutyric acid (GABA)–ergic neurons (Côté and Crutcher 1991). Extrapyramidal movements of parkinsonism and dystonia classically have been thought to result from antipsychotic blockade of dopaminergic nigrostriatal tracts, resulting in a relative increase in cholinergic activity (Snyder et al. 1974). Drugs that either decrease cholinergic activity or increase dopaminergic activity reduce EPS, presumably by restoring the two systems to their previous equilibrium, as demonstrated in ADRs in monkeys (Casey et al. 1980). This feature is the basis for the use of anticholinergics in the treatment of EPS. The etiology of TD is thought to result from more complex changes, which include increased dopamine receptor sensitivity following prolonged dopamine blockade (Gerlach 1977). The production of EPS probably involves more complex interactions of other factors and receptor types, which have become the subject of investigation. Decreased serum calcium has been associated with increased EPS. Calcium is involved in the function of the cholinergic system and in the metabolism of dopamine (Kuny and Binswanger 1989), and antipsychotic drugs bind to the calcium-dependent activator of several enzyme systems. (Calmodulin has been studied by el-Defrawi and Craig [1984].) GABA may have an effect on EPS through inhibitory feedback on the dopaminergic system. Reduced GABA synthesis and reduced GABA levels have been found with TD (Gunne et al. 1984; Thaker et al.

1987). The effect of GABA on ADRs is not as clear. ADRs in baboons were found to be increased by drugs that increased GABA levels, as well as by drugs that decreased GABA (Casey et al. 1980). -Adrenergic mechanisms may be involved in TD, akathisia, and tremor (Wilbur et al. 1988). Clozapine is a potent 1-adrenergic receptor antagonist in the brain, causing

1

receptor upregulation and

increased noradrenergic metabolism, factors that may affect the EPS profile of clozapine (Baldessarini et al. 1992). Free radicals, possibly produced by chronic neuroleptic use, have been proposed as contributors to the development of neuropathic damage and TD. Vitamin E, as an antioxidant that binds free radicals, has been suggested as a treatment for TD by limiting the process (Cadet et al. 1986). Levels of lipid peroxides, theoretically produced by free radicals, have not been found to correlate with TD (McCreadie et al. 1995), nor have changes in levels correlated with treatment with vitamin E, although it was noted that these changes could be occurring centrally (Corrigan et al. 1993). A somewhat related theory suggests that increased iron levels in the basal ganglia may contribute to TD because of the involvement of iron in the production of free radicals (Ben-Shachar and Youdim 1987). However, neuroimaging and pathological studies have not demonstrated increased iron levels on a consistent basis (Elkashef et al. 1994). The metabolism of antipsychotics may contribute to EPS. Haloperidol, when given intravenously, has a much lower incidence of EPS than when it is used orally or intramuscularly, even when given at extremely high doses. Haloperidol is metabolized to reduced haloperidol in the liver. When administered intravenously, haloperidol enters the central nervous system (CNS) before metabolites are produced. It has been proposed that dopamine2 (D2) receptor saturation by haloperidol, rather than by reduced haloperidol, could account for the difference in EPS production (Menza et al. 1987). More recent investigations of clozapine and other novel antipsychotics have focused on dopamine and serotonin (5-HT) receptors (Kapur and Remington 1996). Clozapine, olanzapine, quetiapine, risperidone, and ziprasidone are potent serotonin2A (5-HT2A) receptor antagonists and relatively weaker D2 antagonists, compared with typical antipsychotics. They all have a reduced EPS profile, compared with typical antipsychotics (Meltzer 1999). Typical antipsychotics initially increase dopamine synthesis, turnover, and release in the striatum of baboons (Meldrum et al. 1977). This increased dopamine production reaches a maximum 1–5 hours after a single neuroleptic injection, which corresponds in time with the development of ADRs in baboons. During chronic treatment (up to 11 days), there is a marked diminution in the capacity of the antipsychotics to provoke an increased turnover of dopamine. Chronic haloperidol treatment causes decreased striatal dopaminergic neurotransmission and upregulation of postsynaptic D2 receptors (Ichikawa and Meltzer 1991). In contrast, chronic clozapine treatment causes a slight increase in striatal dopaminergic neurotransmission and no changes in D2 receptors. This has recently also been demonstrated in humans (Silvestri et al. 2000). These differences may partly explain the lack of occurrence of EPS and TD with clozapine and perhaps also with the other novel antipsychotics. Dopamine1 (D1) receptor antagonists have a lower EPS potential than do traditional D2 antipsychotics in nonhuman primates (Coffin et al. 1989). Patients who were clinical responders to antipsychotics and who had lower D2 receptor occupancy by positron emission tomography (PET) analysis were found to have a lower incidence of EPS. Patients treated with clozapine had lower D2 receptor occupancy than patients treated with typical antipsychotics (Farde et al. 1992). The balanced D1/D2 receptor function may prevent development of EPS and TD (Gerlach and Hansen 1992). The rate of dissociation from the D2 receptor may be as important as the degree of D2 blockade, with regard to EPS. Novel antipsychotics have a faster dissociation rate from the D2 receptor than do traditional antipsychotics (Kapur and Seeman 2001).

The high ratio of serotonin2 (5-HT2) receptor blockade to striatal D2 receptor blockade that occurs with clozapine may account for clozapine's lack of EPS (Meltzer et al. 1989). Evidence suggests that decreasing serotonergic neurotransmission reverses or prevents catalepsy induced by D2 receptor blockade (Meltzer and Nash 1991). Clozapine also has a high affinity for dopamine3 (D3) and dopamine4 (D4) receptors (Sokoloff et al. 1990; Van Tol et al. 1991). The binding of clozapine to these receptors has also been proposed as a possible mechanism involved in the favorable EPS profile of clozapine.

Rating Investigations of treatment for EPS led to the need to develop instruments to evaluate and quantify them. An initial EPS scale was shown to have both clinical validity and high interrater reliability, but it did not adequately assess salivation and tremor (G. M. Simpson et al. 1964). Scores were low, despite obvious and disabling tremor or salivation that required treatment with antiparkinson medication. Subsequently, the scale was expanded to 10 items (rated on a five-point scale), including tremor and salivation (G. M. Simpson and Angus 1970). This scale has good psychometric properties and is simple to use and score. It has been modified for outpatient use by eliminating the leg rigidity item and by replacing head dropping with head rotation. Studies using this scale have shown that scores correlate with the dosages and plasma levels of an antipsychotic. The scale is widely used in clinical trials and can be completed by nurses for the routine monitoring of neuroleptic treatment. The Simpson-Angus Scale does not include a direct rating for bradykinesia or akinesia. Mindham (1976) modified the scale to include an item for lack of facial expression. Additional rating scales for EPS have since been developed, including the Chouinard Extrapyramidal Rating Scale (Chouinard et al. 1980), Targeting of Abnormal Kinetic Effects (TAKE) Scale (Wojcik et al. 1980), St. Hans Rating Scale for Extrapyramidal Syndromes (Gerlach et al. 1993), and Dyskinesia Identification System Condensed User Scale (DISCUS; Kalachnik and Sprague 1993). The Modified Simpson-Angus Scale includes a single item for rating akathisia. More comprehensive scales have been devised specifically to rate akathisia, including the Barnes Akathisia Rating Scale (Barnes 1989), Hillside Akathisia Scale (Fleischhacker et al. 1989), and Prince Henry Hospital Akathisia Rating Scale (PHH Scale; Sachdev 1994). Scales have also been developed for the assessment of dyskinetic movements. These include the Abnormal Involuntary Movement Scale (AIMS; Guy 1976) and the Simpson/Rockland Scale (G. M. Simpson et al. 1979). Instrumental devices have been developed for the assessment of EPS, and several have been shown to correlate with clinical scales (Büchel et al. 1995). Instrumental devices have the advantage of increased reliability of quantitative measures, primarily through the elimination of subjective error associated with clinical raters; however, instrumental devices also have disadvantages. They often require greater patient cooperation than do clinical scales. They may require physical contact with the subject, which can affect measurements. They often evaluate a limited area, unlike clinical scales, which evaluate a patient in multiple areas as well as globally. As of this writing, clinical scales generally can be considered to have better global clinical validity with greater ease of use, while instrumental measures provide greater reliability (Büchel et al. 1995).

ANTICHOLINERGIC MEDICATIONS Trihexyphenidyl History and Discovery Antiparkinsonian medications are drugs that have primarily been used to treat EPS and include

anticholinergic, antihistaminic, and dopaminergic agents (Table 34–1). TABLE 34–1. Pharmacological agents for the treatment of neuroleptic-induced parkinsonism and acute dystonic reactions Compound

Relative

Route

Availability

Dosing

Dosage range (mg/day)

equivalence (mg)a Anticholinergic Trihexyphenidyl

2

Oral

Tablets: 2, 5 mg

qd–bid

2–30

qd–bid

1–12

Every 30 minutes

2–8

Elixir: 2 mg/mL Sequels: 5 mg (sustained release) Benztropine

1

(Cogentin)

Oral

Tablets: 0.5, 1, 2

Injectable mg

Biperiden (Akineton)b 2

Oral

Ampules: 1 mg/mL

(until symptom

(2 mL)

relief)

Tablets: 2 mg

qd–tid

2–24

Every 30 minutes

2–8

Injectable Ampules: 5 mg/mL b

(1 mL)

(until symptom relief)

Procyclidine

2

Oral

(Kemadrin)

Tablets: 5 mg

bid–tid

5–20

bid–qd

50–200

qd–bid

100–300

(scored)

Antihistaminic Diphenhydramine

50

(Benadryl)

Oral

Tablets: 25, 50 mg

Injectable Ampules: 50 mg/mL (1 mL, 10 mL) Syringe (prefilled): 1 mL

Dopaminergic Amantadine

N/A

(Symmetrel)

Oral

Tablets: 100 mg Syrup: 50 mg/5 mL

Note. N/A = not applicable; qd = once daily; bid = twice daily; tid = three times daily. a

Adapted from Klett and Caffey 1972.

b

No longer available as an injectable in the United States.

Trihexyphenidyl, a synthetic analogue of atropine, was introduced as benzhexol hydrochloride in 1949. It was found to be effective in the treatment of Parkinson's disease in a study of 411 patients (Doshay et al. 1954). Thereafter, it was also used to treat neuroleptic-induced parkinsonism (NIP) (Rashkis and Smarr 1957).

Structure–Activity Relations Trihexyphenidyl, a tertiary-amine analogue of atropine, is a competitive antagonist of acetylcholine and other muscarinic agonists that compete for a common binding site on muscarinic receptors (Yamamura and Snyder 1974). It exerts little blockade at nicotinic receptors (Timberlake et al. 1961). Trihexyphenidyl and all drugs in this class are referred to as anticholinergic, antimuscarinic, or atropine-like drugs. As a tertiary amine, it readily crosses the blood–brain barrier (Brown and Taylor 1996).

Pharmacological Profile The pharmacological properties of trihexyphenidyl are qualitatively similar to those of atropine and other anticholinergic drugs, although trihexyphenidyl acts primarily centrally, with few peripheral effects and little sedation. In the eye, anticholinergic drugs block both the sphincter muscle of the iris, causing the pupil to dilate (mydriasis), and the ciliary muscle of the lens, preventing accommodation and causing cycloplegia. In the heart, anticholinergic drugs usually produce a mild tachycardia through vagal blockade at the sinoatrial node pacemaker, although a mild slowing can occur. In the gastrointestinal tract, anticholinergic drugs reduce gut motility and salivary and gastric secretions. Salivary secretion is particularly sensitive and can be completely abolished. In the respiratory system, anticholinergic agents reduce secretions and can produce mild bronchodilatation. Anticholinergics inhibit the activity of sweat glands and mildly decrease contractions in the urinary and biliary tracts (Brown and Taylor 1996).

Pharmacokinetics and Disposition Peak concentration for trihexyphenidyl is reached 1–2 hours after oral administration, and its half-life is 10–12 hours (Cedarbaum and McDowell 1987). As a tertiary amine, it crosses the blood–brain barrier to enter the CNS.

Mechanism of Action The presumed mechanism of action of trihexyphenidyl for treatment of EPS is the blockade of intrastriatal cholinergic activity, which is relatively increased, compared with nigrostriatal dopaminergic activity, which has become decreased by antipsychotic blockade. The blockade of cholinergic activity returns the system to its previous equilibrium.

Indications and Efficacy Anticholinergic agents were reported to have been effective treatment for NIP from open empirical trials (Medina et al. 1962; Rashkis and Smarr 1957). Eventually, controlled trials were conducted, with most involving comparisons only with different anticholinergics and not with placebo. Despite the limited evidence of efficacy against placebo, anticholinergic agents became the mainstay of treatment for NIP, and they remain so today. Trihexyphenidyl has U.S. Food and Drug Administration (FDA) approval for treatment of all forms of parkinsonism, including NIP. Daily doses of 5–30 mg have been used in studies of trihexyphenidyl in the treatment of Parkinson's disease and NIP. Much higher dosages (up to 75 mg/day) have been used for the treatment of primary dystonia. However, the benefits of high doses have been limited by the adverse effects on cognition and memory (Jabbari et al. 1989; Taylor et al. 1991). Side effects correlate with blood levels, but efficacy does not (Burke and Fahn 1985). The individual therapeutic dose must be determined empirically and can vary widely.

Side Effects and Toxicology Peripheral side effects The peripheral side effects of trihexyphenidyl result from parasympathetic muscarinic blockade, and they occur in a consistent hierarchy among different organs. They are qualitatively similar to the side effects of atropine and other anticholinergic drugs, but they are quantitatively less because of the reduced peripheral activity of trihexyphenidyl (Brown 1990). Anticholinergic drugs initially depress salivary and bronchial secretions and sweat production. Reduced salivation produces dry mouth and contributes to the high incidence of dental caries among patients with chronic psychiatric problems (Winer and Bahn 1967). Treatment for this condition is unsatisfactory, and chewing sugar-free gum or sucking on hard candy is limited by the need for

constant use. Reduced sweating can contribute to heat prostration and heat stroke, particularly in warmer ambient temperatures. The next physiological effects occur in the eyes and heart. Pupillary dilatation and inhibition of accommodation in the eye lead to photophobia and blurred vision. Attacks of acute glaucoma can occur in susceptible subjects with narrow-angle glaucoma, although this is relatively uncommon. Vagus nerve blockade leads to increased heart rate and is more apparent in patients with high vagal tone (usually younger males). The next effects are inhibition of urinary bladder function and bowel motility, which can produce urinary retention, constipation, and obstipation. Sufficiently high doses of anticholinergics will inhibit gastric secretion and motility (Brown and Taylor 1996).

Central side effects Memory disturbance is the most common central side effect of anticholinergic medications because memory is dependent on the cholinergic system (Drachman 1977). Patients with underlying brain pathology are more susceptible to memory disturbance (Fayen et al. 1988). Patients with chronic psychiatric conditions often have a decreased ability to express themselves, making evaluation of memory more difficult; therefore, subtle memory changes can be missed or attributed to the underlying illness. Memory disturbances have been identified in patients with Parkinson's disease treated with anticholinergics (Yahr and Duvoisin 1968), even in some patients receiving only small doses (Stephens 1967). Patients receiving an antipsychotic and benztropine demonstrated significantly increased overall scores on the Wechsler Memory Scale when benztropine was withdrawn (Baker et al. 1983). Anticholinergic toxicity produces restlessness, irritability, disorientation, hallucinations, and delirium. Elderly patients are at increased risk for both memory loss and toxic delirium, even at very low anticholinergic doses, because of the natural loss of cholinergic neurons with aging (Perry et al. 1977). Toxic doses can produce a clinical situation identical to atropine poisoning, including fixed dilated pupils, flushed face, sinus tachycardia, urinary retention, dry mouth, and fever. This condition can proceed to coma, cardiorespiratory collapse, and death.

Drug–Drug Interactions There may be increased anticholinergic effects, including side effects, when trihexyphenidyl or any anticholinergic is combined with amantadine. Anticholinergic side effects are also much more likely to occur when drugs with anticholinergic properties are combined.

Anticholinergic effect on antipsychotic blood levels Some investigators have suggested that anticholinergic medications can affect antipsychotic blood levels. However, a review of this subject suggests that the available data are too limited to reach a definite conclusion on this matter. The best studies indicate that anticholinergic drugs do not affect antipsychotic blood levels or, at most, that they lower these levels only transiently (McEvoy 1983).

Anticholinergic effect on antipsychotic activity Haase and Janssen (1965) reported from open studies that when anticholinergic drugs are added to antipsychotic drugs given at the neuroleptic threshold, rigidity, hypokinesia, and therapeutic effects disappear but psychopathology worsens. Other studies have demonstrated no change or an improvement in scores of psychopathology, with the addition of anticholinergics (Hanlon et al. 1966; G. M. Simpson et al. 1980).

Anticholinergic Abuse Anticholinergic drugs may be abused for their euphoriant and hallucinogenic effects, and they may be combined with street drugs for enhanced effect (Crawshaw and Mullen 1984). Patients with a history of substance abuse are more likely to abuse anticholinergics (Wells et al. 1989). Cases of abuse have

been reported with all anticholinergics, but trihexyphenidyl apparently is the anticholinergic most likely to be abused (MacVicar 1977). Theoretically, one anticholinergic should be as effective as another, although an idiosyncratic response is possible. The potential for abuse needs to be considered, particularly in patients with a history of substance abuse.

Benztropine History and Discovery Benztropine was synthesized by uniting the tropine portion of atropine with the benzhydryl portion of diphenhydramine hydrochloride. Benztropine was found to be effective in the treatment of 302 patients with Parkinson's disease (Doshay 1956). The best results in the control of rigidity, contracture, and tremor were obtained at doses of 1–4 mg qd for older patients and 2–8 mg qd for younger ones. Doses of 15–30 mg qd caused excessive flaccidity in some patients, who became unable to lift their arms or raise their heads off the bed. Subsequently, benztropine was found to be effective for the treatment of NIP (Karn and Kasper 1959).

Structure–Activity Relations Benztropine is a tertiary amine with activity similar to that of trihexyphenidyl, and as a tertiary amine, it enters the CNS.

Pharmacological Profile Benztropine has the pharmacological properties of an anticholinergic and an antihistaminic; however, it produces less sedation (in experimental animals) than does diphenhydramine.

Pharmacokinetics and Disposition Little is known about the pharmacokinetics of benztropine. A correlation between serum anticholinergic levels and the presence of EPS has been demonstrated (Tune and Coyle 1980). There is little correlation between the total daily dose of benztropine and the serum anticholinergic level, with the serum activity for a given dose varying 100-fold between subjects. When treated with increased doses of anticholinergics, patients with EPS demonstrated increased serum anticholinergic activity and decreased EPS. Relatively small increments in the oral dose of an anticholinergic drug can result in significant nonlinear increases in serum anticholinergic activity levels. Benztropine has a long-acting effect and can be given once or twice a day.

Indications and Efficacy Benztropine has FDA approval for the treatment of all forms of parkinsonism, including NIP. Total daily doses of 1–8 mg have generally been used to treat NIP.

Mechanism of Action, Side Effects, and Drug–Drug Interactions The mechanisms of action and the drug interactions for benztropine are similar to those of trihexyphenidyl. The side effects of these two drugs are also similar, but the degree of sedation produced by benztropine may be less (Doshay 1956). Although not yet confirmed in double-blind studies, this reported difference in sedation might account for the fact that trihexyphenidyl is reportedly the anticholinergic drug more likely to be abused.

Biperiden Biperiden is an analogue of trihexyphenidyl that has greater peripheral anticholinergic activity than trihexyphenidyl and greater activity against nicotinic receptors (Timberlake et al. 1961). Biperiden is well absorbed from the gastrointestinal tract. Its metabolism, though not completely understood, involves hydroxylation in the liver. Its activity, pharmacological profile, and side effects are similar to

those of other anticholinergics. It has FDA approval for use in the treatment of all forms of parkinsonism, including NIP. Total daily doses of 2–24 mg have been used in studies of biperiden for the treatment of parkinsonism and NIP.

Procyclidine Procyclidine is an analogue of trihexyphenidyl (Schwab and Chafetz 1955). Its activity, pharmacology, and side effects are similar to those of other anticholinergics. There is little information about its pharmacokinetics. Procyclidine has FDA approval for use in treating all forms of parkinsonism, including NIP. Total daily doses of 5–30 mg have been used in studies of procyclidine for the treatment of parkinsonism and NIP.

ANTIHISTAMINIC MEDICATIONS Diphenhydramine History and Discovery Antihistaminic agents have been used for the treatment of Parkinson's disease. Diphenhydramine, one of the first antihistamines developed and used clinically (Bovet 1950), has been the primary antihistamine studied in the treatment of EPS. Although some antihistamines may be effective, other antihistamines have not been systematically studied for the treatment of EPS.

Structure–Activity Relations All drugs referred to as antihistamines are reversible competitive inhibitors of histamine at the H1 receptor. Some antihistamines also inhibit the action of acetylcholine at the muscarinic receptor. It is believed that central muscarinic blockade, rather than histaminic blockade, is responsible for the therapeutic effect of antihistamines for EPS. Ethanolamine antihistamines (diphenhydramine, dimenhydrinate, and carbinoxamine maleate) have the greatest anticholinergic activity, and ethylenediamine antihistamines have the least anticholinergic activity. Antihistamines such as terfenadine and astemizole have no anticholinergic activity, while many of the remaining antihistamines have very mild anticholinergic activity (Babe and Serafin 1996).

Pharmacological Profile Antihistamines inhibit the constrictor action of histamine on respiratory smooth muscle. They restrict the vasoconstrictor and vasodilatory effects of histamine on vascular smooth muscle and block histamine-induced capillary permeability. Antihistamines with CNS activity are depressants, producing diminished alertness, slowed reaction times, and somnolence. They can also block motion sickness. Antihistaminic drugs with anticholinergic activity also possess mild antimuscarinic pharmacological properties similar to those of other atropine-like drugs (Babe and Serafin 1996).

Pharmacokinetics and Disposition Diphenhydramine is well absorbed from the gastrointestinal tract. Peak concentrations occur 2–3 hours after oral administration. Its therapeutic effects usually last 4–6 hours, and it has a half-life of 3–9 hours. Diphenhydramine is widely distributed throughout the body, and as a tertiary amine, it enters the CNS. Age does not affect its pharmacokinetics. It undergoes demethylations in the liver and is then oxidized to carboxylic acid (Paton and Webster 1985).

Mechanism of Action Diphenhydramine possesses some anticholinergic activity, which is believed to be the basis for its effect in diminishing EPS.

Indications and Efficacy

Diphenhydramine has FDA approval for parkinsonism, including NIP, in the elderly and for mild cases in other age groups. It is probably not as efficacious for treating EPS as are pure anticholinergic drugs, but it may be better tolerated in patients bothered by anticholinergic side effects, such as geriatric patients. Diphenhydramine also tends to be more sedating than anticholinergics, which can also be beneficial for some patients. The dosage generally ranges from 50 to 400 mg/day, given in divided doses. Diphenhydramine also has indications for multiple other conditions that are unrelated to EPS.

Side Effects and Toxicology The primary side effect of diphenhydramine is sedation. Although other antihistamines may cause gastrointestinal distress, diphenhydramine has a low incidence of such an effect. Drying of the mouth and respiratory passages can occur. In general, the toxic effects are similar to those of trihexyphenidyl and of other anticholinergics.

Drug–Drug Interactions Diphenhydramine has no reported interactions with other drugs, but it has an additive depressant effect when used in combination with alcohol or with other CNS depressants.

DOPAMINERGIC MEDICATIONS Amantadine History and Discovery Anticholinergic side effects and inadequate treatment response eventually led to the investigation of other agents to treat EPS. Initially, both methylphenidate and intravenous caffeine were investigated as treatments for NIP. Neither agent achieved general use, despite apparent efficacy (Brooks 1956; Freyhan 1959). Amantadine is an antiviral agent that is effective against A2 (Asian) influenza (Wingfield et al. 1969). It was unexpectedly found to produce symptomatic improvement in patients with Parkinson's disease (Parkes et al. 1970; Schwab et al. 1969), and soon thereafter, it was reported to be effective for NIP (Kelly and Abuzzahab 1971).

Structure–Activity Relations Amantadine is a water-soluble tricyclic amine. It binds to the M2 protein, a membrane protein that functions as an ion channel on the influenza A virus (Hay 1992). Its activity in reducing EPS is not known, although it has been shown to have activity at glutamate receptors (Stoof et al. 1992).

Pharmacological Profile Amantadine is effective in preventing and treating illness from influenza A virus. It also reduces the symptoms of parkinsonism.

Pharmacokinetics and Disposition In young healthy subjects, amantadine is slowly and well absorbed from the gastrointestinal tract, with unchanged oral bioavailability over the dose range of 50–300 mg. It reaches steady state in 4–7 days. Plasma concentrations (0.12–1.12 g/mL) may have some correlation with improvement in EPS (Greenblatt et al. 1977; Pacifici et al. 1976). Amantadine has relatively constant blood levels and a long duration of action (Aoki et al. 1979) and is excreted unchanged by the kidneys. Its half-life for elimination is about 16 hours, which is prolonged in elderly patients and in patients with impaired renal function (Hayden et al. 1985).

Mechanism of Action

Amantadine inhibits viral replication by binding to the M2 protein on the viral membrane and inhibiting replication (Hay 1992). Its mechanism of action as an antiparkinson agent is less clear. It has no anticholinergic activity in tests on animals, being only 1/209,000th as potent as atropine (Grelak et al. 1970). It appears to cause the release of dopamine and other catecholamines from intraneuronal storage sites in an amphetamine-like mechanism. It has also been shown to have activity at glutamate receptors, which may contribute to its antiparkinsonian effect (Stoof et al. 1992). Amantadine has preferential selectivity for central catecholamine neurons (Grelak et al. 1970; Strömberg et al. 1970).

Indications and Efficacy Amantadine has undergone more extensive investigation than have anticholinergic agents with regard to the efficacy of EPS. Most studies, though not all, found amantadine to be equal in efficacy to benztropine or biperiden in the treatment of parkinsonism (DiMascio et al. 1976; Fann and Lake 1976; Konig et al. 1996; Silver et al. 1995; Stenson et al. 1976). Some studies found amantadine to be more effective than benztropine (Merrick and Schmitt 1973) or effective for EPS that are refractory to benztropine (Gelenberg 1978). However, other studies found that amantadine was inferior to benztropine (Kelly et al. 1974), no more effective than placebo (Mindham et al. 1972), or unable to control EPS when used to replace an anticholinergic agent (McEvoy et al. 1987). The varying results can be attributed to differing methodologies and patient populations. The conclusion that can be drawn from these studies is that amantadine is an effective drug for treating parkinsonism but that there are no clear data to support its use prior to using anticholinergic agents. Most of the studies were of short duration, and in patients with Parkinson's disease, amantadine appears to lose efficacy after several weeks (Mawdsley et al. 1972; Schwab et al. 1972). Similar studies evaluating the long-term efficacy of amantadine have not been conducted for EPS. Amantadine has also been evaluated for the treatment of akathisia, but in only a small number of patients. The conclusion from these studies is that amantadine is probably not effective for treating akathisia (Fleischhacker et al. 1990). Amantadine has FDA approval for the treatment of NIP and Parkinson's disease/syndrome, as well as for the treatment and prophylaxis of influenza A respiratory illness. Dosages of 100–300 mg/day are used for the treatment of NIP, and plasma concentrations may have some correlation with improvement.

Side Effects and Toxicology At dosages of 100–300 mg/day, amantadine does not produce adverse effects as readily as do anticholinergic medications. Side effects of amantadine result from CNS stimulation, with symptoms including irritability, tremor, dysarthria, ataxia, vertigo, agitation, reduced concentration, hallucinations, and delirium (Postma and Tilburg 1975). Hallucinations are often visual. Side effects are more likely to occur in elderly patients and in patients with reduced renal function (Borison 1979; Ing et al. 1979). Toxic effects are directly related to elevated amantadine serum levels (>1.5 g/mL). Resolution of toxic symptoms is dependent on renal clearance and may require dialysis in extreme cases, although less than 5% of amantadine is removed by dialysis. Patients with congestive heart failure or peripheral edema should be monitored because of amantadine's ability to increase the availability of catecholamines. Long-term use of amantadine may produce livedo reticularis in the lower extremities from the local release of catecholamines and resulting vasoconstriction (Cedarbaum and Schleifer 1990). Amantadine should be used with caution in patients with seizures because of possible increased seizure activity. Amantadine is embryotoxic and teratogenic in animals, but there are no well-controlled studies in women regarding teratogenicity.

Drug–Drug Interactions

There are no reported interactions between amantadine and other drugs. There may be increased anticholinergic side effects when amantadine is used in combination with an anticholinergic agent.

-Adrenergic Receptor Antagonists History and Discovery Propranolol was reported to be effective for the treatment of restless legs syndrome (Ekbom's syndrome; Ekbom 1965), which resembles the physical movements of akathisia (Strang 1967). Later it was reported to be effective in the treatment of neuroleptic-induced akathisia (Kulik and Wilbur 1983; Lipinski et al. 1983). Subsequently, other

-blockers have also been investigated for the

treatment of akathisia.

Structure–Activity Relations Competitive

-adrenergic receptor antagonism is the property common to all -blockers.

are distinguished by the additional properties of their relative affinity for (selectivity), lipid solubility, intrinsic

1

and

-Blockers

receptors

2

-adrenergic receptor agonist activity, blockade of

receptors,

capacity to induce vasodilation, and general pharmacokinetic properties (Hoffman and Lefkowitz 1996).

-Blockers with high lipid solubility readily cross the blood–brain barrier.

Pharmacological Profile The major pharmacological effects of

-blockers involve the cardiovascular system.

-Blockers slow

the heart rate and decrease cardiac contractility; however, these effects are modest in a normal heart. In the lung, they can cause bronchospasm, although, again, there is little effect in normal lungs. They block glycogenolysis, preventing production of glucose during hypoglycemia (Hoffman and Lefkowitz 1996).

-Blockers affect lipid metabolism by preventing release of free fatty acids while elevating

triglycerides (N. E. Miller 1987). In the CNS, they produce fatigue, sleep disturbance (insomnia and nightmares), and CNS depression (see Drayer 1987; Gengo et al. 1987).

Pharmacokinetics and Disposition All -blockers, except atenolol and nadolol, are well absorbed from the gastrointestinal tract (McDevitt 1987). All -blockers undergo metabolism in the liver. Propranolol and metoprolol undergo significant first-pass effect, with bioavailability as low as 25%. Large interindividual variation (as much as 20-fold) leads to wide variation in clinically therapeutic doses (Hoffman and Lefkowitz 1996). Metabolites appear to have limited

-receptor antagonistic activity. The degree to which a particular

-blocker enters the CNS is related directly to its lipid solubility (Table 34–2). TABLE 34–2. Beta-blockers investigated in the treatment of akathisia Compound

1

2

blockade

blockade

Lipid

Effective for

Dosage range

solubility

EPS

(mg/day)

Propranolol (Inderal) ++

++

++++

Yes

20–120

Nadolol (Corgard)

++

++

+

Yes

40–80

Metoprolol

++

0 at low doses; + at

++

Yes

~300

(Lopressor)

high doses

Pindolol (Visken)

++

++

++

Yes

5

Atenolol (Tenormin)

++

0

0

No

50–100

Betaxolol (Kerlone)

++

0

+++

Yes

5–20

Compound

1

2

blockade

blockade Sotalol (Betapace,

++

++

Lipid

Effective for

Dosage range

solubility

EPS

(mg/day)

0

No

40–80

Sorine) Note. EPS = extrapyramidal side effects. Source. Adapted from Hoffman and Lefkowitz 1996.

Mechanism of Action The exact mechanism of action of

-blockers in the treatment of EPS is unclear. The existence of a

noradrenergic pathway from the locus coeruleus to the limbic system has been proposed as a modulator involved in symptoms of TD, akathisia, and tremor (Wilbur et al. 1988). It appears that lipid solubility and the corresponding ability to enter the CNS are the most important factors determining the efficacy of a

-blocker in treating akathisia and perhaps other types of EPS (Adler et al. 1991).

Indications and Efficacy -Blockers have FDA approval primarily for cardiovascular indications, and propranolol is also indicated for familial essential tremor, but there are no FDA-approved indications for the treatment of any type of EPS. -Blockers have been studied primarily for the treatment of akathisia. Both nonselective ( 1 and

2

antagonism) and selective ( 1 antagonism) -blockers have been reported to be efficacious. The studies have generally been for short periods of time, involving small numbers of patients who were often receiving varying combinations of additional antiparkinsonian agents or benzodiazepines to which

-blockers had been added (Fleischhacker et al. 1990). From these studies, it is difficult to

draw any firm conclusions, but -blockers probably have some efficacy in the treatment of akathisia. The maximum benefit for propranolol occurred at 5 days (Fleischhacker et al. 1990). Betaxolol may be the

-blocker of choice in patients with lung disease and smokers because of its

1

selectivity at lower

dosages (5–10 mg/day). In addition to essential tremor,

-blockers have also been reported to be beneficial for the tremor of

Parkinson's disease (Foster et al. 1984) and lithium-induced tremor (Gelenberg and Jefferson 1995). However, for neuroleptic-induced tremor, propranolol was found to be not any better than placebo (Metzer et al. 1993), which could be an indication of a difference in etiologies for the different tremors.

Side Effects and Toxicology The side effects of

-blockers result from

receptor blockade.

2

Blockade of bronchial smooth muscle

produces bronchospasm. Individuals with normal lung function are unlikely to be affected, but smokers and others with lung disease can develop serious breathing difficulties.

-Blockers can

contribute to heart failure in susceptible individuals, such as those with compensated heart failure, acute myocardial infarction, or cardiomegaly. Abrupt cessation of

-blockers can also exacerbate

coronary heart disease in susceptible patients, producing angina or, potentially, myocardial infarction (for details, see Hoffman and Lefkowitz 1996). In individuals with normal heart function, bradycardia produced by

-blockers is insignificant;

however, in patients with conduction defects or when combined with other drugs that impair cardiac conduction,

-blockers can contribute to serious conduction problems.

-Blockers can block the tachycardia associated with hypoglycemia, eliminating this warning sign in patients with diabetes.

2

Blockade also can inhibit glycogenolysis and glucose mobilization,

interfering with recovery from hypoglycemia (Hoffman and Lefkowitz 1996).

-Blockers can impair exercise performance and produce fatigue, insomnia, and major depression. However, the development of major depression probably only occurs in individuals with a predisposition to developing depression.

Drug–Drug Interactions -Blockers can have significant interactions with other drugs. Chlorpromazine in combination with propranolol may increase the blood levels of both drugs. Additive effects on cardiac conduction and blood pressure can occur when

-blockers are combined with drugs having similar effects (e.g.,

calcium channel blockers). Phenytoin, phenobarbital, and rifampin increase the clearance of propranolol. Cimetidine increases propranolol blood levels by decreasing hepatic metabolism. Theophylline clearance is reduced by propranolol. Aluminum salts (antacids), cholestyramine, and colestipol may reduce the absorption of

-blockers (Hoffman and Lefkowitz 1996).

BENZODIAZEPINES History and Discovery Diazepam was initially shown to be effective in the treatment of restless legs syndrome (Ekbom's syndrome), which resembles the physical movements of akathisia (Ekbom 1965). Subsequently, diazepam, lorazepam, and clonazepam were reported to be beneficial for neuroleptic-induced akathisia (Adler et al. 1985; Donlon 1973; Kutcher et al. 1987). Clonazepam has also been reported to be beneficial for drug-induced dystonia (O'Flanagan 1975) and TD (Thaker et al. 1987).

Mechanism of Action All benzodiazepines promote the binding of GABA to GABAA receptors, magnifying the effects of GABA. The mechanism of action regarding improvement of EPS is unknown, but it may be related to the augmentation of inhibitory GABAergic effect (Hobbs et al. 1996). For a complete discussion of the properties of benzodiazepines, see Chapter 24.

Indications and Efficacy Benzodiazepines have FDA approval for their use in treating anxiety disorders, agoraphobia, insomnia, management of alcohol withdrawal, anesthetic premedication, seizure disorders, and skeletal muscle relaxation; however, there is no approval for its use in treating any type of EPS. As noted above, a few initial reports have indicated that benzodiazepines are beneficial for the treatment of akathisia. Other studies have also reported similar benefit (Bartels et al. 1987; Braude et al. 1983; Gagrat et al. 1978; Horiguchi and Nishimatsu 1992; Kutcher et al. 1989; Pujalte et al. 1994). Clonazepam has also been reported to be effective in the treatment of TD (Bobruff et al. 1981; Thaker et al. 1990). Doses of 1–10 mg were used in the first study, although the optimal dosage was found to be 4 mg/day, with many patients unable to tolerate higher dosages. In the second study, dosages of 2–4.5 mg/day were used, and tolerance developed after 5–8 months. Although some of the studies were limited by short duration and by the small number of subjects also receiving other antiparkinsonian agents, the overall conclusion was that benzodiazepines probably have some efficacy in the treatment of akathisia and TD. However, the potential problems associated with the chronic use of benzodiazepines (i.e., tolerance and abuse) need to be kept in mind. Lorazepam (intermediate-acting) and clonazepam (long-acting) are the two primary benzodiazepines that have been studied in the treatment of EPS. Because of its long duration of action, clonazepam can often be given once a day. Lorazepam has the advantage of having no active metabolites, which eliminates potential side effects and toxicity.

BOTULINUM TOXIN History and Discovery

Botulinum toxin, produced by Clostridium botulinum, causes botulism when ingested. The first clinical use of the toxin was in the treatment of childhood strabismus (Scott 1980). The first focal dystonia treated was blepharospasm (Elston 1988). Botulinum toxin has been subsequently used to treat a number of other conditions associated with excessive muscle activity, including neuroleptic-induced dystonias (Hughes 1994).

Structure–Activity Relations There are seven immunologically distinct botulinum toxins (L. L. Simpson 1981). Type A is the primary type used clinically (Hambleton 1992). Type F and possibly type B also have clinical utility, but they have much shorter durations of action ( 3 weeks, compared with 3 months for type A) (Borodic et al. 1996). The toxin is quantified by bioassay and is expressed as mouse units, which refers to the dose that is lethal to 50% of animals following intraperitoneal injection (Quinn and Hallet 1989).

Pharmacological Profile Botulinum toxin binds to cholinergic motor nerve terminals, preventing release of acetylcholine and producing a functionally denervated muscle. The prevention of acetylcholine release occurs within a few hours, but the clinical effect does not occur for 1–3 days. The innervation gradually becomes restored, although the number and/or size of active muscle fibers is reduced (Odergren et al. 1994).

Pharmacokinetics and Disposition After binding to the presynaptic nerve terminal, the toxin is taken into the nerve cell and is metabolized. When antibodies are present, the toxin is metabolized by immunological processes.

Mechanism of Action Botulinum toxin acts presynaptically to prevent the release of acetylcholine at the neuromuscular junction. This produces a functional chemical denervation and paralysis of the muscle. When botulinum toxin is used clinically, the aim is to reduce the excessive muscle activity without producing significant weakness (Hughes 1994).

Indications and Efficacy The FDA has approved the use of botulinum toxin for strabismus, blepharospasm, and other facial nerve disorders (see Jankovic and Brin 1991). Botulinum toxin has been used to treat focal neuroleptic-induced dystonias that may occur as part of TD, including laryngeal dystonia (Blitzer and Brin 1991) and refractory torticollis (Kaufman 1994). For laryngeal dystonia, the toxin is injected percutaneously through the cricothyroid membrane into the thyroarytenoid muscle bilaterally. The response rate is 80%–90%, and the effect lasts 3–4 months and sometimes longer. Botulinum treatment of tardive cervical dystonia has been found to be effective; the observed improvement is similar to the improvement seen in the treatment of idiopathic cervical dystonia, although patients with tardive cervical dystonia required higher doses (Brashear et al. 1998).

Side Effects and Toxicology The major potential side effect of botulinum toxin is focal weakness in the muscle group injected—an effect that is usually dose dependent. This effect is generally temporary, given the mechanism of action. Transient weakness can occur through diffusion of the toxin into surrounding noninjected muscles (Hughes 1994). Antibodies to the toxin can occur and thus can prevent a therapeutic response, particularly during subsequent treatments. The two main factors that apparently contribute to the development of antibodies are receiving a dose of the toxin for the first time at an early age and total cumulative dose (Jankovic and Schwartz 1995). Some patients with antibodies will respond to other botulinum

serotypes, such as type F (Greene and Fahn 1993). Local skin reactions can also occur. Some degree of muscle atrophy is apparent in injected muscles (Hughes 1994). Reinnervation usually takes place over the course of 3–4 months (Odergren et al. 1994). There are no known contraindications. Because the effect on the fetus is unknown, use of the toxin is not recommended during pregnancy. In conditions in which there are neuromuscular junction disorders, such as myasthenia gravis, patients could theoretically experience increased weakness. The long-term effects are unknown (Hughes 1994).

Drug–Drug Interactions There are no known interactions of botulinum toxin with other drugs.

VITAMIN E ( -TOCOPHEROL) History and Discovery The existence of vitamin E was postulated in 1922, at which time it appeared that rats required an unknown dietary supplement to sustain pregnancy. That supplement, vitamin E ( -tocopherol), was eventually isolated from wheat germ oil (Evans et al. 1936). Vitamin E deficiency in animals leads to several specific diseases; however, in humans, there is little evidence of any specific metabolic effects or illnesses. Despite the paucity of evidence for its benefit, vitamin E has been used over the years to treat multiple conditions, including infertility, various menstrual disorders, neurological and muscular disorders, and anemias (Marcus and Coulston 1996). Vitamin E was proposed as a treatment for TD after it was noted that a neurotoxin in rats induced an irreversible movement disorder and axonal damage similar to that caused by vitamin E deficiency. It was proposed that chronic neuroleptic use might produce free radicals, which would contribute to neurological damage and TD, and that the antioxidant effect of vitamin E could attenuate the damage (Cadet et al. 1986).

Pharmacological Profile In humans, symptoms of vitamin E deficiency are not very common, and they almost always result from malabsorption (Bieri and Farrell 1976). The only consistent laboratory finding is that subjects with low serum vitamin E levels demonstrate increased hemolysis of erythrocytes exposed to oxidizing agents (Leonard and Losowsky 1967). In addition, patients with glucose-6-phosphate dehydrogenase deficiency may have improved erythrocyte survival when treated with large doses (Corash et al. 1980).

Side Effects and Toxicology Side effects are minimal when vitamin E is given orally. High levels of vitamin E can exacerbate bleeding abnormalities that are associated with vitamin K deficiency. Dosages of up to 3,200 mg/day in studies for other conditions have been used without significant adverse effects (Kappus and Diplock 1992). The only known drug interactions are with vitamin K (when it is being given for a deficiency) and bleeding abnormalities and possibly with oral anticoagulants. High doses of vitamin E can exacerbate the coagulation abnormalities in both cases and therefore are contraindicated (Kappus and Diplock 1992).

Indications and Efficacy The only known indication for vitamin E is treatment of vitamin E deficiency, which almost always results from malabsorption syndromes or abnormal transport, such as with abetalipoproteinemia. In most cases, other vitamins and nutrients are also deficient; therefore, symptoms may not be the result of only vitamin E deficiency. Supplementation in children has been shown to be effective for the neurological symptoms resulting from malabsorption and vitamin E deficiency in chronic cholestasis

(Sokol et al. 1993). Apparently, there is also a rare condition of spinocerebellar degeneration caused by deficiency without malabsorption (Sokol 1988). Early studies of vitamin E treatment of TD demonstrated a range of results from general benefit (Adler et al. 1993; Dabiri et al. 1994; Lohr et al. 1988) to benefit only in subjects with TD of less than 5 years' duration (Egan et al. 1992; Lohr and Caligiuri 1996) to no benefit (Schmidt et al. 1991; Shriqui et al. 1992). Subsequently, a major prospective randomized trial treated 158 subjects with TD for up to 2 years with d-vitamin E (1,600 IU/day) or placebo (Adler et al. 1999). There were no significant effects of vitamin E on total scores or subscale scores for the AIMS, on electromechanical measures of dyskinesia, or on scores for four other scales measuring dyskinesia. The authors concluded that there was no evidence for efficacy of vitamin E in the treatment of TD (Adler et al. 1999).The use of vitamin E supplementation is not without risk. A meta-analysis of high-dosage vitamin E supplementation trials showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/day (E. R. Miller et al. 2005). Given the lack the data demonstrating consistent effectiveness for TD, we do not recommend that vitamin E be used for this purpose.

TREATMENT OF EXTRAPYRAMIDAL SIDE EFFECTS Acute Dystonic Reactions Intramuscular anticholinergics are the treatment of choice for ADRs. Benztropine 2 mg or diphenhydramine 50–100 mg generally will produce complete resolution within 20–30 minutes, with a second dose repeated after 30 minutes if there is not a complete recovery. Benztropine has been shown to resolve ADRs in less time than diphenhydramine (Lee 1979). Starting a standing dose of an antiparkinsonian agent afterward is generally not necessary. ADRs do not recur, unless large doses of high-potency antipsychotics are being used or unless the dose is increased. A more complete discussion of prophylaxis is given below.

Parkinsonism and Akathisia The initial steps in treatment of parkinsonism (Table 34–3) and of akathisia (referred to here as EPS) are identical: evaluating the dose and type of antipsychotic. It has been shown that an increase in dose beyond the neuroleptic threshold will not produce any greater therapeutic benefit but will increase EPS (Angus and Simpson 1970a; Baldessarini et al. 1988; McEvoy et al. 1991). It has also been demonstrated that EPS frequently can be eliminated with a reduction in dosage or a change to a lower-potency antipsychotic (Braude et al. 1983; Stratas et al. 1963). TABLE 34–3. Treatment of parkinsonism Step Action 1

Reduce dose of antipsychotic, if clinically possible.

2

Substitute a lower-potency antipsychotic, or carry out step 8.

3

Add an anticholinergic agent.

4

Titrate anticholinergic to maximum dose tolerable.

5

Add amantadine in combination with anticholinergic or as a single agent.

6

Add a benzodiazepine or a

7

In severe cases of EPS, stop antipsychotic temporarily and repeat process, beginning with step 3.

8

Substitute antipsychotic with atypical antipsychotic or clozapine.

-blocker.

If this approach does not resolve EPS, or if a lower-potency antipsychotic cannot be substituted, the

addition of an anticholinergic drug is the next step. Maximum therapeutic response occurs in 3–10 days, with more severe EPS taking a longer time to respond (DiMascio et al. 1976; Fann and Lake 1976). The anticholinergic dose should be increased until EPS are alleviated or until an unacceptable degree of anticholinergic side effects is obtained. Akathisia frequently does not respond as well to anticholinergic medications and amantadine as do parkinsonism and ADRs (DiMascio et al. 1976). Akathisia is more likely to be responsive to anticholinergic agents if symptoms of parkinsonism are also present (Fleischhacker et al. 1990). If EPS remain uncontrolled, amantadine can be either added to the regimen or substituted as a single agent. The next step would be the addition of a benzodiazepine or a

-blocker, although there are

fewer data supporting both of these treatments. In the case of severe EPS, the antipsychotic should be temporarily stopped, because severe EPS may be a risk factor for the development of neuroleptic malignant syndrome (Levinson and Simpson 1986). Additional drugs have been studied or suggested as treatments for akathisia. The data supporting the use of amantadine for the treatment of akathisia are limited. Clonidine has been studied in a small number of patients, but its benefit was limited by sedation and hypotension (Fleischhacker et al. 1990). Sodium valproate was reported to have had no significant effect on akathisia and was found to increase parkinsonism (Friis et al. 1983). Iron supplementation has been suggested as a possible treatment for akathisia (Blake et al. 1986). A review of this subject concluded that iron supplements would, at best, have no effect on akathisia but that they could potentially worsen the condition and promote further long-term damage (Gold and Lenox 1995). Iron supplementation therefore should not be considered a treatment for akathisia and should not be given indiscriminately.

Atypical Antipsychotics for Treatment of Parkinsonism and Akathisia Patients treated with clozapine were found to have significantly less parkinsonism than patients treated with the combination of chlorpromazine and an antiparkinsonian agent (benztropine) (Kane et al. 1988). The prevalence and incidence of akathisia have also been shown to be less in patients treated with clozapine than in patients treated with typical antipsychotics (Chengappa et al. 1994; Kurz et al. 1995; Stanilla et al. 1995). Subsequently, the new atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) have also been shown to produce less EPS than haloperidol. Paliperidone extended release was compared with placebo and found to have a comparable incidence of EPS. At lower doses, risperidone usually does not produce significant parkinsonism, but unlike clozapine, it can produce significant parkinsonism at higher doses (Chouinard et al. 1993). In initial studies comparing risperidone with haloperidol, the extrapyramidal scores for patients receiving risperidone were not significantly different from the scores of patients receiving placebo at 6 mg qd. Risperidone can cause ADRs, and patients with severe EPS at baseline were more likely to develop EPS when treated with risperidone (G. M. Simpson and Lindenmayer 1997). Subsequent studies have confirmed a reduced level of EPS with risperidone, compared with haloperidol (Csernansky et al. 2002). In general, risperidone has also been shown to produce less akathisia than haloperidol (Wirshing et al. 1999). Olanzapine has been shown to have an antipsychotic effect comparable to that of haloperidol while producing less dystonia, parkinsonism, and akathisia (Tollefson et al. 1997). The reduced incidence of EPS occurred across the entire therapeutic dosage range of 5–24 mg/day. Olanzapine has subsequently been shown to produce less parkinsonism and akathisia, compared with haloperidol, in patients with treatment-resistant schizophrenia (Breier and Hamilton 1999) and in patients with firstepisode psychosis (Sanger et al. 1999). Olanzapine has also been shown to have similar rates of EPS

and akathisia, compared with chlorpromazine, but without the need for any antiparkinsonian drugs (see Conley et al. 1998). Quetiapine has been found to have antipsychotic activity comparable to haloperidol at doses ranging from 150 to 750 mg/day while producing parkinsonism at a level similar to that produced by placebo across the entire dosage range (Arvanitis and Miller 1997; Small et al. 1997). For most patients, there were no significant changes in AIMS scores at baseline and in scores at the end of a 6-week period of treatment. A double-blind, dose-ranging trial comparing ziprasidone with haloperidol found comparable antipsychotic effect at higher dosages of ziprasidone. Concomitant benztropine use at any time during the study was less frequent with the highest dosage (160 mg/day) of ziprasidone (15%) than with haloperidol (53%) (Goff et al. 1998). Studies of ziprasidone found no significant differences in baseline-to-endpoint mean changes in Simpson-Angus Scale and AIMS scores with placebo or ziprasidone (40–160 mg/day) (Keck et al. 2001). Aripiprazole was found to be comparable to risperidone in antipsychotic effect while producing EPS comparable to those seen with placebo (Kane et al. 2002; Potkin et al. 2003). The most recent antipsychotic to gain FDA approval in the United States is paliperidone extended release (ER). Paliperidone ER was found to have an incidence of EPS nearly comparable to placebo (7% vs. 3%) at a dosage range of 3–15 mg/day (Kramer et al. 2007). A study comparing 150 patients who were treated with either risperidone or olanzapine found that a statistically significantly smaller percentage of patients treated with olanzapine (25.3%) required anticholinergic treatment than did patients treated with risperidone (45.3%) (Egdell et al. 2000). Another study involving 377 patients comparing risperidone with olanzapine found EPS to be similar in both groups (24% and 20%, respectively) and of low severity (Conley and Mahmoud 2001). Comparisons between clozapine and risperidone have found a reduced incidence of EPS for clozapine (Azorin et al. 2001). A study comparing the incidence of EPS produced by clozapine, risperidone, and typical antipsychotics found a hierarchy in the production of EPS, with clozapine producing the fewest EPS, followed by risperidone and then the typical antipsychotics (C. H. Miller et al. 1998). In general, the novel antipsychotics have a reduced incidence of EPS compared with high-potency typical antipsychotics. Data from the CATIE study suggest that the difference in incidence of EPS with an atypical antipsychotic may not be as great when compared with a moderate-potency typical antipsychotic. The difference in the incidence of EPS between an atypical antipsychotic and a typical antipsychotic has generally involved the comparison of a high-potency typical, specifically haloperidol. Data from the CATIE studies showed that there was no clinically significant difference in the incidence of parkinsonian symptoms and akathisia between the atypical agents and a moderate-potency typical agent, perphenazine. Although a statistically significantly greater number of perphenazine-treated subjects than of atypical-treated subjects discontinued treatment because of EPS (8% vs. 2%–4%), the incidence was low and of limited clinical significance. In the past, if a patient receiving a typical antipsychotic developed severe parkinsonism or akathisia and did not respond to antiparkinsonian treatment, the recommended strategy was to switch to an atypical antipsychotic. Now, the recommendation can be made to consider the use of a less potent typical antipsychotic as one of the options for treatment, along with possibly changing to an atypical. For patients with severe refractory EPS who have not responded to standard treatments, the use of clozapine specifically to treat the EPS is indicated (Casey 1989). This is particularly true for akathisia, given its significant negative correlation with the outcome of schizophrenia. This is also true for

patients who do not have any psychotic symptoms, if the EPS are judged to be severe enough to be disabling or potentially life-threatening, such as laryngeal dystonia.

Tardive Dyskinesia and Tardive Dystonia Historically, TD has been refractory to treatment, which explains the large number of drugs employed in attempts to alleviate the condition. Treatments investigated have included, but are not limited to, noradrenergic antagonists (propranolol and clonidine), antagonists of dopamine and other catecholamines, dopamine agonists, catecholamine-depleting drugs (reserpine and tetrabenazine), GABAergic drugs, cholinergic drugs (deanol, choline, and lecithin), catecholaminergic drugs (Kane et al. 1992), calcium channel blockers (Cates et al. 1993), and selective monoamine oxidase inhibitors (selegiline) (Goff et al. 1993). Based on the investigations of the above drugs, the American Psychiatric Association Task Force on TD concluded that there is no consistently effective treatment for TD (Kane et al. 1992). There are inherent difficulties in evaluating the effects of any treatment for TD. These include the variability of clinical raters (Bergen et al. 1984), placebo response (Sommer et al. 1994), and the diurnal and longitudinal variability of TD (Hyde et al. 1995; Stanilla et al. 1996). The degree of improvement needs to be greater than the sum of the above variations in order to demonstrate an actual benefit. The first step in evaluating TD is to determine the type of antipsychotic agent that is being used. If a typical antipsychotic is necessary, it is important to use the lowest dose possible (G. M. Simpson 2000). Second, if anticholinergic antiparkinsonian medications are being used, the patient should be gradually weaned from these medications and the medications then discontinued. Anticholinergic medications will make, in contrast to their effect on other extrapyramidal movements, TD movements worse (see Greil et al. 1984; Jeste and Wyatt 1982). Some drugs have been shown to have some benefit in the treatment of TD, but they have limitations. Clonazepam has been reported to reduce the movements of TD for up to 9 months, although tolerance to the benefits developed (Thaker et al. 1990). Additional limitations are the inherent problems associated with chronic use of a benzodiazepine. Botulinum toxin is beneficial for treating localized tardive dystonias, particularly laryngeal and cervical dystonias (Hughes 1994). The injections need to be repeated every 3–6 months, and botulinum toxin is not a general treatment for TD. Vitamin E has not consistently been shown to be beneficial in all studies, and a large long-term double-blind study found no benefit for vitamin E compared with placebo (Adler et al. 1999). Tardive dystonia also tends to be resistant to treatment; however, unlike TD, it may respond to anticholinergic medications (Wojcik et al. 1991) and to reserpine (Kang et al. 1988).

Atypical Antipsychotics for Treatment of Tardive Dyskinesia Clozapine has been shown to decrease the symptoms of TD (G. M. Simpson and Varga 1974; G. M. Simpson et al. 1978), with the greatest improvement occurring in cases of severe TD and tardive dystonia (Lieberman et al. 1991). These findings have been replicated and suggest that clozapine is unlikely to cause TD (Chengappa et al. 1994; Kane et al. 1993). The disadvantages to clozapine are the potential side effects of agranulocytosis and seizures and the need for regular blood monitoring. Three possible mechanisms for clozapine's benefit have been proposed. First, clozapine may suppress TD movements in a fashion similar to that of typical antipsychotics. Second, TD may improve spontaneously, given that the typical antipsychotics are no longer present to cause or sustain TD. Such improvement occurs in some patients when antipsychotics are withdrawn. Third, clozapine may have an active therapeutic effect on TD (Lieberman et al. 1991), but the issue remains to be clarified. In some patients, TD movements have recurred on withdrawal of clozapine.

More data demonstrating the potential benefit of the other novel antipsychotics in the prevention and treatment of TD are being reported. A prospective study examined the incidence of emergent dyskinesia in middle-aged to elderly patients (mean age 66 years) being treated with haloperidol and low-dose risperidone (mean total daily dose of 1 mg). The patients treated with risperidone were significantly less likely to develop TD (Jeste et al. 1999). A double-blind prospective study comparing 397 stable patients with schizophrenia who were switched to either risperidone or haloperidol and followed for at least a year found that only 1 of the patients receiving risperidone developed dyskinetic movements, compared with 5 of the patients receiving haloperidol (Csernansky et al. 2002). In a prospective double-blind study of patients with schizophrenia being treated with either olanzapine or haloperidol and followed for up to 2.6 years, there was a significantly decreased risk for the development of TD with olanzapine. The 1-year risk was 0.52% for olanzapine and 7.45% for haloperidol (Beasley et al. 1999). The data regarding the effect of quetiapine, ziprasidone, aripiprazole, and paliperidone on TD are more limited; however, any drug that is less likely to produce EPS is probably less likely to produce TD. The best treatment for TD is prevention. Of the 1,460 subjects involved in the CATIE study, D. D. Miller et al. (2005) found 212 to have probable TD by Schooler-Kane criteria. They found that subjects with TD were older, had a longer duration of receiving antipsychotic medications, and were more likely to have been receiving a conventional antipsychotic and an anticholinergic agent. They also found that substance abuse significantly predicted TD, as well as subjects with higher ratings of psychopathology, parkinsonian symptoms, and akathisia (D. D. Miller et al. 2005). Patients with TD who are taking typical antipsychotics are candidates for switching to an atypical antipsychotic. In the case of severe TD or dystonia that has been unresponsive to other treatment, the use of clozapine is indicated (G. M. Simpson 2000).

Prophylaxis of Extrapyramidal Side Effects Prophylactic use of antiparkinsonian agents to prevent EPS is a common, but not completely accepted, practice. Most controlled prospective studies regarding prophylactic use of antiparkinsonian medication have shown that prophylaxis can be beneficial for certain patients who are at high risk but that it is not beneficial in routine use across all patient groups (Hanlon et al. 1966; Sramek et al. 1986). Studies that have demonstrated a greater general benefit across all groups have involved the use of very high doses of antipsychotics. Several retrospective studies have also demonstrated that there is a limited need for prophylaxis of EPS (Swett et al. 1977). The retrospective studies that demonstrated a greater benefit from prophylaxis also involved the use of high antipsychotic dosages (Keepers et al. 1983; Stern and Anderson 1979). The prophylactic use of antiparkinsonian medication is not routinely indicated for all patients but should be reserved for those patients at high risk of developing ADRs. The risk factors for developing ADRs include younger age ( PBO

—

11

9

21

CBZ = PBO

—

82

80

28

48%

30%

Post et al. 1987 Emrich et al. 1985 Klein et al. 1984

(HAL) Müller and Stoll 1984;

CBZ vs. PBO adjunct

Goncalves and Stoll 1985

(HAL)

Desai et al. 1987

CBZ vs. PBO adjunct (Li)

Möller et al. 1989

CBZ vs. PBO adjunct (HAL)

Okuma et al. 1989

CBZ vs. PBO adjunct (NL)

Okuma et al. 1979

CBZ vs. NL (CPZ)

32

28

21–35

66%

54%

Grossi et al. 1984

CBZ vs. NL (CPZ)

18

19

21

67%

76%

Emrich 1990

OXC vs. NL (HAL)

19

19

14

OXC = HAL

—

CBZ vs. NL (HAL)

14

18

21

86%

67%

8

9

28

75%

33%

10

10

14

OXC = HAL

—

Stoll et al. 1986

adjunct (CPZ) D. Brown et al. 1989

CBZ vs. NL (HAL) adjunct (CPZ)

Müller and Stoll 1984

OXC vs. NL (HAL) adjunct (HAL)

Lerer et al. 1987

CBZ vs. Li

14

14

28

29%

79%

Small et al. 1991

CBZ vs. Li

24

24

56

33%

33%

Emrich 1990

OXC vs. Li

28

24

14

OXC = Li

—

Lenzi et al. 1986

CBZ vs. Li adjunct

11

11

19

73%

73%

22

22

42

CBZ = Li

—

50

51

28

62%

59%

713

658

(CPZ) Lusznat et al. 1988

CBZ vs. Li adjunct (CPZ, HAL)

Okuma et al. 1990

CBZ vs. Li adjunct (NL)

Total Response ratesa

Response ratesa

CBZ/OXC

55%

monotherapy

(237/433)

NL monotherapy

64% (30/47)

Li monotherapy

50% (19/38)

PBO monotherapy

28% (83/296)

CBZ/OXC adjunctive

59% (106/179)

NL adjunctive

56% (15/27)

Study

Design

CBZ/OXC

Comparator

Duration

CBZ/OXC

Comparator

(N)

(N)

(days)

response

response

Li adjunctive

61% (38/62)

PBO adjunctive

33% (31/93)

Note. CBZ = carbamazepine; CPZ = chlorpromazine; HAL = haloperidol; Li = lithium; NL = neuroleptic; NS = not stated; OXC = oxcarbazepine; PBO = placebo. a

Weighted means of patients with response data.

Two recent trials, which found a proprietary CBZ beaded extended-release capsule formulation (Equetro) superior to placebo, are of particular interest because they used a randomized, double-blind, placebo-controlled paradigm (Weisler et al. 2004, 2005) and yielded an FDA indication for the treatment of acute manic and mixed episodes in patients with bipolar disorder. These recent reports are consistent with multiple earlier studies using placebo–drug–placebo, active-comparator (lithium or neuroleptics), and adjunctive (compared with placebo, lithium, or neuroleptics added to lithium or neuroleptics) designs. Thus, across studies that used diverse paradigms (see Table 37–1), overall antimanic response rates were generally comparable to those seen with lithium or neuroleptics or in other studies with valproate (Ketter 2005). Taken together, this collection of clinical trials provides substantial evidence for the acute antimanic efficacy of CBZ and preliminary evidence for the acute antimanic efficacy of OXC. For CBZ, this current body of existing data appears greater than that initially considered by the FDA in approving lithium for the treatment of acute mania. Improvement appears to occur across the entire manic syndrome and does not seem to be due to nonspecific sedative properties, in that patients often show dramatic clinical improvement in the absence of marked sedation. Because CBZ and OXC are frequently used in combination with other medications in the acute treatment of mania, knowledge of CBZ's extensive and OXC's more limited drug–drug interactions (as described later in this chapter) is often required to achieve optimal outcomes.

Acute Depression There are limited controlled data regarding the acute antidepressant effects of CBZ, and no published controlled studies of the antidepressant effects of OXC (Table 37–2). Although CBZ appears to have weaker antidepressant than antimanic properties, some evidence suggests that it may provide antidepressant benefit in about one-third of treatment-resistant patients (Neumann et al. 1984; Post et al. 1986; Small 1990), and in a Chinese study, CBZ yielded a response rate closer to two-thirds in non-treatment-resistant patients (Zhang et al. 2007). Unfortunately, most of these studies are limited by the use of small samples of heterogeneous (both bipolar and unipolar) and highly treatment-resistant patients. Nevertheless, double-blind off–on–off–on observations and a randomized, double-blind, placebo-controlled trial have provided evidence of individual responsiveness in at least a subgroup of depressed bipolar patients. TABLE 37–2. Carbamazepine (CBZ) in acute depression: four controlled studies Study

CBZ

Comparator

Duration

CBZ

Comparator

(N)

(N)

(days)

response

response

35

35

Median 45

34%

—

Zhang et al. 2007 CBZ vs. PBO

47

23

84

64%

35%

Small 1990

NS

NS

28

32%

13%

5

5

28

CBZ = TMI

—

Post et al. 1986

Design

PBO–CBZ–PBO (24 BP, 11 UP)

CBZ/CBZ + Li vs. Li (4 BP, 24 UP)

Neumann et al.

CBZ vs. TMI (5 BP, 5 UP)

1984 Note. BP = bipolar; CBZ = carbamazepine; Li = lithium; NS = not stated; PBO = placebo; TMI = trimipramine; UP = unipolar.

Prophylaxis Findings from a series of 16 double-blind, randomized, open randomized, or otherwise partially controlled studies (Ballenger and Post 1978; Bellaire et al. 1988; Cabrera et al. 1986; Coxhead et al. 1992; Denicoff et al. 1997; Di

Costanzo and Schifano 1991; Elphick et al. 1988; Greil et al. 1997; Hartong et al. 2003; Kishimoto and Okuma 1985; Lusznat et al. 1988; Mosolov 1991; Okuma et al. 1981; Placidi et al. 1986); Post et al. 1983b; Watkins et al. 1987; Wildgrube 1990) are consistent with a very substantial open literature suggesting that CBZ may be effective in preventing bipolar manic and depressive episodes when administered as long-term prophylaxis, either alone or in combination with lithium, in patients who previously had not responded to lithium (Table 37–3). CBZ may have equal prophylactic antidepressant and antimanic efficacy, in contrast to its less potent acute antidepressant versus antimanic effects. In contrast, there are only sparse data regarding the efficacy of OXC in the prophylaxis of episodes in patients with bipolar disorder. TABLE 37–3. Carbamazepine (CBZ) and oxcarbazepine (OXC) in prophylaxis of bipolar disorder: 16 controlled or quasi-controlled studies Study

Okuma et al. 1981

Design

CBZ

Comparator

Duration

CBZ/OXC

Comparator

(N)

(N)

(years)

response

response

12

10

1

60%

22%

7

7

1.7

86%

—

20

16

3

67%

67%

19

18

1.5

84%

83%

16

15

1

56%

29%

13

15

1

54%

47%

CBZ vs. PBO (B, R)

Ballenger and Post 1978; Post

CBZ vs. PBO

et al. 1983b

(B, M)

Placidi et al. 1986

CBZ vs. Li (B, R)

Watkins et al. 1987

CBZ vs. Li (B, R)

Lusznat et al. 1988

CBZ vs. Li (B, R)

Coxhead et al. 1992

CBZ vs. Li (B, R)

Bellaire et al. 1988

CBZ vs. Li (R)

46

52

1

CBZ = Li

—

Greil et al. 1997

CBZ vs. Li (R)

70

74

2.5

45%

65%

Hartong et al. 2003

CBZ vs. Li (R)

50

44

2

58%

73%

8

8

5

CBZ + Li > Li

—

Di Costanzo and Schifano

CBZ + Li vs. Li

1991

(R)

Mosolov 1991

CBZ vs. Li (R?) 30

30

1

73%

70%

Cabrera et al. 1986

OXC vs. Li (R)

4

6

22

75%

100%

CBZ vs. Li (B,

8

11

0.75

38%

73%

46

50

1

33%

55%

Elphick et al. 1988

C) Denicoff et al. 1997

CBZ vs. Li (B, C)

Kishimoto and Okuma 1985

CBZ vs. Li (C)

18

18

2

CBZ > Li

—

Wildgrube 1990

OXC vs. Li

8

7

33

33%

67%

375

373

(NR) Total Response ratesa

CBZ/OXC

54% (165/303)

Li

64% (185/286)

PBO

22% (2/9)

Note. B = blind; C = crossover; CBZ = carbamazepine; Li = lithium; M = mirror image; NR = not randomized; OXC = oxcarbazepine; PBO = placebo; R = randomized. a

Weighted means of patients with response data.

In one study, the overall analysis suggested that maintenance treatment was more effective with lithium than with CBZ (Greil et al. 1997), but subsequent analysis revealed subgroup differences. Thus, maintenance treatment was

more effective with lithium than with CBZ in patients with "classic" bipolar disorder (bipolar I disorder with no mood-incongruent delusions or comorbidity) but tended to be more effective with CBZ than with lithium in patients with "nonclassic" bipolar disorder (bipolar II disorder, bipolar disorder not otherwise specified, bipolar disorder with mood-incongruent delusions or comorbidity) (Greil et al. 1998). In another study, maintenance treatment appeared to be more effective with lithium than with CBZ in patients with no more than 6 months' prior exposure to either agent (Hartong et al. 2003). However, this advantage was offset by more early discontinuations in the lithium group, so that similar proportions (about one-third) of lithium-treated and CBZ-treated patients completed 2 years with no episode. Patients on lithium compared to CBZ tended to have a somewhat greater risk of episodes in the first 3 months and markedly less risk of episodes after the first 3 months, with a recurrence risk of only 10% per year with lithium after the first 3 months. Patients on CBZ had a more consistent rate of relapse/recurrence of about 40% per year. Some CBZ prophylaxis trials have been criticized due to methodological limitations (D. J. Murphy et al. 1989), but such difficulties are common in maintenance studies. For example, apparently due in part to methodological limitations, divalproex and lithium failed to separate from placebo on the primary efficacy measure in a 1-year maintenance study (Bowden et al. 2000). Taken together, the randomized, placebo-controlled, placebo– drug–placebo, and lithium comparator studies and trials in patients with rapid-cycling or lithium-resistant illness constitute substantial evidence for the efficacy of CBZ (Prien and Gelenberg 1989). CBZ may be effective in some individuals with valproate-resistant illness (Post et al. 1984b), and the CBZ plus valproate combination may be effective in patients who show little or no response to either agent alone (Keck et al. 1992; Ketter et al. 1992). In a retrospective study, although 22 of 34 (65%) patients with treatment-resistant bipolar disorder responded to primarily adjunctive open CBZ acutely, when patients were assessed 3–4 years later, only 7 of 34 (21%) and 2 of 34 (6%) were considered probable and clear responders, respectively (Frankenburg et al. 1988). Post et al. (1990) have suggested that loss of CBZ prophylactic efficacy over time may be related to a unique form of contingent tolerance. In these instances, the optimal algorithm for recapturing CBZ response has not been determined. However, techniques such as switching to another treatment regimen with a different mechanism of action or returning later to CBZ (after a period of not taking CBZ) are worth considering, based on case reports and anecdotal observations. Systematic clinical trials are required to better determine the efficacy of these and other approaches for recapturing CBZ response.

Response Predictors Predictors of CBZ and OXC response have not been adequately elucidated. CBZ appears to be effective in patients with a history of lithium unresponsiveness or intolerance (Okuma et al. 1979; Post et al. 1987). Nonclassic bipolar disorder (Greil et al. 1998; Small et al. 1991) and stable or decreasing episode frequency (Post et al. 1990) have been reported to be associated with CBZ response. Studies have indicated that patients with a history of affective illness in first-degree relatives may have preferential responses to lithium, whereas the converse may be the case for CBZ (Ballenger and Post 1978; Post et al. 1987). Himmelhoch and colleagues (Himmelhoch 1987; Himmelhoch and Garfinkel 1986) have suggested that patients with comorbid neurological or substance abuse problems and inadequate lithium responses might respond to CBZ or valproate. Preliminary observations indicate that baseline cerebral (left insula) hypermetabolism may be a marker of CBZ response (Ketter et al. 1999). There are varying reports with respect to the relationships between CBZ response and dysphoric manic presentations (Lusznat et al. 1988; Post et al. 1989) and illness severity (Post et al. 1987; Small et al. 1991). Although several investigators have suggested that psychosensory symptoms (which have been hypothesized to be due to limbic dysfunction) may indicate preferential response to CBZ and other anticonvulsants, such a relationship has not been observed in acute therapy, and the relationship to prophylactic response remains to be delineated. Antidepressant responses to CBZ may be seen in patients with more severe depression, more discrete depressive episodes, less chronicity, and greater decreases in serum T4 concentrations with CBZ (Post et al. 1991, 1986). Although the initial studies of Post et al. (1987) and Okuma et al. (1981; Okuma 1983) indicated that some rapidcycling patients were responsive to CBZ, other investigators found less robust results (Dilsaver et al. 1993; Joyce 1988). As with lithium, later studies by Okuma (1993) reported a lower CBZ maintenance response rate in rapidcycling compared with non-rapid-cycling illness. However, even these rapid-cycling patients had a CBZ response rate (40%) that was higher than the rates reported for other agents in other studies. Denicoff et al. (1997) also observed that patients with a history of rapid cycling had a lower CBZ maintenance response rate compared with

those without such a history (19% vs. 54%).

SIDE EFFECTS AND TOXICOLOGY Baseline evaluation of bipolar disorder patients includes not only psychosocial assessment but also general medical evaluation, in view of the risk of medical processes, which could confound diagnosis or influence management decisions, and the risk of adverse effects, which may occur with treatment. Assessment commonly includes history; physical examination; complete blood count with differential and platelets; renal, hepatic, and thyroid function; toxicology; pregnancy tests; and other chemistries and electrocardiogram as clinically indicated (American Psychiatric Association 2002). Such evaluation provides baseline values for parameters that influence decisions about choice of medication and intensity of clinical and laboratory monitoring.

Carbamazepine CBZ adverse effects appear to have substantial impact on the utility of CBZ in the treatment of bipolar disorder. For example, in a retrospective study, 12 of 55 (22%) patients with treatment-resistant psychotic disorders (including 34 with bipolar disorder) discontinued primarily adjunctive open CBZ in the first 2 months because of adverse effects (Frankenburg et al. 1988). Also, in a randomized, double-blind crossover maintenance study, significantly more patients receiving CBZ (10 of 46, 22%) than those receiving lithium (2 of 50, 4%) discontinued the drug early because of adverse effects (Denicoff et al. 1997). In a randomized open maintenance study, although nonsignificantly more CBZ (9 of 70, 13%) than lithium (4 of 74, 5%) patients discontinued early because of adverse effects, significantly more CBZ (26 of 33, 79%) than lithium (20 of 51, 39%) patients who completed the study were free of adverse effects (Greil et al. 1997). Thus, adverse effects requiring discontinuation may occur more commonly with CBZ than with other drugs, particularly during acute therapy if CBZ is rapidly introduced. However, some patients may tolerate CBZ better than other agents, particularly during longer-term treatment, as CBZ appears to have a low propensity to cause adverse effects such as weight gain and metabolic disturbance that can limit the utility of some other agents (Ketter et al. 2005). CBZ has several common dose-related adverse effects that can generally be minimized by attention to drug–drug interactions and gradual titration of dosage or reversed by decreasing dosage. At high doses, patients can develop neurotoxicity with sedation, ataxia, diplopia, and nystagmus, particularly early in therapy before autoinduction and the development of some tolerance to CBZ's central nervous system adverse effects occur. However, in contrast to neuroleptic treatment, CBZ therapy is not associated with extrapyramidal adverse effects. Because there is wide interindividual variation in susceptibility to adverse effects at any given concentration, it is most useful clinically to titrate doses against each patient's adverse effects rather than targeting a fixed dosage or serum concentration range. Dizziness, ataxia, or diplopia emerging 1–2 hours after an individual dose is often a sign that the adverse-effect threshold has been exceeded and that dosage redistribution (spreading out the dose or giving more of the dosage at bedtime) or dosage reduction may be required. Use of extended-release formulations can also attenuate CBZ peak serum concentrations, enhancing tolerability. The United States prescribing information for carbamazepine includes black box warnings regarding the risks of aplastic anemia (16 per million patient-years) and agranulocytosis (48 per million patient-years), as well as serious dermatological reactions and the HLA-B*1502 allele. Other warnings include the risks of teratogenicity, and increased intraocular pressure due to mild anticholinergic activity. Thus, CBZ can yield hematological (benign leukopenia, benign thrombocytopenia), dermatological (benign rash), electrolyte (asymptomatic hyponatremia), and hepatic (benign transaminase elevations) problems. Much less commonly, CBZ can yield analogous serious problems. For example, mild leukopenia and benign rash occur in as many as 1 of 10 patients, with the slight possibility that these usually benign phenomena are heralding malignant aplastic anemia and Stevens-Johnson syndrome/toxic epidermal necrolysis, seen in approximately 1 per 100,000 and 1 to 6 per 10,000 patients, respectively (Kramlinger et al. 1994; Tohen et al. 1995). Recent evidence indicates that the risk of serious rash may be 10 times as high in some Asian countries and strongly linked to the HLA-B*1502 allele. Thus, the United States prescribing information states that individuals of Asian descent should be genetically tested before initiating carbamazepine therapy. An individual who is HLA-B*1502 positive should not be treated with CBZ unless the benefit clearly outweighs the risk. In view of the risk of rare but serious decreases in blood counts, it is important to alert patients to seek immediate medical evaluation if they develop signs and symptoms of possible hematological reactions, such as fever, sore throat, oral ulcers, petechiae, and easy bruising or bleeding. Hematological monitoring needs to be intensified in patients with low or marginal leukocyte counts, and CBZ is generally discontinued if the leukocyte count falls below 3,000/mm3 or the granulocyte count below 1,000/mm3.

In early 2008, the FDA released an alert regarding increased risk of suicidality (suicidal behavior or ideation) in patients with epilepsy as well as psychiatric disorders for 11 anticonvulsants (including CBZ and OXC). In the FDA's analysis, anticonvulsants compared with placebo yielded approximately twice the risk of suicidality (0.43% vs. 0.22%). The relative risk for suicidality was higher in patients with epilepsy than in patients with psychiatric disorders. As of late 2008, a class warning regarding this risk had not yet been added to the United States prescribing information for anticonvulsants, but it is anticipated that this may occur. In the instance of benign leukopenia, the addition of lithium can increase the neutrophil count back toward normal (Kramlinger and Post 1990), but this strategy is not likely to be helpful for the suppression of red cells or platelets, which is likely to be indicative of a more problematic process. Rash presenting with systemic illness or involvement of the eyes, mouth, or bladder (dysuria) constitutes a medical emergency, and CBZ should be discontinued immediately and the patient assessed emergently. For more benign presentations, CBZ is generally discontinued, as there is little ability to predict which rashes will progress to more severe, potentially life-threatening problems. However, in rare instances of resistance to all medications except CBZ, a repeat trial of CBZ with a course of prednisone has usually been well tolerated (J. M. Murphy et al. 1991; Vick 1983). If there is evidence of systemic allergy, fever, or malaise, prednisone is less likely to be helpful. A substantial number of patients with CBZ-induced rashes may not have a rash on reexposure (even without prednisone coverage), but if a rash again develops, it usually appears more rapidly than in the first occurrence. Only 25%–30% of the patients who develop a rash while taking CBZ also develop a rash (cross-sensitivity) with OXC. Due to the risk of rare hepatitis, patients should be advised to seek medical evaluation immediately if they develop malaise, abdominal pain, or other marked gastrointestinal symptoms. In general, CBZ (like other anticonvulsants) is discontinued if liver function tests exceed three times the upper limit of the normal range (Martinez et al. 1993). CBZ may affect cardiac conduction and should be used with caution in patients with cardiac disorders such as heart block. A baseline electrocardiogram is worth considering if the patient has a positive cardiac history. Conservative laboratory monitoring during CBZ therapy includes baseline studies and reevaluation of complete blood count, differential, platelets, and hepatic indices initially at 2, 4, 6, and 8 weeks, and then every 3 months (American Psychiatric Association 1994, 2002). Most of the serious hematological reactions occur in the first 3 months of therapy (Tohen et al. 1995). In contemporary clinical practice, somewhat less focus is placed on scheduled monitoring; instead, monitoring as clinically indicated (e.g., when a patient becomes ill with a fever) is emphasized. Patients who have abnormal or marginal indices at any point merit careful scheduled and clinically indicated monitoring. The United States prescribing information for the beaded extended-release capsule CBZ formulation that was recently approved for the treatment of acute mania includes monitoring baseline complete blood count, platelets, ±reticulocytes, ±serum iron, and hepatic function tests; closely monitoring patients with low or decreased white blood cell count or platelets; and considering discontinuation of CBZ if there is evidence of bone marrow depression ("Equetro" 2008). Serum CBZ concentrations are typically assessed at steady state and then as clinically indicated (e.g., by inefficacy or adverse effects). Dividing or reducing doses, moving doses in relation to mealtimes, and changing formulations can attenuate CBZ-induced gastrointestinal disturbances. CBZ suspension may have more proximal absorption and thus exacerbate upper gastrointestinal (nausea and vomiting) or attenuate lower gastrointestinal (diarrhea) adverse effects. The reverse holds for extended-release preparations. Weight gain and obesity are important clinical concerns in the management of bipolar disorder. Medications and the hyperphagia, hypersomnia, and anergy commonly seen in bipolar depression can contribute to this important obstacle to optimal outcomes. CBZ is less likely than lithium (Coxhead et al. 1992; Denicoff et al. 1997) or valproate (Mattson et al. 1992) to yield weight gain. In one study, CBZ caused weight gain in depressed (but not manic) patients, an effect that seemed to be related to the degree of relief of depression (Joffe et al. 1986b). Nevertheless, in view of its relatively favorable effect on weight, CBZ may provide an important alternative to other mood stabilizers for patients who struggle with weight gain and obesity. CBZ can induce hyponatremia that may be tolerated well by some younger patients but can be particularly problematic in the elderly. If confusion develops in an elderly patient, serum sodium should be assessed. In rare instances water intoxication and seizures can occur. In some cases, hyponatremia can be effectively counteracted with the addition of lithium or the antibiotic demeclocycline (Ringel and Brick 1986). CBZ increases plasma high-density lipoprotein (HDL) (O'Neill et al. 1982) and total cholesterol (D. W. Brown et al.

1992) concentrations. However, because the ratio of HDL to total cholesterol does not change (O'Neill et al. 1982), CBZ-induced increases in total cholesterol are not likely to be clinically problematic in regard to atherosclerosis (D. W. Brown et al. 1992). CBZ decreases serum T4, free T4 index, and, less consistently, triiodothyronine (T3) (Bentsen et al. 1983; Connell et al. 1984; Haidukewych and Rodin 1987; Joffe et al. 1986a) but does not substantially alter serum thyroidbinding globulin, reverse T3, basal thyroid-stimulating hormone (TSH) concentrations (Bentsen et al. 1983; Connell et al. 1984), or somatic basal metabolic rates (Herman et al. 1991). In contrast to lithium, the TSH response to thyrotropin-releasing hormone is blunted (Joffe et al. 1986a) or unaltered (Connell et al. 1984) with CBZ therapy, and clinical hypothyroidism during treatment with CBZ is exceedingly rare. CBZ is teratogenic (Pregnancy Category D) and is associated with low birth weight, craniofacial deformities, digital hypoplasia, and (in approximately 3% of exposures) spina bifida (Jones et al. 1989; Rosa 1991). For the latter, folate supplementation may attenuate the risk, and fetal ultrasound studies may allow early detection. In rare patients with severe mood disorders, clinicians may determine in consultation with a gynecologist that the benefits of treating with CBZ outweigh the risks in comparison with other treatment options (Sitland-Marken et al. 1989). CBZ is present in breast milk at concentrations about half those present in maternal blood but may not accumulate in fetal blood (Froescher et al. 1984; Kuhnz et al. 1983; Pynnönen et al. 1977; Shimoyama et al. 2000). Clinicians may prefer to avoid the putative risks of exposing infants to CBZ in breast milk (Frey et al. 2002) and discourage breast-feeding in women taking CBZ ("Carbatrol" 2008; "Tegretol" 2008).

Oxcarbazepine Adverse effects may limit the use of OXC, as with CBZ. In a retrospective study, adverse events were noted in one-third of 947 epilepsy patients (Friis et al. 1993). However, OXC may have tolerability advantages over CBZ, in part perhaps related to the absence of the CBZ-E metabolite. For example, in a 1-year randomized, double-blind study of 235 patients with newly diagnosed epilepsy, OXC monotherapy yielded fewer severe adverse effects than CBZ monotherapy (Dam et al. 1989). OXC and valproate may have similar tolerability; in a 1-year randomized, double-blind study of 249 patients with newly diagnosed epilepsy, monotherapy with these agents had similar rates of adverse effects (Christe et al. 1997). Importantly, OXC yielded anticonvulsant effects similar to those of CBZ and valproate in the above-mentioned studies. Much less is known about the tolerability of OXC in bipolar disorder patients. In randomized, double-blind studies of monotherapy for acute mania, the proportions of patients experiencing adverse effects were lower with OXC 2,400 mg/day (2 of 19, 10%) than with high-dose haloperidol 42 mg/day (7 of 19, 37%) and were not statistically different with OXC 1,400 mg/day (8 of 29, 28%) compared with lithium 1,100 mg/day (5 of 27, 19%) (Emrich 1990). A retrospective study of open OXC in acutely manic inpatients found that by the time of discharge, only 6 of 200 (3%) had discontinued the medication because of adverse effects (3 due to hyponatremia) or potential drug–drug interactions (3 due to concomitant treatment with hormonal contraceptives) (Reinstein et al. 2002). However, in another retrospective study of primarily depressed patients with treatment-resistant bipolar disorder, 7 of 13 (54%) patients discontinued primarily adjunctive OXC because of adverse effects (Ghaemi et al. 2002). OXC appears to yield less neurotoxicity and rash than CBZ. In a retrospective study of 947 epilepsy patients, OXC adverse effects most frequently involved the central nervous system and included dizziness, sedation, and fatigue, each of which was noted in 6% of patients (Friis et al. 1993). Rash was seen in 6% of patients, half of whom had previously experienced CBZ allergic reactions. About 75% of patients with a rash on CBZ will tolerate OXC. Importantly, OXC has not been associated with blood dyscrasias, lacks a boxed warning in the prescribing information, and does not appear to require hematological monitoring. As noted earlier for CBZ, in early 2008 the FDA released an alert regarding increased risk of suicidality (suicidal behavior or ideation) in patients with epilepsy as well as psychiatric disorders for 11 anticonvulsants (including OXC and CBZ). As of late 2008, a class warning regarding this risk had not yet been added to the United States prescribing information for anticonvulsants, but it is anticipated that this may occur. OXC, like CBZ, may produce transaminase elevations and gastrointestinal adverse effects but is associated with less weight gain than valproate (Rattya et al. 1999). In addition, OXC may have less impact on lipids than does CBZ; in 12 male patients with epilepsy, switching to OXC from CBZ yielded decreased serum total cholesterol (but not HDL cholesterol or triglyceride) concentrations (Isojarvi et al. 1994). Hyponatremia occurs with OXC (Friis et al. 1993) and may be the main adverse effect that occurs more commonly

than with CBZ. In one study of 10 male epileptic patients who switched to OXC monotherapy from CBZ monotherapy, mean serum sodium concentrations decreased—in 2 of 10 (20%), below the reference range (Isojarvi et al. 2001a). However, clinically significant hyponatremia is less common than asymptomatic hyponatremia. In a retrospective study of inpatients with acute mania, OXC yielded serum sodium concentrations below the reference range in 24 of 200 (12%), but only 3 of 200 (1.5%) discontinued as a result of hyponatremia with serum sodium less than 125 mmol/L (Reinstein et al. 2002). In comparison with CBZ, OXC has less impact on blood concentrations of thyroid and sex hormones, likely because of its less marked hepatic enzyme induction. In one study, only 24% of 29 male epileptic patients taking OXC—versus 45% of 40 taking CBZ—had low serum total and/or free T4 (but not T3 and thyrotropin) concentrations (Isojarvi et al. 2001b). In addition, male epileptic patients taking CBZ (but not those taking OXC) had decreased serum dehydroepiandrosterone sulfate concentrations (Rattya et al. 2001). Switching to OXC from CBZ in male epileptic patients yielded increased serum dehydroepiandrosterone sulfate concentrations (Isojarvi et al. 1995). In healthy male volunteers, higher ( 900 mg/day) but not lower (PBOCGI-I:

66)PBO (n = 65)

LTG>PBO

Acute monotherapy LTG 100–400 mg/day (n = 10 weeks NS 103)PBO (n = 103)

I

Acute monotherapy LTG 200 mg/day (n =

8 weeks

NS

133)PBO (n = 124) II

Acute monotherapy LTG 200 mg/day (n =

2008 (SCA 100223) depression

8 weeks

111)PBO (n = 124)

MADRS: NSHam-D: NSCGI-I responders: LTG>PBO

Calabrese et al.

Bipolar

2008 (SCA 30924)

depression

E. B. Brown et al.

Bipolar

2006

depression

I

Acute monotherapy LTG 200 mg/day (n =

I

I or II

Acute monotherapy LTG 200 mg/day (n =

NS

mg/day (n = 205)

OFC>LTG

Acute, add-on

LTG 200 mg/day (N =

therapy

64)PBO (N = 60)

Maintenance

LTG 50, 200, or 400

Bipolar depression

Calabrese et al.

Bipolar

2003 (605)

depression

monotherapy

mg/day(n = 221)Li 0.8–1.1

(index

following open

mEq/L (n = 121)PBO (n =

episode)

stabilization

121)

I

Acute monotherapy LTG 50 mg/d (n = 84)Li

(609)

MADRS: OFC>LTGCGI-S:

van der Loos et al.

I

7 weeks

205)OFC up to 12/50

2006

Bowden et al. 2000 Mania

8 weeks

131)PBO (n = 128)

8 weeks

MADRS: LTG>PBOCGI-I: NS

76 weeks LTG>PBOLi>PBO

3 weeks

NS

6 weeks

LTG: NSLi>PBO

0.8–1.3 mEq/L (n = 36)PBO (n = 95)

Bowden et al. 2000 Mania

I

(610)

Acute, add-on

LTG 200 mg/day (n =

therapy

74)Li 0.7–1.3 mEq/L (n = 78)PBO (n = 77)

Bowden et al. 2003 Mania (index (606)

I

episode)

Maintenance

LTG 100–400 mg/day (n = 76 weeks LTG>PBOLi>PBO

monotherapy

59)Li 0.8–1.1 mEq/L (n =

following open

46)PBO (n = 70)

stabilization GlaxoSmithKline

Rapid cycling

I and II

Study* (611) Calabrese et al. 2000 (614)

Rapid cycling

I and II

Prophylaxis,

LTG 100–500 mg/day (n = 32 weeks NS

add-on therapy

68)PBO (n = 69)

Maintenance

LTG 100–500 mg/day (n = 26 weeks LTG>PBO for BP II

monotherapy

92)PBO (n = 88)

following open

Study (protocol

Mood state

number)

Bipolar

Study type

Dose

Duration Response or overall

subtype

efficacy stabilization

Laurenza et al.

Unipolar

1999 (613)

depression

N/A

Acute monotherapy LTG 200 mg/day (n =

8 weeks

142)Desipramine 200

Ham-D: NSMADRS: NSCGI-S: LTG>PBO

mg/day (n = 147)PBO (n = 145) DeVeaugh-Geiss et

Unipolar

al. 2000 (20022)

depression

DeVeaugh-Geiss et

Unipolar

al. 2000 (20025)

depression

N/A

Acute monotherapy LTG 200 mg/day (n =

7 weeks

NS

7 weeks

NS

74)PBO (n = 75) N/A

Acute monotherapy LTG 200 mg/day (n = 151)PBO (n = 150)

* = data on file, GlaxoSmithKline BP I = bipolar I disorder; BP II = bipolar II disorder; CGI-I = Clinical Global Impression–Improvement Scale; CGI-S = Clinical Global Impression–Severity Scale; Ham-D = Hamilton Rating Scale for Depression; Li = lithium; LTG = lamotrigine; MADRS = Montgomery-Åsberg Depression Rating Scale; N/A = not applicable; NS = not statistically significant (P 0.05); OFC = olanzapine– fluoxetine combination; PBO = placebo.

Alternative Clinical Applications Case studies and open-label reports have been published supporting further investigation of lamotrigine for use in the treatment of myriad disorders and behavioral symptoms, including depersonalization disorder (Sierra et al. 2006), impulsive behavior (Daly and Fatemi 1999); Alzheimer's disease (Tekin et al. 1998), aggression in dementia (Devarajan and Dursun 2000), borderline personality disorder (Pinto and Akiskal 1998), posttraumatic stress disorder (Hertzberg et al. 1999), treatment-resistant unipolar depression (Gabriel 2006), alcohol (Rubio et al. 2006) and cocaine dependence (E. S. Brown et al. 2006) comorbid with bipolar disorder, schizoaffective disorder (Erfurth et al. 1998b), Rett syndrome (Stenbom et al. 1998), self-injurious behavior in the profoundly mentally retarded (Davanzo and King 1996), refractory schizophrenia (coadministered with clozapine [Saba et al. 2002]), and decreased consciousness with impaired cognition in severe brain injury (Showalter and Kimmel 2000).

DOSING The recommended titration schedule for lamotrigine added to valproate in adult patients begins at 25 mg every other day for 14 days, advances to 25 mg daily for 14 days, and then increases by 50 mg daily beginning each of the fifth and sixth week of treatment, reaching a target dose of 100 mg daily (Table 39–2). Titration of adjunctive lamotrigine in the presence of an enzyme inducer begins at 50 mg daily for 14 days, advances to 100 mg daily (divided doses) for 14 days, to a target dosage of 400 mg daily (Table 39–3). There are no published data supporting greater efficacy of lamotrigine in the treatment of bipolar disorder at dosages greater than 200 mg/day. Additionally, there is no clear association between serum levels of lamotrigine and measures of affective response. TABLE 39–2. Recommended titration schedule for lamotrigine for patients with bipolar disorder taking valproate Week

Dosage

Weeks 1 and 2

25 mg every other day

Weeks 3 and 4

25 mg daily

Week 5

50 mg daily

Week 6

100 mg daily

Week 7

100 mg daily

The usual maintenance dosage when lamotrigine is added to valproate is 100 mg/day. Source. Adapted from GlaxoSmithKline 2007. TABLE 39–3. Recommended titration schedule for lamotrigine when used as monotherapy and when added to an enzyme-inducing antiepileptic drug regimen* (without valproate) For patients not taking an enzyme-inducing

For patients taking an enzyme-inducing

antiepileptic drug regimen* and not taking

antiepileptic drug regimen* and not taking

valproate

valproate

For patients not taking an enzyme-inducing

For patients taking an enzyme-inducing

antiepileptic drug regimen* and not taking

antiepileptic drug regimen* and not taking

valproate

valproate

Weeks 1 and 2

25 mg daily

50 mg daily

Weeks 3 and 4

50 mg daily

100 mg/day (in two divided doses)

Week 5

100 mg daily

200 mg daily (in two divided doses)

Week 6

200 mg daily

300 mg daily (in two divided doses)

Usual

200 mg daily

400 mg daily (in two divided doses)

maintenance dosage *Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. Source. Adapted from GlaxoSmithKline 2007.

SIDE EFFECTS AND TOXICITY In trials of epileptic patients who received adjunctive or monotherapy lamotrigine, the spectrum of reported side effects included dizziness, headache, diplopia, nausea, and ataxia (Messenheimer et al. 1998). In controlled monotherapy trials in mood disorders, lamotrigine has been associated with headache, changes in sleep habits, nausea, and dizziness (Bowden et al. 2004). Although the prevalence of rash in mood disorder randomized trials did not exceed that of placebo, rash is generally recognized as the side effect most likely to significantly complicate lamotrigine's clinical use (see "Rash" subsection below). A unique feature of lamotrigine in comparison with other agents used in the management of bipolar disorder is its weight-neutral tolerability profile. Among 583 patients with bipolar disorder treated with lamotrigine, lithium, or placebo for 52 weeks, a pooled analysis showed that the percentage of patients with a greater than 7% increase in weight or change in weight did not differ between those treated with lamotrigine and those treated with lithium or placebo (Sachs et al. 2006). A higher percentage of lamotrigine-treated subjects than of lithium-treated subjects lost more than 7% of their body weight. A post hoc analysis revealed that nonobese patients taking lamotrigine are unlikely to experience a change in weight. However, obese patients are significantly more likely to lose weight with lamotrigine and to gain weight with lithium (Bowden et al. 2006). Clinical case reports made since the release of lamotrigine have included rare associations with Tourette's syndrome (Lombroso 1999); obsessionality in the form of intrusive, repetitive phrases (Kemp et al. 2007); nephritis with colitis (Fervenza et al. 2000); eosinophilic hepatitis (Fix et al. 2006); visual loss due to cicatrizing conjunctivitis (McDonald and Favilla 2003); female sexual dysfunction (Erfurth et al. 1998a); lupus erythematosus (Sarzi-Puttini et al. 2000); stupor (Sbei and Campellone 2001); and hyponatremia in patients with diabetes insipidus (Mewasingh et al. 2000). Hypersensitivity reactions (multiorgan failure/dysfunction, hepatic abnormalities, disseminated intravascular coagulation) have also occurred with lamotrigine use.

Rash Incidence and Prevalence In early epilepsy trials, rash led to hospitalization and treatment discontinuation or Stevens-Johnson syndrome in 0.3% of adults treated with lamotrigine. During the controlled phase of 12 multicenter trials, no cases of serious rash occurred in lamotrigine-treated subjects (Calabrese et al. 2002). Among 1,955 patients treated with lamotrigine in an open-label setting, there was 1 case of mild Stevens-Johnson syndrome and 2 cases of serious rash. Both cases of serious rash resolved uneventfully upon lamotrigine discontinuation, with one case requiring additional treatment with oral steroids. The annual incidence of serious drug-based skin reactions associated with lamotrigine was highest in 1993 (4.2%) but steadily declined and had stabilized by 1998 (0.02%). This is likely attributable to the manufacturer's dosage revision in 1994, which advised a more protracted titration schedule (Calabrese et al. 2002; Messenheimer et al. 1998). It is well documented that the risk of rash is heightened in children younger than 12 years, by the coadministration of valproic acid, or by exceeding the recommended initial dosage or rate of dosage escalation of lamotrigine.

Clinical Management

The most common lamotrigine-associated rash is an exanthematic maculopapular or morbilliform eruption that is benign. However, a clinically similar eruption may be associated with more rare and serious systemic hypersensitivity reactions (Guberman et al. 1999). Thus, all patients who develop a rash during the first few months of lamotrigine therapy should be instructed to hold the next dose and immediately seek medical consultation. The greatest risk of rash appears to be during the first 8 weeks of treatment. A rash during the first 5 days of therapy is usually due to a nondrug cause. Figure 39–2 presents a decision-making algorithm for the management of benign and serious rashes. A serious lamotrigine rash is usually confluent with prominent facial and neck involvement. The rash may be tender or have a purpuric or hemorrhagic appearance. It is accompanied or preceded by fever, malaise, pharyngitis, anorexia, or lymphadenopathy (Guberman et al. 1999). Rashes with any feature(s) suggestive of a serious reaction necessitate immediate drug cessation, followed by monitoring for hepatic, renal, and hematological involvement. Tavernor et al. (1995) reported successfully restarting patients on lamotrigine after mild isolated rash; however, re-titration should progress slowly and begin at 5–12.5 mg/day. Patients should not be rechallenged if they have had a serious rash, such as a reaction associated with systemic symptoms or internal toxicity (Besag et al. 2000). Because immune tolerance to lamotrigine is lost following interruption of dosage for more than 1 week, patients should be instructed to resume lamotrigine at the prior initial start-up dose and gradually titrate upwards whenever therapy has been interrupted for more than a few days. FIGURE 39–2. Clinical management of rash related to lamotrigine treatment.

CBC = complete blood count; LFT = liver function test. Source. Reprinted from Calabrese JR, Sullivan JR, Bowden CL, et al: "Rash in Multicenter Trials of Lamotrigine in Mood Disorders: Clinical Relevance and Management." Journal of Clinical Psychiatry 63:1012–1019, 2002. Copyright 2000, Physicians Postgraduate Press. Used with permission. To explore whether the incidence of dermatological reactions could be mitigated by adherence to a series of dermatological precautions, Ketter et al. (2006) led an intervention study that randomly assigned patients to usual precautionary care versus dermatological precautionary care prior to initiation of lamotrigine therapy. Outpatients 13

years of age and older received 12 weeks of open-label lamotrigine and were instructed not to exceed the recommended initial dosage or dosage-escalation schedule. Those in the dermatological precautions group were instructed not to ingest new food, receive immunizations, or use new conditioners, cosmetics, soaps, detergents, or fabric softeners and to reduce exposure to poison ivy. Among 1,139 subjects enrolled into the trial, none experienced a serious rash. The incidence of nonserious rash did not differ between the usual care group (8.8%) and those advised to follow dermatological precautions (8.6%). Attention must be drawn to the black box warning in the prescribing information, which instructs prescribers to ordinarily discontinue lamotrigine "at the first sign of rash, unless the rash is clearly not drug related" because "it is not possible to predict reliably which rashes will prove to be serious or life threatening" (GlaxoSmithKline 2007).

Overdose Among 493 cases of lamotrigine toxicity in overdose, the majority of patients (52.1%) experienced no toxic clinical effects (Lofton and Klein-Schwartz 2004). Common symptoms included drowsiness, vomiting, nausea, ataxia, dizziness, and tachycardia. Rare cases of coma, seizures, heart conduction delay, and respiratory depression have been reported in overdose. Some ingestions of lamotrigine involving quantities up to 15 grams have been fatal.

Use During Pregnancy Lamotrigine may represent an option for women with bipolar disorder during pregnancy due to its favorable tolerability profile and maintenance effects against bipolar depression. An observational study by Newport et al. (2008) examined risk of illness recurrence in pregnant women with stable bipolar disorder who continued lamotrigine treatment during pregnancy (n = 10) versus those who discontinued mood stabilizer therapy during pregnancy (n = 16). The risk of illness recurrence was 3.3 times lower when lamotrigine was continued (30.0% recurrence [3/10] vs. 100% recurrence [16/16] when patients discontinued mood stabilizers; P

Chapter 40. Topiramate HISTORY AND DISCOVERY Topiramate is a derivative of the naturally occurring monosaccharide D-fructose. It was originally synthesized to be a structural analog of fructose-1,6-diphosphatase as part of a project to develop agents that inhibit gluconeogenesis by inhibiting the enzyme fructose-1,6-biphosphatase (Shank et al. 2000). To date, however, it has not been shown by clinical evidence to have direct hypoglycemic activity. Topiramate contains a sulfamate moiety. The structural resemblance of this moiety to the sulfonamide moiety in the established antiepileptic drug acetazolamide prompted researchers to evaluate topiramate for possible anticonvulsant effects. Topiramate subsequently was shown to have potent anticonvulsant properties in a broad range of preclinical epilepsy models (Shank et al. 2000). The drug's efficacy in patients with epilepsy was established in the early 1990s. These studies also showed that topiramate had a favorable pharmacokinetic profile, had a high therapeutic index, was not associated with hematological or hepatic abnormalities, did not require routine serum concentration monitoring, and was associated with anorexia and weight loss (rather than appetite stimulation and weight gain like some other antiepileptic drugs) (Langtry et al. 1997). Topiramate was approved by the U.S. Food and Drug Administration (FDA) for the treatment of epilepsy in 1996. It was approved for migraine prevention in adults in 2004. Reports appearing in the late 1990s of the drug having potential beneficial effects in bipolar disorder led Johnson and Johnson Pharmaceutical Research and Development (PRD), the discoverer and manufacturer of topiramate, to conduct a large clinical study program of topiramate in the treatment of acute bipolar mania (McElroy and Keck 2004). Controlled trials of the drug in bipolar adults with manic symptoms failed to demonstrate significant separation between the topiramate and placebo groups (Chengappa et al. 2006; Kushner et al. 2006). However, topiramate has been shown to be efficacious in placebo-controlled trials in several neuropsychiatric conditions often comorbid with bipolar disorder, including, in addition to migraine, binge-eating disorder (BED), bulimia nervosa, alcohol dependence, borderline personality disorder (BPD), psychotropic-associated weight gain, and obesity.

STRUCTURE–ACTIVITY RELATIONS Topiramate is a sulfamate-substituted monosaccharide derived from D-fructose (Figure 40–1). As such, it is structurally distinct from other antiepileptic medications. Its sulfamate moiety is essential for its pharmacological activity (Shank et al. 2000). It has been postulated that topiramate's multiple pharmacological properties (which are discussed in the following section) are regulated by protein phosphorylation. Specifically, it has been hypothesized that topiramate interacts with voltageactivated sodium channels, -aminobutyric acid (GABA) type A (GABAA) receptors,

-amino-

3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)/kainate glutamate receptors, and high-voltage-activated calcium channels via formation of hydrogen bonds between proton-accepting oxygens in its sulfamate moiety and proton donor groups in tetrapeptide sequences in the latter (Shank et al. 2000). FIGURE 40–1. Chemical structure of topiramate.

PHARMACOLOGICAL PROFILE Topiramate has multiple pharmacological properties that may contribute to its anticonvulsant effects, as well as its therapeutic effects in other neuropsychiatric disorders (Langtry et al. 1997; Rho and Sankar 1999; Rosenfeld 1997; Shank et al. 2000; White 2002, 2005; White et al. 2007). First, topiramate inhibits voltage-gated sodium channels in a voltage-sensitive, use-dependent manner and thus suppresses action potentials associated with sustained repetitive cell firing (Kawasaki et al. 1998; Shank et al. 2000). Second, topiramate increases brain GABA levels, possibly by activating a site on the GABAA receptor, thereby enhancing the inhibitory chloride ion influx mediated by the GABAA receptor and potentiating GABA-evoked currents (Kuzniecky et al. 1998; Petroff et al. 2001; Simeone et al. 2006). Because this action is not blocked by the benzodiazepine antagonist flumazenil, it is thought that topiramate exerts this effect via an interaction with the GABAA receptor that is not modulated by benzodiazepines (White et al. 2000). This action may also be sensitive to GABA concentrations and GABAA receptor subunit composition (Simeone et al. 2006). Third, topiramate antagonizes glutamate receptors of the AMPA/kainate subtype and may selectively inhibit glutamate receptor 5 (GluR5) kainate receptors (Kaminski et al. 2004). It has essentially no effect on glutamate N-methyl-D-aspartate (NMDA) receptors. AMPA/kainate receptors mediate fast excitatory postsynaptic potentials responsible for excitatory neurotransmission; blockade of kainateevoked currents decreases neuronal excitability. Fourth, topiramate negatively modulates high-voltage-activated calcium channels (Zhang et al. 2000). Of note, Shank et al. (2000) proposed that topiramate's combined effects on voltage-activated sodium channels, GABAA receptors, AMPA/kainate receptors, and high-voltage-activated calcium channels are unique as compared with those of other antiepileptic drugs. Indeed, Schiffer et al. (2001) found that pretreatment with topiramate inhibited nicotine-induced increases in mesolimbic extracellular dopamine and norepinephrine but not serotonin. They hypothesized that this property was a result of the drug's ability to affect both GABAergic and glutamatergic function. Fifth, topiramate has weak inhibitory actions against some carbonic anhydrase isoenzymes, including subtypes II and VI. Carbonic anhydrase is essential for the generation of GABAA-mediated depolarizing responses. By inhibiting carbonic anhydrase, topiramate has been shown to reversibly reduce the GABAA-mediated depolarizing responses evoked by either synaptic stimulation or pressure application of GABA (but not to modify GABAA-mediated hyperpolarizing postsynaptic potentials) (Herrero et al. 2002). As a result of the effects of carbonic anhydrase inhibition on intracellular pH, topiramate also may activate a potassium conductance (Herrero et al. 2002). Finally, topiramate has been shown to have a number of other properties. These include an interaction with glycine receptor channels (Mohammadi et al. 2005), effects on mitochondrial permeability (Kudin et al. 2004), and antikindling properties in some animal models (Wauguier and Zhou 1996).

PHARMACOKINETICS AND DISPOSITION Topiramate has a favorable pharmacokinetic profile (Bialer et al. 2004; Doose and Streeter 2002; Langtry et al. 1997; Rosenfeld 1997; Shank et al. 2000). It is rapidly and almost completely absorbed after oral administration, with bioavailability estimated to be about 80%. Peak plasma concentrations are reached within 2–4 hours. Plasma concentration increases in proportion to dose over the pharmacologically relevant dose range. The volume of distribution of topiramate is inversely proportional to the dose, with the drug distributed primarily to body water. It is minimally protein-bound (9%–17%). Topiramate is minimally metabolized by the liver in the absence of hepatic enzyme–inducing drugs. It inhibits cytochrome P450 (CYP) enzyme 2C19 but not other hepatic CYP enzymes. Topiramate is excreted mostly unchanged (approximately 70%) in the urine. The nonrenal (hepatic) clearance of topiramate increases two- to threefold when the drug is administered with hepatic enzyme–inducing drugs such as carbamazepine and phenytoin. Six minor metabolites have been identified (Shank et al. 2000). Topiramate's elimination half-life is 19–25 hours, with linear pharmacokinetics in the dose range of 100–1,200 mg. The pharmacokinetics of topiramate in children are similar to those in adults, except that clearance is 50% higher, resulting in 33% lower plasma concentrations. Moderate or severe renal failure is associated with reduced renal clearance and increased elimination half-life of topiramate. Moderate or severe liver impairment is associated with clinically insignificant increased plasma concentrations of the drug.

MECHANISM OF ACTION Although the mechanism of topiramate's anticonvulsant action is unknown, it has been hypothesized to be due to some combination of the drug's multiple pharmacological properties (Rho and Sankar 1999; Shank et al. 2000; White 2002, 2005; White et al. 2007). As discussed, these include state-dependent blockade of voltage-activated sodium channels, enhancement of GABA activity at the GABAA receptor via interaction with a nonbenzodiazepine receptor site, antagonism of the AMPA/kainate glutamate receptor, antagonism of high-voltageactivated calcium channels, and inhibition of carbonic anhydrase. For example, the drug's anticonvulsant profile, as well as its benefits in substance use and eating disorders, has been hypothesized to be due to its dual actions on the GABAergic and glutamatergic systems (Johnson et al. 2003, 2005; McElroy et al. 2003, 2007b; Rho and Sankar 1999; Schiffer et al. 2001). By contrast, carbonic anhydrase inhibition is thought by some not to play a large role in topiramate's anticonvulsant properties despite acetazolamide's clinical efficacy as an antiepileptic because of topiramate's much weaker potency as an inhibitor (Rho and Sankar 1999). Others, however, have suggested that topiramate's inhibition of carbonic anhydrase contributes to its anticonvulsant properties via reduction of GABAA-mediated depolarizing responses and/or activation of a potassium conductance (Herrero et al. 2002).

INDICATIONS AND EFFICACY FDA-Approved Indications Topiramate is currently indicated by the FDA as initial monotherapy in patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures; as adjunctive therapy for adults and pediatric patients ages 2–16 years with partial-onset seizures or primary generalized tonic-clonic seizures; and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome (van Passel et al. 2006). It is also indicated for the prophylaxis of migraine headache in adults (Brandes 2005; Bussone et al. 2006).

Other Indications

Topiramate is not currently approved by the FDA for use in the treatment of any psychiatric disorder. Because the drug was widely used off-label in the treatment of bipolar disorder after it came to market (see subsection "Bipolar Disorder" below), Johnson and Johnson PRD, the discoverer of topiramate, conducted a large study program of topiramate in adults with acute bipolar mania. These placebo-controlled studies failed to demonstrate a significant benefit of topiramate over placebo on the Young Mania Rating Scale (YMRS) (Chengappa et al. 2001a; Kushner et al. 2006; McElroy and Keck 2004). In contrast, a placebo-controlled trial in pediatric mania, which was prematurely discontinued in the aftermath of the failed adult trials, did show significant efficacy results favoring topiramate based on a retrospective analysis of 56 patients (DelBello et al. 2005). Topiramate has been studied in the treatment of a variety of other neuropsychiatric disorders, many of which co-occur with bipolar disorder. Data from placebo-controlled clinical trials suggest that topiramate is efficacious in BED with obesity (McElroy et al. 2003, 2007b), bulimia nervosa (Hedges et al. 2003; Hoopes et al. 2003; C. Nickel et al. 2005b), alcohol dependence (Johnson et al. 2003, 2007), psychotropic-induced weight gain (Ko et al. 2005; M. K. Nickel et al. 2005b), obesity (McElroy et al. 2008), and neuropathic pain (Raskin et al. 2004). These and other studies will be reviewed below.

Bipolar Disorder Five randomized, placebo-controlled studies have shown that topiramate monotherapy is not efficacious in the short-term treatment of acute manic or mixed episodes in adults with bipolar I disorder (Kushner et al. 2006; McElroy and Keck 2004). All five studies used week 3 as the primary endpoint; in addition, three studies had a week 12 secondary endpoint, two studies had lithium comparator groups, and all trials measured weight as a secondary outcome. Analyses of the 3-week data from all five trials were consistent. In each trial, the primary efficacy outcome—the change from baseline to week 3 in the YMRS score—failed to show a statistically significant separation between topiramate and placebo. There was also no drug–placebo separation in the three trials with week 12 data. By contrast, in the two trials in which lithium was used, lithium did show statistical superiority to placebo. Topiramate, however, showed significant separation from placebo in weight loss, whereas lithium was associated with statistically significant weight gain. Similarly, in the only placebo-controlled study of adjunctive topiramate in bipolar disorder, 287 outpatients experiencing a manic or mixed episode (by DSM-IV [American Psychiatric Association 1994] criteria) and a YMRS score 18 while taking therapeutic levels of valproate or lithium showed similar reductions (40%) in baseline YMRS scores for both topiramate and placebo after 12 weeks (Chengappa et al. 2006). Topiramate, however, was again associated with significant weight loss as compared to placebo. Despite the negative results of the adult acute mania trials, numerous clinical reports suggest that topiramate may have a role in the management of bipolar disorder. In the only placebo-controlled study of topiramate in pediatric bipolar I disorder, 56 children and adolescents (6–17 years) with manic or mixed episodes were randomly assigned to topiramate (n = 29) or placebo (n = 27) for 4 weeks (DelBello et al. 2005). Initially designed to enroll approximately 230 subjects, the study was prematurely discontinued when the adult mania trials were negative. Decrease in mean YMRS score from baseline to final visit using last observation carried forward (LOCF) was not statistically different between treatment groups (–9.7 ± 9.65 for topiramate vs. –4.7 ± 9.79 for placebo, P = 0.152). However, a post hoc repeated-measures linear regression model of the primary efficacy analysis showed a statistically significant difference in the slopes of the linear mean profiles (P = 0.003). No placebo-controlled study of topiramate has yet been done in acute bipolar depression. Results from an 8 week single-blind comparison trial in which 36 outpatient adults with bipolar depression were randomly assigned to receive either topiramate (mean dosage = 176 mg/day; range = 50–300 mg/day) or bupropion SR (sustained release) (mean dosage = 250 mg/day; range = 100–400

mg/day) suggested that the drug might have antidepressant properties in some bipolar patients (McIntyre et al. 2002). The percentage of patients meeting a priori response criteria (50% or greater decrease from baseline in mean total score on the 17-item Hamilton Rating Scale for Depression [Ham-D]) was significant for both topiramate (56%) and bupropion SR (59%). There were no cases of manic switching with either drug. Moreover, numerous open-label reports have described patients with milder forms of bipolarity (i.e., "soft" bipolar spectrum disorders), including those with mixed states or rapid cycling, that respond to topiramate (McElroy and Keck 2004; McElroy et al. 2000; McIntyre et al. 2005). Finally, a number of open-label reports have described the successful topiramate treatment of bipolar disorder with various comorbid psychiatric or general medical disorders ("complicated" bipolar disorder). Comorbid psychiatric conditions in which improvement was seen included alcohol abuse; anxiety disorders such as obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD); eating disorders such as bulimia nervosa, BED, and anorexia nervosa; impulse-control disorders; and catatonia (Barzman and DelBello 2006; Guille and Sachs 2002; Huguelet and MorandCollomb 2005; McDaniel et al. 2006; McElroy et al. 2008; Shapira et al. 2000). Comorbid general medical conditions in which improvement was seen included obesity, psychotropic-induced weight gain, type 2 diabetes mellitus, tremor, and Tourette's disorder (Chengappa et al. 2001b; Guille and Sachs 2002; McIntyre et al. 2005; Vieta et al. 2002). These observations call for controlled studies of topiramate in pediatric bipolar disorder, acute bipolar depression, bipolar II disorder and other "softer" forms of bipolar disorder, and complicated bipolar disorder. No controlled maintenance or prophylactic treatment studies of topiramate in bipolar disorder have yet been completed.

Depressive Disorders In the only controlled study of topiramate in a depressive disorder, 64 females with DSM-IV recurrent major depressive disorder were randomly assigned to topiramate (n = 32) or placebo (n = 32) for 10 weeks (C. Nickel et al. 2005a). Topiramate was superior to placebo in reducing depressive and anger symptoms (as assessed by the Ham-D [P = 0.02] and the State-Trait Anger Expression Inventory [STAXI; P

Chapter 41. Cognitive Enhancers COGNITIVE ENHANCERS: INTRODUCTION Disruption of cholinergic neurotransmission and excitatory amino acids is correlated with the development of cognitive impairment and, specifically, Alzheimer's disease (Mesulam 2004). Multiple mechanisms exist that may account for the progression of cognitive impairment, including those related to cholinesterase, N-methyl-D-aspartate, vascular disease, and oxidative damage (Aisen and Davis 1994; Bartus et al. 1982; Behl 1999; Behl et al. 1992; Jick et al. 2000; Kalaria et al. 1996; Selkoe 2000; Terry and Buccafusco 2003; Wolozin et al. 2000). An outcome of the disruption of many neurotransmitter systems, cognitive impairment may occur at any time during the disease process as synaptic plasticity becomes impaired, degrading the efficiency of neuronal transmission (Malik et al. 2007). It is intuitive that the earliest intervention prior to irreversible disease progression is optimal. Currently, it is unknown when the irreversible disease processes begin; no specific markers have been identified that could guide clinicians to initiate prophylactic treatment prior to the development of cognitive or behavioral manifestations. Cognitive enhancer is a general term that denotes a pharmacological or nutraceutical intervention that improves cognitive functioning in an impaired or normal brain by reversing or delaying underlying neuropathological changes within the brain or by modulating the existing neurochemistry to facilitate a desired performance differential. The molecular pathogenesis of cognitive impairment is not fully understood; thus, an ideal pharmacological agent has been difficult to develop. No single agent developed to date is ideally suited for this task; however, several agents have shown beneficial results. In this chapter, I review the established and the most promising potential cognitive enhancers.

CHOLINESTERASE-RELATED THERAPIES Impairment of cholinergic neurotransmission, especially in the hippocampus and cerebral cortex, has been clearly established over the last 30 years as a significant factor in the clinical signs of cognitive impairment, including those of Alzheimer's disease (Davies and Maloney 1976; Mesulam 2004; Whitehouse et al. 1982). Butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) are the two main types of cholinesterase present in the brain. The development of AChE inhibitors (AChEIs) to increase acetylcholine levels in the brain for enhanced synaptic transmission has been successful, with marginal positive clinical outcomes to date (Birks 2006; Thompson et al. 2004). Four AChEIs have been marketed in the United States for cognitive therapy: tacrine, donepezil, rivastigmine, and galantamine. These pharmaceuticals are primarily for symptomatic relief and have limited current value in stopping or reversing the disease process, although research into subtle neurotrophic and neuroprotective effects of these agents proceeds (Murphy et al. 2006). A significant number of AChEI nonresponders exists (Jones 2003). Improvements in cognitive functioning have been shown with AChEIs without major differences in their efficacy (Birks 2006; Seltzer 2006; Thompson et al. 2004). The major side effects of AChEIs are gastrointestinal.

Recommendations Tacrine is no longer recommended for routine clinical use. Donepezil, rivastigmine, and galantamine

are recommended with or without other cognitive enhancers (e.g., memantine) (Table 41–1). Tolerability is improved by slow dosage titration. All cholinesterase inhibitors have significant potential for side effects; it is difficult to determine whether one AChEI has a significantly better side-effect profile than another AChEI given individual patients' variability. Switching AChEIs can be a reasonable treatment strategy if lack of efficacy or tolerability is an issue. TABLE 41–1. Recommended cholinesterase inhibitors

Cholinesterase

Donepezil (Aricept)

Rivastigmine (Exelon)

Galantamine (Razadyne)

AChE >> BChE

AChE and BChE

AChE > BChE

70 hours

2 hours

6–8 hours

Piperidine based

Carbamyl derivative

Tertiary alkaloid

Reversible, noncompetitive

Reversible (slow)

Reversible, competitive,

inhibition Elimination half-life AChE inhibitor type Type of inhibition

nicotinic modulation

Titration

5 mg/day for 4–6 weeks; 10

1.5 mg twice daily, increasing by

4 mg twice daily, increasing

schedule

mg/day thereafter

1.5 mg every 2 weeks, or 4.6 mg

by 4 mg per dose every 4

skin patch daily for at least 4

weeks up to 24 mg daily

weeks, then 9.5-mg skin patch

total; extended-release form

daily

available for once-daily dosing

Target dose

5 or 10 mg

per day

6, 9, or 12 mg, divided dose, or

16 or 24 mg, divided dose

9.5-mg skin patch daily

Major side

Nausea, vomiting, diarrhea,

Nausea, vomiting, diarrhea,

Same as rivastigmine; 16

effects

anorexia, headache,

anorexia, headache, abdominal

mg/day maximum in

bradycardia, abdominal pain,

pain, weight loss; consider lower

patients with moderate renal

nightmares; consider 5

dose (6 mg daily orally or 4.6-mg

or hepatic disease;

mg/day in patients with

skin patch daily) in patients with

contraindicated with severe

moderate to severe renal

moderate to severe renal or

renal or hepatic disease

disease

hepatic disease

Tablets (oral, disintegrating)

Tablets, oral solution, skin patch

Formulations

Tablets, oral suspension, extended-release tablets

Note. > = greater than; >>> = much greater than; AChE = acetylcholinesterase; BChE = butyrylcholinesterase.

Tacrine Tacrine, a first-generation AChEI and BChE inhibitor (BChEI), is rarely used today due to its (reversible) hepatotoxicity, drug–drug interactions, and the four-times-daily dosing schedule required to achieve adequate central nervous system concentrations for cognitive enhancement. Tacrine is available in an oral tablet formulation. Dosing begins with 40 mg/day given in four 10-mg doses, with titration upward every 4 weeks by 10 mg per dose to a maximal dosage of 160 mg/day (four 40-mg doses). The use of tacrine requires monitoring of liver enzymes. Indole-tacrine heterodimers are being developed as dual-site AChEIs that would also inhibit -amyloid peptide aggregation. Early studies indicated a net reduction of

-peptide plaque formation in an

animal model (Muñoz-Ruiz et al. 2005). The simultaneous targeting of multiple receptor sites, reduction of amyloid burden, and other neuroprotective modulations are the major mechanisms of

combination therapy. Combination therapy approaches likely represent the future for the field of cognitive enhancers.

Donepezil Donepezil, a piperidine-based, reversible, noncompetitive AChEI with a plasma half-life of about 70 hours, was approved for the treatment of mild to moderate Alzheimer's disease in the United States in 1996 and for severe Alzheimer's disease in 2006. Donepezil is given once daily in 5-mg or 10-mg doses; 5-mg therapy is only slightly less effective than 10-mg therapy and can be an appropriate regimen, especially when tolerability is an issue (Birks and Harvey 2006). Donepezil has shown benefit in treating mild, moderate, and severe Alzheimer's disease (Birks and Harvey 2006; Wallin et al. 2007) and is currently being studied for efficacy in patients with mild cognitive impairment (Chen et al. 2006; Seltzer 2007). A recent meta-analysis of pooled data on the use of donepezil indicated caution is warranted in its use to treat mild cognitive impairment due to modest treatment effects with significant side effects (Birks and Flicker 2006). In addition to Alzheimer's disease patients, Parkinson's disease, multiple sclerosis, and vascular dementia patients have benefited from donepezil therapy (Aarsland et al. 2002; Black et al. 2003; Blasko et al. 2004; Christodoulou et al. 2006; Leroi et al. 2004; Rowan et al. 2007; Seltzer 2007; Wilkinson et al. 2003). The use of donepezil as pretreatment in electroconvulsive therapy (ECT) has also been studied; patients who received donepezil prior to ECT have shown significantly faster recovery of cognitive deficits in the post-ECT period (Jyoti et al. 2006).

Rivastigmine Rivastigmine, a carbamyl derivative, is a slowly reversible AChEI and BChEI with an elimination half-life of about 2 hours. It was approved in 2000 for use in the United States to treat mild to moderate dementia of Alzheimer's disease and Parkinson's disease. Rivastigmine inhibits the G1 isoenzyme of AChE selectively up to four times more potently than it does the G4 isoenzyme (Enz et al. 1993). This unique compound with its BChEI properties has been postulated to be of greater benefit than other AChEIs in the treatment of Alzheimer's disease because BChE activity increases in the hippocampus and cortex while AChE activity diminishes (Tasker et al. 2005); to date, this has not been conclusively shown to be of clinical significance. However, as a therapy involving multiple target receptor sites, this agent does have a theoretical advantage over single-target approaches. A rivastigmine skin patch received U.S. Food and Drug Administration approval in 2007; gastrointestinal side effects are reduced in frequency with this drug delivery system. Rivastigmine is initiated at 1.5 mg taken twice daily; the dosage is increased by 1.5 mg every 2 weeks to a daily maximum of 6–12 mg divided into two doses. Transdermal therapy is initiated at one 4.6-mg skin patch applied daily for at least 4 weeks, at which time the dosage may be increased to the 9.5-mg daily patch.

Galantamine Galantamine hydrobromide, a tertiary alkaloid, is a specific, competitive, and reversible AChEI with a plasma half-life of 6–8 hours that was first marketed in the United States in 2001 as a treatment of mild to moderate dementia of Alzheimer's disease. Galantamine is unique in that it modulates neuronal nicotinic receptors (Coyle and Kershaw 2001). Whether this nicotinic receptor modulation imparts any significant clinical benefit in disease modification remains unknown. The optimal dosage range is 16–24 mg/day. The extended-release formulation for once-daily dosing has similar efficacy and side effects as the twice-daily dosing formulation. Pooled data from trials in patients with mild cognitive impairment have shown significantly higher rates of death due to bronchial carcinoma/sudden death, cerebrovascular disorder/syncope, myocardial infarction, and suicide in the galantamine treatment groups (Cusi et al. 2007; Loy and Schneider 2006); follow-up studies are under way to clarify these

findings. One double-blind, placebo-controlled trial of galantamine with antipsychotic medication in the treatment of subjects with schizophrenia did not show significant benefit, although the trend was toward improvement in several cognitive domains (Lee et al. 2007).

Other Agents Physostigmine Physostigmine, a reversible inhibitor of BChE and AChE, is poorly tolerated due to multiple gastrointestinal side effects, especially nausea and vomiting, and has a very short half-life. Physostigmine is inactivated within approximately 2 hours due to hydrolysis. An evaluation of 15 studies using physostigmine showed only marginal clinical efficacy and significant adverse side effects even with controlled-release formulations (Coelho and Birks 2001).

Huperzine Alpha Huperzine alpha (more commonly known as huperzine A) is sold in the United States as a dietary supplement for cognitive enhancement. It was first isolated from club moss (Huperzia serrata) as a sesquiterpene alkaloid and is a slow, reversible inhibitor of AChE. Huperzine A has been shown to significantly improve memory in Alzheimer's disease patients with only limited side effects to date (Zangara 2003; Z. Zhang et al. 2002). It is believed to have neuroprotective effects by reducing neuronal cell death caused by glutamate (Ved et al. 1997). The combination of other AChEIs with huperzine A may exacerbate gastrointestinal side effects; patients' usage of this over-the-counter supplement should be monitored, especially if other AChEIs are considered for treatment.

Metrifonate Metrifonate, a long-acting irreversible cholinesterase inhibitor, was tested in clinical trials, but further development was discontinued after a higher-than-expected incidence of neuromuscular dysfunction and respiratory paralysis was found. Metrifonate recipients with Alzheimer's disease showed significant cognitive improvement compared with placebo recipients at most dosages (50–80 mg/day) (Lopez-Arrieta and Schneider 2006).

Nicotinic Receptor Agonists Selective and nonselective neuronal nicotinic receptor agonists have shown statistically significant cognitive enhancement in young, healthy subjects and in subjects with Alzheimer's disease (Dunbar et al. 2007; Newhouse et al. 1997, 2001; Potter et al. 1999; Sunderland et al. 1988). Some prior research using nicotine skin patches to improve attention in Alzheimer's disease patients has been conducted with limited efficacy shown (White and Levin 1999). Other studies have shown that chronic administration of nicotine using skin patches did improve cognitive functioning in Alzheimer's disease patients (Rusted et al. 2000). The use of selective neuronal nicotinic receptor agonists is an intuitive combination therapy with AChEIs for cognitive enhancement; research continues in this developing area.

N-METHYL-D-ASPARTATE–RELATED THERAPY Glutamate is an agonist of kainate, N-methyl-D-aspartate (NMDA), and

-amino-3-hydroxy-5-methyl-

4-isoxazole propionic acid (AMPA) receptors. Neuronal plasticity of memory and learning is influenced by glutamate's direct modulation of the NMDA postsynaptic receptor; glutamate acts as an excitatory neurotransmitter activating the NMDA receptor. Glutamate excess results in neurotoxicity affecting cognitive functioning (Koch et al. 2005).

Recommendations Memantine appears to reduce the level of cognitive impairment in patients with moderate to severe

Alzheimer's disease. Memantine in combination with an AChEI is an appropriate consideration for improvement in cognition and behavior.

Memantine Memantine is a noncompetitive NMDA receptor antagonist approved in the United States for treating moderate to severe Alzheimer's disease. The NMDA receptor modulates memory function. Memantine may prevent neurotoxicity due to its low-affinity antagonism of glutamate, which has been linked to neurodegeneration and excitotoxicity (Lipton and Rosenberg 1994). Memantine has been shown to be effective in reducing the level of cognitive impairment in patients with moderate to severe Alzheimer's disease (Bullock 2006; Reisberg et al. 2003). Memantine is available in tablets and as an oral solution; dosing should be adjusted for patients with moderate or severe renal impairment. It is recommended that memantine be initiated at a dosage of 5 mg/day for 1 week, increasing weekly by 5 mg/day up to a target dosage of 20 mg/day. Memantine is generally given in twice-daily doses, although the elimination half-life ranges from 60 to 80 hours.

Memantine Combination Therapy Memantine in combination with an AChEI has been shown to improve cognitive domains significantly and to improve behavioral dyscontrol (agitation/aggression, eating/appetite, irritability/lability) (Cummings et al. 2006; Tariot et al. 2004). Given the disruption of multiple neurotransmitter systems and pathways in Alzheimer's disease and other cognitive disorders, the use of adjunctive cognitionenhancing medications is understandable (Grossberg et al. 2006). The specific neurobiological deficit(s) that any pharmacological or nutraceutical intervention may impact should be considered.

VASCULAR AND INFLAMMATION-RELATED THERAPIES Major known modifiable risk factors for vascular cognitive impairment (with or without dementia) include diabetes mellitus, hypertension, cardiac ischemia, atrial fibrillation, smoking, hyperlipidemia, and peripheral vascular disease (Desmond et al. 1993; Rockwood et al. 1997). Controversial risk factors include hyperhomocysteinemia. Established vascular treatment interventions have included low-dose aspirin and other antiplatelet agents, anticoagulation agents, antihypertensives, aggressive management of diabetes mellitus, carotid endarterectomy for selected patients, and the treatment of hyperlipidemia. There is a significant overlap of patients with vascular cognitive impairment and those with Alzheimer's disease (Gearing et al. 1995; O'Brien 1994). Cholinergic receptors (muscarinic and nicotinic) are known modulators of cerebral blood flow (Schwarz et al. 1999; W. Zhang et al. 1998). Ischemia-induced NMDA stimulation may further cognitive impairment. A meta-analysis of four randomized, placebo-controlled studies of AChEIs to treat vascular dementia—two with donepezil and two with galantamine—showed statistically significant cognitive enhancement even though the treatment effect was less than what has been observed in Alzheimer's disease patients (Birks and Flicker 2007). In addition, the authors analyzed pooled results from memantine studies and found statistically significant improvement of cognitive functioning with memantine treatment in patients with vascular impairment similar to that seen with the AChEIs (Birks and Flicker 2007). A Cochrane review indicated that donepezil in doses of either 5 mg or 10 mg improves both functional ability and cognitive symptoms in patients with mild to moderate vascular cognitive impairment; donepezil was well tolerated in this analysis (Malouf and Birks 2004). A more recent Cochrane review of the use of galantamine to treat vascular cognitive impairment showed statistically significant results in terms of cognition and executive function with galantamine versus placebo in one study but not in a second study that had fewer subjects; gastrointestinal side effects were noted to be higher in galantamine recipients (Craig and Birks 2006).

Recommendations AChEIs appear to have a valid role in the treatment of vascular cognitive impairment. Combination

therapy is an important consideration, especially with other known vascular risk modifiers including aspirin, other NSAIDs, and CDP-choline. Randomized, controlled trials do not currently support the use of aspirin or other NSAIDs for the treatment of vascular cognitive impairment. The active use of statins for the prevention and treatment of vascular cognitive impairment is currently not well supported by the literature; however, research with statins remains very active in this pursuit.

Statins -Amyloid formation and accumulation may be modulated by cholesterol. The Cardiovascular Health Study results indicated that the use of statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) was associated with a decrease in cognitive decline that was not attributed to the lowering of serum cholesterol levels (Bernick et al. 2005). Some epidemiological investigations also suggest that the progression of cognitive decline decreases with statin use (Rockwood et al. 2002; Wolozin et al. 2000). Studies to date are not conclusive about the benefit of statins for the long-term treatment of vascular cognitive impairment, however. In a post hoc analysis of pooled data from three placebo-controlled, double-blind studies of patients with Alzheimer's disease who were treated with galantamine or galantamine plus a statin, galantamine was associated with significant benefits in cognitive functioning, whereas the use of statins and galantamine did not result in a significant improvement, only a small positive improvement (Winblad et al. 2007).

CDP-Choline Cytidine 5'-diphosphocholine (CDP-choline), or citicoline, has shown mixed results regarding its potential benefit in the treatment of cognitive impairment (Cohen et al. 2003; Secades and Lorenzo 2006). CDP-choline is an intermediate in the production of phospholipids of cell membranes. Impairment in phospholipids leads to cell function loss and has been shown to be a factor in cerebral ischemia (Klein 2000). A Cochrane review of 14 studies indicated a positive benefit of CDP-choline on memory and behavior (Fioravanti and Yanagi 2005). CDP-choline may have antiplatelet aggregation effects and cholinergic modulation effects and may increase dopamine synthesis in selected brain regions (Secades and Lorenzo 2006).

Aspirin Strong data have not yet emerged supporting the cognitive benefits of aspirin usage to treat vascular cognitive impairment (Kang et al. 2007; Whalley and Mowat 2007). Aspirin remains a cornerstone first-line intervention for decreasing potential cardiovascular comorbidity. As such, aspirin may have a future role as a combination therapy with cognitive enhancers; future longitudinal research will help clarify this position.

Other Nonsteroidal Anti-Inflammatory Drugs Other nonsteroidal anti-inflammatory drugs (NSAIDs) provide a neuroprotective effect and affect amyloid pathology (H. Hao et al. 2005; Siskou et al. 2007; Weggen et al. 2001). A specific role for their use in the treatment of cognitive impairment has not been well established. Significant gastrointestinal side effects remain a concern for long-term usage. Active research continues on novel anti-inflammatory derivatives that have desired properties with limited side effects (Siskou et al. 2007).

ANTIOXIDANT-RELATED THERAPIES Antioxidant-related treatment for cognitive impairment remains poorly supported by placebocontrolled, double-blind studies. Although this may be a potential combination therapy modality, further research is required before endorsing specific treatment recommendations with current antioxidants.

Ginkgo Biloba

Ginkgo biloba could be classified within several potential treatment categories, including antioxidants, nutraceuticals, cholinergic agents, and vasodilators. Ginkgo biloba extract is currently marketed in the United States as a food supplement. Studies have shown potential benefit in using ginkgo to delay the progression of cognitive impairment or to enhance survival rates in humans and animal models (Andrieu et al. 2003; Dartigues et al. 2007; Naik et al. 2006). A review based on Cochrane meta-analyses showed a significant cognitive benefit of ginkgo only with pooled results (Kurz and Van Baelen 2004). Although the use of ginkgo appears to have a definite positive benefit in patients with cognitive impairment, most studies have shown marginal significance. The recommended dosage range is 120–240 mg/day.

Vitamins and Carotenoids Vitamin E (including tocopherols and tocotrienols), vitamin C, and carotenoids are accepted agents with known antioxidant properties. Vitamin E is believed to act as a peroxyl radical scavenger. Reports of its benefit in treating patients with cognitive impairment are mixed, with some studies showing a delay in the progression of Alzheimer's disease symptoms (Engelhart et al. 2002; Sano et al. 1997). Vitamin E can affect blood coagulation and has potential cardiovascular side effects. The research on the efficacy of vitamin C as an antioxidant for treating cognitive impairment is currently less supportive. Carotenoids have a potential role as free radical scavengers; however, current research has not shown a significant time delay in the progression of cognitive impairment with their use. Combination therapy for cognitive impairment may well incorporate judicious amounts of vitamins and carotenoids as future research delineates the specific role of these agents in managing free radicals.

OTHER AGENTS Currently, no recommendations for use of the following agents as monotherapy or combination therapy can be made.

Secretase Inhibitors The use of secretase inhibitors is one of the approaches to reduce the aging brain. The

-amyloid protein load in the

-amyloid precursor protein is cleaved by proteases; the major proteases are

-secretase and -secretase and, to a lesser extent,

-secretase (Hamaguchi et al. 2006).

Mice models using a -secretase inhibitor have shown reduced levels of

-amyloid protein (Asai et al.

2006). Inhibition of -secretase can have an impact on the familial expression of Alzheimer's disease through the genetic influence of presenilin and presenilin-2. However, each of these secretases may impact multiple protein substrates, in which case a nonspecific

- or -secretase inhibitor may yield

major unwanted side effects (Hamaguchi et al. 2006). Secretase inhibition remains an active area of research and has the potential to have a major impact on the treatment of cognitive impairment.

Tramiprosate Tramiprosate is a small-molecule glycosaminoglycan compound that inhibits the development of -amyloid plaque formation, thus reducing neurotoxic effects (Geerts 2004, Molecule of the month 2006). Tramiprosate failed to show significantly better efficacy than placebo in phase III clinical trails. Agents that prevent amyloid production or amyloid aggregation would have great utility in preventing the progression of Alzheimer's disease. Research targeting neuropathological substrates is exploring tau phosphorylation, apoptosis, formation of neurofibrillary tangles, amyloid production, and amyloid aggregation to develop pharmaceuticals with the potential to prevent and treat cognitive impairment, especially Alzheimer's disease.

Modafinil Modafinil is marketed in the United States as a wakefulness-promoting drug. Minimal cognitionenhancing effects have been noted in low-dose (100-mg) treatment in non-sleep-deprived,

middle-age subjects (Randall et al. 2004). Clinicians have used modafinil for the treatment of apathy associated with Alzheimer's disease. Modafinil is not recommended as monotherapy or in combination therapy for cognitive enhancement based on the current literature.

Hormone Replacement Therapy Hormone replacement with estrogen-related compounds is not recommended at this time. For women in early perimenopause, hormone replacement therapy may provide an initial benefit for preventing cognitive decline. Once the clinical symptoms of Alzheimer's disease are present, however, studies have shown that estrogen replacement may have negative effects on sustained cognitive performance (Thal et al. 2003). However, recent research in elderly primates indicates that early intervention with estrogen replacement can significantly benefit the structural and functional integrity of key brain sites by enabling synaptic plasticity (J. Hao et al. 2007). Research on the use of hormone replacement therapy for the prevention and treatment of cognitive impairment in perimenopausal women remains active.

Nutraceuticals To date, randomized, placebo-controlled studies of nutraceutical and herbal treatments for cognitive impairment are limited. Animal studies and limited human studies are of interest but yet not conclusive about the treatments' benefits in humans. Agents of interest include Rubia cordifolia root, sage (Salvia lavandulaefolia), rosemary (Rosmarinus officinalis), and lemon balm (Melissa officinalis) (Kennedy and Scholey 2006; Patil et al. 2006). Sage has been shown to improve immediate word recall in healthy young adults (Tildesley et al. 2003). Various compounds found in these agents have been shown to have AChE and BChE inhibitory properties, possess anti-inflammatory and antioxidant properties, and modulate muscarinic and nicotinic receptors (Kennedy and Scholey 2006). L-theanine, an amino acid found in green tea, has shown limited cognition-enhancing effects (Nathan et al. 2006). If further randomized, placebo-controlled studies show even a modest beneficial effect, these agents would have potential in combination therapy for the prevention and treatment of Alzheimer's disease and other types of cognitive impairment. Prior to recommending any of these agents, clarity with regard to the expected target system is important because combination therapy with existing AChEIs could cause profound exacerbation of side effects.

Dehydro-3-Epiandrosterone Dehydro-3-epiandrosterone (DHEA), including the sulfated ester form, is an adrenal hormone with potential neuroprotective effects and the ability to enhance glutamate's effects. Research results are mixed concerning the potential benefit of DHEA for the treatment of cognitive impairment. Case reports suggest improvement in cognition with DHEA usage. DHEA supplementation has been suggested to have a direct negative effect on cognition (Parsons et al. 2006). A recent Cochrane review of three studies did not find a beneficial effect of DHEA supplementation in a population without dementia; however, the authors noted a need for long-term studies with an adequate number of subjects (Evans et al. 2006). DHEA may have a transient effect on cognitive functioning but not provide sustained cognitive improvement (Wolkowitz et al. 2003).

General Compounds Aniracetam has been shown to improve cognitive impairment from traumatic brain injury to a rat model even after a delay of up to 11 days (Baranova et al. 2006). Piracetam, a cyclic derivative of -aminobutyric acid, has mild beneficial cognitive effects on memory and learning (Winnicka et al. 2005). In animal models, unifiram has been shown to induce acetylcholine release and act as a cognition-enhancing agent (Martini et al. 2005).

Immunomodulatory Agents

Antiamyloid immunization may provide one of the greatest opportunities to prevent -amyloid deposition. Immunization strategies generally focus on active or passive immunization and direct central nervous system delivery of anti–amyloid beta antibodies. Active immunization with

-amyloid

antibodies can reduce plaque formation (Lemere et al. 2006; Solomon 2006). Passive immunization with monoclonal antibodies or preparations of immunoconjugates shows promise for treating cognitive impairment due to Alzheimer's disease and may be safer than active immunization (Geylis and Steinitz 2006; Solomon 2007). Active and passive immunization may cause microhemorrhages, and further research continues to seek safer vaccines. Reversal of plaque load occurred in mutant mice after active immunization with

-peptide (Games et al. 2000; Schenk et al. 1999). However, during early

human trials, meningoencephalitis occurred in up to 5% of the subjects, causing the study to be halted. The occurrence of meningoencephalitis may have been caused by excessive cell-mediated immunity (Asuni et al. 2006). Further research into the potential use of vaccine-driven immunomodulatory approaches is warranted.

CONCLUSION The molecular pathogenesis of nerve cell death remains elusive, especially as it relates to the onset and progression of cognitive impairment. Alzheimer's disease and other types of cognitive impairment represent a wide spectrum of neurosystem dysfunction, and no single treatment modality yet found is sufficient to address the global apoptosis and degeneration that occur. Due to the multiple types of neurochemical and substructure dysfunction occurring in cognitive impairment, multiple-drug interventions will likely be required (Siskou et al. 2007; Sunderland et al. 1992). Future studies will explore second-messenger modulation, inhibition of the synthesis of

-amyloid

using a mimic of the prion protein to inhibit -secretase cleavage of the amyloid precursor protein, amyloid plaque sheet breakers, AMPA receptor modulators, and the role of 1-receptor agonists and selective neuronal nicotinic receptor agonists (Parkin et al. 2007; Rose et al. 2005; Sarter 2006). Currently, the AChEIs and memantine are appropriate choices for slowing the progression of cognitive impairment. Several other promising agents are likely to become available within the next few years.

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Seiji Nishino, Kazuo Mishima, Emmanuel Mignot, William C. Dement: Chapter 42. Sedative-Hypnotics, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.421159. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 42. Sedative-Hypnotics SEDATIVE-HYPNOTICS: INTRODUCTION In this chapter, we examine some of the pharmacological properties of benzodiazepines, barbiturates, and other sedative-hypnotic compounds. Sedative drugs moderate excitement, decrease activity, and induce calmness, whereas hypnotic drugs produce drowsiness and facilitate the onset and maintenance of a state that resembles normal slee in its electroencephalographic characteristics. Although these agents are central nervous system (CNS) depressants, they usually produce therapeutic effects at doses that are far lower than those that cause coma and generalized depression of the CNS. Some sedative-hypnotic drugs retain other therapeutic uses as muscle relaxants (especially benzodiazepines), antiepileptic agents, or preanesthetic medications. Although benzodiazepines are used widely as antianxiety drugs, whether their effect on anxiety is truly distinct from their effect on sleepiness remains unconfirmed. Sedative-hypnotics are also important drugs to neuroscientists. These substances modulate basic behaviors such as arousal and response to stress. With increasing understanding of the molecular structure of the -aminobutyric acid type A (GABAA) receptor, the cellular mechanisms of these compounds' mode of action have become elucidated. Further understanding of their mode of action could thus help to elucidate neurochemical and neurophysiological control of these behaviors.

BENZODIAZEPINES History and Discovery Benzodiazepines were first synthesized in the 1930s but were not systematically evaluated until 20 years later. The introduction of chlorpromazine and meprobamate, which had sedative effects in animals, in the early 1950s, led to the decade of development of sophisticated in vivo pharmacological screening methods that were used to identify the sedative properties of benzodiazepines. More than 3,000 benzodiazepines have been synthesized since chlordiazepoxide, which was synthesized by Sterbach in 1957, was introduced into clinical medicine. About 40 of them are in clinical use. Several drugs chemically unrelated to the benzodiazepines have been shown to have sedative-hypnotic effects with a benzodiazepine-like profile, and these drugs have been determined to act via the benzodiazepine binding site on GABAA receptor. Most of the benzodiazepines currently on the market were selected for their high anxiolytic potential relative to CNS depression. Nevertheless, all benzodiazepines have sedative-hypnotic properties to various degrees, and some compounds that facilitate sleep have been used as hypnotics. Mainly because of their remarkably low capacity to produce fatal CNS depression, benzodiazepines have displaced barbiturates as sedative-hypnotic agents.

Structure–Activity Relations The term benzodiazepine refers to the portion of the structure composed of benzene rings (A in Figure 42–1) fused to a seven-membered diazepine ring (B). However, most of the older benzodiazepines contain a 5-aryl substituent (C) and a 1,4-diazepine ring, and the term has come to mean 1,4-benzodiazepines. FIGURE 42–1. Chemical structures of some commonly used benzodiazepines.

A substituent (most often chloride) at position 7 is essential for biological activity. A carbonyl at position 2 enhances activity and is generally present. Most of the newest products also substitute the 2 position, as with flurazepam. These general features are important for the metabolic fate of the compounds. Because the 7 and 2 positions of the molecule are resistant to all major degradative pathways, many of the metabolites retain substantial pharmacological activity.

Pharmacological Profile Benzodiazepines share anticonvulsant and sedative-hypnotic effects with the barbiturates. In addition, they have a remarkable ability to reduce anxiety and aggression (Cook and Sepinwall 1975). In the mammalian CNS, two subtypes of benzodiazepine omega ( ) receptors have been pharmacologically recognized. Benzodiazepine receptors are sensitive to -carbolines, imidazopyridines (e.g., zolpidem), and triazolopyridazines. Benzodiazepine

2

1

(or BZ1)

(or BZ2) receptors have low affinity for these ligands and

relatively high affinity for benzodiazepines. Benzodiazepine

1

sites are enriched in the cerebellum, whereas

subtypes are found in the cerebral cortex and hippocampus. Benzodiazepine Another subtype,

3,

1

and

2

2

sites are mostly present in the spinal cord, and both receptor

receptor subtypes are also located peripherally in adrenal chromaffin cells.

was identified and is commonly labeled as the peripheral benzodiazepine receptor subtype because of its distribution on glial cell membranes in nonnervou

tissues such as adrenal, testis, liver, heart, and kidney. The subtype was later detected in the CNS, especially on the mitochondrial membrane and not in association with GABAA receptors (Gavish et al. 1992). The 3 receptor subtype has high affinity for benzodiazepines and isoquinoline carboxamides (Awad and Gavish 1987). The functional role of this receptor is unknown, but it may be involved in the biosynthesis and mediation of the sedative-hypnotic effects of some neuroactive steroids (pregnenolone, dehydroepiandrosterone [DHEA], allopregnanolone, tetrahydrodeoxycorticosterone) (Edgar et al. 1997; Friess et al. 1996; Rupprecht et al. 1996). Neurosteroids modulate GABAA-mediated transmission through an allosteric mechanism that is distinct from that of benzodiazepines and barbiturates. By stimulation of

3

receptors with agonists,

cholesterol is transferred from intracellular stores in mitochondria and becomes available to the mitochondrial P450 cholesterol-side-chain-cleavage (P450scc), and neurosteroid biosynthesis begins (Papadopoulos et al. 2001). Benzodiazepine

3

receptor subtypes also may serve as mitochondrial membrane stabilizers and protect against pathologically

induced mitochondrial and cell toxicity (Papadopoulos et al. 2001). The GABAA receptor is a ligand-gated ion channel that mediates fast synaptic neurotransmission in the CNS. When the GABAA receptor is occupied by GABA or GABA agonists such as muscimol, the chloride channels open and chloride ions diffuse into the cell. Schmidt et al. (1967) first reported that diazepam could potentiate the inhibitory effects of GABA on the spinal cord in cats. Later, it was shown that the effect of diazepam could be abolished if the endogenous content of GABA was depleted. These findings established that diazepam (and related benzodiazepines) did not act directly through GABA but modulated inhibitory transmission through the GABAA receptor in some other way. It was subsequently reported that benzodiazepines bind specifically to neural elements in the mammalian brain with high affinity and that an excellent correlation exists between drug affinities for these specific binding sites and in vivo pharmacological potencies (Möhler and Okada 1977; Squires and Braestrup 1977). The binding of a benzodiazepine to this receptor site is enhanced in the presence of GABA or a GABA agonist, thereby suggesting that a functional (but independent) relationship exists between the GABAA receptor and the benzodiazepine receptor (Tallman et al. 1978). Barbiturates (and to some extent alcohol) also seem to produce anxiolytic and sedative effects at least partly by facilitating GABAergic transmission (see section "Barbiturates" in this chapter). This common action for chemically unrelated compounds can be explained by the ability of these compounds to stimulate specific sites on the GABAA receptor. The benzodiazepines bind with high affinity to their binding sites so that the action of GABA on its receptor is allosterically enhanced. GABA can produce stronger postsynaptic inhibition in the presence of a benzodiazepine. Benzodiazepine agonists are assumed to potentiate only ongoing physiologically initiated actions of GABA (at GABAA receptors), whereas barbiturates are thought to cause inhibition at all GABAergic synapses regardless of their physiological activity. In addition, barbiturates appear to increase the duratio of the open state of the chloride channel, whereas benzodiazepines increase the frequency of channel openings with little effect on duration (Twyman et al. 1989). These fundamental differences between the allosteric effects of benzodiazepines within the GABAA receptor and the conducive effects of barbiturates on the chloride ion channel may explain why low doses of barbiturates have a pharmacological profile similar to that of benzodiazepines, whereas high doses of barbiturates cause a profound and sometimes fatal suppression of brain synaptic transmission. Note that selective GABAA agonists, such as muscimol, have no sedative or anxiolytic properties; thus, the whole GABAA– benzodiazepine receptor complex must be involved to possess sedative-hypnotic properties.

Molecular Mechanism of GABAA–Benzodiazepine Receptor Interaction The structure of the GABAA–benzodiazepine receptor complex has been elucidated by the cloning of all the implicated subunit genes and the study of the corresponding encoded proteins. The GABAA receptor is a pentameric protein consisting of five subunits, which forms a rosette surrounding a transmembrane ion channel pore for Cl– (Figure 42–2). The GABAA receptor in humans includes the following known subunits: 1– 6, 1– 4, 1– 4, , , , and (7 kinds of subunits, 18 isoforms total) (Mehta and Ticku 1999). Two alternatively spliced versions of the 2 subunit, 2S and 2L, are also known to exist (Kofuji et al. 1991). FIGURE 42–2. The GABAA–benzodiazepine receptor complex.

(A) Schematic model of the mammalian -aminobutyric acid type A (GABAA) receptor embedded in the cell membrane, representatively possessing the two molecules of GABA to the action site composed of

and

,

, and

subunits (2:2:1). The binding of

subunits causes the opening of the chloride channel pore, and the chloride ions diffuse into the cell. Each subunit comprises four

transmembrane domains (TM1–TM4). The ion channel pore consists of TM2 of five subunits with a rosette formation. (B) Structure of the

1

subunit, with amino acid sequence, indicating amino acid

residues implicated in GABA and benzodiazepine binding domains. Source. Modified from Ueno et al. 2001. Despite many studies, the physiological and neuroanatomical processes mediating benzodiazepine action on the GABAA receptor complex remain poorly understood. One reason is that the GABAergic system is the most widespread of all inhibitory neurotransmitters and could be involved in many circuits responsive to various effects of benzodiazepine agonists. In addition, the various subtypes of GABAA receptor have different ligand affinity and channel functions in response to benzodiazepine agonists. These subtypes of GABAA are broadly distributed in various brain areas to form a mosaic of receptor subtypes (Wisden and Stephens 1999), making it difficult to understand the functional mechanisms of interaction of benzodiazepine agonists on the GABAA-ergic system from the physiological point of view (Rudolph et al. 1999). However, recent site-directed mutagenesis and gene knock-in techniques have identified several important findings about the benzodiazepine action sites on GABAA receptors and their physiological functions. It is postulated that the binding of GABA to N-terminal extracellular domains of

and

subunits causes conformational changes within the subunits. Ion channel pores

subsequently open, and Cl– flows across the neuronal membrane, resulting in neuronal inhibition (Amin and Weiss 1993; Boileau et al. 1999; Sigel et al. 1992; Smith and Olsen 1994) (see Figure 42–2). The extracellular domains of the and benzodiazepines. Pharmacologically classified

and

and

subunits, which consist of about 220 amino acids in the N-terminal region, also have been shown to bind GABA and

2

subunits and the

Extracellular benzodiazepine binding sites on these subunits consist of several divided portions; His101, Tyr159–Thr162, and Gly200–Val211 on

1

subunits, as well as

1

2

receptors are now thought to correspond to GABAA receptors possessing the

1

3

and

5

subunits, respectively.

Lys41–Trp82 and Arg114–Asp161 on 2 subunits, are essential to the formation of the binding pockets (Boileau et al. 1998). Most strikingly, His101 is a critical residue for diazepam to exhibit its sedative effect (Crestani et al. 2001; Low et al. 2000; McKernan et al. 2000; Rudolph et al. 1999). Knock-in mice with displacement of His101Arg are insensitive to benzodiazepine-induced allosteric modulation of the complex but have preserved physiological regulation by GABA (Rudolph et al. 1999). These knock-in mice failed to be sedated by diazepam but retained other effects of diazepam, such as anxiolytic-like, myorelaxant, motor-impairing, and ethanol-potentiating effects. This suggests the possibility that the sedative action of the benzodiazepine is mediated through GABAA receptors possessing the

1

subunit. It is also noteworthy that His101Arg knock-in mic

responded to diazepam and showed similar sleep changes as wild-type mice do, despite the lack of its sedative response in these animals (Tobler et al. 2001). Thus, hypnotic and sedative effects by benzodiazepines may be mediated via different subtypes, with hypnotic effects involving GABAA receptors possessing subunits other than or

5)

1

(i.e.,

2,

3

(Tobler et al. 2001).

Nonbenzodiazepine Hypnotics (Acting on the Benzodiazepine Receptor) Until about 1980, it was widely accepted that the benzodiazepine structure was a prerequisite for the anxiolytic profile and for benzodiazepine receptor recognition and binding. However, more recently, three chemically unrelated drugs—the imidazopyridine zolpidem, the cyclopyrrolone zopiclone (and its S[+]-enantiomer, eszopiclone), and the pyrazolopyrimidine zaleplon—have been shown to be useful sedative-hypnotics with benzodiazepine-like profiles (Figure 42–3). Other chemical classes of drugs that are structurally dissimilar to the benzodiazepines (e.g., triazolopyridazines) but act through the benzodiazepine receptor also have been developed and have anxiolytic activity in humans. FIGURE 42–3. Three nonbenzodiazepine hypnotics—zolpidem (an imidazopyridine), zopiclone (a cyclopyrrolone), and zaleplon (a pyrazolopyrimidine)—have been shown to be useful sedative-hypnotics with benzodiazepine-like profiles.

Nonbenzodiazepine hypnotics have a pharmacological profile slightly different from that of classic benzodiazepines. For example, zolpidem binds selectively to 1 (the 50% inhibitory concentration [IC50] ratio for 1/ 2 is nearly 1:10) and has sedative-hypnotic properties relative to other properties such as anxiolytic activity or muscle relaxation. Zolpidem and zopiclone have short half-lives (3 hours and 6 hours, respectively). These drugs were originally thought not to appreciably affect the rapid eye movement (REM) sleep pattern, whereas the quality of slow-wave sleep (SWS) may be slightly increased (Jovanovic and Dreyfus 1983; Shlarf 1992). Rebound effects (insomnia, anxiety), which are commonly seen following withdrawal of short-acting benzodiazepines, are minimal for zolpidem and zopiclone. These compounds also induce little respiratory depression and have less abuse potential than common clinical benzodiazepine hypnotics. However, much longer clinical trials are needed to show whether the imidazopyridines or cyclopyrrolones have any significant advantages over the short- to medium-half-life benzodiazepines in the treatment of insomnia. Eszopiclone, the active stereoisomer of zopiclone with longer half-life, was recently approved by the U.S. Food and Drug Administration (FDA). The drug was claimed to help for sleep maintaining as well as for sleep induction. Because the compound induces little tolerance, it is suitable for long-term use. Zaleplon (N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide), a pyrazolopyrimidine, also has been developed as a novel nonbenzodiazepine hypnotic (see Figure 42–3). Clinical trials have shown that zaleplon is a well-tolerated, safe, rapidly acting, and effective sedative with advantages over lorazepam with respect to unwanted cognitive and psychomotor impairments (Allen et al. 1993; Beer et al. 1994). Thanks to an increased understanding of the molecular structure of the GABAA receptor and its functional correlates, several pharmaceutical companies are also currently developing subtype-selective GABAA receptor agonists, such as for

1,

3,

and

4

(selective extrasynaptic GABAA receptor agonist) subtypes. Preclinical and clinical studies of

these compounds suggested hypnotic effects, and hypnotic uses of some of these are likely to be approved within few years.

Benzodiazepine Antagonists, Partial Agonists, and Inverse Agonists As knowledge of the relation between the structure of benzodiazepine receptor ligands and their pharmacological properties has increased, potent receptor agonists that stimulate the receptor and produce pharmacological effects qualitatively similar to those of classic benzodiazepines have been developed. Antagonists, which block the effects o the agonists without having any effects themselves, and partial agonists, drugs that have a mixture of agonistic and antagonistic properties, also have been introduced (Haefley 1988). Partial agonists may be particularly important to develop in the future as sedative-hypnotics that lack common side effects such as ataxia and amnesia. At the molecular level, benzodiazepine agonists are defined as drugs that induce a conformational change in the receptor that produces functional consequences in terms of cellular changes, whereas antagonists occupy only the binding site. Braestrup and Nielsen (1986) found that a group of nonbenzodiazepine compounds, the

-carbolines, not

only antagonized the action of the full agonists but also had intrinsic activity themselves. These compounds are called benzodiazepine inverse agonists because they have biological effects exactly opposite to those of the pure agonists while also having intrinsic activity like that of agonists. Their effects are blocked by antagonists; thus, the benzodiazepine receptor is particularly unique in that it has a bidirectional function (Figure 42–4). FIGURE 42–4. Properties of the various types of benzodiazepine receptor ligands.

GABA = -aminobutyric acid.

Natural Ligands for Benzodiazepine Receptors in the Brain The presence of benzodiazepine receptors in the brain suggests that natural ligands modulate GABAergic transmission through these sites. Small amounts of benzodiazepines, such as diazepam and desmethyldiazepam, can be detected in human and animal tissues. This finding was confirmed with human brain tissue samples that had been stored since the 1940s before the first synthesis of benzodiazepines (see Sangameswaran et al. 1986 for details). These benzodiazepines most likely originate from plants, such as wheat, corn, potatoes, or rice, and the levels that are detected are too low to be pharmacologically active (e.g., diazepam,

Chapter 44. Electroconvulsive Therapy ELECTROCONVULSIVE THERAPY: INTRODUCTION Over the past 70 years, electroconvulsive therapy (ECT) has been proven to be one of the most effective somatic treatments for mood disorders (Abrams 1992). Although the serendipitous discovery of psychotropic medications such as chlorpromazine and iproniazid in the 1950s revolutionized psychiatric treatment, clinicians and researchers soon recognized the limitations of psychotropic medications and ECT remained an important therapeutic alternative. The continued use of ECT has provided support for ECT-related research, including exploration of clinical indications, techniques to maximize efficacy and minimize toxicity (especially cognitive and cardiac side effects), and therapeutic mechanisms of action. In this chapter, we review the history of ECT, the preclinical and clinical data on the mechanism of action of ECT, and the relevant literature related to efficacy. We also provide practical guidelines for the administration of ECT, including the efficacy of ECT in treating various psychiatric disorders as well as appropriate patient selection, stimulus settings and electrode placement, pretreatment medical evaluation, and management of the patient during acute, continuation, and maintenance courses of ECT. Finally, we outline an overview of some recent developments to treat depression with nonconvulsive stimuli such as transcranial magnetic stimulation (TMS).

HISTORY OF ECT The development of ECT occurred at a time when few somatic treatments were available for psychiatric disorders and physicians were desperately attempting to find treatments for severely ill psychotic patients. The first attempts at inducing therapeutic seizures in such patients were performed chemically. In 1935, Manfred Sakel (1900–1957) induced hypoglycemic episodes in psychiatric patients (using insulin shock therapy) while in the same year Lazlo Meduna (1896–1964) injected patients with pentylenetetrazol to induce convulsions in order to treat psychosis. Three years later, the Italian psychiatrists Ugo Cerletti (1877–1963) and Lucio Bini (1908–1964) used electroshock treatments to induce seizures. This treatment proved safer and easier to administer than chemically induced seizures and replaced other methods of inducing seizures. Modern psychopharmacology developed with the discovery of lithium (1949) and iproniazid (1957) for the treatment of mood disorders and the synthesis of the first antipsychotic, chlorpromazine (1952); the first tricyclic antidepressant, imipramine (1959); and the first benzodiazepine, chlordiazepoxide (1960). The development of psychotropic medications was associated with a decline in the use of ECT from the 1960s to the 1980s. However, in the 1980s, the use of ECT began to increase, and more than 36,000 patients received ECT in 1986, the last year a national survey on its use was conducted (Thompson et al. 1994). Recent studies in Canada and Denmark have demonstrated relatively stable rates of ECT utilization over the last 15–30 years (Munk-Olsen et al. 2006; Rapoport et al. 2006). Since the 1980s, the safety of ECT has improved significantly with the introduction of sophisticated cardiopulmonary and electroencephalographic monitoring, better anesthetic agents, and the adoption of the brief-pulse stimulus machine. Today, ECT is arguably the fastest, most effective treatment for mood disorders. ECT is possibly the safest procedure performed under general anesthesia, with a mortality rate reported at 0.002% (Abrams 1997).

Yet, despite these advances, the availability and use of ECT varies dramatically in different parts of the United States. A 1988 study of ECT usage rates in 317 metropolitan areas reported a wide variation (from 0.4 to 81.2 patients per 10,000 population), and 36% of the sampled areas did not have ECT available as a treatment (Hermann et al. 1995). The strongest predictors of ECT use were the number of psychiatrists, number of primary care physicians, and number of private hospital beds per capita. The stringency of state regulations restricting ECT was negatively associated with its use. Studies in other countries, including Great Britain, Spain, and Ireland, have shown a similar pattern of variation in rates of ECT use (Bertolín-Guillén et al. 2006; Latey and Fahy 1985; Pippard and Ellam 1981). Although it is unclear whether such differences represent overuse of ECT in some areas or underuse of ECT in other areas, great variability in the use of other medical and surgical procedures has been hypothesized to result from a lack of consensus in the medical community regarding the appropriate use and efficacy of a particular medical procedure (Wennberg et al. 1982). ECT is clearly one of the most controversial procedures in medicine, with widely varying beliefs about the safety and efficacy of the procedure among the lay public and medical students (Walter et al. 2002), as well as psychiatrists and other mental health professionals (Janicak et al. 1985). In the Irish study, one of the most important variables in the availability of ECT was whether the psychiatrist had a favorable attitude toward ECT (Latey and Fahy 1985). The availability of ECT was more closely related to the physician's perceptions of the procedure than to the data indicating the potential benefits of the somatic treatment. Unfortunately, this often leads to a significant lack of access to ECT. Ongoing education of physicians and the public may improve the availability of ECT to all who might benefit from it. In the United States, middle and upper socioeconomic groups receive ECT more frequently than do lower socioeconomic groups (Babigian and Guttmacher 1984; Kramer 1985), possibly because ECT is used more often in private hospitals than in public hospitals (Thompson and Blaine 1987). Private hospitals have fewer regulations governing ECT use, better financial reimbursement, and a higher percentage of patients with mood disorders that respond to ECT (Hermann et al. 1995). As with many medical treatments, financial incentives have shifted ECT toward the outpatient setting, although this is also because of improved safety and increased use of continuation and maintenance courses of ECT. Older adults receive ECT more often than do younger patients (Kramer 1985; Thompson et al. 1994), although a 1992 National Institutes of Health (NIH) consensus panel found that ECT was underused as a treatment for late-life depression ("NIH Consensus Conference" 1992). A survey of older adults with Medicare insurance showed that the overall rate of ECT use increased nearly 30% from 1987 to 1992, particularly among women, white people, and disabled persons (Rosenbach et al. 1997). There are several reasons that women may be overrepresented in ECT populations including the greater prevalence of depression in women and the fact that women live longer than men. Racial differences among patients receiving ECT may be related to the above-mentioned socioeconomic factors or to differing cultural beliefs about ECT or psychiatric illnesses. White people are more likely to receive ECT than black people (Breakey and Dunn 2004), and the paucity of information on ECT use in the growing Hispanic American population has been highlighted (Euba and Saiz 2006; Major 2005).

MECHANISM OF ACTION OF ECT Despite extensive clinical use of ECT for more than 60 years and unequivocal documented efficacy, its mechanism of action remains poorly understood. Theories have ranged from psychological and psychodynamic concepts to theories involving neurotransmitter changes, neuroendocrine effects, alterations in intracellular signaling pathways, and changes in gene expression (Sackeim 1994). Some theories are easy to discard. For example, there is no convincing evidence that ECT causes structural brain damage or that the memory-impairing effects of ECT are associated with clinical improvement (Devanand et al. 1994; R. D. Weiner 1984).

Most serious efforts to understand the mechanisms of ECT have focused on changes in neurotransmitter systems and intracellular biochemical processes (for reviews, see Fochtmann 1994; Newman et al. 1998; Nutt and Glue 1993). Researchers have identified changes possibly leading to therapeutic benefits at cellular and neural system levels using neurochemical information about ECT from studies of electroconvulsive shock (ECS) in rodents. Repeated seizures, whether electrically induced or spontaneous, clearly result in short- and long-term changes in brain function. The assumption is that the effects of repeated generalized seizures in animals reflect the effects of ECT in patients with psychiatric disorders (Lerer et al. 1984). An alternative strategy is to examine the effects of ECT on central nervous system (CNS) processes for which there is better mechanistic understanding. The assumption is that the effects of ECT on CNS processes are related to the known antidepressive effects of other treatments including psychotherapy, pharmacotherapy, and newer brain stimulation techniques such as deep brain stimulation and TMS. Advances in understanding the neurocircuitry and cellular changes associated with major psychiatric disorders offer hope in defining the effects of ECT and are likely to be important. Although all of these strategies have weaknesses, the anticonvulsant hypothesis described below explains both the effects of ECT on an intracellular level and the efficacy of ECT in relation to the anticonvulsant medications used to treat mood disorders.

Anticonvulsant Hypothesis One of the most popular theories defining the mechanism of action of ECT is that the antidepressive efficacy is directly correlated with the anticonvulsant effect of ECT. That is, the therapeutic effect of ECT is proportional to an increase in the seizure threshold during ECT; successive ECT treatments cause both an increase in seizure threshold and a decrease in seizure duration (Sackeim 1999). This theory focuses on changes in neurotransmitter systems and intracellular biochemical processes and is supported by preclinical data of the effect of ECT in modulating the seizure threshold. -Aminobutyric acid (GABA) is the predominant inhibitory transmitter in the brain and is a target for multiple anticonvulsant drugs (e.g., barbiturates, benzodiazepines). Data from animal studies demonstrate increases in the threshold for bicuculline- and pentylenetetrazole-induced seizures following a series of ECS treatments (Nutt et al. 1981; Plaznik et al. 1989). Because bicuculline and pentylenetetrazole act by inhibiting GABA type A (GABAA) receptors, these findings suggest that ECT results in changes in GABAergic inhibition. In addition, GABA levels increase in certain CNS regions after ECS (Green et al. 1982), and there is evidence from magnetic resonance spectroscopy that ECT increases GABA levels in the occipital cortex in humans (Sanacora et al. 2003). These changes in GABA levels suggest that an increase in tonic inhibition may occur after repeated seizures, and effects on GABA-mediated tonic inhibition are increasingly recognized as an important aspect of several neuroactive drugs (Farrant and Nusser 2005). Changes in the GABAA receptor–chloride channels that are the primary postsynaptic GABA receptors are less certain (Fochtmann 1994), although it is clear that different receptor subtypes contribute to tonic and phasic (synaptic) inhibition. There is also evidence that ECS enhances the function of GABAB receptors that mediate presynaptic and postsynaptic inhibition (Lloyd et al. 1985), and this is likely to contribute to an overall depression of CNS excitation. An interesting finding in rodents is that repeated seizures cause the release of an anticonvulsant substance into cerebrospinal fluid. Anticonvulsant activity can be transferred to treatment-naive animals by intracerebroventricular injections of cerebrospinal fluid from animals that have experienced seizures (Tortella and Long 1985, 1988). Tortella et al. (1989) summarized evidence that the anticonvulsant substance is likely to be an endogenous opioid and that treatment with naloxone, an opiate receptor antagonist, blocked the anticonvulsant effects of ECS. There is also evidence that upregulation of delta ( ) opioid receptor binding sites (e.g., sites for D-alanine-D-leucine enkephalin) occurs after repeated seizures (Hitzemann et al. 1987). Whether similar changes occur in humans is

speculative, and, to date, efforts to lengthen ECT-induced seizures using naloxone have not been successful (Prudic et al. 1999; Rasmussen and Pandurangi 1999). Efforts to identify anticonvulsant mechanisms in ECT must account for changes in both seizure threshold and duration because different mechanisms may govern the two processes. Of note is the finding that adenosine is released extracellularly during seizures and may play a role in seizure termination. Adenosine is an important inhibitory neuromodulator that acts on several receptor types. Adenosine A1 receptors are upregulated in the cortex after ECS, but not in the hippocampus or striatum (Gleiter et al. 1989). Clinically, adenosine receptor antagonists such as caffeine and theophylline prolong ECT-induced seizures (Hinkle et al. 1987), with less effect on seizure threshold (McCall et al. 1993a). Furthermore, theophylline use has been associated with prolonged seizures and status epilepticus during ECT (Rasmussen and Zorumski 1993). These observations suggest that release of adenosine, and perhaps increased sensitivity of certain adenosine receptors, may contribute to decreases in seizure duration during ECT, although caffeine and theophylline have other effects that could influence excitability including phosphodiesterase inhibition and release of calcium from intracellular stores (Sawynok and Yaksh 1993). Much of the focus in studying anticonvulsant mechanisms of ECT has centered on changes in neural inhibition after repeated seizures. It is also important to consider how ECT influences excitation, particularly the glutamate system, which serves as the predominant mode of fast excitatory transmission in the CNS. Seizures are accompanied by acute release of glutamate, but we have little information about the effects of repeated seizures on glutamate release, uptake, and receptors. Although the brain damage that accompanies status epilepticus appears to result, in part, from excessive activation of N-methyl-D-aspartate (NMDA)–type glutamate receptors (Clifford et al. 1989), seizure-related brain damage typically requires more than 20 minutes of continuous activity and is therefore unlikely to be relevant to ECT (Devanand et al. 1994; Gruenthal et al. 1986). Furthermore, there is evidence that repeated use of ECS actually prevents seizure-related brain damage in some animal models of status epilepticus (Kondratyev et al. 2001). Repeated ECS treatments increase levels of messenger RNA (mRNA) for the NR2A and NR2B subunits of the NMDA receptor and decrease levels of mRNA for the metabotropic receptor mGluR5b in dentate gyrus and the CA1 hippocampal region (Watkins et al. 1998). These effects are transient and the mRNA levels return to control values within 48 hours. Other studies suggest that repeated ECS treatments decrease NMDA receptor function by altering the potency of glycine for its regulatory site on NMDA receptors, an effect that could diminish the ability of glycine to promote opening of the NMDA ion channel by glutamate (Paul et al. 1994; Petrie et al. 2000).

Effects of Antidepressant Medications and ECT on Mood Disorders: Possible Shared Mechanisms The efficacy of anticonvulsants as mood stabilizers supports the anticonvulsant hypothesis; this hypothesis is appealing in that it can explain the therapeutic effects of ECT in treating both mania and depression (Sackeim 1994, 1999). Yet most antidepressants are not anticonvulsants, and researchers have investigated other possible mechanisms of action that ECT and antidepressant medications may have in common to elucidate the therapeutic effects of ECT. There are a number of common threads in the neurotransmitter changes induced by ECT and antidepressant medications. ECT, like antidepressant pharmacotherapy, has been reported to normalize hypothalamic-pituitary-adrenal axis perturbations associated with major depression (Yuuki et al. 2005). However, a more productive area of research has focused on determining how a course of ECT affects biogenic amines. Of interest is the finding that certain antidepressants cause 1-adrenergic

receptor subsensitivity, and similar effects have been observed with ECS (Nutt and Glue

1993). ECS has multiple other effects on the adrenergic system, including increased norepinephrine turnover, increased

1-adrenergic

receptor sensitivity, and possibly decreased presynaptic

2-adrenergic

receptor sensitivity. ECS also enhances the function of the serotonin system, producing

increased behavioral responses to serotonin agonists and possibly increases in 5-hydroxytryptamine type 2 (5-HT2) receptor binding in the cerebral cortex (Fochtmann 1994; Nutt and Glue 1993; Sackeim 1994). The latter effect was initially observed in rodents and differs from changes induced by chronic use of antidepressant drugs. Studies in nonhuman primates question the rodent results and provide evidence that ECS diminishes 5-HT2 binding in the cortex (Strome et al. 2005). Thus, 5-HT2 downregulation, like

-adrenergic receptor subsensitivity, may be a mechanism common to several

antidepressive treatments. An emerging trend in research on antidepressive mechanisms is the effect of antidepressive treatments on glutamatergic and GABAergic neurotransmission. In particular, a decrease in the function of NMDA receptors appears to be a mechanism shared by several antidepressive treatments, including ECS (Petrie et al. 2000). In the case of ECS, effects on NMDA receptors appear to be mediated by changes in the glycine regulatory site on the ligand-gated ion channels. There is also evidence that ketamine, a noncompetitive NMDA receptor antagonist, has acute antidepressive properties (Berman et al. 2000; Zarate et al. 2006). Coupled with the possibility that untimely NMDA receptor activation may contribute to ECT-induced anterograde memory problems, the antidepressive effects of ketamine raise the possibility that ketamine or other NMDA receptor–blocking anesthetics may be preferred agents for use during ECT. One of the more intriguing avenues of research for understanding the effects of ECT is the neurocircuitry of mood regulation and depression. This circuitry involves connections between and within regions of the prefrontal cortex, anterior cingulate gyrus, subgenual prefrontal cortex, anterior thalamus, and more traditional limbic structures (the hippocampus and amygdala) (Drevets 2000; Seminowicz et al. 2004). There is now evidence of structural changes including cell loss (loss of glia and possibly neurons) in several of these regions in patients with unipolar as well as bipolar mood disorders (Harrison 2002). It also appears that different antidepressive treatments may differentially affect metabolism in the neurocircuitry. Effective treatment with paroxetine appears to increase metabolism in frontal regions while decreasing metabolism in the hippocampus, whereas cognitivebehavioral therapy has the opposite effects (Goldapple et al. 2004; Seminowicz et al. 2004). ECT, in contrast, diminishes metabolism in both the prefrontal cortex and the hippocampus (Nobler et al. 2001). Although it is too early to draw firm conclusions about these observations, it is intriguing that chronic deep brain stimulation targeted toward the subgenual prefrontal region appears to be effective in a small sample of patients with treatment-resistant chronic depression (Mayberg et al. 2005), further implicating neurocircuitry changes in the biology of depression. In addition to the imaging results noted above, there is evidence that several antidepressive treatments, including ECS, have neurotrophic effects and result in neurogenesis in the dentate gyrus of adult rodents (Madsen et al. 2000; Malberg 2000; B. W. Scott et al. 2000). These effects may result from changes in brain-derived neurotrophic factor (BDNF) and the receptor tyrosine kinase (TRKB) through which BDNF exerts its actions, as well as from the treatment's effects on the adenylate cyclase intracellular signaling system, including cyclic adenosine monophosphate (cAMP) response element–binding protein (CREB), a downstream effector (Duman and Vaidya 1998; Nestler et al. 2002; Schloss and Henn 2004). Other evidence suggests that new neurons produced in the dentate gyrus of adult rodents have the properties of functional neurons and participate in synaptic transmission (Song et al. 2002), suggesting that antidepressive treatments, including ECT, may ultimately enhance hippocampal function. Hippocampal changes also appear to include increases in angiogenesis and possibly blood flow in specific subregions of the hippocampus (Hellsten et al. 2005; Newton et al. 2006). Whether effects on neurogenesis are important to the therapeutic effects of ECT and other antidepressive treatments remains speculative, although elegant studies in rodents provide evidence

that neurogenesis is important to at least some behavioral effects of medications (Santarelli et al. 2003). It is uncertain whether similar neurotrophic effects occur with ECT in humans. However, studies using magnetic resonance spectroscopy to monitor regional changes in the glutamateto-glutamine ratio (called Glx), a marker of local intracellular excitatory transmitter metabolism (Hasler et al. 2007), indicate that depressed subjects have low Glx values that increase to normal values with effective ECT (Michael et al. 2003; Pfleiderer et al. 2003). Changes in Glx in depressed patients treated with ECT may reflect alterations in glial function in the circuitry underlying depression. Recent efforts to identify mechanisms contributing to the effects of ECT and antidepressant drugs have included the use of microarrays to study gene expression in multiple brain regions. Although these studies are in their infancy, some evidence indicates that rapidly acting treatments like ECT cause changes primarily in the catecholaminergic system, whereas treatments that act more slowly, like fluoxetine, act predominantly on the serotonergic system. These studies also show strong effects of ECT on BDNF and transcripts encoding proteins involved in hippocampal synaptic plasticity (Conti et al. 2007). Follow-up studies examining the effects of ECT on protein expression and downstream functioning will be important in determining their relevance to ECT's clinical actions.

EFFICACY OF ECT Depression Indications The summary statement by the American Psychiatric Association Task Force on Electroconvulsive Therapy (2001) and research over the past 30 years (Abrams 1992; Fink 1979; O'Connor et al. 2001; Petrides et al. 2001) have confirmed that ECT is an effective treatment for depression in more than 80% of patients with treatment-resistant unipolar major depression or bipolar disorder. A meta-analysis of randomized, controlled trials (RCTs) performed by the UK ECT Review Group (2003) confirmed the following about the efficacy of ECT for major depression: ECT is more efficacious than sham ECT (shown in six RCTs; effect size, 0.91). ECT is more efficacious than antidepressant pharmacotherapy (18 RCTs; effect size, 0.80). Aspects of ECT associated with a positive response include higher total dose and bilateral electrode placement (although many studies likely underdosed patients with unilateral ECT). It is noteworthy, however, that several of these studies compared the response rates in patients receiving ECT with the response rates in patients receiving subtherapeutic doses of antidepressants. Given these data, ECT should no longer be considered a treatment of last resort but a potential first-line treatment when a rapid clinical response is essential in severely ill patients (e.g., those with active suicidal ideation, malignant catatonia, or a compromised medical condition related to depression such as dehydration or malnutrition), when the patient has a history of a positive response to ECT, or when the patient and family request ECT over other treatment options. ECT generally exerts its antidepressive effects more rapidly that pharmacotherapy does, and recent research has confirmed a rapid resolution of suicidal ideation with ECT (Kellner et al. 2005; Patel et al. 2006). Beale and Kellner (2000) argued that the use of ECT after multiple failed medication trials does not take into account the tolerability and efficacy of modern ECT and may lead to needless suffering on the part of the patient. They pointed out that antidepressive treatment algorithms place ECT as a tertiary treatment (e.g., Rush and Thase 1997) instead of recommending that ECT practitioners be consulted early in the treatment process to determine whether ECT would be appropriate therapy. Surveys show that patients who have received ECT rate it as a highly effective treatment (Parker et al. 2001), and that 85% of patients who have received ECT would agree to a second course of ECT if needed (Bernstien et al. 1998). ECT-related relief of depressive symptoms has also been associated with

long-term improvements in health-related quality of life, an increasingly important outcome measure in medical research (McCall et al. 2006).

Predictors of Response Clinical predictors of response to ECT have not been consistent across studies. Potential positive predictors of response include increasing age (Dombrovski et al. 2005; O'Connor et al. 2001) and the presence of psychotic or catatonic symptoms (Birkenhager et al. 2005; Buchan et al. 1992; Petrides et al. 2001). Several studies have reported that patients with longer current episodes of depression (Dombrovski et al. 2005; Prudic et al. 1996) or personality disorders (e.g., borderline personality disorder) (Feske et al. 2004; Parker et al. 2001) are less likely to respond to ECT. Patients with depression complicated by dysthymia (i.e., double depression) appear to respond to ECT to the same extent that patients without dysthymia do (Prudic et al. 1993). Attempts to link subtypes of depression (e.g., melancholic vs. atypical, unipolar depression vs. depression associated with bipolar disorder) to the likelihood of ECT response have generally failed to reveal differences. However, response by session 3 of ECT may predict long-term efficacy in relieving depression (Tsuchiyama et al. 2005). Medication resistance also has correlated with a failure to respond to ECT. Patients who had failed to respond to treatment with one or more antidepressants before receiving ECT responded less favorably to ECT than did patients who had not failed to respond to medication (Devanand et al. 1991; Dombrovski et al. 2005; Prudic et al. 1990; Sackeim et al. 1990). This was true for resistance to the heterocyclic antidepressants but not to the selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs) (Prudic et al. 1996). To date, the most consistent biological marker for ECT response has been increased frontal delta activity (i.e., postictal depression) shown on the electroencephalogram (EEG) after ECT (Mayur 2006; Sackeim et al. 1996), which is associated with decreased cerebral blood flow in the immediate postictal period (Nobler et al. 1994). More sophisticated methods of EEG analysis (e.g., nonlinear analysis) may hold promise in helping to discern electroencephalographic predictors of the antidepressive efficacy of ECT (Mayur 2006). Coffey et al. (1989) described a greater number of structural abnormalities observed on magnetic resonance imaging (MRI) scans of the brain (e.g., deep white matter, basal ganglia, and periventricular hyperintensities) in elderly depressed patients referred for ECT, compared with age-matched control subjects. These preexisting structural brain abnormalities may predispose elderly depressed patients to a less favorable response to ECT (Hickie et al. 1995; Steffens et al. 2001), although case reports indicate that ECT may be helpful in the treatment of depression after a stroke (Currier et al. 1992).

Mania Early anecdotal reports as well as more recent case studies suggest that ECT is beneficial in the treatment of mania associated with bipolar disorder and delirious mania (Fink 2001b, 2006). ECT also has been shown to be effective in patients with treatment-resistant mixed mood disorders (Gruber et al. 2000). Given the benefit of anticonvulsant medications in treating mania and the evidence that ECT may exert its therapeutic effect by raising the seizure threshold (Sackeim 1999), we have a theoretical basis for assuming that ECT is effective in the treatment of mania. Since 1970, several retrospective studies have confirmed the efficacy of ECT in patients with mania, with approximately two-thirds of patients showing marked clinical improvement (Mukherjee et al. 1994). In a prospective, controlled trial, Small et al. (1988) compared the efficacy of ECT with that of lithium in the treatment of mania. Patients who received ECT improved more during the first 8 weeks of treatment than did patients who received lithium. Nevertheless, after 8 weeks of treatment, ECT and lithium were comparable in efficacy. In addition, patients with mixed symptoms of depression and

mania responded particularly well to ECT. Catatonia may be especially common in patients with bipolar disorder, and this represents another scenario in which ECT may offer advantages in efficacy and rapidity of response versus pharmacotherapy (Taylor and Fink 2003). Challenges specific to treating mania with ECT include the following: Concomitant use of anticonvulsants, which may interfere with seizure induction in ECT Reports of prolonged seizures and delirium when ECT is given with lithium (Sartorius et al. 2005), although other authors have reported safe coadministration of ECT and lithium (Dolenc and Rasmussen 2005) Decreased likelihood that manic (vs. depressed) patients will voluntarily consent to ECT treatment Despite a rapid increase in studies evaluating alternative antimania medications, including newer anticonvulsants and the atypical antipsychotics, there is a lack of research comparing the potential benefits of ECT in the acute and maintenance treatment of bipolar disorder (Fink 2001b; Keck et al. 2000). This is regrettable given the advantages of ECT as a true mood stabilizer that can effectively treat both the manic and the depressed phases of the illness. ECT has been given safely to children with intractable mania (Hill et al. 1997) and to patients with dementia and comorbid mania (McDonald and Thompson 2001). ECT also may have an important role in the treatment of mania during pregnancy, given the potential teratogenic effects of many anticonvulsant medications as well as the potential harm to both the mother and the fetus from a prolonged affective episode. Controversy persists over whether unilateral ECT is as effective as bilateral ECT in the treatment of mania. Unfortunately, studies comparing unilateral and bilateral ECT in the treatment of mania have reported neither the amount of electrical charge used nor the percentage by which the electrical stimulus exceeded the seizure threshold. Daly et al. (2001) compared 228 patients with bipolar disorder or unipolar depression who were randomly assigned to ECT conditions that differed in electrode placement and stimulus intensity. They found that the bipolar patients had a rapid response to both unilateral and bilateral ECT and did not differ from the unipolar patients in either the rate of response or the response to unilateral or bilateral ECT. ECT also has been shown to be efficacious in the treatment of mixed mania (Ciapparelli et al. 2001). Future research is certainly needed to clarify the role of ECT in the treatment of mania, although clear evidence indicates that ECT is an effective treatment and should be included in any algorithm of therapy for treatment-resistant or severely disabling mania.

Schizophrenia With the introduction of clozapine and the atypical antipsychotics, ECT has become a third-line treatment for schizophrenia, although it continues to have an important role in the treatment of an acute psychotic episode, catatonic schizophrenia, and neuroleptic malignant syndrome. Although the mechanism of action of ECT in treating psychosis has received much less attention than the mechanism of its antidepressive effects, a possible mechanism of ECT's antipsychotic effects has been inferred from the therapeutic action of ECT in patients with phencyclidine-induced psychosis (Dinwiddie et al. 1988). One of the major actions of phencyclidine and related drugs (e.g., ketamine) is the blocking of open channels for NMDA receptors. Phencyclidine-induced channel blocking is voltage dependent and long lived, with the ion channel closing around the phencyclidine molecule (MacDonald et al. 1991). Relief of channel blocks requires NMDA ion channels to open at depolarized membrane potentials (Huettner and Bean 1988). Thus, neuronal membrane depolarization and glutamate receptor binding are important for allowing phencyclidine to exit the channel. Although it is not certain that blocking of NMDA channels causes phencyclidine-induced psychosis, it is interesting that ECT-induced seizures have the requisite effects to relieve the channel block. During a seizure, neurons depolarize (via synaptic excitation and action potential firing) and glutamate is released at synapses. These events together would be expected to relieve phencyclidine-induced blockage and could provide a rationale for the effectiveness of ECT. As a corollary, this mechanism would also lead to the prediction that the use of ketamine for anesthesia during ECT should be associated with a low

incidence of ketamine-induced psychosis. Fink and Sackeim (1996) reviewed the use of ECT in the treatment of schizophrenia and cautiously noted that most studies examining the efficacy of ECT in treating schizophrenia do not meet current standards for scientific methodology. Nonetheless, the authors concluded that ECT is a highly effective treatment for psychosis and that it should be considered, particularly for patients with schizophrenia and an initial psychotic episode, symptoms of agitation, increased psychomotor activity, delirium, or delusions. The authors also concluded that ECT is effective in treating schizophrenia when catatonia, prominent affective symptoms, or positive symptoms of psychosis (e.g., hallucinations) are present. They speculated that the use of ECT early in the course of schizophrenia may decrease the progressive, debilitating effects of the illness. ECT combined with neuroleptics has been shown to be more effective than ECT or neuroleptics alone in treating schizophrenia (Friedel 1986; Gujavarty et al. 1987; Klapheke 1993; Sajatovic and Meltzer 1993). A recent meta-analysis of the four most methodologically sound studies of ECT augmentation to antipsychotics for treating schizophrenia concluded that ECT offers a modest but significant benefit (equivalent to 5 points on the Brief Psychiatric Rating Scale) compared with neuroleptic therapy alone (Painuly and Chakrabarti 2006). The effects are apparent in the first several weeks of treatment but appear to diminish with prolonged treatment. Interestingly, all of these studies were conducted in India, where the use of ECT to treat schizophrenia appears to be more common than it is in the United States. Notably, open-label studies and case studies suggest that ECT may be safe and helpful in combination with clozapine, another treatment typically reserved for more treatment-refractory illness (Havaki-Kontaxaki et al. 2006). ECT combined with neuroleptic therapy may also be effective in the management of aggressive behavior in patients with schizophrenia (Hirose et al. 2001) and for maintenance treatment of schizophrenia (Chanpattana et al. 1999b). The recommendations of the American Psychiatric Association Task Force on Electroconvulsive Therapy (2001) state that ECT is an effective treatment for schizophrenia in the following clinical conditions: 1) during acute onset of symptoms, 2) when the catatonic subtype of schizophrenia is present, and 3) when there is a history of a positive response to ECT. Not surprisingly, patients with an affective component (i.e., schizoaffective patients) also respond more favorably to ECT than do schizophrenic patients without subsyndromal affective disorders. In addition, ECT represents a potentially life-saving intervention for patients with neuroleptic malignant syndrome that does not respond to more conservative treatments (e.g., supportive care or pharmacotherapy). Clearly, there is a need for further research related to the role of ECT in treating schizophrenia.

Parkinson's Disease ECT has been shown to be effective treatment for the motor symptoms of Parkinson's disease (Faber and Trimble 1991; Kellner et al. 1994; Rasmussen and Abrams 1991), and a recent meta-analysis of five studies confirmed that ECT acutely improves global motor functioning in patients with this disease (Fregni et al. 2005). These reports have included patients with and without psychiatric illnesses; ECT improves the motor symptoms of Parkinson's disease independently of its effects on the patient's mood. Because antimuscarinic drugs are useful in treating parkinsonism, the effects of ECT on central muscarinic systems may be relevant (Fochtmann 1988). However, ECT also alters central dopaminergic systems that are involved in the pathophysiology of Parkinson's disease (Fochtmann 1994). Acutely, ECS increases dopamine levels in the frontal cortex and striatum and has variable effects on basal dopamine levels. Furthermore, dopamine autoreceptor sensitivity is diminished after ECS, an effect that would tend to augment dopamine release. There is also evidence that dopamine1 (D1) receptor agonists increase the stimulation of adenylate cyclase after ECS. However, after ECS, D1 receptor binding is increased in the substantia nigra (Fochtmann et al. 1989), but not in the striatum (Nowak and Zak 1989).

Favorable predictors of response include advanced age, severe disability (on–off syndromes), and painful dyskinesias. Reduction in the symptoms of Parkinson's disease tends to occur during the first several sessions of ECT. However, the effects of ECT are not permanent and usually last from several days to several months, although prolonged improvement has been reported in a few patients. Maintenance ECT also has been shown to be effective for up to 4 years in treating the motor symptoms of Parkinson's disease (Aarsland et al. 1997; Wengel et al. 1998). Because of the increased risk for ECT-induced interictal delirium in patients with Parkinson's disease (or any neurological disease such as Alzheimer's disease or neurological condition such as impairment caused by a stroke), careful consideration must be given to the amount of electrical charge administered, the electrode placement used, and the frequency of treatments (Figiel et al. 1991). The delirium associated with ECT in patients with Parkinson's disease can be significantly reduced without losing effectiveness by doing the following: Using right-unilateral ECT with an initial electrical stimulus approximately 3.5 times the seizure threshold Administering ECT treatments every 3–4 days Withholding the dose of levodopa on the morning of ECT Discontinuing ECT until the cognitive impairment completely resolves if any impairment in attention or orientation develops, then restarting ECT at a lower electrical charge

Other Illnesses ECT can be a life-saving treatment for patients with catatonia regardless of the etiology, including catatonia resulting from a medical disease (e.g., lupus erythematosus), neuroleptic malignant syndrome, schizophrenia, bipolar disorder, and unipolar depression (Fink 1994, 1997). Limited evidence suggests that ECT may relieve symptoms associated with obsessive-compulsive disorder (OCD) (Maletzky et al. 1994; Thomas and Kellner 2003) and schizophrenia complicated by OCD (Lavin and Halligan 1996). Because it raises the seizure threshold, ECT can interrupt status epilepticus (Fink et al. 1999; Lisanby et al. 2001a) and treat intractable seizures (Griesemer et al. 1997; Regenold et al. 1998). ECT also has been shown to be safe and effective in the treatment of comorbid mood disorders in patients with closed head injuries (Kant et al. 1999), dementia (McDonald and Thompson 2001), and mental retardation (Aziz et al. 2001; Fink 2001a; Friedlander and Solomons 2002; Gabriel 1998; van Waarde et al. 2001). ECT may exert some analgesic effects independent of its effects on mood, as evidenced in a recent trial with positive results using ECT to treat fibromyalgia (Usui et al. 2006).

ECT Use During Pregnancy During pregnancy, ECT may be an effective, safe treatment for women with bipolar disorder or major depression and is recommended by the American Psychiatric Association (1994) practice guidelines as a possible first-line treatment for pregnant women with mood disorders. ECT has been safely used in all three trimesters of pregnancy (Rabheru 2001), although prospective, controlled studies of ECT use in pregnancy are lacking. Miller's (1994) review of more than 400 cases of women treated with ECT during pregnancy failed to identify a consistent pattern of complications; more recent case reports have associated ECT with premature labor (Bhatia et al. 1999; Echevarría Moreno et al. 1998). The risks of and risk management strategies for administering ECT during pregnancy have been reviewed by Rabheru (2001). The treatment of mania during pregnancy can be particularly difficult given the reported teratogenicity of several antimania medications. Although early case reports suggested that lithium use in the first trimester is associated with an increased risk of cardiac anomalies, more recent prospective, case–control studies have shown only weak teratogenic effects (L. S. Cohen et al. 1994). Carbamazepine and valproic acid are both associated with neural tube defects (Oakeshott and Hunt

1994). Many of the other medications, including atypical antipsychotics, benzodiazepines, and antidepressants, have less clear effects on the fetus. Yet the complications of untreated or partially treated bipolar disorder endanger both the mother and the fetus and include poor compliance with neonatal care, impaired judgment, substance abuse, poor nutrition and self-care, and depression with suicide attempts (Miller 2001).

STIMULUS DOSING IN ECT FOR TREATMENT OF DEPRESSION Questions about the proper management of the electrical stimulus have been central to the science and practice of ECT since the inception of the treatment. Cerletti and Bini modeled ECT on the success of pharmacologically induced convulsive therapy and assumed that the stimulus should be convulsive. Interestingly, the first ECT session in 1938 involved two subconvulsive stimulations before Cerletti and Bini increased the stimulus intensity to produce a convulsion (Endler 1988). Thus, the first ECT session was a "titrated" ECT session involving the serial application of increasing stimulus intensities passing from the subconvulsive range through the convulsive threshold. Issues in stimulus dosing that have been considered since that time include the following: Whether the stimulus should be subconvulsive or convulsive What the optimal stimulus waveform is If a convulsive stimulus is desired, to what degree the stimulus intensity should be in excess of the convulsive threshold Which physiological parameters, if any, provide useful feedback to continuously refine stimulus dosing throughout the ECT course

Convulsive, Subconvulsive, and Sham Stimulation The use of nonconvulsive electrical stimulation to treat psychiatric disorders preceded the introduction of ECT by decades. Most of the treatments involved administering static electricity to parts of the body including but not limited to the head (Grover 1924). The availability of commercial ECT devices did not lead to the immediate replacement of subconvulsive stimulation with convulsive stimulation. Instead, some practitioners used the devices to deliver lengthy (several minutes long) subconvulsive cranial stimulation. However, it became clear that subconvulsive stimulation was associated with a poorer outcome than conventional psychotherapy in psychoneurotic patients, and the practice of treating patients with subconvulsive stimuli decreased (Hargrove et al. 1953). Now, many years later, the use of rapid-rate transcranial magnetic stimulation (rTMS) has re-opened the question of whether subconvulsive stimuli are an effective treatment for depression; these data are reviewed in a later section (see "Transcranial Magnetic Stimulation and Subconvulsive Stimuli"). The elements of modified ECT (including muscle relaxation and general anesthesia) were described early in the history of ECT. The wide-scale adoption of these modifications raised new questions as to whether seizure is central to the antidepressive efficacy of ECT or whether anesthesia alone would be just as effective. The Northwick Park trial (Johnstone et al. 1980) and the Leicestershire trial (Brandon et al. 1984) are examples of two "sham" ECT studies in which anesthesia alone was compared with real ECT. It was convincingly demonstrated that real ECT is more efficacious, especially for the most severe forms of depression (Brandon et al. 1984; Johnstone et al. 1980). The efficacy of ECT was clearly linked to the production of a seizure. Neither the use of anesthesia alone without the electrical stimulus nor the use of subconvulsive stimuli appears to have real merit in the treatment of depression.

Stimulus Waveform Given that a convulsive stimulus is necessary for the antidepressive effects of ECT, a nearly infinite number of variations are available for formulating the stimulus waveform. The earliest ECT devices delivered a sinusoidal stimulus. Other waveforms available on early ECT devices included the

"chopped" sine wave, the unidirectional pulse square wave, and the alternating brief-pulse square wave. Although some investigators had a suspicion that sine wave stimuli might produce slightly better antidepressive effects than did brief-pulse stimuli, that suspicion was mitigated by a randomized study showing that sine wave ECT produced more memory side effects than brief-pulse ECT, irrespective of the placement of the stimulating electrode (R. D. Weiner et al. 1986). This finding of greater cognitive side effects with sine wave ECT was recently replicated in an efficacy study using a prospective cohort design, which showed that compared with brief-pulse stimulation, sine wave stimulation was associated with a slowing of reaction time that persisted for at least 6 months after ECT (Sackeim et al. 2007). The more severe cognitive side effects produced by sinusoidal stimuli may be explained by the slower rise time for each sine wave cycle as compared with the brief-pulse cycle. Consequent to the slower rise time, much of the sine wave stimulus is subconvulsive and thus presumably adds nothing to the therapeutic effect of ECT, adding only to cognitive side effects. The steep rise in the brief-pulse waveform allows for the entire stimulus to be above the convulsive threshold (suprathreshold). Because much of the sine wave stimulus is nonproductive, being in the subconvulsive range, it would be predicted that brief-pulse stimuli would be more efficient, requiring a stimulus of smaller magnitude to produce a seizure. Standard brief-pulse stimuli are defined by pulse duration of 1–2 milliseconds, while ultrabrief-pulse stimuli are defined by pulse duration of 0.25–0.50 milliseconds. In 1980, Weiner showed that standard brief-pulse stimuli could provoke a seizure with only one-third of the energy required with sine wave stimuli (Weiner 1980). In the last decade, standard brief-pulse ECT devices replaced sine wave devices in the United States (Farah and McCall 1993). New devices using ultrabrief-pulse stimuli have the advantage of improving the efficiency of seizure induction. Abrams (2002) estimated that it takes only about 0.25 milliseconds to initiate neuronal depolarization, and wider pulse widths are inefficient and waste electrical charge. The total energy output of these ultrabrief-pulse modalities is the same as the total energy output of the standard brief-pulse widths; thus, as the stimulus pulse widths are shortened, the stimulus trains are lengthened. Ultrabrief-pulse widths may have an advantage because shorter pulse widths and longer pulse trains have been shown to elicit seizures with a smaller electrical charge and therefore may have fewer cognitive side effects (Sackeim et al. 2001b). Similarly, decreasing the frequency of pulses with a corresponding lengthening of the stimulus train will improve the efficiency of seizure induction (Kotresh et al. 2004).

Magnitude of the Stimulus Dose The consensus regarding the need for convulsive (as opposed to subconvulsive) stimuli and brief-pulse waveforms would seem to make stimulus dosing in ECT a straightforward process, except for the question of the degree to which the stimulus should exceed the convulsive threshold. For years, ECT practitioners were satisfied that the answer to this question was found in the work of Ottosson (1962), who compared routine ECT with ECT modified by pretreatment with intravenous lidocaine. He found that seizures induced by lidocaine-modified ECT were shorter than those induced by routine ECT and observed an inverse relationship between seizure duration and antidepressive effect. From this work, it was widely accepted that stimulus doses producing seizures lasting at least 25 seconds have an antidepressive effect (American Psychiatric Association Task Force on Electroconvulsive Therapy 1978). Initially, ECT was administered using bilateral (typically bitemporal) electrode placement. In 1949, Goldman introduced right-unilateral ECT and placed stimulating electrodes over the right hemisphere rather than the mesial temporal lobes in an attempt to decrease the direct stimulation of language areas and decrease cognitive side effects. Although right-unilateral ECT was associated with fewer cognitive side effects, most studies showed that bilateral ECT had a marked therapeutic advantage over unilateral ECT for depression (d'Elia and Raotma 1975). The clinical wisdom that bilateral ECT was more effective than right-unilateral ECT in treating

depression came into question with the groundbreaking work of Sackeim's research group. Sackeim et al. (1993) reported that when the magnitude of the electrical stimulus was just barely above the convulsive threshold, ECT with right-unilateral electrode placement was not efficacious, despite the production of electrographic seizures typically in excess of 25 seconds. However, as the electrical dose was progressively increased, response rates in right-unilateral ECT improved significantly and approached those of bilateral ECT. In contrast, bilateral ECT was fully efficacious with stimuli minimally above or 2.5 times the seizure threshold, but excess memory side effects accrued at the higher stimulus dose. The dose–response relationship of right-unilateral ECT holds true to the extent that the stimulus exceeds the convulsive threshold for a given patient, but is not related to the absolute magnitude of the stimulus dose. The efficacy of right-unilateral ECT follows a nearly linear relationship to the degree that the stimulus dose exceeds the seizure threshold, at least through 12 times the seizure threshold (McCall et al. 2000). This relationship is analogous to the pharmacological treatment of depression with tricyclic antidepressants: serum blood levels are more important than the absolute oral dose in determining both efficacy and side effects. These findings led to the following conclusions: With standard brief-pulse stimulation delivered with right-unilateral electrode placement, the stimulus should be substantially above the convulsive threshold in order to ensure the effectiveness of ECT. With standard brief-pulse stimulation delivered with bilateral electrode placement, the stimulus should not be excessively above the convulsive threshold, in order to avoid undue cognitive side effects. The convulsive threshold varies by a factor of at least 40 in large patient samples; thus, the mean threshold for a group of patients is useless for individual cases (Sackeim et al. 1991). It is clear that the convulsive threshold is related to age, sex, race, choice of stimulating electrode placement, and, perhaps, cranial dimensions (Chung 2006; Colenda and McCall 1996; McCall et al. 1993b; Sackeim et al. 1991). Still, these factors predict only a small amount of the variance in the convulsive threshold, and statistical models to predict the convulsive threshold, including age-based dosing approaches, fare poorly (Colenda and McCall 1996; Tiller and Ingram 2006).

Seizure Morphology The report of Sackeim et al. (1993) that threshold right-unilateral ECT produced seizures of 25 seconds or longer without antidepressive efficacy cast into doubt the clinical wisdom that the stimulus dose was therapeutic if the electrographic seizure lasted at least 25 seconds. Investigators have sought to find a physiological marker of treatment adequacy to replace seizure duration. The most promising candidate is seizure morphology. Ottosson (1962) reported that lidocaine changed the shape of ECT seizures and affected their duration, although the first finding is largely overlooked. Lidocaine-modified seizures, in addition to being less efficacious than standard ECT seizures, were characterized by loss of spike activity and poor postictal suppression. This finding has been extended by evidence that seizure morphology varies with ECT techniques. That is, greater seizure intensity correlates with ECT techniques that progress from lower efficacy (with right-unilateral electrode placement and low stimulus intensity) to higher efficacy (with bilateral placement and high stimulus intensity) (Krystal et al. 1993). Electrode placement and stimulus intensity have independent and additive effects on seizure morphology. Seizures of greater intensity are characterized by higher peak ictal amplitudes, greater stereotypy of the ictal discharge, greater symmetry and coherence between the left and right cerebral hemispheres, and more profound postictal suppression. Preliminary evidence suggests that greater seizure intensity is predictive of a greater likelihood of response and/or faster response (McCall et al. 1995; Nobler et al. 1993). The natural extension of this reasoning leads to the hope that seizure morphology could guide

decisions about stimulus intensity as the course of ECT progresses. For example, if seizure intensity is poor in the middle of the treatment course, then the treatment technique should be changed (by switching electrode placement and/or increasing the stimulus intensity) in order to optimize the clinical outcome. Manufacturers of ECT devices now incorporate automated measures of seizure intensity onto the ECT chart recorder, and the accompanying owner's manual instructs the practitioner to increase the stimulus intensity if the seizure morphology appears to be degraded. The unstated implication is that poor seizure morphology is a problem and that increasing the stimulus intensity will fix the problem. This instruction might have merit if stimulus intensity were the primary determinant of seizure morphology, but other factors, such as age, baseline convulsive threshold, and other intrinsic patient factors likely play an equal role in determining seizure expression (McCall et al. 1996, 1998). For example, greater seizure durations coupled with greater seizure regularity as shown by electroencephalography at the second ECT session are predictive of a better antidepressive outcome at the conclusion of the ECT course, and this relationship is independent of the choice of stimulus electrode placement (Rosenquist et al. 2007). Poor seizure morphology (e.g., in older patients with high seizure thresholds) is little influenced by increasing the stimulus intensity above 2.5 times the seizure threshold. Therefore, it is premature to recommend stimulus dosing on the basis of seizure morphology. The importance of seizure morphology in predicting clinical outcome is far from being understood, and more work is needed to make it a practical tool for governing ECT technique. Peak heart rate has been proposed as an alternative physiological measure of treatment adequacy, with higher heart rates perhaps indicating better clinical outcomes (Swartz 2000). Again, this approach has yet to be widely accepted.

Integrating the Science of Stimulus Dosing With the Choice of Electrode Placement Estimating the Convulsive Threshold The recent advances in knowledge pertaining to stimulus dosing lead to the conclusion that standard brief-pulse, right-unilateral ECT should be initiated with a stimulus known to be at least five times the seizure threshold, while standard brief-pulse, bilateral ECT should be initiated with a stimulus about 50% above the seizure threshold. Choosing between these two strategies requires consideration of both efficacy and side effects. An indirect comparison was made by Stoppe et al. (2006) in a study of older depressed patients randomly assigned to receive fixed high doses of either right-unilateral ECT (n = 17) or bilateral ECT (n = 22). Although the failure of this study to dose according to a known seizure threshold makes the cognitive findings difficult to evaluate, it did show similar remission rates with right-unilateral ECT (88%) and bilateral ECT (68%), suggesting that efficacy need not be compromised by choosing right-unilateral placement. McCall et al. (2000) conducted the first randomized comparison of low-dose (1.5 times the seizure threshold) bilateral ECT (n = 37) versus high-dose (8 times the seizure threshold) right-unilateral ECT (n = 40). Again, depression remission rates were not significantly different with right-unilateral electrode placement (60%) versus bilateral placement (73%), and memory effects were likewise similar. This study can be criticized for having insufficient power to detect small but meaningful effects. That concern was addressed in a subsequent study by Haskett et al. (2007) contrasting 339 patients randomly assigned to receive either standard brief-pulse, right-unilateral ECT administered at 6 times the seizure threshold or bilateral ECT administered at 1.5 times the seizure threshold. Although differences between the treatments' antidepressive effects were again indistinguishable, the extent of autobiographical memory loss was greater in the bilateral group. This study solidifies the position of high-dose right-unilateral ECT as the preferred initial strategy. Even if patients fail to respond to an initial approach using right-unilateral electrode placement, increasing the stimulus intensity with right-unilateral ECT is associated with a subsequent antidepressive response equal to

the response obtained after switching to bilateral ECT, with fewer cognitive side effects (Tew et al. 2002). The bulk of the evidence thus suggests that it is desirable to set the stimulus dose as a proportion of the convulsive threshold; the convulsive threshold of each patient should be known, preferably by measuring convulsive threshold early in the ECT course. The most accurate means of measuring the convulsive threshold for a given patient is empirical observation: giving intentionally subconvulsive stimuli at the first treatment; then, in the same session, administering successively larger stimuli until a seizure is produced. This stimulus "titration" technique defines the convulsive threshold for each patient. This approach applies to right-unilateral and bilateral electrode placement. If ECT practitioners agree with the above reasoning and use this stimulus dosing technique, they should ascertain the convulsive threshold at the first ECT session. However, some ECT researchers have argued against titration of stimulus doses with unilateral ECT and instead have encouraged practitioners to use fixed high doses of unilateral ECT (Abrams 2002) or fixed moderate doses of bilateral ECT (Kellner 2001). In fact, a survey of ECT practitioners in 1993 showed that only a minority performed titration of the stimulus dose (Farah and McCall 1993). The reasons for this are unclear, but possible explanations include concerns that 1) the subconvulsive stimulation inherent in stimulus titration might be medically dangerous, 2) subconvulsive stimulation might add to memory side effects, or 3) production of a barely suprathreshold seizure with right-unilateral placement would constitute ineffective treatment, thus rendering the first treatment a wasted effort. It is true that subconvulsive stimulation transiently slows the heart rate, and that if subconvulsive stimulation is given to patients who have received a -blocker and no anticholinergic drug, there is risk of substantial asystole (McCall et al. 1994). On the other hand, atropine pretreatment eliminates this risk. The possibility of excess acute cognitive side effects with subconvulsive stimuli has been examined and discounted (Prudic et al. 1994). The possibility of a sluggish antidepressive response when stimulus doses are titrated to a level moderately above the seizure threshold in combination with right-unilateral electrode placement, however, is a real concern. A prospective, randomized trial in elderly depressed subjects showed that a titrated, moderately suprathreshold dosing strategy with right-unilateral electrode placement produced a slower antidepressive response than did fixed high stimulus doses with right-unilateral electrode placement (McCall et al. 1995). Similar results were seen in a naturalistic comparison of young adults receiving titrated, right-unilateral ECT at 2–3 times the seizure threshold versus right-unilateral ECT at a fixed high dose (Ward et al. 2006). Interpretation of these studies is made more difficult by differences between the treatment groups (titrated vs. fixed doses; moderate vs. high doses). At the very least, however, it is clear that different dosing strategies affect the antidepressive outcome of right-unilateral ECT, even when the doses being compared are substantially above the convulsive threshold.

Alternatives to Estimating the Convulsive Threshold Abrams (2002) suggested that the most efficient method of administering right-unilateral ECT is to use 100% of the maximum device capacity and a pulse width of 0.25–0.50 milliseconds and recommended changing to bilateral ECT if the patient does not improve sufficiently. However, insufficient data support the routine use of ultrabrief-pulse widths (Fink 2002), and the use of stimulus titration to establish a dose relative to the seizure threshold would potentially decrease cognitive problems while ensuring an adequate seizure (Rasmussen 2002). Alternatively, twiceweekly bilateral ECT could be initiated using the half-age method (Abrams 2002). In the half-age method, the age of the patient is divided by 2; the resulting number is the percentage of the device's maximal output with which the patient is first treated (e.g., a 50-year-old would be treated at 25% of the machine's maximal output). Kellner (2001) recommended an alternative fixed-dose strategy that involves starting with 75% of maximal output for right-unilateral ECT and 30%–60% of maximal output for bilateral ECT.

Our recommendations for stimulus dosing are made with the following two caveats: 1. Recommendations can be made only in regard to treating major depression, as it is unknown whether dosing strategies for patients with other diagnoses should be the same as those for treating depression. 2. Dosing recommendations can be made only in the context of the chosen electrode placement and the patient's clinical condition. It is clear that a supraconvulsive stimulus is necessary to obtain an antidepressive effect with rightunilateral ECT. It is unclear whether any supraconvulsive stimulus would have equivalent antidepressive efficacy with bilateral electrode placement, but a stimulus of at least 2.5 times the convulsive threshold is required with right-unilateral ECT in most patients.

Choosing an Electrode Placement and Stimulus Dose Those patients with the most serious complications of major depression (i.e., active suicidal behavior in the hospital, catatonia, or food refusal) merit an approach most likely to yield quick antidepressive results. In such circumstances, bilateral ECT with a relatively high fixed stimulus dose (e.g., 50% of the machine's maximal output) could be justified; stimulus dose titration would not be required because concern about cognitive side effects becomes a purely secondary issue, based on the severity of the patient's clinical status. However, whether fixed high-dose right-unilateral ECT could provide an equally fast and effective response needs to be examined. In contrast, a depressed patient in whom medication has failed but who is otherwise not in urgent need of treatment may be an appropriate candidate for right-unilateral ECT at 5–6 times the seizure threshold, especially if cognitive side effects are a concern or if the patient is being treated in an outpatient setting. The patient can start with right-unilateral ECT and after five or six treatments change to bilateral ECT if he or she has not had an adequate response. Other special situations favoring titrated right-unilateral ECT include the treatment of depressed patients with comorbid dementia or other neurological conditions such as Parkinson's disease. The treatment of these patients should minimize even transient memory side effects and may include starting at a very conservative unilateral dose (i.e., 3.5 times the seizure threshold) and increasing the dose as tolerated. Other dosing strategies, such as titrated bilateral or fixed high-dose right-unilateral ECT, occupy the strategic middle ground between titrated right-unilateral and fixed-dose bilateral ECT for patients whose condition is of intermediate acuity. One promising area of research is the development of bifrontal ECT, which has the potential for providing the efficacy of bilateral ECT with a cognitive side-effect profile similar to that of right-unilateral ECT. In bifrontal ECT, the electrodes are placed 5 cm above the lateral angle of each orbit in a line parallel to the sagittal plane in order to directly stimulate the frontal lobes, which have been implicated in the pathology of major depression (Nobler et al. 2000) and response to ECT (Nobler et al. 1993). Compared with bilateral and right-unilateral ECT, bifrontal ECT would potentially spare the temporal lobes and decrease cognitive side effects. Preliminary research has shown that bifrontal ECT is comparable in efficacy to bilateral ECT, and preliminary evidence indicates that bifrontal ECT (at either the seizure threshold or 1.5 times the seizure threshold) has fewer cognitive side effects than bilateral ECT (Bailine et al. 2000; Lawson et al. 1990; Letemendia et al. 1993; Ranjkesh et al. 2005). A retrospective chart review of 76 patients found that bilateral ECT was more effective than bifrontal ECT with modestly increased side effects (Bakewell et al. 2004). In a study comparing right-unilateral and bifrontal ECT, Heikman et al. (2002) randomly assigned 24 depressed patients to receive high-dose right-unilateral ECT (at 5 times the seizure threshold), moderate-dose right-unilateral ECT (at 2.5 times the seizure threshold), or low-dose bifrontal ECT (just above the seizure threshold). Among the 22 patients who completed the study, depression remitted in 7 of 8 patients (88%) treated with high-dose right-unilateral ECT, compared with just 3 of

7 patients (43%) each in the groups treated with moderate-dose right-unilateral and low-dose bifrontal ECT (the difference was not statistically significant). All three groups were similar in terms of cognitive changes measured by the Mini-Mental State Exam (Folstein et al. 1975), it is difficult to know exactly when bifrontal ECT should be used in a clinical ECT service, because the research is lagging behind clinical practice (C. K. Loo et al. 2006). A multisite study funded by the National Institute of Mental Health is under way using more sophisticated cognitive testing and outcome measures to determine whether bifrontal ECT is a viable alternative to high-dose right-unilateral or bilateral ECT.

ECT TECHNIQUES Pretreatment Medical Evaluation Although no medical condition is an absolute contraindication for ECT, several clinical conditions may increase the risk of complications from ECT: Recent myocardial infarction or unstable cardiac conditions Any illness that increases intracranial pressure (e.g., brain tumor) Recent cerebral infarction, particularly hemorrhagic infarction Aneurysm or vascular malformation American Society of Anesthesiology physical status classification level 4 or 5 Severe pulmonary disease When treating high-risk patients with ECT, clinicians must evaluate the effects of ECT on cerebral and cardiac physiology and review data from the extant ECT literature to help develop individual risk–benefit ratios (American Psychiatric Association Task Force on Electroconvulsive Therapy 2001; Applegate 1997; Bader et al. 1995; Krystal and Coffey 1997; Weisberg et al. 1991; Zwil et al. 1992). All patients should undergo a thorough medical and neuropsychiatric review before beginning ECT. Particular emphasis should be placed on diseases affecting the CNS and the cardiovascular system. The pre-ECT evaluation should include a physical examination, detailed neurological examination, mental status examination, medical history, and review of systems. The patient's mental status should be evaluated before initiation of ECT and monitored closely before administration of ECT at every session thereafter. The baseline screening should include some basic laboratory tests (blood count and electrolytes) and an electrocardiogram. Clinicians should obtain a chest X ray for patients with pulmonary disease. Spine films should be considered for patients with a history of back pain, positive findings on physical examination, or medical conditions that may affect the skeletal system. Even patients who are recovering from surgery to repair a broken hip can be safely treated with ECT if appropriate doses of succinylcholine are used to ensure adequate relaxation. The greatest risks for fractures are in the recovery room if the patient has significant postictal confusion and agitation, and during the acute ECT course when patients, particularly the elderly and those with Parkinson's disease, are at increased risk for falling. Information obtained about the patient's neuropsychiatric history should include the following: Complications from anesthesia (including a family or personal history of malignant hyperthermia) Dementia or other neurological disease Any symptoms on neurological examination suggestive of increased intracranial pressure (e.g., severe headaches, new-onset incontinence, or gait ataxia) or primary neurological disease (e.g., lateralizing neurological deficits) Based on the patient's examination, brain imaging may be ordered before ECT. Some (Kellner 1996) have called for a reevaluation of the common practice of obtaining brain imaging for all patients prior to ECT. Kellner argues that with proper screening, the number of patients with significant CNS findings

on imaging who have normal neurological examination findings is very low, and the expense of routine screening is high. The clinician also must assess the patient's cardiovascular status, including evidence for dyspnea on exertion, angina, orthopnea, or conditions that might increase the risk of coronary artery disease (e.g., hyperlipidemia, hypercholesterolemia, poorly controlled hypertension, obesity, or diabetes). ECT in some ways represents a cardiac stress test, with an abrupt rise in the heart rate and blood pressure occurring after the stimulus. Therefore, one of the most important screens to determine whether a patient can tolerate ECT is accurately assessing exercise tolerance. This can be accomplished by asking questions such as the number of stairs a patient can climb without becoming short of breath. Patients with evidence of coronary artery disease can be screened with a relatively inexpensive treadmill test establishing a peak heart rate of approximately 120. However, ECT patients with severe depression are typically sedentary, elderly, and often unable to tolerate even minimal physical activity. Many would be unable to complete a treadmill test; more expensive tests, such as a persantine thallium stress test, can be substituted when appropriate. Establishing a working relationship with a cardiologist is an essential part of developing an ECT service. Often the consulting cardiologist is asked to "clear a patient for ECT" without understanding exactly what effects ECT would have on the patient's cardiovascular system. A significant acute risk to the patient undergoing ECT is the potential for a cardiovascular event, and optimizing the management of cardiovascular disease before and during ECT can decrease this risk. Inviting the consulting cardiologist to observe the ECT procedure and including the cardiologist in discussions with both the patient and the family help ensure that all the involved parties make informed decisions regarding the relative risk–benefit ratio of the procedure. Finally, informed consent should be obtained from all patients before ECT. Patients deemed to be incompetent may require the appointment of a legal guardian for consent. States vary in the legal regulations governing the use of involuntary ECT.

Medications Used During ECT Patients should have nothing by mouth the night before their treatment and should limit the number of medications, and water needed to swallow the medications, on the morning of ECT to cardiac medications (except lidocaine), pulmonary medications (except theophylline), and glaucoma medications (except cholinesterase inhibitors, e.g., echothiophate). Given that the patient's oral intake is restricted, clinicians should also consider withholding any diuretics until after the treatment depending on the patient's cardiac status. It is recommended that theophylline be discontinued and inhalers substituted and brought to the ECT suite to be given immediately prior to the treatment. Theophylline has been associated with status epilepticus during ECT (Devanand et al. 1988). A case review of ECT use in patients with asthma was recently published, noting its overall good safety (Mueller et al. 2006). Patients with glaucoma who are receiving echothiophate should be switched to another medication because echothiophate can potentially interact with succinylcholine and prolong the apneic period. The same is potentially true for the cholinesterase inhibitors used to treat Alzheimer's disease—tacrine, donepezil, rivastigmine, and galantamine—although there are no data to determine whether this interaction is clinically significant. In fact, a preliminary study reported the successful and safe use of donepezil to mitigate cognitive side effects associated with ECT (Prakash et al. 2006). In diabetic patients, hypoglycemic medications are usually withheld on the morning of treatment to minimize the risk of hypoglycemia in a patient who is taking nothing by mouth. The patient's blood sugar level should be checked before ECT, and hyperglycemia or hypoglycemia should be treated appropriately. An ECT treatment will result in a modest short-term increase in the patient's blood sugar. In general, patients with epilepsy or mania should continue taking their anticonvulsants during

ECT. If difficulty arises in eliciting seizures, decreasing the dose of the anticonvulsant can be considered. Lunde et al. (2006) recently summarized reports of ECT use in persons with epilepsy and recommendations for its safe use in this population. In the past, it was recommended in the United States that all psychotropic medications be discontinued prior to beginning ECT. In other countries, it is common practice to continue using antidepressants during ECT (Royal College of Psychiatrists 1995). Available data are mixed regarding the use of antidepressants concurrently with ECT. Previous studies in the 1950s and 1960s suggested a possible better response to ECT in patients receiving tricyclic antidepressants (Dunlop 1960; Kay et al. 1970; Sargant 1961). Later studies also suggested that the response to ECT may be superior when combined with tricyclic antidepressant use but not with the use of SSRIs (Lauritzen et al. 1996; Nelson and Benjamin 1989). Further research is needed to clarify this issue. When neuroleptic agents are necessary to control agitation or psychotic symptoms, a high-potency neuroleptic or an atypical antipsychotic medication is preferable to minimize any hypotension that may develop during ECT. Antipsychotics are generally continued during ECT treatment of persons with primary psychotic disorder (e.g., schizophrenia or schizoaffective disorder). Concerns have been raised over whether MAOIs can be used safely with anesthesia. Although some clinicians still recommend caution and a 7- to 14-day washout period before proceeding with ECT, extensive reported experience with MAOIs and ECT has documented few significant problems (American Psychiatric Association Task Force on Electroconvulsive Therapy 2001; Dolenc et al. 2004). Lithium usually is discontinued at least 48 hours before ECT because a potentially increased risk of delirium and cognitive impairment during ECT has been reported with its use (Ahmed and Stein 1987; Small 1990; Small et al. 1980). In more recent studies, however, the use of lithium was not associated with increased confusion in acute (Jha et al. 1996; Mukherjee 1993) or maintenance (J. T. Stewart 2000) ECT. Benzodiazepines can interfere with the induction of a seizure during ECT, thereby decreasing the efficacy of the treatments (Jha and Stein 1996). As a result, benzodiazepine doses should be reduced to the lowest possible or eliminated before ECT. Patients taking benzodiazepines should be receiving a stable dose for 24–48 hours before ECT in order to reduce the risk of prolonged seizures or status epilepticus during ECT. Flumazenil, a competitive benzodiazepine antagonist, at a dose of 0.4–0.5 mg, has been effective in maintaining seizures without decreasing efficacy in patients who could not be withdrawn from benzodiazepines prior to ECT (Krystal et al. 1998).

ECT Administration ECT sessions usually are scheduled for the morning. The patient's bladder should be emptied before treatment. Patients should not eat or drink for at least 6–8 hours before receiving the treatment. Famotidine or ranitidine is given the night before and the morning of ECT to neutralize the patient's gastric contents. Alternatively, sodium citrate can be given the morning of the treatment and will have an effect within 5–10 minutes. The ECT treatment team consists of a psychiatrist, an anesthesiologist (or nurse anesthetist), and a nursing team that is specially trained in ECT. The ECT treatment area should have resuscitative equipment available in case a medical emergency arises. The historically standard anesthetic agent is methohexital, a short-acting barbiturate with minimal anticonvulsant effects. Methohexital is given in a dose of approximately 0.75–1.0 mg/kg; one alternative is propofol, given in a dose of approximately 0.75–1.50 mg/kg. Methohexital has been used more commonly because of its effectiveness and safety record. Concerns regarding the use of propofol include that it induces shorter seizures than methohexital—with propofol, some patients will not achieve a seizure lasting more than 20 seconds—and increases the number of missed seizures (i.e., delivery of an electrical stimulus without induction of a seizure) (Swaim et al. 2006). However, seizure duration has not been correlated with clinical efficacy, and trials comparing the use of

methohexital versus propofol have not shown significant differences in the antidepressive efficacy of ECT (Avramov et al. 1995) based on the anesthetic agent. Etomidate (0.15–0.3 mg/kg) can be used instead of propofol and is associated with significantly longer seizures (Bergsholm et al. 1996; Stadtland et al. 2002) and, in one retrospective naturalistic study, was associated with a significantly shorter treatment course (Swaim et al. 2006). Another strategy that is suggested by the results of one small randomized trial is to use remifentanil, an ultrafast-acting opioid that is used to induce and maintain anesthesia, in addition to propofol. That study found that adding remifentanil had no adverse anesthetic or cardiovascular effects and patients receiving the combination anesthesia had significantly longer seizures than those receiving propofol alone (Vishne et al. 2005). Immediately after the patient is anesthetized, a muscle relaxant is administered intravenously. Succinylcholine, at doses of 0.75–1.50 mg/kg, is a widely used depolarizing blocking agent. In patients with musculoskeletal disease, a nondepolarizing agent can be considered. Anticholinergic agents, such as atropine or glycopyrrolate, are used to prevent ECT-induced bradycardia and to minimize airway secretions. Glycopyrrolate does not cross the blood–brain barrier and therefore may be associated with less postictal confusion than atropine in the elderly. An anticholinergic agent always should be used in conjunction with a -blocker to control the ECT-induced rise in blood pressure and heart rate. Atropine (0.4–1.0 mg) or glycopyrrolate (0.2–0.4 mg) can be given either intramuscularly 30 minutes before the ECT treatment or intravenously at the time of treatment. The choice of electrode placement was discussed previously (see "Integrating the Science of Stimulus Dosing With the Choice of Electrode Placement"). Regardless of the electrode placement selected, meticulous care should be taken to ensure that the electrodes are properly applied. The scalp should be cleansed and prepared with a saline solution and conductive gel. The electrodes should be adequately spaced to prevent excess shunting of the electrical stimulus and to prevent skin burns. With bilateral ECT, electrodes are placed frontotemporally, with the center of each electrode approximately 1 inch (2.54 cm) above the center of an imaginary line, the endpoints of which are the tragus of the ear and the external canthus of the eye. With unilateral ECT, d'Elia electrode placement is the safest and most effective placement (R. D. Weiner and Coffey 1986). In this technique, one electrode is placed over the nondominant frontotemporal area, and the other electrode is placed high on the nondominant centroparietal scalp, just lateral to the midline vertex. The treating physician may choose to either titrate the first seizure stimulus dose or use fixed-dose ECT. The patient is oxygenated by positive-pressure ventilation from the onset of anesthesia until spontaneous respiration is resumed. In addition, the patient is monitored with a pulse oximeter and should have his or her blood pressure and heart rate continuously monitored. Before the electrical stimulus is administered, a rubber bite block is inserted into the patient's mouth. Regarding dosing of the electrical stimulus, the titration or method-of-limits approach uses a table with incremental increases in the electrical energy to determine the minimal amount of energy necessary to produce a seizure of at least 25 seconds as monitored by electroencephalography. Typically, a seizure lasting 30–90 seconds occurs during treatment. Seizures lasting longer than 3 minutes should be terminated by administering an anticonvulsant (e.g., a second dose of methohexital or a benzodiazepine). Inflating a blood pressure cuff on the right ankle before the muscle relaxant is administered allows the clinician to monitor the motor manifestations of the seizure. Patients usually are alert and oriented 20–45 minutes after receiving an ECT treatment. If no seizure is elicited by the electrical stimulus, a detailed reevaluation should be performed. Often, immediately re-treating the patient with a higher stimulus charge is effective in producing a seizure. Medication use should be reviewed, and anticonvulsant and benzodiazepine doses should be reduced or discontinued, before subsequent ECT treatments. In situations that do not allow the reduction of

benzodiazepine doses, flumazenil, a benzodiazepine antagonist, can be used to help produce seizures.1 Reducing the methohexital dose to the lowest effective level and using vigorous hyperventilation are other relatively easy steps that can be taken to aid in producing a seizure. Some patients who are sensitive to pain at the intravenous site (particularly when an intravenous line is inserted in a small peripheral vein) may be given intravenous lidocaine as a local anesthetic just prior to administering general anesthesia; if possible, however, lidocaine should be omitted because it can shorten the seizure length. If these methods are not effective, switching methohexital to etomidate, which should have less of an effect on the seizure threshold, may be considered (Bergsholm et al. 1996; Folk et al. 2000; Stadtland et al. 2002). Caffeine sodium benzoate (usual dose, 120–140 mg) may be administered intravenously during ECT to maintain adequate seizure duration (Coffey et al. 1987). Caffeine appears to lengthen seizure duration during ECT without lowering the seizure threshold (McCall et al. 1993a). At present, it is not known whether caffeine augments the antidepressive effects of ECT or increases the speed of response to ECT. Theoretically, caffeine would have little therapeutic effect on unilateral ECT because the length of the seizure is less important than the degree to which the seizure stimulus exceeds the seizure threshold. Caffeine use during ECT should be reserved for patients who are having short seizures during ECT and who cannot tolerate higher stimulus doses. Conversely, if the seizure is too long (>180 seconds), the seizure can be terminated using additional intravenous methohexital, propofol, or midazolam. Seizure length is inversely correlated with age and is particularly longer in young women. Propofol can be used as the anesthetic agent to shorten the seizure length (Bailine et al. 2003).

Frequency and Number of Treatments The American Psychiatric Association Task Force on Electroconvulsive Therapy (2001) recommends that an ECT course be completed when a plateau in response occurs. No convincing data support that additional treatments beyond this point reduce the rate of relapse after ECT (Barton et al. 1973). In addition, the Task Force recommendations imply that rather than having clinicians predetermine the number of ECT sessions, the patient's clinical status during the course of ECT should dictate the number of treatments given. Shapira et al. (2000) have shown that ECT administered twice weekly is as effective as treatments administered three times a week. One advantage of a more frequent treatment schedule is a faster rate of response. On the other hand, a disadvantage is the potential development of cognitive side effects. Given these observations, it is recommended that the frequency of ECT treatments be tailored to the individual patient's needs. For example, a patient with a life-threatening illness will benefit from a faster rate of response and should be given more frequent treatments. In patients for whom the risk of cognitive side effects from ECT is a particular concern (e.g., those with Alzheimer's disease, Parkinson's disease, or severe frontal lobe or caudate hyperintensities shown on a brain MRI scan, as well as those receiving outpatient or bilateral ECT), a less frequent ECT treatment schedule is certainly a reasonable choice. 1When flumazenil is administered to counter benzodiazepine use, it should be given immediately after seizure induction because

the patient may experience sudden symptoms of benzodiazepine withdrawal. After the seizure has terminated, intravenous midazolam should be given because flumazenil has a longer half-life than methohexital and the patient may experience withdrawal on emergence from the anesthesia.

MANAGEMENT OF ECT-RELATED SIDE EFFECTS Postictal Agitation Postictal agitation can be a significant practical problem in ECT, with the potential for causing injury to both the patient and the nursing staff caring for the patient (Augoustides et al. 2002). Postictal agitation is difficult to predict in an individual patient but is likely to reoccur if it occurs with the initial

treatment. Postictal agitation must be differentiated from status epilepticus and is clearly distinguished by the random flailing movements of the patient in contrast to the rhythmic convulsions of a seizure and by the fact that the patient does not lose consciousness or demonstrate the fixed gaze of a patient experiencing a grand mal seizure. Several strategies exist for treating postictal agitation, and most involve intravenous access. Midazolam or methohexital will often sedate the patient and can be very effective. Additionally, propofol can be used to manage postictal agitation (O'Reardon et al. 2006). Intravenous haloperidol has been associated with ventricular ectopy (Greene et al. 2000) and should only be used in patients with cardiac monitors. The intramuscular atypical antipsychotic medications can be just as effective, with a more benign cardiac profile. Preventive measures can also be taken, including additional preoperative medication and changing the way ECT is administered to reduce the chance of postictal agitation in future treatments. First, the use of a dissolvable atypical antipsychotic medication such as olanzapine or risperidone 5–10 minutes prior to ECT can be very effective and does not require administration of any additional liquids. Second, current drug use should be reviewed. Lithium has been associated with postictal agitation (el-Mallakh 1988) and should be discontinued throughout the ECT course or withheld the night and morning of ECT treatments. Carbidopa has also been associated with postictal delirium and should be withheld the morning of ECT treatment (Nymeyer and Grossberg 1997). Postictal agitation may be associated with increased serum lactate levels, and some have argued that increasing the succinylcholine dose to decrease ictal muscle activity and subsequent rises in serum lactate levels can decrease postictal agitation (Auriacombe et al. 2000). Another strategy may therefore be to increase the succinylcholine dose if any muscle movement is present during the seizure. However, care should be taken because another potential cause of postictal agitation is the patient awakening from anesthesia with latent paralysis of the respiratory muscles. Patients describe this as frightening and may question continuing ECT. The data on the effect of switching from bilateral to unilateral ECT in order to decrease postictal agitation are unclear (Augoustides et al. 2002); the success of this approach is probably dependent on several factors including ECT dosage and the patient's age.

Interictal Delirium Interictal delirium develops during a course of ECT and persists on days when the patient does not receive a treatment. This side effect is observed primarily in elderly patients and increases in incidence with advancing age (Figiel et al. 1990). ECT-induced interictal delirium is associated with prolonged hospitalization and an increased risk of falls. Among the elderly, additional risk factors for interictal delirium are 1) Parkinson's disease, 2) Alzheimer's disease, 3) one or more cardiovascular risk factors, and 4) preexisting structural changes in the caudate nucleus observed on brain scans. Patients who develop postictal confusion are likely to have greater retrograde amnesia in the weeks and months after ECT (Sobin et al. 1995). The incidence of delirium during a course of ECT can vary dramatically depending on the ECT technique used. As a rule, ECT-induced interictal delirium is a short-lived, reversible side effect if identified early. Once it has been identified, ECT treatments should be withheld until the delirium resolves. Subsequent treatments should be administered less frequently and/or at a lower electrical charge.

Cardiovascular Side Effects ECT is associated with an increased risk of cardiovascular complications in elderly patients who have, or who are at risk for, cardiovascular disease. Studies have found widely varying rates of cardiac complications in the elderly receiving ECT. The retrospective design of the studies, the lack of

continuous cardiovascular monitoring, and the different definitions of what constitutes a cardiac complication probably account for the discrepancies in the results. Despite the inconsistencies, most studies have found a correlation between cardiac complications and age. ECT often produces transient systemic hypertension and abrupt transitions in cardiac rate, which can result in myocardial ischemia or arrhythmias. The increased incidence of cardiac complications among elderly patients is probably associated with the increased rate of preexisting cardiac conditions such as hypertension, coronary artery disease, and arrhythmias. On the basis of these observations, several authors have recommended the use of prophylactic cardiac medications to dampen cardiovascular responses during ECT in elderly patients who have (or are at risk for) cardiovascular disease. Research has now documented that labetalol (a medication with both activity), esmolol (a shorter-acting

- and

-adrenergic–blocking

-blocker), and nifedipine (a calcium channel–blocking agent with

vasodilating effects) can be safely used to attenuate the cardiac response during ECT (Cattan et al. 1990; Figiel et al. 1994; McCall et al. 1991; Stoudemire et al. 1990; Zielinski et al. 1993). Nicardipine (a shorter-acting calcium channel blocker) is routinely substituted for nifedipine because it can be given intravenously and has a shorter half-life. It is recommended that adequate doses of an anticholinergic medication (intravenous atropine or glycopyrrolate) be used to prevent bradycardia whenever

-blockers are used during ECT. To help

prevent ECT-induced hypotension, it is additionally recommended that all patients be adequately hydrated before undergoing ECT. If patients experience significant orthostatic hypotension in the recovery room, labetalol can be switched to the shorter-acting pure

-blocker esmolol.

The anesthetic agent propofol has been shown to have lesser cardiovascular effects than methohexital and can be used in patients with preexisting cardiac conditions requiring an attenuated hemodynamic response during treatment (Bailine et al. 2003). As noted earlier, the trade-off is a shortening of the seizure length with the use of propofol (see "ECT Administration" subsection).

Cognitive Side Effects The greatest area of concern about ECT among the lay public, patients, and their families is the potential development of adverse cerebral and cognitive changes. The medical community's concerns about cognitive side effects and the negative images of ECT in the media also are important factors in determining the availability of ECT. The technique by which ECT is administered determines the incidence and severity of cognitive side effects that may develop during a course of ECT. Specifically, electrode placement, the type of electrical waveform, the intensity of the electrical stimulus, and the frequency of ECT sessions determine the type and severity of cognitive side effects from ECT. Preexisting structural brain changes and medical illness, advancing age, and concomitant administration of certain psychotropic medications also may be factors. It is important to recognize that depression itself (especially late-life depression) often causes cognitive deficits, such that successful treatment of depression with ECT may actually improve some aspects of cognition in certain patients. Hihn et al. (2006) showed that prefrontally mediated aspects of cognition, such as attention and immediate encoding, improved during ECT treatment of depression, whereas long-term memory functions remained impaired. The memory loss attributed to ECT is typically anterograde and retrograde and has a temporal gradient, being more profound around the time of treatment and continuing several weeks after the ECT course (American Psychiatric Association Task Force on Electroconvulsive Therapy 2001; Sackeim 2000). The retrograde memory loss extends to months before the treatment. In most patients the anterograde memory loss clears quickly after ECT, but the retrograde memory loss can be permanent in some patients and may even extend to years before the ECT. Clearly, the degree of amnesia incurred during a course of ECT is greater with bilateral ECT than with unilateral ECT (Lisanby et al. 2000) and increases with the number of treatments administered and the stimulus intensity (Sackeim

et al. 2000). Although unilateral ECT is associated with fewer memory problems, the cognitive deficits that occur show a dose relationship and increase as the stimulus dose is increased to 8–12 times the seizure threshold (McCall et al. 2000). Research comparing bilateral and unilateral ECT has not addressed the important question of whether right-unilateral ECT given at a dose of 10–12 times the seizure threshold would cause more cognitive side effects than bilateral ECT that is minimally above or 1.5 times the seizure threshold. Sine wave stimulus produces greater amnestic deficits than does a brief- or ultrabrief-pulse stimulus. Furthermore, Sackeim et al. (1991, 1993) reported that within a specific waveform, the magnitude by which an electrical dose exceeds the seizure threshold (rather than the absolute electrical dose) is related to the severity of cognitive defects that develop during ECT. In a prospective, naturalistic longitudinal study of cognitive outcomes in depressed patients treated with ECT at seven facilities in the New York City metropolitan area (Sackeim et al. 2007), sine wave stimulation resulted in pronounced slowing of reaction time, both immediately and 6 months following ECT. As expected, bilateral ECT resulted in more severe and persistent retrograde amnesia than right-unilateral ECT. The researchers found that several clinical variables also were associated with post-ECT memory problems, including older age, lower premorbid intellectual function, and female sex. In addition, Shapira et al. (2000) reported that twice-weekly treatments produced less cognitive impairment than did treatments administered three times a week. The causes of the memory disturbance associated with ECT are thus multifactorial and likely include the effects of anesthetic drugs, electrode placement, stimulus waveform, generalized seizures, and electrical dose (Sackeim et al. 2007). Progress in understanding the neural mechanisms underlying memory makes it possible to consider how neurotransmitter changes might contribute to ECT-induced memory dysfunction. Muscarinic cholinergic receptors participate in some forms of memory, and antimuscarinic drugs are associated with memory impairment in humans (Krueger et al. 1992). In animals, the effects of ECS on central muscarinic systems have been variable (Fochtmann 1994). However, some studies suggest that ECS treatments diminish muscarinic binding in the cortex and hippocampus. Twenty-four hours after a series of ECS-induced seizures, decreases in levels of mRNA for M1 and M3 muscarinic receptors are seen in the hippocampus, although mRNA levels are significantly higher 28 days after the last seizure (Mingo et al. 1998). Other studies indicate that behavioral responses to muscarinic agonists are diminished after ECS and that brain choline acetyltransferase and acetylcholine levels are decreased (Nutt and Glue 1993). These findings suggest that alterations in muscarinic neurotransmission may contribute to memory impairment. Long-term, use-dependent plasticity of glutamatergic synapses appears to play a major role in memory processing in the CNS, and disruption of this plasticity could contribute to anterograde amnesia. The term long-term potentiation (LTP) typically refers to a persistent enhancement of glutamate-mediated transmission that follows repeated high-frequency synapse use, and LTP is a potential synaptic memory mechanism. Repeated ECS treatments disrupt the induction of LTP and produce memory impairment in animals (Anwyl et al. 1987; C. Stewart and Reid 1993), suggesting a possible tie to anterograde memory problems. Several ECS-induced changes, including effects on muscarinic and adrenergic neurotransmission, could contribute to the disruption of LTP. The enhanced inhibition that may contribute to the anticonvulsant effects of ECT could play a role because these inhibitory systems modulate efficacy at glutamatergic synapses. The release of glutamate during a seizure may also contribute to memory impairment. In many CNS regions, the induction of LTP depends on NMDA receptors. However, untimely activation of NMDA receptors before delivery of a stimulus that usually induces LTP results in LTP inhibition, a process broadly referred to as metaplasticity. Metaplasticity may result from activation of certain intercellular messengers, such as nitric oxide, or from the activation of phosphatases that alter the phosphorylation of key synaptic proteins (Zorumski and Izumi 1993).

Longer-term effects of ECS on basal synaptic transmission or NMDA receptor function could also contribute to memory impairment (Petrie et al. 2000). To date, there is little clinical evidence favoring any of these mechanisms in ECT-induced memory impairment, although several avenues are worth pursuing. There is some interesting evidence that verbal memory improves when an anesthetic agent that blocks NMDA receptors, ketamine, is used rather than etomidate, a GABAergic anesthetic (Krystal et al. 2003; McDaniel et al. 2006). There is also evidence that propofol, an agent that enhances GABAergic transmission but also partially inhibits NMDA receptors at anesthetic concentrations, may have beneficial effects on memory following ECT compared with thiopental (Butterfield et al. 2004).

Effects on Cerebral Physiology Immediately after an ECT treatment, the EEG shows generalized slowing of brain wave activity. This slowing tends to increase and persist longer after successive treatments. After a course of ECT is completed, slow-wave activity gradually decreases, and EEGs show a reversion to baseline activity within 3 months (R. D. Weiner et al. 1986). Rarely, electroencephalographic abnormalities may persist for more than 3 months. Prior electroencephalographic abnormalities may increase the risk for developing prolonged abnormalities after ECT, but the clinical significance of these abnormalities is unknown. Electrically induced seizures in animals and humans have been shown to produce transient increases in permeability of the blood–brain barrier (Laursen et al. 1991). These findings are consistent with a brain MRI study in which increased T1 relaxation times were observed after ECT (A. I. Scott et al. 1990). Laursen et al. (1991) reported that the ECT-induced increase in blood–brain barrier permeability is associated with increased stimulus intensity and an increased number of ECT treatments. In addition, Bolwig et al. (1977) were able to reduce changes in blood–brain barrier permeability during ECT by blocking ECT-induced hypertensive response with high-spinal anesthesia. Because a disturbed blood–brain barrier may predispose some patients to ECT-induced neurological complications, research is needed to examine the ways that ECT-induced changes in blood–brain barrier permeability can be minimized, such as by attenuating the ECT-induced cardiovascular response or by reducing the amount of the stimulus charge. The combination of increased carbon dioxide production, decreased pH, and systemic hypertension that occurs with ECS treatment can cause the cerebral blood flow to increase to 300% of baseline measurements and the cerebral metabolic rate to increase by 200% (Ingvar 1986). The transient increase in cerebral blood flow results in a sharp rise in both intracranial and intraocular pressure (Maltbie et al. 1980). Both the cerebral blood flow (Saito et al. 1995) and the cerebral metabolic rate (Ackermann et al. 1986) return to baseline values during the postictal period. Methods that limit the accumulation of carbon dioxide in the bloodstream, such as forced hyperventilation, or that attenuate the increase in blood pressure tend to diminish the rise in intracranial pressure associated with ECT.

Does ECT Cause Brain Damage? Human autopsy studies of patients who have received ECT have shown no convincing evidence of irreversible brain damage when ECT was administered with current techniques (Devanand et al. 1994; R. D. Weiner 1984). These findings are supported by a brain MRI study in which no significant structural brain changes were found immediately or 6 months after the completion of ECT (Coffey et al. 1991). In a study of six depressed patients, cerebrospinal fluid markers of neuronal/glial degeneration ( protein, neurofilament, and S-100

protein) were measured before and after a

successful course of ECT and showed no biochemical evidence of neuronal/glial damage or blood–brain barrier dysfunction (Zachrisson et al. 2000).

Minor Complications Patients often report nausea and headaches after ECT; these complaints usually are easily treated and

do not appear to be related to electrode placement or stimulus dose (Devanand et al. 1995). The exact incidence of nausea is not known; estimates indicate that approximately one-quarter of patients complain of some nausea (Gomez 1975). Treatments for nausea include prochlorperazine, metoclopramide, and ondansetron. If effective, they can be given prior to ECT on subsequent treatments. The anesthetic propofol can also be substituted for etomidate or methohexital to reduce post-ECT nausea and vomiting (Bailine et al. 2003). The incidence of ECT-induced headaches is also unknown; however, some estimates are that up to 45% of patients have headaches after ECT (Devanand et al. 1995; S. J. Weiner et al. 1994). Acetaminophen or nonsteroidal anti-inflammatory agents, including intravenous ketorolac, usually are effective. The etiology of the ECT headache is unclear, but a vascular process (S. J. Weiner et al. 1994) has been suggested, and sumatriptan can also be effective (Fantz et al. 1998). Patients who have a history of migraine headaches should be given their migraine medication before ECT; prophylactic treatment with these agents immediately prior to the ECT treatment usually is effective in reducing the severity of post-ECT headaches.

PROPHYLACTIC SOMATIC TREATMENT AFTER ACUTE RESPONSE TO ECT Although the short-term therapeutic benefits of ECT are clearly established, the 6-month relapse rate after ECT to treat depression remains high (Bourgon and Kellner 2000). The debate over appropriate prophylactic treatment for patients with an acute response to ECT has focused on the clinical decision to either continue therapy with antidepressant medications or initiate maintenance ECT. Confusion in this area persists because of the lack of controlled studies comparing the efficacy of antidepressants with that of maintenance ECT. Most study designs have been naturalistic. O'Leary and Lee (1996) evaluated the 7-year mortality and hospital readmission rates in the Nottingham ECT cohort of patients hospitalized for major depression and found that the risk of death was double the risk in the general population, and the probability of not being readmitted was 0.79 at 16 weeks and only 0.27 over the 7-year follow-up period. Delusions were the most important clinical characteristic predicting relapse. Two studies (Aronson et al. 1987; Spiker et al. 1985) evaluated adult patients after an acute course of ECT for psychotic depression and found a combined relapse rate of 68% (n = 53) at 1 year. Spiker et al. (1985) reported a 1-year relapse rate of 50% in patients with delusional depression who initially responded to an acute course of ECT. Aronson et al. (Aronson et al. 1987) followed patients with delusional depression who had responded to either medication or ECT and found that 80% of the medication-responsive patients and 95% of the ECT-responsive patients relapsed in the first year after hospitalization. These studies did not compare the adequacy of the initial (pre-ECT) medication trial or the continuation medication trial. In a prospective, naturalistic study of 347 depressed patients at seven hospitals, Prudic et al. (2004) found that between 30% and 47% of patients met criteria for remission at the end of their acute course of ECT. In the 24-week follow-up period, 64% of remitters relapsed. Among those patients who did not achieve remission during the acute course, only 23% had sustained remission during the 6-month follow-up period. Sackeim et al. (1990) followed 58 patients for 1 year after ECT and found a differential relapse rate of 64% in those with major depression (with and without psychotic features) in whom an adequate pre-ECT medication trial had failed. In contrast, the relapse rate in patients who did not receive an adequate pre-ECT antidepressant trial was only 32%. Other clinical and demographic factors, including the presence of delusions, were not significant in predicting relapse. The adequacy of the post-ECT maintenance medication did not correlate with relapse rates. However, as in the studies cited above, maintenance medications post-ECT were not standardized, and evaluation of the pre-ECT medication trial was retrospective. The conclusion of this study is intuitively appealing: Patients whose symptoms do not respond to antidepressant medication before ECT are those most likely to

relapse with maintenance medication. With relapse occurring in almost two-thirds of such patients within 1 year after ECT, the relapse rate is alarmingly high. In a prospective, randomized, double-blind trial, Sackeim et al. (2001a) compared three maintenance strategies: placebo, nortriptyline (target steady-state level, 75–125 ng/mL), and nortriptyline plus lithium (target steady-state level, 0.5–0.9 mEq/L). Over the 24-week trial, the depression relapse rate was 84% with placebo, 60% with nortriptyline, and 39% with nortriptyline plus lithium, indicating a statistically significant advantage for combination therapy. In another prospective study, Shapira et al. (1995) found that patients who responded to an acute course of ECT and subsequently received maintenance therapy with lithium for 6 months had a relapse rate of only 36%. Of the 22 patients, the 8 who relapsed did so in the first 13 weeks. Several clinical factors were associated with relapse; these included a shorter duration of the index depressive episode, an additional depressive episode in the 12 months prior to ECT, and, again, failure of an adequate trial of antidepressant therapy before the ECT course. Lauritzen et al. (1996) randomly assigned patients with major depression who were receiving ECT to also receive either paroxetine 30 mg, imipramine 150 mg, or placebo and to continue the medication treatment after they had responded to ECT. In the continuation phase of the study, paroxetine was superior to both imipramine and placebo in preventing relapse: 65% of the placebo recipients relapsed, compared with 30% of the patients treated with imipramine and 10% of the patients treated with paroxetine. The elderly are particularly prone to increased disability from depression and form a substantial proportion of patients in an acute ECT program. Data from naturalistic studies confirm that the relapse rates for elderly patients treated with ECT are high. These rates have varied from 21% within 6 months (Karlinsky and Shulman 1984) to 50% (10 of 20 patients) within 1 year (Murphy 1983). A naturalistic study that followed 94 patients over 3 years after an acute course of ECT noted a rehospitalization rate of 44% (Stoudemire et al. 1994). Of the 10 patients in the Murphy study who did not relapse within 1 year, 1 developed dementia and 4 died; thus, only 5 of the 20 elderly patients were well 1 year after ECT. These studies indicate that the elderly are at risk for relapse after acute ECT. However, two small studies in adolescent populations showed that younger patients also have high relapse rates: 40% within 1 year (D. Cohen et al. 1997) and 38% within 3 years (Moise and Petrides 1996). Studies, primarily in the 1980s, have focused on finding a biological marker that would predict relapses after ECT; the possible markers included nonsuppression of cortisol in response to a challenge dose of dexamethasone (in the dexamethasone suppression test, or DST), blunted thyrotropin response to thyrotropin-releasing hormone (TRH; in the TRH stimulation test), and shortened rapid eye movement latency on a sleep EEG. These studies had many methodological flaws, including the fact that most of the studies were retrospective reviews, had nonblinded raters and a small number of subjects, and used nonstandardized follow-up treatment after ECT. Given these limitations, preliminary evidence suggests that patients who continue to show a biological marker consistent with depression after responding to ECT (e.g., a positive DST result) are at increased risk for relapse. In Bourgon and Kellner's (2000) review, six of the nine studies in which the DST was used, two of the four studies in which the TRH test was used, and the one sleep study in which shortened rapid eye movement latency was used showed that persistent abnormalities in these biological markers after ECT are predictive of relapse.

Continuation/Maintenance ECT The high relapse rates of depression in patients receiving antidepressant medications after a successful course of ECT have led clinicians to use alternative therapies, such as continuation/maintenance ECT, in patients who are at high risk for recurrence of their mood disorder.

Continuation ECT is defined as ECT for up to 6 months after the acute ECT course (i.e., aimed at relapse prevention). Continuation ECT is differentiated from maintenance ECT, which is defined as ECT that continues for more than 6 months after the initial course (i.e., aimed at recurrence prevention). In this chapter, the term prophylactic ECT is used to refer to any ECT treatments given as continuation or maintenance therapy. Many of the studies reviewed here do not differentiate patients receiving continuation ECT from those receiving maintenance ECT, although treatment indications, side effects, and outcomes may be different for the two types of prophylactic ECT. According to clinical guidelines, candidates for prophylactic ECT include patients who have recurring affective episodes that are responsive to ECT and/or who are resistant to, intolerant of, or noncompliant with antidepressant medications (American Psychiatric Association Task Force on Electroconvulsive Therapy 2001). Prophylactic ECT strategies are increasingly being used to treat major depression and bipolar disorder in patients thought to be at high risk for relapse. A 1985 survey of private psychiatric hospitals showed that 64% of the hospitals that provided ECT also provided prophylactic ECT (Levy and Albrecht 1985). Kramer (1987) found a similar pattern of use in a survey of ECT practitioners, with 59% of the 86 respondents using prophylactic ECT, primarily for recurrent depression. Several theories have been advanced to explain the potential effectiveness of prophylactic ECT versus medication: 1. Bourne and Long (1954) suggested that patients with psychotic depression may become "convulsion dependent" such that they need to be tapered from ECT to prevent relapse. 2. Prophylactic ECT has a different mechanism of action than antidepressants, and patients with medicationresistant illness do respond to an acute course of ECT. The corollary is that patients who respond preferentially to ECT may have lower relapse rates with prophylactic ECT than with medication. 3. Prophylactic ECT may not provide a better therapeutic benefit than medication at all. Rather, the benefit may be the result of better treatment compliance in the groups receiving ECT than in those receiving maintenance medication. Most reports of relapse rates in patients receiving prophylactic ECT include only those patients who were compliant and presented for their treatments. As Clarke et al. (1989) pointed out, when patients receiving continuation ECT do not complete 6 months of treatment, relapse rates approach the 50% rate seen in patients receiving maintenance medication. Thus, future studies of ECT need to include both compliant and noncompliant patients in their outcome measures. A recent case study of an elderly woman with recurrent psychotic depression receiving maintenance ECT showed a correlation between resolution of cerebral hypoperfusion and a treatment response to her depressive symptoms (Suzuki 2006). At baseline, the patient demonstrated anterior cerebral hypoperfusion on single photon emission computed tomography (SPECT), which did not change 12 days after the first course of ECT. After the acute ECT course she continued to have residual depressive symptoms. Two weeks later she experienced a relapse, but her condition improved again after a second course of acute ECT. The hypoperfusion improved after the second course of ECT and resolved completely after 2 years of maintenance ECT. This case report is particularly interesting given the data by Prudic et al. (2004) demonstrating the relationship between residual depressive symptoms and relapse. Another case study, of two patients, found that cerebral blood flow and metabolic rates were no different than in control subjects prior to ECT, but that at the end of a successful continuation course of ECT, cerebral blood flow and metabolic activity in the prefrontal cortex had decreased (Conca et al. 2003), which is consistent with findings about changes in cerebral activity in response to an acute course of ECT (e.g., Nobler et al. 2001). Most of the information on the use of prophylactic ECT has come from case reports and retrospective case series. The more recent studies have a naturalistic design with relatively few subjects, but they

generally describe a marked decrease in the number of hospitalizations, the number of days spent in the hospital, and depressive symptoms; an increase in functional status; and stable cognitive functioning for the period of continuation ECT (Clarke et al. 1989; Decina et al. 1987; Fox 2001; Gagne et al. 2000; Kramer 1999; Russell et al. 2003; Thienhaus et al. 1990; Thornton et al. 1990). These positive results extend to elderly depressed patients (Dubin et al. 1992; H. Loo et al. 1991), patients with bipolar disorder (Husain et al. 1993; Nascimento et al. 2006; Sienaert and Peuskens 2006; Tsao et al. 2004; Vanelle et al. 1994), schizophrenic patients (Shimizu et al. 2007; Suzuki 2006), and patients with Parkinson's disease (Faber and Trimble 1991; Shulman 2003). A moderately sized study of treatment-resistant schizophrenia patients who were responsive to acute treatment with a combination of ECT plus antipsychotic medication found that these individuals fared better with the combination of continuation ECT plus the antipsychotic medication than with either treatment alone (Chanpattana et al. 1999a). In a prospective study, Clarke et al. (1989) used continuation ECT in 27 patients who received an acute course of ECT to treat major depression because of a history of medication intolerance or resistance. The rate of rehospitalization was six times lower (8%) in patients who completed a 5-month course of continuation ECT than in patients who did not complete the protocol (47%). Swoboda et al. (2001) prospectively followed 13 patients diagnosed with major depression and 8 patients who had schizoaffective disorder who were administered maintenance ECT and compared them with controls who received maintenance pharmacotherapy alone. The maintenance ECT group had a significantly lower rate of rehospitalization at 1 year than control subjects, although the schizoaffective patients had a poorer outcome overall than patients with major depression. The largest prospective study of continuation ECT to date included 184 patients who were randomly assigned to receive either maintenance pharmacotherapy with a combination of lithium and nortriptyline or continuation ECT for 6 months; both treatments had limited efficacy, with more than half of patients in each group either relapsing or dropping out of the study (Kellner et al. 2006). Although these results were disappointing, the efficacy of continuation ECT was being compared with that of the "gold standard" of nortriptyline and lithium, and both treatments were superior to placebo (using historical placebo controls) or follow-up with monotherapy. There are few other prospective studies and/or controlled trials of continuation or maintenance ECT. Studies that have evaluated the side effects of maintenance ECT on memory are limited. A retrospective study of 18 patients receiving maintenance ECT for 3–10 months showed minimal memory side effects and an excellent clinical response (Abraham et al. 2006). Three patients (17%) had slightly impaired memory, which improved to normal, and one patient experienced severe memory problems in the third month and discontinued treatment. Another study found no difference in the neuropsychological functioning of 13 patients receiving maintenance pharmacotherapy and 11 patients receiving maintenance ECT after an acute course of ECT (Vothknecht et al. 2003). A telephone screening system for evaluating cognitive side effects of maintenance ECT has been proposed that successfully identified a patient with significant deficits the day after an ECT treatment (Datto et al. 2001). This type of monitoring would be practical for evaluating patients receiving maintenance ECT in both clinical and research settings. Guidelines for the use of prophylactic ECT unfortunately remain vague, primarily because of the paucity of data on which to base guidelines. Monroe (1991) delineated the contradiction of the increasing use of prophylactic ECT and the lack of research defining the parameters of administering the treatments and their potential side effects and contraindications. More recently, the National Institute for Clinical Excellence (NICE) Technology Appraisal, "Guidance on the Use of Electroconvulsive Therapy," questioned the use of continuation and maintenance ECT because of the lack of empirical evidence. From their examination of the data, the authors concluded that ECT is "not recommended as a maintenance therapy in depressive illness" (NICE 2003). Other researchers have challenged this conclusion, pointing out that the typical patient receiving continuation or maintenance

ECT has chronic relapsing depression that has failed to respond to multiple medication trials (Frederikse et al. 2006). In fairness, it should be pointed out that the NICE report was published before the above-cited studies by Prudic et al. (2004) and Kellner et al. (2006), two prospective studies supporting the use of continuation ECT.

Patients Who May Benefit From Prophylactic ECT Patients who receive prophylactic ECT after an acute course of ECT usually fall into one of three categories: 1. Patients whose illness has failed to respond to previous trials of medications and are therefore relatively medication resistant 2. Patients who are severely ill (e.g., psychotic or suicidal) 3. Patients who cannot tolerate the side effects of antidepressant medications, because of either concomitant medical illness or a personal sensitivity to antidepressants' side effects, or who are noncompliant with their medication These groups overlap and include patients who, because of their own experience or the experiences of acquaintances or relatives, prefer ECT to the traditional somatic treatments.

Patients Who Have Failed to Respond to Previous Trials of Medication A significant minority of patients with major depression are relatively medication resistant despite adequate medication trials (trials of antidepressants with adequate doses and length of treatment to elicit a response). Sackeim et al. (1990) noted that the most important factor in relapse after an acute course of ECT that enables a patient to achieve remission is whether the patient participated in an adequate medication trial prior to ECT. The relapse rate in the 6 months following ECT was found to be twofold higher in patients who had participated in an adequate medication trial than in those who had not (Sackeim et al. 1990). Shapira et al. (1995) also found that patients who had received adequate previous treatment with pharmacotherapy relapsed post-ECT (while receiving lithium maintenance therapy) at a significantly higher rate than did patients who had not received adequate prior medication. Interestingly, Grunhaus et al. (1990) reported a relapse rate of only 17% in patients in whom a previous medication trial had failed and who received up to 12 weeks of prophylactic ECT after a successful initial course of ECT. Patients in whom an adequate medication trial failed before ECT was initiated should be informed of the risk of relapse and given the option of receiving continuation ECT for 6 months, followed by maintenance medication. The clinical decision of whether to continue ECT beyond 6 months should be made on an individual basis, weighing the risks (primarily the cognitive effects of ongoing ECT vs. the risk of suicide or recurrent psychosis if the patient relapses while taking medication) and benefits (the long-term effects of a period of mood stability).

Patients Who Are Severely Ill Some researchers have found that the 1-year relapse rate in patients with psychotic depression treated with medication alone may be as high as 95% (Aronson et al. 1987; Spiker et al. 1985). Petrides et al. (1994) retrospectively examined the records of patients with delusional depression treated with prophylactic ECT and found the relapse rate at 1 year to be only 42%. They compared their findings with those from the study by Aronson et al. (1987). Both patient groups were drawn from the same institution, although prophylactic ECT was not available at the time that Aronson et al. (1987) reported relapse rates of 95% in patients with delusional depression who were taking antidepressants. Vanelle et al. (1994) prospectively administered maintenance ECT, often with concomitant antipsychotic medication, approximately once a month for 1 year to a group of patients with psychotic depression and found full or partial remission in 80% of the patients. Grunhaus et al.

(1990) also found an excellent clinical response in patients with psychotic depression who were administered prophylactic ECT. Prophylactic ECT may therefore be a viable option in patients with delusional depression and should be discussed with these patients and their families.

Patients Who Cannot Tolerate the Side Effects of Antidepressant Medications or Who Are Noncompliant With Their Medication Most patients who cannot tolerate the side effects of antidepressant medications because of either concomitant medical illness or a personal sensitivity to antidepressants' side effects can benefit from trying maintenance medication after a successful course of ECT. Many patients who are acutely ill may be extremely sensitive to the side effects of medications but may tolerate the same medication once they have responded to acute treatment with ECT. Conditions associated with depression, such as malnutrition and dehydration, may worsen the orthostatic hypotension caused by tricyclic antidepressants. In a patient with agitated depression, minimal activation from the SSRIs may be experienced as extreme agitation. Once the depressive episode has remitted, patients usually can tolerate an additional trial of medication. Patients who are noncompliant with their antidepressant medication should be evaluated on an individual basis and, after discussions with the patient and the family, the risks and benefits of prophylactic ECT should be weighed against those of an additional medication trial.

Guidelines for Prophylactic ECT Treatment Parameters The electrode placement and dose parameters used in the initial course of ECT are maintained during continuation and maintenance ECT. Retrospective reviews have not found that stimulus placement affects the clinical outcome (Petrides et al. 1994), although no systematic studies have compared unilateral and bilateral placement in prophylactic ECT. Since seizure threshold can increase during acute treatment because of the frequency of treatments, the threshold would be expected to decrease during prophylactic ECT. In one small study the threshold was shown to decrease significantly when the treatments were separated by 60 days or more (Wild et al. 2004). Few guidelines exist on what frequency of prophylactic ECT is optimal to maintain mood stability. The intervals between courses of continuation ECT in the studies reviewed vary from 3–5 weeks (H. Loo et al. 1991) to 4–8 weeks (Thienhaus et al. 1990). Other clinicians argue that treatments should be gradually tapered from once a week to once a month, depending on clinical response (Aronson et al. 1987; Clarke et al. 1989; Matzen et al. 1988). Kramer (1987) surveyed 51 clinicians in 24 states and found the frequency and duration of maintenance ECT to vary from as often as two treatments per week to once every 3–4 weeks for 30 months to one treatment every 6 months for 60 months to as long as 48 years. In Kramer's survey, clinicians described continuing ECT until the patient was asymptomatic for a predetermined period ranging from 1 month to 2 years. Grunhaus et al. (1990) assessed individual patients' clinical histories and assigned them to receive either abbreviated continuation ECT (once or twice a week for 4–12 weeks) or full continuation ECT (gradually tapering ECT frequency to once a month over 3 months and continuing ECT once a month for 6 months). Abbreviated continuation ECT was used when symptoms were unresponsive to medication after the index depressive episode and lasted more than 12 months, or when the patient relapsed after a successful course of ECT or had difficulties tolerating continuation pharmacotherapy. Full continuation ECT was used in patients who relapsed after a successful course of ECT despite adequate pharmacotherapy. Among 10 patients, these researchers found an excellent response in 6 (5 of 6 patients receiving abbreviated continuation therapy; 1 of 4 patients receiving full continuation therapy), particularly in those with delusional depression. In their prospective study, Vanelle et al. (1994) administered maintenance ECT with an average

frequency of once every 3.5–3.9 weeks for 1 year and found that 64% of the patients (n = 22) needed shorter intervals between treatments to prevent a recurrence of their depressive disorders. The patients who required a shorter interval were older and had a longer duration of illness. Vanelle et al. (1994) posited that the older patients may have had a shorter time to relapse, a suggestion that is consistent with data showing that older patients tend to have accelerated mood cycles (Zis et al. 1980). Others have suggested tapering the ECT treatments from once a week for 4 weeks to once every 2 weeks for 4 weeks and then to once monthly for 4–6 months (Fox 2001).

Treatment Considerations The greatest risk of relapse after ECT is within the first few months after acute treatment (Clarke et al. 1989; Sackeim et al. 1990; Shapira et al. 1995). During this crucial period, many patients and their families describe a recurrence of symptoms of depression when prophylactic ECT treatment intervals are extended by even a few days. This pattern of response has resulted in the development of a continuation ECT protocol in which treatment intervals are extended in increments—from once a week for the first four treatments to every 10 days for the next three treatments and then to every 2 weeks for the final 4 months. During the initial 6 months of prophylactic ECT, treatments are not extended beyond every 2 weeks. If a patient becomes symptomatic, the treatment interval is again shortened until the patient is clinically stable. Usually this requires an additional 3–4 treatments and not a full acute course of 6–10 treatments. The patient then resumes the longest ECT treatment interval during which he or she remained healthy. Patients are encouraged to continue ECT for at least 6 months. In the final month of continuation ECT, treatment with an antidepressant is initiated. However, which antidepressant drugs can be safely and effectively used during continuation ECT requires further study. For patients who relapse quickly after continuation ECT ends, maintenance ECT should be considered.

Informed Consent Individual hospital policies and state laws dictate the procedure for obtaining informed consent. The administration of prophylactic ECT on an outpatient basis is subject to the same guidelines that apply to the ambulatory surgery service in the treating hospital. In general, the same policies governing consent for the initial ECT course apply to the prophylactic course of ECT. The consent procedures have been reviewed extensively elsewhere (Abrams 1997; American Psychiatric Association Task Force on Electroconvulsive Therapy 2001). A new consent should be obtained before each course of prophylactic ECT, when a patient changes from inpatient to outpatient status, and at least every 6 months. The physician also should document at the beginning of each ECT course (i.e., at the time of the consent) the justification for the prophylactic ECT.

Cognitive Complications Few data exist on the cognitive changes that patients experience while receiving repeated ECT treatments over a period of months to years. Most of the available reports in which prophylactic ECT has been used describe only minor subjective complaints (e.g., Fox 2001). Grunhaus et al. (1990) reported that the patients in their study experienced minor memory difficulties (recent recall and names) that resolved within 6–8 months. Patients in the study by Vanelle et al. (1994) (mean age, 70 ± 13 years) described either no subjective memory problems (n = 8) or minor subjective cognitive complaints (n = 14). Petrides et al. (1994) noted only minor subjective memory problems in 30 patients (mean age, 52 ± 15 years) who received an average of seven continuation ECT treatments over 2 months. Thienhaus et al. (1990) found stable cognitive function (as measured on the Mini-Mental State Exam) in six elderly patients (mean age, 71 ± 5 years) receiving prophylactic ECT for 1–5 years. A naturalistic 1-year study of 20 persons receiving maintenance ECT found no global cognitive decline over the course of the study (Rami et al. 2004).

TRANSCRANIAL MAGNETIC STIMULATION AND SUBCONVULSIVE STIMULI To date, there are a number of subconvulsive treatments for depression including TMS, vagus nerve stimulation (VNS), and deep brain stimulation, all of which hold promise both for the treatment of depression and for elucidating the underlying biology of depression. These treatments bring into question the axiom that subconvulsive stimuli cannot be therapeutic. Prototypes of the modern subconvulsive brain stimulation devices were first developed by Pollacsek and Beer in 1903. These colleagues of Sigmund Freud used electromagnetic currents to stimulate cortical neurons, but it was not until 80 years later that Barker developed modern TMS equipment (Barker et al. 1985) and research began to focus on the effects of TMS on psychiatric disorders. TMS equipment is relatively simple and uses capacitors to store an electrical charge. The charge is then discharged through a coil and produces a magnetic field that lasts from 100 to 200 milliseconds. When placed over the skull, the magnetic field passes unimpeded into the brain, stimulating the underlying brain regions; TMS can be used to assess both motor function (Homberg et al. 1991) and other complex brain functions such as speech (Epstein et al. 1996) and visual information processing (Beckers and Zeki 1995). Early preclinical studies of TMS in rats showed that TMS had effects similar to those of ECS in behavioral models of depression, including enhancement of apomorphine-induced stereotypy, reduction of immobility in the Porsolt swim test, and increases in seizure threshold on subsequent stimulation (Fleischmann et al. 1995; Lisanby and Belmaker 2000).

Rapid-Rate Transcranial Magnetic Stimulation Within a decade of the development of modern TMS equipment, TMS was being used to treat depression and schizophrenia (Grisaru et al. 1994; Hoflich et al. 1993; Kolbinger et al. 1995). These studies used TMS coils that were nonfocal, and the antidepressive effects were limited. Additional work by George et al. (1995) provided the impetus for a renewal in TMS research in mood disorders. These studies used rTMS—repetitive or rapid-rate TMS—to apply multiple stimuli in one session and target treatment to the prefrontal cortex, an area that has been shown to be important in the response to ECT (Nobler et al. 2001). Imaging studies have demonstrated a response to rTMS based on changing metabolic patterns in the frontal cortex (Kimbrell et al. 1999). Yet the magnitude of the response to rTMS is rarely more than a 50% decline in the depression rating scales (e.g., clinical criteria for response), and few patients meet the criteria for clinical remission (or an absolute value for a scale that indicates no evidence of depression). A meta-analysis noted that although rTMS was clearly superior to sham stimulation and the effect size was moderate (effect size = 0.81 [95% confidence interval = 0.42–1.20; P

Chapter 46. Neurobiology of Schizophrenia NEUROBIOLOGY OF SCHIZOPHRENIA: INTRODUCTION Schizophrenia is a complex disorder defined by positive symptoms (hallucinations, delusions, thought disorder), negative symptoms (apathy, alogia, anhedonia, blunted affect), and deterioration of the patient's personal, social, and occupational functioning. Recent advances in elucidating the neurobiology of schizophrenia have capitalized on progress in clinical and basic neuroscience that has contributed to the integration of neurobiology with the clinical features of the disorder. In this chapter, we highlight selected areas emphasizing recent progress and short-term future goals. Noteworthy advances link clinical and basic neuroscience research, address mechanisms underlying this challenging disorder, and have implications for treatment. Such progress includes strong evidence of selective cognitive deficits against a background of global impairment, aberrations in electrophysiological activity in response to sensory input, and abnormalities in brain anatomy and physiology through the application of structural and functional neuroimaging methods; a shift from examining the genetics of diagnostic categories to a focus on endophenotypic markers with parallel paradigms in humans and animals; identification of specific candidate genes from genomewide scans and microarray technologies; evidence of cellular and molecular abnormalities in diverse brain regions; and a growing appreciation of schizophrenia as a life span neurodevelopmental disorder. Considered jointly, these advances establish a firm foundation for hypothesis-driven research that systematically examines core neurobiological abnormalities underlying schizophrenia. When evaluating the body of data on the neurobiology of schizophrenia, two important questions deserve further consideration. First, are the findings specific to schizophrenia? That is, are the brain abnormalities observed on multiple levels of analysis unique to schizophrenia, or do they characterize psychosis? Although the literature across the methods we summarize is limited regarding direct prospective comparisons between patients with schizophrenia and patients with bipolar disorder, overall it appears that patients with schizophrenia are distinct from those with bipolar disorder. Thus, despite commonality in some underlying affected brain systems, the extent and topography of aberrations observed differentiate schizophrenia from bipolar disorder. Second, do the abnormalities observed relate to clinical subtypes as defined by DSM-IV-TR (American Psychiatric Association 2000) or to symptom dimensions such as positive and negative symptoms of schizophrenia? The literature, in general, suggests "a signature" across subtypes of schizophrenia and symptom dimensions, with some variability related to illness duration and severity. We are now at the cusp of advancing the understanding of brain circuitry that examines neurocognitive and affective processes that relate to social cognition in schizophrenia. As progress is made, it can guide novel therapeutics that target these deficits more directly.

NEUROBEHAVIORAL DEFICITS Impaired cognition in schizophrenia, leading to early conceptualizations of "dementia praecox" (Kraepelin 1919), is well recognized and fundamental to the disorder. While the clinical symptoms and course of the disorder are heterogeneous, most patients with schizophrenia exhibit cognitive deficits

that are present at the onset of illness and persist following improvement in their psychosis. Neuropsychological studies have found impairments in multiple domains, including perception, attention, visuospatial abilities, language, memory, emotion, executive function, and coordination (Sharma and Harvey 1999). However, within this diffuse impairment, attention, working and episodic memory, and executive functioning are more severely impaired (Cornblatt and Keilp 1994; Heinrichs and Zakzanis 1998; Saykin et al. 1994). While neurocognitive measures have shown limited, albeit consistent, relation to clinical symptoms, they appear more closely related to functional outcome (Goldberg and Gold 1995; Green 1996; Green et al. 2000). In addition to the relevance of neuropsychological measures to functioning and outcome, they have stimulated the investigation of their underlying neurobiology. Several brain systems are implicated by these deficits. The attention-processing circuitry includes brain stem–thalamo-striato-accumbenstemporal-hippocampal-prefrontal-parietal regions. Deficits in working memory implicate the dorsolateral prefrontal cortex, and the ventromedial temporal lobe is implicated in deficits in episodic memory. A dorsolateral-medial-orbital prefrontal cortical circuit mediates executive functions. Relative to the extensive and well-documented cognitive deficits in schizophrenia, more recently, emotion-processing and olfaction deficits have also been noted. Clinically, emotional impairment is manifested in flat, blunted, inappropriate affect and in depression (Gur et al. 2006; Kohler et al. 2000b). Although these clinical features have been detailed as part of the disorder, the methodologies for neuroscience research have lagged behind research on cognition. Studies have reported emotionprocessing deficits in identification, discrimination, and recognition of facial expressions (Kring and Neale 1996). Although these deficits may represent generalized cognitive impairment (Kerr and Neale 1993), they relate specifically to symptoms and neurobiological measures (Kohler et al. 2000a). Animal and human investigations have implicated the limbic system, primarily the amygdala, hypothalamus, and mesocorticolimbic dopaminergic systems, and cortical regions including orbitofrontal, dorsolateral prefrontal, temporal, and parts of the parietal cortex (LeDoux 2000). Psychophysical studies of schizophrenia have described impairments in elementary sensory perceptual processing. Patients are impaired in their ability to detect and identify odors (Moberg et al. 1999). Olfactory deficits are present at the onset of illness, do not relate to disease severity or treatment, and are possibly progressive (Kopala et al. 1993). It is unclear whether the deficits are part of the generalized neurocognitive impairment (Moberg et al. 2006). The neuroanatomical differences noted in patients (Turetsky et al. 2000) suggest that olfactory bulb changes and medial temporal lobe abnormalities could mediate the observed behavioral aberrations. In the visual domain, abnormalities in elementary contrast sensitivity and functional dyslexia have been described (Butler and Javitt 2005; Kurylo et al. 2007; Revheim et al. 2006), and electrophysiological studies have suggested dysfunction of the thalamic lateral geniculate's magnocellular processing stream as playing a role in these deficits. In the auditory domain, deficits in tone discrimination and matching have been reported (Javitt et al. 2000), consistent with many electrophysiological studies and recent postmortem evidence of primary auditory cortex abnormality in schizophrenia (Sweet et al. 2007). The application of neurobehavioral probes (Gur et al. 1992) in functional imaging studies has helped elucidate links between neurobehavioral deficits and the underlying brain dysfunction evident in schizophrenia. With these paradigms, we can examine the topography of brain activity in response to engagement in tasks in which deficits have been noted in patients. This provides "on-line" correlation between brain activity and performance in a way that permits direct examination of brain–behavior relations.

ELECTROPHYSIOLOGY Event-related potentials (ERPs), coupled with specific stimulus events and cognitive tasks, enable monitoring of associated brain activity in real time. There is an extensive literature on ERP

abnormalities in schizophrenia (Adler et al. 1982; Erwin et al. 1991; Grillon et al. 1991) including deficits in early preattentive stages of information processing and relatively late higher cortical processes. Aberrations in encoding of input may involve difficulty in screening out information and inhibiting responses to irrelevant stimuli. There may be reciprocal deficits in response facilitation to salient stimuli. Various ERP indices have been examined in schizophrenia—including the P50 (Erwin et al. 1991; Freedman et al. 1991) and startle prepulse inhibition (PPI; Braff et al. 1992)—that suggest failure of inhibitory processes. Later potentials related to detection of deviant or novel stimuli, including the N100, mismatch negativity (MMN), and P300, also show abnormalities in schizophrenia. The N100 is an obligate response sensitive to the physical characteristics of a stimulus but not to its context. By contrast, the MMN is elicited by deviant or novel sounds presented amid repeated trains of identical tones. It reflects sensory or echoic memory processes that facilitate response to unexpected environmental changes. Auditory MMN originates in the auditory cortex and is N-methyl-D-aspartate (NMDA) sensitive (Javitt et al. 1996). A semblance of the MMN has been described in the hippocampus and thalamus as well (Alho 1995). The most widely studied late ERP is the P300 (Patel and Azzam 2005; Polich 2004). The P300 reflects higher-order processing of a deviant or novel stimulus that surpasses a threshold to elicit orienting (P3a) or matches with a consciously maintained working memory trace (P3b). Analogs of these ERPs have been established in rodents, allowing experimentation not feasible in humans. Latencies are shorter in rodents, but the P20, N40, MMN, and P120 in mice share stimulus and pharmacological response properties with the human P50, N100, MMN, and P3a, respectively (Connolly et al. 2003; Siegel et al. 2003; Umbricht et al. 2004). The established ERP methods highlighted above examine latencies and amplitudes of averaged evoked responses. Newer measures, which characterize electroencephalogram (EEG) activity in terms of underlying constituent oscillations, more directly represent the synchronized activity of aggregate neuronal assemblies. Evoked oscillations (time- and phase-locked to stimulus) and induced oscillations (loosely time-locked, not phase-locked) are thought to reflect different dynamic neurophysiological processes (Pfurtscheller and Lopes da Silva 1999). Scalp-recorded evoked oscillations reflect the summed postsynaptic potentials of local assemblies of cortical pyramidal neurons. Induced oscillations reflect changes in the dynamic interactions within and among brain structures. These interactions may be subcorticocortical or corticocortical and may underlie dynamic processes such as long-range integration, feature binding, or memory formation (Bastiaansen and Hagoort 2003). Gamma (40 Hz) and theta (4–7 Hz) frequency oscillations, in particular, appear to be intrinsically involved in the processes of stimulus perception, integration, novelty detection, and recognition. Induced gamma oscillations are proposed to "bind" the spatially and temporally discrete neuronal representations of features of a complex stimulus (Bertrand and Tallon-Baudry 2000; Pantev et al. 1991). The growing literature on the gamma band suggests reduced oscillatory power and decreased phase synchrony in schizophrenia, associated with disturbances in the cognitive processes of feature binding and perceptual integration in both the visual (Spencer et al. 2003) and auditory modalities (Lee et al. 2003). Theta oscillations are observed consistently in the hippocampus, where long-term potentiation depends on the phase of the theta rhythm (Sederberg et al. 2003). Induced theta oscillations are also increased diffusely in the cortex during working memory tasks (Raghavachari et al. 2001) and frontally during orienting to novel stimuli. The theta literature in schizophrenia is limited. Notably, the neural mechanisms—glutamatergic and

aminobutyric acid

(GABA)–ergic—that regulate both synchronized gamma and theta rhythms are implicated in the pathophysiology of schizophrenia. Thus, disturbances in glutamatergic and GABAergic function could provide the neurophysiological basis for impairments in sensory evoked potentials, MMN, and synchronized rhythmic EEG oscillations in schizophrenia.

NEUROIMAGING

Advances in neuroimaging technologies have created opportunities to examine schizophrenia as a brain disorder, and investigators have applied diverse methods to study brain structure and function (Gur et al. 2007a). With progress in quantitative computational anatomy methodologies we are at the cusp of an exciting era in neuroscience research that can capitalize on the ability to study the living brain with refined approaches both for hypothesis testing and for exploration. In vivo measurement is afforded by magnetic resonance imaging (MRI) examining neuroanatomy through structural MRI (sMRI), connectivity through diffusion tensor imaging (DTI), and neurochemistry through magnetic resonance spectroscopy (MRS). MRI also enables examination of brain physiology using functional MRI (fMRI) methods that measure changes in signal intensity attributable to cerebral blood flow. Other functional neuroimaging methods include positron emission tomography (PET), which enables measurement of local cerebral glucose metabolism, blood flow, and receptor function. Single photon computed emission tomography (SPECT) can also be used to measure cerebral perfusion and receptor function.

Structural Imaging An extensive literature of whole-brain volume and specific regions of interest documents consistent morphometric differences between patients with schizophrenia and healthy people. Structural neuroimaging studies with MRI have highlighted diffuse reductions in cortical gray matter volumes as well as diverse but selective regional abnormalities in schizophrenia (Gur et al. 2000a, 2000b; Konick and Friedman 2001; Nelson et al. 1998; Shenton et al. 2001; Wright et al. 2000). Most consistent have been reports of ventricular enlargement and reduced volumes of temporal lobe, superior temporal gyrus, and medial temporal lobe structures. Somewhat less consistent have been reports of abnormal volumes of prefrontal cortex, parietal lobe, thalamus, basal ganglia, cerebellar vermis, and olfactory bulbs, among others regions. Differences in reported results can be attributed to methodologies applied. For example, morphometric prefrontal studies differed in magnetic field, scanning parameters, slice thickness and contiguity, image processing, and regions examined. Consequently, findings seem inconsistent, with some noting no differences between patients and healthy participants and others observing volume reduction in gray matter, white matter, or both tissue compartments. Relatively fewer studies have related subregional volumes to clinical or neurocognitive measures. These studies support the hypothesis that increased volume is associated with better performance (Antonova et al. 2004). Automated methods for regional parcellation and voxel-based morphometry can now efficiently yield information on the entire brain, permitting validation of reported findings and identification of new possible regions. Such studies corroborate the region of interest approach showing gray matter density reductions in medial temporal lobes and the superior temporal gyrus (Honea et al. 2005). There are also replicated associations between superior temporal gyrus volume and positive symptoms and between medial temporal lobe volume reduction and memory impairment (Gur et al. 2007a). Furthermore, based on morphological parameters, it is possible to apply high-dimensional nonlinear pattern classification techniques to quantify the degree of separation of patients with schizophrenia and healthy control subjects. Such procedures enable testing the potential of sMRI as an aid to diagnosis. In a study of patients with schizophrenia and healthy control subjects, such a procedure demonstrated average classification accuracy of 82% for women and 85% for men (Davatzikos et al. 2005). While such automated methods are promising, further investigation is needed in their potential integration into diagnostic procedures. The abnormalities evident in brain anatomy should be considered in relation to several potential confounding factors including illness chronicity, treatment with antipsychotic medications, and comorbid diagnosis such as substance abuse. The study of first-episode schizophrenia provides an opportunity to examine if morphometric abnormalities are evident early in the course of illness. A recent review of sMRI studies in first-episode schizophrenia confirms only a reduction in the volumes

of the whole brain and of the hippocampus (Vita et al. 2006). There is therefore a need for additional studies of recent-onset patients to determine if other abnormalities are evident at that time or if they are progressive (Ho et al. 2003). Distinguishing the effects of illness duration from the effects of ongoing antipsychotic treatment is likely impossible. Most MRI studies that examined the specific regions of interest also evaluated possible relationships with antipsychotic medications. An association with treatment has been reported for the basal ganglia, where an increase of up to 20% in the volume of the globus pallidus has been related to first-generation (typical) antipsychotic medication dose (Wright et al. 2000). For second-generation (atypical) antipsychotics, there is an insufficient body of literature to document specific effects on neuroanatomy. In addition, because substance abuse is so common in schizophrenia, the possible effects of such substances merit consideration. Alcohol abuse has diffuse effects on the brain, with greater impact on the prefrontal cortex than on the temporal lobe, which is the area with the greatest volume reduction in schizophrenia. Moreover, the volume abnormalities are present in patients with no history of alcohol abuse. The potential effect of other substances, such as cannabis, on brain structure is unclear, and volume reduction is evident in patients without a history of cannabis abuse. The study of people at risk for schizophrenia is an additional strategy to evaluate vulnerability markers for the disorder. Early MRI studies that applied the region of interest approach focused on the amygdala and hippocampus. These found volume reduction in first-degree relatives compared with control subjects, with the family members showing a degree of volume reduction intermediate to that shown in patients and control subjects. Literature reviews and meta-analysis concluded that reduced hippocampal volumes were likely to be a vulnerability marker for schizophrenia (Boos et al. 2006; Lawrie et al. 2004).

Diffusion Tensor Imaging DTI examines white matter integrity and is a more recent addition to structural measures. The availability of DTI enhances the ability to evaluate compartmental brain tissue abnormalities. Although gray matter volume deficits are more marked than white matter abnormalities in schizophrenia, reduced anisotropy, a measure of directionality of flow of water molecules in axons, providing an index of white matter integrity, is observed with DTI in multiple brain regions. The application of this rapidly developing technology is relatively new, and different approaches are used for data acquisition and analysis. Thus, a consistent literature in schizophrenia has yet to emerge. Abnormalities have been reported in interhemispheric connectivity, as well as in intrahemispheric connectivity among frontal, temporal, and occipital lobes via association fibers (Foong et al. 2002; Kubicki et al. 2005). It is possible that white matter structures may be disorganized in schizophrenia rather than reduced in size (Kanaan et al. 2005). With the growing efforts to understand brain development in infancy and childhood through the application of MRI technology (Giedd et al. 1999; Matsuzawa et al. 2001), the neuroimaging literature in schizophrenia is consistent with diffuse disruption of normal maturation.

Magnetic Resonance Spectroscopy MRS is a noninvasive method for investigating brain metabolites. Most of this research has focused on investigating phosphorus (31P MRS) and proton-containing metabolites (1H MRS). Proton MRS metabolites such as N-acetylaspartate (NAA), which may provide a measure of neuronal integrity, are reduced in schizophrenia, especially in the hippocampus and frontal cortex (Steen et al. 2005). NAA reductions have been associated with decreased cortical volume and correlate with clinical features of the disorder, including illness duration, negative symptoms, and cognitive deficits (Keshavan et al. 2000; Stanley et al. 2000). Notably, NAA reductions have been observed in first-degree relatives of patients with schizophrenia and in prodromal cases and therefore may represent an indicator of vulnerability to the illness (Jessen et al. 2006; Tibbo et al. 2004).

31

P MRS studies in neuroleptic-naive first-episode patients suggest increased membrane breakdown

with reduced membrane generation throughout the course of illness (Jensen et al. 2004; Stanley et al. 1995). Such changes are commonly evident during cell generation, synaptogenesis, and degeneration and may reflect diverse processes affecting the brain of patients with schizophrenia. Notably, adolescents at genetic risk for schizophrenia manifest membrane alterations similar to those observed in patients early in the course of illness.

Neuroreceptor Imaging PET and SPECT provide an important avenue for examining in vivo neurochemistry. The investigation of receptor function with PET followed progress with in vitro binding measurements and autoradiography. Early ligand studies in schizophrenia examined primarily dopamine receptors, especially dopamine2 (D2). Results were somewhat inconsistent, most likely because of differences in patient populations, ligands, and modeling methods used (Andreasen et al. 1988). As neuroleptic-naive patients participated in such studies, the samples were still relatively small, with fewer than 20 patients per study. However, several reviews concluded that increases in both D2 receptor density and affinity are present in schizophrenia. A consistent literature has emerged indicating increased presynaptic dopaminergic turnover in schizophrenia. Such studies measured striatal fluorodopa uptake as an index of increased dopa decarboxylase activity and greater presynaptic dopamine turnover in the striatum. Increased activity of dopamine neurons in the striatum appears to be associated with clinical status and is more evident during acute exacerbations and presence of positive symptoms (Erritzoe et al. 2003). Such effects are consistent with studies of neuropharmacological stimulants, such as amphetamine, and cannot be attributed to antipsychotic medication, as approximately half the studies were conducted in medication-free (including neuroleptic naive) patients. Increased striatal dopamine, most evident in patients with active psychotic symptoms, has been related to the positive symptoms of schizophrenia. More recently, neuroreceptor studies have related dopamine function to cognitive processes in schizophrenia. Cortical dopamine transmission via dopamine1 (D1) receptors may play a role in impaired working memory and negative symptoms (Abi-Dargham 2004), whereas striatal dopamine activity via D2 receptors may modulate response inhibition, temporal organization, and motor performance (Cropley et al. 2006). Receptor imaging by PET and SPECT allows investigation of in vivo targets for antipsychotic drug action (Talbott and Laruelle 2002). It is now known that extrapyramidal (parkinsonian) side effects of first-generation antipsychotic drugs result from high striatal D2 receptor blockade (~75%), whereas second-generation antipsychotic drugs produce therapeutic benefit in relation to modest and transient striatal D2 receptor occupancy levels (~65%). These neuroimaging observations point to a rationale for the use of relatively low doses of first-generation antipsychotics and equivalent doses of secondgeneration antipsychotics (Tauscher and Kapur 2001), although use of neuroimaging to determine dosage ranges in a given patient is far from practical. Neuroreceptor PET and SPECT studies are valuable research tools that can help examine compounds that may regulate or stabilize dopamine, as well as nondopaminergic pathways—such as serotonin, glutamate, and GABA—that may offer promising targets for drug development.

Functional Imaging The early emphasis on "hypofrontality" in schizophrenia has been refined. The transition from isotopic methods, such as PET, to fMRI for measuring regional brain activation has offered several advantages, including higher spatial and temporal resolution, noninvasiveness, lack of ionizing radiation, direct correlation with anatomical imaging, greater repeatability, and economy. Consequently, numerous studies have applied neurocognitive paradigms in fMRI aimed at dissecting complex behavior. Most of these studies have been in healthy people, applying the blood oxygenation level–dependent (BOLD)

method using blocked designs and, in recent years, event-related paradigms. Diverse neurobehavioral probes have been applied in activation paradigms designed to elucidate the underlying brain circuitry in schizophrenia. Tasks applied have evaluated executive function, such as attention, abstraction, and working memory, as well as declarative and procedural memory, language, spatial, sensorimotor, and emotion processing. A potential strength of activation studies is the ability to relate the extent of activation to performance obtained "on line." However, relative underactivation in patients who have difficulties performing a task may reflect either a deficit in underlying processes related to that task or a lack of engagement (Davidson and Heinrichs 2003; K. Hill et al. 2004). PET and fMRI studies that attempted to correct for patient impairment by balancing performance of patients and healthy control subjects often failed to find hypofrontality, and some even found hyperfrontality (Honea et al. 2005). In two recent reviews, 12 N-back (working memory) fMRI studies and 18 episodic memory studies with PET or fMRI found hypofrontality in dorsolateral and inferolateral prefrontal cortex, respectively (Achim and Lepage 2005; Glahn et al. 2005). Hyperfrontality was also reported in medial areas, including the (dorsal) anterior cingulate. Antipsychotic medication is likely to normalize performance on these tasks and hypofrontality (Davis et al. 2005). Regarding the temporal lobe, studies noted increased temporal lobe cortical activity in SPECT and PET studies (Zakzanis et al. 2000), as well as bilateral reductions in perfusion in the medial temporal lobes. Perhaps a hypothesis that will incorporate these findings will evaluate the interaction between laterality and frontality. The relations between frontal and temporal activity merit further investigation and have been related to the hypothesis of decreased connectivity in schizophrenia (Stephan et al. 2006). PET, SPECT, and fMRI studies of disconnectivity are also supported by electrophysiological findings of reduced coherence and gamma asynchrony in schizophrenia (Uhlhaas et al. 2006). The application of neurobehavioral probes during functional imaging studies has contributed to the effort to investigate involvement of defined neural systems in the pathophysiology of schizophrenia (Gur et al. 1992). Such neurobehavioral probes document deficits in performance associated with abnormal brain activation and implicate the ventromedial temporal lobe, prefrontal cortices, and limbic subcortical nuclei mediating memory, executive functioning, and attention. These systems are characterized by dynamic plasticity, high connectivity, and vulnerability to insult (Arnold and Trojanowski 1996c; Harrison 1999), consistent with the hypothesis that abnormal plasticity is a core neurobiological feature of schizophrenia. Such fundamental mechanisms of abnormal structural, molecular, or physiological plasticity should be evident throughout the central nervous system (CNS) but may be most prominently expressed in neural systems mediating the highly activity-dependent cognitive processes of attention, memory, and executive functioning.

GENETICS Schizophrenia is a heritable complex brain disorder. Although the mode of inheritance is unknown, the disorder likely results from multiple genes of variable effect interacting with environmental factors. Linkage for schizophrenia has been reported in several regions: 1q32–q41 (Hovatta et al. 1999), 5q31 (Schwab et al. 1997), 6p24–p22 (Straub et al. 1996; Wang et al. 1995), 6q25.2 (Lindholm et al. 2001), 6q13–q26 (Cao et al. 1997), 8p21 (Blouin et al. 1998), 8p23.3 (Suarez et al. 2006), 10p15–p11 (Faraone et al. 1998, 1999), 13q32 (Blouin et al. 1998), 10q22 (Fallin et al. 2003), 10q25.3–q26.3 (Williams et al. 2003), and 22q12–q13 (Brzustowicz et al. 2000; Pulver et al. 1994a, 1994b). While some independent samples have detected linkage in the same or overlapping regions (6p24–p22, 6q13–q26, 10p15–p11, 13q32, 22q12–q13), many have failed to do so (Blouin et al. 1998; Cao et al. 1997; Moises et al. 1995; Schwab et al. 1995a, 1995b, 1998). Lack of overlap may reflect false-positive results or genetic heterogeneity. A meta-analysis of 20 published genomewide scans revealed evidence for linkage on chromosome 2q (C. M. Lewis et al. 2003). Eleven additional loci had suggestive linkage. Because power to detect linkage is limited for genes of intermediate or small

effect size (Risch and Merikangas 1996), these variable findings are not surprising. It is noteworthy that several of the genes identified are directly linked to glutamatergic presynaptic or postsynaptic functioning, and others can be indirectly linked. Association studies have used primarily functional, rather than positional, candidate gene markers (Shirts and Nimgaonkar 2004). Recent studies report some consistent associations, possibly due to evaluation of positional candidate genes, such as dysbindin, neuregulin 1, and G72 (Harrison and Weinberger 2005; Owen et al. 2005). The risk conferred by associated alleles is modest (odds ratio [OR] ~1.2). The primary risk alleles have not been identified at these genes. Because schizophrenia is phenotypically heterogeneous (Gottesman and Gould 2003), it may be helpful to identify variables correlated with liability. A complementary approach to dissecting the genetic architecture of schizophrenia is to examine the neurobiological traits associated with genetic susceptibility. Here the phenotype is not a clinical diagnosis but a neurobiologically defined trait. Given the heterogeneity of schizophrenia at the phenotypic and likely genotypic levels, analyzing neurobiological phenotypes may improve power by constraining some heterogeneity. Whereas an unequivocal clinical diagnosis may be difficult to establish, quantitative neurobiological phenotypes can be reliably measured in family members. Therefore, chromosomal regions showing inconsistent linkage results, or subthreshold LOD scores with the clinical phenotype, may yield stronger linkage to a neurobiological phenotype. The challenge is selection of informative endophenotypic markers that will efficiently lead to a mechanistic model of schizophrenia. The neurocognitive measures tap neural systems that can be directly studied with structural and functional neuroimaging. The potential of neurocognitive measures as markers of genetic liability is suggested by the presence of intermediate deficits in unaffected family members of schizophrenia probands (Calkins et al. 2005; Egan et al. 2001a; Thompson et al. 2005). Supporting an additive model, simplex families (those with one individual is affected) have less impairment than multiplex families (those with two or more individuals affected) in language processing (Shedlack et al. 1997), intelligence, verbal learning and memory, visual reproduction (Faraone et al. 2000), visual working memory (Tuulio-Henriksson et al. 2003), verbal learning, delayed visual recall, and perceptual–motor and pure motor speed (Hoff et al. 2005). These results are consistent with several recent reports showing significant heritability of these features (Gur et al. 2007b). Such findings support the role of neurocognitive measures in molecular genetic studies in healthy people (Burdick et al. 2006; de Frias et al. 2005; Plomin and Kosslyn 2001; Posthuma et al. 2005) and in schizophrenia (Bilder et al. 2002; Burdick et al. 2006; Hallmayer et al. 2005; Hennah et al. 2005; Szekeres et al. 2004). As an example, one candidate gene that has been extensively reported on in the schizophrenia endophenotype literature is the gene encoding catechol-O-methyltransferase (COMT). Consistent with the role of COMT in controlling prefrontal cortex phasic dopamine levels (D. A. Lewis et al. 2001; Sesack et al. 1998; Weinberger et al. 2001), subjects with the COMT Val/Val genotype performed worse on executive functions (Egan et al. 2001b) and working memory (Goldberg et al. 2003) compared with those with other genotypes. However, subsequent studies suggest a more complex relationship (Tunbridge et al. 2006). Only 1–2 polymorphisms are typically analyzed at each locus, and we need to investigate additional polymorphisms and study their neurobiological context. Furthermore, studies that evaluate a specific cognitive domain and differential deficit require understanding of a profile (Saykin et al. 1991). By providing quantitative measures of brain structure and function, neuroimaging has become the main approach to the study of brain and behavior in health and disease, fueling the nascent field of imaging genomics (Callicott and Weinberger 2003). Twin studies with sMRI reported heritability estimates greater than 0.90 for whole-brain volume, with lower heritability for regional volumes (Wright et al. 2002). In schizophrenia, the potential of volumetric measures as endophenotypic markers is suggested by reduced brain volume in unaffected siblings compared with control subjects

(Gogtay et al. 2003; Staal et al. 2000) and reduced parahippocampal volume in multiplex, relative to simplex, healthy family members (Seidman et al. 2002). Molecular genetic studies with sMRI have observed smaller hippocampal volumes in Val/Val compared with Met/Met genotypes of COMT (Szeszko et al. 2005); an association of disrupted-in-schizophrenia 1 (DISC1)/translin-associated factor X (TRAX) haplotypes with schizophrenia and reduced prefrontal gray matter, which in turn were associated with impaired memory (Cannon et al. 2005); and reduced dorsolateral prefrontal cortex volume associated with regulator of G protein signaling 4 (RGS4) polymorphisms in firstepisode schizophrenia patients (Prasad et al. 2005). The application of fMRI in genetic paradigms is more limited and has focused on the COMT Val/Met polymorphism and dorsolateral prefrontal cortex activation in healthy people and schizophrenia patients (Egan et al. 2001b; Winterer et al. 2004). Individuals homozygous for the Met allele showed diminished hippocampal engagement during performance of episodic memory encoding and retrieval compared with Val/Val subjects (Hariri et al. 2003). Such studies support use of multimodal imaging in genetic paradigms.

NEUROPATHOLOGY Neuropathological studies of brain tissues from patients with schizophrenia have reported a wide variety of morphometric, cellular, subcellular, and molecular abnormalities in diverse brain regions. While many findings are controversial or require confirmation, common themes have emerged from the data. Among these themes are abnormal neurodevelopment, abnormal synaptic integrity and plasticity, glutamatergic and GABAergic system abnormalities, mitochondrial dysfunction, and abnormal white matter integrity. Notably, all of these abnormalities occur in the absence of any grossly observable evidence of neural injury or neurodegenerative lesions common in other brain diseases (Arnold et al. 1998).

Abnormal Neurodevelopment While clinical and epidemiological findings present a compelling case for the role of abnormal neurodevelopment in schizophrenia, characterizing the cellular and molecular mechanism(s) by which this might occur has been a challenge. Neurons are born, migrate, and assume their mature phenotype, and the major axon pathways are laid down in a complex and highly orchestrated process during fetal development and early childhood (Arnold and Trojanowski 1996a, 1996b; Hatten 1999; Nowakowski and Rakic 1981). By the time schizophrenia is clinically expressed, typically in adolescence or young adulthood, much of development has transpired. Limited numbers of new neurons continue to be generated in the adult human brain in certain areas (e.g., the dentate gyrus [Eriksson et al. 1998]), but their number is small and their functionality is still being investigated (Eisch 2002). In contrast, there is ongoing synaptogenesis and synaptic remodeling within all major axon terminal fields throughout life. Aberrant neurodevelopment in schizophrenia has been inferred by findings from several postmortem research approaches. Among the earliest and most influential neuropathological findings of the modern era were reports of cytoarchitectural disorganization of hippocampal subfields and the entorhinal cortex, a limbic periallocortex intimately related to the hippocampus (Arnold et al. 1991a, 1991b; Conrad et al. 1991; Falkai et al. 1988; Jakob and Beckmann 1986, 1989, 1994; Kovelman and Scheibel 1984). Specific abnormalities have included misalignment of pyramidal cell neurons in ammonic subfields of the hippocampus, abnormal clustering and heterotopic displacement of neurons in the entorhinal cortex, and abnormalities in neuronal densities in different layers of the entorhinal cortex. Similar approaches in other corticolimbic regions, especially anterior cingulate cortex, also have revealed subtle cytoarchitectural differences in schizophrenia compared with control subjects (Benes and Bird 1987; Benes et al. 1992; Chana et al. 2003). However, not all of these findings have been replicated (Akil and Lewis 1997; Altshuler et al. 1987; Arnold et al. 1995; Benes et al. 1991; Krimer et al. 1997; Zaidel et al. 1997).

Another cytoarchitectural approach has been to map the number and position of interstitial white matter neurons lying deep to cerebrocortical gray matter. These neurons are considered to be remnants of the cortical subplate and are thought to reflect incomplete neuronal migration during brain development. Furthermore, because the subplate is important in directing the establishment of normal connectivity, disturbance of the subplate could lead to altered formation of connections. Several groups of investigators reported abnormal numbers or positions of neurons positive for nicotinamide adenine dinucleotide phosphate (NADPH)–diaphorase or microtubule-associated protein 2 (MAP2) within white matter of frontal, temporal, and parahippocampal cortices in schizophrenia, although the specific parameters of maldistribution varied among studies (Akbarian et al. 1993, 1996; Anderson et al. 1996; Kirkpatrick et al. 1999; Rioux et al. 2003). To explain these phenomena, researchers have proposed that the migration of neurons from the subventricular zone to the appropriate cortical lamina during fetal development is disturbed, that select populations of neurons fail to survive, and/or that neurons fail to generate axonal and dendritic processes appropriately, thus altering their normal orientation or placement. Complex and concerted, generative and regressive neurobiological processes determine the ultimate cytoarchitecture of a given region. In addition to neuronal migration, a host of intrinsic signaling mechanisms responding to extrinsic growth factors and neurotransmitters influence neuron survival, morphology, neurite outgrowth, and patterns of synapse formation. Young neurons that fail to establish adequate synaptic connectivity and access to trophic factors do not survive. Furthermore, the spatial organization of neurons depends not only on the number of neurons that migrate to a particular position and survive but also on the neuropil space in which those neurons reside. Increases or decreases in this space due to its many cellular (e.g., dendritic, axonal, glial processes) and extracellular matrix constituents will affect the spatial distribution of neurons. This has been a major interpretation of reports of reductions in neuropil space in the dorsolateral prefrontal cortex in schizophrenia (Selemon et al. 1998). Finally, environmental factors during growth and development (e.g., infection, ischemic injury, trauma) as well as regressive changes that are part of normal aging may further alter the cytoarchitecture that is observed at postmortem examination.

Abnormal Synaptic Integrity and Plasticity Synapses have been investigated by a variety of means in postmortem tissues in schizophrenia. At the ultrastructural level, studies described abnormalities in the densities and aggregation of synapses (Aganova and Uranova 1992; Kung et al. 1998; Soustek 1989), dendritic spine morphology and morphometry (Kolomeets and Uranova 1999; Roberts et al. 1996), axon terminal mitochondria (Kolomeets and Uranova 1999; Uranova et al. 1996), and various other changes in axospinous densities and morphologies (for a review, see Honer et al. 2000). Abnormalities in dendritic arborization and dendritic spines have been reported. Golgi impregnation studies have described decreased spine densities in prefrontal and temporal cortices and in the hippocampus (Garey et al. 1998; Glantz and Lewis 1995; D. A. Lewis and Glantz 1997; Rosoklija et al. 2000), decreased densities of pyramidal basilar dendrites in prefrontal cortex pyramidal neurons (Broadbelt et al. 2002), and increased densities of dentate gyrus granule cell basilar and recurrent dendrites (Lauer et al. 2003). Another index of dendritic densities that has been used in schizophrenia is immunolabeling for the MAP2 that is selectively expressed in the somatodendritic domain of neurons. Several studies have reported a decrease in the density of MAP2 expression in the hippocampus and prefrontal cortex (Arnold et al. 1991b; Jones et al. 2002; Rosoklija et al. 1995, 2005), although other groups have not found this (Cotter et al. 2000; Law et al. 2004). Molecular components of dendritic spines have also been assessed in schizophrenia, with reports of decreased spinophilin messenger RNA (mRNA) in the hippocampus (Law et al. 2004) and decreased mRNA expression of members of the rhoGTPase family, especially Cdc42 and Duo, in dorsolateral prefrontal cortex (J. J. Hill et al. 2006).

Molecules enriched in axon terminals and the presynaptic machinery for neurotransmitter release have been examined in postmortem tissues using a variety of methods, including Western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, in situ hybridization, Northern blotting, and quantitative real-time polymerase chain reaction (qPCR), as well as gene expression microarrays. Among the many proteins that have been investigated are synaptic vesicle membrane docking and fusion proteins such as synaptophysin, synapsin, synaptosome-associated protein of 25,000 daltons (SNAP-25), complexins I and II, Rab3a, and syntaxin; synaptic plasticity proteins such as growth-associated protein 43 (GAP-43) and neural cell adhesion molecules (NCAMs); and neurotransmitter system–specific proteins such as vesicular glutamate transporters (VGluTs) and vesicular GABA transporters (VGATs). The regions most commonly examined have been the hippocampus, dorsolateral prefrontal cortex, anterior cingulate, thalamus, and, more recently, the superior temporal gyrus. Most studies reported significant decreases in presynaptic terminal markers, although this has not been without controversy (Eastwood and Harrison 2001; Harrison and Eastwood 2001; Honer and Young 2004; Honer et al. 2000; Mirnics et al. 2001; Sweet et al. 2007).

Glutamatergic and GABAergic System Abnormalities The glutamate hypothesis of schizophrenia originated with the observations that dissociative anesthetics produce psychotic effects (Luby et al. 1959) and that the NMDA antagonists ketamine and phencyclidine induce schizophrenia-like psychosis and cognitive deficits (Javitt and Zukin 1991). Supporting data in schizophrenia include ketamine induction of eye-tracking abnormalities, impaired prepulse inhibition of the startle response, frontal hypometabolism, abnormal cortical ERPs, and enhanced subcortical dopamine release (Coyle 2004). Molecular neuropathological studies have produced complex and at times conflicting data on glutamatergic synapses in schizophrenia. Most have examined glutamate receptors, with the principal regions of interest being the hippocampus, prefrontal cortex, and thalamus. There are numerous findings of abnormal expression of NMDA receptor subunits NR1 and NR2B; the kainic acid receptor; -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, phosphorylation of NR1; postsynaptic density proteins PSD95, SAP102, and SAP97; excitatory amino acid (EAA) transporters EAAT1 and EAAT2; and the N-acetylaspartyl-glutamate (NAAG)–degrading enzyme glutamate carboxypeptidase II (Coyle 2004; Dracheva et al. 2005; Harrison et al. 2003). Although it is currently difficult to weave these diverse findings into a coherent mechanism, the weight of the evidence indicates significant derangement in postsynaptic glutamatergic neurotransmission in schizophrenia. Compared with data on glutamate, clinical evidence for major GABA involvement in schizophrenia is less compelling. However, substantial postmortem data indicate that GABA markers are abnormal (Benes and Berretta 2001; Blum and Mann 2002; D. A. Lewis et al. 2005; Wassef et al. 2003). In the hippocampus, prefrontal cortex, and elsewhere, there are reports of decreased expression of the GABA-producing enzyme glutamic acid decarboxylase67 (GAD67) mRNA and probably protein (but not GAD65), decreased GABA membrane transporter 1 (GAT1), decreased densities of nonpyramidal (presumably GABA) neurons, decreased calbindin-containing neurons, decreased parvalbumin mRNA, increased GABAA ligand binding, and increased GABAA

1

mRNA levels. In an elegant and compelling

set of experiments in localized microcircuitry of the prefrontal cortex, D. A. Lewis et al. (2005) provided evidence for a deficit of GAD67 mRNA expression in presynaptic GAT1 in chandelier interneurons and compensatory changes in postsynaptic GABAA receptors. They have suggested that these GABA changes may be relatively specific for the prefrontal cortex; however, a similarly detailed investigation has not been conducted elsewhere. One interpretation of GABA deficits in schizophrenia is that GABA activity is secondarily downregulated due to decreased glutamatergic stimulation. Genetic data associating a growing number of glutamatergic genes with schizophrenia (Harrison and Weinberger 2005) are consistent with primary glutamatergic abnormalities. Other data indicating that a primary glutamate deficit could

account for GABA abnormalities include evidence that administration of NMDA antagonists or surgical ablation of glutamatergic innervation to prefrontal cortex in rodents decreases GABA markers in prefrontal cortex (Cochran et al. 2003; Lipska et al. 2003; Paulson et al. 2003). However, other findings have suggested that GABA deficits are potentially primary (Addington et al. 2005; Caruncho et al. 2004; Guidotti et al. 2000; Hashimoto et al. 2005).

Mitochondrial Dysfunction Mitochondrial metabolic pathways represent an emerging area of interest in postmortem studies of schizophrenia. Certainly, the long history of findings of brain metabolic abnormalities from PET, SPECT, and fMRI (see "Neuroimaging" section) provide indirect support for the notion that metabolic pathways are dysfunctional in the disease, and, conversely, psychosis and other psychiatric symptoms have been reported as presenting symptoms in bona fide mitochondrial diseases (Fattal et al. 2006). Mitochondria are cellular organelles, which produce energy as adenosine triphosphate (ATP) via the electron transport chain and the oxidative phosphorylation system and help in the synthesis of other important cell constituents, including amino acids, phospholipids, and nucleotides. A few ultrastructural studies of postmortem tissues have described decreased densities and abnormal morphological profiles of mitochondria in limbic cortices, striatum, and substantia nigra (Kolomeets and Uranova 1999; Kung and Roberts 1999; Uranova et al. 1989). At the molecular level, Middleton et al. (2002) used complementary DNA (cDNA) microarrays to profile the expression of genes in a large number of metabolic pathways in the dorsolateral prefrontal cortex of subjects with schizophrenia and control subjects. They found consistent decreases in the expression levels of genes involved in five specific pathways: ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Prabakaran et al. (2004) used parallel gene expression microarray, proteomic, and metabolomic approaches to examine prefrontal cortex and reported 28 significantly downregulated metabolic pathways and 13 upregulated pathways in schizophrenia. Abnormal pathways included glycolytic and oxidative metabolism, intracellular and vesicle-mediated transport, and pathways involved in defense against reactive oxygen species. In a third microarray study, Iwamoto et al. (2005) reported a global downregulation in mitochondrial genes in schizophrenia and bipolar disorder, although they suggested that this was more related to antipsychotic medication than to disease. Targeted studies of mitochondrial metabolism have reported alterations in mitochondrial enzyme activities for cytochrome c oxidase, succinate dehydrogenase, and NADPH–cytochrome c reductase and mitochondrial complex I expression (Cavelier et al. 1995; Karry et al. 2004; Maurer et al. 2001; Prince et al. 1999; Whatley et al. 1996). While still relatively few, these promising studies indicate a need for increased investigation of mitochondrial metabolic pathways in schizophrenia.

Abnormal White Matter Integrity Another relatively new area of neuropathological interest in schizophrenia has been oligodendroglia and myelin integrity in schizophrenia. White matter abnormalities have long been hypothesized in schizophrenia. As noted above, clinical neuroimaging and electrophysiological research have yielded evidence of poor functional connectivity between and within brain regions, and some sMRI studies have shown reductions in white matter volumes. Most recently, magnetic transfer and diffusion tensor MRI studies have reported abnormalities in axon membrane integrity and anisotropy. Postmortem studies have found white matter–related abnormalities at cellular and molecular levels in schizophrenia. A seminal microarray study by Hakak et al. (2001) used a large oligonucleotide microarray to examine dorsolateral prefrontal cortex in an elderly cohort with highly chronic schizophrenia. Although abnormal expression of a variety of genes was reported, the authors were especially impressed with the decreased expression of oligodendroglial genes, including myelin-

associated glycoprotein (MAG), 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP), myelin and lymphocyte protein (MAL), gelsolin, erbB3, and transferrin. Subsequent studies with qPCR and in situ hybridization continued to find decreased myelin-related gene abnormalities in other samples and brain regions (Dracheva et al. 2006; McCullumsmith et al. 2007) as well as marginal decreases in CNP and MAG using immunohistochemistry (Flynn et al. 2003). Cellular and subcellular abnormalities of white matter have also been reported. Ultrastructural studies have described decreased compaction of myelin sheath lamellae and abnormal inclusion bodies as well as signs of oligodendroglial degeneration in schizophrenia samples (Uranova et al. 2001). Cell counting studies have reported decreased densities and altered spatial distribution of oligodendroglia in white matter (Hof et al. 2003; Rajkowska et al. 2001).

GENES ASSOCIATED WITH SCHIZOPHRENIA: IMPLICATIONS FOR NEUROPATHOLOGY As evident from the foregoing sections, the cellular and molecular neuropathological findings in schizophrenia are widespread in location, diverse in nature, and difficult to weave together mechanistically. Much more research needs to be done on multiple levels to advance our understanding of this complex and severe illness. However, recent advances in the genetics of schizophrenia provide some reason for optimism. In the past decade, associations between schizophrenia and a number of specific genes have been reported (for reviews, see Harrison and Weinberger 2005; O'Donovan and Owen 1996; Riley and Kendler 2006), suggesting molecular pathways and pathophysiological mechanisms that, at least theoretically, play diverse roles in the development and ongoing health of the nervous systems. Among the most highly replicated susceptibility genes are neuregulin-1, dysbindin, and DISC-1, along with COMT discussed previously. While variations in each of these genes confers only a modest increase in risk for the disorder, their discovery nonetheless identifies candidate proteins and molecular pathways that may substantially contribute to the pathophysiology of schizophrenia. This opens the door to a functional genomics of schizophrenia. It is noteworthy that most of these genes play important roles in neurodevelopment, neurotransmission, and neuroplasticity. Neuregulin-1 is a complex molecule with at least 15 different isoforms that have varied functions in the CNS (Buonanno and Fischbach 2001). Neuregulin-1 plays important roles in neurogenesis, neuronal migration, neuronal survival, axon and dendrite outgrowth, modulation of NMDA signaling via erbB4 receptors, and astroglia and oligodendroglia development via erbB3 receptors, among others. While levels of neuregulin-1 and erbB receptor expression do not appear to be abnormal in schizophrenia, markedly abnormal activation of neuregulin–erbB4 signaling has been found (Hahn et al. 2006). Dysbindin protein has only recently been characterized (Benson et al. 2001; Li et al. 2003; Talbot et al. 2006). It is neuron-specific; widely distributed in the CNS; present in presynaptic vesicles, postsynaptic densities, neuronal cytoskeleton, and cell nucleus; and important in intracellular trafficking and vesicle formation. So far, dysbindin expression has been found to be decreased in the hippocampus and dorsolateral prefrontal cortex in schizophrenia and may at least in part affect presynaptic glutamate release (Numakawa et al. 2004; Talbot et al. 2004; Weickert et al. 2004). DISC-1 has been characterized only recently also, after its association with schizophrenia was discovered (Ishizuka et al. 2006). DISC-1 is preferentially expressed in the forebrain and has multiple isoforms with potential posttranslational modifications. It is present in multiple subcellular compartments, including the actin and microtubule cytoskeletons, centrosomes, postsynaptic densities, mitochondria, and the nucleus. It appears to be important in the centrosome–dynein cascade and cyclic adenosine monophosphate (cAMP) signaling. While its expression level appears to be unaltered in schizophrenia, the expression levels of important binding partners (i.e., fasciculation

and elongation protein zeta-1 [FEZ1], lissencephaly 1 protein [LIS1], and nuclear distribution element-like [NUDEL]) are significantly reduced in schizophrenia (Lipska et al. 2006). COMT is an enzyme involved in the clearance of catecholamines from synapses and thus could be involved in regulation of neurotransmission related to schizophrenia both in development and maturity (Craddock et al. 2006). A functional polymorphism involving the presence of either valine or methionine at a specific codon affects the enzyme's activity. Variants with methionine have lower activity, and thus, people with two copies of the methionine allele may be expected to have higher dopamine and norepinephrine levels. Given the critical roles these neurotransmitters play in the development of the nervous system and mental functioning especially relevant to psychiatric illness, abnormal levels could have far-reaching cellular, molecular, and clinical effects.

CONCLUSION Considerable advances with a range of technologies have been made in the efforts to advance the understanding of the neurobiology of schizophrenia. Elucidating the vital neurobiological mechanisms at play is a continuing challenge. Given the complexity of the disorder, we do not expect a single gene, pathological lesion, cellular, molecular or neurochemical abnormality, or even neural system to be nodal to schizophrenia. Indeed, abnormalities are evident at many levels of neurobehavioral and neurophysiological processing and in multiple neural systems—from the cerebellum to diencephalon to diverse primary, association, and limbic cortices to the olfactory bulb and epithelium. However, these diffuse abnormalities, which implicate neurodevelopmental aberrations, are not fully expressed phenotypically until after brain development and maturation are largely completed. The recognition that the underlying pathological processes of schizophrenia are present throughout the CNS suggests that there may be some core defects in neurotransmission whereby the ability of neurons to respond to and process stimuli is curtailed. However, within the context of global abnormalities, some neural systems are differentially affected. Brain regions with greater vulnerability, such as the hippocampus, prefrontal cortex, and olfactory system, are dynamic and maintain a high degree of plasticity during brain maturation and thereafter. Thus, neuronal plasticity —evident in molecular, chemical, morphological, and physiological modifiability with neural activity—is abnormal in schizophrenia. This may ultimately be manifested in the array of complex features that characterize schizophrenia. However, functions mediated through other neural systems, where greater plasticity is not required, show subtle abnormalities, and motor abilities, sensation, and autonomic functions are relatively spared. These challenges are further compounded by the absence of suitable animal models for the disorder as currently phenotypically defined, buttressing the need to identify endophenotypes that can be studied in both humans and animals. For example, sensorimotor gating and encoding can be characterized in animals and in humans. The identification of such endophenotypes in schizophrenia that have counterparts in rodents enables investigation of the genetic, molecular, biochemical, anatomical, and physiological aspects of these behaviors in ways not possible in the human. Findings from studies in rodents will continue to provide new information about these behaviors and elucidate the effects of genetic, pharmacological, and behavioral manipulations, which can be pursued in humans. This top-down/bottom-up translational interchange holds great promise for advancing our understanding of the pathophysiology of schizophrenia. As progress is made, we will be in a better position to relate neurobiological processes to major clinical phenotypic characteristics of schizophrenia with the hope of targeted therapeutics that enhance cognition and ameliorate the negative symptoms associated with poor outcome.

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Jonathan M. Amiel, Sanjay J. Mathew, Amir Garakani, Alexander Neumeister, Dennis S. Charney: Chapter 47. Neurobiology of Anxiety Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.422869. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 47. Neurobiology of Anxiety Disorders NEUROBIOLOGY OF ANXIETY DISORDERS: INTRODUCTION Our understanding of the neurobiological basis of fear and anxiety continues to improve at a rapid pace. The principal brain regions involved in processing and responding to anxiety are known, many neurochemical systems mediating responses to fearful stimuli have been identified, and new technologies are advancing the study of the interactions of these brain regions with one another. There is also active investigation regarding the relationship between genes and the environment in the development of chronically dysregulated anxiety with the hope that characterizing the neurobiology of anxiety will bring forth therapeutic advances that reduce the significant burden and long-term functional impairment associated with anxiety disorders. In this chapter, we review preclinical and clinical data relevant to normal and pathological anxiety states. We begin with a brief summary of paradigms of fear learning. We then relate these preclinical paradigms with their neuroanatomical functional localization observed in animals models and more recently in humans with anxiety disorders. Subsequently, we present the major neurochemical systems mediating anxiety processes with a selection of supporting preclinical and clinical data. We then briefly describe findings specific to several of the individual anxiety disorders—panic disorder with and without agoraphobia, specific and social phobias, and posttraumatic stress disorder (PTSD)—and we comment on the state of investigations into the genetic basis of anxiety. We conclude with some of the key questions that will drive future research investigations. The neural circuitry of generalized anxiety disorder (GAD) may be distinct from the disorders noted above (Coplan et al. 2006; Mathew et al. 2008), and will not be further addressed in this chapter. Likewise, although obsessive-compulsive disorder (OCD) is categorized as an anxiety disorder in DSM-IV-TR (American Psychiatric Association 2000), there appears to be sufficient symptomatic and epidemiological heterogeneity between OCD and the other anxiety disorders that it will not be addressed in this chapter (Hollander et al. 2007).

NEURAL PARADIGMS OF FEAR AND ANXIETY Fear Learning Processes Investigations into anxiety states depend on a heuristic by which an individual becomes frightened of a novel stimulus and develops means to avoid this stimulus and its implied danger. These means include forming a short-term memory of the stimulus and consolidating this fleeting memory into a long-term memory associated with an avoidant behavior. The retained memories are dynamic and, when evoked by subsequent experience, are subject to change including retention (reconsolidation) or deletion (extinction). Anxiety is the emotional response to new and remembered frightening stimuli. Formal studies of fear learning processes date back to the experiments of the Russian physiologist Ivan Pavlov in the late nineteenth century. Pavlov's conditional reflex, an involuntary response that was conditionally based on prior experiences, formed the basis for the enduring fear learning paradigm of classical conditioning (Pavlov 1927). Pavlov observed that dogs have habitual responses to salient stimuli, such as salivating when presented with food. He then observed that animals

exposed to a neutral stimulus, such as the sound of a bell, repeatedly paired with a salient stimulus would associate the two stimuli, and the environment in which they were trained, and enact the same habitual response whether presented with the salient stimulus, the neutral stimulus, or even just the environment in which they were trained. Thus, the dog that salivates when presented with food also salivates to the sound of a bell or when entering the training laboratory. The salient stimulus was termed an unconditioned stimulus (US), the neutral stimulus was termed the conditioned stimulus (CS), the habitual response to the US was termed the unconditioned response (UR), and the habitual response to the CS was termed the conditioned response (CR). The association of the CS with the US is learning by explicit cue, whereas the association of the CS with the training environment is learning by context. The principles of classical conditioning apply to fear learning when the US is aversive and the UR includes the range of motor, autonomic, and endocrine behaviors of the fight-or-flight response. Whereas in healthy people fear learning allows for situational anticipation of danger and generates an adaptive and protective vigilance, people with anxiety disorders frequently mount this response to misinterpreted or neutral stimuli. These maladaptive hypervigilant responses, and their associated avoidant behaviors, are likely to be central to the "fear circuitry" anxiety disorders, including panic disorder, specific and social phobias, and PTSD.

Memory, Consolidation, and Reconsolidation The conversion of experience into memory is called consolidation and relies on changes in synaptic affinity first proposed by the Spanish neuroanatomist Santiago Ramón y Cajal (1894). With brief stimulation, neuronal interconnections transiently strengthen while stimulation of sufficient quantity and appropriate quality causes enduring changes in synaptic strength and structure (reviewed by Bailey et al. 2004). The brief and transient retention of memory is called sensitization and occurs due to enhancement of glutamatergic transmission via the

-amino-3-hydroxy-5-methylisoxazole-

4-propionic acid (AMPA) receptor, while long-term potentiation (LTP) refers to the lasting changes in synaptic affinity in which persistent glutamatergic stimulation of the N-methyl-D-aspartate (NMDA) receptor initiates a signaling cascade ending in gene transcription and protein synthesis (reviewed in Malenka and Bear 2004). The hippocampus and amygdala are key areas in which LTP and, therefore, consolidation, occur. This finding was particularly evident in the case of H. M., a young man who underwent bilateral medial temporal resections to treat his intractable epilepsy and after surgery experienced complete anterograde amnesia and, to a lesser degree, retrograde amnesia (Scoville and Milner 1957). Many animal models have replicated this clinical finding, and hippocampal LTP was recently documented in an in vivo mouse model (Whitlock et al. 2006). As in Pavlov's experiments, stimuli that are pertinent, or salient, are more likely to be remembered than neutral events. Fear-inducing or emotion-evoking experiences generate a glucocorticoid and catecholamine flux, as we will describe below, which selectively enhances memory consolidation by activating the basolateral complex of the amygdala, an effect which can be blocked by administration of

-adrenoreceptor antagonists (Roozendaal et al. 2006). This paradigm holds true in humans, where

memory for an emotional story is superior to memory for a nonemotional story (Cahill et al. 1994). A study showing increased noradrenergic activity after viewing an emotional story suggests that similar neurochemical signaling may be implicated (Southwick et al. 2002). However, clinical trials studying secondary prevention of PTSD with propranolol shortly after exposure to trauma have been equivocal (reviewed in Pitman and Delahanty 2005). An interesting finding from the late 1960s suggested an additional level of complexity to memory mechanisms. Classically conditioned rats undergoing electroconvulsive shock, which reliably induces retrograde amnesia, 1 day after training (a long enough period of time for consolidation to have

occurred) retained their training, but rats that were reexposed to the CS shortly before electroconvulsive treatment lost their conditioning (Misanin et al. 1968). This finding suggested that when retrieved, long-term memories are subject to modification and must undergo reconsolidation (reviewed in Riccio et al. 2006). Like consolidation, reconsolidation is enacted through a signaling cascade ending in protein synthesis, though these two processes employ independent and dissociable cellular processes (Lee at al. 2004).

Extinction After Pavlov classically conditioned his dogs to salivate (UR) to the sound of a bell (CS), he found that repeated presentation of the bell (CS) in the absence of food (US) diminished the dogs' salivatory response in a process called extinction (Pavlov 1927). Rather than erasing the conditioning process from memory, extinction is a process of integrating new memory that may reverse with a change of context or renewed pairing with the US (Bouton 2004). Like consolidation, extinction involves a cell-signaling cascade and protein synthesis. Glutamatergic NMDA receptors in the amygdala play a key role, and extinction may be blocked by NMDA receptor antagonists like AP5 (Falls et al. 1992) or -aminobutyric acid (GABA), an effect that is reversible with D-cycloserine (DCS), an NMDA partial agonist (Akirav 2007). Extinction is thought to occur by the medial prefrontal cortex's inhibiting the lateral amygdala under hippocampal modulation (Sotres-Bayon et al. 2006). Inactivation of the medial prefrontal cortex by surgical lesion (Milad and Quirk 2002) or local chemical blockade of protein synthesis disables extinction (Santini et al. 2004). Supporting this model, people with PTSD have been found to have depressed ventral medial prefrontal cortex activity during exposure to traumatic reminders (Bremner et al. 1999b). Clinically, employing extinction to "de-link" neutral stimuli from aversive responses is an important goal of psychotherapy and pharmacotherapy of anxiety disorders. Small clinical trials have shown some benefits to augmenting exposure therapy or cognitive-behavioral therapy with medications to enhance the extinction learning process. In one trial, DCS combined with exposure therapy improved acrophobic symptoms early in treatment and maintained benefit at 3 months (Ressler et al. 2004). This benefit was not observed in the treatment of spider or snake phobias (Guastella et al. 2007a, 2007b). A recent trial of DCS given prior to exposure therapy in people with social anxiety disorder showed significant but modest effects in symptom severity, cognitive dysfunction, and functional impairment (Guastella et al. 2008). A number of larger trials of DCS in several of the anxiety disorders are currently under way.

NEUROANATOMY OF FEAR AND ANXIETY The neuroanatomical substrates of anxiety detect, process, modulate, and respond to fearful stimuli serially and in parallel with one another, with varying degrees of conscious awareness. Afferent structures are the visual, auditory, vestibular, gustatory, and somatosensory receptors that transmit stimuli to the thalamus. The thalamus distributes signals to brain stem nuclei for automatic reflexes, to the basolateral amygdala via a direct subcortical "short loop" for rapid processing, and to primary and associative sensory, insular, cingulate, and prefrontal cortices that feed back to the amygdala via an indirect "long loop" for higher-order processing and modulation (LeDoux 2000). Olfactory afferents bypass the thalamus and project directly to the entorhinal cortex and the amygdala. Viscerosensory afferents communicate primarily with the nucleus of the solitary tract in the brain stem that relays signals to the central nucleus of the amygdala. Primary sensory cortices and their related association areas form a reciprocal neural circuit with the amygdala and hippocampus by which continued processing, comparison, and learning take place. Expressions of fear are effected through the motor pathways and the neuroendocrine autonomic pathways involving the hypothalamus and pituitary glands, the bed nucleus of the stria terminalis (BNST) and the raphe nuclei, periaqueductal gray

matter, and locus coeruleus of the brain stem. In normal function, this network of afferent, modulatory, and efferent pathways offers protection from physical and psychological threats. When dysregulated, pathological anxiety imposes undue behavioral inhibition and resultant decline in social functioning (Figure 47–1). FIGURE 47–1. Brain circuits implicated in fear and anxiety.

A major function of the amygdala is the integration of information from the thalamus and cortical regions into efferent signals (thick arrows). Integration of signals occurs in the basolateral amygdaloid complex, whereas efferent responses are mediated by the central nucleus. Reciprocal circuits to the cortex and the hippocampus are particularly relevant to affective modulation and contextual memory (thin arrows). The existence of direct and indirect pathways to amygdalar activation via the short and long loops suggests that the amygdala integrates sensory information with previous experience to determine the significance of complex stimuli and trigger responses based on the determined value of the stimuli. The lasting changes that occur in the amygdala in response to fearful cues occur via LTP in the

pathways involving AMPA and NMDA glutamate receptors, calcium fluxes, and protein synthesis described above (reviewed in LeDoux 2007). The pharmacological inhibition of glutamatergic tone and, to a lesser degree, calcium fluxes has been shown to reduce anxiety in several anxiety disorders (reviewed in Amiel and Mathew 2007; Balon and Ramesh 1996). Recent functional magnetic resonance imaging (MRI) studies of the processing of conscious and unconscious fearful images have implicated subspecificity within the amygdala, with conscious processing modulated in the dorsal amygdala and unconscious processing modulated in the basolateral complex (Etkin et al. 2004). In contrast, contextual fear learning also requires the recruitment of the hippocampus and the BNST (Walker and Davis 1997). When fear-evoking stimuli are perceived and their processing and modulation do not result in inhibition of the stimulus, the efferent mechanisms of the anxiety–fear circuit generate a range of autonomic, neuroendocrine, and motor responses originally named by Walter Cannon (1915) as the fight-or-flight response. In particular, the lateral nucleus and intercalated cells of the amygdala engage the central nucleus that is the principal output of the amygdala (see Figure 47–1). The central nucleus activates the sympathetic nervous system via the lateral hypothalamus, the parasympathetic nervous system via the dorsal motor nucleus of the vagus nerve, the endogenous opioid system via the periaqueductal gray matter, and the major neurotransmitters of the central nervous system (norepinephrine, dopamine, serotonin, and acetylcholine) via their brain stem nuclei (Schafe et al. 2001). The amygdala also engages the motor system through its connectivity with the motor cortex and the extrapyramidal cortico-striatal-pallidal motor system (McDonald 1991). Interestingly, while the experience of an aversive stimulus generates motor activation, there is functional MRI evidence that anticipation of an aversive stimulus causes marked inhibition of primary motor cortex with reciprocal hyperactivity in the basal ganglia (Butler et al. 2007).

NEUROCHEMISTRY AND GENETICS OF FEAR AND ANXIETY The anatomical substrates for fear and anxiety described above interact via a diversity of neurochemical messengers. Acute stress triggers the release of these neurotransmitters and neuropeptides, enhancing attention, motor, and memory systems to defend against the present threat and to avoid it in the future. The body upregulates metabolic activity through a surge of catecholamines and glucocorticoids that synergistically increase oxygenation, channel blood flow to the brain and muscle, and make stored energy available. These neurochemical systems operate in a vast and complex network of excitatory, inhibitory, and modulatory circuits. In this section we review the major neurochemical systems that contribute to the fear response under conditions of acute and chronic stress. As anxiety disorders have estimated heritabilities ranging from 30% (Hettema et al. 2001) to 60% when factors of measurement error and gene–environment interactions are controlled (Kendler et al. 1999), we will also discuss data pertaining to genes encoding the receptors that participate in synaptic transmission and modulation of impulses. The heritable component of anxiety is undoubtedly polygenetic, and classical genetic findings that have yielded elegant pathophysiological mechanisms in fields such as oncology and immunology have been elusive.

Noradrenergic System Noradrenaline/norepinephrine (NE) is a catecholamine that broadly activates cortical, subcortical, and cardiovascular systems via G protein–coupled adrenergic receptors. NE is synthesized from tyrosine peripherally in the adrenal medulla and postganglionic sympathetic efferents and centrally in the locus coeruleus. The locus coeruleus is a small blue-tinted pontine nucleus that constitutes the major noradrenergic cell body aggregate in the brain and is activated most notably in fear states by inputs from the amygdala and the lateral hypothalamus (reviewed in Charney and Drevets 2002). Noradrenergic stimulation of limbic and cortical regions is involved in the elaboration of adaptive responses to stress (Morilak et al. 2005).

Increased NE function accounts for many symptoms of pathological anxiety, such as panic attacks, insomnia, startle, and autonomic hyperarousal (Charney et al. 1987). Cerebrospinal fluid (CSF) NE concentrations are abnormally elevated in PTSD (Geracioti et al. 2001). Platelet 2-adrenergic receptor density, platelet basal adenosine, isoproterenol, forskolin-stimulated cyclic adenosine monophosphate (cAMP) signal transduction, and basal platelet monoamine oxidase (MAO) activity were decreased in PTSD—findings hypothesized to reflect compensatory responses to chronically elevated NE release (reviewed in Southwick et al. 1999b). Feedback inhibition appears to play a major role in the regulation of NE activity. Agonists of the presynaptic

2-adrenergic

receptor, including endogenous NE and epinephrine as well as drugs such

as clonidine, inhibit the release of NE.

2-adrenergic

receptor antagonists such as yohimbine or

idazoxan stimulate the release of NE. People with panic disorder are very sensitive to the anxiogenic effects of yohimbine (Charney et al. 1987). They also have exaggerated plasma 3-methoxy4-hydroxyphenylglycol (MHPG), cortisol, and cardiovascular responses to the administration of this compound (Charney et al. 1992). People with combat-related PTSD exposed to yohimbine also were reported to have enhanced behavioral, biochemical, and cardiovascular responses (Southwick et al. 1999a). Children with anxiety disorders show greater anxiogenic responses to yohimbine than do nonanxious comparison children (Sallee et al. 2000). The responses to the

2-adrenergic

receptor

agonist clonidine are also abnormal in people with panic disorder. Clonidine administration caused greater hypotension and decreases in plasma MHPG, and less sedation, in people with panic disorder than in control subjects (Uhde et al. 1988). 2-Adrenergic

receptor antagonists have been found to sensitize the locus coeruleus such that

excitatory stimuli generate increased responsiveness in the absence of an altered baseline activity, a phenomenon known as sensitization (Simson and Weiss 1988). Clinically, sensitization appears particularly relevant to symptoms of anxiety and PTSD such as tension, irritability, hypervigilance, and exaggerated startle reactivity. The hypothesis that sensitization is implicated in the development of pathological anxiety is supported by clinical studies indicating that repeated exposure to stress is an important risk factor for the development of anxiety disorders, particularly PTSD (Heim and Nemeroff 2001). Investigation into polymorphisms of the adrenergic receptor has revealed an intriguing insight into the genetic predisposition for the development of pathological anxiety involving noradrenergic synapses. Healthy people homozygous for an in-frame deletion in a subtype of the

2-adrenergic

receptor ( 2C-Del322–325) show higher baseline NE levels and more sustained increases in NE levels, heart rate, and anxiety than do control subjects when exposed to yohimbine (Neumeister et al. 2005). A follow-up study of people with this polymorphism and with remitted major depressive disorder found altered recruitment of cortical and limbic brain regions compared with control subjects, suggesting that variability in NE function impacts emotional processing (Neumeister et al. 2006).

Corticotropin-Releasing Hormone Corticotropin-releasing hormone (CRH) is a principal mediator of the stress response through its well-characterized indirect effects in activating the hypothalamic-pituitary-adrenal (HPA) axis and its lesser-known direct effects in the brain. CRH-containing neurons are located throughout the brain, including the central nucleus of the amygdala, prefrontal and cingulate cortices, BNST, nucleus accumbens, periaqueductal gray, and the noradrenergic locus coeruleus and serotonergic raphe nuclei (Steckler and Holsboer 1999). In response to stress, CRH levels rise and locally activate their target organs via regionally localized CRH1 and CRH2 receptors (Sanchez et al. 1999). Animal models studying the differences between CRH1 and CRH2 receptor activation suggest opposing function. Mice deficient in CRH1 display decreased anxiety-like behavior and an impaired stress response (Bale et al. 2002). In contrast, CRH2-deficient mice display increased anxiety-like behavior and are hypersensitive to stress (Bale et al. 2000; Coste et al. 2000). People with high levels of anxiety and

depression, though not depression alone, and homozygous for a GAG haplotype in the CRH1 locus, were found to respond more robustly to selective serotonin reuptake inhibitors than those without the same polymorphism (Licinio et al. 2004). Stress-related CRH secretion inhibits a variety of neurovegetative functions such as food intake, sexual activity, and endocrine programs for growth and reproduction. Exposure to stress in early life can produce long-term elevation of CRH (i.e., exaggerated CRH release) and sensitization of CRH neurons to subsequent stress. The long-term response to heightened CRH is individual and may depend on the social environment, trauma history, and behavioral dominance (Strome et al. 2002). Early exposure of the hippocampus to elevated levels of CRH may be associated with hippocampal damage later in life (Brunson et al. 2001). CSF concentrations of CRH in people with PTSD are increased relative to those in healthy control subjects (Baker et al. 1999). However, cortisol levels in these samples were not increased, as is the case in most PTSD studies. CSF CRH concentrations are not correlated with plasma cortisol (Baker et al. 1999). High levels of cortisol decrease hypothalamic CRH but increase CRH in areas such as the amygdala (Schulkin et al. 1998). A number of CRH1 receptor antagonists are currently being evaluated in preclinical and early clinical trials for their efficacy as anxiolytics and antidepressants and their utility in the treatment of substance abuse. Preclinical data show the promise of one of these compounds, R-121919, in treating symptoms of substance withdrawal (Funk et al. 2007). Although clinical data remain preliminary, R-121919 also may have clinical utility in treating depression and anxiety (Ising and Holsboer 2007). These findings await replication in larger randomized trials.

Arginine Vasopressin Like CRH, arginine vasopressin (AVP) is a major secretagogue of the HPA/stress system. AVP is produced by the parvicellular neurons of the hypothalamic paraventricular nucleus and secreted into the pituitary portal circulation from axon terminals projecting to the external zone of the median eminence. AVP release is triggered primarily by increasing serum osmolality, hypovolemia, hypotension, and hypoglycemia. AVP has corticotropin-releasing properties when administered alone in humans, a response that may depend on the ambient endogenous CRH level. Following the combination of AVP and CRH, a much greater corticotropin response is seen. The sensitivity of CRH and AVP transcription to glucocorticoid feedback apparently differs, and AVP-stimulated corticotropin secretion may be refractory to glucocorticoid feedback. AVP regulation of the HPA axis may therefore be critical for sustaining corticotropin responsiveness in the presence of high circulating glucocorticoid levels or supersensitive glucocorticoid receptors. Thus, in animals deficient for the CRH1 receptor, there is a selective compensatory activation of the hypothalamic AVP system, which maintains basal corticotropin secretion and HPA activity. Similar response patterns have been observed following chronic stress, leading to a hypothesis that CRH plays a predominantly permissive role in HPA regulation but that AVP represents the dynamic mediator of corticotropin release. Extrahypothalamic AVP-containing neurons also have been characterized in the rat, notably in the medial amygdala, where they project to limbic structures such as the lateral septum and the ventral hippocampus and are thought to act as neurotransmitters. Central AVP receptors include V1A and V1B, which are found in the septum, cortex, and hippocampus (Hernando et al. 2001). V1A knockout mice were found to have reduced anxiety in tasks such as the elevated plus-maze and forced swim (Bielsky et al. 2004; Egashira et al. 2007), and conversely, mice overexpressing V1A were found to be more anxious (Bielsky et al. 2005). Preclinical trials of V1B receptor antagonists such as SSR149415 have been promising in showing anxiolytic and antidepressant effects of blocking the activity of AVP on these receptors (Griebel et al. 2002). There is work under way to develop these agents as antidepressants and anxiolytics (Serradeil–Le Gal et al. 2005).

Cortisol Cortisol is a steroid hormone secreted by the zona fasciculata of the adrenal cortex. Under normal physiological conditions, cortisol levels peak just before awakening and reach a nadir soon after the onset of sleep. With stress, HPA axis activation causes an increase in serum cortisol levels (Morgan et al. 2000). Higher cortisol levels mobilize energy stores, inhibit activity of the growth and reproductive systems, and contain the immune response. Cortisol also may contribute to the recruitment of higher cortical functions to ensure arousal, vigilance, focused attention, rapid recall, and efficient memory encoding and storage. Preclinical data have shown that glucocorticoids can enhance amygdala activity (Charney et al. 1992; Makino et al. 1994), increase the effects of CRH on conditioned fear, and facilitate the encoding of emotion-related memory via an NE-dependent pathway (Roozendaal et al. 2006). Although transiently elevated serum cortisol may serve adaptive purposes in combating fearful stimuli, long-term exposure to high levels of cortisol have significant deleterious effects, both peripherally and in the central nervous system. Under normal conditions, cortisol feeds back on hypothalamic receptors to inhibit further HPA activation. When this feedback system fails to inhibit cortisol secretion, excessive and sustained cortisol secretion causes hypertension, osteoporosis, immunosuppression, insulin resistance, dyslipidemia, dyscoagulation, atherosclerosis, and cardiovascular disease (Karlamangla et al. 2002). In the brain, a sustained increase in glucocorticoid levels impairs cell survival, alters metabolism and neuronal morphology, and adversely affects hippocampal-dependent cognitive and memory function (McEwen 2000). There is inconsistent evidence regarding cortisol levels in people with anxiety disorders. People with PTSD generally have normal or decreased 24-hour serum and urine cortisol levels and in some studies have had increased intra-day variability in levels suggestive of increased adrenal reactivity with a reduced threshold for hypothalamic suppression, a finding consistent with pharmacological suppression data (reviewed in Yehuda 2006). A recent small study found that people with PTSD have higher CSF cortisol, which may represent a dissociation between peripheral and central levels (Baker et al. 2005). Similarly, HPA studies in people with panic disorder have yielded inconsistent results, but it appears that there exists a consistent HPA hyperreactivity to novel fear-provoking cues (Abelson et al. 2007).

Neuropeptide Y Neuropeptide Y (NPY) is a 36–amino acid peptide found mostly in the locus coeruleus, hypothalamus, amygdala, hippocampus, basal ganglia, and midbrain nuclei. NPY is expressed under fearful conditions and appears to inhibit or contain the stress response (reviewed in Heilig 2004). Localized microinjections of NPY in the rat amygdala reduce anxiety and impair memory retention, whereas injections in the locus coeruleus are inhibitory (Flood et al. 1989; Heilig et al. 1989). NPY knockout rats demonstrate increased emotionality in the face of stress and impaired spatial learning (Thorsell et al. 2000), whereas rats in which NPY is overexpressed spend more time in open arms of mazes, implying decreased anxiety (Primeaux et al. 2005). The anxiolytic effects of NPY appear to be mediated in part by glutamate receptor ligands in a manner reversible by Y1 and Y2 receptor antagonists (Smiaowska et al. 2007). The balance between NPY and CRH neurotransmission may be important to emotional responses to stress. NPY counteracts the anxiogenic effects of CRH, and a CRH antagonist blocks the anxiogenic effects of an NPY–Y1 receptor antagonist. Brain regions that express CRH and CRH receptors also contain NPY and NPY receptors, and the functional effects are often opposite, especially at the level of the locus coeruleus, amygdala, and periaqueductal gray (reviewed in Kask et al. 2002). The reciprocal antagonism appears to be related to bidirectional GABAergic transmission in the BNST (Kash and Winder 2006).

Human studies have found that NPY levels are not significantly different in subjects with PTSD after combat or domestic violence (Morgan et al. 2003; Seedat et al. 2003). Soldiers who underwent distressing interrogation and were found to have clinically significant dissociation had elevated plasma NPY levels (Morgan et al. 2000) that were later found to correlate with improved performance (Morgan et al. 2002). This finding was reinforced by another study that showed that elevated NPY levels were associated with PTSD symptom improvement and may represent a biological correlate of resilience (Yehuda et al. 2006).

Galanin Galanin is a 30–amino acid neuropeptide involved in emotion-related behaviors including cognition, nociception, sexual behavior, feeding, sleep, and reward (reviewed in Holmes and Picciotto 2006). In rodent studies, galanin collocates with the ascending monoamine systems and, consequently, is found in the locus coeruleus, the raphe nuclei, and the ventral tegmental area and inhibits monoamine, glutamate, and acetylcholine release via three known G protein–coupled receptors (Gal1, Gal2, and Gal3) in the brain stem as well as its subcortical and cortical projections (reviewed in Karlsson and Holmes 2006). Several preclinical studies have shown a role for galanin in modulating anxiety. Centrally administered galanin produced conflicting results in rats, with some studies showing anxiolytic effects (Bing et al. 1993) and others showing anxiogenic effects (Khoshbouei et al. 2002; Moller et al. 1999). In vivo microdialysis studies have shown that galanin is released in the amygdala in the context of stress and presynaptic

2-adrenergic

receptor blockade, independently of noradrenergic influence from the locus

coeruleus (Barrera et al. 2006). In the hippocampus, local overexpression or administration of galanin impairs fear conditioning (Kinney et al. 2002), and Gal1 receptor–deficient mice show increased anxiety-like behavior. Preclinical pharmacological studies have shown anxiolytic and antidepressant effects of galanin receptor agonists. Galnon, a nonselective galanin receptor agonist, was shown to have anxiolytic properties reversible with M35, a nonselective galanin receptor antagonist (Rajarao et al. 2006). A similar finding was reported on a forced swim test with rats, suggesting an antidepressant effect of galanin as well (Kuteeva et al. 2007). However, two Gal3 receptor antagonists, SNAP 37889 and SNAP 398299, were found to have anxiolytic and antidepressant properties in several animal models, such as forced swim and stress-induced hyperthermia (Swanson et al. 2005). To date, only one known study has examined galanin in anxiety disorders. Women with panic disorder and two polymorphisms of the galanin gene were found to have more severe symptoms than women with other haplotypes, a finding that did not extend to the men tested (Unschuld et al. 2008). These findings, in light of the preclinical data reviewed above, suggest a potential role for agents modulating the galanin system in the treatment of anxiety.

Dopamine Dopamine (DA) is a catecholamine involved in a number of emotional processes including reward, affect, and anxiety. Under conditions of acute stress, DA is released via mesocortical projections in the medial prefrontal cortex and, to a lesser degree, via subcortical projections in the nucleus accumbens and the basolateral amygdala. Stress causes DA to be released and metabolized in the medial prefrontal cortex with an associated inhibition in mesoaccumbens dopaminergic tone (King et al. 1997) via an amygdala-dependent pathway (Goldstein et al. 1996). These inverse effects on the medial prefrontal cortex and the nucleus accumbens suggest an aversive subjective experience that may play a role in stress-induced depression. In the forced swimming test animal model for depression, mice vulnerable to stress-induced despair stopped swimming almost immediately and were found to have high mesocortical DA metabolism and low mesoaccumbens DA

metabolism compared to normal mice; these findings were reversed by either chemical lesioning of the medial prefrontal cortex or treatment with the tricyclic antidepressant clomipramine (Ventura et al. 2002). Interestingly, lesions of the medial prefrontal cortex inhibit extinction, a situation hypothesized to occur in PTSD (Morrow et al. 1999). Thus, excessive medial prefrontal cortex DA results in helplessness, while insufficient medial prefrontal cortex DA retards extinction, leading to the hypothesis that there exists an optimal range of medial prefrontal cortex DA activation necessary to preserve the reward function of the nucleus accumbens while maintaining the ability to extinguish conditioned emotional memories. These processes may be relevant to understanding the high mood disorder comorbidity observed across all the anxiety disorders. Clinical research on DA function in anxiety disorders is relatively sparse. To date, investigations into serum and CSF levels of DA or its metabolites have not yielded convincing evidence of alterations in global DA activity. Recently, genetic analyses into polymorphisms of the major DA metabolizing enzyme catechol-O-methyltransferase (COMT) have suggested an association between specific polymorphisms and anxiety disorders. In one study, healthy women with the Val158Met COMT polymorphism were found to have higher levels of phobic anxiety (McGrath et al. 2004). A meta-analysis of six case–control studies of COMT polymorphisms did not replicate the Val158Met finding but did find an ethnicity effect, whereby white populations with the 158Val allele and Asian populations with the 158Met allele were found to have a higher incidence of panic disorder (Domschke et al. 2007).

Serotonin Serotonin (5-HT) is a monoamine neurotransmitter with a diversity of neural, gastrointestinal, and cardiovascular functions. Under conditions of acute stress, regional increases in 5-HT turnover occur in the prefrontal cortex, nucleus accumbens, amygdala, and lateral hypothalamus (Kent et al. 2002). 5-HT release has both anxiogenic and anxiolytic effects, depending on the brain region involved and the receptor subtype activated. One theory is that 5-HT plays a dual role in anxiety, enhancing learned responses to distal threat through projections to the amygdala and the prefrontal cortex while inhibiting unconditioned responses to proximal threats through projections to the periaqueductal gray matter (reviewed in Graeff 2002). 5-HT stimulation of the 5-HT2A receptor is generally anxiogenic, whereas stimulation of the 5-HT1A receptor is generally anxiolytic (Graeff 2004). Investigation into the function of the 5-HT1A receptor has yielded interesting insights into the role of 5-HT in anxiety. 5-HT1A is primarily inhibitory and is found as a presynaptic autoreceptor in the neurons of the raphe nuclei, whereas it is postsynaptic in the hippocampus, septum, and cortex. 5-HT1A knockout mice exhibit increased anxiety-like behaviors (Parks et al. 1998) which can be reversed if gene expression is conditionally inhibited in adulthood but not in early life (Gross et al. 2002). These findings imply that 5-HT1A receptor activity is required for normal development of the neural circuits regulating anxiety. Clinically, people with panic disorder and social anxiety disorder have a lower density of 5-HT1A receptors in limbic structures including the amygdala, raphe nuclei, and anterior cingulate gyrus (Lanzenberger et al. 2007; Neumeister et al. 2004). This finding was not replicated after exposure to stress in people with PTSD (Bonne et al. 2005). The 5-HT transporter (5-HTT) and its encoding gene SCL6A4 also play a significant role in the neurobiology of anxiety. Polymorphisms of the SCL6A4 promoter 5-HTTLPR encoding a short (S) or long (L) allele have been linked to mood and anxiety disorders. Carriers of the S allele have lower expression of 5-HTT, decreased 5-HT reuptake, and a higher incidence of anxious traits (Lesch et al. 1996), as well as increased amygdalar activation in response to fearful faces (Hariri et al. 2002, 2005). Children homozygous for the S allele are more shy than controls and may be more vulnerable to developing anxiety disorders later in life (Battaglia et al. 2005). The S allele also confers a depressive and anxious diathesis when combined with early-life stressors. Carriers of the S allele with a history of early-life stress have a higher incidence of depression and behavioral inhibition as children (Fox et al.

2005; Kaufman et al. 2004) and rates of depression as adults (Caspi et al. 2003). A significant number of negative studies also exist in which there is no association between the presence of the S allele, adverse life events, and the incidence of anxiety disorders, confirming the multifactorial nature of the pathophysiology of anxiety. Similarly, pharmacological dissection of serotonergic systems has not yet established the role of 5-HT in the pathogenesis of anxiety disorders. Panic disorder has been most closely studied, and pharmacological challenges with the 5-HT precursors L-tryptophan (Charney and Heninger 1986) and 5-hydroxytryptophan (DenBoer and Westenberg 1990) or the tryptophan depletion challenge (Goddard et al. 1994) failed to elicit or inhibit panic symptoms in people suffering from panic disorder compared with healthy controls. Fenfluramine, an agent triggering release of 5-HT, has been shown to be anxiogenic and stimulate the HPA axis in people with panic disorder (Targum and Marshall 1989). In sum, it appears that 5-HT dysfunction plays an indirect role in the pathogenesis of anxiety disorders through its modulatory effects on other neurotransmitter systems.

GABA and Benzodiazepines GABA is the main inhibitory neurotransmitter of the central nervous system and binds to rapid ionotropic GABAA and GABAC receptors and slow metabotropic GABAB receptors most densely concentrated in the cortical gray matter (Bormann 2000). In general, GABAergic tone counteracts excitatory glutamatergic tone, and thus plays a major role in the pathophysiology and treatment of anxiety disorders (Nemeroff 2003). GABAA and GABAC receptors contain a chloride channel mediating neuronal hyperpolarization and consequent inhibition. The role of GABAB receptors is less clearly understood but appears to modulate excitatory transmission and LTP (Chang et al. 2003). In general, agents that enhance GABA receptor activity are anxiolytic, while those that inhibit GABA receptors are anxiogenic. There are various mechanisms of GABA receptor enhancement and inhibition. Agents that mimic GABA or increase its synaptic concentrations include ethanol, valproate, gabapentin, tiagabine, vigabatrin, and some neurosteroids (reviewed in Kalueff and Nutt 2007). Benzodiazepine agents bind to distinct benzodiazepine (BDZ) receptors on GABAA receptors, potentiating and prolonging the synaptic actions of GABA binding by increasing the frequency of GABA-mediated chloride channel openings (Smith 2001). The physiological role of BDZ receptors is unknown. Although there is evidence of endogenous BDZ receptor agonists, or endozapines, in unusual conditions including idiopathic recurrent stupor (Tinuper et al. 1994) and hepatic encephalopathy (Cossar et al. 1997), attempts to characterize an endozapine as common as its receptor have been unsuccessful. It is possible that rather than serving a physiological function, the physiological function of the BDZ receptor site is as an intrinsic modulator of GABA receptor activity. GABAA receptors contain a chloride channel mediating neuronal hyperpolarization and consequent inhibition. Specific subunits of the GABAA receptor have been implicated in anxiogenic and anxiolytic phenomena. Preclinical investigations using inverse agonists (Atack et al. 2006), selective agonists (Dias et al. 2005), and behavioral paradigms (Morris et al. 2006) have shown that the

2

and

3

subunits have a primary role in modulating anxiety. Furthermore, preclinical models of acute stress have revealed reduced BDZ receptor binding, as well as reduced amygdala and hippocampus expression of the

2

subunit, which correlate with clinical neuroimaging findings of reduced BDZ

receptor binding in people with panic disorder and PTSD (reviewed extensively in Kalueff and Nutt 2007). Pharmacological modulation of the GABA receptor has revealed interesting findings regarding the role of the GABAergic system in anxiety. Administration of flumazenil, a BDZ receptor antagonist, provokes panic attacks in people with panic disorder, but not in healthy control subjects (Nutt et al. 1990) or in people with other anxiety disorders (reviewed in Nutt and Malizia 2001).

Glutamate

Glutamate is the principal excitatory neurotransmitter in the CNS and also a precursor to the inhibitory neurotransmitter GABA, in addition to its central roles in protein synthesis and metabolism. Glutamatergic networks mediate associative functions of the cortex and hippocampus, sensory relay operations of the hypothalamus, danger-processing functions of the amygdala, and motivation systems in the basal forebrain (Chambers et al. 1999). Glutamatergic neurotransmission is also central to CNS mechanisms of plasticity, such as long-term potentiation or depression and short-term potentiation (Sheng and Kim 2002). Stress-related glutamatergic hyperactivity of sufficient magnitude may lead to increased intracellular calcium levels and neuronal toxicity. Such effects are described in concert with increased glucocorticoid levels and adversely affect varied brain structures, notably hippocampi (Sapolsky 1996). Given the repeated descriptions of reduced hippocampal volume in PTSD, this attribute of glutamate is of particular interest. Preclinical studies have shown that immediate increase in glutamate efflux in prefrontal cortex and hippocampus occurred after induction of acute stress (Bagley and Moghaddam 1997). NMDA receptors may mediate lasting increases in anxiety-like behavior brought on by the stress of predator exposure. Ketamine (an NMDA antagonist) administration at a subanesthetic dosage in humans induced alterations in identity and perception resembling dissociation, a symptom of PTSD and panic attacks. These phenomena were attenuated by administration of the glutamate antagonist lamotrigine (Anand et al. 2000). Programmatic investigation into the clinical application of glutamate-modulating drugs for treating anxiety is under way. Small trials have suggested the efficacy of a range of medications including anticonvulsants and the glutamate release inhibitor riluzole (reviewed in Amiel and Mathew 2007). New drugs under investigation include agonists of presynaptic metabotropic glutamate receptors, glycine receptor antagonists, NMDA subtype selective antagonists, and glutamate glial transport blockers.

Neurosteroids Steroids influence neuronal function through binding to intracellular receptors, which may act as transcription factors in the regulation of gene expression (reviewed in Rupprecht 2003). Several neurosteroids, particularly 3 -reduced metabolites of progesterone and deoxycorticosterone, modulate ligand-gated channels via nongenomic mechanisms (Strömberg et al. 2006). Neurosteroids enhance the function of GABAA receptors by interacting with NMDA receptors in the central nucleus of the amygdala (Wang et al. 2007) and appear to be anxiolytic in preclinical models (Vanover et al. 2000). Neurosteroid production is postulated to counteract the negative effects of acute stress. In response to stress, levels of neurosteroids increase rapidly first in the brain and then in the blood. Clinical studies have found that pharmacologically induced panic attacks with cholecystokinin-tetrapeptide (CCK-4) or lactate are associated with decreased 3 -reduced neurosteroids in people with panic disorders, whereas healthy control subjects showed an increase in 3 ,5 -tetrahydrodeoxyxortixosterone, also known as allopregnanolone (reviewed in Eser et al. 2006). These findings imply a decreased GABA tone in people with panic disorder. Progesterone also has been found to be anxiolytic in animals and humans by upregulating allopregnanolone (Reddy et al. 2005) independently of classic progesterone receptors (Frye et al. 2006). Pregnant animals show a decrease in anxiety behaviors correlating with elevated levels of serum progesterone that is reversible with finasteride, an inhibitor of the enzyme 5- -reductase responsible for the synthesis of allopregnanolone (de Brito-Faturi et al. 2006). Pregnancy has also been found to reduce anxiety and increase allopregnanolone in healthy women (Paoletti et al. 2006) and in women with panic disorder (reviewed in Hertzberg and Wahlbeck 1999). Other studies of serum progesterone metabolite levels in anxiety disorders have been inconsistent, though

premenopasual women with PTSD were found to have reduced CSF allopregnanolone levels (Rasmusson et al. 2006). Interestingly, drugs that are classically known as 5-HT reuptake inhibitors increase allopregnanolone levels at doses insufficient to block reuptake (Pinna et al. 2006). Further investigations into the interaction between 5-HT and neuropeptides may yield interesting new targets for novel pharmacotherapy of anxiety and affective disorders. The study of the anxiolytic and antidepressant effects of synthetic neurosteroids such as ganaxolone, now being tested in epilepsy, has been proposed (Eser et al. 2006).

Cholecystokinin Cholecystokinin (CCK) is a neuropeptide, originally discovered in the gastrointestinal tract, found in high density in the cerebral cortex, amygdala, hippocampus, midbrain periaqueductal gray, substantia nigra, and raphe. Its major effect is anxiogenic, and it has important functional interactions with other systems implicated in fear and anxiety (reviewed in Harro 2006). Rodent models have shown that CCK-like agents induce anxiety, whereas agents that block the effects of CCK are anxiolytic (Bourin and Dailly 2004; Hano et al. 1993). Furthermore, the panicogenic effects of cholecystokinin-tetrapeptide, a CCK2 receptor agonist acting on the periaqueductal gray matter, are blocked by administration of LY-225910, a CCK2 receptor antagonist (Bertoglio and Zangrossi 2005; Bertoglio et al. 2007; Netto and Guimaraes 2004; Zanoveli et al. 2004). Pharmacological challenge with CCK increases anxiety in people with panic disorder (Bradwejn et al. 1994) and PTSD (Kellner et al. 2000), but not in people with social phobia (Katzman et al. 2004). CCK antagonists, propranolol, and imipramine seem to reduce the anxiogenic effects of CCK (Bradwejn and Koszycki 1994), suggesting that CCK interacts with the NE system in a manner reversible by the

-adrenergic

receptor–downregulating effects of imipramine. There is some evidence of CCK-B gene polymorphisms in subjects with panic disorder, suggesting a possible genetic vulnerability (Hösing et al. 2004). Although these data suggest that CCK receptor antagonists have a role in the treatment of anxiety, placebo-controlled trials have not shown effects in panic disorder or generalized anxiety disorder (Adams et al. 1995; Goddard et al. 1999; Kramer et al. 1995; Pande et al. 1999; van Megen et al. 1997). Further elucidation of the receptor specificity, regional effects, and neurotransmitter system interactions of CCK may aid in the identification of therapeutic applications.

Endogenous Opioids The endogenous opioids are a group of neuropeptides including endorphins, enkephalins, dynorphins, and orphanins/nociceptins that bind to opioid receptors. In particular -opioid receptors are distributed throughout the brain and are found in higher concentrations in limbic regions including the amygdala, the periaqueductal gray matter, the ventral pallidum, and the cingulate gyrus (Lever 2007). Endogenous opioids have a role in nociception, social attachment, and reward. Preclinical models have shown that uncontrollable stress induces significant analgesia (Fanselow 1986) and that reexposure to less intense shock in the acute period also results in analgesia (Madden et al. 1977), but that chronic unpredictable stress inhibits nociception, causing hyperalgesia (PintoRibeiro et al. 2004). It also appears that endogenous opioids act on the periaqueductal gray matter in rat models of fear learning, which is blocked with naloxone, indicating that endogenous opioids may be important for extinction (Cole and McNally 2007). An antagonistic interaction with CCK has also been described (reviewed in Hebb et al. 2005). Human correlates of endogenous opioid abnormalities related to anxiety have also been described. In people with PTSD,

-endorphin levels have been found to be decreased in plasma (Hoffman et al.

1989) but elevated in CSF (Baker et al. 1997). Combat veterans with PTSD were found to have naloxone-reversible pain insensitivity in comparison with combat veterans without PTSD (Pitman et al.

1990). Women who have suffered domestic violence show a correlation between stress-induced analgesia and the development of PTSD hyperarousal 3 months after the trauma (Nishith et al. 2002). Neuroimaging has shown that people with PTSD have increased activation of -opioid receptors in the anterior cingulate but decreased activation of these receptors in the amygdala and thalamus (Liberzon et al. 2007). Therapeutic trials have shown that treatment with opiates reduces the incidence of PTSD in hospitalized children by reducing separation anxiety (Saxe et al. 2006), and opioid antagonists reduce PTSD hyperarousal symptoms (Petrakis et al. 2007). In sum, it appears that endogenous opiates offer protection from unbearable pain during acute stress or danger, but that with chronic stress, a dysregulation of the endogenous opioid system occurs characterized by altered nociception and extinction. Genetic investigations into the endogenous opioid system are preliminary, but individuals with high levels of worry and homozygous for the met158 polymorphism of the COMT allele were found to have regionally blunted -opioid response to pain and increased report of subjective pain and distress in comparison with heterozygotes (Zubieta et al. 2003).

NEUROCIRCUITRY OF SPECIFIC ANXIETY DISORDERS Panic disorder, specific and social phobias, and PTSD share many mechanisms underlying fear and anxiety responses and may best represent the "fear-based" anxiety disorders. The regions most often implicated with psychopathology include the limbic, paralimbic, and sensory association areas. Below we review key findings in these disorders.

Panic Disorder Panic disorder is characterized by recurrent, short-lived, but intense panic attacks and a continuous but more moderate type of anxiety (termed anticipatory anxiety). Studies in the "resting state" are assumed to represent the latter type of anxiety. Earlier resting-state studies initially found an asymmetry (left less than right) of blood flow and oxygen metabolism in the hippocampus and parahippocampal gyrus (for a review, see Charney and Drevets 2002). Abnormal glucose metabolism in this region, but with the opposite laterality (i.e., elevated metabolism in the left hippocampal/parahippocampal area), was reported in a more recent study (Sakai et al. 2005). However, decreased resting-state bilateral perfusion also was reported in lactate-sensitive subjects with panic disorder compared with control subjects. Functional imaging of subjects with panic disorder also has been performed during experimentally induced panic attacks. Because states of extreme fear are also observed or induced in healthy control subjects, it is unknown if the neuroanatomy of panic attacks would be similar or different in healthy subjects and people with panic disorder. Regional cerebral blood flow (CBF) increases in the anterior insula, anteromedial cerebellum, and midbrain were observed after sodium lactate infusion–induced panic attacks in people with panic disorder. Anxiety attacks induced in healthy humans with cholecystokinin-tetrapeptide (CCK-4) also were associated with CBF increases in similar regions and the anterior cingulate cortex. Yohimbine administration increased medial frontal CBF in healthy control subjects but decreased relative prefrontal cortical perfusion in people with panic disorder relative to control subjects. People with panic disorder, but not healthy control subjects, had reductions in absolute measures of global CBF under CO2 provocation (Ponto et al. 2002). In pentagastrin-induced panic attacks, hypoactivity in people with panic disorder, compared with control subjects, was found in the precentral gyrus, inferior frontal gyrus, right amygdala, and anterior insula. Hyperactivity in people with panic disorder was observed in the parahippocampal gyrus, superior temporal lobe, hypothalamus, anterior cingulate gyrus, and midbrain (Boshuisen et al. 2002). Positron emission tomography (PET) studies have shown that doxapram-induced paniclike states are associated with decreased prefrontal activity and increased amygdala and cingulate activation in people with panic disorder, but not in healthy control subjects, further supporting the model that prefrontal inhibition is

important in attenuating anxiety (Garakani et al. 2007). In a preliminary functional MRI study comparing people with panic disorder and healthy subjects during mental imagery of high anxiety states, people with panic disorder showed increased activity in the inferior frontal cortex, hippocampus, and anterior and posterior cingulate gyrus, extending into the orbitofrontal cortex and encompassing both hemispheres (Bystritsky et al. 2001). In the first report of functional MRI of spontaneous panic attack, a woman with panic disorder was found to have markedly increased activity in the right amygdala (Pfleiderer et al. 2007). Only a few structural MRI studies have investigated morphometric or morphological abnormalities in panic disorder. Ontiveros et al. (1989) reported qualitative abnormalities of temporal lobe structure in panic disorder, although these findings have not been replicated. Vythilingam et al. (2000) reported that hippocampal volume did not differ between people with panic disorder and healthy control subjects, but the entire temporal lobe volume was reduced bilaterally in the people with panic disorder. However, this finding was difficult to interpret, because when normalized to whole-brain volume, the differences in temporal lobe measures between panic disorder and control samples had magnitudes of 2%. A volumetric MRI study found bilaterally reduced amygdala volumes in patient with panic disorder without associated differences in hippocampal or overall temporal lobe size (Massana et al. 2003). Neuroimaging studies found reduced BZD receptor binding in people with anxiety disorders (reviewed earlier in this chapter in the subsection "GABA and Benzodiazepines").

Phobias The phobic response is phenomenologically similar to a panic attack. It has been imaged by acquiring blood flow scans while exposing people to their feared object (for review, see Charney and Drevets 2002). A progressive pattern of regional CBF responses was observed during successive scans. Perfusion initially increased in the lateral orbital/anterior insular cortex bilaterally, in the pregenual anterior cingulate cortex, and in the anteromedial cerebellum. During continued presentations of the phobic stimulus, the magnitude of the hemodynamic response diminished in the anterior insula and the medial cerebellum but increased in the left posterior orbital cortex. The CBF increase was inversely correlated with decreases in heart rate and anxiety ratings. In a PET [15O]butanol study of people with simple spider phobia, phobic stimulation elevated regional CBF bilaterally in the secondary visual cortex compared with neutral stimulation but reduced regional CBF in the hippocampus and in the prefrontal, orbitofrontal, temporopolar, and posterior cingulate cortices (Pissiota et al. 2003). A recent functional MRI study (Paquette et al. 2003) reported reversal of phobic (spider) provocation increases in the dorsolateral prefrontal cortex (Brodmann area 10) and parahippocampal gyrus in people with simple phobia after clinically successful treatment with cognitive-behavioral therapy. These authors concluded that effective psychotherapeutic treatment (i.e., cognitive-behavioral therapy) can modify dysfunctional neural circuitry associated with pathological anxiety. Several functional imaging studies have focused on social phobia. When speaking in public, people with social phobia had elevated CBF in the amygdaloid complex and reduced CBF in orbitofrontal and insular cortices and the temporal pole relative to comparison subjects (Tillfors et al. 2001). It is hypothesized that in social phobia, as in PTSD (see the following subsection, "Posttraumatic Stress Disorder"), exaggerated fear response is related to an absence of cortical inhibition. Another study compared subjects with social phobia scanned either before or after speaking in public (Tillfors et al. 2002). In the anticipation group, increased CBF was found in the right dorsolateral prefrontal cortex, left inferior temporal cortex, and left amygdaloid–hippocampal region, and decreased CBF was found in the left temporal pole and bilaterally in the cerebellum. Anticipatory anxiety in people with social phobia may involve a fear network encompassing the amygdaloid–hippocampal region and prefrontal and temporal areas, much like the anticipatory anxiety neurocircuitry of people with panic disorder. Another PET study by the same group (Furmark et al. 2002) reported that clinical improvement in

social phobia, obtained by treatment with group psychotherapy or citalopram, was accompanied by similar decreases in provocation-induced regional CBF in the amygdala, hippocampus, and periamygdaloid, rhinal, and parahippocampal cortices. CBF in these regions decreased significantly more in responders compared with nonresponders, particularly in the right hemisphere. Tc-99m hexamethylpropyleneamine oxime ([99mTc]-HMPAO) single photon emission computed tomography (SPECT) was used to evaluate resting-state regional CBF ratios in a group of 15 people with social phobia before and after treatment with citalopram (Van der Linden et al. 2000). Regional CBF was significantly reduced in the anterior and lateral part of the left temporal cortex; the anterior, lateral, and posterior part of the left midfrontal cortex; and the left cingulum. Results from both treatment studies are conceptually and anatomically similar to those obtained from the above-described treatment studies in simple phobia and panic disorder, suggesting a mutual neurocircuitry for fear responses in diverse anxiety disorders. Functional MRI studies have been useful in assessing regional brain activity in phobic individuals. In comparison with healthy control subjects, people with social phobia have larger increases of the amygdala (Stein et al. 2002) and anterior cingulate (Amir et al. 2005) blood oxygen level–dependent signal when viewing angry faces rather than happy faces. Arachnophobic individuals experiencing anticipatory anxiety have fMRI hyperactivation of anterior cingulate, insula, thalamus, and visual areas as well as the BNST (Straube et al. 2007). Interestingly, group exposure therapy was found to reduce amygala and insula hyperactivation in arachnophobic subjects over the course of treatment (Schienle et al. 2007). These findings are consistent with the hypothesis of a hyperactive limbic/amygdala response to anxiogenic stimuli in anxiety and stress-related disorders.

Posttraumatic Stress Disorder Activation brain imaging studies comparing people with PTSD with healthy or trauma-exposed control subjects were expected to detect differences in the amygdala, hippocampus, and medial prefrontal cortex, because it was assumed that there was an exaggerated fear response in the absence of cortical inhibition. Amygdala activation was observed as PTSD subjects were compelled to reexperience trauma (Liberzon et al. 1999; Rauch et al. 1996; Shin et al. 1997). Other studies found no significant changes in amygdala CBF under similar conditions (Bremner et al. 1999a, 1999b; Shin et al. 1999). In contrast to the inconsistencies in amygdala activation, the pattern of CBF changes in the medial prefrontal cortex consistently differentiated between PTSD and healthy subjects, showing increased activation in the latter group (Bremner et al. 1999b; Shin et al. 1997, 1999). In the infralimbic cortex, CBF decreased in subjects with combat-related PTSD but increased in matched, non-PTSD control subjects during exposure to combat-related stimuli (Bremner et al. 1999b). The findings of decreased anterior cingulate and increased amygdala function after traumatic recall have been interpreted as a failure of cortical inhibition of amygdala-mediated fear responses. Findings from two functional MRI studies support anterior cingulate hypofunction in PTSD, particularly in the emotional component of this structure. Reduced perfusion in the anterior cingulate in PTSD subjects compared with trauma-exposed control subjects was found after activation by the emotional Stroop test (Shin et al. 2001) and traumatic recall (Lanius et al. 2001). Given preclinical evidence that the anterior cingulate and infralimbic cortices play roles in extinguishing fear-conditioned responses (Milad and Quirk 2002), failure to activate the anterior cingulate cortex in PTSD suggests impairment of neural substrate mediation extinction in PTSD. A preliminary functional MRI study found exaggerated amygdala response in PTSD subjects relative to trauma-matched control subjects during exposure to masked-fearful faces relative to masked-happy faces (Rauch et al. 2000). Because participants were only aware of seeing the mask, the increased activation of the amygdala can be understood as a "bottom-up" phenomenon, suggesting an inherent malfunction in the amygdala regardless of the presence or absence of cortical inhibition.

Structural imaging of hippocampal volume in PTSD was stimulated by preclinical studies reporting hippocampal neuronal loss and dendritic atrophy following exposure to chemical or psychosocial stress (McEwen 1999). Structural MRI studies of PTSD have identified subtle reductions in the volume of the hippocampus in PTSD samples relative to healthy or traumatized, non-PTSD control samples (for review, see Hull 2002; Villarreal et al. 2002). These studies mainly investigated people with chronic PTSD, often associated with comorbid mental disorders, pharmacological treatment, and alcohol and substance abuse, although most studies attempted to control for these factors. However, Agartz et al. (1999) have shown that in the presence of alcohol abuse, the additional occurrence of PTSD has no added effect on hippocampal volume. De Bellis et al. (2000) reported a decrease in hippocampal volume in young adults with adolescent-onset alcohol use disorder. A few studies did not report hippocampal reduction in PTSD. Prospective longitudinal studies of acute single civilian trauma survivors found no difference in hippocampal volume between healthy trauma survivors and people with PTSD at two time points as well as across time (for review, see Hull 2002). The difference in hippocampal volume in PTSD may apply to specific subtypes of the disorder (i.e., chronic vs. acute trauma), reflect chronic stress associated with long-term PTSD, or indicate a biological antecedent that may confer risk for developing PTSD.

CONCLUSION Physiological and pathological anxiety likely represent a spectrum of hyperactivation of specific neurochemical axes and neuroanatomical circuits. There are significant genetic contributions to the anxiety diathesis, but undoubtedly the experience of fearful stimuli in the environment plays a major role in inducing, reinforcing, and sometimes generalizing the fear response. We have reviewed polymorphisms associated with clinical findings in the noradrenergic, HPA, dopaminergic, serotonergic, and endogenous opioid systems. There is also active investigation of the genetics of intracellular processes associated with learning and unlearning that will undoubtedly relate to the study of anxiety. In addition, explorations in the field of epigenetics, or nongenomic variations in gene expression and protein synthesis, are just beginning. Evolving technologies of gene arrays and automated screening, as well as the linkage of imaging modalities with genetic research, will offer new insights into the neurobiology of anxiety disorders. In this chapter, we attempted to provide a framework for understanding these phenomena, linking potential and still largely hypothetical neural mechanisms derived from preclinical research to the neurobiological findings in people with anxiety disorders. We presented data showing an association among neurotransmitters, neuropeptides, and hormones and various states of anxiety. A neurocircuitry apparently shared by many anxiety disorders was illustrated. Several important questions are raised in light of this review: Are there qualitative differences in the neurocircuitry of fear and anxiety in pathological versus physiological anxiety? How do the neurobiological systems implicated in anxiety change over time and with new experiences? How do pharmacological and behavioral interventions alter the neurobiology of anxiety? Is the neurobiology of each DSM-IV-TR anxiety disorder distinct, or do they represent subtle variations of a shared etiology? Continuing research into the epidemiology, genetics, neurochemistry, and functional anatomy of physiological anxiety, pathological anxiety, and the effect of therapeutic interventions will address these questions and inform clinical practice by supporting or refuting currently accepted nosologies and pharmacological and psychotherapeutic interventions.

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Albert A. Davis, James J. Lah, Allan I. Levey: Chapter 48. Neurobiology of Alzheimer's Disease, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.415496. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 48. Neurobiology of Alzheimer's Disease NEUROBIOLOGY OF ALZHEIMER'S DISEASE: INTRODUCTION Of the broad spectrum of brain diseases that can produce dementia, Alzheimer's disease (AD) is the most common. AD is a devastating disorder characterized by progressive loss of memory and intellectual abilities, affecting more than 40% of individuals older than 85 years of age. The remarkable increase in disease prevalence that has accompanied the growth of the oldest segment of the population has heightened public awareness and accelerated research efforts to understand the disease. AD has been recognized as a clinical and neuropathological entity for more than 100 years, but specific therapies were unavailable until the development of the first cholinesterase inhibitor, tacrine, about 20 years ago. Since that time, several new cholinesterase inhibitors have been approved for the treatment of AD patients, and novel therapies, such as the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, have shown modest benefit in improving cognitive function in patients with AD. Common clinical practice has also embraced the use of high-dose vitamin E as an antioxidant that may provide some neuroprotective benefit. Research on AD funded by the government, private foundations, and the pharmaceutical industry commits billions of dollars annually for achieving better understanding of the disease and for developing more effective treatments. These efforts will inevitably lead to continued improvement in clinical practice in the coming years. AD is complex, with multiple genetic components, risk factors, neuropathological features, and theories of pathogenesis. This chapter provides an update on our current understanding of the biological basis of the disease and background for understanding the anticipated rapid changes in the clinical approach to AD. Because our understanding of AD is still evolving, it is difficult to predict the form of future clinical applications. Some of these will certainly be surprising. However, the most dramatic advances and changes in clinical management of AD are likely to emerge from the rational development of treatments to modify the basic mechanisms of disease. With this in mind, we begin this chapter by reviewing well-established neuropathological and neurochemical changes observed in AD. These abnormalities are particularly relevant for understanding the rationale for the use of cholinesterase inhibitors and other drugs for ameliorating cognitive, emotional, and behavioral symptoms. Next we examine epidemiological studies that have revealed several risk factors for AD and have offered clues to potentially important mechanisms in disease pathogenesis and possible prevention. AD genetics is a rapidly expanding field, and some of the more salient observations are noted here. We conclude the chapter by considering several theories of AD etiopathogenesis as well as future directions of research and disease therapy. This discussion will certainly require modification and refinement as new research findings emerge. However, these theories provide the rationale for most of the current efforts to develop new therapies that will produce a significant impact on preventing, halting, or perhaps reversing the disease process. [The authors are grateful to Dr. Marla Gearing for providing photomicrographs and for critical reading of the text.]

PATHOLOGY The primary pathological hallmarks of AD, described a century ago by Alois Alzheimer (1906), consist of senile (neuritic) plaques and neurofibrillary tangles (Figure 48–1). These morphological changes,

which are visible on silver-stained specimens, provide important clues to the biology of AD. Neuritic plaques are complex structures that consist of extracellular aggregates of the amyloid-beta (A ) peptide, surrounded by swollen dystrophic neurites and infiltrated by microglia and reactive astrocytes. Neurofibrillary tangles are intracellular accumulations of hyperphosphorylated tau, a cytoskeleton-associated protein organized in disease states as paired helical filaments. Grossly, there is often atrophy of the frontal, parietal, and temporal lobes in brains with AD. The medial temporal lobe structures, including the amygdala, hippocampus, and entorhinal cortex, are usually markedly shrunken. While atrophy is not specific to AD, the areas of atrophy reflect the selective vulnerability of certain brain regions and correspond to the microscopic accumulation of plaques and tangles. FIGURE 48–1. Pathological hallmarks of Alzheimer's disease.

(A) Low-magnification view of cerebral cortex showing multiple A -immunopositive plaques. (B) Higher magnification of a Bielschowsky silver stain showing argyrophilic amyloid plaques (arrow) and neurofibrillary tangles (arrowhead) in cerebral cortex. (C) High-magnification view of a single neuritic plaque. The central core of the plaque contains amyloid peptides that are surrounded by a clear halo and then swollen silver-positive dystrophic neurites. (D) High-magnification view of a neurofibrillary tangle. In addition to plaques and tangles, other pathological changes are visible in the AD brain (Terry et al. 1994). Amyloid deposition in leptomeningeal blood vessel walls, known as amyloid angiopathy, results in increased frequency of lobar hemorrhages. Neuropil threads are short neuronal processes that are marked by silver stains, thioflavin, and tau immunoreactivity, found mostly in cortical regions associated with tangle pathology. Hirano bodies are rod-like filaments composed of actin and other microfilaments, most commonly occurring in pyramidal neurons in the hippocampus. Granulovacuolar degeneration, detectable by the appearance of large cytoplasmic membrane-delimited vacuoles, is often found in the same regions. These vacuoles also contain cytoskeleton-associated proteins. All of the pathological lesions occur in "normal" aging to a limited extent, but they occur much more frequently in the hippocampus, neocortex, and other areas in AD. Cellular and synaptic alterations also occur in AD. There is a loss of large neurons, particularly in layer II of the entorhinal cortex, pyramidal neurons in layers III and V of neocortex, cholinergic neurons in the basal forebrain, and in select subcortical nuclei. Loss of synapses is an important change because this pathology presumably results in the disconnection of cortical association areas. Indeed, of all pathological alterations measured to date, synapse loss best correlates with cognitive deficits. There are also a variety of intracellular changes in endomembranous compartments. For example, the biosynthetic machinery, including the Golgi apparatus, is shrunken (Salehi et al. 1994), and there is

an expansion of endosomal compartments (Cataldo et al. 1995, 1996; Nixon 2005). Endosomal changes occur early in the disease, even at preclinical stages in vulnerable neurons, and appear to be intimately associated with genetic factors in AD. The wide variety of pathological changes raises questions about their sequence of occurrence; that is, a more complete understanding of the disease's pathogenesis rests on the identification of the primary changes that cause the disease versus the secondary changes that occur in later stages of neurodegeneration. This key issue remains unresolved. Moreover, it is possible that there may be several distinct mechanisms that are capable of initiating the pathogenic cascade. For example, genetic studies indicate that mutations in several genes (amyloid precursor protein [APP], presenilin 1 [PSEN1], and presenilin 2 [PSEN2]) are sufficient to initiate disease and that polymorphisms in other genes can accelerate the process. Ultimately, the development of strategies to modify the course or to prevent the disease demands understanding of the mechanisms by which genetic and environmental factors interact to cause disease. These factors are further discussed in the sections that follow. Advances in understanding the biology of all phases of AD will impact drug development. In particular, the improved understanding of the neurochemical changes has opened the door for the first successful attempts to develop efficacious drugs.

NEUROCHEMISTRY AND NEUROPHARMACOLOGY Numerous studies have examined the neurochemical changes that occur in the brains of individuals with AD. The most consistent changes involve loss of cholinergic, serotonergic, and glutamatergic markers (Bowen and Francis 1990). The acetylcholine and serotonin neurons are located in the basal forebrain and upper brain stem, respectively, and their degeneration results in the loss of ascending modulatory effects on neocortical and hippocampal function. In contrast, the loss of glutamate, the primary excitatory neurotransmitter, reflects degeneration of cortical pyramidal neurons. Abundant evidence suggests that the clinical syndrome involves failed neurotransmission at cholinergic synapses in neocortex and hippocampus (Coyle et al. 1983). This concept is based on numerous observations. First, presynaptic cholinergic markers are decreased in neocortex and hippocampus in AD, and they have been found to correlate with dementia severity (Bowen and Francis 1990; Davies and Maloney 1976). Second, basal forebrain neurons, which provide the majority of cholinergic innervation to the neocortex and hippocampus, degenerate in AD (Whitehouse et al. 1982). Third, basal forebrain lesions or pharmacological blockade of muscarinic acetylcholine receptors (mAChR) impairs learning, memory, and attention (Bartus et al. 1982; Damasio et al. 1985; Drachman 1977). Fourth, clinical trials of acetylcholinesterase (AChE) inhibitors show improved cognition and quality of life, reduced behavioral problems, and delayed institutionalization (Cummings and Cole 2002; Dooley and Lamb 2000; Knopman et al. 1996; Lamb and Goa 2001; Olin and Schneider 2002). Finally, brains from Parkinson's disease patients treated chronically with antimuscarinic drugs show increased AD neuropathology compared to brains from untreated or acutely treated patients (Perry et al. 2003). Perturbations in specific cholinergic markers seem to occur at different stages of the disease (Mufson et al. 2003). For example, the numbers of neurons in the basal forebrain that express choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are not altered in cases of mild cognitive impairment (MCI; a prodrome of clinically defined AD) or even in the early stages of AD (Gilmor et al. 1999). However, the numbers of basal forebrain neurons expressing p75NTR, a low-affinity neurotrophin receptor (NTR), are significantly decreased in both AD and MCI (Mufson et al. 2002). These findings have been suggested to reflect a phenotypic alteration in cholinergic basal forebrain neurons that precedes absolute neuron loss, and they highlight the importance of developing neuroprotective strategies that could be utilized, even after symptoms emerge, to prevent or slow the degeneration of cholinergic and other neurons. There are also complex changes in cortical markers of cholinergic neurotransmission. In early stages, ChAT, the rate-limiting enzyme for

acetylcholine synthesis, is not decreased (Davis et al. 1999; DeKosky et al. 2002). As the disease progresses, however, the activity of ChAT, together with AChE (the degradative enzyme for acetylcholine), diminishes. Of interest, molecules selectively present in cholinergic nerve terminals in cortex, including ChAT, VAChT (responsible for packaging acetylcholine into synaptic vesicles), and the high-affinity choline transporter (responsible for the uptake of choline), seem to increase, suggesting compensatory changes in surviving terminals. The diversity of molecules involved in different aspects of cholinergic transmission (Figure 48–2) provides a variety of potential strategies for reducing the dysfunction of cholinergic systems in AD. FIGURE 48–2. Molecular basis of cholinergic neurotransmission.

Acetylcholine (ACh) is synthesized in the nerve terminal cytoplasm and is incorporated into synaptic vesicles via the vesicular acetylcholine transporter (VAChT). Upon nerve impulse, cholinergic vesicles release ACh into the synaptic cleft, where the transmitter binds to pre- and postsynaptic muscarinic and nicotinic receptor subtypes. Transmission is terminated by the rapid hydrolysis of ACh by acetylcholinesterase (AChE). The degradation product choline is recycled into the terminal by the high-affinity choline transporter (CHT). This reuptake process is a key regulated and rate-limiting step in ACh synthesis. AcCoA = acetyl coenzyme A.

AChE inhibitors are currently the primary symptomatic treatment for AD. There are different types of cholinesterase enzymes, including an AChE and a butyrylcholinesterase type, both of which degrade acetylcholine. AChE is the primary enzyme expressed by neurons, and complete disruption of the gene for this enzyme in mice results in the overactivity of cholinergic systems in both brain and peripheral nervous system. Moreover, mice deficient in AChE display significant changes in the levels, cellular distribution, and function of muscarinic acetylcholine receptors, phenomena that may antagonize the potential benefit of cholinesterase inhibitors (Volpicelli-Daley et al. 2003a, 2003b). The goal of cholinesterase inhibition in humans is to prevent the degradation of acetylcholine once it is released from surviving cholinergic nerve terminals. The typical degree of AChE inhibition achievable with available drugs is only about 30% (Kuhl et al. 2000), which provides one explanation for their modest efficacy. However, because the same activity is essential for cholinergic function in the gut and in other organs receiving autonomic innervation, more complete inhibition would likely increase the side effects that already limit the dosing of cholinesterase inhibitors. In addition, cardiac and neuromuscular blockade are major concerns with more potent and irreversible drugs that inhibit acetylcholine breakdown. Although AChE inhibitors provide an important advance, they are limited by the above considerations. The development of compounds that bind directly to cholinergic receptors is an alternative approach to enhancing cholinergic transmission. Moreover, the discovery of families of mAChR (Bonner et al. 1987; Peralta et al. 1987) and nicotinic receptor (Sargent 1993) subtypes may enable the development of selective drugs to overcome many of the side effects associated with AChE inhibitors and nonselective agonists. Receptor subtypes often have opposing actions; therefore, targeting one subtype produces more robust effects (Bymaster et al. 1998; Farber et al. 1995). Most studies have focused on mAChRs, because this receptor family has better-defined roles in central cholinergic transmission and functions, such as learning and memory (Bartus et al. 1982; Coyle et al. 1983). The nicotinic receptors also play an important role in cognition and neurodegenerative disease (Romanelli et al. 2007). Thus, selective drugs targeted at receptor subtypes offer hope for better cholinergic-based therapies for AD and other disorders involving central cholinergic systems. The mAChR family consists of five distinct subtypes, M1–M5, encoded by different genes and all expressed in the brain. The M1, M2, and M4 receptors are the most abundant subtypes. Their precise roles in central cholinergic function and their potential for AD treatments remain uncertain (Levey 1996), but several lines of evidence suggest that M1 may be a key target. M1 is the most abundant receptor in the cortex and hippocampus; it is postsynaptic on pyramidal neurons and plays an important role in enhancing glutamatergic transmission via NMDA receptors (Marino et al. 1998). M1 also activates protein kinase pathways involved in the long-term changes in gene expression that underlie learning and memory (Berkeley et al. 2001). There is some loss of M1 receptor protein and high-affinity states involving coupling to G proteins (Flynn et al. 1991, 1995). M2 is the primary autoreceptor on cholinergic terminals in cortical structures, and it is also present on inhibitory interneurons. Loss of M2 receptors in AD probably involves both neuronal populations. M4, the most abundant receptor in the striatum, is a presynaptic heteroreceptor on commissural projections in cortex, suggesting that it is involved in the regulation of excitatory associational connections. Of interest, this subtype is increased in AD. Subtype-selective agonists and antagonists have been difficult to develop, but they remain promising. One of the first relatively selective M1 agonists, xanomeline, showed significant clinical efficacy in a double-blind multicenter study (Bodick et al. 1997). Some of the most remarkable benefits were in the reduction of agitation, delusions, and hallucinations, providing evidence that the cholinergic system plays an important role in behavior as well as in cognition. Subsequent studies of cholinesterase inhibitors have reinforced this idea (Cummings and Cole 2002) and have provided a rationale for long-term treatment and use of these agents in later stages of AD. In addition to their potential benefit in ameliorating symptoms, direct-acting muscarinic receptor agonists may also alter the course of the

disease. Several preclinical studies have established distinct roles of muscarinic receptor subtypes in regulating amyloidogenesis, and an M1 muscarinic agonist reduced both amyloid plaque and neurofibrillary tangle pathology in a transgenic mouse model of AD (Caccamo et al. 2006). In human studies, M1 agonist treatment reduced cerebrospinal fluid (CSF) amyloid levels (Hock et al. 2003). In addition, postmortem analysis of Lewy body dementia cases treated with cholinesterase inhibitors showed significantly less amyloid pathology than cases examined prior to the advent of these drugs (Ballard et al. 2007). While these studies suggest that cholinergic treatment has the potential to be disease modifying, the therapeutic potential of drugs selective for cholinergic receptor subtypes remains to be determined. Neurochemical alterations in serotonin, norepinephrine, and glutamate also have important therapeutic implications for AD. Serotonin plays a key role in mood and anxiety disorders, which commonly coexist with dementia in AD. Selective serotonin reuptake inhibitors are frequently used for these patients and have demonstrated efficacy. There is a loss of noradrenergic neurons in the locus coeruleus in AD, although the significance of this change and its implications for therapeutic intervention are only beginning to be systematically investigated. Preclinical studies have suggested that noradrenergic neurotransmission may have a role in disease modification. For example, locus coeruleus degeneration exacerbated amyloid pathology, behavioral deficits, and neuron loss in a transgenic mouse model of AD, suggesting that loss of noradrenergic neurotransmission may be a contributing factor in the development or progression of AD (Heneka et al. 2006). Drugs that modulate glutamatergic transmission also have potential utility for the cognitive and behavioral symptoms of AD. In addition, since excitotoxicity may play some role in the neurodegenerative process, such drugs could potentially be neuroprotective. Ampakines, a class of drugs that modulate amino-3-hydroxy5-methyl-4-isoxazole propionic acid (AMPA) subtypes of glutamate receptors, are under development. Memantine, a noncompetitive NMDA antagonist, is now approved for the treatment of AD in the United States. Although clinical trials of high-affinity NMDA antagonists have been hindered by serious side effects, memantine seems to be well tolerated. Recent clinical trials indicate a significant benefit of this drug in AD patients, particularly with respect to language and memory domains (Peskind et al. 2006; Pomara et al. 2007).

RISK FACTORS AND CLUES TO THE BIOLOGY OF ALZHEIMER'S DISEASE Aging is the biggest risk factor for AD, and the prevalence of AD doubles about every 5 years after age 65 years, increasing to about 40% by age 85 years. This relationship has contributed to speculations that AD is simply accelerated aging (rather than a disease) and that everyone would develop AD if they lived long enough. However, the risk may actually decline after age 90 years (Lautenschlager et al. 1996), indicating that AD is not an inevitable result of aging. Because age alone is insufficient to cause the disease, other risk factors must therefore interact with the aging process (Table 48–1). Of the many factors that have been examined, retrospective studies indicate that individuals with severe traumatic brain injury have a higher-than-expected incidence of AD pathology (Jellinger et al. 2001). Head injury also seems to interact with genetic predisposition (ApoE 4) to decrease the age at AD onset (Mayeux et al. 1995; Schofield et al. 1997). Down syndrome is another well-established risk factor. Virtually all Down syndrome patients who are older than 40 years of age exhibit the hallmark neuropathology of AD (Karlinsky 1986). However, clinically evident AD is less common. There is also an increased risk for mothers of children with Down syndrome (Schupf et al. 2001). TABLE 48–1. Risk factors for developing Alzheimer's disease (AD) Category

Factor

Influence on AD risk

Life events

Aging

Risk increases with increasing age

Early-life linguistic ability

Decreases risk

Traumatic brain injury

Increases risk

Category

Factor

Influence on AD risk

Genetics

Down syndrome

Greatly increases risk

ApoE 4

Increases risk

Female vs. male

Females have increased risk

Estrogen replacement

Sustained estrogen replacement may lower

Sex

risk Diet/medication

Vitamin/nutrient supplementation

Vitamins C and E may be protective

Nonsteroidal anti-inflammatory drug

Decreases risk

use

Cardiovascular risk

Statin use

Decreases risk

Hypercholesterolemia

Increases risk

Hypertension

Increases risk

Elevated plasma homocysteine

Increases risk

Diabetes mellitus

Increases risk

factors

Several studies suggest that education (D. A. Evans et al. 1997; Katzman 1993; Stern et al. 1994) and early cognitive and linguistic abilities (Snowdon et al. 1996; Whalley et al. 2000) correlate with decreased risk for AD. In many studies, a higher level of education is associated with a lower risk of developing AD (D. A. Evans et al. 1997; Katzman 1993; Stern et al. 1994). Participation in other activities that require cognitive ability is also associated with a lower risk of AD (Wilson et al. 2002). One possible explanation is that people who are more intelligent and healthy have a higher "cerebral reserve" and thus do not manifest signs of dementia until more brain tissue is damaged. In a longitudinal study of AD in a group of nuns, linguistic ability in early life strongly predicted cognitive abilities in old age (Snowdon et al. 1996). In addition, neuropathological analysis has documented significant correlations between low idea density in early-life autobiographies and neuropathological signs of AD (Riley et al. 2005). Similarly, in a Scottish study, lower performance on childhood school tests was associated with increased late-life dementia (Whalley et al. 2000). Despite obvious limitations in these types of correlational studies, the strength of the associations raises the intriguing possibility that developmental mechanisms or early education may play a role in the development of AD in late life. Epidemiological studies indicate that AD is more common in women, and initial reports suggested that postmenopausal estrogen replacement is associated with a lower incidence of AD. There is experimental evidence that estrogen may modify the production of A

peptide (Xu et al. 1998), linking

the epidemiological data with a potential biological mechanism. Additional studies of hormone replacement therapy have produced conflicting data. In the Women's Health Initiative Memory Study (WHIMS), both estrogen plus progestin and estrogen therapy alone were found to be associated with an increased risk of developing dementia (Shumaker et al. 2003, 2004). However, the Cache County Study found that hormone replacement therapy is associated with a lower risk of late-onset AD in a manner dependent on the duration of exposure. In this study, women taking hormone replacement therapy for more than 10 years showed the greatest reduction of AD risk (Zandi et al. 2002). The observed gender bias may reflect biological factors underlying disease susceptibility or, alternatively, the greater longevity of females (Hebert et al. 2001). Other gender-specific factors may exist, however. For example, the offspring of a father with AD have a 1.4-fold greater risk than if the mother was affected (Lautenschlager et al. 1996). Despite an increasing understanding of the interaction between hormones and the risk of dementia, the precise role of gender in AD pathogenesis remains to

be clarified. Epidemiological studies have revealed patterns of medication use associated with altered risk of AD, including exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). The magnitude of the reduced risk associated with NSAIDs, estrogen, or statins is similar, ranging from ~30% to 80%. As with any epidemiological study, a variety of biases are possible, and results do not imply a causal relationship. Nevertheless, several epidemiological investigations, including one large prospective population-based study, have found the relative risk of AD to be lower with long-term use of NSAIDs (in t' Veld et al. 2001). Thus far, only two small prospective clinical trials of NSAIDs have indicated a protective effect in AD. Notably, all trials involving selective cyclo-oxygenase-2 (COX-2) inhibitors have been negative, a finding that may shed light on the biological mechanism by which certain nonselective anti-inflammatory agents exert their protective effect (Aisen et al. 2003; McGeer and McGeer 2007). There is accumulating evidence that some NSAIDs modulate the activity of the -secretase enzyme independently of their effect on cyclo-oxygenase enzymes, and Phase II clinical trials have shown that the A 42-lowering drug R-flurbiprofen may have cognitive and behavioral benefits in AD. It is unclear whether NSAIDs will ultimately prove to be beneficial in AD, but because these medications have serious potential side effects, the evidence to date does not warrant recommendations for use as a primary treatment for AD. Epidemiological studies have also shown that statins are associated with a significantly lower relative risk of AD (Jick et al. 2000; Rockwood et al. 2002; Wolozin et al. 2000) and that the association seems specific, compared with the use of other lipid-lowering agents and cardiovascular drugs. Given that hypercholesterolemia is a potential risk factor for developing AD (Kivipelto et al. 2001; Notkola et al. 1998), the data linking statin use and decreased risk of AD strengthen the biological relationship between cholesterol homeostasis and AD. The results of additional research, including ongoing multicenter clinical trials, will ultimately determine the role for statins in the growing armamentarium of AD therapies. Taken together, these associations provide potential insights into the biology of AD. Specifically, they implicate hormones, inflammation, and cholesterol as relevant factors for further study in the pathogenesis of the disease. It has been postulated that several lifestyle factors, including dietary habits, physical activity, and leisure activities (Scarmeas et al. 2001), play a role in the development of AD. Dietary intake of several vitamins and nutrients has been studied. Subclinical deficiencies of vitamin B6, vitamin B12, and folate are associated with poorer cognitive function in the elderly, and AD patients tend to have lower levels of these vitamins (Clarke et al. 1998; H. X. Wang et al. 2001). These vitamins are essential cofactors in the generation of donor methyl groups, which in turn are necessary for the biosynthesis of numerous neural components, such as neurotransmitters and myelin. Therefore, mild defects in the methyl donor pathway might have subtle effects on neuronal function and viability. Alternatively (or additively), the deleterious effects of B vitamin or folate deficiency may be mediated by elevated homocysteine, a metabolite of the methyl donor pathway. Homocysteine causes vascular damage and has been linked to ischemic changes in the brain, as well as in other organs. Beginning several years before diagnosis, patients with AD have elevated homocysteine levels (Seshadri et al. 2002), regardless of vitamin B12/folate status. This observation adds to the growing connection between vascular disease and AD (Kivipelto et al. 2001). Vitamin D deficiency, a common disorder among the elderly, has been recently linked with poor cognitive performance in participants of a study of memory and aging (Wilkins et al. 2006). The antioxidant vitamins C and E have been associated with reduced risk of AD (Engelhart et al. 2002). Despite an initial finding that vitamin E slows disease progression in patients with AD (Sano et al. 1997), another study demonstrated that vitamin E had no apparent effect on progression from MCI to AD, even among high-risk subjects (ApoE 4 positive) (Petersen et al. 2005). However, major differences in the study populations may have influenced the outcomes. AD has also been linked to dietary fat intake—namely, with higher levels of total and saturated fat and cholesterol and with lower levels of fish oils, which contain polyunsaturated fats.

While it is not clear exactly how these dietary factors impact the development and progression of AD, if the associations are confirmed in clinical trials, which are currently under way, specific nutritional interventions may be warranted as a means of preventing or slowing the onset of disease. The effects of ethanol and smoking remain unclear. Heavy ethanol use produces a characteristic dementia syndrome that shares some features with AD. Of interest, several studies have found that moderate consumption of red wine was associated with a decreased risk of AD (Luchsinger et al. 2004; Orgogozo et al. 1997). Moderate ethanol intake has been linked to improved cardiovascular health, which may account for this effect. Conflicting evidence exists regarding the effects of smoking. Some studies have found an increased incidence of AD in smokers, which could be caused by the well-established deleterious effects of smoking on cardiovascular health. Other studies have observed that smokers have a lower risk of AD. Although surprising, this latter observation might be attributable to the stimulatory effects of nicotine at nicotinic acetylcholine receptors. In addition, decreased leisure activity in midlife is a risk factor for AD (Scarmeas et al. 2001). Although people who remain active may be enhancing their cerebral reserve, it is also possible that decreased leisure activity is an early sign of subclinical cognitive impairment.

GENETICS AD is a complex genetic disease. Multiple genes are associated with the disease, with mutations in some genes linked to fully penetrant cases with autosomal dominant inheritance and polymorphisms in other genes linked to disease risk. To date, four genes—APP, PSEN1, PSEN2, and APOE—have been consistently linked to AD in studies around the world (Blacker and Tanzi 1998; Selkoe and Podlisny 2002). Many other genes have been associated with AD in only a few studies and/or remain controversial, and these genes will not be discussed here unless otherwise specified. It is clear that several other genes with strong links to AD remain to be identified. The diversity of genes and other factors result in two major presentations of illness: familial and sporadic. Less than 5% of all cases of AD are familial—mostly with an early onset (i.e., younger than 65 years)—and they seem to follow an autosomal dominant mode of inheritance. In these families, mutations in three distinct genes—APP on chromosome 21, PSEN1 on chromosome 14, and PSEN2 on chromosome 1—have been linked to the affected individuals. Although important for understanding the biology of AD, APP mutations are extremely rare. PSEN1 mutations account for the majority of the familial cases with early-onset disease. Although APP and PSEN1 mutations are linked exclusively to families with early onset, some families with PSEN2 mutations exhibit symptom onset in their late 60s or 70s, suggesting that the pathogenic mechanisms are less severe. PSEN2 mutations are mostly associated with descendants of Volga Germans. Collectively, APP, PSEN1, and PSEN2 mutations account for most families with autosomal dominant AD, but for at least 30% of familial cases, other responsible genes remain to be elucidated (Liddell et al. 2001). The vast majority of AD cases are termed sporadic, in that they do not have a definite familial clustering or linkage to a known disease-causing mutation. However, in many of these cases, careful family histories suggest that relatives have been affected, indicating contributions from genetic factors. For example, about one-third of sporadic AD cases are associated with a positive family history (Rosen et al. 2007). Only one gene, APOE, has been reproducibly associated with AD risk in virtually all populations and studies. The APOE genotype is not causative (as in the case of the autosomal dominant APP, PSEN1, and PSEN2 mutations), but inheritance of different alleles is significantly associated with a modified risk of AD. APOE exists as three allelic variants ( 2, 3, and 4), and inheritance of the APOE4 allele confers a greater risk of AD. Individuals who are homozygous for APOE4 have a substantially greater risk of developing AD than individuals with no APOE4 alleles (APOE 2/2, 2/3, or 3/3 genotype), and individuals with a single APOE4 allele (APOE 2/4 or 3/4) have an intermediate risk (Chartier-Harlin et al. 1994; Corder et al. 1993; Saunders et al. 1993). The age at

disease onset is lower among AD patients who possess an APOE4 allele (Corder et al. 1993; Tsai et al. 1994). These genetic associations strongly suggest that the APOE genotype plays an important contributing role in the development of sporadic AD. In addition to APOE4, there are likely to be many other genes that contribute to AD susceptibility, albeit with lesser influence on risk. It has been difficult to identify these other genes because of the smaller degree of risk associated with them. However, numerous genetic association studies have examined many other candidate genes for the risk of sporadic or late-onset AD, and some positive associations have been reported. Polymorphisms in the SORL1 gene, which encodes the neuronal receptor LR11/sorLA, have recently been associated with AD in multiple populations (J. H. Lee et al. 2007; Rogaeva et al. 2007). Given the strong biological evidence for the role of this receptor in AD pathogenesis (Andersen et al. 2005; Offe et al. 2006; Scherzer et al. 2004), further research is warranted to elucidate the pathogenic mechanisms of genetic variants of SORL1. Interest in genes with potential biological plausibility has increased, particularly those linked to mechanisms such as inflammation (interleukin 1 [IL-1] and

-macroglobulin) and amyloidogenesis (nicastrin, insulin-

degrading enzyme, and neprilysin). However, almost all of these studies have been underpowered, and the results have not been reliably confirmed in multiple studies using large independent populations. Nonetheless, abundant evidence suggests that several other genes contribute to the risk of sporadic AD. Undoubtedly, additional genetic factors will be identified in the near future, providing new clues to the pathogenesis of the disease. As knowledge of genetic associations in AD continues to grow, it will be important to integrate this information in a systematic manner. A recent meta-analysis has catalogued all published studies of genetic associations in AD and has made this information publicly available in a continuously updated online forum (Bertram et al. 2007). Coordinated efforts such as this will undoubtedly catalyze rapid progress in the understanding of this disease as well as treatment strategies.

THEORIES OF ETIOPATHOGENESIS The cause of most cases of AD remains unknown. As discussed above, autosomal dominant single-gene mutations in APP, PSEN1, and PSEN2 are sufficient to cause disease in a small percentage of cases, but even in these familial cases, the relationship between mutant genes and neurodegeneration is not completely understood. Postmortem observations in brains with AD, including changes in neurotransmitter systems, accumulation of amyloid plaques, intraneuronal neurofibrillary tangles, inflammatory changes, increased oxidative stress, mitochondrial dysfunction, and reactivation of cell cycle–related gene products, have spawned numerous theories regarding the etiopathogenesis of AD. It is likely that many of these observations reflect different aspects of disease initiation and progression, and one of the key goals in AD research is to develop a unifying theory that accurately identifies the triggering event(s) and explains the relationship between apparently distinct elements of disease biology and neuropathology. Achievement of this daunting task will provide a foundation for developing rational therapeutic approaches for treating patients with AD at different stages of illness. Although a complete discussion of all of the theories of the pathogenesis of AD is beyond the scope of this chapter, the amyloid cascade hypothesis has gained increasing support in recent years and merits more detailed discussion. It should be understood that whereas this is the theory currently favored by many investigators, the hypothesis is not proven. Indeed, evolution and refinement of the hypothesis are quite likely. Nevertheless, it does have considerable value in establishing a rationale for developing and testing potential therapies. In addition to the amyloid hypothesis, other theories have particular relevance for current clinical practice. The involvement of cholinergic systems was discussed earlier, and the roles of inflammation and oxidative injury in the pathogenesis of AD are discussed briefly below.

Amyloid Cascade Hypothesis

Since its identification as the primary component of senile plaques in 1984, the A precursor molecule, amyloid-

peptide and its

precursor protein (APP), have been the targets of intense research

interest. The importance of these molecules in the pathogenesis of AD is supported by neuropathological observations and a variety of experimental data. As noted previously, amyloidcontaining senile plaques are invariably present in the brains of patients with AD. More recently, characterization of genes associated with early-onset familial AD (APP, PSEN1, and PSEN2) and late-onset sporadic AD (APOE) has strengthened the notion that abnormal metabolism of A plays a central role in disease pathogenesis. The amyloid hypothesis of AD proposes that amyloid production and accumulation play the central role in initiating a cascade of events that leads to cellular dysfunction, neuron loss, and eventual clinical disease manifestations. Downstream effects may involve cytoskeletal dysfunction, inflammation, oxidative injury, neuronal apoptosis, and other mechanisms that result in neurodegeneration, but a critical tenet of the hypothesis is that abnormal A

metabolism represents the principal triggering

event. An important corollary to this hypothesis is that interventions that reduce the production and deposition of amyloid may provide an effective means of ameliorating symptoms, halting progression, and possibly preventing disease. The amyloid cascade hypothesis has become widely accepted, and most current efforts to develop new therapies for AD directly or indirectly target this mechanism (Hardy and Selkoe 2002).

Mechanisms of Amyloidogenesis Production of A from APP is regulated by three enzymes ( -, Initial cleavage by

-, and -secretases) (Figure 48–3).

-secretase precludes A production by cleaving APP within the A domain.

Alternatively, cleavage by

-secretase, followed by -secretase activity, produces A . Although the

predominant A species is a peptide that is 40 amino acids in length (A 40), a slightly longer form (42 amino acids [A 42]) seems to have particular pathogenic significance. Because of its biophysical properties, A 42 is substantially more fibrillogenic than A 40 (Barrow and Zagorski 1991; Burdick et al. 1992; Knauer et al. 1992), and it is believed that extracellular aggregation of A 42 provides a nidus on which additional A deposition and plaque formation can occur. Pathological examination of brains with AD suggests that A 42 is present at early stages of amyloid deposition in diffuse plaques, whereas A 40 is prominent in mature neuritic plaques (Iwatsubo et al. 1994). The physiological significance of A 42 was highlighted by the recognition that pathogenic mutations in PSEN1 and PSEN2 invariably increase the production of A 42, relative to A 40 (Borchelt et al. 1996; Citron et al. 1997; Duff et al. 1996; Scheuner et al. 1996; Tomita et al. 1997). To date, more than 125 distinct mutations in PSEN1 and PSEN2 have been reported in human pedigrees associated with autosomal dominant familial AD. All of these mutations enhance the production of the longer form of the A peptide, suggesting that overproduction of A 42 plays an important role in the pathogenesis of aggressive early-onset forms of AD. FIGURE 48–3. Proteolytic cleavage of amyloid precursor protein (APP) and amyloidogenesis.

The APP molecule is metabolized via alternate pathways with distinct cleavages. A nonamyloidogenic pathway involves an -secretase cleavage (1) within the A peptide sequence (lightly shaded), shedding an N-terminal ectodomain. Degradation of the membrane-bound C-terminus does not produce A , because part of the peptide sequence has been cleaved. In contrast, A is produced via the amyloidogenic pathway involving sequential cleavages by

-secretase (2) and -secretase (3). Presenilin is a necessary component for -secretase activity.

The final -secretase cleavage releases A peptides of predominantly 40–42 amino acids. The longer 42-residue peptide is more toxic and hydrophobic, and it seeds aggregation into extracellular deposits of amyloid plaques. BACE = beta-site APP cleaving enzyme. Intense research efforts have yielded rapid advances in our understanding of the mechanisms mediating A

production. The enzyme responsible for

-secretase cleavage of APP has been identified

(Hussain et al. 1999; Vassar et al. 1999; Yan et al. 1999). Beta-site APP cleaving enzyme (BACE) represents the primary

-secretase activity in brain tissue, and initial results from BACE knockout mice

suggested that disruption of BACE expression could drastically reduce brain A

production without

causing significant developmental problems or toxicity in adult animals (Cai et al. 2001; Luo et al. 2001; Roberds et al. 2001). However, a recent study has documented that deletion of BACE in mice results in hypomyelination of peripheral nerves (Willem et al. 2006), raising concerns about potential side effects of BACE inhibitors. Nevertheless, pharmacological inhibitors of BACE are under active development and may represent a viable therapeutic approach to AD. It is important to note that BACE is a member of a conserved family of membrane-bound aspartic proteases of unknown functions (Lin et al. 2000; Turner et al. 2002). The existence of these related enzymes poses uncertain risks, and the potential usefulness of

-secretase inhibitors will depend greatly on the ability to design

pharmacological agents capable of specifically inhibiting brain

-secretase activity without affecting

the biological activity of related enzymes. The discovery of -secretase as a complex of multiple proteins, including presenilin, represents a critical advance in the understanding of APP processing and has presented an additional avenue of therapeutic intervention for AD (Edbauer et al. 2003; Kimberly et al. 2003). As discussed above, pathogenic mutations in PSEN1 and PSEN2 alter -secretase cleavage of APP, resulting in enhanced production of the longer (42-amino-acid) A . The precise mechanism by which mutations alter APP cleavage remains unclear, but presenilin appears to be involved in the active site of the enzyme.

Pivotal observations in PSEN1 knockout mice revealed dramatic reduction in A

production (De

Strooper et al. 1998). Subsequently, it was recognized that two highly conserved aspartate residues in PS1 and PS2 are critical for -secretase activity, suggesting the possibility that presenilins might possess intrinsic protease activity (Wolfe et al. 1999). In addition, transition-state enzyme inhibitors modeled on the -secretase active site seem to physically interact with presenilin (Esler et al. 2000; Y. M. Li et al. 2000; Shearman et al. 2000). The structure of presenilins, which contain multiple membrane-spanning domains, is distinctly unusual for aspartyl proteases. The -secretase complex is tightly regulated and appears to require coordinated expression for normal maturation and stability of the components (Periz and Fortini 2004). Presenilins appear to play an essential role in the final cleavage step that produces A , presenting another potential target for new therapeutic agents. Unlike BACE, however, loss of PSEN1 has clearly detrimental effects in animal models. Targeted gene disruption and loss of PSEN1 in knockout mice result in a late embryonic lethal phenotype associated with severe developmental defects (Shen et al. 1997). These effects arise from an unexpected link between -secretase activity and Notch, a receptor that plays a critical role in cell fate decisions during development. In addition to APP, presenilin and -secretase regulate the proteolytic processing of a growing list of important molecules, including Notch, erb4, the epidermal growth factor (EGF) receptor, the p75NTR low-affinity neurotrophin receptor, and many others (De Strooper et al. 1999; Jung et al. 2003; H. J. Lee et al. 2002; Struhl and Greenwald 1999; Weihofen et al. 2002; Ye et al. 1999). These additional functions present a serious challenge for developing -secretase inhibitors as potential therapeutic agents for AD. Nevertheless, -secretase inhibitors are still undergoing clinical trials, and improved understanding of presenilin function may reveal effective approaches for disrupting -secretase activity in a brain- and APP-specific manner.

Mechanisms of Amyloid-Beta Peptide Clearance A

production from APP has been studied more intensively than perhaps any other process in protein

biochemistry. The other half of the equation, the clearance of A , has received less attention but may be equally important in regulating A . The mechanisms responsible for amyloid degradation and clearance are not fully understood, but several metallopeptidases, including the insulin-degrading enzyme (IDE), are known to have A -degrading activity (Kurochkin 2001; Qiu et al. 1998). Of interest, the IDE gene is present on chromosome 10q, near a region of linkage with late-onset AD. While results from genetic analyses have varied (Abraham et al. 2001; Bertram et al. 2000), current findings support both genetic and functional links between IDE and AD pathogenesis (Bertram et al. 2007; Kim et al. 2007). Administration of thiorphan, a potent inhibitor of the neprilysin family of zinc metalloproteinases, increased A

deposition in rat brain (Carson and Turner 2002; Iwata et al. 2000).

Abnormalities in endosomal–lysosomal function may also be relevant to A -degrading activity in neurons. These changes are among the earliest neuropathological changes present in AD brains, visible in presymptomatic individuals at high risk of developing AD, and they appear to be fundamentally linked to APP expression (Cataldo et al. 2000, 2003; Troncoso et al. 1998). Although genetic evidence from familial AD pedigrees associated with APP, PSEN1, and PSEN2 mutations identifies abnormal production of A

as a pivotal mechanism in disease pathogenesis, abnormal

degradation and clearance of amyloid may be an equally important mechanism in sporadic cases of AD. As noted above, the APOE gene exists in three different allelic forms ( 2, 3, and 4), and the 4 allele has been shown to be an important risk factor for sporadic late-onset AD. Studies of this gene have revealed a number of potential links to amyloidogenesis. The apoE protein is present in amyloid deposits, and plaque burden is increased in individuals with AD possessing 4 alleles (Gearing et al. 1995; Rebeck et al. 1993; Schmechel et al. 1993). One possible explanation for this may be that the apoE4 protein isoform enhances the deposition of fibrillar A

peptides (Castano et al. 1995; K. C.

Evans et al. 1995; Wisniewski et al. 1994). Interaction between A and apoE4 may promote extracellular amyloid deposition and trigger the cascade of events leading to the development of AD (Wisniewski et al. 1994). An alternative means by which apoE may influence amyloidogenesis involves a brain apoE receptor called low-density lipoprotein (LDL) receptor–related protein (LRP) (Kounnas et al. 1995). This receptor mediates internalization of apoE-containing lipid particles, and through its interaction with

2-macroglobulin,

LRP can also mediate clearance of A

(Kang et al. 2000; Shibata et

al. 2000). The LDL- and sortilin-related receptor LR11/SorLA has recently been shown to modulate amyloidogenesis, presumably by regulating APP traffic through endosomal compartments (Andersen et al. 2005; Offe et al. 2006). Since LR11/SorLA is also an apoE receptor, this represents yet another possible mechanism by which apoE may influence AD development and progression. As noted above, variants in SORL1, the gene that encodes LR11/SorLA, are associated with late-onset AD in multiple populations (J. H. Lee et al. 2007; Rogaeva et al. 2007). Further investigation is warranted to fully determine the cell biological significance of this receptor in normal neuronal function and disease states, but its identification represents a major advance in understanding the basis of late-onset AD, the most common form of the illness. The appearance of dense deposits of amyloid in senile plaques produces the impression that they are static lesions. However, evidence from transgenic mouse models of AD suggests that extracellular amyloid may be much more dynamic than previously believed. Examination of plaque formation in live animals indicates that plaques can form rapidly, disrupting the architecture of dendrites in their vicinity. Remarkably, administration of anti-A

antibodies to plaque-forming mice results in rapid

clearance of amyloid plaques and restoration of normal dendritic morphology (Lombardo et al. 2003; Spires et al. 2005). In addition, vaccination to induce production of anti-A antibodies has shown a dramatic ability to prevent or reverse the accumulation of amyloid plaques in animal models (Morgan et al. 2000). These observations suggest that the induction of immunity to A may be a viable treatment for AD. The first clinical trial employing this approach was halted because of safety concerns and the development of encephalitis in some patients receiving the A vaccine, but the notion of promoting amyloid clearance as a potential treatment strategy remains viable. Of particular note, participants in the original trial who were good antibody responders had better outcomes than placebo-treated patients in cognitive as well as pathological assessments (Fox et al. 2005; Gilman et al. 2005). Furthermore, cognitive improvement was correlated with antibody titer, suggesting a direct relationship between anti-A anti-A

immune response and favorable clinical outcome. Several humanized

monoclonal antibodies are currently being tested, and vaccine and passive immunization

strategies designed to minimize adverse side effects are under way in early phases of human clinical trials.

Inflammation and Alzheimer's Disease Inflammation is a key component of AD (Eikelenboom et al. 2000; McGeer and McGeer 2001a; McGeer et al. 2006). In fact, the presence of an inflammatory response is a key feature that distinguishes the pathological neuritic plaque from the benign diffuse plaque. Neuritic plaques are surrounded by activated astrocytes and microglia, the resident immune cells of the central nervous system. Activated complement, including membrane attack complexes, is prominent on damaged neurons and dystrophic neurites. A classical antibody-mediated pathway or an alternative antibody-independent pathway can activate complement, but brains from patients with AD do not show increased antibodies or T cells, indicating that a specific immune response is not responsible for complement activation. The most likely trigger for complement activation in AD is A itself. Several inflammatory proteins are also elevated in AD. These include C-reactive protein, amyloid P,

2-macroglobulin,

intercellular

adhesion molecule–1 (ICAM-1), and proinflammatory cytokines, such as IL-1, interleukin 6 (IL-6), and tumor necrosis factor–

(TNF- ). Many of these proteins can influence APP expression and processing,

and many associate with A IL-1, TNF- , and

in plaques. Genetic polymorphisms in proinflammatory genes, including

2-macroglobulin, have been associated (albeit inconsistently) with an increased

likelihood of developing AD or an earlier age at disease onset (McGeer and McGeer 2001b). The role of anti-inflammatory agents in the treatment of AD remains unclear. In numerous epidemiological studies, the use of NSAIDs was suggested to prevent or delay AD (in t' Veld et al. 2001; Stewart et al. 1997). However, randomized trials with NSAIDs (as well as with other anti-inflammatory agents, such as COX-2 inhibitors and steroids) have shown little benefit. Because the strongest association of NSAIDs in epidemiological studies is with drug exposure that is at least 2–3 years before disease onset, it is possible that anti-inflammatory agents may have a protective role only at earlier preclinical stages of AD. In addition, the lack of positive outcomes in prospective anti-inflammatory drug trials may also reflect inappropriate choice of drugs or suboptimal dosages. Numerous biochemical and transgenic mouse model studies now support the hypothesis that some, but not all, NSAIDs lower A 42 by directly modulating the activity of -secretase in a manner independent of their action on COX-1 and COX-2 (Eriksen et al. 2003; Weggen et al. 2001, 2003). Considering this, it may be important to consider alternative mechanisms other than COX inhibition (such as -secretase regulation) when selecting anti-inflammatory drugs for human AD trials.

Aging, Oxidative Injury, and Mitochondrial Dysfunction Oxidative injury is caused by the reaction of free radicals with cellular components. The major source of oxygen-containing free radicals is incomplete reduction of oxygen by the mitochondrial electron transport chain. Oxygen free radicals are highly reactive and can damage cellular lipids, proteins, and DNA. The brain is particularly susceptible to oxidative injury for several reasons: high oxygen consumption; increased levels of transition metals, which act as catalysts for free radical generation; low levels of endogenous antioxidants; and an abundance of polyunsaturated lipids, which are more prone to free radical modification. Extensive evidence supports a role for oxidative damage in AD. Numerous studies have shown higher levels of oxidized lipids, proteins, and DNA in brains from AD patients. Of significance, oxidative damage is highest in brain areas that are most heavily affected in AD (e.g., neocortex and hippocampus) and lowest in areas that are spared (e.g., cerebellum) (Praticò 2002). Neurofibrillary tangles and amyloid plaques show signs of oxidative injury. Oxidative damage may play a central role in the formation of these pathological hallmarks by promoting protein cross-linking and aggregation. The cytotoxic effect of A is mediated by reactive oxygen species; antioxidants can attenuate amyloidinduced neuronal cell death in vitro (Markesbery 1999). Oxidative injury also increases with normal aging, providing a possible explanation for the association between aging and AD. Is oxidative stress a key player in disease etiology, or is it merely a secondary effect of neuronal damage? Increasing evidence implies that oxidative damage may be an early event (Beal 2005). In AD brains, healthy neurons in vulnerable brain areas have increased amounts of 8-hydroxy-guanosine (8-OHG), a marker of recent oxidative damage (Smith et al. 2000). In contrast, neurons with neurofibrillary tangles have low levels of 8-OHG, implying that oxidative injury precedes tangle formation. In transgenic mouse models of AD, mice expressing a mutant form of APP show increased lipid peroxidation months before amyloid deposits are first detected (Praticò et al. 2001). Strikingly, loss of one allele of the manganese superoxide dismutase (MnSOD) gene significantly increases amyloid plaque deposition in APP transgenic mice (F. Li et al. 2004). Potential sources of early oxidative stress include mitochondrial dysfunction and changes in cytoplasmic transition metals like copper and zinc. The role of oxidative stress in AD has implications for both disease diagnosis and treatment. Increased levels of oxidized lipid metabolites are detectable in the CSF, serum, and urine of patients with AD. Levels of one metabolite, an isomer of prostaglandin F2, are elevated in the CSF of patients with mild cognitive impairment, a condition that progresses to AD in 50% of cases (Praticò et al. 2002). Thus, detection of increased oxidative stress may be useful for the diagnosis of existing or future AD.

Antioxidants may also play an important role in AD therapy. Observations from the Cache County Study Group have indicated reduced risk of AD among participants taking vitamin C and E supplements, and better cognitive performance was noted among participants who reported a diet rich in antioxidants (Wengreen et al. 2007; Zandi et al. 2004). However, data from controlled clinical trials have been mixed. The antioxidants vitamin E and selegiline have been shown to slow disease progression by 6–12 months in patients with moderate AD (Sano et al. 1997). However, another recent trial found no benefit from vitamin E in preventing the development of AD in patients with mild cognitive impairment (Petersen et al. 2005). Additional trials with more potent antioxidants are also in progress.

FUTURE DIRECTIONS Although much progress has been made toward understanding the biological basis of AD, it is clear that further advances are required to identify individuals at risk and develop effective treatments to prevent or reverse disease progression. As is the case with other neurodegenerative diseases, early detection is paramount to the success of treatment of AD. In the past 5 years, exciting progress has been made in the development of molecular probes and imaging techniques to monitor the development and progression of AD neuropathology in living human subjects. As these technologies improve, they will permit earlier and more accurate diagnosis of AD and enable scientists and clinicians to evaluate the efficacy of treatments. The identification of biomarkers specific for AD will aid tremendously in the development of screening tools that can be used efficiently to detect the early stages of AD in the general population. It is also becoming clear that AD has a substantial genetic component (distinct from the small percentage of "familial" AD cases that are attributable to known genes), and the elucidation of new AD-associated genes will certainly improve the ability of the medical community to counsel and treat those at increased risk of developing the disease. The treatments for AD are evolving from a strategy of neurotransmitter replacement (via inhibition of AChE) to therapies that target discrete molecular events in the disease pathogenesis. Ongoing research in A

immunotherapy and clearance, neuroprotective and antioxidant agents, and

compounds designed to modulate endogenous signaling pathways promises to revolutionize the way AD is approached as an illness. Consequently, it can be expected that the results of AD therapies will soon move beyond modest amelioration of symptoms, providing tangible improvements in cognitive function, memory formation and retrieval, and interpersonal behavior. Finally, the pace of basic science research into AD continues to gain momentum. The accumulation of knowledge of the pathophysiological basis of AD will serve to guide future diagnostic and treatment modalities, and the importance of continued investigation cannot be overstated.

CONCLUSION Since Alzheimer's observations, more than 100 years ago, of the pathological hallmarks of the disease that would later bear his name, tremendous progress has been made in the many areas reviewed in this chapter. Remarkably, the pace of discovery into the biological basis of AD continues to accelerate. Inevitably, perspectives on the findings presented here will change as new discoveries are made. Exciting progress can be anticipated on several fronts. Genes at several chromosomal loci linked to AD will likely be identified in the near future. The study of the biology of the gene products will yield insights into the basic biological processes at play in the disease. The role of diet and environmental factors in AD will continue to evolve, and the roles of gene–environment interactions will follow. Existing theories of etiopathogenesis undoubtedly will be modified, and new theories will arise. We can also safely anticipate that the improved understanding of the biology of AD will have a huge impact on clinical practice. New insights into the biology of AD will help in the identification of biomarkers and in the development of novel strategies to aid in early diagnosis and guide therapy. The neuropharmacology for this disease will continue to shift from an approach based on simple

neurotransmitter replacement to one that capitalizes on the multiplicity of receptors and signaling pathways to develop more effective and better-tolerated medications to ameliorate symptoms. Moreover, the neuropharmacology will evolve together with the knowledge of etiopathogenesis to focus on new disease-modifying therapies.

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Ashley P. Kennedy, Clinton D. Kilts: Chapter 49. Neurobiology of Substance Abuse and Addiction, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.433008. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 49. Neurobiology of Substance Abuse and Addiction NEUROBIOLOGY OF SUBSTANCE ABUSE AND ADDICTION: INTRODUCTION Drug addiction is characterized by pathological motivation for drug-seeking and -use behaviors associated with the inability to inhibit such behaviors in spite of their clear adverse consequences (Kalivas and Volkow 2005). These features are clinically operationalized as a diagnosis of drug dependence based on an individual's fulfilling at least three of seven criteria defined by DSM-IV-TR (American Psychiatric Association 2000). The authors conform to the position (O'Brien et al. 2006) that drug addiction rather than dependence is more appropriate in referring to this maladaptive behavioral disorder and refer to drug dependence only when referring to clinical populations defined by DSM-IV-TR criteria. Drug addiction represents a major public health concern due to its high population prevalence, associated suffering and disability, and limited efficacy of extant therapies to promote recovery and relapse prevention. Understanding the underlying neurobiology of drug abuse and addiction offers the best promise to control drug addiction by identifying the bases of risk for addiction and targeting intervention strategies, uncoupling relapse from its precipitants, and minimizing the personal and social burden of addiction. This chapter represents a critical review of the current state of this understanding and a synthesis of knowledge into present and future directives for managing drug abuse and addiction. The treatment here of this topic is not meant to be comprehensive, but rather focuses on the authors' prioritization of those scientific areas of discovery that are perceived to be most relevant to curbing drug addiction. Attempts have been made to direct interested readers to more exhaustive treatments of less prioritized areas of addiction research findings. Using a theoretical model of the addiction process (Figure 49–1), this review focuses on the neurobiological events that underlie the transition from initial drug use to addiction, the events that maintain its enduring nature, and the events that underlie the immense socioeconomic costs of being drug addicted. This stage model is introduced, and several examples of population stratifying factors that alter a simple neurobiological explanation are discussed. Next, the major tools of neurobiological investigation of the addiction process are discussed. The neurobiology of the acquisition/transition stage of the addiction process is then discussed, as well as its modulation by genetic, environmental, and neurodevelopmental factors. A major section of this chapter deals with the burgeoning neurobiology of the chronically relapsing nature of drug addiction and focuses on contrasting the three major precipitants of relapse. This section is followed by a discussion of the little-studied neurobiology of the immense socioeconomic costs of end-stage drug addiction and of the relapse prevention and recovery goals of addiction therapies. Finally, a closing, brief discussion of perceived future directions for addiction neuroscience research is provided. FIGURE 49–1. Theoretical model of the causes and consequences of drug addiction.

A three-stage model is proposed that entails the addiction process from initial drug use, the transition to chronic drug abuse and addiction, the chronically relapsing nature of addiction, and the social and personal costs of end-stage addiction. The roles of learning, memory, reward sensitivity, and emotion regulation are highlighted. Factors that positively and negatively modulate the addiction acquisition stage are shown. Psychosocial factors include the influence of peers, family, cultural variables, social and religious beliefs, socioeconomic status, drug attitudes, and the illicit versus licit nature of the drug of abuse. Genetic factors include allelic and haplotypic variation for genes regulating cognitive functions, drug pharmacokinetics and pharmacodynamics, and personality traits. Neurodevelopmental factors include risks posed by the adolescent period and by childhood maltreatment. Brain anatomical and neurotransmitter substrates are proposed for the different stages of the addiction process. CRF = corticotropin-releasing factor; OFC = orbitofrontal cortex; SES = socioeconomic status.

THE DRUG ADDICTION PROCESS The organization of this discussion of the neurobiology of drug abuse and addiction is based on a now-common view of addiction as a multistage process (see Figure 49–1). This theoretical framework involves an addiction process that extends from initial drug use to the long-term consequences of end-stage addiction and focuses on the three stages of acquisition of the addicted state, its maintenance as a chronically relapsing state, and the long-term personal and social sequelae or consequences of end-stage drug addiction. In this model, drug abuse acquisition and subsequent addiction are mediated by a transition of drug incentives from reinforcing to habit-based effects associated with altered reward sensitivity, which is positively and negatively modulated by multiple factors, and mediated by maladaptive alterations in patterns of neural activity in striatal and frontal cortical areas and their modes of functional connectivity. In this model, the chronically relapsing nature of the addicted state is maintained by pathological motivations for drug-related behaviors unchecked by a diminished behavioral control that are precipitated by conditioned drug cues, stress, and the drug itself, as well as drug motivation related to a wish to relieve aversive drug withdrawal states. The concept of drug addiction as a disorder of too much gas related to the drug-seeking and -use behaviors associated with too little brakes to stop such behavior is an increasingly used analogy. While less studied as a component of the addiction process, the neurobiology of the social and personal expression of drug addiction is considered here, as these factors underlie the immense socioeconomic costs of addiction. The neurobiology of the drug addiction process is complex and includes numerous population stratifying factors. Noteworthy among these are differences due to the sex of the individuals and their racial and ethnic backgrounds. Although it is beyond the scope of this discussion to treat these factors in detail, we offer the following, as any discussion of the neurobiology of drug abuse and addiction is incomplete without considering these important variables.

Sex Differences in the Addiction Process There are prominent differences between the sexes in the clinical presentation and neurobiology of drug addiction. While such differences are often described as gender differences, we adhere to their distinction as being based on the categorical distinction between men and

women rather than the gender dimension of masculine and feminine characteristics. Whereas drug abuse and addiction are problems often attributed to men, and males have been the focus of the majority of drug abuse research, women are also clearly affected. However, significant sex differences are apparent in the patterns of drug abuse and addiction. It has been suggested that sex differences in behavioral responses to drugs render women more susceptible to drug addiction than men (Lynch et al. 2002; Quiñones-Jenab 2006). Cocaine-dependent men and women display differing clinical characteristics in that women are more likely to have an earlier age at onset of cocaine use than men, women tend to use more cocaine on more days in a given month and take less time to become addicted following initial drug use compared with men, and women enter treatment earlier and present a greater severity of abuse when admitted to treatment programs (Griffin et al. 1989; Kosten et al. 1993; R. D. Weiss et al. 1997). Cocaine-dependent women also demonstrate greater depressive symptomatology and severity of family/social problems, while men are more likely to have antisocial personality disorders (Dudish and Hatsukami 1996; Elman et al. 2001; Griffin et al. 1989; Kosten et al. 1993; R. D. Weiss et al. 1997). Although clinical studies imply that cocaine-dependent women are more negatively affected by cocaine than are men, it has been demonstrated that women relative to men have better treatment outcomes in remaining cocaine abstinent at 6-month follow-up (Kosten et al. 1993; R. D. Weiss et al. 1997). McKay et al. (1996) also determined that women are more likely to seek help after relapsing, whereas men engage in self-justification after relapsing. Differences between the sexes in the neurobiology of relapse to drug seeking and use behaviors are increasingly apparent. Cocainedependent men and women activate different regions of the brain when exposed to drug- and stress-related cues. Clinical research studies have demonstrated that women compared to men have higher levels of drug craving when exposed to drug cues (Elman et al. 2001; Robbins et al. 1999). Women and men exhibit different patterns of neural activation in response to conditioned cocaine cues, which suggests that drug cue–induced relapse involves differing neural pathways in men and women (Kilts et al. 2001, 2004). Cocaine craving in women was associated with less activation of the amygdala, insula, ventral cingulate cortex, and orbitofrontal cortex and greater activation of the anterior cingulate cortex compared with men. Cocaine-dependent women, compared to their male counterparts, showed greater stressinduced activation of the inferior frontal cortex, left insula, dorsal anterior cingulate cortex, and right posterior cingulate cortex (C. S. Li et al. 2005). These results are consistent with the contention that women exhibit less cocaine addiction–related pathology of the frontal cortex than do men (Chang et al. 1999; Levin et al. 1994).

Racial and Ethnic Differences in the Addiction Process Racial and ethnic differences in socioeconomic status and cultural acceptance contribute to a differing exposure and vulnerability to a host of social problems, with one of the most problematic being drug abuse and addiction. For some drug addictions, the personal and social costs of drug addiction are disproportionately greater for blacks and Hispanics relative to their white counterparts (Wallace 1999). For example, African Americans and Hispanics represent the majority of arrests and incarceration for drug-related crimes in the United States (King and Mauer 2002). Stratifying factors such as allele frequency for risk genes, personality characteristics, substance use among family members and friends, level of drug availability, and neighborhood poverty can all influence drug abuse and addiction in various populations (Wallace 1999). Elevated risk can also be attributed to racial and ethnic group differences in socioeconomic factors such as income, net worth, employment, and poverty. Social frameworks and the neighborhood environment can also be disadvantageous as blacks and Hispanics are more likely to live in rural and urban areas of concentrated poverty (Jones-Webb et al. 1997). A recent functional magnetic resonance imaging (fMRI) study compared African American and white smoking populations and demonstrated that differences in the brain response to smoking cues exist between African American and white smokers (Okuyemi et al. 2006). This difference in the neural representation of relapse suggests racial group differences in the neurobiology of nicotine addiction that, further, may contribute to differences in the effectiveness of drug addiction treatments for individuals of different racial and ethnic backgrounds. Increasingly recognized differences in risk factors for drug abuse and addiction related to racial and ethnic backgrounds warrant a greater future emphasis on these complex population variables when characterizing the neurobiology of drug addiction. Such research is necessary to define, identify, and study high-risk populations for drug addiction.

NEUROSCIENTIFIC APPROACHES TO THE DRUG ADDICTION PROCESS The neuroscience of drug abuse and addiction represents a rapidly advancing edge in the larger field of discovery related to the biological bases of psychiatric disorders. Much of this recent scientific progress is attributable to the evolving tools and technologies available to addiction researchers and their complementary use. Here we focus on two such tools or technologies: animal models and in vivo neuroimaging approaches.

Animal Models Animal models of normal and abnormal human behavior have value as simpler, more accessible analogs of complex, inaccessible human conditions. Animal models of the drug addiction process represent arguably the best validated, most widely used animal models of psychiatric disorders. The interested reader should consult Shalev et al. (2002) for a more thorough description of animal models of the drug addiction process. There are numerous animal behavioral models that have been developed and used extensively to elucidate the human drug addiction process. Here we consider the condition place preference (CPP) paradigm and the reinstatement model. The CPP paradigm models the ability of contextual cues associated with drug states to provoke drug-seeking behavior as a function of their properties as rewards (Calcagnetti and Schechter 1993; Schechter and Calcagnetti 1998). The CPP paradigm is based on classical (Pavlovian) conditioning, as contextual cues acquire secondary reinforcing (conditioned stimulus [CS]) properties through their temporal pairing with a psychoactive drug that functions as an unconditioned stimulus (US) (Calcagnetti and Schechter 1993). In this model, a drug is administered to an animal immediately before placement in an environment with distinctive contextual stimuli (olfactory, visual, tactile). Drug-seeking behavior related to the reinforcing property of a drug is then subsequently assessed by the animal's preference for the drug-paired versus unpaired environment expressed in time spent in each environment. As discussed below, drug addiction is characterized by the high rate of relapse related to drug-seeking and -use behaviors. The reinstatement animal model of relapse represents a critical tool in attempts to characterize the neural mechanisms of relapse and the development of medications promoting relapse prevention in addicted human populations. In the self-administration version of the reinstatement procedure, drug addiction–related relapse refers to the precipitated resumption of drug seeking after extinction of drug-reinforced responding (Epstein et al. 2006; Fuchs et al. 2003; Lynch et al. 2002; Shaham et al. 2003). In reinstatement, operant responding (e.g., lever pressing) resulting in drug self-administration is extinguished after a period of drug availability. Following extinction, noncontingent presentation of the previously self-administered drug (Shaham et al. 2003) or exposure to conditioned drug cues

or stressors reinstates responding (Brown and Erb 2007; de Wit and Stewart 1981; Fuchs et al. 1998; Goddard and Leri 2006; Meil and See 1996; Shelton et al. 2004; Worley et al. 1994). The similarity of these relapse precipitants between the animal model and human drug addiction renders significant face validity to the reinstatement model (Epstein et al. 2006). The model also has good predictive validity and unestablished but building construct validity as an animal model of relapse associated with addiction (Epstein et al. 2006). Reinstatement can also be modeled using the CPP paradigm in which CPP is induced by drug administration, extinguished, and then reinstated by drug-priming injections (Mueller and Stewart 2000). Thus, the drug reinstatement model in animals has important and valid utility in exploring the factors underlying relapse in drug-addicted individuals. Although animal behavioral models represent valuable tools in exploring the acquisition and maintenance of human drug addiction, genetic animal models provide further insights into the brain mechanisms involved in the acquisition and maintenance of drug addiction. Cocaine blocks the activity of neuronal plasma membrane transporters for dopamine (DAT [dopamine transporter]) as well as serotonin (SERT [serotonin transporter]) and norepinephrine (NET [norepinephrine transporter]) (Kuhar et al. 1991). Genetic models of transgenic knockout mice for these transporters have been studied extensively in establishing the role of each monoamine transporter in the neuropharmacology of cocaine. DAT knockout mice self-administer cocaine and exhibit cocaine-induced CPP (Giros et al. 1996; Medvedev et al. 2005; Rocha et al. 1998; Sora et al. 1998). Knockouts of SERT and NET also display cocaine reward or reinforcement (Sora et al. 1998; Xu et al. 2000). Mice with no DAT and either no or one SERT gene copy display no cocaine-induced CPP (Hall et al. 2002; Shen et al. 2004; Sora et al. 2001). This example suggests that DAT inhibition is not solely required for the reinforcing effects of cocaine. Animal genetic models represent powerful tools in the study of the drug addiction process.

In Vivo Molecular, Anatomical, and Functional Neuroimaging The development of in vivo neuroimaging technologies such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) has dramatically altered the study of the relationship between the brain and behavior. These technologies have furnished important, novel insights into the neurobiology of the addiction process; specific examples are provided in other sections of this chapter. The radiometric imaging procedures PET and SPECT represent scanners designed to provide two-dimensional and three-dimensional localizations of photon emissions resulting from radionuclide decay for radiopharmaceuticals that react with or bind to brain proteins involved in the regulation of neurotransmission. Such proteins include enzymes, receptors, and transporters. Although the number of valid PET radioligands that satisfy the requisite affinity, selectivity, metabolic stability, binding site kinetics, and physicochemical properties is limited, the strength of this imaging modality lies in the potential diversity of brain "functions" that can be imaged. Images of neurotransmitter receptor density and occupancy, neurotransmitter release, neurotransmitter synthesis, and metabolic and blood flow corollaries of neural activity in human and nonhuman primates and in small animals have been acquired in support of drug addiction research. As a nonradiometric imaging technology, MRI also offers multimodal imaging opportunities based on the spatial tuning using gradient coils of the behavior of protons in a large magnetic main field. Optimized pulse sequences permit the acquisition of MRI of hemodynamic corollaries of neural activity, of brain gray and white matter, and of neurochemicals. Images of brain gray and white matter support morphometric and morphological magnetic resonance imaging (mMRI) of the roles of altered brain anatomy in the drug addiction process. For example, drug addiction has been linked to abnormal patterns of regional gray and white matter volumes or densities in the brain of drug-dependent individuals using voxel-based morphometry (VBM). Cocaine- and alcohol-dependent individuals had decreased gray matter densities in the amygdala, frontal cortex, orbitofrontal cortex, cingulate gyrus, temporal cortex, cerebellum, and premotor cortex when compared with control individuals (Franklin et al. 2002; Matochik et al. 2003; Mechtcheriakov et al. 2007; Sim et al. 2007). Numerous examples of the application of in vivo functional neuroimaging approaches such as fMRI and PET to the investigation of the neurobiology of the drug addiction process are discussed in subsections of this chapter; fewer illustrations of the application of magnetic resonance spectroscopy (MRS) are also provided. These examples illustrate the argument that in vivo brain imaging technologies have led to unparalleled advances in the understanding of the neural basis of the acquisition and maintenance of human drug addiction.

THE ACQUISITION OF ADDICTION Many individuals experiment with drugs of abuse. For many and perhaps all such drugs, their activation of the mesolimbic dopamine projections to the ventral striatum plays a pivotal role in their reinforcing effects (Abi-Dargham et al. 2003; Rodd-Henricks et al. 2002; Volkow et al. 1997), resulting in further experimentation. However, while exact numbers are lacking, only a small percentage of individuals who try drugs of abuse proceed to the compulsive and uncontrolled abuse that characterizes addiction. Individuals comprising this minority share a predisposition that is generally attributed to genetic or environmental factors and their interactions. The neurobiology of the transition by some susceptible individuals from drug abuse to addiction has been best informed by animal models of drug self-administration. Rats given extended versus limited access to cocaine or heroin self-administration exhibit an escalation of drug intake and an enhanced reinstatement of extinguished drug-seeking behavior by the systemic administration of the self-administered drug—responses that represent well-accepted symptoms of human drug addiction (Ferrario et al. 2005; Knackstedt and Kalivas 2007; Koob and Kreek 2007; Lenoir and Ahmed 2007). Whether this transition occurs in the presence or absence of behavioral sensitization of drug effects remains controversial (Ferrario et al. 2005; Knackstedt and Kalivas 2007; Lenoir and Ahmed 2007). The specific neuroadaptations that underlie this transition include empirical and theoretical accounts of altered striatal and prefrontal cortex circuits. One model attributes the acquisition of addiction to a synaptic reorganization of the core subdivision of the nucleus accumbens that results in a pathological increase in the incentive value of drugs (Ferrario et al. 2005). Another model emphasizes an allostatic decrease in reward system responsivity as the mechanism of escalated drug intake (Ahmed and Koob 2005). A third model emphasizes a neural transition from prefrontal cortical to striatal control over drug-seeking and drug-use behavior and a progression from ventral to more dorsal divisions of the striatum (Everitt and Robbins 2005). The significance of the dorsal striatum and its dopaminergic innervations to the transition from drug use to abuse to addiction is supported by their demonstrated roles in habit formation in humans and animal models (Faure et al. 2005; Yin et al. 2004). In addition to striatal and frontal cortex involvement in the acquisition of drug addiction, other brain areas code the associative learning and memories reflecting the conditioning of the reinforcing actions of drugs of abuse with the environmental and other contexts of drug use that

promote further conditioned drug abuse. Inactivation of the basolateral amygdala disrupts the learning of the conditioned reinforcing effects of drug-paired stimuli (Kruzich and See 2001). The well-recognized role of the hippocampus in the formation and processing of contextual memories (Holland and Bouton 1999) suggests its involvement in the formation and retrieval of cognitive representations of contextual memories of drug reinforcement. The critical role of the dorsal hippocampus and its projections in the ventral subiculum in the drug cue–induced reinstatement of drug-seeking behavior (Fuchs et al. 2005; Sun and Rebec 2003; Zhao et al. 2006) supports their involvement in the retrieval of associative memories of drug reinforcement. However, the dorsal subiculum may have a selective role in the formation of contextual memories of drug reinforcement as its transient inactivation during conditioning blocked the acquisition of drug-seeking induced by drug-paired stimuli in the reinstatement model (Martin-Fardon et al. 2008). Collective insights from animal models yield a neurobiology of the acquisition of drug-addicted states that includes the engagement of limbic, striatal, and prefrontal cortex areas in drug-related behavioral reinforcement and learning and memory processes that imbue drug-related stimuli with incentive motivation, rewarding, contextual, and habitual properties.

Genetic Influences Human studies of the neurobiology of the transition from drug use to abuse and addiction have focused more on the roles played by genetic and environmental risk factors (see Figure 49–1). Environmental and genetic factors contribute to individual differences in vulnerability to initiating use of drugs of abuse and in vulnerability to the shift from drug use to addiction (Goldman et al. 2005). Drug addictions represent some of the most heritable psychiatric disorders. Heritabilities differ for different drug addictions, ranging from moderate values (0.39) for hallucinogens to high heritabilities (0.72) for cocaine (Goldman et al. 2005). Estimated heritabilities for the initiation and use of drugs of abuse are typically lower than those for addiction (M. D. Li et al. 2003). The obvious questions are what exactly is being inherited by individuals and populations that enhances the risk for drug use and addiction, and what are the relative contributions of genetic and environmental factors to the observed heritabilities? The genetic determinants of drug abuse and addiction include the regulation of pharmacodynamic and pharmacokinetic processes that determine drug sensitivity and the genetic regulation of intermediate cognitive, personality, and other phenotypes that influence the addiction process (Goldman et al. 2005). The neurobiological corollaries of the genetics of addiction that confer vulnerability for, and protection from, drug abuse and addiction are in an early stage of identification. The emerging field of "imaging genetics" (Meyer-Lindenberg and Weinberger 2006) is based on the use of in vivo neuroimaging approaches to define the neurobiology mediating the influence of genetic variation on the expression of normal and abnormal human behavior. These approaches provide clues as to what is being inherited in the form of identified gene influences on brain morphology and morphometrics, task-related brain activity, functional and anatomical connectivity between brain areas comprising neural circuits and pathways, and the expression and occupancy of neurotransmitter receptors, transporters, and enzymes. Due to the demonstrated roles of neurotransmitter alterations in the addiction process, variations in genes that regulate neurotransmission have been the primary focus of efforts to identify addiction-related genes. Quantitative trait locus (QTL) analyses of ethanol-related behaviors including preference and sensitivity to withdrawal and sedation in mice implicate gene clusters harboring the

aminobutyric acid

A (GABAA) receptor (Crabbe et al. 1999). While a detailed discussion of the neurobiology of genetic risk for drug abuse and addiction is beyond the scope of this chapter, we offer the following as examples of the impact of, and insights from, early approaches. Dopamine-related genes have been implicated in the addiction process, particularly functional polymorphisms for genes encoding catecholO-methyltransferase (COMT), the human dopamine transporter (DAT1), and the D2 and D4 dopamine receptors (DRD2 and DRD4, respectively). The level of expression of D2 receptors in the prefrontal cortex as defined by [11C]raclopride PET imaging determines the subjective experience of pleasure following the administration of methylphenidate and presumably other psychostimulants (Volkow et al. 2005). Interindividual differences in the structure or expression of genes involved in dopaminergic neurotransmission (e.g., DRD2) could account for some of the genetically mediated variability in substance abuse behaviors in humans (Uhl et al. 1993). Allelic variation for the DRD2 Taq1 restriction fragment length polymorphism (RFLP) regulates the craving response to conditioned drug cues associated with nicotine (Erblich et al. 2005) and heroin (Y. Li et al. 2006) addiction. Recent [11C]raclopride PET imaging studies indicate that variable number of tandem repeat (VNTR) polymorphisms in the DAT1 and DRD4 genes, and a single nucleotide polymorphism (SNP) in the COMT gene, regulate the release of ventral striatal dopamine in response to cigarette smoking, with the response inversely related to cigarette craving (Brody et al. 2006). Many studies also suggest that SLC6A3, the gene that encodes DAT, has a genetic link with cocaine addiction (Haile et al. 2007). Individual variation in dopamine-related genes may thus regulate individual differences in acquisition of drug addiction and risk for relapse. The genetic regulation of cognitive functions related to the addiction process, or of personality traits that modulate risk for drug abuse and addiction, represents another source of the observed heritability of addictive disorders (Kreek et al. 2005). Personality traits such as impulsivity, risk taking, and novelty seeking are associated with drug addiction (Moeller et al. 2001) and with risk for drug abuse and addiction (Dawe and Loxton 2004; Kreek et al. 2005). These traits are regulated by serotonin-related genes that encode the brain isoform of tryptophan hydroxylase (TPH2) (Zhou et al. 2005) and the serotonin transporter (SERT) (Gerra et al. 2005). Allelic variation of the TPH2 gene (TPH2) and the SERT gene (5-HTTLPR) regulates the neural response to demands for cognitive and affective processing (Canli et al. 2008; Herrmann et al. 2007). Similarly, cognitive functions related to the addiction process, such as inhibitory executive control, the processing of incentives and rewards, and delay discounting, have a neurobiology that is profoundly influenced by polymorphic variation in genes regulating dopamine neurotransmission. Putative functional polymorphisms in COMT and DAT1 additively regulate the neural basis of reward sensitivity (Yacubian et al. 2007) and thus, potentially, vulnerability to drug abuse and addiction. Importantly, genes that regulate pharmacodynamic, pharmacokinetic, and cognitive functions and personality traits exhibit epistatic gene–gene interactions that convey multiplicative contributions to risk for drug abuse and addiction in allele carriers (Yacubian et al. 2007).

Environmental Influences Genetic factors explain, on average, only about half of the total variability in drug addiction, with the remaining variability influenced by environmental factors. Also, genetic risk may be differentially expressed in the presence versus absence of particular environmental conditions (Lessov et al. 2004). Environmental factors that can contribute to drug abuse and addiction include psychosocial factors such as socioeconomic status, peer influence, and family dissension and early-life adversity such as physical, sexual, and emotional abuse and/or neglect (see Figure 49–1). More than half of drug abusers entering addiction treatment report a history of childhood physical or sexual abuse (Pirard et al. 2005). High rates of childhood maltreatment (e.g., childhood physical, sexual, and emotional abuse and/or neglect) have

been associated with drug abuse and addiction (Simpson and Miller 2002). Studies also suggest that relationships between drug use and abuse and childhood maltreatment are stronger in women (Hyman et al. 2005; MacMillan et al. 2001). Childhood maltreatment was also associated with a younger age of first cocaine use and a greater lifetime severity of drug use (Hyman et al. 2006). Women also typically had more instances of sexual and emotional abuse and overall childhood maltreatment, while in men emotional abuse was the main type of abuse reported. Recent findings suggest that having a history of childhood maltreatment may influence how recently abstinent cocaine-dependent individuals experience and cope with stress, a recognized relapse factor (Hyman et al. 2007). Cocaine-dependent individuals have a higher incidence of trauma and comorbid posttraumatic stress disorder (PTSD) (Back et al. 2000). The neurobiology of childhood abuse and neglect is intimately intertwined with the neurobiology of drug abuse and addiction. For instance, the observation that childhood maltreatment is associated with a persistent, perhaps permanent, sensitization of the endocrine and autonomic response to stress (Heim et al. 2000) implies a related sensitization of drug-addicted individuals with childhood maltreatment histories to stress-induced relapse. The impossibility of understanding the neurobiology of the acquisition of drug addiction without appreciating the genetic and environmental determinants of individual differences in the risk for abuse and addiction and in the response to addiction therapies is increasingly obvious.

Neurodevelopmental Influences Adolescence is a time of high-risk behavior and increased exploration. The neurodevelopmental period of adolescence represents typically the first experimentation with drugs of abuse and is associated with an increased risk to develop drug addiction in adulthood (see Figure 49–1). Adolescents typically exhibit higher rates of experimental drug use and abuse disorders than adults (Chambers et al. 2003). Recognized risk factors for adolescent drug abuse include early marijuana and cigarette use, deviant behavior, negative family interactions, poor parent–child communication, school disengagement, family drug problems, drug availability, and prodrug attitudes and intentions (Ellickson and Morton 1999; Kliewer and Murrelle 2007). Adolescence also represents a critical period for factors such as parental support or nonfamily mentors to exert their durable protective effects on drug abuse and addiction. Adolescence is a critical period for maturation of neurobiological processes that underlie higher cognitive functions and social and emotional behavior (Yurgelun-Todd 2007). Functional neuroimaging studies indicate that brain regions that underlie attention, reward evaluation, affective discrimination, response inhibition, and goal-directed behavior undergo structural and functional organization throughout late childhood and early adulthood (Bjork et al. 2004; Galvan et al. 2006; Yurgelun-Todd 2007). The vulnerability of adolescents to drug abuse and addiction may reflect the delayed brain maturation of executive processes of behavioral regulation relative to those that encode incentive valuation. Adolescents, relative to children and adults, exhibited increased nucleus accumbens activity relative to prefrontal cortex activity during reward valuation, whereas the orbitofrontal cortex response was similar to that of children and less than that of adults (Galvan et al. 2006). Greater motivational drives for rewards, coupled with an immature neural mechanism of inhibitory control, could predispose adolescents to impulsive actions and risky behaviors including experimentation with drugs of abuse (Chambers et al. 2003). Elucidating the developmental timing of the neural processing of incentive valuation, goal representation, delay discounting, response inhibition, and other behaviors related to the addiction process using technologies such as fMRI over the adolescent period would clearly inform the pathogenesis of substance use disorders and inform intervention strategies for preventing drug abuse and other high-risk behaviors in youth.

RELAPSE TO DRUG-SEEKING AND DRUG USE BEHAVIORS Drug addiction in treatment-seeking individuals is associated with high rates of recidivism (O'Brien 1997). Attentional and motivational responses to conditioned drug cues represent powerful precipitants of relapse in drug-addicted individuals (Kalivas and Volkow 2005). There has been scant research focusing on identifying neural markers of relapse in drug-dependent human populations, in spite of the clear value of such predictors to defining relapse risk and treatment prognosis. A recent fMRI study in treatment-completing methamphetaminedependent subjects examined the relationship between the magnitude of the distributed neural response to a decision-making task and the incidence of relapse over a 1-year follow-up interval (Paulus et al. 2005). Lower task-related activation of the right middle frontal gyrus, middle temporal gyrus, and posterior cingulate cortex best predicted time to relapse. These predictive neural responses suggest their representation of deficit functions related to decision making that bias individuals for relapse. The process of relapse to drug-seeking and -use behavior is multidetermined, with at least three putative precipitants that are recognized in drug-addicted human subjects and reliably modeled in reinstatement versions of animal drug self-administration paradigms (Figure 49–2). The formation of learned associations between drug-use reminders, or cues, and the euphoria or "high" associated with drug use underlies the pathological motivations for drug seeking and use that define relapse due to conditioned drug cues (Figure 49–2A). Such cues are diverse in nature and include exteroceptive stimuli, such as persons, places, or sensory cues, as well as interoceptive stimuli, such as mood states. The experience of stress represents a second well-recognized precipitant of relapse (Figure 49–2B). Drug use itself is also recognized as a precipitant of motivation for further drug abuse in the form of drug bingeing (Figure 49–2C). The interested reader should consult Epstein et al. (2006) for a thoughtful discussion of the validity of the reinstatement procedure as an animal model of drug relapse. FIGURE 49–2. Models of neurobiological mechanisms of relapse to drug seeking and drug use.

To elucidate the emerging neurobiology of mechanisms of relapse to drug-seeking and -use behaviors associated with drug addiction, we consider and compare three potential precipitants of relapse: conditioned drug-use reminders or cues (A, Cue-induced relapse model), stress (B, Stress-induced relapse model), and use/administration of the drug itself (C, Drug-induced relapse model). For each model presented, the neuroanatomical areas and neurotransmitter mechanisms involved (as defined by investigation of the reinstatement animal model of relapse) are shown on the right, and the distributed neural processing associated with experiencing the relapse precipitant (as defined by human in vivo functional neuroimaging studies in males) is shown on the left. It should be emphasized that these neurobiological mechanisms reflect major but not all research findings and represent an as-yet-incomplete characterization of the mechanisms of relapse. Therefore, strict comparisons of the underlying mechanisms between the three relapse precipitants should be done with caution. ACC = anterior cingulate cortex; Amyg = amygdala; BLA = basolateral amygdaloid nucleus; BNST = bed nucleus of the stria terminalis; CB = cerebellum; CE = central amygdaloid nucleus; CRF = corticotropin-releasing factor; CRF1R = corticotropin-releasing factor 1 receptor; CRF2R = corticotropin-releasing factor 2 receptor; D3R = D3 dopamine receptor; dACC = dorsal anterior cingulate cortex; dlPFC = dorsolateral prefrontal cortex; dStr = dorsal striatum; HC = hippocampus; Ins = insula; lOFC = left orbitofrontal cortex; mCC = middle cingulate cortex; MTG = medial temporal gyrus; Nac = nucleus accumbens; OFC = orbitofrontal cortex; pCC = posterior cingulate cortex; PFC = prefrontal cortex; VIS = visual cortex; VP = ventral pallidum; vStr = ventral striatum;

VTM = ventral tegmentum. The human motivational state for drug use that propels drug-seeking behavior is often referred to as "craving." Empirically, drug craving is defined by subjective measures of self-rated intensities of craving, using Likert or other scales, or by objective measures of craving-related arousal, such as skin conductance, heart rate, blood pressure, or pupil diameter. The following describes research findings related to the functional neuroanatomy and neurochemistry of precipitated drug craving defined by animal models or human neuroimaging studies. While often assumed, the true relationship between craving and relapse is complex and only modestly established at this time (Epstein et al. 2006). It is also noteworthy that a neuroanatomy of precipitated drug seeking based on the collected findings from even a single animal model is less than definitive as different means of probing the involvement of a given brain area (e.g., tetrodotoxin, receptor antagonists or agonists, lesions) yield conflicting outcomes (Bossert et al. 2005). As such, the following discussion of the neurobiology of relapse comparing the drug-seeking condition defined by the reinstatement animal model and human drug craving defined in the laboratory should be critically considered.

Relapse Related to Conditioned Drug Cues In drug-dependent subjects, exposure to drug-related stimuli (e.g., drug paraphernalia, drug-taking environment) elicits intense craving and increases the probability of relapse even following prolonged abstinence (Childress et al. 1988; Ehrman et al. 1992; Jaffe et al. 1989; Johnson et al. 1998). The neural representation of conditioned cue–induced drug craving has been explored in the reinstatement model in rats, in which a conditioned stimulus (e.g., a light) that was paired with access to cocaine in a self-administration paradigm reinstates drug-seeking behavior (i.e., lever pressing) following extinction of the drug access contingency of the lever. Understandably, there is considerable overlap of affected brain regions with brain regions thought to be involved in appetitive conditioning and the retrieval of conditioned associations (Kelley et al. 2005; See 2002; Thomas and Everitt 2001). A combination of results from lesioning and pharmacological inactivation studies, intracerebral microdialysis, electrophysiology, and molecular markers of neuronal activity implicates the amygdala (Hayes et al. 2003; Thomas and Everitt 2001), the anterior cingulate and orbitofrontal cortex (McLaughlin and See 2003), and the dorsal (Ito et al. 2002) and ventral (Ghitza et al. 2003) striatum in the drug motivational response to conditioned drug cues (Figure 49–2A). Beyond their use in elucidating the neuroanatomy of conditioned cue–induced drug craving, animal models have uniquely contributed to our understanding of the specific neurotransmitters involved in the coupling of drug-predictive stimuli with drug-seeking behavior. Conditioned drug cues are associated with glutamate release in the nucleus accumbens and dopamine release in the amygdala, nucleus accumbens, dorsal striatum, and prefrontal cortex (Ito et al. 2002; Phillips et al. 2003; Vanderschuren et al. 2005; F. Weiss et al. 2000) (see Figure 49–2A). It is noteworthy that the neuroanatomy and neurobiology of drug seeking precipitated by conditioned drug cues differs when the drug-paired cue is a discrete cue, discriminative cue, or contextual cue (Bossert et al. 2005). Interested readers should consult Kalivas and Volkow (2005) or Bossert et al. (2005) for more elaborated models of the roles of alterations in cellular signaling, receptor translocation, and cell morphology in the neural basis of the relapse process. In vivo functional neuroimaging approaches have provided novel insights into the distributed patterns of neural processing that transduce the experience of conditioned drug-use reminders into drug craving and relapse in human drug addicts. Here, a clear challenge has been to capture the neural response to drug cues within the nonnaturalistic environment of a PET, SPECT, or MRI scanner for drug-use reminders that are highly individualized and context-dependent. In response to these challenges in experimental design, researchers have devised generalized drug cues represented by videotape and still images of drug-use behavior, the handling of drug paraphernalia, individualized drug cues in the form of the mental imagery of personal drug use guided by autobiographical scripts, and compound drug cues represented by virtual reality environments. Additional experimental design challenges are posed by the need to document and quantify the induced drug motivational state and to compare it to responses to control conditions that correct for sensory, motor, attentional, mnemonic, and other features of cue processing. The combination of subjective self-ratings of the intensity of drug-use urges and of corollary emotional states with objective psychophysiological measures (heart rate, skin conductance, pupil diameter, or respiratory rate) of craving-related arousal has emerged as a best approach to defining and quantifying cue-induced drug craving. Implementing the ideal control condition(s) has been a more elusive aspect of experimental design. Finally, the characteristics of the sample of drug-dependent individuals studied represents a critical determinant of the neural response to drug cues. Features such as age, sex (Kilts et al. 2004), duration of drug abstinence, treatment enrollment (Wilson et al. 2003), specific drug dependency, expectancy of drug availability (McBride et al. 2006; Wertz and Sayette 2001), comorbid psychiatric illness or drug dependencies, or experiences of recent stress or early-life adversities critically modulate the neural processing of conditioned drug cues. The interested reader should consult Kilts et al. (2001) for a more detailed treatment of experimental approaches to the use of in vivo functional neuroimaging technology to define the neurobiology of the drug motivational state. The neurobiology of cue-induced craving in drug-addicted human subjects exhibits many parallels with findings from the reinstatement animal model (see Figure 49–2A). First, [11C]raclopride PET imaging studies of cocaine abusers demonstrated that the occupancy of D2 receptors in the human dorsal (but not ventral) striatum was increased by exposure to cocaine cues (Volkow et al. 2006; Wong et al. 2006), and imaging of alcoholic subjects has revealed increased D2 receptor occupancy in both striatal subdivisions in response to exposure to alcohol cues (Heinz et al. 2004). This cue response presumably reflects a cue-induced increase in dorsal striatal dopamine release and was positively correlated with both the intensity of self-reported cocaine craving and the severity of addiction-related functional impairment. Conditioned cocaine cues increase dorsal striatal dopamine release in cocaine-dependent human subjects and animal models of cocaine self-administration, implicating this cue response in the processing of cues as reward predictors and as a biomarker of the habitual nature of addiction. Second, the distributed neural response to drug cues in drug-dependent human subjects involves many of the same brain areas implicated by the response to discrete drug-paired stimuli in rats. Figure 49–2 presents a summary of human study findings across diverse experimental approaches. Brain areas activated by the passive or active processing of conditioned drug cues include the anterior and posterior cingulate cortex, amygdala, ventral striatum, insula, orbitofrontal cortex, dorsolateral prefrontal cortex, cerebellum, and visual cortex (Anderson et al. 2006; Bonson et al. 2002; Childress et al. 1999; Daglish et al. 2001; Garavan et al. 2000; Grant et al. 1996; Heinz et al. 2004; Kilts et al. 2001, 2004; Maas et al. 1998; Wexler et al. 2001). The results of correlational and other approaches to data analysis, expanded experimental designs (e.g., the inclusion of attempts to volitionally inhibit the craving response), and comparisons of localized brain responses with other imaging studies furnish plausible

inferences of the roles of each neural activation site to the complex state of conditioned drug craving and relapse. Consistent drug cue–induced activation of the amygdala may reflect the motivational evaluation of emotional and other associations to drug cues (Kilts et al. 2004). Cue-induced activation of the dorsal anterior cingulate cortex (dACC) may reflect the computation of conditional drug probabilities (Kilts et al. 2004) and the related processing of response conflict due to drug nonavailability in the scanner context. Greater dACC activation to drug cues may reflect an adaptive regulatory role that dampens the drug cue evaluative functions of brain areas mediating their sensory and motivational processing when drug availability is low or when drug use is resisted (Brody et al. 2007; Kilts et al. 2004). The dorsolateral prefrontal cortex activation by drug cues may reflect the access to mental representations of drug use and/or the engagement of executive control of drug-related behaviors signaled by the dACC response. Cue-induced activation of the insula may reflect the access of somatic representations of drug states and/or the aversive properties of experiencing drug motivation in the absence of availability. Activation of the ventral striatum by drug cues may reflect the processing of the strong incentive motivational property of drug cues, while activation of the precommissural dorsal striatum may reflect the retrieval of motor cognitions related to habits of drug abuse. These findings suggest a complex relationship between the experiencing of drug-use reminders and motivation for drug abuse. The interested reader should consult Kilts et al. (2001) for a more thorough description of the human functional brain imaging studies and their designs that have investigated the neural response to conditioned drug cues in diverse drug addictions. Much has been learned about the neurobiology of conditioned drug craving from animal model and human studies. In several instances this knowledge has driven the development of novel treatments for drug addiction. As an example, the findings that the reinstatement of drug-seeking behavior by conditioned drug cues in rats was related to deficits in frontal–striatal glutamate signaling that was rescued by stimulation of the cysteine–glutamate exchanger by administration of the cysteine prodrug N-acetylcysteine (Zhou and Kalivas 2008) led to the demonstration that N-acetylcysteine administration reduces the urge to use cocaine provoked by drug cues in cocaine-dependent human subjects (LaRowe et al. 2007).

Relapse Related to Stressful Events Stress is another factor that can precipitate intense drug wanting or craving. The neural representation of stress-induced drug craving has been explored in the reinstatement model in rats in which stressors (typically footshock) reinstate drug-seeking behavior (i.e., lever pressing) following extinction of the drug access contingency of the lever. In this animal model, stress-induced drug-seeking behavior shares many of the neural substrates associated with cue-induced drug seeking including the midbrain ventral tegmentum, prefrontal cortex, and dorsal and ventral striatum (Figure 49–2B). A glutamatergic projection from the prefrontal cortex to the ventral striatum has been proposed as a final common pathway for the precipitation of drug seeking by stress, conditioned drug cues, or the drug itself (Kalivas and Volkow 2005). The neural pathways associated with stress- and drug cue–induced drug seeking are, however, distinct in other ways (Shalev et al. 2002). Unlike cue-induced drug seeking, stress-primed drug seeking does not involve the basolateral amygdala (McFarland et al. 2004), but rather engages the bed nucleus of the stria terminalis and other brain areas comprising the extended amygdala (Shaham et al. 2002). Stress and drug cues exhibit additive effects on drug seeking related to their shared activation of the corticotropin-releasing factor (CRF) system (Liu and Weiss 2002). However, the role of CRF signaling in stress-induced relapse is particularly important and related to multiple actions at CRF1 and CRF2 receptors regulating dopamine and glutamate release in midbrain and forebrain elements of drug motivational pathways (Wang et al. 2007) (see Figure 49–2B). Recent evidence supports the relatedness of stress-related increases in drug craving to cocaine relapse outcomes in cocaine-dependent individuals (Sinha et al. 2006). The intensity of stress-induced increases in drug craving and hypothalamic-pituitary-adrenal (HPA) axis responses predicted a shorter time to relapse and higher amounts of cocaine use per occasion, respectively. Recent in vivo functional neuroimaging studies have also provided novel insights into the distributed patterns of neural processing that transduce the experience of acute stress into drug craving and relapse in drug-addicted human subjects. In studies employing script-guided mental imagery as a means of exposure to a stressor in a scanner environment, a mixed-sex sample of cocaine-dependent subjects exhibited decreased activation in paralimbic (anterior cingulate) and limbic (hippocampus) regions and increased activation in the dorsal striatal region in response to stress relative to comparison subjects (Sinha et al. 2005) (see Figure 49–2B). The dorsal striatal response scaled with the intensity of stressinduced cocaine craving. The implication of these findings is that stress diminishes responses associated with the self-regulation of affectand drug-related behaviors and activates the habit pattern of compulsive drug abuse (Sinha et al. 2005). As discussed previously, a comparison of male and female cocaine-addicted subjects supported significant differences between the sexes in the neural response to a stressor, in spite of equivalent anxiety and craving responses (Sinha et al. 2005). Compared with males, cocaine-dependent females exhibited greater paralimbic and left frontal responses, suggesting activation of greater conflict detection and response inhibition in reacting to stress. The functional neuroanatomy of stress-induced drug craving in drug-addicted humans is critically uninformed, as drug dependencies other than cocaine have not been examined and the dependence of observed neural responses on the nature of the acute stress and its interaction with prior and early-life stress has not been defined. In contrast to the extensive research conducted in animal models, the comparative neurobiology of drug cue–induced and stress-induced drug craving in human addicts has been little explored. A comparison of script-guided mental imagery paradigms indicated that drug cue and stress imagery in cocaine-dependent subjects similarly activated the HPA and autonomic components of the stress response system (Sinha et al. 2003). Findings from the reinstatement animal model indicate that stress-induced and drug cue–induced drug-seeking behavior exhibits an additive interaction (F. Weiss 2005). A recent fMRI study in cocaine-dependent men demonstrated a greater drug cue–induced activation of the posterior cingulate and parietal cortex response in the presence versus absence of an acute stressor (anticipation of electric shock) (Duncan et al. 2007). These results indicate that stress and conditioned drug cues interact to augment drug-seeking behavior and that stress may provoke relapse by activating brain areas involved in processing the incentive and attention biasing properties of drug-use reminders. Much has been learned about the neurobiology of stress-induced drug craving from animal model and human studies. In several instances this knowledge has driven the development of novel treatments for drug addiction. As an example, the demonstration in rats that activation of

2-adrenergic receptors by the administration of lofexidine or clonidine attenuated footshock-induced reinstatement of cocaine or heroin

seeking (Erb et al. 2000; Shaham et al. 2002) led to the subsequent preliminary demonstration that lofexidine attenuates stress-induced drug craving and promotes drug abstinence rates in opiate-addicted subjects (Sinha et al. 2006).

Relapse Related to Drug Use

The neural representation of drug-induced drug craving has been explored in the reinstatement model in rats in which noncontingent administration of the self-administered drug reinstates drug-seeking behavior (i.e., lever pressing) following extinction of the drug access contingency of the lever. This drug-primed reinstatement of drug seeking has been observed for cocaine, heroin, alcohol, and nicotine self-administration; generalizes to other members of the same pharmacological class; exhibits cross-reinstatement for drugs from different classes than the self-administered drug; and is positively correlated in its magnitude with the priming dose (Shalev et al. 2002). Like stressand drug cue–induced reinstatement of drug seeking, drug-primed reinstatement involves the prefrontal cortex and its glutamatergic projections to the nucleus accumbens (Bossert et al. 2005; Kalivas and Volkow 2005; McFarland and Kalivas 2001) (Figure 49–2C). However, evidence from animal models indicates that drug-induced relapse differs neurobiologically from relapse precipitated by conditioned drug cues or stress. While the prefrontal cortex is consistently implicated in the reinstatement of drug seeking, different subregions of the medial prefrontal cortex appear to be involved in drug-induced, drug cue–induced, and stress-induced reinstatement (Capriles et al. 2003; Fuchs et al. 2004).Temporally, mice exhibited a transient (5 months), suggesting the involvement of differing neuroadaptations for the two relapse factors (Yan et al. 2007). Human in vivo functional neuroimaging studies have examined the neural responses associated with subjective drug abuse experiences, including drug craving. The neurobiology of drug craving, as elucidated through in vivo functional neuroimaging of cocaine's effects in drug-addicted human subjects, also exhibits clear parallels with findings from research paradigms employing the reinstatement animal model of relapse (see Figure 49–2C). Passive delivery of cocaine to cocaine-dependent subjects produced experiences of "high" that were temporally correlated with fMRI responses in the ventral tegmentum, dorsal striatum, and anterior and posterior cingulate cortices, whereas experiences of craving correlated with activity in the ventral striatum, anterior and posterior cingulate cortices, parahippocampal gyrus, and amygdala (negative correlation) (Breiter et al. 1997). A more recent fMRI study examining the neural correlates of "high" and craving during cocaine self-administration noted that self-reported craving correlated positively with activity in the anterior cingulate cortex, ventral striatum, and lateral orbitofrontal cortex, whereas cocaine-induced "high" correlated negatively with activity in the same brain regions (Risinger et al. 2005). Cocaine-induced craving was negatively correlated with activity in the middle cingulate cortex and thalamus. A related PET study noted that methylphenidate-induced craving in cocaine-addicted individuals was also associated with activation of the orbitofrontal cortex (Kalivas and Volkow 2005). These convergent findings indicate that the drug motivational state precipitated by noncontingent and contingent drug administration is transduced by the distributed activation of limbic, paralimbic, and striatal brain areas involved in incentive processing/valuation, cognitive control, and habit learning.

NEURAL SUBSTRATES UNDERLYING THE ASSOCIATION OF DRUG ADDICTION WITH IMPULSIVE AGGRESSION AND VIOLENCE Many of the neuroadaptive responses to prolonged drug intake are enduring and persist even following long periods of drug abstinence. Drug-addicted individuals are vulnerable to relapse for years after initiating and maintaining abstinence. This section deals with the social neuroscience of drug addiction, specifically the impact of end-stage drug addiction on the perception of social signals, the organization of reciprocal social responses, and the regulation of antisocial behavior. Is there a neurobiology of the social cost of drug addiction? A recent characterization of the prevalence and population estimates of violent behavior among individuals with DSM-IV-TR psychiatric disorders demonstrated that substance use disorders were by far the most significant contributors to the public health burden of violent behavior (Pulay et al. 2008). This discussion will focus on the neurobiology of the specific social cost due to the association of drug abuse with escalation of aggression and violence in some drug cultures (Boles and Miotto 2003; Fals-Stewart et al. 2003; Hoaken and Stewart 2003). The introduction of crack cocaine in an urban area in the 1980s was marked not so much by drug arrests as by crimes of assault and emergency room data related to the corollary escalation of aggression and violence. The economic costs of crime related to drug abuse and addiction are enormous. A large proportion of violent and property crimes in the United States involve drugs of abuse. Costs associated with medical care, property loss, future earnings, and adjudication, and pain and suffering associated with drug-related crime exceed $200 billion per year in the United States (Miller et al. 2006). Emergency room studies indicate that 35%–40% of injuries are associated with illicit drug use that is confirmed by toxicology (Vitale and van de Mheen 2006), particularly in association with intentional violent crime (Macdonald et al. 2003). Complex, multifactorial relationships exist between aggressive behavior and drug abuse and addiction that are moderated by situational and personal variables (Ousey and Lee 2004). This stage of the addiction process constitutes the greatest social and personal cost of addiction, yet, paradoxically, has been the least studied and characterized (see Figure 49–1). Key to understanding the escalation of interpersonal aggression and violence associated with some drug addictions is an understanding of its neurobiology in valid animal models and human populations. Initial insights into the neural substrates of the association of drug addiction with impulsive aggression and violence were provided by the relationship between anger traits (Goldstein et al. 2005) and anger states (Drexler et al. 2000) with decreased neural activity in the lateral orbitofrontal cortex of cocaine-addicted men. These finding suggest that the behavioral regulatory roles of the orbitofrontal cortex and other brain areas are compromised in cocaine addiction, resulting in unchecked impulsive aggression in response to anger-provoking situations. These associations, however, lack the social context necessary to establish a relationship between experiences of anger, inhibitory control failures, and aggressive behavior in drug-addicted populations. Currently, these relationships may be best explored by the combination of in vivo functional neuroimaging technology and game behavior to define the neural responses of drug-addicted individuals to aggressive and affiliative behaviors emitted by playing partners in ongoing social dyadic interactions (Rilling et al. 2002). Such simulated social interactions in the context of game behavior offer novel insights into the impact of state (e.g., drug withdrawal) and trait (e.g., personality, race/ethnicity) variables on the brain response to real-world prosocial and antisocial behaviors. For example, using an iterated prisoner's dilemma game, Rilling et al. (2007) demonstrated that individuals scoring higher on psychopathic traits (versus those scoring lower on such traits) employed a more interpersonally aggressive game strategy that was associated with blunted amygdala responses to unreciprocated cooperation, consistent with less aversive conditioning to these social outcomes. High psychopathy trait scores were also associated with blunted anterior cingulate and dorsolateral prefrontal cortex responses when subjects chose to defect on their playing partners, a finding consistent with lesser conflict and cognitive control related to such antisocial behaviors. A game-based study of reactive aggression in a general population sample indicated that the decision to act aggressively was associated with paralimbic cortex activation consistent with conflict between emotional motivations to act and cognitive control processes regulating the tendency to act impulsively (Kramer et al. 2007). It would seem of significant interest whether drug addiction is associated with diminished functional activation and/or connectivity

in brain areas involved in monitoring or resolving emotional conflict or in implementing cognitive control in response to a stimulus or opportunity for impulsive aggression. The further study of at-risk populations using game-based elicitation of aggression and functional neuroimaging would be useful in exploring a cause-versus-effect explanation of observed neural processing deficits associated with impulsive aggression.

DRUG ADDICTION TREATMENT OUTCOME Currently used therapies promoting recovery and relapse prevention in drug-addicted individuals are largely behavioral approaches such as 12-Step programs, cognitive-behavioral therapy (CBT), contingency management, and cognitive skills training (Carroll and Onken 2005). Indeed, behavioral therapies for drug addiction represent arguably the oldest, most prevalent forms of behavioral therapy in medicine. These approaches attempt to thwart the addiction process at multiple levels (Table 49–1). TABLE 49–1. Stages of the addiction process targeted by addiction therapies Decrease the incentive motivational value of the drug (U.S. devaluation) Increase the willful control of drug-related behavior Increase the salience and motivational value of nondrug reinforcers Inhibit conditioned responses to drug-predictive stimuli Source. Adapted from Kalivas and Volkow 2005. Despite the fact that such treatments for drug addiction have long been recognized to be efficacious, surprisingly little research effort has been directed toward examination of the neurobiology underlying treatment-related recovery, relapse prevention, and predictors of treatment response versus nonresponse. This virtual absence of neuroscientific investigation of the efficacy and effectiveness of addiction therapies is related to the fact that the scientific rigor of controlled clinical trial designs has only recently been applied to addiction behavioral therapies (Carroll and Onken 2005) and thus, empirical evidence of their absolute and relative efficacy remains largely unestablished. However, a brief consideration of the largely cognitive underpinnings of major addiction therapies (see Table 49–1) illustrates that fact that they seek to engage the processes of incentive valuation, learning, memory, and inhibitory control that are currently highly active areas of human neuroscience research in non-drug-addicted individuals. Therefore, immense opportunities exist to pair addiction therapies with longitudinal functional neuroimaging studies to define the specific ways in which the brain changes when relapse prevention occurs and to define neural predictors of relapse. As a relapse prevention therapy, CBT targets the extinction of conditioned drug associations as a means of dissociating cocaine-related cues and intense drug motivations. CBT helps cocaine-dependent individuals "relearn" a distinct association or contingency between conditioned drug cues and drug-seeking and -use behaviors. CBT is based on the tenet that learning processes play an important role in the acquisition and maintenance of drug addiction and that these same learning processes can be used to help individuals reduce their drug use (Carroll 2002). CBT focuses on treating substance abuse as a learned behavior that can be modified by fostering the motivation for drug abstinence, coping with drug cravings, and enhancing drug refusal skills (Carroll et al. 1994). Components of CBT include a functional analysis of drug use in which the patient identifies thoughts, feelings, and circumstances before and after drug use and skills training through which subjects learn strategies for modifying these behaviors, moods, or cognitions. CBT has proven efficacy in the treatment of drug-dependent populations (Covi et al. 2002; Maude-Griffin et al. 1998) and may have long-term durability in promoting drug abstinence (Carroll et al. 1994). In contingency management, patients receive incentives or rewards for meeting addiction treatment goals (e.g., negative urine drug screen). Contingency management is based on operant conditioning in which behavior that is followed by positive consequences is more likely to be repeated (Carroll and Onken 2005). Several studies utilizing contingency management have demonstrated the efficacy of voucher-based incentives contingent on the patient providing a drug-free urine sample in reducing drug use, enhancing treatment retention, and maintaining cocaine abstinence (Higgins et al. 2000, 2003; Petry et al. 2004). Twelve-Step recovery programs such as Alcoholics Anonymous are spiritually based in which drug-dependent individuals relinquish power over their addiction by yielding to a higher power. The literature contains limited evidence supporting the efficacy of 12-Step programs; however, 12-Step group participation in a given month predicted less cocaine use in the next month, and patients who increased their 12-Step group participation during the first 3 months of treatment had significantly less cocaine use and lower addiction-related functional impairments (R. D. Weiss et al. 2005). Exploring the neural basis of response to extant addiction therapies arguably represents the most impacting future area of neuroscientific exploration targeting the reduction of the occurrence and costs of drug addiction.

FUTURE DIRECTIONS The immense social, economic, and public health costs of drug abuse and addiction have been little checked by government interdiction policies. The "war on drugs" would be unquestionably advanced by programs of evidence-based prevention and treatment enabled by a more concise and comprehensive understanding of the neurobiology of the stages of the drug addiction process. Such an understanding demands the merger of the fields of social, affective, cognitive, cultural, behavioral, and molecular neuroscience to address the many and diverse driving mechanisms behind this complex process. In this chapter, the specific areas of emphasis on the neurobiology of the addiction process reflect not only a review of the corpus of relevant research findings but also the authors' opinions as to the needed areas of neuroscientific investigation from which a comprehensive and translationally significant understanding of the addiction process would be derived. Defining the influence of differences due to sex or to racial or ethnic background on the neurobiology of drug addiction is deemed imperative. Defining the neurobiology of largely neglected areas of crime and violence related to drug addiction and of response to addiction behavioral therapies is also of high priority. Innovative research approaches to treatment such as the exploration of the use of neurofeedback supported by real-time fMRI (deCharms et al. 2005; Weiskopf et al. 2004) of responses to relapse precipitants are needed. Much has been learned but much more research knowledge is needed to enable science, rather than interdiction policies, to lead the "war on drugs."

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Walter H. Kaye, Michael A. Strober: Chapter 50. Neurobiology of Eating Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.423240. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 50. Neurobiology of Eating Disorders NEUROBIOLOGY OF EATING DISORDERS: INTRODUCTION Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by aberrant patterns of feeding behavior and weight regulation and disturbances in attitudes and perceptions toward body weight and shape. The distinguishing features of AN are an inexplicable fear of weight gain, unrelenting obsession with fatness, and extreme cachexia, to which the person appears strikingly indifferent. In BN, the differentiating characteristics are binge eating of variable frequency and intensity, usually emerging after a period of dieting and which may or may not have been associated with weight loss, and either self-induced vomiting or some other means of compensation for the excess of food that is consumed. Unlike in AN, weight does not decrease to dangerously low levels. In most people affected with BN, feeding patterns are disrupted and satiety may be impaired. However, although abnormally low body weight is an exclusion for the diagnosis of BN, a significant proportion of persons affected with this illness have a prior history of AN (Eddy et al. 2007). AN and BN are cross-transmitted in families (Strober et al. 2000), often transform from one subtype to another over the course of the illness (Eddy et al. 2002; Milos et al. 2005), and share common traits and liability factors (Lilenfeld et al. 2000). Moreover, studies in the literature have often not clearly distinguished subtypes. In addition, state-related influences of malnutrition and weight loss (which tend to be worse in AN) have confounded symptoms and neurobiological measures. Thus, as we move through this chapter, rather than dividing our discussion of the two conditions along strictly categorical lines, we will highlight where they overlap and how they diverge. The clinical distinction between AN and BN of obvious importance is that of emaciation, and while temperamental features of inhibition, restraint, and conformity are especially prominent in AN (Strober 1980), there are many areas of overlap and commonality. Persons with either condition have pathological overconcern with weight and shape, and common to both AN and BN are low self-esteem, perfectionism, depression, and anxiety (Fairburn et al. 1997, 1999). The diagnostic labels are misleading, too, as individuals with AN rarely have complete suppression of appetite but rather exhibit a motivated, and more often than not ego-syntonic, resistance to feeding drives while eventually becoming preoccupied with food and eating rituals to the point of obsession. Similarly, persons with BN, rather than suffering from a primary pathological drive to overeat, have a seemingly relentless drive to restrain their food intake, an extreme fear of weight gain, and a distorted view of their actual body size and shape. Loss of control of normative feeding patterns usually occurs intermittently and typically only some time after the onset of dieting behavior. Furthermore, episodes of binge eating ultimately develop in a significant proportion of people with AN (Halmi et al. 1991), and some 3%–5% of those starting out with BN will eventually develop AN (Fichter and Quadflieg 2007; Milos et al. 2005). Thus, because restrained eating behavior and dysfunctional cognitions relating weight and shape to self-concept are shared by patients with both of these syndromes, and because diagnostic crossover is not unusual, it has been argued that AN and BN share at least some risk and liability factors in common. The etiology of AN and BN is presumed to be complex and multiply influenced by developmental, social, and biological processes (Treasure and Campbell 1994), the exact nature of which remain

poorly understood. Certainly, cultural attitudes toward standards of physical attractiveness have relevance, but it is unlikely that sociocultural influences in pathogenesis are preeminent. First, dieting behavior and the drive toward thinness are unusually common in industrialized countries throughout the world, yet AN and BN affect only an estimated 0.3%–0.7%, and 1.7%–2.5%, respectively, of females in the general population. Moreover, numerous, seemingly unambiguous descriptions of AN date from the middle of the nineteenth century (Treasure and Campbell 1994), suggesting that factors other than the modern social milieu play a more powerful causal role. Second, these syndromes, AN in particular, have a relatively stereotypical clinical presentation, sex distribution, and age at onset, supporting the plausibility of intrinsic biological vulnerabilities.

CLINICAL PHENOMENOLOGY AND DISEASE COURSE Following the points above, variations in feeding behavior have been the basis for subdividing AN into diagnostic subgroups that have been shown to differ in other psychopathological characteristics (Garner et al. 1985). In the restricting subtype of AN, subnormal body weight is sustained by unremitting food avoidance, whereas in the bulimic subtype, there is comparable weight loss and malnutrition, yet the illness course is punctuated by intermittent episodes of binge eating. Interestingly, individuals with this binge subtype exhibit other dyscontrol phenomena, including histories of self-harm, affective and behavioral disorder, substance abuse, and overt family conflict in comparison to those with the restricting subtype. Regardless of subtype, individuals with AN are characterized by marked perfectionism, harm avoidance, low novelty seeking, conformity, and obsessionality, most of which appear in advance of the onset of weight loss and which tend to persist even after long-term weight recovery, indicating that they are not merely epiphenomena of acute malnutrition or disordered eating behavior (Casper 1990; Srinivasagam et al. 1995; Strober 1980). Individuals with BN remain at normal body weight, although many aspire to preferred weights far below the range of normalcy for their age and height. The core features of BN include repeated episodes of binge eating followed by compensatory self-induced vomiting, laxative abuse, or pathologically extreme exercise, as well as abnormal concern with weight and shape. DSM-IV-TR (American Psychiatric Association 2000) specifies a distinction within this group between those individuals with BN who engage in self-induced vomiting or laxative, diuretic, or enema abuse (purging type) and those who exhibit other forms of compensatory action such as fasting or exercise (nonpurging type). Beyond these differences, it has been speculated (Vitousek and Manke 1994) that there are two clinically divergent subgroups of individuals with BN: a so-called multi-impulsive type in which bulimia occurs in conjunction with more pervasive difficulties in behavioral self-regulation and affective instability, and a second type whose distinguishing features include self-effacing behaviors, dependence on external rewards, and extreme compliance. Individuals with BN of the multi-impulsive type are far more likely to have histories of substance abuse, and they characteristically display other impulse-control problems, such as shoplifting and self-injurious behaviors. Considering these differences, it has been postulated that multi-impulsive BN individuals rely on binge eating and purging as a means of regulating intolerable states of tension, anger, and fragmentation, whereas individuals of the latter type have binge episodes precipitated through dietary restraint, with compensatory behaviors maintained through reduction of guilty feelings associated with fears of weight gain. For most who are affected, AN is a protracted disease; roughly 50%–70% of affected individuals will eventually have reasonably complete resolution of the illness, but the time to achieve this state is, for the most part, quite lengthy. Thus, a significant proportion of persons with AN express subthreshold levels of illness that wax and wane in severity long into adulthood, with some individuals having a chronic, wholly unremitting course, and with 5%–10% of those affected eventually dying from complications of the disease or from suicide. For BN, the course trajectory is somewhat different. Rather than continuously presenting symptoms that persist for years without periods of full recovery,

follow-up studies of 5–10 years in duration show that 50% of BN individuals have recovered while nearly 20% continue to meet full syndromal criteria for BN (Keel and Mitchell 1997). The typical course pattern is one of unpredictable vacillation between periods of restricted food intake, gorging, and vomiting, one that will wax and wane over the course of several years.

FAMILY EPIDEMIOLOGY AND GENETICS Family and Twin Studies Findings from systematic case–control studies (Lilenfeld et al. 1998; Strober et al. 2000) suggest a 7to 12-fold increase in the prevalence of AN and BN in relatives of eating disorder probands compared with never-ill control subjects. These significant familial recurrence risks of AN and BN provide impressive evidence of the transmissibility of both phenotypes. Twin studies of AN and BN are still few in number, but evidence to date suggests greater resemblance among monozygotic twins relative to dizygotic twins for both AN and BN, with 58%–76% of the variance in AN (Klump et al. 2001a; Wade et al. 2000) and 54%–83% of the variance in BN (Bulik et al. 1998; Kendler et al. 1991) accounted for by additive genetic factors, estimates that accord with those found in studies of schizophrenia and bipolar disorder. In accord with previous discussion of clinical overlap and longitudinal continuities, AN and BN appear to have familial liabilities shared in common. Convergent findings from family and twin studies indicate an increased coaggregation of AN and BN among relatives of AN and BN probands (Lilenfeld et al. 1998; Strober et al. 2000; Walters and Kendler 1995), suggesting both unique and common familially transmitted causative elements. In this vein, the transmitted liability to eating disorders may express a more diffuse phenotype of continuous traits. In support of this model of transmitted vulnerability is strong evidence of the heritability of disordered eating attitudes, weight preoccupation, dissatisfaction with weight and shape, dietary restraint, binge eating, and self-induced vomiting in the general population, with 32%–72% of the variance in these behavioral features potentially accounted for by additive genetic factors (Klump et al. 2000b; Rutherford et al. 1993; Sullivan et al. 1998; Wade et al. 1998, 1999). In addition, subthreshold forms of eating disorders have also been shown to coaggregate in families with full-syndrome AN and BN (Strober et al. 2000), lending added support to the idea of a continuum of transmitted liability in at-risk families manifesting a broad spectrum of eating disorder phenotypes. That risk is mediated by developmental processes is supported by recent data (Klump et al. 2000b, 2007) from the Minnesota Twin Family Study, which examined the effects of age and pubertal status on the heritability of eating attitudes and behaviors. In the first of these studies (Klump et al. 2000b), the differential influence of genetic versus environmental effects was compared in 11-year-old twins (n = 680) and 17-year-old twins (n = 602). Whereas genetic influence on weight preoccupation and overall eating pathology was negligible for the younger age cohort, more than half of the variance in these attitudes and behaviors could be accounted for by genetic factors in the 17-year-old cohort. The follow-up analysis of the data set (Klump et al. 2007), in which the younger cohort was subdivided by pubertal status, revealed a more powerful effect of puberty than of age per se, suggesting a potential role of pubertal ovarian steroid activity in activating genes of etiological importance in eating disorders.

Genetic Findings Comprehensive genomic studies of AN and BN remain sparse. The first genomewide search for potential disease susceptibility genes in AN (Kaye et al. 2000) was an international collaboration that applied a nonparametric allele-sharing linkage analysis to data from 192 kindreds with at least one affected relative pair with AN and related eating disorders, including BN (Grice et al. 2002). Although evidence for linkage in the entire sample was negligible, an analysis using a narrow affection status

model composed only of relatives with restricting-type AN generated a peak multipoint nonparametric linkage score of 3.45 in the 1p33–36 region. In a further analysis (B. Devlin et al. 2002), two variables incorporated as covariates into the linkage analysis—drive for thinness and obsessionality—yielded several regions of suggestive linkage, one close to genomewide significance on another region of chromosome 1 (logarithm of odds [LOD] score = 3.46). Although considered preliminary, these initial findings suggest genetic heterogeneity in eating disorders and the potential value of applying more refined genomic analyses on large samples of AN subjects. A growing number of studies using a case–control design have examined the potential association of various candidate genes with AN and BN (see reviews by Klump et al. 2001b; Tozzi et al. 2002). Evidence linking AN and BN to monoamine functioning (see below) has led researchers to target serotonin-related (5-HT2A, 5-HT1D , 5-HTT, 5-HT7, tryptophan hydroxylase receptor) and dopaminerelated (D3, D4) genes, but findings to date have been inconsistent or negative. Our group has followed up the initial report of linkage of restricting AN to the chromosome 1p region (Grice et al. 2002), with evidence of significant association with two genes under this linkage peak, the 5-HT1D (HTR1D) and delta opioid (OPRD1) receptors, along with the dopamine receptor on chromosome 11 (Bergen et al. 2003), and a British group has reported a confirmation of the HTR1D and OPRD1 association in a case–control study (Brown et al. 2007). The presumptive role of atypicalities in feeding and energy expenditure in the pathophysiology of AN and BN has led researchers to examine genes related to these processes. Findings suggest possible associations between AN and the UCP-2/UCP-3 gene (Campbell et al. 1999), the estrogen receptor gene (Rosenkranz et al. 1998), and the gene for agouti-related protein (Vink et al. 2001), but here, too, no consistently replicated evidence for association with either AN or BN has accrued to date. Association studies of BN are scant, with one study (Bulik et al. 2003) reporting significant linkage on chromosome 10p and another (Steiger et al. 2005) suggesting that the short (S) allele in the promoter region of the 5-HTT gene may confer risk for affective and behavior dysregulation among persons with BN. In general, the results in this area to date argue convincingly for the importance of characterizing the latent phenotypic structure underlying these conditions and the application of more refined covariate and quantitative trait locus models of genomewide association and linkage analyses (Bacanu et al. 2005; Bulik et al. 2005) in the search for genes of potential relevance.

Associations With Other Behavioral Phenotypes As noted, a variety of behavioral symptoms and traits occurs prominently in people with AN. Accordingly, several family and twin studies have examined the covariation between eating disorders and various other psychiatric conditions. These studies have been reviewed in detail (Lilenfeld et al. 1998; Strober et al. 2000). With regard to major affective illness, studies of AN probands have yielded familial risk estimates in the range of 7%–25%, with relative risk estimates in studies employing healthy control subjects in the range of 2.1–3.4. Likewise, studies of BN probands have shown, with rare exception, that their first-degree relatives are several times more likely to develop affective disorders than are relatives of control subjects (Mangweth et al. 2003). Several recent twin and family studies support this conclusion, as both found evidence for shared as well as unique genetic influences on major depression in both AN and BN (Kendler et al. 1995; Wade et al. 2000). In short, and lending further support to the notion of shared liability in AN and BN, both conditions often co-occur with major mood/anxiety disorders, which likewise cluster in family members. An interesting potential discontinuity is with regard to substance use disorders. Although several studies (Kaye et al. 1996; Schuckit et al. 1996) found no evidence of cross-transmission of BN and substance use disorder in families, and twin data (Kendler et al. 1995) have shown that the genes influencing susceptibility to alcoholism were independent of those underlying BN risk, one recent

study suggests some sharing of genetic influences that confer risk to drug use disorder and BN (Baker et al. 2007). Independent familial transmission of obsessive-compulsive disorder (OCD) and both AN and BN was recently found in a controlled family study of eating disorders (Lilenfeld et al. 1998). By contrast, shared transmission was found between broadly defined AN and BN and various anxiety disorder phenotypes (Miller et al. 1998), and a genetic correlation has been reported between BN and both phobia and panic disorder (Kendler et al. 1995). Preliminary data also suggest common familial transmission of AN and obsessive-compulsive personality disorder (OCPD) (Lilenfeld et al. 1998; Strober et al. 2007). These results point in the general direction of linking genetic risk factors for various anxiety-related phenomena to susceptibility to eating disorders.

NEUROBIOLOGY OF EATING DISORDERS Overview The assumed absence of confounding nutritional influences in recovered eating-disordered women suggests that persistent psychobiological abnormalities and atypical behaviors might be trait related and etiopathogenetic. Investigators (Casper 1990; Kaye et al. 1998; Srinivasagam et al. 1995; Strober 1980; Wagner et al. 2006a) have found that many women who were in long-term recovery from AN and BN have persistence of anxiety, harm avoidance, perfectionism, and obsessional behaviors. Moreover, persons recovered from AN and BN often express associated eating disorder psychological symptoms, including ineffectiveness, drive for thinness, and significant psychopathology related to eating habits. Therefore, persistence of certain features after recovery raises the question of whether a disturbance of such behaviors may in fact occur premorbidly and contribute to the pathogenesis of AN and BN. The role of biology in the etiology of AN has been proposed for many decades (Treasure and Campbell 1994). New understandings of the neurotransmitter modulation of appetitive behaviors have raised the question of whether such disturbances cause eating disorders (Fava et al. 1989; Morley and Blundell 1988). Moreover, technologies that permit direct measurement of complex brain functions and their relationships to behavior are shedding new light on the pathophysiology of these disorders.

Imaging Studies It is well known that ill subjects with AN have enlarged ventricles and sulci widening (see review by Ellison and Foong 1998). Proton magnetic resonance spectroscopy (1H-MRS) revealed reduced lipid signals in the frontal white matter and occipital gray matter and was associated with decreased body mass index (BMI) (Roser et al. 1999). Whether these abnormalities persist to a lesser degree after weight restoration is less certain, since some studies show persistent alterations (Katzman et al. 1996) but other studies show normalization of gray and white matter after recovery in AN and BN (Wagner et al. 2006b). I. Gordon et al. (1997) found that 13 of 15 ill AN subjects studied had unilateral temporal lobe hypoperfusion that persisted after weight restoration. A later study (Chowdhury et al. 2001) found that adolescent AN subjects had unilateral temporoparietal and frontal lobe hypoperfusion. Kuruoglu et al. (1998), studying two ill AN patients, found bilateral hypoperfusion in frontal, temporal, and parietal regions that normalized after 3 months of remission. Takano et al. (2001) found hypoperfusion in the medial prefrontal cortex and anterior cingulate and hyperperfusion in the thalamus and amygdalo–hippocampal complex. Rastam et al. (2001) found temporoparietal and orbitofrontal hypoperfusion in ill and recovered AN subjects. Fewer studies have assessed glucose metabolism using positron emission tomography (PET). Delvenne et al. (1995) studied ill AN subjects who, in comparison with control subjects, had frontal and parietal hypometabolism that normalized with weight gain. More recently, single photon emission computed tomography (SPECT) studies of

resting blood flow in restricting-type AN patients before and after weight restoration have suggested reduced blood flow in the anterior cingulate in both state conditions, compared with control subjects (Kojima et al. 2005a). Few brain imaging studies have examined BN subjects, but findings from several groups (Andreason et al. 1992; Delvenne et al. 1999; Nozoe et al. 1995; Wu et al. 1990) have raised the possibility of frontal or temporal alterations and hemispheric asymmetry. In summary, these studies show temporal, frontal, parietal, and cingulate region disturbances in AN subjects, both when ill and after various degrees of recovery. Although these studies show some consistency, particularly in terms of temporal involvement, it should be noted that the numbers of subjects in each study tended to be small, and definitions of subgroups and states of illness were often inconsistent. Small sample sizes and irregular definitions make it difficult to know whether these are lateralizing findings or there are differences between subtypes of eating disorders. The meaning of these findings is open to interpretation. At the least, they suggest that regions of the brain involved in the modulation of mood, cognition, impulse control, and decision making may be altered in AN and BN.

Body Image Distortion A most puzzling symptom of AN is the severe and intense body image distortion, in which emaciated individuals perceive themselves as fat. Wagner et al. (2003) confronted AN patients and age-matched healthy control subjects with their own digitally distorted body images as well as images of a different person using a computer-based video technique. These studies reported a hyperresponsiveness in brain areas belonging to the frontal visual system and the attention network (Brodmann area 9) as well as the inferior parietal lobule (Brodmann area 40), including the anterior part of the intraparietal sulcus. Bailer et al. (2004) reported negative relationships between 5-HT2A receptor activity and the Eating Disorder Inventory Drive for Thinness scale in the left parietal cortex and other regions. Uher et al. (2005) showed a cohort of women (9 with BN, 13 with AN, and 18 healthy controls) line drawings of female bodies and found that the subjects with eating disorders had reduced hemodynamic response in the right parietal (Brodmann area 40) cortex. It is intriguing to raise the possibility that parietal disturbances may contribute to body image distortion. Theoretically, body image distortion might be related to the syndrome of neglect (Mesulam 1981), which may be coded in parietal, frontal, and cingulate regions that assign motivational relevance to sensory events. It is well known that lesions in the right parietal cortex not only may result in denial of illness or anosognosia, somatoparaphrenia, and numerous misidentification syndromes but also may produce experiences of disorientation of body parts and body image distortion. It has long been recognized that the parietal cortex mediates perceptions of the body and its activity in physical space (Gerstmann 1924). Recent work extends this concept to suggest that the parietal lobe contributes to the experience of being an "agent" of one's own actions (Farrar et al. 2003).

Appetitive Regulation Individuals with AN and those who have had lifetime diagnoses of both AN and BN (AN-BN) tend to have negative mood states and dysphoric temperament. There is evidence that there is a dysphoria reducing character to dietary restraint in AN (Kaye et al. 2003; Strober 1995; Vitousek and Manke 1994) and binge/purge behaviors in BN (Abraham and Beaumont 1982; Johnson and Larson 1982; Kaye et al. 1986). This would suggest some interaction between pathways regulating appetitive behaviors and emotions. In fact, imaging studies support this hypothesis. When emaciated and malnourished AN individuals are shown pictures of food, they display abnormal activity in the insula and orbitofrontal cortex as well as in mesial temporal, parietal, and anterior cingulate cortex (Ellison et al. 1998; C. M. Gordon et al. 2001; Naruo et al. 2000; Nozoe et al. 1993, 1995; Uher et al. 2004). In addition, studies using SPECT, PET (with 15O), or functional magnetic resonance imaging (fMRI) found that when subjects ill with AN ate food or were exposed to food, they showed activation in temporal

regions and often experienced increased anxiety (Ellison et al. 1998; C. M. Gordon et al. 2001; Naruo et al. 2000; Nozoe et al. 1993). Those results could be consistent with anxiety provocation and related amygdala activation and with the notion that the emotional value of an experience is stored in the amygdala (LeDoux 2003). Uher et al. (2003) used pictures of food and nonfood aversive emotional stimuli and fMRI to assess ill and recovered AN subjects. Food stimulated medial prefrontal and anterior cingulate cortex in both recovered and ill AN subjects but lateral prefrontal regions only in the recovered group. The prefrontal cortex, anterior cingulate cortex, and cerebellum were more highly activated after food intake in recovered AN subjects compared with both control subjects and subjects chronically ill with AN. This finding suggested that higher anterior cingulate cortex and medial prefrontal cortex activity in both ill and recovered AN women compared with controls may be a trait marker for AN. A recent study (Wagner et al. 2008) used fMRI to investigate the effect of administration of nutrients. In comparison with controls, recovered AN subjects had a significantly reduced fMRI signal response to the blind administration of sucrose or water in the insula, anterior cingulate, and striatal regions. For controls, self-ratings of pleasantness of the sugar taste were positively correlated to the signal response in the insula, anterior cingulate, and ventral and dorsal putamen. By contrast, recovered AN individuals failed to show any relationship in these regions to self-ratings of pleasant response to a sucrose taste. A large literature shows that the anterior insula and associated gustatory cortex respond not only to the taste and physical properties of food but also to its rewarding properties (O'Doherty et al. 2001; Schultz et al. 2000; Small et al. 2001). Insular inputs to the ventrolateral striatum are hypothesized to mediate behaviors involving eating, particularly of highly palatable, high-energy foods (Kelley et al. 2002). AN subjects tend to avoid high-calorie, high-palatability food. In theory, this is consistent with abnormal responses of insula–striatal circuits that are hypothesized to mediate behavioral responses to the incentive value of food.

Implications Do individuals with AN have an insular disturbance specifically related to gustatory modulation or a more generalized disturbance related to the integration of interoceptive stimuli? This is of interest because the insula is thought to play an important role in processing interoceptive information (Craig 2002). Interoception, which can be defined as the sense of the physiological condition of the entire body, has long been thought to be critical for self-awareness, because it provides the link between cognitive and affective processes and the current body state. Aside from taste, interoceptive information includes sensations such as temperature, touch, muscular and visceral sensations, vasomotor flush, air hunger, and others (Paulus and Stein 2006). It remains to be determined which altered insula function contributes to symptoms in AN, such as disturbed self-awareness (e.g., ego-syntonic denial and impaired central coherence), lack of recognition of the effects of starvation and pain tolerance, and perhaps body image distortions. Finally, it is possible that AN individuals have reduced insula and striatal "reward" response to palatable foods. Because food may lack reward value or may be paradoxically anxiolytic for individuals with AN, they may not be able to respond to normal homeostatic mechanisms that drive hunger, thus becoming emaciated.

STUDIES OF NEUROTRANSMITTERS Neuropeptides The past decade has witnessed accelerating basic research on the role of neuropeptides in the regulation of feeding behavior and obesity. The mechanisms for controlling food intake involve a complicated interplay between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. Thus, studies in animals show that neuropeptides—such as cholecystokinin, the endogenous opioids (e.g.,

-endorphin), and neuropeptide Y—regulate the rate,

duration, and size of meals, as well as macronutrient selection (Morley and Blundell 1988; Schwartz et al. 2000). In addition to regulating eating behavior, a number of CNS neuropeptides participate in the regulation of neuroendocrine pathways. Thus, clinical studies have evaluated the possibility that CNS neuropeptide alterations may contribute to dysregulated secretion of gonadal hormones, cortisol, thyroid hormones, and growth hormone in the eating disorders (Jimerson et al. 1998; Stoving et al. 1999). While there are relatively few studies to date, most of the neuroendocrine and neuropeptide alterations apparent during symptomatic episodes of AN and BN tend to normalize after recovery. This observation suggests that most of the disturbances are consequences rather than causes of malnutrition, weight loss, and altered meal patterns. Still, an understanding of these neuropeptide disturbances may shed light on why many people with AN or BN cannot easily "reverse" their illness. In AN, malnutrition may contribute to a downward spiral sustaining and perpetuating the desire for more weight loss and dieting. Symptoms such as increased satiety, obsessions, and dysphoric mood may be exaggerated by these neuropeptide alterations and thus contribute to the downward spiral. Additionally, mutual interactions between neuropeptide, neuroendocrine, and neurotransmitter pathways may contribute to the constellation of psychiatric comorbidity often observed in these disorders. Even after weight gain and normalized eating patterns, many individuals who have recovered from AN or BN have physiological, behavioral, and psychological symptoms that persist for extended periods of time. Menstrual cycle dysregulation, for example, may persist for some months after weight restoration. In the following sections we provide a brief overview of studies of neuropeptides in AN and BN.

Corticotropin-Releasing Hormone When underweight, patients with AN have increased plasma cortisol secretion that is thought to be at least in part a consequence of hypersecretion of endogenous corticotropin-releasing hormone (CRH) (Gold et al. 1986; Kaye et al. 1987b; Licinio et al. 1996; Walsh et al. 1987). Given that the plasma and cerebrospinal fluid (CSF) measures return toward normal, it appears likely that activation of the hypothalamic-pituitary-thyroid axis is precipitated by weight loss. The observation of increased CRH activity is of great theoretical interest in AN, given that intracerebroventricular CRH administration in experimental animals produces many of the physiological and behavioral changes associated with AN, including markedly decreased eating behavior (Glowa and Gold 1991).

Opioid Peptides Studies in laboratory animals raise the possibility that altered endogenous opioid activity might contribute to pathological feeding behavior in eating disorders because opioid agonists generally increase, and opioid antagonists decrease, food intake (Morley et al. 1985). State-related reductions in concentrations of CSF

-endorphin and related opiate concentrations have been found in both

underweight AN and ill BN subjects (Brewerton et al. 1992; Kaye et al. 1987a; Lesem et al. 1991). In contrast, using the T lymphocyte as a model system, Brambilla et al. (1995a) found elevated -endorphin levels in AN, although the levels were normal in BN. If

-endorphin activity is a facilitator

of feeding behavior, then reduced CSF concentrations could reflect decreased central activity of this system, which then maintains or facilitates inhibition of feeding behavior in the eating disorders.

Neuropeptide Y and Peptide YY Neuropeptide Y (NPY) and peptide YY (PYY) are of considerable theoretical interest, because they have potent endogenous effects on feeding behavior within the CNS (Kalra et al. 1991; Morley et al. 1985; Schwartz et al. 2000). Underweight individuals with AN have been shown to have elevated CSF levels of NPY but normal levels of PYY (Kaye et al. 1990b). Clearly, elevated NPY does not result in increased feeding in underweight AN individuals; however, the possibility that increased NPY activity underlies the obsessive and paradoxical interest in dietary intake and food preparation is a hypothesis

worth exploring. On the other hand, CSF levels of NPY and PYY have been reported to be normal in women with BN when measured while subjects were acutely ill. Although levels of PYY increased above normal when subjects were reassessed after 1 month of abstinence from bingeing and vomiting, levels of the peptides were similar to control values in long-term recovered individuals (Gendall 1999). More recently, it has been reported that the plasma concentration of NPY was lower in patients with AN than in control subjects, whereas patients with BN had elevated NPY levels (Baranowska et al. 2000). Other data indicate that basal plasma PYY levels in AN are similar to or elevated in comparison with control values, with variability in postprandial PYY responses also noted across studies (Germain et al. 2007; Misra et al. 2006; Nakahara et al. 2007; Otto et al. 2007; Stock et al. 2005). Initial studies indicate that basal plasma PYY levels in BN are similar to control values but that the postprandial response is significantly blunted in the patient group (Kojima et al. 2005b; Monteleone et al. 2005). Additional research will be needed to assess the potential behavioral correlates of these findings.

Cholecystokinin Cholecystokinin (CCK) is a peptide secreted by the gastrointestinal system in response to food intake. Release of CCK is thought to be one means of transmitting satiety signals to the brain by way of vagal afferents (Gibbs et al. 1973). In parallel to its role in satiety in rodents, exogenously administered CCK reduces food intake in humans. The preponderance of data suggests that patients with BN, in comparison with control subjects, have diminished release of CCK following ingestion of a standardized test meal (M. J. Devlin et al. 1997; Geracioti and Liddle 1988; Phillipp et al. 1991; Pirke et al. 1994). Measurements of basal CCK values in blood lymphocytes and in CSF also appear to be decreased in patients with BN (Brambilla et al. 1995a; Lydiard et al. 1993). It has been suggested that the diminished CCK response to a meal may play a role in diminished postingestive satiety observed in BN. The CCK response in bulimic patients was found to return toward normal following treatment (Geracioti and Liddle 1988). Studies of CCK in AN have yielded less consistent findings. Some studies have found elevations in basal levels of plasma CCK (Phillipp et al. 1991; Tamai et al. 1993), as well as increased peptide release following a test meal (Harty et al. 1991; Phillipp et al. 1991). One study found that blunting of CCK response to an oral glucose load normalized in AN patients after partial restoration of body weight (Tamai et al. 1993). Other studies have found that measures of CCK function in AN were similar to or lower than control values (Baranowska et al. 2000; Brambilla et al. 1995b; Geracioti et al. 1992; Pirke et al. 1994). Further studies are needed to evaluate the relationship between altered CCK regulation and other indices of abnormal gastric function in symptomatic BN and AN patients (Geliebter et al. 1992).

Leptin Leptin, the protein product of the ob gene, is secreted predominantly by adipose tissue cells and acts in the CNS to decrease food intake, thus regulating body fat stores. In rodent models, defects in the leptin coding sequence resulting in leptin deficiency or defects in leptin receptor function are associated with obesity. In humans, serum and CSF concentrations of leptin are positively correlated with fat mass in individuals across a broad range of body weight. Obesity in humans is not thought to be a result of leptin deficiency per se, although rare genetic deficiencies in leptin production have been associated with familial obesity. Underweight patients with AN have consistently been found to have significantly reduced serum leptin concentrations in comparison with normal-weight control subjects (Baranowska et al. 2001; Grinspoon et al. 1996; Hebebrand et al. 1995; Mantzoros et al. 1997). Based on studies in laboratory animals, it has been suggested that low leptin levels may contribute to amenorrhea and other hormonal changes in the disorder (Mantzoros et al. 1997). Although the reduction in fasting serum

leptin levels in AN is correlated with reduction in BMI, there has been some discussion of the possibility that leptin levels in patients with AN may be higher than expected based on the extent of weight loss (Frederich et al. 2002; Jimerson 2002). Mantzoros et al. (1997) reported an elevated CSF-to-serum leptin ratio in AN patients compared with control subjects, suggesting that the proportional decrease in leptin levels with weight loss is greater in serum than in CSF. A longitudinal investigation during refeeding in patients with AN showed that CSF leptin concentrations reach normal values before full weight restoration, possibly as a consequence of the relatively rapid and disproportionate accumulation of fat during refeeding (Mantzoros et al. 1997). This finding led the authors to suggest that premature normalization of leptin concentration might contribute to difficulty in achieving and sustaining a normal weight in AN. Plasma and CSF leptin levels appear to be similar to control values in long-term recovered AN subjects (Gendall 1999). More recent studies indicate that patients with BN, in comparison with carefully matched control subjects, have significantly decreased leptin concentrations in serum samples obtained after an overnight fast (Baranowska et al. 2001; Brewerton et al. 2000). Initial findings in individuals who have achieved sustained recovery from BN, compared with control subjects with closely matched percentages of body fat, suggest that serum leptin levels remain decreased. This finding may be related to evidence for a persistent decrease in activity in the hypothalamic-pituitary-thyroid axis in long-term recovered BN individuals. These alterations could be associated with decreased metabolic rate and a tendency toward weight gain, contributing to the preoccupation with body weight characteristic of BN.

Ghrelin Intracerebroventricular injections of the gut-related peptide ghrelin strongly stimulated feeding in rats and increased body weight gain. When administered to healthy human volunteers, ghrelin results in increased hunger and food intake (Wren et al. 2001). In addition, it has been reported that fasting plasma ghrelin concentrations in humans are negatively correlated with BMI (Shiiya et al. 2002; Tanaka et al. 2002), percentage body fat, and fasting leptin and insulin concentrations (Tschop et al. 2001). As recently reviewed, a number of studies have shown elevation in circulating ghrelin levels in AN, with a return to normal levels as patients regain weight (Jimerson and Wolfe 2006). Further research is needed to explore the possible existence of ghrelin resistance in cachectic states related to the eating disorders. Studies comparing fasting plasma ghrelin concentrations in patients with BN and healthy controls have yielded variable results (Jimerson and Wolfe 2006). It is of interest, however, that the postprandial decrease in ghrelin levels appears to be blunted in patients with BN (Kojima et al. 2005b; Monteleone et al. 2005), consistent with other evidence for diminished satiety responses in the disorder.

Monoamine Systems There is an abundance of evidence that individuals with AN and BN have disturbances of monoamine function in the ill state. While less well studied, monoamine disturbances appear to persist after recovery.

Dopamine Altered dopamine activity has been found among ill AN and BN individuals. Homovanillic acid (HVA), the major metabolite of dopamine in humans, was decreased in CSF of underweight AN subjects (Kaye et al. 1984). Although ill subjects with BN, as a group, have normal CSF levels of HVA, several studies have shown significant reductions of CSF HVA levels in BN patients with high binge frequency (Jimerson et al. 1992; Kaye et al. 1990a). Individuals with AN have altered frequency of functional polymorphisms of dopamine D2 receptor genes that might affect receptor transcription and translation

efficiency (Bergen et al. 2005) and impaired visual discrimination learning (Lawrence 2003), a task thought to reflect dopamine signaling function. CNS dopamine metabolism may explain differences in symptoms between AN, AN-BN, and BN subjects. Our group (Kaye et al. 1999) found that recovered AN subjects had significantly reduced concentrations of CSF HVA in comparison with recovered AN-BN or BN women. A PET imaging study (Frank et al. 2005) found recovered AN subjects had increased binding of D2 and D3 receptors in the anteroventral striatum. Dopamine neuronal function has been associated with motor activity (Kaye et al. 1999) and with optimal response to reward stimuli (Montague et al. 2004; Schultz 2004). Individuals with AN have stereotyped and hyperactive motor behavior and anhedonic and restrictive personalities.

Serotonin 5-HT pathways play an important role in postprandial satiety. Treatments that increase intrasynaptic 5-HT or that directly activate 5-HT receptors tend to reduce food consumption, whereas interventions that dampen 5-HT neurotransmission or block receptor activation reportedly increase food consumption and promote weight gain (Blundell 1984; Leibowitz and Shor-Posner 1986). Moreover, CNS 5-HT pathways have been implicated in the modulation of mood, impulse regulation and behavioral constraint, and obsessionality, and they affect a variety of neuroendocrine systems. There has been considerable interest in the role that 5-HT may play in AN and BN (Brewerton 1995; Jimerson et al. 1990; Kaye and Weltzin 1991; Kaye et al. 1998; Steiger et al. 2005; Treasure and Campbell 1994). In part, this interest derives from study findings of alterations in 5-HT metabolism in AN and BN. When underweight, individuals with AN have a significant reduction in basal concentrations of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) in the CSF compared with healthy control subjects, as well as blunted plasma prolactin response to drugs with 5-HT activity and reduced 3H-imipramine binding. Together, these findings suggest reduced serotonergic activity, although this may arise secondarily to reductions in dietary supplies of the 5-HT–synthesizing amino acid tryptophan. By contrast, CSF concentrations of 5-HIAA are reported to be elevated in long-term weight-recovered AN individuals. These contrasting findings of reduced and heightened serotonergic activity in acutely ill and long-term recovered AN individuals, respectively, may seem counterintuitive; however, since dieting lowers plasma tryptophan levels in otherwise healthy women (Anderson et al. 1990), resumption of normal eating in individuals with AN may unmask intrinsic abnormalities in serotonergic systems that mediate certain core behavioral or temperamental underpinnings of risk and vulnerability. Considerable evidence also exists for a dysregulation of serotonergic processes in BN. Examples include blunted prolactin response to the 5-HT receptor agonists m-chlorophenylpiperazine (m-CPP), 5-hydroxytryptophan, and dl-fenfluramine and enhanced migraine-like headache response to m-CPP challenge. Acute perturbation of serotonergic tone by dietary depletion of tryptophan has been linked to increased food intake and mood irritability in individuals with BN compared with healthy control subjects. Also, as in AN, women with long-term recovery from BN have been shown to have elevated CSF concentrations of 5-HIAA as well as reduced platelet binding of paroxetine (Steiger et al. 2005).

Serotonin and Behavior There is an extensive literature associating the serotonergic systems and fundamental aspects of behavioral inhibition (Geyer 1996; Soubrie 1986). Reduced CSF 5-HIAA levels are associated with increased impulsivity and aggression in humans and nonhuman primates, whereas increased CSF 5-HIAA levels are related to behavioral inhibition (Fairbanks et al. 2001; Westergaard et al. 2003). Thus, it is of interest that women who had recovered from AN and BN showed elevated CSF 5-HIAA concentrations. Behaviors found after recovery from AN and BN, such as obsessionality with symmetry and exactness, anxiety, and perfectionism, tend to be opposite in character to behaviors displayed by people with low 5-HIAA levels. Together, these studies contribute to a growing literature suggesting

that reduced CSF 5-HIAA levels are related to behavioral undercontrol, whereas increased CSF 5-HIAA concentrations may be related to behavioral overcontrol. The possibility of a common vulnerability for BN and AN may seem puzzling, given the well-recognized differences in behavior in these disorders. However, studies suggest that AN and BN have a shared etiological vulnerability—that is, there is a familial aggregation of a range of eating disorders in relatives of probands with either BN or AN, and these two disorders are highly comorbid in twin studies. BN responds to 5-HT-specific medications. Few controlled trials of 5-HT-specific medication have been done in AN, and it remains uncertain whether there is a beneficial response. Both disorders have high levels of harm avoidance (Klump et al. 2000a), a personality trait hypothesized to be related to increased 5-HT activity. These data raise the possibility that a disturbance of 5-HT activity may create a vulnerability for the expression of a cluster of symptoms that are common to both AN and BN. Other factors that are independent of a vulnerability for the development of an eating disorder may contribute to the development of eating disorder subgroups. For example, people with restricting-type AN have extraordinary self-restraint and self-control. The risk for obsessive-compulsive personality disorder is elevated only in this subgroup and in their families and shows a shared transmission with restricting-type AN (Lilenfeld et al. 1998). In other words, an additional vulnerability for behavioral overcontrol and rigid and inflexible mood states, combined with a vulnerability for an eating disorder, may result in restricting-type AN. The contribution of 5-HT to specific human behaviors remains uncertain. 5-HT has been postulated to contribute to temperament or personality traits such as harm avoidance (Cloninger 1987) and behavioral inhibition (Soubrie 1986) or to categorical dimensions such as OCD (Barr et al. 1992), anxiety and fear (Charney et al. 1990), and depression (Grahame-Smith 1992), as well as satiety for food consumption. It is possible that separate components of 5-HT neuronal systems (i.e., different pathways or receptors) are coded for such specific behaviors. However, that may not be consistent with the neurophysiology of 5-HT neuronal function.

PET Studies Using 5-HT Receptor Radioligands The marriage of PET imaging with selective neurotransmitter radioligands has resulted in a technology permitting new insights into regional binding and specificity of 5-HT and dopamine neurotransmission in vivo in humans and their relationship to behaviors. The 5-HT1A autoreceptor is located presynaptically on 5-HT somatodendritic cell bodies in the raphe nucleus, where it functions to decrease 5-HT neurotransmission (Staley et al. 1998). High densities of postsynaptic 5-HT1A exist in the hippocampus, septum, amygdala, and entorhinal and frontal cortex, where they serve to mediate the effects of released 5-HT. Studies in animals and humans implicate the 5-HT1A receptor in anxiety (File et al. 2000) and depression and/or suicide (Mann 1999). Pharmacological and knockout studies implicate the 5-HT1A receptor in the modulation of anxiety (Gross et al. 2002). Bailer et al. (2007) reported that ill AN individuals had a 50%–70% increase in 5-HT1A receptor–binding potential in subgenual, mesial temporal, orbitofrontal, and raphe brain regions, as well as in prefrontal, lateral temporal, anterior cingulate, and parietal regions. Increased 5-HT1A postsynaptic activity has been reported in ill BN subjects (Tiihonen et al. 2004). Recovered binge-eating/purging–type AN subjects and BN subjects (Bailer et al. 2005; W. Kaye, unpublished data, March 2008) showed significant (20%–40%) increases in 5-HT1A receptor binding potential in these same regions compared with healthy control subjects (Bailer et al. 2005). By contrast, recovered restricting-type AN women showed no difference in 5-HT1A receptor binding potential compared with control subjects (Bailer et al. 2005). AN and BN are frequently comorbid with depression and anxiety disorders. However, reduced 5-HT1A receptor binding potential has been found in ill (Drevets et al. 1999; Sargent et al. 2000) and recovered (Bhagwagar et al. 2004) depressed subjects, as well as in a primate model for depression

(Shively et al. 2006). Parsey et al. (2005) found no difference in carbonyl-11C]WAY100635 binding potential in major depressive disorder, although a subgroup of never-medicated subjects had elevated carbonyl-11C]WAY100635 binding potential. Recent studies have found reduced [11C]WAY100635 binding potential in social phobia (Lanzenberger et al. 2007) and panic disorder (Neumeister et al. 2004). These findings suggest that AN and BN, anxiety, and depression share disturbances of common neuronal pathways but are etiologically different. Postsynaptic 5-HT2A receptors, which are present at high densities in the cerebral cortex and other regions of rodents and humans (Burnet et al. 1997; Saudou and Hen 1994), are of interest because they have been implicated in the modulation of feeding and mood as well as in selective serotonin reuptake inhibitor response (Bailer et al. 2004; Bonhomme and Esposito 1998; De Vry and Schreiber 2000; Simansky 1996; Stockmeier 1997). Ill AN subjects were found to have normal 5-HT2A receptor binding potential values in one study (Bailer et al. 2007) and reduced binding potential in another study (Audenaert et al. 2003) in the left frontal, bilateral parietal, and occipital cortex. After recovery, individuals with restricting-type AN had reduced 5-HT2A receptor binding potential in mesial temporal and parietal cortical areas as well as in subgenual and pregenual cingulate cortex (Frank et al. 2002). Similarly, recovered binge-eating/purging–type AN women had reduced 5-HT2A receptor binding potential in the left subgenual cingulate, left parietal, and right occipital cortex (Bailer et al. 2004), and recovered BN women had reduced [18F]altanserin binding potential relative to controls in the orbitofrontal region (Kaye et al. 2001). The PET imaging studies in ill and recovered AN and BN subjects described above found significant correlations between harm avoidance and binding for the 5-HT1A, 5-HT2A, and dopamine D2/D3 receptors in mesial temporal and other limbic regions. Bailer et al. (2004) found that recovered AN-BN subjects showed a positive relationship between [18F]altanserin binding potential in the left subgenual cingulate and mesial temporal cortex and harm avoidance. For ill AN subjects, [18F]altanserin binding potential was positively related to harm avoidance in the supragenual cingulate, frontal, and parietal regions. 5-HT2A receptor binding and harm avoidance were shown to be negatively correlated in the frontal cortex in healthy subjects (Moresco et al. 2002) and in the prefrontal cortex in patients who attempted suicide (van Heeringen et al. 2003). Clinical and epidemiological studies have consistently shown that one or more anxiety disorders occur in the majority of people with AN or BN (Godart et al. 2002; Kaye et al. 2004; Kendler et al. 1995; Walters and Kendler 1995). Silberg and Bulik (2005), using twins, found a unique genetic effect that influences liability to early anxiety and eating disorder symptoms. When a lifetime anxiety disorder is present, the anxiety most commonly occurs first in childhood, preceding the onset of AN or BN (Bulik et al. 1997; Deep et al. 1995; Godart et al. 2000). Anxiety and harm avoidance remain elevated after recovery from AN, AN-BN, and BN (Wagner et al. 2006a), even if individuals never had a lifetime anxiety disorder diagnosis (Kaye et al. 2004). Finally, anxiety (Spielberger et al. 1970) and harm avoidance from Cloninger's Temperament and Character Inventory (Cloninger et al. 1994) have been a robust signal in genetic studies (Bacanu et al. 2005). In summary, the premorbid onset and the persistence of anxiety and harm avoidance symptoms after recovery suggest these are traits that contribute to the pathogenesis of AN and BN. The PET imaging data suggest that such behaviors are related to disturbances of 5-HT and dopamine neurotransmitter function in limbic and executive pathways. This technology holds the promise of a new era of understanding the complexity of neuronal systems in human behavior. For example, postsynaptic 5-HT1A receptors (Celada et al. 2001; Richer et al. 2002; Sibille et al. 2000; Szabo and Blier 2001) have downstream effects and interactions with other neuronal systems, such as norepinephrine, glutamate, and -aminobutyric acid (GABA). Enhanced 5-HT1A activity in AN and BN may cause or reflect an altered balance between these neuronal systems. Moreover, 5-HT1A receptors interact with other 5 HT receptors such as 5-HT2A (Martin et al. 1997;

Szabo and Blier 2001). 5-HT1A postsynaptic receptors mediate locus coeruleus firing through 5-HT transmission at 5-HT2A receptors (Szabo and Blier 2001). Theoretically, increased 5-HT1A and reduced 5-HT2A postsynaptic receptor activity in AN might result in an increase in noradrenergic neuron firing (Szabo and Blier 2001). Moreover, postsynaptic 5-HT1A receptors hyperpolarize and 5-HT2A receptors depolarize layer V pyramidal neurons (Martin-Ruiz et al. 2001). In AN, synergistic effects of these receptors, which are collocated on pyramidal neurons, may reduce pyramidal neuronal excitability. In summary, these PET–radioligand studies confirm that altered 5-HT neuronal pathway activity persists after recovery from AN and BN and support the possibility that these psychobiological alterations might contribute to traits, such as increased anxiety, that may contribute to a vulnerability to develop an eating disorder.

CONCLUSION There remain daunting challenges to the investigation of neurobiological mediators of risk and clinical pathology in AN and BN. To what extent abnormalities detected are consequences of pathological eating behavior, malnutrition, or their long-term sequelae remains speculative. Data on the functional status of these neurobiological systems are too sparse to allow for definitive conclusions regarding the possible etiological significance of differences reported between individuals with eating disorders and healthy control subjects. Clearly, many of the alterations in neuropeptide and monoaminergic function in eating disorders are state dependent; however, given the effects of these systems on mood, anxiety, memory organization, and body physiology, these alterations may well have significant pathogenic influences, both sustaining and exacerbating certain psychological and cognitive elements of these syndromes. Thus, neurobiologically mediated effects may be contributing factors to the frequently long-term, pernicious, and self-sustaining course of illness, at least in many patients. These associations, although speculative, nevertheless underscore the importance of aggressive and sustained treatment of both the nutritional and the behavioral/psychological elements of the syndromes to allow for stabilization and possible normalization of neuropeptidergic and monoaminergic functions. Still, several lines of evidence from family and twin research, premorbid and retrospective data, and studies with recovered individuals suggest that traits, perhaps related to 5-HT modulation of anxiety and perfectionistic obsessiveness, create a susceptibility for some people to develop an eating disorder. Adolescence is a time of transition, where individuals leave the security of their home environment and must learn to balance immediate and long-terms needs and goals in order to achieve independence. For such individuals, learning to flexibly interact and master complex and mixed cultural and societal messages and pressures, or cope with stress, may be difficult and overwhelming, exacerbating underlying traits of harm avoidance and a desire to perfectly achieve. To a large extent, current treatments for AN and BN have been based on therapies developed for other psychiatric disorders. While these are effective to some degree, particularly for BN, many individuals with AN and BN remain ill for many years and have only partial resolution of symptoms with treatment. Thus, there is a substantial need to understand how neurobiological risk factors contribute to symptoms, as well as the interaction of temperament with the environment, in order to develop specific and more effective therapy for these disorders.

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Royce Lee, Emil F. Coccaro: Chapter 51. Neurobiology of Personality Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.433298. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 51. Neurobiology of Personality Disorders NEUROBIOLOGY OF PERSONALITY DISORDERS: INTRODUCTION The personality disorders as represented in the DSM-IV-TR (American Psychiatric Association 2000) and ICD-10 (World Health Organization 1992) classification systems are characterized by trait-like disturbances in emotion, cognition, and social function. As a group, they share the important commonalities of chronic course with early onset, relative preservation of intelligence, and absence of gross neurological deficit. In order to summarize the neurobiological literature, we have chosen a heuristic organization that emphasizes the location of "lesion" of personality disorder within neural networks mediating mental activity. This is opposed to a model that locates the lesion in personality, phenomenology (Siever and Davis 1991), or molecules. All of these are equally valid as heuristics. The advantage of this approach is that it allows a novel, useful reorganization of the existing database, characterized by a close relationship between the identified neurobiological abnormalities and a neurobiologically plausible brain-based model. We propose that three principal neurobiological processes may be affected lastingly in personality disorder: 1) representation, the working memory process whereby information about the environment is accurately held in biological neural networks; 2) metarepresentation, multidimensional representations of aspects of the self, the environment, and others that permit self-consciousness and social interaction; and 3) motivation and emotion, the process by which discrepancy between an internal motivational state and current state is registered by neurotransmitter- and/or neuropeptidemediated feedback loops. This model is clearly not complete, nor is it intended to propose the existence of three biologically discrete categories of personality disorder. Its value is that it facilitates organization of recent findings regarding the neurobiology of personality disorder into a model of mind–brain operations that will remain compatible with rapid advances in the neurosciences in the near future.

WHAT IS A NEUROBIOLOGY OF PERSONALITY DISORDERS? There is no question that the brain mediates normal and abnormal mental activity. However, it is fair to ask if speaking of a neurobiology of personality disorders is a category mistake, a mixture of incompatible forms of knowledge. On the one hand, there is general agreement that some aspects of personality disorder (e.g., anxiety proneness, impulsivity) are validly modeled by genetically based, molecularly mediated traits that are preserved across cultures (Yamagata et al. 2006). Such traits can be biologically and behaviorally modeled in nonhuman animals. This approach is firmly validated by the remarkable preservation of the molecular building blocks of brain and nervous function throughout evolution and across species, as exemplified by the similarity of amino acid sequences for neurotransmitters, neuropeptides, and associated receptor systems across phylogenies. Alterations of these systems bias behavior and mentation probabilistically. This molecularly based, dimensional trait perspective has proven to be of value in reducing the complexity of brain and behavioral relationships. However, the dimensional trait perspective does not account for other important features of personality disorder (e.g., suicide, self-injury, social dysfunction) that do not yet have animal model equivalents and to date are most readily studied in human volunteers, using techniques such as behavioral measurements, electrophysiology, functional neuroimaging, and quantitative assay of

biological specimens. It is assumed that these complex phenomena develop over time, with interaction between genes and environment, and involve decision-making processes. It is not yet clear if these represent trait-like dimensions, or if there are clear demarcations between abnormality and normality. As has been pointed out by Kendler (2005), overly strict biological reductionism is an insufficient approach, insofar as the complexity of the molecular determinants is more than matched by the complexity of neuronal networks that have developed in interaction with the environment. However, personality disorders are still clearly biological in the sense that their symptoms are mediated by dysfunction in neuronal networks located in the brain. Definitive progress will eventually depend on our ability to adequately model the biological neural networks and developmental processes that underlie what has traditionally been understood in psychiatry in psychological or folk psychological terms. A heuristic approach to organizing the existing database is justified by the lack of certainty that existing personality disorder categories truly carve "at nature's joints." The most recent behavioral genetic studies confirm the existence of complex genetic relationships between and within the Cluster A, B, and C disorders as currently defined (Fogelson et al. 2007; Kendler et al. 2007; ReichbornKjennerud et al. 2007; Torgersen et al. 2008). The results are too complex to summarize here, but they simultaneously confirm some and dispute other cluster, dimensional, and categorical attempts at personality disorder description. An important conclusion of this work is that speaking of the neurobiology of any given specific Axis II disorder is premature without the caveat that the current Axis II nosology contains heterogeneity and overlap. Thus, becoming overly focused on differences and similarities between disorders (e.g., antisocial vs. borderline personality disorder) could result in conclusions that are invalid due to invalid premises.

REPRESENTATION The process whereby information regarding the environment is represented in symbolic form by electrophysiological activity in biological neural networks is known as representation. Abnormalities in representation are the prominent feature of schizotypal personality disorder, but stress may cause transient abnormal representation in the Cluster B disorders as well. Representation is mediated by reverberant neural activity (i.e., oscillations) over widely distributed and highly interconnected networks of pyramidal cells and associated neurons. Persistence of activity in networked circuits of corticothalamic and cortico-cortico neurons can sustain a neural representation even after the original stimulus is no longer present. If the representation concerns an environmental stimulus, the corresponding areas of primary and secondary sensory cortex mediate representation of sensory information, but other brain regions are also activated in the process. For example, verbal working memory tasks are associated with activation of parietal and cerebellar brain regions, in addition to prefrontal and temporal regions (Paulesu et al. 1993). To what extent neural resources are utilized for the representation of a stimulus is partially determined by the salience of the stimulus. The anticipated reward value of a stimulus is reflected in the gain of delay activity (persistent activity) of the dorsolateral prefrontal cortex (Postle 2006; Sawaguchi and Yamane 1999), although not all information processed in the brain necessarily passes through circuits in the dorsolateral prefrontal cortex. Thus, working memory processes are shaped by the interaction of attention and representation (Fuster 2006). It is useful here to review the biological building blocks of working memory before moving on to abnormalities associated with personality disorder. Synchronization of network oscillations is regulated by fast-spiking -aminobutyric acid (GABA) neurons, which are in turn modulated by glutamate inputs. Network oscillations facilitate information transfer across different brain regions, and according to the global workspace theory, their synchronization is important for the binding of disparate aspects of a stimulus in conscious awareness. According to the Cohen-Braver-Brown hypothesis (Cohen et al. 2002), dopamine plays a key role in modulating the activity of oscillating

cortical circuits. An optimal balance of tonic (D1) and phasic (D2) dopaminergic tone shapes the signal-to-noise characteristics of information flow in the prefrontal cortical neural networks. Tonic D1 receptor stimulation stabilizes neural network activity around attractors. Phasic "bursts" of D2 receptor stimulation in the striatum reset prefrontal cortical neural networks and open a subcortical, striatal "gate" for salient information. D1 and D2 functions are interrelated, with D1 tone restraining D2 activity. The end result of low D1 tone according to the computation model is reduced signalto-noise ratio, instability of neural network state, and aberrant assignment of salience to information. This may be apparent to an outside observer as increased distractibility and unreliable or invalid salience being attributed to stimuli. It may also be measured by an observer as eye-tracking abnormalities. The reason for this is that tracking of a moving object in space with the eyes requires working memory "buffers" to constantly update and store visual information and eye movement position.

Abnormalities in the Neurobiology of Representation in Schizotypal Personality Disorder It is of great interest then that schizotypal personality disorder has been associated with eye-tracking abnormalities (Siever et al. 1991) and that eye-tracking abnormalities are correlated with the dimensional severity of psychotic-like and schizotypal-like characteristics (Siever et al. 1984). Confirmation of connections between eye-tracking abnormalities and schizotypy comes from follow-up studies of visual and auditory attention/working memory (Condray and Steinhauer 1992; Harvey et al. 1996; Lees Roitman et al. 1997; Siever 1985). Neurophysiological studies have found disturbed neural network function during working memory tasks in schizotypal personality disorder, in the form of diminished slow negative potential magnitude (or contingent negative variation) (Klein et al. 1999). Additionally, electroencephalographic activity in the theta-band, believed to correspond to memoryrelated representational processes and originating from the hippocampal generators, has been found to be decreased in patients with schizotypal personality disorder versus controls (Lazarev 1998). As dopamine receptor blockade is essential for antipsychotic drug efficacy, dopamine is a candidate neurotransmitter mediator of psychosis and working memory breakdown. Homovanillic acid (HVA), the product of dopamine metabolism, is measurable in the cerebrospinal fluid (CSF) and may serve as an index of brain dopamine activity. CSF HVA levels are positively related to severity of psychotic-like symptoms in schizotypal personality disorder (Siever et al. 1991), as has been found in schizophrenia (Pickar et al. 1990). Elevated brain HVA concentration may reflect diminished D1 receptor activity; D1 receptors are more widely expressed in the brain relative to D2 or other dopamine receptors, and administration of D1 receptor antagonists is associated with increased local HVA concentration (See et al. 1991). As dopamine receptors are most densely expressed in the striatum, dysfunction in this brain region may be related to dopaminergic problems. Lower left and right caudate nucleus volumes have been found in schizotypal personality disorder subjects compared with normal control subjects (Levitt et al. 2002). Consistent with this, schizotypal personality disorder patients exhibit lower resting regional glucose metabolism in the caudate, as compared with patients with schizophrenia or normal control subjects (Shihabuddin et al. 2001). Structural and functional regional findings in the putamen mirror those of the caudate, with schizotypal personality disorder associated with decreased putamen size (Shihabuddin et al. 2001) and resting metabolism (Buchsbaum et al. 1992), although increased putamen resting glucose metabolism is also reported (Shihabuddin et al. 2001). In general, these findings are consistent with underlying abnormalities in striatal structure and function, and they support the plausibility of a dopamine-related functional deficit in striatal gating of information in schizotypal personality disorder. It would be premature to conclude that there is a localized striatal or frontal "lesion" underlying schizotypal personality disorder, however. The neural circuits implicated in working memory deficits in schizotypal personality disorder are widely distributed across the brain and include the frontal,

temporal, and parietal cortex (Koenigsberg et al. 2005). Additionally, brain structural differences between schizotypal personality disorder subjects and controls implicate a wider circuit that includes the temporal lobes and thalamus (Dickey et al. 2002). In summary, a significant body of work describes abnormal function and structure of widely distributed neural circuits involved in working memory and representational processes. Dopamine plays a key role in these processes, and indices of abnormal dopamine function have been associated with schizotypal personality disorder. Other biological factors such as GABA and glutamate are also likely to play a role in dysfunctional representational processes in schizotypal personality disorder but have not yet been extensively studied.

Genetics of Cluster A Personality Disorders Schizotypal personality disorder is more prevalent among first-degree relatives of persons with schizophrenia. This relationship to schizophrenia seems to be specific to schizotypal personality disorder, as it is present only in diminished form with paranoid, schizoid, and avoidant personality disorder and is absent with borderline personality disorder (BPD) (Fogelson et al. 2007; Kendler et al. 1993). It is thought that the trait of schizotypy is conserved because of the increase in fitness that accompanies some aspects of it, such as creative nonconformity (Nettle 2006) on the behavioral level or neural network complexity on the molecular level (Burns 2004). High heritability (72%) has been found for dimensional measures for schizotypy. Molecular genetics studies confirm shared susceptibility between schizotypal personality disorder and schizophrenia (Fanous et al. 2007). Schizotypy has been associated with a high-activity catechol-O-methyltransferase (COMT) genotype in a single study (Schurhoff et al. 2007), as well as a functional polymorphism of the neuroregulin-1 (NG1) gene (Lin et al. 2005). However, the field is still quite far from understanding the molecular determinants of schizotypy.

METAREPRESENTATION Disturbed self-concept, empathy, social attribution, and social interaction are critical aspects of personality disorder that are mediated in brain neuron networks by metarepresentation (sometimes referred to as metacognition). Metarepresentation refers to the symbolic representation of the self in the context of its environment. The environment is not merely the physical environment but could include "meta" spaces such as a social environment. Metarepresentational abnormalities include visuospatial processing deficits (BPD), aberrant social cognition (in nearly all personality disorders), and deficiencies in self-awareness (alexithymia, poor self-concept, and inaccurate sense of social worth, primarily in borderline, narcissistic, histrionic, dependent, and avoidant personality disorder). In addition to the working memory processes of the prefrontal cortex, metarepresentation additionally relies on analog and digital-like computational processes native to the parietal cortex (Tudusciuc and Nieder 2007). Neural networks in these regions are specialized in multimodal sensory and object processing and visuospatial processing, as well as the processing of symbolic objects (i.e., mathematics and language). Importantly, representation of the position of the self in physical space is dependent on intact parietal function, as lesions here result in the rapid decay of the sense of one's own body position. Movement-related proprioceptive information can refresh the sense of the body in space, but the information rapidly decays until movement occurs again (Arzy et al. 2006a). All available evidence points toward overlapping neural circuits involved in the processing of the body in physical space and in "social" space. So-called mirror neurons in the parietal lobe respond automatically to the body movements of the self and others and reflect the importance of the parietal lobe in social communication, as well as the automatic parallel structure of social cognitive processing. It is not yet clear to what degree these processes are automatic or require effortful attention (reviewed in Satpute and Lieberman 2006). Preliminary findings suggest that at least some portion of metarepresentational processes that mediate social cognition is automatic. Examples include

temporoparietal alpha-band electroencephalographic activity evoked during human social interaction and parietal neuron spiking in socializing nonhuman primates (Fujii et al. 2007). Effortful social cognition, such as empathy or accurate attribution, is likewise associated with the activity of the parietal cortex (Fogassi et al. 2005), although prefrontal regions may be necessary for processing of emotion-related information (Saxe 2006). Self-consciousness is another form of metarepresentation that similarly relies on distributed networks that include the frontal, temporal, and parietal brain regions. Intact function of the parietal precuneus may be a necessary condition for self-consciousness, as deactivation of the precuneus with anesthetic agents is characterized specifically by a temporary loss of high-order representation of body or self (Cavanna and Trimble 2006; Maquet et al. 1999). Dissociative episodes can be marked by disturbed awareness of one's own body. It is of interest then that stimulation of the temporoparietal junction results in out-of-body experiences similar to those experienced during intense episodes of depersonalization (Arzy et al. 2006b). Cholinergic neurons from the substantia inominata/nucleus basalis magnocellularis enervate the frontal and parietal cortex. Disruption of the cholinergic neurons of the parietal cortex is associated with impaired attention and learning, in the absence of deficits in classical conditioning, suggesting a role for these parietal neurons in effortful learning (Thiel et al. 2005). Serotonin (5-HT) is also important in the development and function of the parietal cortex. During in utero and infant development, serotonin is a powerful signal for cortical development. Disrupted 5-HT metabolism results in the poorly differentiated laminar cortical barrels (Osterheld-Haas and Hornung 1996), with severe deficits in the development of sensory and cognitive capacities related to the type of cortex affected. Less dramatic variations in 5-HT metabolism, in the form of genetic polymorphisms of the 5-HT transporter and/or monoamine oxidase A enzyme, probably exert their greatest effect during neural development. In adulthood, 5-HT alters signal-to-noise characteristics of pyramidal cell networks, and administration of fluoxetine grossly increases the metabolic rate of the parietal cortex (Buchsbaum et al. 1997). It is established that metarepresentational capacities are shaped by gene–environment interaction. Biologically informed neural network models confirm the importance of parietal and frontal lobe interactions in shaping development (Edin et al. 2007). The development of visuospatial working memory ability in humans over the first two decades of life is paralleled by age-related changes in frontoparietal network activations during visuospatial working memory performance (Kwon et al. 2002); the protracted time course of this development suggests that the process is complex. Accordingly, connectivity between frontal and parietal lobes has been shown to increase in early childhood and continue to increase through adolescence, as measured by diffusion tensor imaging (DTI) (Olesen et al. 2003). It is biologically plausible that disruptions in normative processes such as abnormal parental care or exposure to environmental toxins could derail optimal development. As an example, in animals early-life environment has been demonstrated to affect the expression of parietal serotonin2A (5-HT2A) receptor mRNA (Vazquez et al. 2000).

Parietal Lobe Dysfunction in Borderline Personality Disorder Patients with BPD have difficulties with visual memory and visuospatial abilities in the absence of gross deficits of executive function (Beblo et al. 2006b). This raises the possibility that in addition to frontolimbic connectivity (see below), BPD may be associated with abnormal frontoparietal connectivity. Electrophysiological evidence corroborating deficits in frontoparietal connectivity includes findings of decreased P300 amplitude to novel stimuli in a multitude of event-related potential (ERP) studies (reviewed in Boutros et al. 2003) and decreased gamma frequency range neural synchrony of posterior cortical regions during early phases of stimulus processing (Williams et al. 2006). Criminal psychopaths have also been found to have decreased amplitude of late (>300 msec) positivity over parietal electrodes to novel stimuli (Howard and McCullagh 2007), suggesting

that this abnormal parietal neural synchronization may underlie the known overlap between borderline and antisocial personality disorder. In addition to the electrophysiological abnormalities, BPD has been consistently linked to structural and functional parietal findings. Patients with BPD compared with matched controls have smaller parietal lobe volume (Irle et al. 2005) and diminished resting parietal metabolic rate (Lange et al. 2005; Lepping and Swinton 2004). During tasks designed to stress cortical circuits, BPD patients show exaggerated parietal metabolism (Beblo et al. 2006a; Schnell et al. 2007). This is interpretable as a compensatory mechanism for decreased processing efficiency. Parietal serotonergic function may be impaired as well, as there is evidence of decreased parietal metabolic activation following pharmacochallenge with the 5-HT releasing agent fenfluramine in BPD (Soloff et al. 2000).

Disturbances in Awareness Dissociation is perhaps the most dramatic disturbance of metarepresentation, in which the experience of the self is disturbed. Dissociation usually occurs during a stressful experience and is most closely associated with BPD. Although dissociation is usually associated with psychopathology, it can also be evoked in healthy individuals, although without the same level of severity. Evidence suggests that the tendency to dissociate is heritable (Jang et al. 1998) and is associated with emotion dysregulation and suspiciousness (de Ruiter et al. 2007). Thus, its neurobiology should be tractable to investigation. States of stress and high arousal are characterized by glutamatergic, dopaminergic, and noradrenergic hyperactivity that may impair prefrontal cortical information-processing ability. Dopamine and norepinephrine function are thought to exhibit an inverted U-shaped relationship with prefrontal cortical information-processing capacity. It has been hypothesized that dissociation permits learning during an otherwise overwhelmed, dysfunctional state (de Ruiter et al. 2007), or it may serve to decrease arousal by modulating neural function in the prefrontal, limbic, and parietal brain regions, in much the same way that hypnosis decreases pain perception by modulating brain function (Roder et al. 2007). On the other hand, dissociation does not always occur in reaction to stress. In depersonalization disorder, individuals may feel dissociated in the absence of stress, and during these episodes, metabolism is increased in the right parietal lobe (Simeon et al. 2000). Individuals with depersonalization disorder, like patients with BPD, also show deficits in visuospatial information processing, with deficits in visual working memory and spatial reasoning. Therefore, individuals prone to dissociation may have an underlying parietal cortex vulnerability or faulty connectivity with the parietal cortex. This vulnerability could manifest itself at baseline with subtle difficulties in visual working memory; under stress, the vulnerability may be unmasked in a breakdown in metarepresentation of the self or even in representation of the environment. We do not yet know whether the underlying biological abnormalities also affect self-awareness in social cognition (e.g., representation of one's own social value). However, a lack of awareness of one's actual social worth is manifested in narcissistic and antisocial personality disorder as overestimation of one's self-worth and contempt for others. In BPD and histrionic personality disorder, it is manifested by contempt for the self and dependency on others. Very little attention has been paid to why these seemingly opposite tendencies occur in genetically related disorders and whether this phenomenon represents a sexually dimorphic expression of a common neurobiological problem.

Perfectionism Perfectionism is a psychological tendency to hold the self or others to an unnatural standard with respect to performance, beauty, or other attributes. It is most closely associated with obsessivecompulsive personality disorder (OCPD) (Halmi et al. 2005), especially when OCPD is comorbid with an eating disorder or obsessive-compulsive disorder (OCD) (Coles et al. 2008). Abnormal dopaminergic function is implicated in perfectionism. OCPD has been associated with polymorphisms of the dopamine D3 receptor gene (Light et al. 2006). The association is plausible, as stimulation of

the striatal D3 receptors can cause compulsive, repetitive behavior. The severity of perfectionist traits in eating disorders has been associated with DRD4 polymorphisms (Bachner-Melman et al. 2007). Dopaminergic abnormalities would be expected to heighten approach/avoidance conflicts that occur during evaluation of self or others. Such a process in theory would result in behavioral manifestations of perfectionism. 5-HT dysfunction may also play a role. By inhibiting reversal learning, serotonergic deficits may contribute to the narrow focus on seemingly arbitrary or inappropriate goals (Clarke et al. 2007). Further work is necessary to explore specific relationships between serotonergic function and perfectionism in OCPD.

MOTIVATION AND EMOTION Disturbances in brain-based motivational and emotion systems result in some of the most self-destructive symptoms of personality disorder, such as suicidality, self-injury, violence, and reckless behavior. Psychological conceptualizations of emotion have tended to emphasize the subjective experience of affect and how this is mediated by brain activity. Although useful, this emphasis runs the danger of placing a hidden observer in an infinitely receding phrenological conception of brain function and when overemphasized results in a conceptual and clinical dead end. Neural network models of brain function focus on the more tractable issue of feedback systems for control. Hence, E. T. Rolls (2000) defined emotion is an internal motivational state transiently evoked by positive or negative reinforcers. The experience of affect provides motivation for motor behavior, whether it is appropriate and/or adaptive or not. So-called primary reinforcers include stimuli with intrinsic negative or positive survival significance (e.g., the pleasant taste of palatable food). So-called secondary reinforcers are more complex, involving multidimensional representations (e.g., a context of perceived social threat). Thus, emotional processes involve the modification of representations of the reinforcement value of an attended stimulus (e.g., the appetitive aspects of the odor of food) by a continuously updated representation, or metarepresentation, of motivational state (e.g., nutritional need). Thus, both emotion and motivation are slightly different aspects of a complex system that has evolved to guide decision making and behavior. Circuits that traverse, among other brain regions, the amygdala and orbitofrontal cortex are necessary to be able to update the reinforcement value of a stimulus held in working memory with new information. Circuits including the medial prefrontal cortex, orbitofrontal cortex, insula, amygdala, bed nucleus of the stria terminalis, parietal lobes, and cerebellum are involved in the maintenance of internal motivational states and affect. Induction of such subjective states can predictably bias the interpretation of internal and external stimuli and thus have a strong but probabilistic effect on motor response. Abstract representations of motivational state are mediated by hypothalamic and brain stem networks. Within these structures, neuropeptides such as corticotropin-releasing hormone (CRH), vasopressin, and oxytocin play important signaling roles. Disruption of normal neuropeptide signaling results in abnormal development and severe dysregulation of motivated behaviors such as feeding, sex, and attachment. Neuropeptide signaling appears to play a deterministic role on behavior. Sometimes, but not necessarily always, these modifications can be accompanied by the induction of a subjective state (e.g., hunger). Finally, working memory and metarepresentation are both implicated in emotion in motivation, as these processes require reinforcement information to be sustained and processed. All three of the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) have receptors in frontal cortical and limbic brain regions. Stimulation of monoamine receptors with a change in synaptic monoamine neurotransmitter level alters the input gain and output gain of information-processing circuits of predominantly pyramidal cell neurons in the cortex. This permits systematic and coordinated adjustment of the signal-to-noise properties of neuronal networks in the cortex. The resulting change in information processing can thus have effects on emotion and motivation. When monoamines are altered by a drug or medication, an artificial state is induced. It is

important to remember that usually the brain stem nuclei coordinate changes in monoamine neurotransmitter drive in concert with changes in internal motivational state. Stimulation of monoamine receptors in brain regions such as the hypothalamus can also alter neuropeptide release, and neuropeptides can have more direct effects on emotion and motivation. Finally, monoamine receptor stimulation of brain stem structures may stimulate autoreceptors, which may have global effects on monoamine function. Thus, it is not surprising that altering any one of the three monoamines with psychotropic drugs can reliably alter emotional state. Dopamine powerfully affects the striatum and can thus directly the hedonic quality of stimuli and can quickly affect the motor response to motivational states. Norepinephrine powerfully stimulates the amygdala, prefrontal cortex, and hypothalamus and thus can cause arousal. Even in phylogenetically distant animals such as the mollusk, 5-HT release is involved in the regulation of approach and avoidance behaviors (Inoue et al. 2004). 5-HT is complex in its actions, with phasic-like serotonergic function being implicated in states of high arousal and heightened emotionality and tonic-like serotonergic function being implicated in the regulation of other biological systems such as the hypothalamic-pituitary-adrenal (HPA) axis and dopaminergic function in the striatum and cortex. Additionally, modulation of 5-HT by proserotonergic drugs is known to facilitate reward processing (Vollm et al. 2006). Nonmonoamine neurotransmitters are also implicated in the neurobiology of abnormal emotion in personality disorder. These include the excitatory neurotransmitters (glutamate), inhibitory neurotransmitters (GABA), and the neuropeptides (vasopressin, oxytocin, cholecystokinin, CRH, thyroid hormone). We have selected four common symptoms of personality disorder that reflect disrupted emotion/motivation systems: 1) impulsivity, 2) aggression, 3) affective instability, and 4) suicide. It is clear that the underlying neurobiology of these "symptoms" overlap, and so it is not surprising that when one is present, the chance of finding others is high.

Impulsivity, Serotonin, and the Orbitofrontal Cortex Although the term impulsivity is sometimes casually employed to describe recklessness, a more careful accounting provides better insight into the underlying process of impulsivity. The ability to delay gratification (or tolerate frustration) relies on delay discounting, mediated by the so-called delay neurons of the orbitofrontal cortex. These neurons encode the time-decay function of the reinforcement value of a stimulus. In general, future rewards are devalued relative to immediate rewards. The steepness of the time-decay function may be modulated by intense motivational states, and thus the steepness probabilistically affects a motor response. Consistent with an underlying orbitofrontal cortex–based defect in the representation of time-delayed reinforcement value, patients with BPD exhibit an abnormal sense of elapsed time (Berlin and Rolls 2004) that is actually more accelerated even than in patients with orbitofrontal cortex lesions. Patients with antisocial personality disorder also show acceleration of time estimation, and this deficit is accompanied by either higher amplitude or faster rise time of the Contingent Negative Variation, a slow (>300 msec) negatively sloped change in cortical electrical field potential over the frontal cortex (Bauer 2001). It is possible that this behavioral abnormality is related to abnormal ventral prefrontal structural connectivity (Rüsch et al. 2007), functional connectivity (New et al. 2007), or function (Soloff et al. 2003). Impulsivity related to intolerance of frustration can be conceptualized as a manifestation of so-called frustrative nonreward, the phenomenon of increased arousal and appetitive behavior in response to surprising or inconsistent reinforcement. Frustrative nonreward is an aversive state. It is associated with hypothalamic-pituitary activation (Lyons et al. 2000), as well as noradrenergic activation. Indeed, severity of impulsivity is correlated with sensitivity to frustrative nonreward (Douglas and Parry 1994). As frustrative nonreward involves the neural circuits controlling appetitive behavior, it is abolished by depletion of dopamine, which is released in response to reward availability (Taghzouti et al. 1985). Trait impulsivity is also linked to dopamine, as individuals with higher trait impulsivity show

greater sensitization of dopamine release in the ventral striatum, dorsal caudate nucleus, and putamen, as measured by [11C]raclopride binding (Boileau et al. 2006). Additionally, genetic polymorphisms of COMT and DRD2 (the gene encoding the D4 dopamine receptor) predict impulsivityrelated personality traits (Reuter et al. 2006). Impulsive reward-sensitive individuals are more likely to experience frustrative nonreward (Corr 2002). 5-HT has been demonstrated to have a constraining effect on impulsivity. It is possible that personality disorder patients high in impulsivity may thus have deficiencies in serotonergic modulation of the aversive aspects of frustrative nonreward and consequently have greater difficulty suppressing appetitive behaviors even when they are harmful. Impulsive BPD patients have higher availability of the 5-HT transporter in the hypothalamus and brain stem, as measured by [I123]ADAM (2-([2-([dimethylamino]methyl)phenyl]thio), a 5-HT transporter– specific radioactive ligand (Koch et al. 2007). They may also have lower 5-HT synthesis capacity in the medial prefrontal gyrus, anterior cingulate gyrus, temporal gyrus, and striatum, as evidenced by a brain PET imaging using the tryptophan precursor tracer

-[11C] methyl-L-tryptophan ( -[11C]MTrp)

(Leyton et al. 2001). Increased 5-HT transporter availability and decreased 5-HT synthesis could result in a relative hyposerotonergic state, which in turn could decrease frustration tolerance or increase frustrative nonreward, thereby contributing to impulsivity. While impulsivity in BPD is linked to emotion dysregulation, some manifestations of impulsivity may be linked to emotional underarousal and insensitivity to negative reinforcement. In psychopathic individuals with antisocial personality disorder, impulsivity has been linked to decreased trait anxiety (Fowles 2000) and decreased skin conductance (sympathetic underarousal). These deficits most likely reflect inadequate or abnormal reactivity of limbic and prefrontal neuronal networks. This has been demonstrated as decreased blood oxygen level–dependent (BOLD) signal response in limbic and prefrontal networks following exposure to arousing and aversive stimuli (Birbaumer et al. 2005). In contrast to impulsivity, deceitful aspects of psychopathy may be related to increased, rather than decreased, serotonergic function, as measured by prolactin response to fenfluramine (Dolan and Anderson 2003). These findings would predict that augmenting serotonergic function with medications would not be expected to alter deceitful aspects of psychopathy. On the other hand, knowledge of subsensitivity to punishment and anxiety, and relative hypersensitivity to reward, may be utilized in the treatment of individuals with substance abuse disorders, many of whom exhibit psychopathic traits (Messina et al. 2003).

Aggression Aggression encountered in personality disorder is typically classified as impulsive versus nonimpulsive. There is little evidence of a biological distinction between the two subtypes, but the most systematic work has focused on so-called impulsive, reactive, or affective aggression. Impulsive aggression in personality disorder is typically encountered in patients with Cluster A or B disorders. Impulsive aggressive episodes do not typically result in homicide but may result in injury, property damage, or reputation damage. By definition, they cause dysfunction in social relationships. Triggers for acts of impulsive aggression are usually either agonistic social interactions or frustration. Neuropeptides such as CRH, vasopressin, and oxytocin play an important role as mediators of change in social motivational state. Monoamines, as reviewed above, are important in mediating emotional reactivity (anger, contempt) and in processes related to impulsivity (frustrative nonreward). Thus, impulsive aggression represents a complex phenomenon, concatenating social behavior, emotion, and impulsivity. A considerable amount of research has focused on the finding of low 5-HT metabolite levels in abnormal aggression. A simple correlation between 5-HT "level" and aggression is probably invalid, given the complexity of 5-HT's role in a wide range of neural functions. 5-HT levels in the brain are at their lowest during rapid eye movement sleep, but are acutely and phasically released in the brain during agonistic social encounters between conspecifics. Interestingly, prefrontal cortical levels of

5-HT and 5-hydroxyindoleacetic acid (5-HIAA) decrease preceding an aggressive attack (van Erp and Miczek 2000), suggesting that regardless of what happens after an aggressive encounter, low prefrontal 5-HT remains a risk factor for aggressive behavior. In total, these data suggest that low 5-HT in prefrontal cortical circuits may prime an aggressive response, while elevated 5-HT levels during agonistic encounters reflect 5-HT released during motor activity. Early human studies found reduced levels of CSF 5-HIAA to be associated with aggression and suicidal behavior (Brown et al. 1979) and impulsive homicide (Linnoila et al. 1983), although not all studies to date have found an inverse relationship between CSF 5-HIAA and aggression (Balaban et al. 1996). CSF 5-HIAA provides an incomplete picture of serotonergic function, and thus other indices have been examined. Fenfluramine, which is an agonist at the 5-HT2A and/or 5-HT2C receptor site, has been used extensively to study postsynaptic 5-HT receptor function by measuring the pituitary prolactin response to fenfluramine challenge (Coccaro et al. 1996; Park and Cowen 1995). Coccaro et al. (1989) found that aggression was correlated with decreased prolactin response to fenfluramine in personality disorder subjects. The correlation of decreased responsiveness of the serotonergic system with impulsive aggression has been replicated in personality disorder subjects (Stein et al. 1996), in antisocial violent offenders (O'Keane et al. 1992), and in primates (Botchin et al. 1993) and remains one of the most replicated findings in biological and clinical psychiatric research. A separate strand of research has focused on the role of the prefrontal cortex in impulsive aggression. Aggressive personality disorder individuals have reduced resting state metabolism in the orbitofrontal cortex and right temporal lobe (Goyer et al. 1994). These metabolic abnormalities may be related to an underlying structural abnormality in neural circuits residing in prefrontal cortical gray matter, which is reduced in volume in aggressive antisocial personality disorder individuals (Raine et al. 2000). Impulsive aggressive individuals have exaggerated amygdala blood flow increases and orbitofrontal blood flow decreases in response to passive viewing of angry facial expressions (Coccaro et al. 2007). As impulsive aggression has previously been associated with difficulty in correctly identifying angry and disgusted facial expressions (Best et al. 2002), this suggests that the increased amygdala blood flow response measured by functional magnetic resonance imaging (fMRI) during viewing of angry faces may reflect inefficiency in neural network processing, in line with resting state and structural study findings. Findings of disturbed structure of inferior frontal white tracts in impulsive, hostile BPD (with comorbid attention-deficit/hyperactivity disorder [ADHD]) patients provide confirmatory evidence of abnormal prefrontal cortex neuronal network architecture as a biological risk factor (Rüsch et al. 2007). Uniting findings of the serotonergic deficits with prefrontal cortex deficits, several studies now have found serotonergic abnormalities on the brain regional level. Administration of 5-HT receptor agonists in impulsive aggressive individuals results in blunted metabolic activations in orbitofrontal, ventromedial, parietal, and cingulate cortex (New et al. 2002; Siever et al. 1999; Soloff et al. 2000). Putting these findings together, the following interpretations are plausible. The first possibility is that 5-HT receptor subsensitivity in the prefrontal cortex may reflect decreased dynamic range of 5-HT-related neuronal function, and this in turn contributes to aggressive behavior. The second possibility is that aggressive behavior, or other high arousal states, results in compensatory blunting of postsynaptic serotonergic function. Arguing for the validity of the first interpretation and a causal role for serotonergic dysfunction in aggression is the finding that treatment with selective serotonin reuptake inhibitor (SSRI) drugs such as fluoxetine has been shown to decrease aggression in personality disorder patients (Coccaro et al. 1997). Additionally, treatment with fluoxetine is associated with increased resting orbitofrontal cortical metabolism, as measured by positron emission tomography (PET) imaging (New et al. 2004), with some evidence of greater efficacy in patients who carry the L allele versus the less potent S allele of the 5-HT transporter (Silva et al. 2007). Animal studies have clearly implicated vasopressin as a neuropeptide mediator of aggressive behavior (Ferris et al. 1994). Coccaro et al. (1998) found that resting CSF vasopressin level correlated directly

with life history measures of aggression in personality disordered subjects, whereas CSF oxytocin correlates inversely (unpublished data). Although in rodents vasopressin has been demonstrated to directly affect aggressive behavior, it also affects nonaggressive social behaviors such as flank marking. Thus, vasopressin appears to modulate social motivation, above and beyond its effects on aggressive behavior. Social motivation shares with emotion the representation of an internal motivational state (affiliation and/or dominance) and is highly conserved in vertebrates. The ability to use visual information regarding spatial position as feedback regarding social dominance is confirmed even in fish (Grosenick et al. 2007). Metarepresentation of the social environment may rely on circuits that originally served in the metarepresentation of spatial self–other relationships. As an example, the spatial position of an individual bird in a flock can powerfully predict feeding success and protection from predators (Krause 1994). Finally, the internal motivational state may itself be shifted by hormonal factors into new configurations, such as the effect of testosterone on dominance (Gould and Ziegler 2007) or menstrual cycle–related changes on sexual desire. Incentive-driven social behavior probably relies on the same limbic neurocircuitry that guides other incentive-driven behaviors, as is illustrated by the effect of amygdala lesions on dominance status (Bauman et al. 2006). Further work needs to be done in order to better understand how changes in social motivational state may alter impulsive aggression.

Affective Instability, Frontolimbic Brain Function, and Acetylcholine In BPD, affective instability is manifest as excessive mood lability and stress reactivity. In histrionic personality disorder, it is manifest as shallow, shifting affect. In comparison with affective disorder patients, affective instability in BPD patients shows more circadian variability and a more random distribution of mood changes (Cowdry et al. 1991) rather than fluctuations between depressive and elated affects (Larsen and Diener 1985). Psychophysiological data help to confirm that at least some portion of the affective instability of BPD represents excessive reactivity to stressful stimuli, and not simply a reporting bias or willful social manipulation. In response to startling noise bursts, individuals with BPD exhibit an enhanced startle reflex (Ebner-Priemer et al. 2005). Additionally, the induction of an aroused negative mood state potentiates startle magnitude to a greater degree in BPD patients versus controls (Hazlett et al. 2007). Given that the brain stem and spinal cord basis of the startle reflex is subject to top-down modulation by prefrontal and limbic circuits, these findings are suggestive of disinhibition of the startle reflex by either limbic hyperreactivity or deficient prefrontal cortical control. Neuroimaging studies have focused on abnormalities of the limbic system. BPD has been associated with decreased left amygdala volume (Driessen et al. 2000; Tebartz van Elst et al. 2007), as well as decreased hippocampal volume (Brambilla et al. 2004). Decreased hippocampal volume has also been associated with history of childhood trauma (Vythilingam et al. 2002) and dissociative identity disorder with posttraumatic stress disorder (Vermetten et al. 2006), raising the possibility that exposure to traumatic stress may cause or magnify a structural brain defect. Given the high rates of abuse and neglect in the childhood history of many patients with Cluster B disorders, this is an important question for future research. Although the amygdala may be smaller than normal in some BPD patients, it appears to be functionally hyperreactive during tasks of emotion processing (Minzenberg et al. 2007), especially in response to emotionally ambiguous contexts (Schnell et al. 2007). Because of the importance of reciprocal connections between frontal and limbic brain regions in control and communication, structural and functional connectivity has been investigated in BPD. DTI of white matter microstructure has revealed aberrant white matter tracts in the inferior prefrontal cortex in patients diagnosed with comorbid BPD and ADHD (Rüsch et al. 2007), suggestive of connectivity abnormalities within prefrontal circuits, between prefrontal and limbic circuits, or between thalamus and prefrontal cortex. A major shortcoming of this work is its lack of clinical

applicability (as of yet) and its nonspecificity with regard to personality disorder versus affective or anxiety disorder. Cholinergic neuronal activity in limbic neural circuits is important for information processing and plasticity. Administration of anticholinergic drugs interferes with emotion-related memory processes (Kamboj and Curran 2006a). Anticholinergic drugs have also been found to selectively impair the recognition of anger and disgust (Kamboj and Curran 2006b). Challenge with cholinergic agents causes limbic activation, which can be detected by changes in limbic blood flow and corresponding induction of mood states of fear and euphoria (Ketter et al. 1997). Following challenge with physostigmine, a procholinergic drug, patients with BPD show more severe depressive mood changes compared with other personality disorder patients. Furthermore, the severity of the depressive response was greater in patients with prominent affective instability (Steinberg et al. 1997). 5-HT plays in an important role in cortical information processing and also in constraining the intensity of limbic and hypothalamic stress reactivity. BPD has been associated with 5-HT-related genetic polymorphisms, including the S allele of the 5-HT transporter (Steiger et al. 2005), and polymorphisms encoding high activity of the monoamine oxidase (MAO) gene (Ni et al. 2007). Serotonergic abnormalities have been linked to affective symptoms. 5-HT2A receptor binding is greater in BPD patients with a history of depression, suggesting a role for the 5-HT2A receptor in at least depressive mood changes (Soloff et al. 2007). Patients with histrionic personality disorder, who exhibit rapidly shifting affects, have increased loudness dependence of auditory evoked potentials (AEPs), which is inversely related to serotonergic tone in the cortex (Wang et al. 2006). Further work needs to be done regarding the uniqueness of association of 5-HT-related genetic polymorphisms with personality disorder versus other disorders. Studies of the hypothalamic-pituitary axis in BPD have found inconsistent results. Data from studies of the dexamethasone suppression test (Beeber et al. 1984; Sternbach et al. 1983) and the thyrotropinreleasing hormone (TRH) stimulation test (Kavoussi et al. 1993) have been inconclusive. These results highlight the biological heterogeneity of the existing categorical groups and suggest that BPD is not as closely associated with HPA axis abnormalities as is affective disorder. On the other hand, central CSF CRH levels are positively related to the severity of early-life parental abuse and neglect in personality disorder (Lee et al. 2005, 2006). This could be of considerable importance, given the inordinately high rates of history of abuse and/or neglect across personality disorder diagnoses. Additionally, it is consistent with preclinical investigation findings that central CRH drive is lastingly affected by early-life disruption of parental care (Coplan et al. 1996; Plotsky and Meaney 1993) and with evidence of peripheral downregulation of pituitary sensitivity to exogenous CRH from our laboratory (unpublished data) and other laboratories in non–personality disorder populations (Heim et al. 1998). What is the consequence of increased central CRH drive as a result of early-life trauma on the brain and behavior? Given the known effect of administering exogenous CRH on inhibiting socialization in primates (Strome et al. 2002), we would postulate that increased CRH drive would induce a form of social anhedonia, which is partially supported by our finding of an association of paranoid personality disorder with elevated CSF CRH (Lee et al. 2006). Although CRH plays a physiological role in normal behavior that provides phenotypic plasticity during times of stress, decreased dynamic range of CRH systems would render the system inflexible to the environment. This work would suggest that CRH receptor antagonists could be of value in the treatment of paranoid anxiety, as is found in paranoid personality disorder. In summary, it seems that dysregulation of the HPA axis in the Cluster B personality disorders may reflect either underlying affective disorder or exposure to trauma.

Suicide A mechanistic neurobiological understanding of suicide remains out of reach. Most of the work to date has been an effort to identify biological correlates of psychosocial risk factors. A limited amount of data suggests that self-injurious behavior in personality disorder patients is related to serotonergic

abnormalities. New et al. (1997) found that suicidal and self-injurious behavior was associated with blunted prolactin and cortisol responses to D,L-fenfluramine. In a separate study, those with both impulsive and premeditative self-injury were found to have blunted prolactin response to D-fenfluramine

compared with normal subjects, suggesting postsynaptic 5-HT receptor

downregulation (Herpertz et al. 1995). However, several recent studies have implicated increased 5-HT2A receptor binding in suicide and impulsivity, including studies of patients with BPD (Soloff et al. 2007). These results support a possible antisuicide effect of chronic antidepressant treatment and/or atypical antipsychotic drugs. Suicide victims have increased CRH and vasopressin immunoreactivity in the brain, implicating biological mediators of emotional or social motivation in successful suicide (Merali et al. 2006). This important finding provides biological confirmation of data from psychological autopsies of suicide victims; recent social stress is a potent risk factor for suicide. The mechanism whereby environmental stress and the ensuing stress response increase the probability of a suicidal act is not yet identified.

Predictions and Limitations of the Model One important prediction of our model is that a problem with representation would go on to affect complex processes that rely on representation, such as metarepresentation and/or motivation. The clinical implication would be that patients with working memory deficits might also be expected to additionally exhibit social or emotional deficits. This notion is supported by the high rates of Axis I–Axis II comorbidity in the clinic and the tendency for these comorbidities to occur across cluster categories. The other important clinical implication is that the circuits that are affected in personality disorder are the same circuits that are affected in Axis I disorders such as schizophrenia, anxiety, and depression. This is reflected in ubiquitous Axis I–Axis II comorbidity. Another important prediction of our model is that the array of neurobiological deficits in clinical patients may be quite complex, and simple models of personality psychopathology based on "limbic hyperreactivity" or "hypofrontality" fail to account for prominent symptom classes such as disturbed sense of self or dissociative symptoms. With regard to these specific symptoms, there may be some benefit in looking outside psychiatry in fields such as learning disorders, which have focused on the parietal cortex as a biological mediator and so-called metacognition for therapeutic approaches. Although it is often stated that emotional lability is the cause of the unstable sense of self and others found in the Cluster B personality disorders, this has not actually been proven to be true. We would argue that it is plausible that the opposite mechanism may be equally valid, that inaccurate or distorted social cognition/motivation could result in emotional instability. This remains a testable hypothesis. A model should be able to make quantitative predictions. Our model is clearly not yet quantitative, although it is compatible with a computational approach. For this reason, it remains a heuristic model of personality disorder. Brain/neuron-based computational models of personality disorder are not yet available for research purposes but may prove to be useful, if not absolutely necessary, to develop more sophisticated, reliable, and effective approaches to neuropsychopharmacology in this population. Finally, we have also not focused on precise mechanisms of development and change. Although the current emphasis on regional functional brain imaging has resulted in canonization of the lesion model of psychopathology, time may prove this overemphasis to have limits. Careful examination of the literature also reports positive changes in personality disorder–related behavior after frontal head injuries (Labbate et al. 1997). Findings such as these call into question the validity of lesion-based models. They also suggest that not-yet-identified compensatory mechanisms in neural network function, rather than restoration of a "lesion," may play a role in both spontaneous (without therapeutic intervention) or therapeutically induced remission from personality disorder.

CONCLUSION Meaningful progress in our understanding of the neurobiology of personality disorders brings hope that in the near future this understanding will result in substantive progress in treating these disorders. Clinicians recognize that these disorders can represent serious mental illness, with potentially crippling disability, disproportional public health care expenditure, and tremendous suffering. That progress in our understanding of the neurobiology of personality disorder comes in parallel with growing sophistication of both the basic and clinical neurosciences means that old conceptualizations must be challenged and tested. One advantage of a non-symptom-based heuristic is that the conceptual dissonance caused by the natural overlap of Axis I and Axis II disorders is deemphasized. In other words, this model highlights the biological overlap between these two subclasses of disorders. While previous symptom-based heuristics remain valid, we hope that this one raises new and fruitful questions.

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Daniel S. Pine: Chapter 52. Neurobiology of Childhood Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.433538. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 52. Neurobiology of Childhood Disorders NEUROBIOLOGY OF CHILDHOOD DISORDERS: INTRODUCTION Mental health sciences witnessed a paradigm shift in the late twentieth century through the influence of three research themes. First, a focus on biology emerged following changes in psychiatric nomenclature and psychopharmacology. Second, advances in neuroscience provided heretofore unseen insights on the relationship between neural and information-processing functions, paving the way for a clinical neuroscience approach to mental illness. Third, the school of developmental psychopathology emerged, based on the recognition that most chronic mental illnesses have their roots in childhood. The current chapter, which focuses on the biology of childhood mental disorders, integrates these three themes. Given the breadth of work in each area, let alone the combination of the three, this chapter cannot provide a comprehensive review. Rather, I summarize major themes while providing illustrative examples from research on specific disorders. In this chapter I present data on nine families of disorders: 1) pervasive developmental disorders (PDDs) such as autism, 2) schizophrenia and other psychoses, 3) learning disorders such as dyslexia, 4) disruptive behavior disorders (DBDs) and attention-deficit/hyperactivity disorder (ADHD), 5) bipolar disorder, 6) major depressive disorder (MDD), 7) obsessive-compulsive disorder (OCD) and Tourette's syndrome, 8) posttraumatic stress disorder (PTSD), and 9) pediatric anxiety disorders. Aspects of clinical presentation and therapeutics are reviewed in other chapters. The chapter unfolds in four sections. The first section presents principles that provide a framework within which current biological research can be placed. The second section reviews current approaches in genetics research, which raises questions on the manner in which genes ultimately influence behavior emerging in a developmental context. In the third section, data on informationprocessing functions are reviewed, considering data from cognitive and affective neuroscience. These data suggest that specific neural information-processing pathways might provide the conduit through which genes sculpt behavior as genes interact with the environment. The final section reviews data on brain circuitry structure, function, and modulation, with a strong focus on brain imaging.

INTEGRATION OF DEVELOPMENTAL PSYCHOPATHOLOGY AND BIOLOGY Virtually all chronic mental disorders are conceptualized as disorders of brain maturation. This view emerged from an integration of research in epidemiology and neuroscience. From the epidemiological perspective, the school of developmental psychopathology recognizes that diverse behaviors show consistent, robust patterns of change as children mature through adolescence (Rutter et al. 2006). Marked individual variability results from differences in the timing of these changes, revealing childspecific risks. From the neuroscience perspective, adult patterns of information processing emerge from development, since the immature brain is uniquely susceptible to both genetic and environmental influences (Nelson et al. 2002). Individual variability reflects variations in the timing of these influences. Together, this literature suggests that chronic psychiatric disorders emerge from the effects of genes and the environment on brain development. Despite the insights emerging from these breakthroughs, research on the biology of pediatric mental disorders has proceeded less quickly than research on adult mental disorders. This discrepancy has

resulted from many factors, including the dearth of experienced researchers, the complex ethical issues confronting efforts to launch such studies, and the inherent difficulty of assessing both behavior and biology in the context of development. Due to these limitations, enthusiasm has emerged from avenues outside of biological research with children.

Epidemiology Developmental psychopathology, as a distinct theoretical school, emerged following changes in psychiatric nomenclature in the 1970s. The advent of a standard nosology set the stage for longitudinal and family-based research. Armed with new assessment techniques, large cohorts of children received serial, standardized psychiatric assessments over time, beginning in the school age years and spanning into adulthood. Three key insights emerged from this work: 1. Longitudinal community-based research demonstrated the surprisingly high prevalence of pediatric mental disorders, revealing as many as a third of individuals to be affected before adulthood (Rutter et al. 2006). Interestingly, many common conditions were shown to be transient in children followed longitudinally, whereas rarer disorders, such as the PDDs, typically were persistent. Nevertheless, the roots of chronic psychopathology were shown to lie both in rare, persistent disorders and in the exceedingly common, typically transient conditions, such as the anxiety disorders. Longitudinal studies showed that most adult mental disorders arose in individuals who had manifest psychopathology as children, typically in the most common forms of pediatric mental illnesses. This truism held for virtually all forms of psychopathology. 2. Longitudinal family-based research confirmed these observations while establishing the familial nature of mental illnesses. Again, for most psychopathology, including PDDs, psychosis, mood disorders, anxiety disorders, and DBDs, disorders were shown to be developmental and family based (Caspi and Moffitt 2006; Dickstein and Leibenluft 2006; Merikangas et al. 1999; Rutter 2005; Weissman et al. 2006). Offspring of adults with various mental syndromes face a high risk for psychiatric illness. Moreover, even in children free of overt psychopathology, signs of risk are manifest in patterns of information processing (Merikangas et al. 1999). Finally, manifestations of risk change developmentally. For example, offspring of parents with MDD might show high rates of anxiety as opposed to MDD, whereas offspring of parents with bipolar disorder might show high rates of MDD rather than mania (Dickstein and Leibenluft 2006). As some children of MDD parents with anxiety disorders mature, they manifest MDD, whereas some children of parents with bipolar disorder ultimately manifest bipolar disorder (Rutter et al. 2006). 3. A focus on risk factors for mental illness emphasized the need for research on biology. Although longitudinal studies established the clear relationship between social risk factors (e.g., poverty) and psychopathology, a surprisingly high number of children were resilient (Rutter 2000). The recognition of marked individual differences in susceptibility to risk raised questions on the role of biology in the modulation of risk. Moreover, some biological factors were shown to predispose toward pediatric mental illness even in the absence of social risks. Initial work emphasized the strong relationship between epilepsy and mental disorders, particularly the PDDs (Rutter 2005). These observations soon extended to a wealth of other neurological conditions, such as brain injury manifesting either in overt developmental delays or in more subtle indicators of brain dysfunction. With continued refinements, epidemiological research extended to focus on ever-subtler developmental influences. This included research relating teratology, such as from maternal smoking, to pediatric DBDs, as well as studies linking various perinatal immunological or nutritional compromises to psychosis (Rutter et al. 2006). Finally, findings from work that focused on very young children, a group thought to be particularly susceptible to environmental and social influences, further contributed to this focus on early biology. Temperamental profiles, such as behavioral inhibition, were identified in these studies. Such profiles were ultimately shown to be stable across many environments, influenced by genes, and associated with biological profiles (Fox et al. 2005).

Developmental Neuroscience Advances in developmental neuroscience proceeded in parallel with advances in clinical

conceptualization. Considerable work prior to the 1980s had established the importance of developmental events for the foundation of healthy neurological function. Some of the strongest evidence in this regard focused on relatively extreme manipulations involving events that seemed relatively removed from those implicated in developmental psychopathology. For example, work on the visual system firmly established the presence of age-related differences in susceptibility to alterations in environmental input: complete deprivation of visual input to one eye early in life produced long-term robust effects on visual function. Similarly profound deprivations in early-life social experience had demonstrated the malleability of emotional functioning. Work in the final decades of the twentieth century revealed the broader applicability of the developmental neuroscience approach. Even relatively subtle variations in developmental events were shown to produce robust changes in behavior that appeared relevant to emerging views of psychopathology. One relevant example emerged through research using relatively subtle manipulations of the rearing environment (Meaney 2001). This work demonstrated long-term effects on emotional systems. Much of the early work in this area relied on experiments with rodents, where pups and dams were separated for brief periods of time. Such manipulations produce lifelong alterations in the pups' response to stress. The robust, replicable nature of these findings facilitated work on the neural architecture mediating these effects: changes in glucocorticoid receptor biology, with reverberating effects on measures of information processing and threat-response behavior, instantiated in the hypothalamic-pituitary-adrenal (HPA) axis, the medial temporal lobe, and the prefrontal cortex (PFC). As this work continued, the molecular underpinnings were revealed, involving epigenetics. Finally, studies in both humans and nonhuman primates began to demonstrate parallel effects and associations (Gross and Hen 2004). Enthusiasm for extensions to research on the biology of pediatric mental disorders soon followed. Another relevant example emerged from work on genetic manipulations in mice. Research throughout the 1980s had firmly established the modulatory role of serotonin (5-hydroxytryptamine; 5-HT) over complexly organized high-level behaviors, such as those engaged by threats and danger (Gross and Hen 2004). For example, deletion of the 5-HT type 1A (5-HT1A) receptor in the mouse altered the threshold for engaging in these behaviors. Further research elucidated the developmental context in which these effects emerge: 5-HT1A receptor deletion in the mature mouse produced no detectable effects on threat-response behavior, whereas transient deletion only in the immature mouse produced a long-lasting effect well into adulthood, even in mice with transiently abnormal 5-HT1A activity as juveniles and normal 5-HT1A profiles as adults. As with work on the HPA axis, studies in primates complemented these findings. Given the role of the amygdala in rodent fear, for example, studies in nonhuman primates examined developmental influences on amygdala function. This work showed that the effects of amygdala lesions on fear varied as a function of development (Prather et al. 2001). As work from these and other projects accumulated, enthusiasm for extensions to developmental psychopathology grew.

Endophenotypes Initial attempts to integrate findings from clinical and basic science called attention to significant hurdles complicating such integrative research. Primary among these were questions on the validity of clinical phenotypes. Initial questions arose from limitations in the assessment techniques, related to complications in combining information from multiple informants and the need to ground assessments of pathology in understandings of normal variations in behavior. However, even after these problems were solved, major questions on phenotypes persisted. For example, studies in the PDDs found that relatively few relatives of children with autism manifest overt diagnoses of autism, yet such relatives often manifest subtle variants of core symptoms in autism, such as mild problems in language or social relatedness (Rutter 2005). Similarly, studies in MDD found that many children at high-risk for MDD were free of psychopathology but exhibited subtle subclinical perturbations in their responses to

threats or rewards (Grillon et al. 2005). These observations elucidated the need for alternative approaches to phenotype classification in children, given demonstrations of changing manifestations in risk across the life span. A focus on endophenotypes provided the opportunity to ground classifications of children in emerging understandings of neuroscience (Gottesman and Gould 2003). Thus, potential endophenotypes were selected based on understandings of brain–behavior relationships. As the sophistication of these understandings grew, the applicability of this perspective increased, ushering in new frameworks for the conceptualization of developmental psychopathology and its relationship to biology.

Current Frameworks Figure 52–1 illustrates one current framework for conceptualizing the biological correlates of pediatric mental illnesses. Material covered in the remainder of this chapter can be organized around this figure. Thus, the origins of mental illness are shown on the left side of this figure, where genetic and environmental events impinge on development, ultimately through effects on brain development. In this framework, considering individual disorders, distinct genetic and environmental effects produce effects on distinct but overlapping neural circuits, accounting for the specific manifestations of pediatric psychopathologies. For some conditions, these effects are likely to be overwhelmingly genetic, at least in their earliest inception. For other conditions, these effects are likely to involve stronger environmental components. FIGURE 52–1. A conceptual framework for biological research.

This figure illustrates a framework in which to place current research on the biology of pediatric mental syndromes. The framework attempts to link understandings of brain function to clinical categorization by examining the relationship between variations in brain function and specific information-processing functions. ADHD = attention-deficit/hyperactivity disorder; DBDs = disruptive behavior disorders; PDDs = pervasive developmental disorders. A major challenge is to map the manner in which variations in brain function (shown on the left side of the figure) give rise to variations in psychopathology, represented as phenotypes (shown on the right side of the figure). For studies in juveniles, the magnitude of this challenge is particularly large, given the need to delineate a constantly changing relationship between brain function and behavior. One approach delineates brain–phenotype relationships by focusing on measures of information processing, as depicted in the middle box of Figure 52–1. Research that connects elements of information processing (the middle box in the figure) to the clinical phenotypes (the box on the right) capitalizes on the success of neuroscience research linking understanding of brain function and information processing, thus connecting the middle and the left boxes in Figure 52–1. Taken together, this research allows clinical–neuroscience integration. The remainder of this chapter reviews the manner in which ongoing research on childhood mental disorders maps relationships between genes and the environment, through measures of brain function and associated information-processing profiles, onto clinical phenotypes. This review is organized around three sections. For the first two sections, the review focuses more on aspects of methodology than on specific pediatric mental disorders, discussing findings in specific disorders only for illustrative purposes. Thus, the initial section, on genetics, focuses more on available methods than on findings in one or another disorder. Similarly, the next section, on information processing, focuses on the four cognitive domains depicted in the middle box of Figure 52–1 linked to distinct neural circuitry function, again without comprehensively reviewing findings in specific disorders. Greater depth is provided, however, in the final section ("Brain Function"). Given the promise of brain imaging, this section summarizes findings across diverse clinical domains, considering conditions broadly grouped into five categories: PDDs; psychosis; DBDs and ADHD; mood disorders; and anxiety disorders. Ultimately, this work is likely to lead to conceptual changes, as nomenclature moves toward classifications based on pathophysiology. Scientific and practical complications limit efforts to ground such research in studies of juveniles. Nevertheless, evidence delineating the importance of the developmental approach emphasizes the importance of addressing these complications.

GENETICS As indicated in Figure 52–1, three research areas document genetic influences on developmental psychopathology: behavioral genetics, specific genetic syndromes, and molecular genetics.

Behavioral Genetics Observations of strong, consistent familial aggregation encouraged efforts to identify genetic and environmental correlates of psychopathology. As with most research on pathophysiology, this work began with studies based in adults. Such work showed that retrospectively assessed factors operating in childhood modulated the impact of genetic and environmental effects on risk for psychopathology. This generated enthusiasm for implementing such studies directly in children. Initial results in children have demonstrated both commonalities with and differences from findings of research in adults. As in adult disorders, wide variability exists for the pediatric mental disorders in the contributions of environmental and genetic effects. Thus, some disorders, particularly PDDs and ADHD, have been shown to be overwhelmingly genetic, whereas most common disorders are influenced heavily by nonshared environmental effects (Thapar and Rutter 2008). Certain DBDs have emerged as the rare examples of conditions with strong shared environmental influences. As in adults,

these data emphasize the importance of genetic and environmental contributions. Findings in children have also generated novel insights, relative to studies in adults. For example, genetic contributions to a disorder in adulthood (e.g., MDD) might be shared with genetic contributions to a different type of disorder in childhood (e.g., anxiety) (Thapar and Rutter 2008). Alternatively, some disorders classified as nosologically similar might exhibit distinct genetics, such as has been shown for some forms of conduct disorder. Behavioral genetics research in juveniles has also benefited from the opportunity to directly assess environmental contributors to psychopathology, going beyond indirect statistical measures. Such work has emphasized the role of gene–environment interactions, operating in a developmental context, to shape risk for many of the more common disorders (Thapar and Rutter 2008). These include DBDs, mood disorders, and anxiety disorders.

Genetic Syndromes Interest in molecular genetics has been stimulated further by research demonstrating behavioral correlates of developmental syndromes associated with specific genetic alterations. Some chromosomal syndromes either are relatively common (e.g., Down syndrome) or are associated with extreme alterations in behavior (e.g., Lesch-Nyhan syndrome). With these conditions, focus on the psychiatric concomitants emerged shortly after the syndromes were first described, and these features were attributed at least partially to consequences of intellectual disability, given its recognized role in shaping risk for psychopathology. Accordingly, few implications emerged for understandings of psychopathology as typically manifested in the community. More recently, continued advance in molecular genetics techniques has generated interest in a wider array of developmental syndromes and their relevance for psychopathology in the community (Thapar and Rutter 2008). For these conditions, insights on gene–behavior associations have begun to broadly shape thinking on developmental psychopathology. For example, deletion at chromosome band 22q11.2 gives rise to velocardiofacial syndrome (VCF), which manifests in cutaneous, cardiac, and neurological changes. VCF is associated with a high risk for psychosis, generating interest in the role of genes lying within this region of chromosome 22. Suggestive findings in adult patients with schizophrenia, in the absence of VCF, increase interest in this area, as do recent brain imaging studies on neural correlates of VCF. Similarly, William's syndrome results from a deletion on the long arm of chromosome 7 (band 7q11.23). This syndrome also presents with a unique behavioral pattern, characterized by intellectual deficits and high levels of anxiety but surprisingly high levels of sociability. Here, too, findings using brain imaging technology raise questions on the role of chromosome 7 in the regulation of social experience in behavior. For these two syndromes, VCF and William's syndrome, the presence of intellectual deficits raises questions about the role of indirect mechanisms contributing to the observed psychiatric profiles. However, studies in other single-gene disorders that typically manifest in childhood, such as 21-hydroxylase deficiency, have generated further interest in understanding the role of specific genes in shaping behavior across development (Ernst et al. 2007). As reviewed elsewhere (Thapar and Rutter 2008), considerable other research in a range of genetic disorders has delineated the promise of this approach. Finally, other work in sporadically appearing cases of conditions that are typically highly familial has informed targeted focusing on specific genes, as illustrated in recent work on Tourette's syndrome (Abelson et al. 2005). Alternatively, work in highly familial forms of language dysfunction also has led to the identification of novel genes.

Molecular Genetics Much like research among adults, studies in children have begun to rely on the techniques of both genetic linkage and genetic association to delineate the role of specific genes in relatively common psychiatric disorders ascertained in the community or the mental health clinic. As a rule, work using the technique of genetic association generally has fared better in generating replicated findings,

though suggestive findings have emerged from linkage studies focused on PDDs and dyslexia. Reviews of these findings can be found elsewhere (Faraone and Khan 2006; Gupta and State 2007; Swanson et al. 2007; Thapar and Rutter 2008). The best-replicated work in genetic association derives from studies of ADHD, where research in many thousands of patients implicates genes for various monoamines in the disorder (Faraone and Khan 2006; Swanson et al. 2007). As with all association studies, work on ADHD is facilitated by research on pathophysiology implicating one or another pathway in the disorder, where the robust efficacy of psychostimulants has provided important clues. Associations with both the dopamine4 (D4) receptor and the dopamine transporter appear reasonably well replicated. Similarly strong evidence has emerged in association studies of PDDs and OCD, with work on 5-HT genetics extending earlier studies on 5-HT neurochemistry and therapeutics in both of these disorders (Gupta and State 2007). For other disorders, findings generally are less well established. Nevertheless, a steady stream of biological clues has provided many targets for a range of clinical phenotypes in children. Thus, brain-derived neurotrophic factor has been implicated in pediatric MDD; the glutamate transporter gene solute carrier family 1, member 1 (SLC1A1) gene has been implicated in OCD; and various 5-HT–related or HPA-related genes have been implicated in one or another anxiety phenotype. Across genetic research on children, the magnitude of association generally has been small, rarely increasing the risk for one or another psychopathology by more than twofold (Thapar and Rutter 2008). This suggests that pediatric mental illnesses arise from complex cascades of genetic and environmental events. Such realizations have encouraged efforts to map these specific cascades, as exemplified by recent work on gene–gene interactions in risk for adverse reactions to trauma and by recent work on gene–environment interactions in risk for DBDs and MDD. For example, Caspi and colleagues mapped one such interaction in research conducted with the so-called Dunedin cohort from New Zealand, one of the best-characterized longitudinal, epidemiological samples (Caspi and Moffitt 2006). In this cohort, environmental risk for conduct problems and associated DBDs was modulated by genetic variation in the gene for monoamine oxidase A, a gene that had been selected for study based on earlier work in a family with a rare deletion of this gene. Such findings have generated enthusiasm more broadly in efforts to map the complex way in which individual genetic and environmental events shape risk.

INFORMATION PROCESSING The current framework rests heavily on research examining information processing, because studies in this area play a unique role in the integration of research on brain function and phenotypes, as shown in Figure 52–1. Work in this area relies heavily on studies from the fields of cognitive and affective neuroscience. Tools from these fields index observable variations in behavior, and these behaviors are selected based on knowledge of the underlying neural architecture and associated information-processing functions. If variations in these behaviors can be linked to clinically relevant phenotypes, it is possible to bridge research on brain function and its influence by genes or the environment with research on clinical phenotypes. Moreover, this research can be based in a developmental context, allowing changes in such behaviors to be mapped to changes in associated brain function. Given the explosion of work in this area, the current chapter cannot exhaustively summarize all aspects of the relevant work. Rather, I highlight illustrative examples where information-processing functions with known neural architecture have been most consistently linked to childhood mental disorders. This section focuses on the four information-processing functions delineated in Figure 52–1: cognitive control and reward, language and reading, social information processing, and threat processing. For each of these four functions, the section summaries prior research on the neural

architecture of each function before highlighting key findings relating the function to psychopathology.

Cognitive Control and Reward Research on choice behaviors in the context of competing goal demands implicates a specific neural circuit in decision making. Much of this work relies on experimental paradigms in which a subject must make a difficult choice, perhaps because one or another response is rendered pre-potent due to the rapid pace of the task or because the appropriate choice is ambiguous, as exemplified by the "stop" task, various Go/No-Go paradigms, and the flanker tasks. In these tasks, behavior is thought to be regulated by components of the PFC that represent aspects of the task's rules, whereas interactions between the PFC and striatum facilitate efforts to adjust behavior when task contingencies change (Blair et al. 2005). This occurs, for example, on events with high conflict, such as "stop" trials on the stop task. Children with a select group of pediatric psychopathologies exhibit perturbations on these tasks, providing a strong foundation for integration of clinical and research perspectives in these disorders. Thus, this research implicates PFC–striatal dysfunction in ADHD, PDDs, and OCD while distinguishing these conditions from non-OCD anxiety disorders or MDD, where performance is intact (Nigg 2007; Swanson et al. 2007). The affective salience of these so-called cognitive control tasks can be augmented by manipulating the costs and benefits of one or another decision. For example, a subject might be rewarded on a select series of trials for a correct response or punished on other trials for an incorrect response. The difficulty of the task can be increased by focusing on a child's ability to alter responses as task contingencies change. Figure 52–2 illustrates one such task, based on the so-called response reversal paradigm, wherein a subject is required to select one of two objects to obtain rewards in the context of continually changing contingencies (Budhani et al. 2007). This task engages brain systems that facilitate adaptive behavior required when task rules change, such as when contingencies reverse. As shown in the figure, in the context of the need to reverse choices, these paradigms influence activity in medial PFC. Other work shows that children with DBDs and related disorders perform poorly on such tasks (Blair et al. 2005; Nigg 2007; van Goozen et al. 2007). Thus, through the use of these and other manipulations, considerable research implicates PFC–striatal circuitry in reward-related behaviors, ADHD, trauma, and mood disorders. FIGURE 52–2. Response reversal and the medial prefrontal cortex.

This figure shows details of a probabilistic response reversal task (A). In this task, subjects begin by trying to select a rewarded target (e.g., the giraffe) while avoiding a punished target (e.g., the elephant). Following acquisition of this "giraffe-reward" rule, the contingencies change in the reversal phase of the task. Functional magnetic resonance imaging (B) demonstrates that during this learning-related process, decreased engagement of the medial prefrontal cortex (PFC) occurs in trials when adult subjects commit errors by failing to learn the new "elephant-reward" rule. Deficient medial PFC engagement on such tasks in some pediatric mental syndromes might reflect a role for perturbed medial PFC function in the condition. BOLD = blood oxygenation level– dependent. Source. (A) Reprinted from Finger EC, Marsh AA, Mitchell DG, et al: "Abnormal Ventromedial Prefrontal Cortex Function in Children With Psychopathic Traits During Reversal Learning." Archives of General Psychiatry 65:586–594, 2008. Copyright 2008, American Medical Association. Used with permission. (B) Reprinted from Budhani S, Marsh AA, Pine DS, et al: "Neural Correlates of Response Reversal: Considering Acquisition." Neuroimage 34:1754–1765, 2007. Copyright 2007, Elsevier. Used with permission.

Language and Reading The effects of brain lesions on cognition generated early interest in elucidating relevant neural pathways. The development of language abilities and the development of reading abilities represent two of the most significant aspects of cognitive development, and considerable work in cognitive neuroscience examines the underlying circuitry. Research on language development has pursued diverse avenues. One set of studies extended observations in children with specific language impairment. This condition is hypothesized to result from a relatively specific deficit in decoding subtle temporal variations in phonemes. Consistent with this possibility, focused training designed to compensate for this specific deficit was shown to remedy the language deficit in some children (Tallal and Gaab 2006). In other work, children with unusual familial forms of language dysfunction were found to exhibit a unique neural and molecular profile (Vargha-Khadem et al. 2005). Research on both normal and abnormal reading abilities, as manifested in developmental reading disorder or dyslexia, has followed similarly divergent pathways. Considerable work with typically developing children has isolated the cognitive processes that provide foundations for successful reading. This work has delineated the typical development timing during which these processes mature, as well as the complex collection of brain regions required (Joseph et al. 2001). This provides

a rich backdrop against which to place dyslexia. A parallel series of studies implicates specific processes in reading disorders (Joseph et al. 2001). As with the work on specific language impairment, these insights have provided novel insights on treatments. Such treatments have been tailored to correct relatively specific core underlying deficits in the relevant psychological process. In emerging work, this model of developing remedial training after identifying a specific deficit in a relatively pure cognitive disorder has been extended to other disorders, such as ADHD, that are less typically considered purely cognitive conditions.

Social Information Processing Perturbations in social relationships represent core features of many disorders. Recent developments implicate specific neural circuitry in the regulation of human interaction, providing a rich context in which to place research on developmental psychopathologies. In this area, the most consistent findings emerge in studies of PDDs, DBDs, traumatic exposure, and bipolar disorder. Major disruptions in social relatedness represent one of the three key features of PDDs, along with deficits in language and stereotypical behaviors. Given the profound nature of clinical deficits, it should come as no surprise that children with PDDs also exhibit deficits on social neuroscience paradigms (Rutter 2005). For example, one set of studies, which relied on examinations of eye-scanning patterns, showed that individuals with PDDs attend to distinctly different social cues compared with healthy individuals, with very large effect size differences (Volkmar et al. 2004). Similarly, individuals with PDDs also have been shown to exhibit deficits on so-called theory-of-mind tasks that require the decoding of complex social motivations of peers. Both areas rely on relatively complex aspects of social information processing. Studies of more elementary processes, such as the labeling of face emotions, also have revealed deficits in children with PDDs. Although perturbed social information processing might be expected in PDDs, other syndromes associated with less severe social deficits also have been linked to poor ability to decode social signals. Such deficits are likely to arise from many different pathways, as they have been found in children exposed to traumatic circumstances, which might lead to environmentally mediated deficiencies, as well as in children with psychopathy, a condition where the deficit in social processing is thought to result from genes (Blair et al. 2005). Children with bipolar disorder also show such deficits (Leibenluft et al. 2003). Of note, these deficits are relatively specific to this family of conditions; children with ADHD, other DBDs, anxiety disorders, and MDD show no such deficits.

Threat Processing Research on threat processing has benefited from advances in affective neuroscience, a field focused specifically on the role of emotionally salient events in regulating the processing of information. Threats have been shown to heavily influence many aspects of behavior, through effects on diverse information-processing functions. Some of the most consistent findings have emerged in research finding that threats show a greater capacity than neutral material to influence attention (Pine 2007). For example, threats are recognized more quickly than neutral stimuli in some paradigms, whereas they interfere more strongly than neutral stimuli in other paradigms. These effects have been mapped to specific neural circuits encompassing the amygdala and PFC. Most importantly, these paradigms have been used to differentiate children with various psychopathologies, particularly the anxiety disorders, in which threats exhibit a particularly marked effect on attention. This work has generated interest in the use of other paradigms, co-opted from basic science, which require coordinated engagement of the amygdala and PFC. For example, considerable work suggests that anxiety disorders reflect a perturbation in processes related to fear conditioning and extinction. Work on other disorders emphasizes the effects of threats or other emotional stimuli on processes distinct from attention. For example, in work on MDD, effects appear larger in memory than in attention paradigms. Similarly, work on bipolar disorder has documented a range of perturbations in

threat-response behavior.

BRAIN FUNCTION As shown in Figure 52–1, knowledge of brain function derives from research in two areas: functioning of relevant brain circuitry and modulation of this circuitry through autonomic, hormonal, and chemical influences. For studies in children, some of the most promising insights linking brain function to clinical phenotypes have emerged through research using brain imaging to examine circuitry. Research on modulation of circuitry has provided less profound influences on current clinical thinking. As a result, in the first portion of this section on brain function, I only briefly summarize research on brain circuitry modulation, whereas in the remainder of the section I provide a more detailed review of imaging studies in specific developmental psychopathologies. This review delineates relevant findings by focusing on normal development and the five classes of disorders illustrated on the right side of Figure 52–1, depicted as groups of phenotypes: PDDs, psychosis, DBDs and ADHD, mood disorders, and anxiety disorders.

Modulation of Circuitry Autonomic, hormonal, and monoamine systems modulate activity in key neural systems, either when chemicals act directly on neural structures or when chemicals enable communication among components of circuitry-based feedback loops. These modulatory influences can be assessed by measuring variations in peripheral physiological indices. Considerable work in children relies on these measures, given ethical constraints on more invasive measures. Nevertheless, this chapter only briefly summarizes these findings. Work on modulation of circuitry has had a less profound influence on current clinical thinking than brain imaging research in recent years, because measures derived from imaging provide a more direct index, relative to measures of autonomic, hormonal, or monoamine system modulation, of neural system function associated with mental illnesses.

Autonomic Activity Activity in the sympathetic and parasympathetic systems is influenced by the amygdala and associated systems. As a result, considerable work has attempted to infer the nature of individual differences in amygdala function through an examination of individual differences in autonomic parameters. Probably the most consistent findings in this area have emerged from research on the association between low heart rate and conduct problems in children (van Goozen et al. 2007). This association is thought to reflect blunted amygdala sensitivity to punishment cues, consistent with current models of some DBDs. Conversely, other work has linked elevated heart rate to various forms of pediatric anxiety, including behavioral inhibition, viewing these associations as a sign of amygdala hypersensitivity to threat (Fox et al. 2005; Pine 2007). Because these differences in heart rate could arise from differences in either parasympathetic or sympathetic systems, other work has used spectral analysis of heart period variability to draw inferences specifically on parasympathetic regulation. Findings in this area generally have been less consistent than findings linking differences in heart rate to differences in pediatric psychopathology. Beyond work on cardiac activity, other research links childhood psychopathology to respiratory perturbation, extending work on the biology of adult panic disorder. Here, a consistent association has emerged between respiratory dysregulation and pediatric separation anxiety disorder, consistent with other work linking separation anxiety and panic disorders (Pine 2007). Of note, pediatric social anxiety disorder involves normal respiratory regulation, suggesting that individual anxiety disorders display unique biology. While findings in this area have generated consistent interest in biological correlates, recent work has focused more closely on cognitive neuroscience than autonomic physiology. This provides a more direct measure of activity in neural systems that are thought to mediate observed associations

between autonomic physiology and psychopathology.

Hypothalamic-Pituitary-Adrenal Axis Interest in the association between pediatric mental illness and HPA axis function follows from work relating variations in HPA activity of the rat pup to lifelong emotional response patterns (Gunnar 2003). As with work on autonomic function, the most consistent association has emerged in studies of DBDs, where a subgroup of children has been shown to exhibit low cortisol levels, possibly through the effects of the early-life rearing environment (Gunnar 2003; van Goozen et al. 2007). Consistent with this possibility, a recent randomized, controlled trial demonstrated an association between changes in DBD symptoms and increases in HPA axis activity (Brotman et al. 2007). Each of these findings is thought to reflect perturbed amygdala-based regulation of HPA axis activity. On the other hand, many other areas of research have found inconsistent associations between HPA axis activity and pediatric psychopathology. For example, work in MDD has found less consistent associations in children and adolescents, relative to the associations found in adults. This contributes to some questions on the utility of further work focused on the HPA axis in the absence of concomitant direct assessment of underlying brain system function.

Monoamine Function Two findings have stimulated interest in monoamine function. First, considerable work implicates monoamines in adult disorders, and the developmental conceptualization of these adult psychopathologies encourages efforts to link pediatric syndromes to monoamine dysfunction. Second, effective psychotropic agents exert robust effects on monoamine systems. Despite consistent enthusiasm, it has been more difficult to implement work in children than in adults, given the limited availability of ethically permissible measures of central monoaminergic function. Efficacy data in pediatric mood and anxiety disorders have generated interest in the serotonin (5-HT) and norepinephrine systems. The superior efficacy of the selective serotonin reuptake inhibitors compared with the tricyclic antidepressants has generated considerable interest (Emslie and Mayes 2001). Some suggest that the differing neurochemical profiles of these medication classes support a stronger role for 5-HT than for norepinephrine in pediatric syndromes targeted by antidepressants. Consistent with these suggestions, relatively few studies have documented associations between pediatric mental illnesses and individual differences in norepinephrine system functioning, although some work implicates the norepinephrine system in pediatric anxiety disorders (Pine 2007). Considerable research implicates 5-HT dysfunction in pediatric mental syndromes. This includes most consistently PDDs, MDD, and DBDs (Birmaher and Heydl 2001; Rutter 2005; van Goozen et al. 2007). Work in this area has relied on a wealth of techniques, including assessment of peripheral 5-HT–related parameters such as whole-blood 5-HT or platelet 5-HT receptor profiles, cerebrospinal fluid 5-HT metabolite levels, and neuroendocrine assessment following administration of 5-HT agonists. One of the major questions emerging from this work examines the degree to which development impinges on the 5-HT–behavior association in humans, as it does in rodents and primates. Some physiology data suggest the presence of human developmental variation (van Goozen et al. 2007), and this is consistent with data documenting age-related changes in the adverse effects of treatment with selective serotonin reuptake inhibitors (Emslie and Mayes 2001). Nevertheless, it remains unclear how to extend such findings, given that positron emission tomography techniques that are currently used in research on 5-HT correlates of adult psychopathology are poorly suited for research with juveniles. Work on the dopamine system has also generated consistent interest. The robust efficacy of the psychostimulants in ADHD and other DBDs indirectly implicates dopamine dysfunction in these conditions, as do the genetic association studies reviewed above. Preliminary positron emission tomography studies have provided further support (van Goozen et al. 2007). Work in this area also is

relevant for developmental conceptualizations of psychosis, which is rare before puberty, and of substance abuse, which typically intensifies in adolescence. Consistent with these age-related changes in risk, which have been attributed to maturation of the dopamine system, pharmacological studies have documented developmental changes in the response to dopamine challenge across the period around puberty (Spear 2000). Moreover, this work is also relevant for current models of psychosis implicating interactions between the dopamine system and glutamate systems. Much like developmental changes for dopamine response, the response to glutamate manipulations also has shown robust age-related changes (Olney 2003). Taken together, these data implicate developmental changes in the dopamine and glutamate systems, and their interactions, in developmental changes in risk for various mental disorders. However, as with work on the 5-HT system, complications in assessment of dopamine or glutamate function in children place limits on the degree to which future research can explore the neural basis of such developmental changes.

Brain Function: Circuitry Assessed With Brain Imaging In many ways, biological research on childhood mental disorders has only recently begun to come of age, with advances in brain imaging techniques. For the first time, these advances have allowed a direct assessment of neural structure and functions in children with levels of temporal and spatial resolution appropriate for extensions to developmental work in animal models. This final section provides examples illustrating the manner in which brain imaging research facilitates integration of basic and clinical research. Relevant examples have emerged from research in diverse areas, including both normal and pathological variations in behavior, utilizing diverse techniques, including structural and functional magnetic resonance imaging approaches (sMRI and fMRI), magnetic resonance spectroscopy (MRS), event-related potentials (ERPs), and quantitative electroencephalography. As with summaries of research in other areas, the current summary does not provide an exhaustive review but rather illustrates the manner in which research in specific clinical areas provides a bridge to findings emerging both from basic science research in rodents or nonhuman primates and from cognitive or affective neuroscience research in humans. I have organized this review in six sections, beginning with a summary of findings on normal development, followed by a review of key findings in the five clinical domains depicted in Figure 52–1.

Normal Development The ability to directly visualize brain development has strengthened interest in developmental aspects of psychopathology. Recently emerging data chart robust changes in brain structure and function that extend from early childhood through late adolescence. These data support the view emerging from epidemiological studies that most chronic psychopathologies are disorders of brain development. These data also resonate with data in cognitive neuroscience delineating the developmental trajectories for specific information-processing functions. Much of the interest in neural development comes from sMRI findings demonstrating robust regional variations across development in the architecture of gray and white matter. These variations follow three basic trends (Sowell et al. 2004; Steinberg et al. 2006; Toga and Thompson 2003): 1. Consistent with postmortem work in humans and basic science studies in nonhuman primates, human brain development as shown in sMRI exhibits a clear trend to progress from primary sensory or motor cortices, which mature early, to association cortices, which mature late. This is also reflected in the spatial posteriorto-anterior gradient on which the progression from primary to association cortex is arranged. 2. Human brain development shows a general trend for a plateau of gray matter volume in childhood, with a progressive reduction through adolescence in tandem with a parallel increase in white matter volume. Taken together, these two trends lead to a progressive increase in the white-to-gray-matter volume ratio,

consistent with a growing emphasis on integrative functions in the nervous system with maturation. 3. This general trend of a decrease in gray matter volume does not occur in all brain areas, as circuitry involving frontotemporal association cortices involved in linguistic maturation shows an opposite trend of increasing gray matter volume. Taken together, these findings have generated considerable interest in mapping the relationships that such structural changes show with various measures of brain function, as manifested in direct measures of functional activity, as well as measures manifested in the environment, either on neuropsychological tests or in everyday experience. Data from fMRI studies in developing humans generally confirm findings in sMRI studies (Nelson et al. 2002). Although far fewer studies rely on fMRI than sMRI, trends in fMRI research support the view of brain maturation as a process that extends well through late adolescence, with particularly later maturation of association cortices. Considerable interest has focused on functional aspects of medial temporal, striatal, and PFC development, given evidence from studies of behavior and sMRI studies suggesting these regions exhibit protracted development (Steinberg et al. 2006). Although many questions remain, the weight of the data suggests that each of these regions undergoes protracted development.

Pervasive Developmental Disorders Current theories of PDD pathophysiology have been informed by data emerging using virtually every imaging modality. Together, this work extends insights emerging from other findings in epidemiology and cognitive neuroscience research. For example, early epidemiological studies raised questions on gross patterns of brain development in autism, based on perturbations in early-life head growth; sMRI studies confirmed that these differences in head growth are reflected in patterns of brain growth while also noting many regionally specific alterations in brain development in the cerebellum, amygdala, and other regions where one would expect perturbations, based on findings in cognitive neuroscience (Rutter 2005). These prior findings in cognitive neuroscience have generated specific interest in functional aspects of brain regions implicated in the regulation of social experience. Ongoing fMRI research also successfully extends this work. For example, eye-movement data implicating perturbed attention control when processing social stimuli are consistent with fMRI studies documenting abnormal engagement of the amygdala, fusiform gyrus, and other components of neural circuitry implicated in the assessment of social significance (Volkmar et al. 2004). Similarly, cognitive neuroscience findings documenting perturbed abilities at imitation in PDDs have been extended through fMRI studies documenting abnormal engagement of so-called mirror-neuron systems implicated in imitation. Such fMRI work has unique advantages related to the excellent spatial resolution of the technique. However, the findings have also been extended through research using ERPs, with their superior spatial resolution, demonstrating the time course over which social processing dysfunction in PDDs manifests. Taken together, this work has generated considerable enthusiasm for refining our understandings of PDD pathophysiology by grounding these understandings in knowledge of neural development.

Psychosis Data in child-onset schizophrenia uniquely demonstrate the advantages afforded by longitudinal examination of brain development, as is possible with sMRI. A central question emerging from early theories of psychosis focuses on contributions of static and dynamic neural developmental processes in changing manifestations of the illness. One of the most influential theories had suggested that a static temporal lesion interacts with dynamic changes in PFC structure emerging at adolescence to unmask a latent risk for psychosis. sMRI allows repeated assessment of brain structure across developmental periods with precise spatial localization of relevant static or changing morphology

(Greenstein et al. 2006). This provides an assessment of the degree to which the structures of specific brain regions change and adapt as children develop and show changing manifestations of the illness. Figure 52–3 illustrates the possibilities inherent with this technique, revealing the degree to which specific brain regions show distinct developmental topographies in typically developing children and children with schizophrenia. These findings document very large differences between children with overt manifestations of schizophrenia and healthy children. The demonstrable utility of this approach raises essential questions on applications to other forms of psychosis. For example, using this approach, it may be possible to capture emerging patterns of neural changes that place children at risk for psychosis before the full manifestation of pathological clinical syndromes. This may provide unique insights for both identification of at-risk individuals and targeted treatments designed to disrupt the ongoing pathological process before it has become fully entrenched. FIGURE 52–3. Changes in cerebral cortex in childhood-onset schizophrenia.

Serial acquisition of structural magnetic resonance imaging data was used to map portions of the cerebral cortex (shown in scatterplots on the right side of the figure) where patients with childhood-onset schizophrenia (COS) { } show distinct changes in brain structure relative to healthy peers (control subjects) { }. Part A shows normalization in posterior regions in COS patients; part B shows divergence from control subjects in anterior regions. *A false discovery rate procedure was used to determine the threshold for significance at t = 2. No covariates were included in the model. Source. Reprinted from Greenstein D, Lerch J, Shaw P, et al.: "Childhood Onset Schizophrenia: Cortical Brain Abnormalities as Young Adults." Journal of Child Psychology and Psychiatry 47:1003–1012, 2006. Copyright 2006, Wiley-Blackwell. Used with permission.

Disruptive Behavior Disorders and ADHD As with research on PDDs, work on DBDs and ADHD has relied on virtually every suitable imaging modality in research that directly extends findings generated in cognitive neuroscience. Without question, more research considers aspects of ADHD than DBDs, but important insights are beginning to emerge on differences among these disorders, each of which shows strong relationships in family-based and longitudinal research. In research on ADHD, the most consistent approach extends findings emerging from research on cognitive control and reward processing. Studies in this area implicate a distributed neural circuit in the condition, encompassing the PFC as it connects with the striatum and cerebellum. sMRI studies provide some support for theories that implicate this circuitry in ADHD (Nigg 2007). However, overall reduction in brain volume represents a more consistent finding than selective reductions in these specific regions, independent of the more general reduction in brain volume. fMRI research provides more consistent support in that consistent dysfunction in the striatum and in the medial and ventral PFC emerges in this work, which supports findings from cognitive neuroscience research (Nigg 2007; Swanson et al. 2007). Data emerging from ERP research further refine understandings of the manner in which this circuit might be perturbed. Due to the superior temporal resolution of this technique, ERP data generate insights on the role of each PFC subregion and the striatum in perturbed cognitive control. As these findings have been steadily accumulating, questions have arisen concerning the degree to which one or another finding in brain imaging relates specifically to risk for ADHD, to overt manifestations associated with severity of the disorder, or to long-term trajectories of ADHD symptoms. The clinical utility of imaging approaches would be enhanced if data could be mapped onto distinct aspects of ADHD risk, presentation, or trajectory. Emerging data suggest that this may be possible. Beyond research on ADHD, research data in other DBDs suggest that brain imaging measures might allow a refined categorization of behavior disorders (Blair et al. 2005; van Goozen et al. 2007). Although considerable research documents parallels in the neural correlates of ADHD and DBDs, emerging findings also suggest that a subgroup of children with DBDs can be differentiated from other children with DBDs and children with ADHD, based on functional aspects of brain circuitry engaged by emotionally salient events. One relevant theory in this respect suggests that a unique subgroup of children with DBDs exhibits a particularly poor prognosis and an unusually strong genetic component to their disorder (Blair et al. 2005). Current theory suggests that this profile is reflected in patterns of amygdala–PFC function during the evaluation of emotionally salient stimuli. Emerging brain imaging work generates findings generally consistent with this theory. As with work on ADHD, continued refinements of this approach may provide novel means for classifying pediatric DBDs based on associated neural circuitry dysfunction.

Mood Disorders Data from cognitive neuroscience studies in pediatric bipolar disorder implicate two informationprocessing functions in the condition: cognitive control and social information processing. Given knowledge on neural correlates of these information-processing functions, data from brain imaging studies are consistent with these findings in cognitive neuroscience. Specifically, cognitive control has been linked to functional aspects of frontostriatal circuitry. Both sMRI and fMRI studies in pediatric bipolar disorder implicate this circuit in the condition (Dickstein and Leibenluft 2006; Leibenluft et al. 2003; Rich et al. 2006). Similarly, social information processing has been linked to amygdala function. Again, findings from sMRI and fMRI studies in pediatric bipolar disorder also support findings in cognitive neuroscience. Reduced amygdala volume in pediatric bipolar disorder is probably the best-replicated finding emerging from all of the imaging work in any pediatric mood disorder. Moreover, fMRI studies find evidence of enhanced amygdala activation, specifically under conditions where deficits in social information processing manifest.

Considerable controversy surrounds the diagnosis of pediatric bipolar disorder. Ideally, emerging findings in brain imaging will provide some insights helpful in resolving this controversy. Although imaging work is only beginning to speak to issues of classification, some evidence suggests that future work in this area may be helpful in refining understandings of bipolar phenotypes. Figure 52–4 illustrates one relevant finding using ERP technology (Rich et al. 2007). Much of the controversy in nomenclature concerns the classification of children presenting with marked irritability and hyperarousal in the absence of classic symptoms of mania, particularly distinct periods of elevated mood. Figure 52–4 shows that children presenting with these features can be differentiated from children with classic presentations of mania, whereas other findings from the same study also show that these children can be differentiated, using other ERP measures, from healthy peers as well as from children with classic bipolar presentations. FIGURE 52–4. Event-related potentials in pediatric bipolar disorder.

This figure shows P3 event-related potential (ERP) amplitude at the parietal Pz site during performance of a frustrating task. The task, which requires subjects to quickly identify a target, is made quite difficult, leading to frustration through frequent incorrect responses (A). As shown in B, when patients with bipolar disorder (n = 35; blue) make errors, ERP amplitude, phase-locked to these errors, is significantly lower than in both healthy peers (n = 26; red) (P

Chapter 54. Treatment of Bipolar Disorder TREATMENT OF BIPOLAR DISORDER: INTRODUCTION Bipolar disorder is a common, recurrent, often severe psychiatric illness that, without adequate treatment, is associated with high rates of morbidity and mortality (Goodwin and Jamison 2007). In the Global Burden of Disease survey, bipolar disorder was the sixth leading cause of disability worldwide in 1990 and, without improved access to treatment, was projected to remain so well into this century (Murray and Lopez 1996). Morbidity from bipolar disorder often extends well beyond manic, hypomanic, mixed, and depressive episodes. Full recovery of functioning can lag many months behind symptomatic improvement, and repeated episodes can lead to lasting functional impairment (Judd et al. 2005). Recent naturalistic outcome studies indicate that many patients with bipolar disorder spend protracted periods of time neither well nor syndromally ill but rather suffering from chronic subsyndromal, especially depressive, symptoms (Judd et al. 2002, 2003). Bipolar disorder is also among the most heritable of all medical illnesses (Goodwin and Jamison 2007). The goals of treatment of bipolar disorder are similar to those of management of many chronic illnesses: rapid, complete remission of acute episodes; prevention of further episodes; suppression of subsyndromal symptoms; and optimization of functional outcome and quality of life (Keck et al. 2001). However, the treatment of bipolar disorder is often complicated. Although classified as a mood disorder, bipolar disorder is also characterized by disturbances of behavior, cognition, and perception. Thus, successful treatment requires that these multiple symptom domains be addressed. Treatment is further complicated by the diversity of illness presentation (e.g., pattern, frequency, and severity of episodes; presence of psychosis, comorbid illnesses, acute or chronic environmental stressors) and course among individuals. Some medications have particular efficacy in one phase of illness but not in another, and some may actually increase the likelihood of precipitating a reciprocal mood episode. The treatment of bipolar disorder has traditionally been divided into the management of acute manic, mixed, and depressive episodes and the prevention of further episodes and symptoms (Hirschfeld et al. 2002). Rush (1999) conceptualized a "strategies and tactics" approach to the management of major depressive disorder, with principles of pharmacotherapy that are readily applicable to bipolar disorder (Table 54–1). In this chapter we review strategies (i.e., what treatments to choose) and tactics (i.e., how to implement these strategies once chosen and what dose and duration of the chosen medication are to be used) for treating bipolar disorder, drawing primarily on data from randomized, controlled trials. Where such data are lacking, strategies based on data from open trials, naturalistic studies, and expert consensus guidelines are included. The treatment of bipolar disorder in children and adolescents is covered elsewhere in this book (see Chapter 63 in this volume, "Treatment of Child and Adolescent Disorders," by Wagner and Pliszka). TABLE 54–1. Treatment principles for bipolar disorder Individually tailor guidelines. Use proven treatments first. Select best medication that is

Safe and tolerable. Easiest to use (for the patient). Easiest to manage (for the physician). Aim for symptom remission, not just response. Measure symptomatic outcome. Remember that no medication is a panacea. Do not give up. Recognize that psychosocial restoration follows symptom relief. Interpersonal, family, educational, and social rhythm–targeted psychotherapies can help. More chronic illness may respond more slowly. Source. Adapted from Rush AJ: "Strategies and Tactics in the Management of Maintenance Treatment for Depressed Patients." Journal of Clinical Psychiatry 60 (Supplement 14):21–26, 1999.

FORMULATION AND IMPLEMENTATION OF A TREATMENT PLAN Patients with bipolar disorder enter into treatment at various phases of illness. Regardless of illness phase, treatment begins with a thorough diagnostic assessment (Hirschfeld et al. 2002). In addition to the clinical features of bipolar disorder described in DSM-IV-TR (American Psychiatric Association 2000), patients with bipolar disorder also commonly experience symptoms of anxiety, impulsivity, recklessness, elevated libido, poor insight, inattention, and sensory hyperacuity during manic or mixed episodes (Keck et al. 2001). Bipolar disorder frequently presents with depressive episodes. A family history of bipolar disorder or early age at onset of depression should raise diagnostic questions about bipolar disorder in an individual presenting for treatment of depression. Studies suggest that 15%–30% of patients treated for apparent major depressive disorder in outpatient settings subsequently receive a diagnosis of bipolar I or II disorder (Manning et al. 1997, 1998). The Mood Disorder Questionnaire (MDQ) is a 13-item self-report screening instrument for bipolar disorder that has been successfully tested in psychiatric clinics (Hirschfeld et al. 2000) and in the general population (Hirschfeld 2002). Bipolar disorder is associated with elevated rates of substance use, anxiety, eating, attentiondeficit/hyperactivity, and impulse-control disorders and migraine (Birmaher et al. 2002; McElroy et al. 2001). Thus, the presence of these illnesses should be assessed in patients with bipolar disorder, and conversely, bipolar disorder should be assessed in patients presenting with these other illnesses. Other elements of a complete psychiatric evaluation are summarized in the American Psychiatric Association's (1995) "Practice Guideline for Psychiatric Evaluation of Adults." The American Psychiatric Association's revised "Practice Guideline for the Treatment of Patients With Bipolar Disorder" (Hirschfeld et al. 2002) lists a number of other important elements in the treatment of patients with bipolar disorder (Table 54–2). Evaluation of safety of the patient and others and determination of the appropriate treatment setting are essential because of the risks of suicide, recklessness, and violence associated with mood episodes (Lopez et al. 2001) (Table 54–3). Establishing and maintaining a treatment alliance are early and ongoing goals to facilitate patient and family education, treatment adherence, and identification of precipitants and prodromal symptoms. Monitoring treatment response and providing illness education can be enhanced by using the Life-Chart Method (Denicoff et al. 2002) or other similar longitudinal self-assessments. In addition, a number of well-validated rating scales exist for monitoring mood symptoms in patients with bipolar disorder cross-sectionally. These include the Young Mania Rating Scale (R. C. Young et al. 1978) for manic symptoms and the Montgomery-Åsberg Depression Rating Scale (Montgomery and Åsberg

1979) for depressive symptoms, among others. Because bipolar disorder can lead to disability and varying degrees of functional impairment in all aspects of life, specific psychotherapeutic and rehabilitation interventions may be needed. TABLE 54–2. Clinical components of the management of bipolar disorder Perform a diagnostic evaluation. Evaluate the safety of the patient and others and determine a treatment setting. Establish and maintain a therapeutic alliance. Monitor treatment response. Provide education to the patient and significant others. Enhance treatment compliance. Promote awareness of stress and regular patterns of activity and sleep. Work with the patient to anticipate and address early signs of relapse. Evaluate and manage functional impairments. Source. Reprinted from Hirschfeld RMA, Bowden CL, Gitlin MJ, et al.: "Practice Guideline for the Treatment of Patients With Bipolar Disorder (Revision)." American Journal of Psychiatry 159 (Supplement):1–50, 2002. Copyright 2002, American Psychiatric Association. Used with permission. TABLE 54–3. Characteristics to evaluate in an assessment of suicide risk in patients with bipolar disorder Presence of suicidal or homicidal ideation, intent, or plans Access to means for suicide and the lethality of those means Presence of command hallucinations, other psychotic symptoms, or severe anxiety Presence of alcohol or substance use History and seriousness of previous attempts Family history of or recent exposure to suicide Source. Adapted from American Psychiatric Association: "Practice Guideline for the Treatment of Patients With Major Depressive Disorder (Revision)." American Journal of Psychiatry 157 (Supplement):1–45, 2000. Copyright 2000, American Psychiatric Association; Hirschfeld RMA, Bowden CL, Gitlin MJ, Keck PE, Perlis RH, Suppes T, Thase ME: "Practice Guideline for the Treatment of Patients With Bipolar Disorder (Revision)." American Journal of Psychiatry 159 (Supplement):1–50, 2002. Copyright 2002, American Psychiatric Association. Used with permission.

DEFINITIONS: WHAT IS A MOOD STABILIZER? The treatment of bipolar disorder is among the most challenging of all treatments for psychiatric illnesses for a variety of reasons, one of which is that some agents effective in the treatment of one pole can exacerbate or cause a switch into another pole. Goodwin and Jamison (2007) have defined mood stabilizer as an agent that demonstrates efficacy in the acute treatment of both mania and depression, as well as in the prevention of both types of mood episodes (ideal definition) or an agent that is efficacious in two of these three aspects of treatment (strict definition). In this chapter, we use the term mood stabilizer according to the strict definition. To date, there is no ideal agent, although data from randomized, controlled trials suggest that lithium and olanzapine probably come closest.

TREATMENT OF ACUTE BIPOLAR MANIC AND MIXED EPISODES Manic and mixed episodes are medical emergencies and frequently require treatment in a hospital to ensure safety of patients and those around them. The primary goal of treatment of manic and mixed

episodes is rapid symptom reduction, followed by full remission of symptoms and restoration of psychosocial and vocational functioning (Hirschfeld et al. 2002). These are straightforward goals, but tailoring treatment to specific patients requires consideration of presenting symptoms and their severity (e.g., presence or absence of psychosis, manic or mixed episode, proximal frequency of episodes). Pharmacotherapy is the cornerstone of treatment of acute manic and mixed episodes and of bipolar disorder in general. A number of medications have demonstrated efficacy in the treatment of acute manic and mixed episodes (Table 54–4). Lithium, divalproex, carbamazepine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, haloperidol, and chlorpromazine have shown efficacy as monotherapy in the treatment of acute mania in randomized, placebo-controlled trials (McElroy and Keck 2000; Perlis et al. 2006c). Although these agents typically produce rates of response (defined as 50% reduction in manic symptoms from baseline to endpoint) of approximately 50% in short-term (3- to 4-week) trials, relatively few patients (

Chapter 55. Treatment of Schizophrenia TREATMENT OF SCHIZOPHRENIA: INTRODUCTION Schizophrenia is a debilitating brain disorder characterized by a chronic relapsing and remitting course of psychosis that is superimposed on persistent "deficit" features such as cognitive dysfunction and negative symptoms. It appears to be equally prevalent across geographical and cultural boundaries (see Jablensky et al. 1992), afflicting approximately 1% of the population (Perala et al. 2007). The etiology and pathophysiology of schizophrenia remain poorly understood, but the importance of genetic factors is consistently supported by twin (Gottesman 1991; Kendler 1983), family (Gottesman 1991; Kendler 1983; Tsuang et al. 1980), and adoption (Kety et al. 1964, 1994) studies. In the past few years, a number of genes have been identified as being associated with schizophrenia. Furthermore, intensive research has focused on trying to understand how these candidate genes may play a role in the pathophysiology of schizophrenia (G. Harrison 2004; P. J. Harrison and Owen 2003; Porteous et al. 2006; Stefansson et al. 2004). Although the heritability of schizophrenia is high, it appears that environmental events, such as stress (Moghaddam and Jackson 2004), or epigenetic factors (E. Costa et al. 2003, 2006; Tsankova et al. 2007) also play an important role in modulating the expression of the disease genes and, therefore, in the development of particular schizophrenia phenotypes. This notion is highlighted by the observation that the concordance rate for schizophrenia in monozygotic twins is far less than 100%; it usually lies between 46% and 53% (Gottesman 1991). The environmental factors that have been suggested to contribute to the pathophysiology of schizophrenia include in utero virus (Browne et al. 2000; Buka et al. 2001; Mednick et al. 1988), toxoplasmosis (Dickerson et al. 2007; Hinze-Selch et al. 2007; Mortensen et al. 2007), malnutrition (A. S. Brown et al. 1996), cannabis use (Macleod et al. 2006), and obstetric or perinatal complications (Cannon 1997; Cannon et al. 2000; Geddes and Lawrie 1995). Although significant progress has been made in recent years toward understanding the neural basis of schizophrenia, the exact cascade of events—for example, how interactions between genes and environmental factors lead to the emergence of the illness—has yet to be elucidated (Ross et al. 2006; Tsankova et al. 2007; Weinberger 1996). Considerable progress has been made in the pharmacological treatment of schizophrenia since the serendipitous discovery in the early 1950s of chlorpromazine as the first effective antipsychotic medication (Lehmann and Hanrahan 1954). Many other antipsychotic agents, all sharing chlorpromazine's dopamine D2 receptor–blocking ability, were subsequently developed. These "conventional," or first-generation, antipsychotics are all effective in the treatment of positive symptoms of psychosis, but they all have limited beneficial effects on negative symptoms and cognitive deficits. Furthermore, these first-generation agents commonly produce extrapyramidal side effects (EPS), including parkinsonism, akathisia, and tardive dyskinesia. Since 1990, a second generation of antipsychotic drugs has become available in the United States. These second-generation agents are also commonly referred to as "atypical" or "novel" antipsychotics, largely because of their reduced propensity, compared with the conventional agents, to cause EPS. It has been postulated that this unique property (i.e., the low risk of EPS) may reflect

the potent serotonin2A (5-HT2A) receptor antagonistic effects or, more specifically, the high ratio of 5-HT2A to D2 receptor occupancy of these drugs (Meltzer 1989). More recently, it has been proposed that the rapid dissociation (high dissociation constant) of these drugs from D2 receptors may be another very important pharmacological property that determines "atypicality" (Kapur and Remington 2001; Seeman 2002). With the introduction and widespread use of the second-generation antipsychotics, the focus of treatment has been gradually expanding beyond targeting psychotic or positive symptoms of the illness alone. Second-generation agents have been reported to improve some aspects of negative symptoms and cognitive impairment—elements of the disorder not typically responsive to firstgeneration antipsychotics, at least the high-potency ones (see below). An ability to ameliorate cognitive deficits, in particular, would be important, because such deficits have been found to be strong predictors of long-term functional outcome of the illness (M. F. Green 1996; M. F. Green and Nuechterlein 1999). In fact, development of compounds that can improve cognition has rapidly become one of the main foci in schizophrenia research in just the past few years (Fenton et al. 2003; Hyman and Fenton 2003; Marder 2006). It should be stressed, however, as will be elaborated in this chapter, that although some of the data on the efficacy of second-generation antipsychotics in the treatment of negative symptoms and cognitive impairment are encouraging, they are by no means conclusive. It may be that rational development of yet newer drugs with novel mechanisms may be necessary before negative symptoms and cognitive deficits can be treated in a clinically meaningful manner (Carpenter and Gold 2002; M. F. Green 2002). This drug discovery and development process is likely to rely critically on an improved understanding of the neurobiological basis of both negative symptoms and cognitive deficits. In recent years, the field has developed a focused interest in early diagnosis and early intervention in patients who are just becoming psychotic. Studies are under way to determine whether it is possible to delay or even prevent the emergence of psychosis. In the years to come, it is likely that this emphasis on early intervention will expand with further research on the treatment of prodromal states, in an attempt to improve the overall course or perhaps even prevent the actual onset of overt illness in individuals who appear likely to develop schizophrenia. [The authors would like to acknowledge the contribution of Holly L.L. Pierce in the preparation of this chapter.]

CLINICAL MANIFESTATIONS OF SCHIZOPHRENIA There is a growing consensus, following the seminal work of several investigators (e.g., Andreasen 1985; Crow 1985), that schizophrenia can be conceptualized as a disorder with at least two more or less orthogonal dimensions of symptomatology: positive and negative symptoms. Positive, or psychotic, symptoms usually are the symptoms that first trigger psychiatric attention, and traditionally, the onset of schizophrenia is clinically synonymous with the emergence of overt psychosis. This concept, however, is gradually changing, because accumulating evidence indicates that the schizophrenia disease process probably begins long before the onset of psychosis. For example, existing evidence from animal studies suggests that brain insults occurring during the first trimester of pregnancy and/or during the perinatal period could have late-occurring detrimental effects on the normal functioning of the brain (Bertolino et al. 2002; D. A. Lewis and Levitt 2002; O'Donnell et al. 2002; Waddington et al. 1998; Weinberger 1987). Interestingly, subtle neurological abnormalities, as well as intellectual and cognitive difficulties, have been observed in children who later show symptoms of schizophrenia (Walker et al. 1999). Finally, research suggests that patients begin to experience a gradual decline in their level of social and cognitive functioning for a period of up to 5 years before the onset of overt psychosis. During this time, they characteristically have symptoms that are similar to the negative symptoms of schizophrenia (Cannon et al. 2007; Hafner et

al. 1994, 1999; Yung and McGorry 1996b). Furthermore, it appears that during this prodromal stage of the illness, several regions of the cerebral cortex undergo pronounced volumetric reduction (Borgwardt et al. 2007; Pantelis et al. 2003).

Positive Symptoms Positive symptoms are perceptual or cognitive features that "normal" individuals usually do not experience. They include hallucinations, delusions, and disorganized thinking, although disorganization also can be conceptualized as an independent symptom dimension (Liddle et al. 1989). As a general rule, positive symptoms tend to respond to treatment with antipsychotic medications; traditionally, they have been the focus of treatment with these medications. Although positive symptoms are dramatic, and while in the midst of them, patients' ability to function is usually severely disrupted, studies have quite consistently shown that such symptoms do not appear to bear any significant association with or predict the long-term functional outcome of the illness (M. F. Green et al. 2000). It also should be emphasized that psychotic symptoms are not specific to schizophrenia; they can occur in a wide spectrum of other psychiatric, neurological, and medical disorders. Therefore, it is essential to rule out other possible causes of psychosis before a diagnosis of schizophrenia is made.

Negative Symptoms Negative symptoms represent a "loss" of functions or abilities that people without schizophrenia normally possess. They include anhedonia, affective flattening, alogia, avolition, and asociality. Negative symptoms are somewhat associated with intellectual and neurocognitive impairment (Dickerson et al. 1996; Harvey et al. 1998), and they are better predictors of long-term functional outcome and psychosocial functioning of schizophrenia patients than are positive symptoms (Buchanan et al. 1994; Dickerson et al. 1996; Harvey and Keefe 1998). However, neurocognitive deficits, as discussed below, remain the strongest predictors of outcome (M. F. Green 1996). As mentioned above, negative symptoms may have developed long before the actual "onset" of the illness (Hafner et al. 1994, 1999; Yung and McGorry 1996b), which is traditionally defined as the beginning of psychosis. In fact, many prodromal symptoms of schizophrenia may be phenomenologically indistinguishable from negative symptoms. Importantly, EPS produced by antipsychotic medications can sometimes resemble negative symptoms of schizophrenia. To clarify matters, the concepts of primary versus secondary negative symptoms have been introduced (Carpenter et al. 1988). Thus, primary negative symptoms represent the core negative symptoms reflecting the schizophrenia disease process. Secondary negative symptoms, on the other hand, may resemble primary negative symptoms, but they are caused by or are secondary to positive symptoms of psychosis or the antipsychotic medications themselves. This distinction has important treatment implications. For example, a reduction in medication dosage may alleviate some secondary negative symptoms, but this strategy is unlikely to have a beneficial effect on primary negative symptoms.

DIAGNOSIS OF SCHIZOPHRENIA According to DSM-IV-TR (American Psychiatric Association 2000), to make the diagnosis of schizophrenia, there must be evidence of continuous symptomatic disturbance for at least 6 months accompanied by a decline from the premorbid level of functioning. Thus, in line with the Kraepelinian concept (Kraepelin 1919/1971), DSM-IV-TR emphasizes the longitudinal course of deterioration of the illness. This 6-month period can include functional deterioration occurring during the prodromal phase before the onset of overt psychosis. Within the 6-month period, the patient must have two or more of the following symptoms for at least 1 month: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms. If the duration of psychotic symptoms is less than 1 month because of successful treatment with antipsychotic medication, a diagnosis of

schizophrenia still may be made. Of course, before the diagnosis of schizophrenia is made, other medical or psychiatric conditions need to be considered and ruled out.

NEUROCOGNITIVE DEFICITS IN SCHIZOPHRENIA In the early Kraepelinian formulation of schizophrenia (or dementia praecox), cognitive impairments represented core deficits (Kraepelin 1919/1971). This Kraepelinian concept was somewhat displaced by an emphasis on psychotic symptoms in the diagnosis and treatment of schizophrenia until recently, when the field of schizophrenia research witnessed substantial resurgence of interest in neurocognitive dysfunction in schizophrenia. Research on cognition may facilitate the identification of endophenotypes (i.e., genetic traits) of schizophrenia and also may have significant treatment implications: cognitive deficits are strong predictors of long-term functional outcome of patients with schizophrenia, and unfortunately, they are also among the features that are most resistant to treatment (M. F. Green 1996; M. F. Green et al. 2000). Further research on cognitive deficits may result in the development of more effective pharmacological, cognitive, and psychosocial interventions in the management and perhaps treatment of these deficits. Schizophrenia appears to be associated with a decline in general cognitive function at some point during the course of the illness. Various studies have shown that this decline may either predate the onset of psychosis (Aylward et al. 1984; David et al. 1997; Nelson et al. 1990; Russell et al. 1997; Simon et al. 2007) or occur concurrently with or subsequent to the first psychotic episode (Nelson et al. 1990). It appears that after this initial decline, the level of cognitive impairment follows a relatively stable course for several decades without evidence of further significant deterioration (Elvevag and Goldberg 2000; Goldberg et al. 1993). Several aspects of cognitive impairment that are well documented in schizophrenia are briefly discussed below.

Verbal Declarative Memory Among the cognitive functions that are known to be disturbed in schizophrenia, verbal declarative memory impairment, which can be manifested as disturbances in the encoding, storage, and retrieval of mnemonic items, is one of the most consistent findings. It also represents one of the most severe deficits (Saykin et al. 1991, 1994) that is independent of other cognitive impairment, such as attentional deficits. Memory impairment may represent a core feature of the illness (Saykin et al. 1991), one that is stable over time and relatively independent of clinical course (Censits et al. 1997; Gur et al. 1998). It does not appear to be an artifact of antipsychotic medications because memory impairment occurs in drug-naive first-episode patients (Saykin et al. 1994). In addition, it also occurs in otherwise psychiatrically healthy close relatives of schizophrenia patients (Toomey et al. 1998), suggesting that verbal memory impairment may be an endophenotype of schizophrenia. Interestingly, an association between the degree of memory impairment and the severity of negative symptoms has been found (Harvey et al. 1998; Zakzanis 1998). Like memory deficits, negative symptoms also appear to be quite resistant to treatment and are relatively stable during the course of the illness. Thus, memory impairment and negative symptoms in schizophrenia may involve a shared neuroanatomical substrate. Because memory function is largely mediated by medial temporal structures and negative symptoms are generally associated with prefrontal deficits, information-processing disturbances between the prefrontal and the temporal cortices may represent a prominent feature of schizophrenia (Gur et al. 1998; Heckers et al. 1998).

Working Memory Working memory is the ability to hold information on-line when other perceptual, cognitive, or mnemonic information is not immediately present in order to guide future behavior and action (Baddeley 1986). This function is mediated by a neural system of which the prefrontal cortex is a key component (Goldman-Rakic 1996). There have been robust findings of impaired performance of schizophrenic patients on tasks that tap working memory (Park and Holzman 1992), impairments that

do not appear to be caused by antipsychotic medications (Goldberg and Weinberger 1996). The fact that working memory impairment is also observed in many first-degree relatives of patients with schizophrenia (Park et al. 1995) suggests that this feature, like verbal declarative memory deficits, may conceivably represent an endophenotype of the illness. Finally, working memory has been extensively studied in nonhuman primates, and the neural elements that support working memory are relatively well understood (Fuster 2000; Goldman-Rakic 1996). Interestingly, postmortem studies have found that many of these neural elements appear to be disturbed in schizophrenia (D. A. Lewis and Lieberman 2000; D. A. Lewis et al. 2005).

Executive Function Traditionally, the term executive function has been used to describe the specific role of the prefrontal cortex in the temporal organization, planning, and sequential execution of goal-directed behavior based on representational information that is constantly being generated and updated (Stuss and Benson 1986). Executive function deficits in schizophrenia, such as those tapped by the Wisconsin Card Sorting Test (WCST), have been frequently described. In a series of well-controlled experiments, Weinberger et al. (1986) showed that during the performance of the WCST, normal control subjects differed from schizophrenic subjects by the selective activation of the dorsolateral prefrontal cortex, as shown by a differential increase in the regional cerebral blood flow (rCBF) to this part of the prefrontal cortex. The lack of action of the prefrontal cortex has been referred to as "hypofrontality" (Ingvar and Franzen 1974). This observation was replicated in subsequent studies when the prefrontal cortex was functionally challenged with the performance of cognitive tasks (K. F. Berman and Weinberger 1999; Carter et al. 1998), although negative findings also have been reported (e.g., Frith et al. 1995; Manoach et al. 1999; Spence et al. 1998).

Attention Attention plays a key role in mediating many cognitive processes. Attention deficits are well documented in schizophrenia and may in part contribute to the many cognitive disturbances seen in this illness (Braff 1993, 1999; Nuechterlein and Dawson 1984). For example, schizophrenic subjects tend to perform poorly on the Continuous Performance Test, a commonly used task to tap sustained attention. Attention deficit in schizophrenia may reflect an underlying "gating" deficit in which patients have difficulties "filtering out" information that is context-irrelevant or distracting (Braff 1993). One of the most consistent findings in patients with schizophrenia is a deficit in the phenomenon of prepulse inhibition (PPI). For example, a sound (prepulse) that occurs 30–500 msec before a sudden loud tone (i.e., a stimulus that normally triggers a startle response) will prevent or reduce the amplitude of the startle response (Braff et al. 1992). However, in patients with schizophrenia, this PPI of the response to the stimulus is diminished (Braff et al. 1992). Interestingly, PPI deficits are also observed in unaffected relatives of patients with schizophrenia (Cadenhead et al. 2000), a finding that is consistent with the notion that such deficits may serve as a trait marker or an endophenotype of schizophrenia.

COURSE OF SCHIZOPHRENIA Schizophrenia is a chronic illness with the onset of psychotic symptoms usually occurring around late adolescence and early adulthood (D. A. Lewis and Lieberman 2000). The age at onset is approximately 5 years later in women than in men (Angermeyer et al. 1990; Faraone et al. 1994; Hambrecht et al. 1992; Szymanski et al. 1995). The onset of illness also tends to be more acute in women, as compared with the typically more insidious onset in men, and women tend to have had a higher level of premorbid functioning. Although there may be no clear sex differences in cross-sectional symptomatology of the illness (Hafner et al. 1993; Szymanski et al. 1995), the differences in the age at onset, tempo of onset, and level of premorbid functioning, all of which are prognostic factors, are consistent with the fact that women in general tend to have a more favorable outcome.

Accumulating evidence suggests that schizophrenia is a neurodevelopmental disorder (D. A. Lewis and Levitt 2002; Murray 1994; Pilowsky et al. 1993; Waddington 1993; Weinberger 1987, 1996). It has been postulated that disturbances in brain development during the first and second trimesters may contribute to the pathophysiology of the illness (Waddington 1993). Other factors such as obstetric complications may further alter the course of brain development (Cannon 1997; Cannon et al. 2000; Geddes and Lawrie 1995). Minor physical anomalies (Lane et al. 1997), neurological soft signs (Browne et al. 2000; Lawrie et al. 2001; Rosso et al. 2000), and neuromotor abnormalities (Walker et al. 1999) have been observed in children who later develop schizophrenia, consistent with the notion that the pathophysiological process leading to schizophrenia appears to have begun much earlier than the onset of psychosis. For a period of 2–5 years before the onset of the first overt psychotic episode, up to three-quarters of the patients who eventually develop schizophrenia show a wide spectrum of "prodromal" symptoms (Docherty et al. 1978; Freedman and Chapman 1973; Hafner et al. 1992, 1993, 1994; G. Huber et al. 1980; Lieberman 2006; Simon et al. 2007; Varsamis and Adamson 1971; Yung and McGorry 1996a, 1996b). During the prodromal period, behavior changes, such as deterioration in school, work, social, and interpersonal functioning, are often noted. Prodromal symptoms are usually affective or cognitive in nature (e.g., depressed mood, social withdrawal, decreased concentration and attention, decreased motivation, agitation, anxiety, and sleep disturbances). Many of these symptoms are highly reminiscent of and, in fact, perhaps clinically indistinguishable from the negative symptoms and cognitive deficits seen in schizophrenia itself. Other symptoms occurring in the prodromal period, such as suspiciousness, magical thinking, and paranoia, may resemble positive or psychotic symptoms but tend to be transient and not particularly complex; these quasi-psychotic symptoms eventually coalesce into full-blown psychotic symptoms that characterize the onset of the illness. After the onset of the first episode of psychosis, the course of the illness is often characterized by a gradual and at times continuous deterioration, especially in the first 2–5 years (McGlashan 1998). Some evidence suggests that functional deterioration may be accompanied by a gradual loss of gray matter volume of the cerebral cortex (DeLisi et al. 1997; Kasai et al. 2003a, 2003b; Salisbury et al. 2007; van Haren et al. 2007; Zipursky et al. 1992). In addition, there has been speculation that these observations of functional and structural brain changes after the onset of psychosis may reflect a neurodegenerative process (DeLisi 1999; DeLisi et al. 1997; Lieberman 1999). However, the available evidence in support of the neurodegeneration hypothesis of schizophrenia remains weak (Carpenter 1998; Weinberger and McClure 2002). Conventionally, the hallmark of neurodegeneration is neuronal death, which is generally not believed to be occurring, at least not in large scale, in schizophrenia (Selemon and Goldman-Rakic 1999). However, it is possible that, short of leading to cell death, neuronal injury can be manifested as loss of dendrites and synapses, which can contribute to the observation of progressive gray matter loss. Furthermore, gray matter volume reduction can alternatively be explained as reflecting an exaggerated synaptic pruning process that is normally occurring during the period of late adolescence and early adulthood (Huttenlocher 2002). After an initial period of functional deterioration, symptoms tend to become more or less stabilized. Some degree of amelioration of positive symptoms (and, to a lesser extent, of disorganization symptoms) may not be uncommon in older patients (Davidson et al. 1995; Harding et al. 1987; Pfohl and Winokur 1982; Schultz et al. 1997). However, findings of amelioration of psychotic symptoms should be interpreted in light of the fact that these are also the symptoms most responsive to treatment with antipsychotic medication, making it difficult to distinguish between the natural course of the disorder and the accumulated response to treatment. Positive symptoms usually respond to treatment, whereas negative symptoms are believed to be relatively treatment resistant and may tend to become increasingly prominent during the course of the illness (Breier et al. 1991). Many, but not all, studies (Ho et al. 2000) have implied that early intervention during the very first

episode of psychosis could be associated with better overall prognosis, as measured by fewer relapses, shorter duration between initiation of antipsychotic treatment and response, and fewer residual symptoms (Birchwood 1992; Haas et al. 1998; Johnstone et al. 1986; Loebel et al. 1992). However, these same studies also have shown that the time between the onset of symptoms and the patient's first presentation to psychiatric care (i.e., the duration of untreated psychosis) is far from optimal: the average duration of untreated psychosis is about 1–2 years. Thus, a major goal in the treatment of schizophrenia is early recognition of illness and timely treatment.

MANAGEMENT OF SCHIZOPHRENIA Acute Psychosis The acute phase of schizophrenia is characterized by psychotic symptoms and often by agitation. Affective symptoms such as depression and mania also may occur. The severity of symptoms may vary widely, requiring careful evaluation to determine the most optimal treatment setting and management strategy. The decision to hospitalize a patient usually is based on whether the patient has the ability to care for him- or herself or whether he or she poses any risks of harm to self or others. Regardless of whether treatment is provided in a hospital or in an outpatient setting, acute psychosis requires use of antipsychotic medication. Management of an acutely agitated and psychotic patient can pose a challenge. It may be necessary to physically restrain the patient for his or her own safety and also for the safety of others. Medications given orally or, in the event of severe agitation, parenterally may be indicated. Although the practice patterns for treatment of acute psychosis are changing following the introduction of atypical agents, for initial acute management of severe behavioral dyscontrol, many physicians still use a high-potency first-generation antipsychotic either alone or in conjunction with a benzodiazepine (such as lorazepam) and/or an anticholinergic drug (such as benztropine). Prior to medicating a patient, it is important to inquire about a history of allergic or severe adverse reactions to the medications to be prescribed. For example, the clinician should be particularly cautious when deciding to prescribe a high-potency first-generation antipsychotic agent to a patient with a history of acute dystonic reaction and should avoid such agents in a patient with a history of neuroleptic malignant syndrome. If the patient has a history of treatment with antipsychotic medications, one needs to ascertain whether the current psychosis is the result of noncompliance or a "breakthrough" episode because of loss of therapeutic response to the medications. Noncompliance with antipsychotic medications is common and is one of the major causes of symptom exacerbation or full-blown relapse (Crow et al. 1986; Lieberman et al. 1993; Robinson et al. 1999). Causes of noncompliance vary, but the most common reasons are side effects, lack of insight into the illness, delusional interpretations about medication, substance abuse, and lack of a supportive environment (Kampman and Lehtinen 1999). If the psychotic episode appears to result from medication noncompliance, the clinician may decide to restart the same medications in the patient, but it is imperative to focus on improving adherence by providing psychoeducation to the patient (and family, if available) and discussing with the patient the reasons for nonadherence. Depot medications also should be considered if noncompliance is a persistent or recurring problem. Of course, in the case of apparent breakthrough psychosis, change in the patient's medication regimen may be indicated. Other causes of exacerbation of psychosis may include comorbid substance abuse or dependence and comorbid depression, as well as psychosocial stressors including difficulties with housing, employment, benefits, insurance, disability, family, and friends. Therefore, although medications are undoubtedly the mainstay for initial treatment of psychosis, other treatment such as psychotherapy, group therapy, family therapy, dual-diagnosis treatment, social skills training, and case management are important adjuncts to pharmacological management.

First-Episode Psychosis

Emphasis on the early diagnosis and treatment of the first psychotic episode of schizophrenia arises from the recent evidence from some, but not all (Ho et al. 2000), studies suggesting that the duration of untreated psychosis may be associated with poorer overall outcome (Birchwood 1992; Loebel et al. 1992; Wyatt 1991). One hypothesis to account for this observation is that shortening of duration of untreated psychosis by early treatment with antipsychotics may decrease the long-term morbidity of the illness. An alternative hypothesis is that prolonged duration of untreated psychosis represents a different, more severe form of schizophrenia that, by itself, is associated with poorer outcome (McGlashan 1999). For example, the delay in obtaining treatment may indicate a more insidious course of onset of psychosis, which is thought to be associated with increased long-term morbidity; alternatively, patients who seek treatment earlier may experience a more acute form of psychosis, which has been suggested to be a predictor of better prognosis (McGlashan 1999). This hypothesis, however, was not supported by a study in which the mode of onset of psychosis, whether insidious or acute, was not correlated with outcome (Loebel et al. 1992). In summary, although some studies have indicated that duration of untreated psychosis is correlated with outcome, whether a prolonged duration of untreated psychosis could be a marker or a determinant of poor outcome remains to be elucidated (McGlashan 1999). Because of the more favorable neurological side-effect profile—mainly the reduced risks of adverse neurological events such as parkinsonism, akathisia, and tardive dyskinesia—the second-generation antipsychotics are often considered for the initial treatment of first-episode psychosis. However, as discussed below, many of these medications carry other medically important side effects, including weight gain. Because patients are likely to require long-term treatment, clinicians should pay close attention to antipsychotic side effects and to their potential morbidity. In general, a conservative titration schedule is appropriate for first-episode patients, in part to minimize side effects but also to take into account that these patients may require only low doses for the control and remission of symptoms (Remington et al. 1998; Robinson et al. 1999; Schooler et al. 2005; Wyatt 1995). After remission of an initial episode of psychosis in a patient with a diagnosis of schizophrenia, potential discontinuation of medication, even if done very gradually, is controversial and often not attempted. Any decision about this should be made in light of studies showing that the relapse rate is very high after medication discontinuation in first-episode schizophrenia (Crow et al. 1986; Johnson 1985; Kane et al. 1982; Robinson et al. 1999). Gitlin et al. (2001), using a low threshold to define recurrence of symptoms, reported that the relapse rate in the first year after medication discontinuation was 78% and increased to 98% by the end of the second year. Moreover, Robinson et al. (1999) found that the relapse rate among self-selected first-episode patients who discontinued their medication was five times the rate among those who continued taking medication. Studies suggest that relapse rates may be lower if uninterrupted medication treatment occurs for at least 1 year after the resolution of psychosis (Kissling et al. 1991). If a decision is made to initiate a trial of medication discontinuation, the discontinuation should be done very gradually, and the patient should continue to be monitored closely for an extended period. Fortunately, in one study of medication discontinuation in recent-onset patients (Gitlin et al. 2001), the combination of close clinical supervision after medication discontinuation and rapid reinstatement of treatment at the first signs of symptom exacerbation was able to prevent frank psychosis and rehospitalization in most patients.

Choice of Antipsychotics Since the early 1990s, second-generation antipsychotics have been used widely with the belief that these agents were more effective, better tolerated, and ultimately more cost-effective than firstgeneration antipsychotics. However, little data comparing first- and second-generation antipsychotics existed. To address this knowledge gap, the National Institute of Mental Health (NIMH) sponsored the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (Lieberman et al. 2005). The

study was designed to compare the effectiveness of four second-generation antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) and a representative first-generation antipsychotic (perphenazine) in "real world" schizophrenia patients. The primary outcome parameter was discontinuation of treatment. Of the 1,432 subjects who received at least one dose, 74% discontinued study medication before 18 months: 64% of subjects on olanzapine discontinued, compared with 74%–82% on perphenazine, quetiapine, risperidone, and ziprasidone. More subjects receiving olanzapine discontinued due to weight gain and metabolic effects, whereas more subjects assigned to perphenazine discontinued due to EPS (Lieberman et al. 2005). Interestingly, individuals assigned to olanzapine and risperidone who were continuing with their baseline medication had significantly longer times until discontinuation than did those assigned to switch antipsychotics (Essock et al. 2006). Phase 2 of the CATIE study included two treatment pathways (efficacy and tolerability) with randomized follow-up medication based on the reason for discontinuation of the previous antipsychotic drug (McEvoy et al. 2006; Stroup et al. 2006). For subjects who failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another atypical antipsychotic (McEvoy et al. 2006), and in patients who failed to respond to perphenazine, olanzapine and quetiapine were more effective than risperidone (Stroup et al. 2006). Moreover, in subjects who discontinued an atypical agent due to tolerability or efficacy but who were unwilling to be randomized to clozapine, risperidone and olanzapine were more effective than quetiapine or ziprasidone (Stroup et al. 2006). Finally, while the CATIE cost-effectiveness analysis found perphenazine to be less costly and similarly effective (based on quality adjusted life-years) than each of the atypical antipsychotics, the authors note that these results cannot be generalized to all patient populations, and they suggest that these findings do not warrant policies that would unconditionally restrict access to a particular medication (Rosenheck et al. 2006). Similar to the NIMH-sponsored CATIE study, the United Kingdom's National Health Service funded the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS). This study of 227 schizophrenia-spectrum patients randomly assigned to first- and second-generation antipsychotics (other than clozapine) found no difference between the groups in quality of life, symptoms, or health care costs at 1 year (P. B. Jones et al. 2006). The applicability of these results to U.S. populations may be difficult as this study included several medications that are not available in the United States. Neither the CATIE nor the CUtLASS study addressed the comparative effects of oral and long-acting injectable antipsychotics. Older mirror-image studies in which patients served as their own controls provide evidence of substantial benefit for first-generation long-acting injectable (LAI) antipsychotics over first-generation oral medications (Schooler 2003). Risperidone is the only second-generation antipsychotic currently available in an LAI formulation. Further research evaluating the comparative effects of risperidone LAI to oral atypical agents is needed. Taken together, the CATIE and the CUtLASS studies indicate that antipsychotic medications are generally effective but have a variety of shortcomings. Moreover, the effectiveness of a given antipsychotic appears to vary according to clinical circumstances, suggesting the need for individualized therapy based on differences in efficacy and tolerability and, perhaps, reflecting why several medication trials may be necessary in the treatment of patients with schizophrenia (Stroup et al. 2007). Additionally, this variation in effectiveness may underlie the increasing use of antipsychotic polypharmacy, for which there is no empirical basis. Physicians must thoroughly inquire about the patient's past experience with medications and side effects when selecting an antipsychotic, discuss risks and benefits of each treatment option, and consider the patient's preference. Attempts to optimize current medication regimens (e.g., dosage adjustments or psychosocial interventions) may be useful before deciding to switch medications (Essock et al. 2006). Clozapine should be considered for patients who have failed to respond to other second-generation medications. LAI antipsychotics may be considered for patients with poor

adherence. Physicians need to be well informed about the differential tolerability of all antipsychotics. First-generation agents clearly have the highest risk of EPS and tardive dyskinesia (Glazer 2000b; Jeste et al. 1998; Tollefson et al. 1997). Risperidone and the newly available paliperidone tend to elevate serum prolactin levels and may cause EPS at higher doses. Although weight gain and metabolic disturbances are associated with all of the second-generation agents (with the possible exception of ziprasidone and aripiprazole), olanzapine and clozapine appear to have the highest likelihood of causing these side effects (Allison et al. 1999; American Diabetes Association et al. 2004). Sedation is commonly observed in patients receiving quetiapine, olanzapine, or clozapine. Both ziprasidone and paliperidone carry product labeling for QTc prolongation and should be used with caution in patients at risk for QTc prolongation. Finally, clozapine, because of its side effects of agranulocytosis, seizures, and myocarditis, is generally reserved for patients with treatment-resistant illness or suicidality.

Maintenance Treatment The major goals of maintenance treatment are prevention of relapse and improvement in psychosocial and vocational function. The primary methods used to achieve these goals are, as at all phases, an integration of optimal psychopharmacological and psychosocial treatments. Treatment and prevention of other psychiatric comorbidities, such as substance abuse and dependence, are important aspects of maintenance treatment. Also, with the use of the second-generation antipsychotics in particular, treatment and prevention of medical comorbidities that may be associated with these drugs, as well as those that may result from the lifestyle of some patients with schizophrenia who are given these drugs, have become a very important part of long-term management. Prevention of relapse improves long-term clinical outcomes (Wyatt et al. 1998) and reduces the associated economic burden of the illness (Bernardo et al. 2006). With each relapse, the time it takes to achieve clinical stability lengthens, with the possible consequence of ultimate unresponsiveness to treatment (Lieberman et al. 1993; Wyatt et al. 1998). Several studies have demonstrated that higher rates of relapse are associated with medication discontinuation (Beasley et al. 2003; Carpenter et al. 1990; Herz et al. 1991; Jolley et al. 1990; Kramer et al. 2007; Muller et al. 1992; Pietzcker et al. 1993; Schooler et al. 1997). All available atypical antipsychotics have been granted U.S. Food and Drug Administration (FDA) approval for the maintenance treatment of schizophrenia. Moreover, some evidence suggests that atypical antipsychotics may be more effective than conventional agents in forestalling relapse (Conley and Kelly 2002; Csernansky et al. 2002; Leucht et al. 2003a; Schooler 2006; Tran et al. 1998). While it is not clear whether this apparent advantage for atypicals over conventional antipsychotics is related to better tolerability and adherence (Leucht 2004), nonadherence to medication is a significant predictor of relapse (Schooler 2006). LAI atypical antipsychotics have the potential to improve medication adherence and thus improve long-term outcomes, but this requires further research. New research on long-term clinical outcomes in patients with schizophrenia will be aided by the newly proposed and validated remission criteria for the disorder (Andreasen et al. 2005; van Os et al. 2006). An ongoing treatment alliance among the patient, the family, and the treating clinicians is a crucial factor in maximizing medication and overall treatment adherence. Psychoeducation about illness, relapse, and side effects, as well as specific strategies to manage or avoid particular side effects in the context of an ongoing treatment partnership, helps to increase compliance. Medication adherence is the cornerstone of treatment throughout all phases of schizophrenia.

Treatment-Resistant Schizophrenia Within this chapter, we have emphasized the pervasive nature of negative symptoms and neurocognitive deficits and their resistance to treatment. However, even if we focus only on psychotic symptoms, which tend to respond favorably to antipsychotic medications, at least 30% of patients still

can be classified as having incomplete to poor response to antipsychotics, with persistent psychotic symptoms (Kane et al. 1988, 2007; Tamminga 1999). Furthermore, patients may show differential therapeutic response to medications; the fact that a patient fails to respond to one or two antipsychotic medications does not necessarily imply that he or she will not respond to a third agent. For research purposes, Kane et al. (1988) operationally defined treatment resistance as 1) lack of significant response to at least three adequate trials of neuroleptics from at least two different chemical classes in the past 5 years and 2) persistently poor social and occupational functioning. Most of the available data suggest that clozapine is the most effective drug for treatment-resistant schizophrenia (Kane et al. 2001; S. W. Lewis et al. 2006; McEvoy et al. 2006). However, because of the serious side effects produced by clozapine and the requirement for frequent white blood cell count monitoring, some patients and some psychiatrists are reluctant to use it, and some patients are unable to tolerate it. However, whether the other second-generation agents even approach the effectiveness of clozapine for the treatment of these chronically ill patients is unclear. In studies that have compared the efficacy of risperidone and clozapine in treatment-resistant schizophrenia, risperidone has been shown to be either as effective as (Bondolfi et al. 1998) or less effective than (Breier et al. 1999; Volavka et al. 2002) clozapine. Moreover, patients with treatment-resistant illness may require high doses of risperidone, increasing the likelihood of EPS. Some evidence has indicated that olanzapine at higher dosages (e.g., 30 mg/day) may be as effective as clozapine in improving both positive and negative symptoms (Tollefson et al. 2001; Volavka et al. 2002), although not all studies agree (Buchanan et al. 2005). Other preliminary data also suggest the possible utility of quetiapine, aripiprazole, and ziprasidone in treatment-resistant patients (Emsley et al. 2000; Kane et al. 2006, 2007). In summary, clozapine remains the primary medication for treatment-resistant schizophrenia, although some studies suggest that other second-generation agents also may have a role in the management of this disorder. Clinically, judicious combinations of antipsychotics from different classes are sometimes used for patients who fail to respond to monotherapy (including those who fail to respond to clozapine), as may the addition of other agents, such as mood stabilizers. Unfortunately, however, no controlled data suggest that any specific combination is more effective than others. Some of the more commonly used regimens include the combination of an atypical agent with a high-potency conventional agent such as haloperidol and the combination of two atypical agents. Clearly, more research is needed to guide treatment in such patients.

Neurocognitive Deficits Neurocognitive deficits, especially disturbances in executive functioning, memory, and attention (M. F. Green 1996; M. F. Green et al. 2000), are closely associated with the long-term functional outcome of patients with schizophrenia. It appears that second-generation antipsychotics may improve some aspects of cognition in schizophrenia, as found in a meta-analysis of 15 studies on the cognitiveenhancing effects of these drugs (Bilder et al. 2002). In contrast, conventional antipsychotics have usually been believed not to be efficacious in alleviating these deficits (Cassens et al. 1990; Spohn and Strauss 1989), although findings from the CATIE study suggest that at least some of them might be (Keefe et al. 2007). The therapeutic effects of the newer antipsychotics are most notable in measures of verbal fluency and executive functioning, whereas improvement in memory may be more limited. One recently published study suggested that clozapine, olanzapine, and risperidone all showed superiority over haloperidol in the improvement in global neurocognitive measures, including assessments of memory, attention, motor speed, and executive functions (Bilder et al. 2002). However, it must be noted that the available studies are limited, and many are methodologically compromised (Harvey and Keefe 2001). Thus, whether such improvement represents a genuine amelioration of cognitive deficits as a result of correction of the underlying neural system dysfunctions or rather simply epiphenomenal improvement resulting from the differential side-effect profiles

between the first- and the second-generation drugs remains debatable (Carpenter and Gold 2002). Moreover, in contrast to the idea that second-generation drugs are superior to the older drugs in the treatment of neurocognitive deficits, data obtained from the CATIE trial (Keefe et al. 2007) show that at 18 months of treatment, perphenazine was actually more effective than any of the secondgeneration drugs in improving all domains of neurocognitive deficits (Keefe et al. 2007). The authors postulate that a number of factors could potentially explain this unexpected finding, including sample size, differences between mid-potency drugs such as perphenazine and high-potency drugs (e.g., haloperidol) that were commonly used in prior studies, the "real-world" features of the CATIE sample, and prior drug trials before entering the study (Keefe et al. 2007). Finally, regardless of the comparable efficacy of first- and second-generation compounds, a critical question that remains unanswered is whether any of the apparent statistically significant improvements in neurocognitive deficits measured in the laboratory can actually be translated into improved functional outcomes, for example, in terms of employment, school performance, or social role (for a discussion, see M. F. Green 2002).

PSYCHOSOCIAL TREATMENT OF SCHIZOPHRENIA Despite the proven efficacy of antipsychotics in the treatment of schizophrenia, most patients continue to have some degree of residual positive symptoms, negative symptoms, and cognitive deficits, and many (even those who take their medications regularly) have difficulty attaining or regaining their desired level of social and occupational functioning. Thus, the optimal treatment of patients with schizophrenia requires the integration of pharmacotherapy with psychosocial interventions that target functional goals. Treatment is ideally offered by a multidisciplinary team that includes, at a minimum, a medication prescriber and a clinician who understands psychosocial rehabilitation but may also include employment and housing specialists. Programs that utilize clinical case managers to directly assist patients in accessing services and to provide the psychosocial interventions are ideal (Rapp and Goscha 2004). To date, several different types of psychosocial interventions have been empirically shown to reduce rates of relapse and rehospitalization, and a variety of treatments may assist patients in acquiring social and vocational skills and possibly in managing residual psychotic symptoms (Bustillo et al. 2001; Lauriello et al. 1999; Penn and Mueser 1996). Furthermore, the interaction between pharmacological and psychosocial treatments appears to be more than additive because each can enhance the effects of the other and affect different domains of outcome (Marder 2000).

Relapse Prevention It has long been noted that patients with highly critical or overinvolved family members (so-called high-expressed-emotion [EE] families) have a higher risk of relapse (G. W. Brown and Rutter 1966). In a classic study, M. J. Goldstein et al. (1978) reported that a 6-week therapy focusing on teaching families more effective communication dispute-resolution skills reduced relapse rates for up to 6 months. Many other studies have since confirmed the efficacy of family psychoeducation interventions (involving education, training in problem-solving techniques, and/or in cognitive and behavioral management strategies) to prevent relapse and to improve other outcomes (Falloon et al. 1982; Pilling et al. 2002; Pitschel-Walz et al. 2001; Tarrier et al. 1988). In addition, the positive impact of family interventions seems to persist beyond the time of intervention (Sellwood et al. 2001). Finally, despite the fact that families and patients at different stages of the illness may have specific needs and preferences (e.g., first-episode patients may need more intensive and personalized intervention, whereas families of patients with long-term illness may need continuous long-term support [Montero et al. 2005]), the effectiveness of family psychoeducation in preventing relapse has been found to be independent of either the specific form or the intensity of the intervention (Bustillo et al. 2001). Another psychosocial intervention that has been shown to be effective in preventing relapse or rehospitalization in schizophrenia is assertive community treatment (ACT). This intervention, which

involves intensive multidisciplinary team management and service delivery in both community and inpatient settings, is designed for individuals who experience intractable symptoms and high levels of functional impairment. At least 30 studies of ACT have shown advantages over standard community treatment in reducing symptoms, family burden, and hospitalization and in improving independent living, housing stability, and quality of life (Mueser et al. 1998; Phillips et al. 2001; Stein and Test 1980). However, it appears that the advantages of ACT do not persist after discontinuation of the program, even after prolonged delivery of services. Finally, ACT also does not have much effect on social adjustment or competitive employment.

Improvement of Psychosocial Functioning Most patients with schizophrenia have personal goals that involve social and occupational functioning in the community. Hence, psychosocial treatment of patients with schizophrenia targets impairments in these areas. While past research (e.g., the Camarillo State Hospital Study [May et al. 1978]) showed that dynamic psychotherapy was unsuccessful in the treatment of patients with schizophrenia, other forms of individual and group psychotherapy may improve social adjustment and symptom management. In a 3-year study, Hogarty et al. (1997a) found that weekly individual personal therapy, in which an incremental psychoeducational approach based on the patient's phase of recovery was used, had a significant advantage over supportive therapy, family therapy, and combined treatment in improving social adjustment. Yet personal therapy did not appear to be more effective than the other treatments in preventing relapse (Hogarty et al. 1997b). Interestingly, cognitive-behavioral therapy (CBT) may have a role in the management of persistent psychotic symptoms, particularly delusions, in patients with schizophrenia (Chadwick et al. 1994; Granholm et al. 2005; Tarrier et al. 2000). CBT involves the use of techniques such as distraction, cognitive reframing of psychotic beliefs or experiences, and verbal challenge followed by reality testing (Penn and Mueser 1996). Review and meta-analyses of CBT for psychosis suggest a positive effect, although not for reducing relapse (Bellack 2004; C. Jones et al. 2004; Pilling et al. 2002). Further study is needed to demonstrate the efficacy of this treatment paradigm for the management of psychotic symptoms. Social skills training (SST) is one treatment strategy to help individuals acquire interpersonal disease management and independent living skills that can be delivered in the context of a comprehensive treatment approach. Reviews of SST (Bellack and Mueser 1993; Kopelowicz et al. 2006) have described three models of SST: basic, social problem solving, and cognitive remediation. Within the basic model, complex social scenarios are broken down to simpler components, the therapist models correct behaviors, and the patient learns through repeated role-play. This model has been shown to be potentially effective in improving specific social skills for 1 year (Bellack and Mueser 1993). Additionally, the combination of this form of SST with antipsychotic medication appears to be more effective than medication alone in reducing relapse, provided weekly SST is maintained (Hogarty et al. 1986). However, despite skill acquisition, this learning does not appear to generalize to improved social competence within the community (Dilk and Bond 1996). The social problem-solving model focuses on impaired information processing, which is thought to cause social skills deficits, in hopes of achieving a generalized improvement in social adjustment. This model targets symptom and medication management, recreation, basic conversation, and self-care in educational modules, and it has been shown to be effective in enhancing skills (Eckman et al. 1992), although improvements in adaptive functioning within the community are still modest (Liberman et al. 1998; Marder et al. 1996). To enhance generalization to community functioning, interventions that utilize cueing and support in everyday community interactions by "indigenous supporters" such as clinicians, friends, or family seem to improve transfer of newly learned social skills to everyday community interactions (e.g., Glynn et al. 2002). Finally, the cognitive remediation model of SST targets more fundamental cognitive deficits, in areas

such as attention, memory, and planning, with the aim of supporting more complex cognitive processes used in learning social skills. Although initial studies following this model have shown some benefit on basic cognitive processes (Brenner et al. 1992), small studies of more complex cognitive and social skills have been mixed (Hodel and Brenner 1994; Spencer et al. 1994; Wykes et al. 1999). One study of cognitive enhancement therapy, an integrated approach to the concomitant training of neurocognitive and social cognitive abilities as well as social skills, showed improvement in social adjustment (Hogarty et al. 2004) that persisted over 3 years (Hogarty et al. 2006). Recent work to improve social functioning has focused on social cognition, the capacity to perceive the intentions and dispositions of others (Penn et al. 2006). Interventions targeting social cognition attempt to improve areas that are problematic in individuals with schizophrenia: 1) theory of mind (the ability to represent the mental states of others and make inferences about another's intentions); 2) attributional style; and 3) the ability to perceive facial affect in others. A preliminary study of social cognition and interaction training during 18 weekly sessions comprised of emotion training, figuring out situations, and integration of skills into real life suggests that this may be a promising approach for improving interpersonal functioning and for directly managing symptoms of psychosis (Combs et al. 2007). Illness management and recovery (IMR) is a manualized package of empirically supported approaches (psychoeducation, cognitive-behavioral approaches for medication adherence, relapse prevention planning, SST, and coping skills training) delivered in weekly group or individual sessions that are utilized with a recovery focus that targets each individual's personal life goals (Mueser et al. 2006). Preliminary research shows that this combination of approaches results in improved symptoms and community functioning (Mueser et al. 2006). Whereas family psychoeducation, CBT, SST, and IMR may improve symptoms and/or social functioning, they do not appear to affect employment status. In addition, traditional vocational rehabilitation programs have assisted with transitional and sheltered employment, but they have not been successful in helping patients with schizophrenia to obtain and maintain competitive employment (Lehman 1995). However, more than 14 studies suggest that supported employment programs, which use rapid job searches, on-the-job training, continuous job support, and integration with mental health treatment, are more effective than traditional methods in helping patients obtain competitive employment (Bond 2004). Research is currently under way to investigate modifications of supported employment, the role of cognitive remediation (McGurk et al. 2007), and other strategies to improve the ability of supported employment to help patients maintain employment. In addition to employment, the ability to maintain a residence in the community is an important marker of community functioning and a frequently voiced personal goal of patients with schizophrenia. A variety of approaches have been studied to help these patients obtain and maintain stable community residential tenure. Simple provision of access to affordable housing by Section 8 certificates improves housing stability (Hurlburt et al. 1996b). Supported housing, broadly defined as access to independent housing of the patient's choice (often supported with housing subsidies) that is coupled with access to community mental health and support services, improves residential stability and reduces hospitalization (Rog 2004). ACT for homeless individuals has also been shown to reduce homelessness (Coldwell and Bender 2007). As multiple effective psychosocial interventions exist and are still being developed, the choice of which intervention to apply should depend not only on therapeutic efficacy but also on each individual's goals and preferences. Patients and their families need to be given information about treatment options and should be engaged in discussions with their treatment providers about how treatments can be useful in the context of an individual's symptoms, comorbidities, and needs and preferences.

MANAGEMENT OF MEDICAL COMORBIDITY Obesity, Metabolic Syndrome, and Diabetes Mellitus Medication side effects, as well as lifestyle and disease factors, place patients with schizophrenia at increased risk of developing obesity and metabolic side effects, including glucose intolerance, type 2 diabetes, diabetic ketoacidosis, and hyperlipidemia (Dixon et al. 2000; Meyer and Koro 2004; Wirshing et al. 2002, 2003). While clinically significant weight gain occurs in a substantial proportion of patients receiving an antipsychotic medication (Baptista 1999), a convincing body of evidence indicates that certain atypical antipsychotics cause more weight gain than other agents (Allison et al. 1999; Lieberman et al. 2005; Wirshing et al. 1999). A large meta-analytic study of atypical and typical antipsychotics (Wirshing et al. 1999) found a mean weight gain of 9.8 lbs with clozapine, 9.1 lbs with olanzapine, and 4.6 lbs with risperidone, compared with 2.4 lbs with haloperidol, while the atypical antipsychotic ziprasidone was associated with a less than 1-lb weight gain. Furthermore, the CATIE study demonstrated a greater than 7% weight gain from baseline in 30% of patients receiving olanzapine, 16% of those receiving quetiapine, 14% of those receiving risperidone, 12% of those receiving perphenazine, and 7% of those receiving ziprasidone (Lieberman et al. 2005). Weight gain induced by antipsychotic medication is usually most rapid early in treatment and may plateau after 1–2 years (Allison et al. 1999; Stanton 1995). Young patients and those with a low baseline body mass index may be at increased risk for weight gain (Kinon 1998). This noticeable and often unacceptable side effect of antipsychotics may contribute to medication noncompliance and increase the risk of obesity-related comorbidities, such as diabetes and adverse serum lipid profile (Allison et al. 1999; A. I. Green et al. 2000). Diabetes mellitus is estimated to occur two to four times more frequently in patients with schizophrenia compared to the general population (Dixon et al. 2000; Goff et al. 2005; Henderson et al. 2000; Mukherjee et al. 1996; Wirshing et al. 1998). While the risk of diabetes in schizophrenia is likely multifactorial, accrued evidence indicates that atypical antipsychotics are associated with glucose dysregulation (Jin et al. 2004). Several case reports (Koller and Doraiswamy 2002; Koller et al. 2001, 2003), retrospective studies (Dixon et al. 2000; Wirshing et al. 2002), epidemiological investigations (Gianfrancesco et al. 2002), and limited prospective studies (Henderson et al. 2000) of hyperglycemia, new-onset diabetes mellitus, and diabetic ketoacidosis led to heightened attention to and concern over the metabolic effects of atypical antipsychotics, resulting in the issuance of warnings by regulatory authorities and class labeling (Jin et al. 2004). Moreover, in 2004 the American Psychiatric Association, together with the American Diabetes Association, published consensus guidelines on monitoring and described the differential risk of metabolic effects for the atypical antipsychotics (American Diabetes Association et al. 2004). Clozapine and olanzapine are described as having the greatest effect on weight (with increased risk for diabetes), whereas risperidone and quetiapine are described as having an effect on weight (but with unclear risk for diabetes). Aripiprazole and ziprasidone are described as having small or no effect on weight and without risk for diabetes. Certain atypical antipsychotics (particularly clozapine, olanzapine, and quetiapine) and low-potency conventional agents have been shown to be associated with hyperlipidemia (Henderson et al. 2000; Meyer and Koro 2004; Osser et al. 1999), whereas ziprasidone and aripiprazole do not appear to carry this adverse effect (Kingsbury et al. 2001; Meyer and Koro 2004). The co-occurrence of atherogenic dyslipidemia with abdominal adiposity, insulin resistance, impaired fasting glucose or overt diabetes mellitus, and hypertension constitutes the cluster of clinical features known as the metabolic syndrome, or syndrome X. Given the well-established and close relationship between metabolic syndrome and coronary heart disease (Isomaa et al. 2001) and the growing awareness of a range of metabolic issues in patients with schizophrenia, researchers and clinicians are now focusing on identifying the metabolic syndrome in patients with schizophrenia. Baseline data from the CATIE study

indicated that more than 40% of subjects had metabolic syndrome. Moreover, the CATIE males were 138% more likely to have metabolic syndrome than matched controls, and the CATIE females were 251% more likely to have metabolic syndrome than matched controls (McEvoy et al. 2005). To minimize iatrogenic medical problems and to ensure optimal treatment outcome, prevention and management of weight gain and obesity-related conditions in patients with schizophrenia are essential. In addition to receiving ongoing education about the potential for weight gain, patients should be counseled about dietary choices, encouraged to exercise, and weighed frequently. In a recent review of behavioral interventions for weight management, the authors concluded that such interventions may prevent further weight gain and in some cases may result in weight loss (Loh et al. 2006). Centrally acting weight-loss drugs that have the potential to increase biogenic amine activity could theoretically exacerbate symptoms of psychosis in this population. However, anecdotal reports suggesting the utility of nizatidine, citmetadine, metformin, topiramate, sibutramine, and amantadine in the prevention or treatment of antipsychotic-associated obesity exist (Werneke et al. 2002) but have not been substantiated with well-controlled trials. Orlistat, the non–centrally acting weightcontrol drug, may theoretically have a role in helping patients with schizophrenia lose weight, although no clinical trials have been reported to date (A. I. Green et al. 2000). One case series (Hamoui et al. 2004) suggested that bariatric surgery was as effective in promoting weight loss in patients with schizophrenia as it is in other obese patients. The differential propensity of the various agents to cause weight gain, and glucose and lipid dysregulation, should be taken into consideration when treating individuals at increased risk. Clinicians should employ monitoring, such as that recommended by the American Diabetes Association–American Psychiatric Association consensus panel (American Diabetes Association et al. 2004). Patients who develop glucose intolerance or diabetes may require treatment with hypoglycemic agents, and those with hyperlipidemia may require lipid-lowering agents in collaboration with an internist. Although to the best of our knowledge no studies of the long-term effects of these simple interventions in minimizing the overall morbidity of this patient population have been done, such interventions may be important in the lowering of long-term morbidity.

Cigarette Smoking Reports indicate that up to approximately 90% of patients with schizophrenia smoke cigarettes, over three times the rate seen in the general population (S. Brown et al. 2000; Dalack et al. 1998; Meyer and Nasrallah 2003). Heavy cigarette smoking contributes to the risk of coronary heart disease, which accounts for over 50% of the mortality in patients with schizophrenia (Hennekens et al. 2005). Beyond health, tobacco use results in financial consequences, with some schizophrenia patients spending nearly a third of their disability income on cigarettes (Steinberg et al. 2004). It has been proposed that the high rates of smoking may relate to abnormalities in brain reward circuitry (including presynaptic nicotinic acetylcholine receptors within mesolimbic and mesocortical dopamine pathways) and self-medication of clinical symptoms and cognitive deficits (George and Vessicchio 2001; Knott et al. 2006; Ripoll et al. 2004; Sacco et al. 2005). Indeed, such hypotheses and observations may provide insight into the neurobiology of schizophrenia and targets for treatment of both schizophrenia and nicotine addiction (Meyer and Nasrallah 2003). Treatment of nicotine addiction in the schizophrenia population has been met with limited success and appears to be even more difficult for this patient population compared with both the general and other psychiatric populations (Covey et al. 1994). Nonetheless, evidence suggests that a multimodality approach, which integrates motivation-based treatment, addiction treatment, and tobacco dependence treatment into mental health settings, may be beneficial (Ziedonis et al. 2003). Group therapy, when combined with a nicotine patch, may help reduce smoking (George et al. 2000), and

bupropion in combination with psychotherapy may reduce tobacco use in patients with schizophrenia (Evins et al. 2005; Weiner et al. 2001). Additionally, in a case series of patients previously unable to quit smoking despite tobacco dependence treatment, use of nicotine nasal spray was associated with substantial reduction in or abstinence from smoking in 9 of 12 patients (J. M. Williams et al. 2004). Interestingly, whereas typical antipsychotic medications may be associated with an increase in smoking (McEvoy et al. 1995a), treatment with clozapine may lead to a decrease (George et al. 1995; McEvoy et al. 1995b). Finally, some other atypical antipsychotic medications may facilitate the ability of the nicotine patch itself to decrease smoking (George et al. 2000).

HIV and Hepatitis Risks Patients with schizophrenia, especially those with substance abuse, are at high risk for HIV and hepatitis B and C (Cournos and Bakalar 1996; Meyer and Nasrallah 2003; Rosenberg et al. 2001). A cross-sectional Medicaid claims analysis found that patients with schizophrenia spectrum illnesses were 1.5 times as likely to have a diagnosis of HIV compared to recipients without a diagnosis of serious mental illness (Blank et al. 2002). Additionally, recent retrospective evaluations of both large Department of Veterans Affairs and civilian populations indicate that patients with schizophrenia or severe mental illness have rates of hepatitis C virus (HCV) seropositivity of approximately 20% (Huckans et al. 2006; Meyer and Nasrallah 2003) and that the rate of HCV infection in patients with schizophrenia is 11 times higher than found in the general population (Osher et al. 2003; Rosenberg et al. 2001). Risk factors such as unsafe sexual practices, combined with multiple partners, place patients with schizophrenia at heightened risk for sexually transmitted diseases (Sewell 1996). Patients should be asked about their sexual practices and, when indicated, tested for HIV and hepatitis. Discussions that provide education about safe sex are important. For those schizophrenic patients with HIV/AIDS or hepatitis, a close collaboration with a medical specialist is essential, as treatment may be complicated by poor adherence, neuropsychiatric consequences of antiviral therapies (e.g., interferon), and drug–drug and drug–disease interactions.

Extrapyramidal Side Effects The term extrapyramidal side effects (EPS) describes a spectrum of adverse reactions, including akathisia, parkinsonism, and acute dystonia, induced in some patients by antipsychotic medications. Parkinsonism and acute dystonia are associated with the degree of dopamine D2 receptor occupancy in the striatum (Kapur and Remington 1996). Thus, high-potency first-generation antipsychotics, such as haloperidol, have the greatest propensity (especially at high doses) to cause these side effects, but many second-generation agents, such as risperidone, olanzapine, and ziprasidone, also may cause EPS in a dose-dependent manner. The CATIE study found that the rate of drug discontinuation due to reported EPS was 8% in the patient group treated with the typical antipsychotic perphenazine, with rates of 4% for ziprasidone, 3% for risperidone and quetiapine, and 2% for olanzapine (Lieberman et al. 2005). Among the second-generation agents, quetiapine and clozapine do not appear to produce clinically significant parkinsonism or dystonia. In addition, aripiprazole has a low propensity to cause EPS (Ohlsen and Pilowsky 2005), although there are case reports of akathisia (Cohen et al. 2005) and parkinsonism (Cohen et al. 2005; Sharma and Sorrell 2006; Ziegenbein et al. 2006) occurring with this drug. Akathisia, a disturbing sense of inner restlessness and the inability of the patient to stay still, is associated with seemingly purposeless movements (such as tapping or pacing) that may be noticeable to the examiner. The restlessness of akathisia may be misdiagnosed as an increase in psychosis, one that worsens when treated by higher doses of antipsychotic medication. Like other EPS, akathisia appears less likely to occur with second-generation agents (Glazer 2000b). Although lowering the dose of the antipsychotic is an obvious treatment for akathisia, addition of a

-blocker (e.g.,

propranolol) is often effective. Anticholinergic drugs and benzodiazepines are generally not that effective but can be tried in patients who fail to respond to -blockers, and anticholinergics also may

be useful in patients with coexisting parkinsonism. Parkinsonism (Osser 1999), characterized by tremor, rigidity, and bradykinesia, can occur early in treatment, usually within the initial weeks or months. Bradykinesia includes generalized slowing of movement and a mask-like face (with a loss of facial expression); it may be confused with depression or negative symptoms. One variant of parkinsonism, akinesia, can coexist with bradykinesia (but without tremor or rigidity) and may be associated with symptoms of apathy and fatigue. The "rabbit syndrome" (Casey 1999), occurring after months or years of antipsychotic drug treatment, is also a variant of parkinsonism and is characterized by a perioral and jaw tremor. As with other forms of EPS, the second-generation antipsychotics appear less likely to cause parkinsonism than the older agents (Glazer 2000b), although the rate of parkinsonism may be dose related with some of the newer agents. Anticholinergic medications are the treatment of choice and usually are effective. Lower doses of antipsychotics and a switch to an agent less likely to produce EPS also may be helpful. Acute dystonia occurs most commonly during the week after initiation of antipsychotics or following an abrupt and rapid dose increase (Ayd 1961; Barnes and Spence 2000; Remington and Kapur 1996). Age is an important risk factor; dystonia occurs most commonly in children and young adults, especially in males. The dystonia may appear as torticollis, trismus, tongue protrusion, pharyngeal constriction, laryngospasm, blepharospasm, oculogyric crisis, or abnormal contractions of any part of the body. Clinically, in addition to the dystonic muscular contractions that may be immediately noticeable, the patient may complain of tongue thickening, throat tightening, and difficulty speaking or swallowing. Acute treatment with either an anticholinergic agent or an antihistamine is usually highly effective but may need to be repeated at intervals if acute dystonia recurs (before the dose of the anticholinergic is stabilized). Should respiratory difficulty develop, medications may need to be given parenterally.

Tardive Dyskinesia and Tardive Dystonia Tardive dyskinesia, which is a syndrome of potentially irreversible involuntary movements, and tardive dystonia, which is characterized by sustained muscle contractions, can gradually emerge after a prolonged period of treatment with antipsychotic medications. Accumulating evidence suggests that the second-generation antipsychotics are less likely to cause these tardive syndromes than the firstgeneration drugs (Jeste et al. 1998; Kane et al. 1993; Marder et al. 2002; Margolese et al. 2005; Shirzadi and Ghaemi 2006; Tarsy and Baldessarini 2006; Tollefson et al. 1997). However, since many patients have had exposure to more than one second-generation agent, it is difficult to determine the risk associated with individual agents. It appears that compared with the first-generation agents, collectively the second-generation drugs carry one-fifth to one-twelfth the risk of causing tardive dyskinesia and tardive dystonia (Correll et al. 2004; Kane 2004; Leucht et al. 2003b; Margolese et al. 2005; Tarsy and Baldessarini 2006). The most common form of tardive dyskinesia involves dyskinetic movements of the orofacial and buccolingual musculature, manifesting as grimacing, facial tics, lip smacking, chewing, and wormlike movements of the tongue. Involvement of the neck, axial, and extremity musculature also may occur in the form of choreoathetoid movements, which on rare occasions may involve laryngopharyngeal and respiratory muscles. Tardive dystonia may occur earlier in treatment than tardive dyskinesia and is characterized by slow, sustained twisting movements of the head, neck, trunk, and extremities; blepharospasm, torticollis, facial grimacing, back arching, and hyperextension and rotation of the limbs may also be seen (Simpson 2000). Among the risk factors for tardive dyskinesia, age appears quite important; elderly individuals have an incidence five to six times higher than that in younger people (Kane 2004). Tardive dyskinesia occurs more frequently in older female patients (Jeste 2000; Saltz et al. 1991), whereas tardive dystonia is more common in younger patients and males. Other risk factors for tardive dyskinesia include mood

disorders (Keck et al. 2000), race/ethnicity (African American) (Keck et al. 2000), high doses of medication (Glazer 2000a, 2000c), previous evidence of parkinsonian side effects from antipsychotics (Keck et al. 2000), early onset of extrapyramidal syndromes (Kane 2004), and substance abuse (Miller et al. 2005). Although no treatment has been proven to be effective for tardive dyskinesia, several management strategies may be clinically useful. Clinicians should screen patients taking antipsychotic medications on a regular basis. If tardive dyskinesia develops, switching from a first-generation to a secondgeneration drug may be helpful. For those patients who are taking a second-generation agent, a switch to another second-generation drug may be considered. Among the second-generation drugs, evidence suggests that clozapine may reduce symptoms of tardive dyskinesia (Glazer 2000a; Lieberman et al. 1991). Symptoms may also be suppressed, at least temporarily, by increasing the dosage of the antipsychotic medications that produce tardive dyskinesia; however, this strategy runs the risk of causing or worsening EPS and possibly increasing tardive dyskinesia over time. Patients with tardive dyskinesia who are taking anticholinergic medications should have these medications discontinued, because they can worsen tardive dyskinesia. Finally, the symptoms of tardive dystonia may be alleviated by reducing the dosages of the antipsychotics, by switching from first-generation to second-generation agents (including clozapine), by using anticholinergics, and/or by administering dopamine-depleting agents, such as reserpine or tetrabenazine (Simpson 2000).

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS), which occurs in about 1%–2% of patients receiving typical antipsychotic medication and is potentially fatal in up to 20% of the cases (without treatment), has been reported to occur during treatment with both the typical (Caroff and Mann 1993) and the atypical (Ananth et al. 2004; Hasan and Buckley 1998; Wirshing et al. 2000) antipsychotics. Several factors may increase risk, including intramuscular injections, rapid escalation of high doses of antipsychotic medication, dehydration, restraint use, and high temperatures. Catatonia and severe disorganization are clinical symptoms that may be associated with a high risk for NMS (Berardi et al. 2002). Symptoms of NMS include hyperpyrexia, altered consciousness, muscle rigidity and dystonia, autonomic nervous system dysfunction, and laboratory tests indicating elevated creatine phosphokinase, liver enzymes, and white blood cell count. Early detection and rapid treatment of this medical emergency are crucial and include discontinuation of the antipsychotic, treatment in a medical setting that can support vital functioning, and in some cases the use of a dopamine agonist such as bromocriptine or dantrolene, a muscle relaxant (Koppel 1998; Susman 2001).

Hyperprolactinemia Antipsychotic medications—particularly typical agents, risperidone, and paliperidone—can produce an increase in serum prolactin levels (Dickson and Glazer 1999; Marder et al. 2004). Although early studies reported few negative consequences of long-term prolactin elevation (Meltzer 1985), this topic has received increased attention in recent years. It is well known that hyperprolactinemia secondary to medical disorders (e.g., pituitary tumor) can produce galactorrhea, hypogonadism (evidenced by sexual and menstrual dysfunction and diminished gonadal hormone levels), and osteoporosis, all of which have also been reported in patients with schizophrenia (Abraham et al. 1996; Ghadirian et al. 1982; Riecher-Rossler et al. 1994; Windgassen et al. 1996; Yazigi et al. 1997). Yet the relationships between antipsychotic-induced hyperprolactinemia and these conditions, perhaps with the exception of galactorrhea (Windgassen et al. 1996), remain unclear, with conflicting reports in the literature (Canuso et al. 2002; A. M. Costa et al. 2007; Hummer et al. 2005; Kinon et al. 2006; Kleinberg et al. 1999; O'Keane and Meaney 2005). Interestingly, several reports suggest that hypoestrogenism in schizophrenia occurs in women with and without hyperprolactinemia (Bergemann et al. 2005; Canuso et al. 2002; T. J. Huber et al. 2004). Thus, while prolactin-related hypogonadism may contribute to the increased risk of these conditions, it appears that patients with schizophrenia

may be at inherent risk for hypogonadism. The important question of whether drug-induced hyperprolactinemia increases long-term breast cancer risk has also been raised. Although a large claims database analysis found a 16% increase in the risk of breast cancer in women exposed to dopamine antagonists, the authors concluded that these results are preliminary and potentially confounded and should not necessarily lead to changes in treatment strategies (Wang et al. 2002). Finally, a recent retrospective review of pharmacovigilance data suggested that treatment with potent D2 receptor antagonists, such as risperidone, may be associated with increased risk for pituitary tumors (Szarfman et al. 2006). Prospective studies are needed to confirm this association. Clinicians should inquire about possible adverse effects of hyperprolactinemia and aim to diminish them. If a patient is symptomatic, prolactin levels should be obtained and medical causes of hyperprolactinemia ruled out. Prolactin elevation associated with galactorrhea, or sexual and menstrual dysfunction, may be minimized by dosage reduction or by a medication change to an atypical antipsychotic with less prolactin-elevating potential (Canuso et al. 1998; Dickson and Glazer 1999). Because patients with schizophrenia generally require chronic treatment with antipsychotics, those who have had prolonged hyperprolactinemia may be at an increased risk for osteoporosis (Abraham et al. 1996) and may be appropriate candidates for screening with bone densitometry. Female patients should have routine mammography in accordance with the screening guidelines set forth for all women.

PSYCHIATRIC CONDITIONS COMORBID WITH SCHIZOPHRENIA AND THEIR TREATMENT Substance-Related Disorders Nearly one-half of the patients with schizophrenia are reported to have a lifetime history of an alcohol or a substance use disorder, compared with 16% of the general population (Regier et al. 1990). Alcohol is the most commonly abused substance in chronically ill patients, followed by cannabis and cocaine (Selzer and Lieberman 1993; Sevy et al. 1990); first-episode patients appear more likely to abuse cannabis over other substances (Rolfe et al. 1999). As in the general population, men with schizophrenia are more likely to abuse substances than are women (Mueser et al. 1995). The use of alcohol, marijuana, cocaine, and other substances can cause serious problems for patients with schizophrenia. Comorbid substance use has a deleterious effect on both physical health and the long-term course of schizophrenia itself (Grech et al. 1999); use of even small amounts can produce negative effects (D'Souza et al. 2005; Drake et al. 2001). Patients with schizophrenia and substance abuse are at increased risk for infectious diseases such as HIV, hepatitis B, and hepatitis C (Rosenberg et al. 2001); in addition, alcohol and substance use is associated with clinical worsening, poor functioning, and an increased rate of hospitalizations and homelessness (Dixon et al. 1990; Drake and Mueser 1996; Hurlburt et al. 1996a; Negrete et al. 1986; Soni and Brownlee 1991). In some studies, more than 50% of the first-episode patients have been reported to have cannabis use disorder (Rolfe et al. 1999), often complicating the diagnosis of a psychotic disorder (Addington 1999). Comorbid alcohol and substance use often has an overwhelmingly negative effect on the ability of patients to function at their highest possible level (Dickey and Azeni 1996). Given the negative consequences of substance abuse in these patients, investigators have tried to understand the basis of such use. One theory, the "self-medication" hypothesis, suggests that alcohol and substances of abuse help to decrease negative symptoms of schizophrenia and the EPS produced by antipsychotic medications (Glynn and Sussman 1990; Khantzian 1985; Siris 1990). However, although alcohol and substances of abuse may in fact transiently alleviate negative symptoms and EPS, our group has suggested that the existence of negative symptoms or EPS of antipsychotics may not be causally related to the substance use (A. I. Green et al. 1999). Some studies indicate that patients with few negative symptoms may actually use substances more than do those with more negative symptoms (Buchanan et al. 1997; Lysaker et al. 1994). Also, first-episode patients, who have

not yet been exposed to antipsychotic medication and who therefore could not have EPS, are quite likely to use alcohol or substances (A. I. Green et al. 2004). We (A. I. Green et al. 1999; Roth et al. 2005) have introduced a neurobiological formulation, based on animal studies (Svensson et al. 1995), suggesting that a deficiency in the dopamine-mediated mesocorticolimbic brain reward circuit of patients with schizophrenia may underlie the use of alcohol and substances in these patients. This formulation posits that alcohol and substances of abuse may ameliorate this deficiency by improving the "signal detection" capability of dopamine-rich systems, by which they reduce negative symptoms and EPS while enhancing the reward system (Fadda et al. 1989; Goeders and Smith 1986; A. I. Green et al. 1999). A related neurobiological formulation also has been proposed by Chambers et al. (2001). Although obtaining information from patients about the use of substances of abuse should be a standard part of a medical history, alcohol or substance abuse is often underrecognized and undertreated in mental health settings (Ananth et al. 1989). Because patients often deny the use of alcohol and drugs, clinicians also should pursue collateral reports from family members, case managers, and others involved in the delivery of services to patients. Unfortunately, the traditional separation of mental health and substance abuse services compounds the problems of detection. Patients with schizophrenia and a comorbid alcohol or substance use disorder require specialized treatment for both disorders (Bellack and DiClemente 1999), optimally in programs that provide integrated mental health and substance abuse treatment, as well as medication management (Drake and Mueser 2001; Minkoff 1989; Osher and Kofoed 1989). Drake and Mueser (2001) reported that the treatment of comorbid substance abuse requires long-term comprehensive services (Osher and Kofoed 1989), including individual treatment planning tailored to the patient's ability to engage in treatment and assertive outreach (Drake and Mueser 2000; Ziedonis et al. 2000), with interventions within the social support system. The specific integrated interventions for substance abuse in patients with schizophrenia with the most evidence are group counseling with cognitive-behavioral and motivational components (Bellack et al. 2006; Weiss et al. 2007), contingency management (Drebing et al. 2005; Ries et al. 2004), and, for patients who do not respond to less intensive interventions, long-term residential programs (Brunette et al. 2004). Although there is no agreed-upon pharmacological treatment approach for patients with schizophrenia and comorbid alcohol or substance use disorders (A. I. Green et al. 2007, 2008; Wilkins 1997), some investigators have been interested in the potential role of atypical antipsychotics in these patients. The atypical antipsychotic that has been studied most in this population is clozapine. Three preliminary studies—a naturalistic study (Drake et al. 2000) and two retrospective studies (A. I. Green et al. 2003; Zimmet et al. 2000)—reported a large reduction in alcohol use in patients taking clozapine; evidence also was found for a reduction in cannabis and cocaine use. Two other studies (Buckley et al. 1999; Lee et al. 1998) also have reported this beneficial effect of clozapine in patients with schizophrenia and comorbid substance use disorder. Clozapine was also associated with reduced rates of relapse to substance abuse in patients who had been in remission (Brunette et al. 2006). Randomized trials of clozapine needed to confirm these preliminary studies are currently under way. The data concerning the potential effect of the other atypical antipsychotics are even more preliminary. Reports on risperidone appear to be conflicted (Albanese 2000; A. I. Green et al. 2003), although a report by Smelson et al. (2000) found that cocaine-abusing schizophrenic patients treated with risperidone experienced less craving, had fewer relapses, and remained in treatment longer than did those treated with typical antipsychotics. Recently, Rubio et al. (2006) reported that the new LAI form of risperidone was more effective in improving substance abuse than a depot form of the typical agent zuclopenthixol (which is not available in the United States), but the difference was small and probably not clinically significant. However, a report of data from a large Veterans Administration treatment group showed no advantage for either risperidone or olanzapine compared with typical

antipsychotics on clinical substance abuse measures (Petrakis et al. 2006). Two other open prospective studies of olanzapine treatment noted improvements in substance use, but one of them (Noordsy et al. 2001), which might have been limited by statistical power, did not find significant advantages of olanzapine over typical antipsychotic treatment (Littrell et al. 2001; Noordsy et al. 2001). Two randomized trials of olanzapine's impact on cocaine craving and use compared to typical antipsychotics also reported conflicting results (Sayers et al. 2005; Smelson et al. 2006). Preliminary research on quetiapine and aripiprazole is promising. Two open studies of quetiapine (E. S. Brown et al. 2003; Potvin et al. 2006) and of aripiprazole (Beresford et al. 2005; E. S. Brown et al. 2005) suggest that these medications may be helpful for alcohol and/or cocaine use disorders in patients with schizophrenia. No research has assessed the impact of ziprasidone. Other possible pharmacological options for treatment of alcohol or substance use disorder in schizophrenia include the following: 1) disulfiram (Kofoed et al. 1986), which one randomized, placebo-controlled trial (Petrakis et al. 2005) and one open trial (Mueser et al. 2003) suggest is effective for alcohol dependence in patients with schizophrenia but requires monitoring (Kofoed et al. 1986); 2) naltrexone, which was found to decrease alcohol use among patients with schizophrenia in two randomized, placebo-controlled trials (Petrakis et al. 2004, 2005); 3) the tricyclic antidepressants desipramine or imipramine for the treatment of comorbid cocaine disorders (Siris et al. 1993; Ziedonis et al. 1992); and 4) bupropion for the treatment of nicotine dependence in these patients (George et al. 2002). Acamprosate, although shown to be effective for alcohol dependence in placebo-controlled trials, has yet to be studied in patients with schizophrenia. Clearly, more studies need to be undertaken to develop optimal pharmacological strategies for the treatment of these comorbid disorders.

Depression Schizophrenia is often associated with depressive states, from dysphoria to major depression. The Epidemiologic Catchment Area study suggests that those with schizophrenia have a 14-fold greater risk of depression than the general population (Fenton 2001). At various times, depression has been viewed as an aspect of schizophrenia (McGlashan and Carpenter 1976; Sax et al. 1996), as a response to psychosis (McGlashan and Carpenter 1976; Sax et al. 1996), or as a state occurring after the cessation of frank psychotic symptoms (Birchwood et al. 2000). Depressive symptoms can occur throughout the course of schizophrenia, including in first-episode patients (Hafner et al. 2005; Koreen et al. 1993), but in chronically ill patients in particular, these symptoms appear to be associated with risk of relapse (Mandel et al. 1982) and suicide (Drake et al. 1986). Assessing patients with schizophrenia for the presence of depression requires knowledge of the types of depressive states in patients with schizophrenia and the conditions, such as negative symptoms and EPS, that can be confused with depression. In detecting depression, the presence of a core depressed mood and related neurovegetative symptoms should be distinguished from flatness of affect and anhedonia (McGlashan and Carpenter 1976). Depression occurring during an exacerbation of psychosis may remit with treatment of the psychosis (Birchwood et al. 2000; Koreen et al. 1993; Tollefson et al. 1999). However, postpsychotic depression classically develops after the resolution or improvement of psychotic symptoms, particularly in first-episode patients (Birchwood et al. 2000; Koreen et al. 1993). Moreover, dysphoria and demoralization frequently occur in patients with schizophrenia (Iqbal et al. 2000; Siris 2000a), as patients struggle with illness-related disability, but these symptoms may not be associated with the classical neurovegetative symptoms of depression (Bartels and Drake 1988). Treatment of depression in patients with schizophrenia may include both psychopharmacological and psychosocial components (Siris 2000b). Because depression may presage an increase in psychosis, the adequacy of pharmacological treatment of psychotic symptoms should be assessed. Treatment of depression in acute psychosis may be accomplished through the use of antipsychotic medication

alone, especially the atypical antipsychotics (Banov et al. 1994; Levinson et al. 1999; Marder et al. 1997; Tollefson et al. 1998). However, major depression developing after the remission of psychosis often requires more specific intervention, such as treatment with combinations of antipsychotics and antidepressants or mood stabilizers (Levinson et al. 1999). Postpsychotic depression may benefit from the addition of tricyclic antidepressants or serotonin reuptake inhibitors to the antipsychotic medication (Hogarty et al. 1995; Kirli and Caliskan 1998; Siris et al. 1987). However, demoralization and dysphoria do not appear to be responsive to antidepressants (Iqbal et al. 2000; Levinson et al. 1999); rather, appropriate psychosocial interventions (e.g., stress management, job training, cognitive therapy, support) may be most helpful (Siris 2000b).

Suicide Suicide is the leading cause of premature death in patients with schizophrenia, who have a 10% lifetime risk of suicide. Nearly 50% of the patients with schizophrenia attempt suicide during their lifetime (Black et al. 1985; Tsuang et al. 1999a). The risk of suicide is as high in patients with schizophrenia as in patients with mood disorder and is 10-fold higher than in the general population (Baxter and Appleby 1999). Several factors are associated with an increased risk of suicide in patients with schizophrenia: depression and the diagnosis of schizoaffective disorder (Harkavy-Friedman et al. 2004; Radomsky et al. 1999), social isolation (Drake et al. 1986; G. Goldstein et al. 2006; Potkin et al. 2003), and feelings of hopelessness and disappointment over failure to meet high self-expectations (Kim et al. 2003; Westermeyer et al. 1991). Patients with a higher level of insight and awareness of their illness may be at increased risk (Amador et al. 1996; Bourgeois et al. 2004; Crumlish et al. 2005), as may patients with a poor level of functioning (Kaplan and Harrow 1996). A history of suicide attempts is one of the strongest predictors of suicide in patients with schizophrenia (Rossau and Mortensen 1997; Roy 1982a). In a large 2-year prospective study of 980 schizophrenia and schizoaffective disorder patients at high risk for suicide, multivariate analysis found the number of lifetime suicide attempts, number of hospitalizations to prevent suicide in the previous 3 years, history of alcohol or substance abuse, baseline anxiety scale score, and severity of parkinsonism to be the strongest predictors of suicide (Potkin et al. 2003). Moreover, a recent meta-analysis of 29 case–control and cohort studies indicated that suicide risk factors included previous depressive disorders, drug abuse, agitation or motor restlessness, fear of mental disintegration, poor adherence to treatment, and recent loss (Hawton et al. 2005). Gender also appears to be a risk factor (Rossau and Mortensen 1997); men with schizophrenia commit suicide at an earlier age than do women with schizophrenia (Roy 1982a). An increased risk of suicide is present in the early phase of the illness (Drake et al. 1985; Kuo et al. 2005; Ran et al. 2005), especially in those patients with an earlier age at onset of schizophrenia (Gupta et al. 1998). The risk of suicide appears to peak immediately after admission and shortly after discharge (Qin and Nordentoft 2005; Rossau and Mortensen 1997), especially in patients who are hospitalized for short periods (Qin and Nordentoft 2005) and in those who return to a socially isolated environment (Drake et al. 1986). Patients in an active phase of the illness (Heila et al. 1997) or with positive symptoms (Kelly et al. 2004) may be at risk, especially if they have prominent symptoms of suspiciousness and delusions (Fenton et al. 1997). A national clinical survey conducted in Great Britain, based on a 4-year (1996–2000) sample of people who died by suicide, found that the deaths of schizophrenia patients were characterized by more violent methods: they were more likely than others to be young, male, unmarried, and from an ethnic minority, with high rates of unemployment (Hunt et al. 2006). Moreover, rates of previous violence and drug abuse were high, and suicide victims were proportionally more likely to be inpatients at the time of death and to have been noncompliant with medication (Hunt et al. 2006). In another study (Roy 1982b), half of all patients who committed suicide had been seen in the week prior, and in another study (Heila et al. 1997), between 49% and 96% of the patients had been seen within 3

months of the suicide. The treating clinician should regularly evaluate the patient's condition, assess for suicide risk factors, and aim to enhance protective factors such as social support and positive coping skills (Montross et al. 2005). Patients who present with suicidal thoughts or behavior require close follow-up and intensive outreach. For the isolated or newly diagnosed patient, a clear aftercare plan (often in a day treatment center) should be in place before discharge from the hospital (Drake et al. 1986; Harkavy-Friedman and Nelson 1997). Improved ward safety, effective substance abuse treatment, affective symptom control, and ensured medication adherence are all measures that may prevent suicide (Hawton et al. 2005; Hunt et al. 2006). Additionally, evidence suggests that community programs for early detection of schizophrenia may reduce suicidality risk (Melle et al. 2006). Psychopharmacological treatment plays a crucial role in the prevention of suicide. In one study, more than half of the patients who committed suicide were either medication noncompliant or prescribed inadequate doses of antipsychotics, and 23% of the sample were thought to be nonresponsive to treatment (Heila et al. 1999). Moreover, a landmark study of nearly 1,000 patients with schizophrenia and schizoaffective disorder who were at risk for suicide (but who were not necessarily classically treatment resistant) indicated that treatment with clozapine was more likely to decrease suicidality than was treatment with olanzapine (Meltzer et al. 2003).

Obsessive-Compulsive Symptoms Obsessive-compulsive symptoms are seen in 8.8%–30% of patients with schizophrenia (I. Berman et al. 1995a; Byerly et al. 2005; Cassano et al. 1998; Ongur and Goff 2005). Although obsessivecompulsive symptoms may be difficult to distinguish from delusions (Eisen et al. 1997), they are important to identify because they may indicate a poor prognosis, yet they may be responsive to specialized treatment regimens. Most studies have indicated that obsessive-compulsive symptoms are associated with unfavorable outcomes—with increased social isolation, longer hospitalizations, greater psychopathology, and poor treatment response (Fenton and McGlashan 1986; Hwang et al. 2000; Ongur and Goff 2005). By contrast, a more recent study (N = 58) suggested that the presence of obsessive-compulsive symptoms does not impact clinical outcomes (Byerly et al. 2005). The obsessive-compulsive symptoms in schizophrenia are similar to those found in obsessive-compulsive disorder (Tibbo et al. 2000), although they may not be ego-dystonic in patients with schizophrenia. Treatment of obsessive-compulsive schizophrenia may require the use of a tricyclic antidepressant or a serotonin reuptake inhibitor with a typical antipsychotic (I. Berman et al. 1995b; Chang and Berman 1999; Poyurovsky et al. 2000). The data regarding the role of atypical agents in these patients are mixed (Fenton 2001). Some reports suggest that atypical antipsychotics may exacerbate obsessivecompulsive symptoms, whereas others suggest that they may be helpful (Baker et al. 1992, 1996; Kopala and Honer 1994; Morrison et al. 1998; Ongur and Goff 2005; Strous et al. 1999). Although the addition of a serotonin reuptake inhibitor to an atypical antipsychotic may decrease obsessivecompulsive symptoms in these patients (as the addition of a serotonin reuptake inhibitor to some typical agents does), the combined use of serotonin reuptake inhibitors with clozapine, especially, may require care because of the possible increase in blood levels of clozapine.

FUTURE DIRECTIONS Novel Pharmacotherapeutic Treatment Although all existing antipsychotic medications have effects on the dopamine system, other neurotransmitter systems are increasingly being recognized as possible therapeutic targets. For instance, the glutamate hypothesis of schizophrenia (Coyle 1996; Goff and Coyle 2001; Javitt and Zukin 1991; Olney and Farber 1995) suggests that modulation of glutamatergic activity could be a potential target for pharmacological treatment of schizophrenia. The glutamate hypothesis is, to a

large extent, derived from the observation that treatment of healthy subjects with N-methylD-aspartate

(NMDA) antagonists, such as ketamine and phencyclidine (PCP), produces symptoms

reminiscent of schizophrenia (Adler et al. 1998; Newcomer et al. 1999). Most important, in addition to the psychotic symptoms, which can be induced by a variety of central nervous system stimulants or hallucinogens, NMDA antagonists uniquely produce many of the cognitive deficits associated with schizophrenia (Krystal et al. 1994) and symptoms that resemble the negative symptoms of the illness (Abi-Saab et al. 2001). Thus, it would follow that drugs that enhance NMDA receptor function might be beneficial in the treatment of negative symptoms of schizophrenia (Javitt 2006; Javitt and Coyle 2004). Because of the possible risks of neurotoxicity as a result of direct stimulation of NMDA receptors, drugs that indirectly enhance NMDA neurotransmission by modulating other binding sites on the NMDA receptor complex have been studied. For example, D-cycloserine (a partial agonist) (Goff et al. 1999), D-serine (Tsai et al. 1998), D-alanine (Tsai et al. 2006), glycine (Heresco-Levy et al. 1996a, 1996b; Javitt et al. 2001), agonists of the glycine binding site (located adjacent to the NMDA ion channel), and sarcosine (a glycine transporter-1 inhibitor) (Tsai et al. 2004) have been shown to have therapeutic potential. Preliminary data are quite promising, in that all of these agents appear to be effective in improving negative symptoms of schizophrenia, although their effects on positive symptoms, if any, tend to be very modest (Goff and Coyle 2001; Tsai et al. 1998), and it appears that they may not be effective in patients treated with clozapine (Goff et al. 1996; Potkin et al. 1999); but see Javitt et al. 2001). Non-NMDA glutamate receptors may also be potential targets for treatment. For example, a recent preliminary study demonstrated that a selective agonist of metabotropic glutamate 2/3 (mGlu2/3) receptors, used as monotherapy, was efficacious in reducing both positive and negative symptoms in 196 patients with schizophrenia (Patil et al. 2007). MGlu2/3 agonists, which blunt the effects of PCP in animals, are thought to work in part by modulating glutamate release (Patil et al. 2007). This study suggests that agents that do not directly block dopamine receptors may have therapeutic potential in schizophrenia. Another novel approach to the treatment of schizophrenia is the development of drugs that act as partial dopamine agonists. These drugs bind to dopamine receptors, including the presynaptic autoreceptors, with high affinity but with variable intrinsic activity, depending on the activity level of the target system (Tamminga 2002). Because of this, they exert a wide range of modulatory effects on the dopaminergic system. The first FDA-approved drug with this mechanism is aripiprazole. Given the increasing evidence suggesting that neurocognitive deficits are pervasive in patients with schizophrenia and that they are important determinants of long-term functional outcome, there has been considerable interest in developing compounds that target these deficits. Drugs that may be effective, at least in theory, in the treatment of neurocognitive deficits include muscarinic agonists, alpha 7 nicotinic receptor agonists (Martin et al. 2007), ampakines (agonists of the AMPA [amino3-hydroxy-5-methyl-4-isoxazole propionic acid] class of glutamate receptors) (Goff and Coyle 2001), class I metabotropic glutamate receptor agonists (Moghaddam 2004), dopamine D1 receptor agonists (G. V. Williams and Castner 2006), and alpha 2 -aminobutyric acid (GABA) type A (GABAA) receptor agonists (D. A. Lewis and Gonzalez-Burgos 2006). Although clinical experience with these drugs is quite limited, there are ongoing clinical trials to test the possible efficacy of at least some of these compounds.

Early Intervention and Prevention of Schizophrenia As emphasized earlier in this chapter, some investigators have suggested that early detection and treatment of first-episode psychosis may improve the long-term prognosis of schizophrenia. In recent years, there have even been attempts to identify individuals who are in the prodromal phase of

schizophrenia but have not yet developed psychosis (Yung and McGorry 1996b), with the notion that intervention, including psychopharmacological treatment, during this period of the illness may be able to prevent the onset of full-blown psychosis (McGorry et al. 2002). However, as has been discussed in this chapter, many of the prodromal symptoms, among which depression and anxiety are common manifestations, are not specific to schizophrenia and are not uncommonly observed in otherwise healthy adolescents (McGorry et al. 1995). The issue of misidentification of individuals who are not at risk for psychosis must be considered. The current challenge is to establish the predictive validity of specific traits or prodromal symptoms of the diagnosis or recognition of the prodrome as a syndrome. However, even if these individuals can be reliably identified, the modes of treatment, including the specific classes of medications, that may be most effective in preventing the onset of psychosis are at present virtually unknown (Cannon et al. 2007; McGlashan et al. 2007). Another concept that may help clarify prodrome is the notion of schizotaxia, which was originally put forward by Meehl (1962, 1989) and reformulated by Faraone et al. (2001) to describe a constellation of negative symptoms and neuropsychological deficits present in 20%–50% of the first-degree relatives of patients with schizophrenia. Preliminary findings from treatment of six such relatives meeting criteria for schizotaxia with low-dose risperidone (up to 2 mg) for 6 weeks suggested that this treatment may improve the deficits associated with this condition (Tsuang et al. 1999b). If the validity of schizotaxia as a "preschizophrenic" trait could be established (Tsuang et al. 2000), it would be important to determine whether treatment of schizotaxia in individuals with prodromal symptoms could actually be associated with a decrease in the incidence of schizophrenia.

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Jonathan R. T. Davidson, Kathryn M. Connor, Wei Zhang: Chapter 56. Treatment of Anxiety Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.424275. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 56. Treatment of Anxiety Disorders TREATMENT OF ANXIETY DISORDERS: INTRODUCTION Over the past decade and a half, there has been substantial progress in our understanding of the anxiety disorders. Particularly fruitful has been the search to develop new treatments for the six major anxiety disorders: obsessive-compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder), specific phobia, generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD). In this chapter, we review the main findings from double-blind, and some open-label, trials in each disorder. Both short-term and continuation/maintenance treatment studies are included.

OBSESSIVE-COMPULSIVE DISORDER When Kierkegaard wrote that "no grand inquisitor has in readiness such terrible tortures as has anxiety, which never lets him escape," he may well have been thinking of OCD, one of the few conditions that has the capacity to produce a lifetime of psychological torture. Before the existence of serotonin reuptake–inhibiting drugs, especially clomipramine, and selective serotonin reuptake inhibitors (SSRIs), biological treatments generally had little effect, producing mild palliation at best. According to the Epidemiologic Catchment Area study (Myers et al. 1984; Robins et al. 1984), OCD carries a lifetime prevalence of 2.5% in the United States and 6-month and 1-month prevalence rates of 1.5% and 1.3%, respectively, although a more recent analysis from the National Comorbidity Survey Replication (NCS-R) suggested slightly lower rates of 1.6% and 1.0% for the lifetime and 12-month prevalence of OCD, respectively (Kessler et al. 2005a, 2005b). Its economic toll is also substantial (Hollander et al. 1997). OCD has been recognized as the tenth leading cause of disability worldwide (Murray and Lopez 1996). Treatment can be grouped broadly into psychosocial and psychopharmacological approaches, the latter being our focus here. First, we present information on monotherapy with serotonin reuptake–inhibiting drugs, followed by management of partial responders or nonresponders, and we conclude with comments on less frequently used treatments. The chief rating scale for treatment studies of OCD remains the Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Goodman et al. 1989), a 10-item observer-rated measure. Self-ratings are of less importance in the OCD literature and have traditionally received little weight.

Monotherapy In 1967, Fernandez-Cordoba and Lopez-Ibor reported beneficial effects of the nonselective serotonin reuptake inhibitor (SRI) tricyclic antidepressant (TCA) clomipramine in treating OCD. Following this important insight, a series of placebo-controlled studies were completed in the late 1980s and the early 1990s, leading eventually to the first approved treatment of OCD in the United States and other countries (Clomipramine Collaborative Study Group 1991). Clomipramine differs from other tricyclic drugs in that it has a particularly potent serotonin reuptake–inhibiting effect. The drug is not selective for serotonin, however, in that its demethylated metabolite is a norepinephrine reuptake inhibitor. The anti-OCD effect of clomipramine correlates with the plasma level of the parent drug, which is an SRI, suggesting that reuptake inhibition of serotonin is the critical factor underlying the drug's benefit. Moreover, some studies have shown lack of effect for selective norepinephrine reuptake–inhibiting drugs, such as nortriptyline and desipramine, in OCD (Leonard et al. 1988; Thoren et al. 1980). An

interesting aspect of the pharmacokinetics of clomipramine is the ability of fluvoxamine to inhibit its demethylation, thereby increasing the amount of clomipramine relative to desmethylclomipramine, which can produce a potentiating effect in partial responders. In the influential Clomipramine Collaborative Study Group (1991) trial, the Y-BOCS score was reduced by about 40% in patients taking the drug as compared with 5% in patients receiving placebo, bearing out findings by Mavissakalian et al. (1990) that OCD has a remarkably low placebo response rate. At one point, it was thought that clomipramine may have a larger effect size than SSRIs in the treatment of OCD (Greist et al. 1995b), but subsequently this finding has been interpreted as more likely to have been due to sampling differences between studies. In general, it is held that clomipramine and SSRI drugs are equivalent in the treatment of OCD (Koran et al. 1996). Nonetheless, clomipramine still may be a drug to consider in SSRI nonresponders. For the most part, in view of its greater side effects and risks, as well as dose-related risks of seizures, clomipramine would be regarded as a second-line treatment. Today, SSRIs are considered first-line treatments for OCD, particularly the SSRIs fluvoxamine, fluoxetine, sertraline, and paroxetine, all of which have a U.S. Food and Drug Administration (FDA) indication for the treatment of OCD (Greist et al. 1995a, 1995b; Tollefson et al. 1994). Clomipramine, fluvoxamine, fluoxetine, and sertraline also have been shown to be effective in treating OCD in children, with an indication for treatment in such patients (Flament et al. 1985; Liebowitz et al. 2002; March et al. 1998; Riddle et al. 2001). Escitalopram is also efficacious in OCD at a daily dose of 20 mg on all main measures of efficacy, while 10 mg of escitalopram and 40 mg of paroxetine were superior to placebo on some measures but took longer to work (D. J. Stein et al. 2007). Paroxetine and fluoxetine appear to be more effective at higher doses, whereas no clear relation between dose and effect was seen with sertraline, although a paradoxical finding of lesser efficacy at 100 mg/day was most likely an artifact. The results for escitalopram suggest that possibly a higher does of 20 mg is preferred, although 10 mg is somewhat effective. Recent results (Ninan et al. 2006) suggest additional benefit for increasing the dosage of sertraline up to 400 mg/day in nonresponders. Thus, when an SSRI drug is to be used in the treatment of OCD, not only may it need to be given in higher doses, but also it may take a longer time to work effectively. Most people believe that treatment should be long term to reduce the chance of relapse (Pato et al. 1990), although the dosage might be lowered without loss of benefit (Ravizza et al. 1996).

Long-Term Treatment and Relapse Prevention Long-term pharmacological treatments of OCD have suggested sustained response of an effective medication beyond the acute treatment phase. In addition, clomipramine, paroxetine, sertraline, and most recently, escitalopram all have been shown to be more effective than placebo in preventing relapse in OCD (Fineberg et al. 2005, 2007). SSRIs appear to be well tolerated in these studies.

Augmentation, Combination, and Other Strategies Up to 60% of individuals with OCD show a response to SSRIs according to a conventional and conservative criterion, full remission is rare, and response is often no more than partial. Relapse can occur even while patients continue taking an SSRI, and comorbidity is often a complicating factor in managing the disorder. The following augmentation, combination, and other novel strategies have been reported as offering benefit: Combining fluvoxamine with clomipramine (Szegedi et al. 1996) and the intravenous use of clomipramine as monotherapy (Fallon et al. 1992; Koran et al. 1997) are both approaches to consider in individuals who have shown a partial response to clomipramine. The rationale for combining fluvoxamine with clomipramine was explained in the previous section, but some caution is in order given the possibility of increased side effects and risk of seizure. Monitoring of plasma levels and electrocardiograms is important with this

combination. The use of intravenous clomipramine derives from the fact that first-pass metabolism is avoided, and there is some suggestion that side effects are less severe. The benzodiazepine clonazepam has been added to clomipramine with mixed benefits (Pigott et al. 1992) and to sertraline with no added benefit (Crockett et al. 1999). Each of these findings was based on a doubleblind, placebo-controlled trial. Patients with OCD refractory to SRI treatments may benefit from additional antipsychotic augmentation. A meta-analysis of double-blind, randomized trials demonstrated significant benefits of haloperidol and risperidone over placebo augmentation for OCD patients who failed to show treatment response after an adequate trial of SRI, whereas evidence for the efficacy of olanzapine and quetiapine is less conclusive (Bloch et al. 2006). Despite the fact that this approach appeared to benefit only a limited number of subjects (although it was more beneficial among subjects who suffered from comorbid tic disorders), any increased chance of improvement is worth striving for. Greist and Jefferson (1998) have reported four studies in which SSRI and behavior therapy approaches were compared and/or combined. Three of these studies gave some modest support to the idea that combined treatment produces an enhanced effect. Also, rates of relapse after discontinuing behavior therapy are considerably lower than those after discontinuing drug therapy. Other studies of SRI and cognitive-behavioral therapy (CBT) using exposure and ritual prevention techniques have yielded inconsistent results as to the benefits of combining drug and CBT over CBT alone (Cottraux et al. 1993; Foa et al. 2005). The addition of lithium, buspirone, desipramine, or gabapentin has produced very limited benefits in studies to date, although there may be occasional patients for whom such combinations are helpful.

Other Approaches One report suggested that St. John's wort (Hypericum perforatum) produced some improvement after 12 weeks of treatment in 12 patients with OCD (Taylor and Kobak 2000). The promise of this early finding has been dampened by failure of the same group to establish efficacy for St. John's wort in a subsequent and adequately powered placebo-controlled study (Kobak et al. 2005). A double-blind trial of intravenous clomipramine suggested greater benefit than oral loading (Koran et al. 1997). Inositol, a naturally occurring second-messenger precursor, led to greater improvement than placebo at a dosage of 18 g/day for 6 weeks (Fux et al. 1996). Neurosurgical approaches, wherein either cingulotomy or anterior capsulotomy are carried out, can be helpful for refractory OCD. Between 25% and 30% of the subjects show marked improvement, and the side-effect burden of this procedure is small (Baer et al. 1995; Jenike et al. 1991). Limited but promising studies also suggested other potential approaches such as deep brain stimulation for severely treatment-refractory OCD patients (B. D. Greenberg et al. 2006; Nuttin et al. 1999). CBT is well established for treating OCD, and evidence for efficacy is strong (e.g., Eddy et al. 2004; Foa et al. 2005). In most types of CBT for this disorder, exposure with response prevention is used. CBT is a first-choice option for OCD.

PANIC DISORDER Panic disorder is a chronic and costly (P. E. Greenberg et al. 1999) condition that affects approximately 1%–3% of the population (Alonso et al. 2004; Kessler et al. 2005b). It often presents as a medical emergency and is associated with substantial comorbidity and increased suicidal risks (Roy-Byrne et al. 2000). Effective treatment results in reduced emergency department and laboratory resource utilization (Roy-Byrne et al. 2001). Five core areas of the disorder require treatment: 1) full and limited symptom panic attacks, 2) anticipatory anxiety, 3) phobias related to panic, 4) general well-being, and 5) disability (Ballenger et al. 1998a). Treatment outcome can be comprehensively and succinctly measured with the Panic

Disorder Severity Scale (PDSS), which can be administered both as a clinician-rated and as a self-rated scale (Shear et al. 1997).The PDSS contains seven domains relevant to panic disorder and agoraphobia. Other widely used measures include the Sheehan Panic and Anticipatory Anxiety Scale (PAAS; Sheehan 1986) and the self-rated Marks-Matthews Fear Questionnaire (FQ; Marks and Matthews 1979). Ideally, as with all of the anxiety disorders, the desired endpoint is full remission. However, this is not always attainable. The earliest groups of drugs to show robust efficacy relative to placebo were the TCAs and the monoamine oxidase inhibitors (MAOIs) (Mavissakalian and Perel 1989; Sheehan et al. 1980). However, even before any randomized clinical trials had been published to support the use of SSRI drugs, the experts who were convened for the International Psychopharmacology Algorithm Project (Jobson et al. 1995) indicated that their preferred first-line approach was to use an SSRI. The other main approach would be to use benzodiazepine drugs, such as alprazolam or clonazepam (Lydiard et al. 1992; Rosenbaum et al. 1997; Tesar et al. 1991). Initial drug selection, to be based on discussion between the patient and the physician, would take into account issues of prior response, proneness to abuse of medication, tolerability, safety, comorbidity, and presenting clinical picture (e.g., degree of agitation).

First-Line Drug Treatments Selective Serotonin Reuptake Inhibitors In 1995, Boyer reported that SSRI drugs were more effective than imipramine and alprazolam in treating panic disorder, although a recent meta-analysis by Otto et al. (2001) failed to confirm these findings. Evidence is now available in support of citalopram (Wade et al. 1997), escitalopram (Stahl et al. 2003), fluoxetine (Michelson et al. 1998, 2001), fluvoxamine (Asnis et al. 2001; Black et al. 1993), paroxetine (Ballenger et al. 1998b; Oehrberg et al. 1995; Sheehan et al. 2005), and sertraline (Londborg et al. 1998). In addition, clomipramine has been shown to have efficacy in panic disorder (Lecrubier et al. 1997). Fluoxetine, paroxetine, and sertraline have been approved by the FDA for treatment of panic disorder. Although SSRI drugs are favored as first-line treatment, the following points need to be kept in mind. Patients with panic disorder are often extremely sensitive to activating effects of antidepressants and have poor tolerance of symptoms such as palpitations, sweating, and tremor. It is therefore not uncommon for them to quickly lose faith and discontinue treatment or even drop out without a full discussion having taken place. This problem can almost always be obviated, either by coprescribing a benzodiazepine or by starting with extremely low doses of an SSRI and gradually building up as tolerated. Also, perhaps of most importance is the availability of the physician and thorough and reassuring preparation of patients ahead of time. Other problems of SSRIs to be concerned about in panic disorder are those common to all other conditions for which SSRIs are used (e.g., problems associated with weight gain, sexual dysfunction, impairment of sleep, and potential drug–drug interactions). Discontinuation of treatment can be a significant concern in panic disorder. Besides the obvious issue of relapse, SSRIs, with the exception of fluoxetine, may sometimes produce troublesome discontinuation symptoms. Many of these symptoms mimic panic disorder itself and can be quite distressing. Gradual dosage reduction is usually recommended, along with adequate patient education and physician availability. Coping strategies, including behavior therapy (Otto et al. 1993), are an option. Switching to an SSRI such as fluoxetine also may be considered because this drug has a slow built-in taper. One also might consider using serotonin2 (5-HT2) or serotonin3 (5-HT3) receptor antagonists, such as mirtazapine, nefazodone, and ondansetron, to limit some of the symptoms that are mediated through these pathways (e.g., insomnia, agitation, gastrointestinal distress).

Benzodiazepines

In the late 1980s, alprazolam received an FDA indication for treatment of panic disorder, making it the first product so licensed. An important byproduct of this indication was raising general awareness of the condition as well as helping to differentiate panic disorder with agoraphobia from other kinds of anxiety. Several trials showed that alprazolam was more effective than placebo. These included the Cross-National Collaborative Panic Study (1992), wherein imipramine and alprazolam were both more effective than placebo. Lydiard et al. (1992) reported that alprazolam 2 mg/day was more effective than placebo, and benefit for alprazolam was shown in other trials. Efficacy for clonazepam was also demonstrated in panic disorder (Davidson and Moroz 1998; Rosenbaum et al. 1997; Tesar et al. 1991). Although alprazolam has been widely used for panic disorder, it is now regarded more as a second-line treatment. Problems include the need for frequent administration, tendency to produce sedation at higher doses, abuse liability, and discontinuation-related distress. Lesser et al. (1992) showed that higher plasma levels (i.e., >70 ng/mL) were associated with greater likelihood of response as compared with lower levels (in the 20–40 ng/mL range). Thus, higher doses may have an advantage, particularly in managing phobic avoidance, but often at the price of more side effects or discontinuation difficulty. Comparable efficacy and tolerability have been demonstrated for the sustained-release formulation of alprazolam (Pecknold et al. 1994; Schweizer et al. 1993). Clonazepam, which is also FDA approved for panic disorder, has an advantage over alprazolam in that its half-life is considerably longer and the drug can be dosed once or twice a day. However, it shares the usual class effects of benzodiazepines and can produce sedation, depression, and discontinuation syndrome. A particular concern with benzodiazepines is their use in the elderly. The elderly are not only more prone to developing side effects, including sedation and falls that result in fractures and potential head injury, but also more likely to experience problems upon discontinuation of the drug. In a fixed-dose study, clonazepam 1 mg/day was more effective than placebo on nearly all major measures; however, clonazepam 0.5 mg/day was ineffective except on the Hamilton Anxiety Scale (Ham-A; Hamilton 1959). In general, escalating the dosage up to 4 mg/day did not provide greater benefit, suggesting that such higher dosages should be reserved for patients who are refractory to treatment at lower dosages. In the clonazepam studies, ratings of actual panic attacks tended to be the least likely to detect drug and placebo differences. As pointed out by Bandelow et al. (1995), overreliance on reduction of panic attacks as the principal outcome measure is an unsatisfactory marker of overall treatment benefit. Despite the almost universal unhappiness with this measure, it continues to be chosen as a primary outcome for regulatory studies. One interesting and important finding to emerge from the studies of clonazepam in panic disorder is its substantial benefits on quality of life and work productivity. A broad-spectrum effect was noted on all five measures of mental health–related quality of life. During a 6-week clinical trial, patients moved from the seventh percentile for all adult Americans with regard to mental health component score (MCS) of the Short Form–36 (SF-36) to the seventeenth percentile. By contrast, the placebo group moved only from the eighth to the twelfth percentile during this time. With respect to work productivity, the difference between the effects of clonazepam and placebo during a 6-week treatment period amounted to an additional 6 hours of full productivity during a 40-hour workweek (Jacobs et al. 1997).

Other Pharmacological Approaches Tricyclic Antidepressants Several studies have reported benefit for clomipramine and imipramine in the treatment of panic disorder (Andersch et al. 1991; Cross-National Collaborative Panic Study 1992; Fahy et al. 1992; Lecrubier et al. 1997; Mavissakalian and Perel 1989; Modigh et al. 1992). The norepinephrine reuptake inhibitor desipramine also was more effective than placebo (Lydiard et al. 1993). TCAs are second-line treatments for panic disorder at best. They are certainly effective, but the

associated autonomic side effects, cardiovascular problems, weight gain, and potential lethality in overdose are all matters of concern. Dosing with TCAs may be critical. Mavissakalian and Perel (1995), for example, found that phobic symptoms responded best if the plasma level of imipramine and desmethylimipramine was in the range of 110–140 ng/mL, whereas control of panic attacks tended to occur at lower plasma levels. As with SSRIs, low starting dosages in the range of 10–25 mg/day are in order, with gradual titration thereafter in accordance with patient tolerance.

Monoamine Oxidase Inhibitors Sheehan et al. (1980) found that phenelzine, along with imipramine, was more effective than placebo in the treatment of panic disorder with agoraphobia, which they referred to as "endogenous anxiety." Lydiard and Ballenger (1987) expressed the opinion that MAOIs may be superior to TCAs. Although these debates were fruitful in the 1980s, MAOIs have been swept aside by the remorseless tide of history, as have TCAs to some degree. These drugs now have been relegated to a lower echelon. Although for some patients MAOIs may still be the best treatment, their overall role in managing anxiety disorders is now fairly small. The role of the safer reversible inhibitor of monoamine oxidase A (RIMA) in panic disorder is unclear. Brofaromine and moclobemide have shown comparable efficacy and tolerability to clomipramine (Bakish et al. 1993; Kruger and Dahl 1999) and moclobemide also to fluoxetine for up to 1 year (Tiller et al. 1999); however, the significance of these findings is questionable in the absence of a placebo control. When compared with CBT and placebo, the effect of moclobemide was no different from placebo and failed to enhance the effect of CBT (Loerch et al. 1999).

Other Drugs The extended-release (XR) formulation of venlafaxine, a serotonin–norepinephrine reuptake inhibitor (SNRI), has demonstrated greater efficacy than placebo in patients with panic disorder (Bradwejn et al. 2005) and has received FDA approval for the treatment of panic disorder. Following 10 weeks of treatment, patients receiving venlafaxine XR (mean dosage = 163 mg/day) experienced fewer panic attacks, greater freedom from limited symptom attacks (but not full symptom attacks), improvement in anticipatory anxiety and avoidance, and higher rates of response and remission compared with placebo. The drug was well tolerated, with an adverse-effect profile comparable with that of the drug in depression and other anxiety disorders. Mirtazapine, a noradrenergic and specific serotonergic antidepressant, has also demonstrated anxiolytic activity. Possible benefit in panic disorder has been reported for the drug (Boshuisen et al. 2001; Ribeiro et al. 2001; Sarchiapone et al. 2003); however, double-blind, placebo-controlled trials have yet to be conducted. It is noteworthy that mirtazapine has been associated with the induction of panic attacks in depressed patients undergoing dose escalation and discontinuation (Berigan 2003; Klesmer et al. 2000). Reboxetine, a selective reuptake inhibitor of norepinephrine, has been found to produce greater benefit than placebo in patients with panic disorder (Versiani et al. 2002). At dosages of 6–8 mg/day, the drug produced greater improvement in the number of panic attacks and phobic symptoms, as well as reduction in score on the Hamilton Rating Scale for Depression (Ham-D; Hamilton 1960), the Hopkins Symptom Checklist–90, and the Sheehan Disability Scale. It also produced significantly higher levels of dry mouth than placebo but in general was well tolerated. In a more recent randomized, single-blind study comparing reboxetine with paroxetine, paroxetine was more effective on panic attacks, but no differences were noted between the treatments on anticipatory anxiety and avoidance (Bertani et al. 2004). These findings suggest perhaps different roles of norepinephrine and serotonin in the treatment of panic disorder. In those countries where reboxetine has been approved for depression and is therefore available, it might be a useful backup drug for use in SSRI and benzodiazepine nonresponders. Given its antidepressant properties, it might be advantageous over

benzodiazepines. However, the selective noradrenergic reuptake inhibitor maprotiline appears to be ineffective in panic disorder (Den Boer and Westenberg 1988), while the data for bupropion are inconclusive (Sheehan et al. 1983; Simon et al. 2003). Trazodone was less effective than imipramine and alprazolam in the treatment of panic disorder (Charney et al. 1986). Buspirone, a 5-HT1A partial agonist, was ineffective in panic disorder (Sheehan et al. 1990). The anticonvulsant gabapentin was also generally ineffective in panic disorder, though post hoc analyses suggest an anxiolytic effect in more severely ill patients (Pande et al. 2000). Possible benefit has been reported for other anticonvulsant drugs, including levetiracetam, tiagabine, and valproic acid (Keck et al. 1993; Papp 2006; Zwanzger et al. 2001), but double-blind trials have not been undertaken. Preliminary data suggest improvement in refractory panic disorder when atypical antipsychotics are prescribed to augment an SSRI (risperidone: Simon et al. 2006; olanzapine: Sepede et al. 2006) or at higher doses as monotherapy (olanzapine: Hollifield et al. 2005); however, doubleblind, placebo-controlled trials are needed. Metabotropic glutamate type 2 receptor agonists have shown promise in preclinical models of anxiety but have yet to demonstrate clinical efficacy in panic disorder (Bergink and Westenberg 2005). Similarly, the effect of a cholecystokinin-B receptor antagonist was no different from placebo in patients with panic disorder (Pande et al. 1999a).

Combination Pharmacotherapy The activating side effects of SSRIs can be quite troublesome for anxiety patients, particularly when beginning pharmacotherapy in patients with panic disorder. Coadministration of a long-acting benzodiazepine for the first several weeks of treatment may help improve SSRI tolerability and provide more rapid stabilization of panic symptoms than SSRI treatment alone (Goddard et al. 2001; Pollack et al. 2003).

Long-Term Management Maintenance treatment is recommended for at least 12–24 months, if not longer. The long-term treatment of panic disorder has been reviewed elsewhere (Davidson 1998). In a controlled trial of paroxetine, clomipramine, and placebo, 84% of the paroxetine-treated patients eventually became panic free over the 9-month period (Lecrubier and Judge 1997). In a 4-year naturalistic follow-up study of 367 patients with panic disorder, greater improvements in panic attacks, phobic avoidance, and daily functioning were observed in those who received continuation treatment for 4 years, compared with 1 year (Katschnig et al. 1995), suggesting that recovery continues over several years. Long-term randomized, controlled trials have reported efficacy for citalopram (Lepola et al. 1998), clomipramine (Fahy et al. 1992), fluoxetine (Michelson et al. 1999), paroxetine (Lecrubier and Judge 1997; Lydiard et al. 1998), and sertraline (Rapaport et al. 2001). In a relapse prevention trial following 3 months of successful open-label treatment with the drug, Ferguson et al. (2007) showed that over the course of 7 months, relapse on placebo was 50%, whereas relapse among those remaining on venlafaxine XR was 22%. From an early long-term study of imipramine (Mavissakalian and Perel 1992), it appeared that relapse may diminish with the passage of time, provided effective psychopharmacological cover has been provided, but a later trial by the same group failed to confirm this (Mavissakalian and Perel 2002).

Discontinuation Even though there is some similarity between symptoms of relapse and symptoms of drug withdrawal, the existence of discontinuation symptoms from stopping medication is unarguable. If poorly managed, discontinuation can be fraught with problems. Some strategies are likely to make withdrawal of medication more tolerable. The first strategy is a slow taper. Indeed, for some benzodiazepines, it may be necessary to taper the drug over many weeks or even months. Second, timing of the taper may be important. This is best accomplished when other variables in a patient's life

are as stable as possible. Switching to a longer-acting benzodiazepine, such as clonazepam, also may be helpful. Some authors (Pages and Ries 1998) have advocated consideration of anticonvulsants, such as carbamazepine and valproate. Otto et al. (1993) also found behavior therapy to be helpful in this regard. Various elaborations of CBT, including self-help books, and telephone- and Internet-delivered therapy, have demonstrated efficacy on a consistent basis for panic disorder, with the common elements being education, cognitive strategies, and exposure to feared sensations and situations (Clum and Surls 1993; Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Panic Disorder and Agoraphobia 2003). CBT is a first-line choice, and even when pharmacotherapy is given as main treatment, principles of CBT should be incorporated into the management plan. As noted, it can be of benefit during the process of drug discontinuation, and perhaps in lessening the chance of relapse afterwards.

SOCIAL PHOBIA Social phobia, also referred to as social anxiety disorder, can be grouped into generalized and nongeneralized types. Generalized social phobia is more commonly seen in clinical settings, is usually more disabling, and is associated with greater levels of comorbidity and genetic loading than nongeneralized social phobia. Most of our knowledge about pharmacotherapy for social phobia derives from generalized social phobia, and the literature suggests that different medication approaches may be called for in treating the two subtypes. Comprehensive treatment of social phobia requires that the symptoms of fear, avoidance, and physiological distress are brought under control, comorbidity is treated, disability and impairment are improved, and quality of life is enhanced. Furthermore, evidence from maintenance and relapse prevention studies has confirmed the value of long-term therapy in treatment responders. Instruments commonly used to measure treatment change in social phobia include the clinician- and self-rated Liebowitz Social Anxiety Scale (LSAS; Liebowitz 1987), which assesses 24 performance or interpersonal situations for fear and avoidance. A score of 30 or less is considered to equate with remission. The Social Phobia Inventory (SPIN) is a useful 17-item self-rating instrument that assesses fear, avoidance, and physiological distress (Connor et al. 2000) and, like the LSAS, is able to detect treatment differences on all its subscales.

Pharmacotherapy Most clinicians consider SSRI drugs as the first choice for generalized social phobia, with either -blockers or benzodiazepines being the first choice for nongeneralized social phobia. Second-line drugs for generalized social phobia comprise the benzodiazepines, perhaps venlafaxine (an SNRI), and maybe other antidepressants, including nefazodone and mirtazapine. MAOIs also have a role. Bupropion and TCAs have been generally disappointing.

Serotonergic Drugs Fluvoxamine has been widely studied and has the longest track record of success in the treatment of social phobia. In 1994, van Vliet et al. showed superiority for fluvoxamine over placebo, with response rates of 46% and 7%, respectively. M. B. Stein et al. (1999) later confirmed the efficacy of fluvoxamine relative to placebo on all symptom domains of social phobia (i.e., fear, avoidance, and physiological arousal). Studies have also looked at the controlled-released (CR) form of fluvoxamine and found it to be superior to placebo (Davidson et al. 2004c; Westenberg et al. 2004). In the study by Davidson et al. (2004c), baseline symptom severity was higher than in most other clinical trials, yet drug therapy was still effective. In addition to these studies conducted in the United States or Europe, a more recent study in Japan also found fluvoxamine to be effective compared to placebo in reducing symptoms and associated psychosocial disability among Japanese patients with generalized social

anxiety disorder (Asakura et al. 2007). Sertraline also has been studied (Blomhoff et al. 2001; Katzelnick et al. 1995; Liebowitz et al. 2003; Van Ameringen et al. 2001; Walker et al. 2000). In the study by Van Ameringen et al. (2001), 53% responded to sertraline as compared with 29% to placebo. As with the fluvoxamine study of M. B. Stein et al. (1999), the Brief Social Phobia Scale was a primary outcome measure, and in both instances, the drug was shown to produce benefit on all three symptom domains. In a primary care setting, Haug et al. (2000) showed that cognitive therapy and sertraline could be effectively delivered, although the combination did not really show any superiority over treatment with drug alone. Effectiveness for paroxetine was shown relative to placebo in both short-term efficacy and relapse prevention. In the short-term studies by M. B. Stein et al. (1998), Allgulander (1999), and Baldwin et al. (1999), rates of response to paroxetine were 55%, 70%, and 66%, respectively, as compared with placebo response rates of 24%, 8%, and 32%. These differences are substantial and suggest a marked effect for paroxetine in social phobia. All subjects in the paroxetine trials fulfilled criteria for generalized social phobia and showed benefit on the primary measure, the LSAS. Between 2 and 4 weeks was required for paroxetine to show significant superiority. Fluoxetine, while superior to placebo on primary outcomes in one study (Davidson et al. 2004c), failed to separate from placebo in another (Kobak et al. 2002). In the latter study, placebo seemed to yield a greater response (30%) than most other studies of SSRIs in social phobia. Another study comparing cognitive therapy, fluoxetine plus self-exposure, and placebo plus self-exposure in social phobia found cognitive therapy to be superior to fluoxetine plus self-exposure and placebo plus self-exposure on measures of social phobia, with no difference between the latter two groups (D. M. Clark et al. 2003). Interestingly, another serotonergic agent, nefazodone, also failed to separate from placebo on most outcome measures in a recent report of Canadian outpatients with social phobia (Van Ameringen et al. 2007). Placebo-controlled data with citalopram have not been presented for social phobia. However, trials with escitalopram have shown superiority over placebo in short-term, long-term, and relapse prevention studies of generalized social phobia (Kasper et al. 2005; Lader et al. 2004; Montgomery et al. 2005). Venlafaxine XR has also shown superiority over placebo in two double-blind trials of generalized social phobia (Allgulander et al. 2004; Liebowitz et al. 2005). A double-blind, placebocontrolled trial of mirtazapine in women showed statistically significant superiority for drug over placebo (Muehlbacher et al. 2005). Paroxetine, sertraline, and venlafaxine XR are currently the only FDA-approved drugs for the treatment of social phobia, although the controlled-release form of fluvoxamine is likely to be approved for social anxiety disorder in the near future.

Benzodiazepines Three major placebo-controlled trials have shown efficacy for benzodiazepines in social phobia. First, Gelernter et al. (1991) showed a very modest effect for alprazolam over placebo and a generally inferior picture for alprazolam relative to phenelzine. The response rate with alprazolam, at a mean daily dose of 4.2 mg, was 38%, a rate significantly better than the 20% response rate to placebo. Davidson et al. (1993) conducted a moderately large trial in 75 patients taking clonazepam or placebo and found a substantial 70% response rate to clonazepam compared with a 20% response rate to placebo. Clonazepam worked rapidly and effectively and had a broad-spectrum effect in the disorder. Bromazepam also has been found to work more effectively than placebo (Versiani et al. 1997). A magnetic resonance spectroscopy study of clonazepam in social phobia has shown that even when clonazepam is effective, there are no changes in the extent of N-acetylaspartate, choline, and myo-inositol, suggesting that these particular changes within the central nervous system are not state

dependent. Some benzodiazepines (clonazepam and bromazepam) provide a marked response yet do not find favor as first-line drugs because of their more limited spectrum of action, as well as potential withdrawal difficulties. However, they work rapidly, are well tolerated, and may be particularly useful for individuals with periodic performance-related social anxiety.

Anticonvulsants Gabapentin and pregabalin produce significant effects in social phobia. Pande et al. (1999b) found a superior effect for gabapentin over placebo, with response rates of 39% and 17%, respectively. Baseline symptom scores were comparatively high and overall response rates relatively low, suggesting a degree of treatment resistance in the population. A flexible dosage of gabapentin was used, ranging from 900 to 3,600 mg, with 2,100 mg/day being the most commonly chosen final dosage. The newer anticonvulsant drug pregabalin has shown benefit in generalized social phobia. Although 150 mg/day of pregabalin was no different from placebo, 600 mg/day produced greater effects than placebo, with response rates of 43% and 22%, respectively. At 600 mg/day, pregabalin produces a relatively high rate of side effects, and it is probably necessary to explore lower dosages for social phobia. Further work with anticonvulsants is called for because they are generally well tolerated, safe, and less likely to produce difficulties during discontinuation than many SSRIs and benzodiazepines.

Reversible Inhibitors of Monoamine Oxidase Moclobemide initially appeared to be a safer and very promising alternative to older MAOIs. A study by Versiani et al. (1992) showed that moclobemide worked almost as effectively as phenelzine and significantly better than placebo but that it was slower to take effect compared with phenelzine. Response rates to moclobemide and placebo in the study were 65% and 15%, respectively, with a fairly high dosage of moclobemide being attained (581 mg/day). However, these exciting early findings have not been borne out by subsequent studies. For instance, Noyes et al. (1997) reported no significant advantage for moclobemide at several dosages as compared with placebo. Schneier et al. (1998) showed a poor effect for the drug in a single-center trial, and the International Multicenter Clinical Trial Group on Moclobemide in Social Phobia (1997) found a modestly greater response rate (47%) for moclobemide at 600 mg/day than for placebo (34%). Based on the two positive trials, moclobemide has received a license in some countries but is not available in the United States. Another RIMA, brofaromine, has shown promise in three trials, with response rates of 78%, 50%, and 73%, respectively, compared with placebo response rates of 23%, 19%, and 0% (Fahlen et al. 1995; Lott et al. 1997; van Vliet et al. 1992).

Irreversible Inhibitors of Monoamine Oxidase Phenelzine has been studied in four double-blind, placebo-controlled trials and showed positive benefit in all cases (Gelernter et al. 1991; Heimberg et al. 1998; Liebowitz et al. 1992; Versiani et al. 1992). Response rates to phenelzine were 69%, 85%, 64%, and 65%, respectively, as compared with 20%, 15%, 23%, and 33%, respectively, to placebo. Even though phenelzine is so consistently effective, perhaps as a result of its combined noradrenergic, dopaminergic, and serotonergic effects, its poor tolerance, as well as greater risks, makes it an unsuitable choice for most patients. However, it should not be completely ignored and may make a major difference in the lives of some patients whose symptoms do not respond to other drugs.

Other Drugs Olanzapine yielded greater improvement than placebo in a preliminary double-blind, placebocontrolled monotherapy trial of social anxiety disorder (Barnett et al. 2002), suggesting atypical antipsychotics may deserve further investigation in this area of research. Ondansetron, while

producing a statistically significant effect relative to placebo, seems to be of very limited benefit (Bell and DeVeaugh-Geiss 1994; Davidson et al. 1997b), but it might be a useful backup or adjunct in some cases. Its cost is a major problem. Buspirone was ineffective in a double-blind trial, producing only a 7% response rate (van Vliet et al. 1997). Despite their intuitive appeal,

-blockers have shown poor effect in treating generalized social phobia.

For example, atenolol failed to separate from placebo in two trials (Liebowitz et al. 1992; Turner et al. 1994).

-Blockers do show some value in performance social anxiety, perhaps by virtue of their ability

to reduce peripheral autonomic arousal and block negative feedback. Nefazodone, bupropion, and selegiline have not shown impressive results in open-label reports (Emmanuel et al. 1991; Simpson et al. 1998; Van Ameringen et al. 1999). A novel therapeutic approach is suggested by the findings of Hofmann et al. (2006), who administered a single dose of D-cycloserine or placebo to patients with social anxiety disorder treated with CBT. The drug was given prior to each CBT session and enhanced the benefit of CBT to a greater extent than did placebo. The postulated mechanism of action relates to drug-facilitated extinction of learned fear via glutamatergic pathways.

Treatment in Children and Adolescents One interesting placebo-controlled trial of fluvoxamine in children ages 6–17 years showed that it was superior to placebo in social phobia, GAD, or the combination: 76% of the fluvoxamine group responded, as compared with 19% of the placebo group (Research Unit on Pediatric Psychopharmacology Anxiety Study Group 2001). Double-blind trials of paroxetine immediate-release (IR) (Wagner et al. 2004) and venlafaxine XR (March et al. 2007) have produced positive results in children and adolescents with generalized social anxiety disorder. Response rates for paroxetine and placebo were 78% and 38%, respectively; in the venlafaxine study, they were 56% and 37%. An open-label trial by Compton et al. (2001) suggested some value for sertraline in children and adolescents with social phobia, but we are unaware of any published placebo-controlled trials.

Duration of Treatment Because social phobia is a chronic illness, treatment is generally recommended for years. Sutherland et al. (1996) reported that at 2-year follow-up, subjects who had received an active drug rather than placebo in a double-blind trial were doing better. Relatively few relapse prevention studies have been done. In a 12-month trial with clonazepam, Connor et al. (1998) showed a 20% relapse rate in those switched to placebo compared with 0% in those who continued taking clonazepam. On other measures, there was an upward drift in fear and phobia scores in subjects who were withdrawn from clonazepam. However, in the study with its very slow taper, it was encouraging that withdrawal symptoms were rare and not problematic. M. B. Stein et al. (1996) reported that 62% of the subjects relapsed when switched double-blind from paroxetine to placebo after 12 weeks, compared with only 12% who relapsed during maintenance treatment with paroxetine.

Other Issues CBT is efficacious in social anxiety disorder, being comparable to pharmacotherapy (Davidson et al. 2004b; Fedoroff and Taylor 2001), but little is known as to whether adding CBT to medication lowers the relapse rate, and so far the limited evidence does not suggest any potentiating effects when the treatments are combined (Davidson et al. 2004b). It does appear as if exposure consistently produces gain, but adding cognitive elements does not confer further benefit (Haug et al. 2003; Hofmann 2004). In a comparative study of drug and psychotherapy, Heimberg et al. (1998) showed that phenelzine and CBT were approximately similar, although phenelzine had an edge in more severely symptomatic patients. On the other hand, when subjects who had discontinued treatment were followed up, rates of relapse tended to be lower in those who had received CBT than in those who had

taken phenelzine. Turner et al. (1994) found that atenolol was not as good as social skills training, and D. B. Clark and Agras (1991) showed a relatively poor response with buspirone over exposure therapy in performance social phobia. Despite the obvious benefits of drug therapy in social phobia, medication often falls short of producing remission, and a pressing need remains to find better drugs, better combinations, and the ways in which drug therapy and psychosocial treatments might be most productively used, whether in sequence, simultaneously, or according to some other formula. Nevertheless, compared with the situation 15 years ago, prospects for recovery from social phobia are perhaps better than they have ever been.

SPECIFIC PHOBIA Specific phobia is among the most common psychiatric disorders, with a lifetime prevalence of 8%–12.5% (Alonso et al. 2004; Kessler et al. 2005b) and 12-month prevalence of 3.5%–9% (Alonso et al. 2004; Kessler et al. 2005a). While the disorder is characterized by an early age of onset (median age at onset is 7 years) (Kessler et al. 2005b), most of those with the disorder are unimpaired by their symptoms; hence, few individuals actually seek treatment for their specific phobia (Magee et al. 1996; Stinson et al. 2007; Zimmerman and Mattia 2000). However, for a minority of individuals, specific phobia causes significant disability and requires treatment. The generally accepted treatment of choice is exposure therapy, which is uniformly and rapidly effective, with techniques including virtual reality or in vivo exposure, and muscle tension exercises (for blood–injury phobia) (Swinson et al. 2006). Few studies have evaluated the efficacy of pharmacological approaches, and no drug has yet been approved by the FDA for treating specific phobia. No standard ratings exist for this disorder, although the Marks-Matthews FQ is quite suitable for blood–injury phobia and some other fears. A modification of this scale, the Marks-Sheehan Main Phobia Severity Scale (MSMPSS; Sheehan 1986) can be recommended. Serotonergic drugs have shown efficacy in treating symptoms of fear and avoidance in a variety of anxiety disorders and thus would seem logical choices in treating specific phobias. It is therefore not surprising that studies of pharmacological treatments for specific phobia have focused on serotonergic agents. In a double-blind, controlled trial, 11 subjects were treated for 4 weeks with either paroxetine (up to 20 mg/day) or placebo (Benjamin et al. 2000). As measured by the Marks-Matthews FQ and the Ham-A, 60% of the subjects (3 of 5), compared with 17% taking placebo (1 of 6), responded to treatment with paroxetine. A more recent randomized, double-blind pilot trial compared the effects of escitalopram versus placebo over 12 weeks in 12 adults with specific phobia (Alamy et al. 2008). While no difference was observed on the primary outcome, response based on a Clinical Global Impression Scale (CGI) Improvement score of 1 or 2 was noted in 60% of subjects who received escitalopram, compared with 29% on placebo (effect size = 1.13). The findings from these two small trials suggest promise for the SSRIs in specific phobia; however, larger controlled trials are needed. In contrast, in a controlled trial of the serotonergic and noradrenergic drug imipramine in 218 phobic subjects (agoraphobic, mixed phobic, or simple phobic) receiving 26 weeks of behavior therapy, no difference was observed between imipramine and placebo (Zitrin et al. 1983). Intermittent use of benzodiazepines also may be helpful in the acute treatment of the somatic anxiety that accompanies specific phobia, although this usage has not been an area of active investigation. In a long-term controlled study of clonazepam in social phobia, Davidson et al. (1994) observed that clonazepam was superior in reducing symptoms of anxiety related to blood–injury phobia as measured by changes in the blood–injury phobia subscale of the Marks-Matthews FQ. Some caution should be used with these drugs, however, because there is risk of physiological dependence. Using a novel approach, Ressler et al. (2004) investigated the effect of a cognitive enhancer, D-cycloserine,

as an adjunct to psychotherapy, hypothesizing that the drug would accelerate the

associative learning processes that contribute to ameliorating psychopathology. D-Cycloserine is a N-methyl-D-aspartate (NMDA) receptor partial agonist that has demonstrated improvement in extinction in rodents. Subjects with acrophobia (n = 28) were randomized to receive a single dose of D-cycloserine

or placebo prior to each of two virtual reality exposure therapy sessions. The

combination of D-cycloserine and exposure therapy was associated with greater improvement in the virtual-reality setting, as well as on a variety of anxiety domains. These changes were noted early in treatment and were maintained at 3-month follow-up. Specific phobia tends to be a chronic condition. Although psychotherapeutic approaches can be beneficial in the short term, evidence suggests that the initial gains noted with treatment may not be sustained over the long term (Lipsitz et al. 1999). Pharmacological augmentation may help to extend the benefits of exposure therapy over time. It also has been hypothesized that specific phobia may represent a phenomenological marker for a vulnerability to developing other anxiety disorders that are characterized by more general avoidance (Goisman et al. 1998). As such, perhaps early recognition and treatment in individuals at risk could reduce the occurrence of more severe anxiety disorders in this population. Further study of these hypotheses is needed.

GENERALIZED ANXIETY DISORDER GAD is a common anxiety disorder, with a lifetime prevalence of 5%–6% (Wittchen and Hoyer 2001) and is the most prevalent anxiety disorder in primary care, with rates that exceed 8% (Goldberg and Lecrubier 1995). GAD tends to be a chronic and disabling condition with lifetime rates of comorbidity as high as 90% (Wittchen et al. 1994), particularly depression (prevalence rate greater than 60%) (Wittchen et al. 1994), which can increase the severity and burden of the disorder. GAD is characterized by persistent and excessive worry that is difficult to control and is accompanied by symptoms of anxiety, tension, and autonomic arousal. Effective treatments include anxiolytic drugs, such as benzodiazepines and azapirones. These drugs can be helpful for symptoms of anxiety, but they are not generally considered satisfactory in the treatment of depression. In addition, the side-effect profile of benzodiazepines and potential for physiological dependence limit their use in many patients and have resulted in growing interest in the search for alternative treatments. In recent years, growing evidence supports the role for antidepressants in treating GAD, especially in patients with comorbid depression. The goals of pharmacotherapy for GAD include treatment of the symptoms of worry, anxiety, tension, somatic distress, and autonomic arousal. Ideally, treatments will have a rapid onset of action in reducing these core symptoms; will be effective in treating the associated disability, psychosocial impairment, and comorbidity; and will be safe for longer-term use in chronic GAD. Assessment of response in almost all pharmacotherapy trials of GAD has involved use of the clinicianadministered Ham-A (Hamilton 1959), which measures psychic (i.e., psychological) and somatic symptoms of anxiety and broadly maps onto the clinical features of GAD. Remission is usually defined as a Ham-A score of 7 or less. The Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith 1983) is also widely used and is capable of detecting differences in treatment efficacy. An advantage of the HADS lies in the fact that its items are independent from the confounding influence of psychotropic drug side effects. It also has widely established population norms.

Anxiolytics Benzodiazepines Benzodiazepines have been widely used to treat acute and chronic anxiety since their introduction in the 1960s. Their activity is mediated through potentiation of the inhibitory neurotransmitter -aminobutyric acid (GABA) at the GABAA receptor. The efficacy and relative safety of benzodiazepines

in short-term use, over several weeks or months, are well established (Rickels et al. 1983; Shader and Greenblatt 1993). However, the use of these drugs over longer periods is more controversial, and long-term use can be associated with the development of tolerance, physiological dependence, and withdrawal (if abruptly discontinued), as well as troublesome side effects, including ataxia, sedation, motor dysfunction, and cognitive impairment. Furthermore, these drugs should be avoided in patients with a history of substance use disorders, and long-term use may infrequently lead to the development of major depression (Lydiard et al. 1987). Benzodiazepines have been shown to be effective in GAD, as reported by Rickels et al. (1993) in an 8-week study of diazepam in patients with DSM-III (American Psychiatric Association 1980)–diagnosed GAD. The appeal of these drugs lies in their rapid onset of action, ease of use, tolerability, and relative safety. However, few controlled data support their use over the long term in GAD. Findings from several 6- to 8-month trials of maintenance treatment for chronic anxiety have indicated continued efficacy of benzodiazepines over time (Rickels et al. 1983, 1988a, 1988b; Schweizer et al. 1993). Because GAD tends to be a chronic disorder, many patients may need to continue pharmacotherapy with benzodiazepines or other drugs for many years. Estimates suggest that approximately 70% of patients with GAD will respond to an adequate trial of a benzodiazepine (Greenblatt et al. 1983). An adequate treatment trial corresponds to the equivalent of a 3- to 4-week treatment course of up to 40 mg/day of diazepam or 4 mg/day of alprazolam (Schweizer and Rickels 1996). If a decision is made to discontinue treatment, the drug should be tapered slowly to minimize the effects of withdrawal, the development of rebound anxiety, and the potential for relapse. Some evidence suggests that benzodiazepines may be more effective in treating particular GAD symptoms, such as autonomic arousal and somatic symptoms, but less effective for the psychic symptoms of worry and irritability (Rickels et al. 1982; Rosenbaum et al. 1984). As our understanding of the phenomenology of GAD has grown and as the diagnostic criteria have evolved from DSM-III to DSM-IV (American Psychiatric Association 1994), there has been a greater emphasis on the psychic component of the disorder, with de-emphasis of the autonomic and somatic components. Given these changes, along with the high rates of comorbid depression in GAD and the anxiolytic activity of many of the newer classes of antidepressants, the utility of benzodiazepines as a primary treatment for GAD is uncertain. However, even though somatic symptoms are no longer featured as diagnostic criteria, they are frequently seen as presenting clinical symptoms in practice. A degree of uncertainty still hangs over the most appropriate way to classify GAD. Even as DSM-IV was being crafted, debate centered around the extent to which GAD could be separated from mood disorders, such as dysthymia and major depression (Moras et al. 1996). This question has never been well resolved, and it is possible that with so much in common between GAD and depressive disorders, its classification primarily as an anxiety disorder may change in DSM-V.

Azapirones The azapirones are structurally distinct from the benzodiazepines and are believed to exert their anxiolytic effect through partial agonism of 5-HT1A receptors. Several trials have indicated that buspirone is superior to placebo and comparable to benzodiazepines in treating GAD, with fewer side effects and without concerns for abuse, dependence, and withdrawal (Cohn et al. 1986; Enkelmann 1991; Petracca et al. 1990; Rickels et al. 1988b; Strand et al. 1990), although other studies have reported conflicting results (Fontaine et al. 1987; Olajide and Lader 1987; Ross and Matas 1987). Buspirone appears more effective in treating the psychic component of anxiety (Rickels et al. 1982) and possibly anxiety with mixed depressive symptoms (Rickels et al. 1991) than the somatic and autonomic symptoms of anxiety (Schweizer and Rickels 1988; Sheehan et al. 1990). An adequate trial of buspirone in GAD would be 3–4 weeks of treatment at a dosage of up to 60 mg/day, in divided doses. Treatment-limiting effects of the drug include greater potential for side effects at higher dosages, slower onset of action, more variable antidepressant effect, and possibly reduced

effectiveness in patients with a prior favorable response to benzodiazepines (Schweizer et al. 1986).

Tricyclic Antidepressants Retrospective studies of subjects with "anxiety neurosis" suggested that TCAs may be effective in treating anxiety states similar to GAD (Cohn et al. 1986; Johnstone et al. 1980). Data in support of these findings come from controlled studies of imipramine and trazodone in GAD (Hoehn-Saric et al. 1988; Rickels et al. 1993). In a 6-week trial comparing imipramine and alprazolam, similar improvement was observed with both treatments by week 2; however, imipramine appeared to be more effective in treating the psychic anxiety associated with GAD, whereas alprazolam was more effective in attenuating somatic symptoms (Hoehn-Saric et al. 1988). In an 8-week double-blind, placebo-controlled trial of imipramine, trazodone, and diazepam (Rickels et al. 1993), early onset of effect was noted with diazepam by week 2, with effect primarily on somatic symptoms. Over the next 6 weeks, however, symptoms of psychic anxiety were more responsive to treatment with the antidepressants. Overall, imipramine was more efficacious than diazepam, whereas the effect of trazodone was comparable to that of diazepam, and all treatments were superior to placebo. In a controlled trial comparing imipramine, paroxetine, and 2'-chlordesmethyldiazepam, early onset of action was again noted with the benzodiazepine by week 2, but overall greater improvement was noted with the antidepressants by week 4, with particular benefit noted in psychic symptoms (Rocca et al. 1997). Potential advantages of the TCAs over the benzodiazepines include their ability to treat symptoms of both anxiety and depression, the absence of potential for abuse and physiological dependence, and their effectiveness in the management of discontinuation of long-term benzodiazepine therapy (Rickels et al. 2000a). TCAs, however, can be accompanied by a variety of troublesome side effects related to pharmacological blockade of histamine1 (H1),

1-adrenergic,

and muscarinic receptors, and

these effects can limit their use. Frequently reported adverse effects include weight gain, orthostatic hypotension, edema, urinary retention, blurred vision, dry mouth, and constipation. Sedation is also commonly noted; for some patients this is an adverse event, whereas for others it is of therapeutic benefit. The utility of the TCAs is also limited by their cardiotoxic potential and lethality in overdose.

Selective Serotonin Reuptake Inhibitors and Serotonin–Norepinephrine Reuptake Inhibitors A number of SSRIs are effective in GAD. Paroxetine IR at 20–50 mg per day has been shown to be as effective as imipramine and more effective than 2'-chlordesmethyldiazepam, with the antidepressants again demonstrating greatest effect on symptoms of psychic anxiety (Rocca et al. 1997). Compared with placebo, a similar dosage range of paroxetine IR was associated with significant reduction in anxiety after 8 weeks of treatment (Bellew et al. 2000; Pollack et al. 2001), with an improvement in psychic anxiety as measured by reduction in the anxious mood item of the Ham-A scale, observed as early as 1 week after initiating treatment (Pollack et al. 2001). Paroxetine IR also improves social functioning in patients with GAD (Bellew et al. 2000). Rickels et al. (2003) have reported superior benefit of paroxetine IR in GAD, relative to placebo. Three 8-week placebo-controlled trials have found efficacy for escitalopram in a 10- to 20-mg dose range on a variety of measures, of both anxiety symptoms and disability or quality of life (Davidson et al. 2004a; Goodman et al. 2005). In a 6-month trial, Bielski et al. (2005) found equivalent benefit for paroxetine IR and escitalopram. In a larger placebo-controlled trial of three doses of escitalopram and 20 mg paroxetine IR, 10 mg escitalopram demonstrated superiority over 20 mg paroxetine, 10 and 20 mg escitalopram were superior to placebo, while 5 mg escitalopram and 20 mg paroxetine IR were superior on some secondary outcomes (Baldwin et al. 2006). A relapse prevention study found that sustained treatment with escitalopram 20 mg/day up to 74 weeks reduced the rate of relapse relative to placebo substitution (Allgulander et al. 2006). Relapse rates were for 19% for escitalopram versus

56% for placebo. Two studies have shown benefit for sertraline over placebo in GAD (Allgulander et al. 2004; BrawmanMintzer et al. 2006). Several placebo-controlled trials have confirmed the short-term efficacy of venlafaxine XR in GAD over 8 weeks, with improvement noted in both the psychic and the somatic symptoms of the disorder. In one trial, 365 adult outpatients received treatment with venlafaxine XR (75 mg/day or 150 mg/day), buspirone (30 mg/day), or placebo (Davidson et al. 1999). The adjusted mean scores on the Ham-A anxious mood and tension items were significantly improved at both dosages of venlafaxine XR compared with placebo; however, the adjusted mean Ham-A total score failed to distinguish between the groups. Venlafaxine XR was superior to buspirone on the Anxiety subscale of the HADS. In a second trial, 541 outpatients were given either venlafaxine XR (37.5 mg/day, 75 mg/day, or 150 mg/day) or placebo (Allgulander et al. 2001). By the end of the study, the 75-mg and 150-mg doses of venlafaxine showed superior efficacy to placebo on all primary outcome measures, whereas the 37.5-mg dose was superior on only one measure (the Anxiety subscale of the HADS). Significant improvement was noted in symptoms of psychic anxiety by week 2 of treatment with venlafaxine, with reduction of somatic symptoms noted a bit later, following 4–8 weeks of treatment. A third trial evaluated fixed dosages of venlafaxine XR at 75 mg/day, 150 mg/day, and 225 mg/day (Rickels et al. 2000b). Venlafaxine XR was superior to placebo on all outcome measures, although the most robust effects were observed with 225 mg/day. In addition, venlafaxine XR significantly reduced psychic anxiety but was no different from placebo in treating somatic symptoms of anxiety. Venlafaxine XR also has shown long-term efficacy in GAD. In two 6-month controlled trials of fixed (37.5 mg, 75 mg, 150 mg/day) (Allgulander et al. 2001) and flexible (75–225 mg/day) (Gelenberg et al. 2000) doses of venlafaxine XR, significant improvement in anxiety was observed as early as 1 week, and efficacy was sustained over the 28-week treatment period. In the fixed-dose study, the greatest effect was observed with the 150-mg/day dose. In addition, significant improvement in social functioning was noted at the two higher doses by week 8 and sustained over the 6 months of the trial. Venlafaxine XR is also effective in treating GAD with comorbid depression (Silverstone and Salinas 2001). After 12 weeks of treatment with venlafaxine XR (75–225 mg/day), fluoxetine, or placebo, significant reduction was observed in both anxiety and depression, as measured by the Ham-A and the Ham-D, respectively, only in subjects receiving venlafaxine XR. The response was delayed somewhat in subjects with comorbid GAD and depression, as compared with those with depression alone, suggesting that those with comorbidity may benefit from a longer course of treatment. The traditional treatment goal for GAD and many other psychiatric disorders has been attainment of response, defined as 50% improvement relative to baseline. There is a growing consensus in the field, however, that this goal is not sufficient for many patients and that the goal of treatment should instead be remission, defined as 70% or greater improvement from baseline and/or minimal or absent symptoms (i.e., Ham-A score

7). Pooled analysis of data from the two long-term studies noted above

has determined that remission is attainable in GAD (Meoni and Hackett 2000). By 2 months, approximately 40% of those receiving venlafaxine responded to treatment (response defined as 50% reduction in Ham-A score from baseline), and 42% attained remission (defined as a Ham-A score

7).

By 6 months, the proportion of those in remission increased to almost 60%, whereas responders declined to 20%, in contrast to a remission rate of less than 40% with placebo. Venlafaxine XR has some advantages over the benzodiazepines—notably, antidepressant activity, lack of potential for abuse and dependence, and efficacy in treating symptoms of psychic anxiety. Nonetheless, venlafaxine can be associated with some adverse effects, even though the incidence of these effects diminishes markedly with long-term treatment. Adverse events may be noted with

long-term therapy, however, and include sexual dysfunction and blood pressure elevation in some patients. In addition, abrupt discontinuation of treatment can be associated with unpleasant side effects, most commonly dizziness, light-headedness, tinnitus, nausea, vomiting, and loss of appetite, and the discontinuation syndrome is worse if one abruptly stops from higher dosage levels (Allgulander et al. 2001). Duloxetine, also an SNRI antidepressant, has shown superior efficacy to placebo in GAD (Allgulander et al. 2007; Rynn et al. 2008) in the range of 60–120 mg per day, as well as lessening the chance of relapse during maintenance therapy.

Noradrenergic and Specific Serotonergic Antidepressants (Mirtazapine, Bupropion) The antidepressant mirtazapine also has demonstrated anxiolytic properties (Ribeiro et al. 2001). However, published reports of its effect in GAD are limited to a small open-label study in major depression and comorbid GAD (Goodnick et al. 1999). Although the results were encouraging, data from controlled trials are needed to adequately assess a possible role for mirtazapine in GAD. One double-blind trial, published in abstract form, found that bupropion XL produced a higher remission rate than escitalopram, as well as better coping skills (Bystritsky et al. 2005). Notwithstanding these intriguing findings, the body of clinical evidence for now supports the use of serotonergic drugs, or dual serotonergic/noradrenergic reuptake inhibitors, before agents that are primarily noradrenergic in action. However, the Bystritsky et al. findings suggest the potential importance of noradrenergic mechanisms in GAD and its therapeutics.

Hydroxyzine Hydroxyzine, a drug that blocks both H1 and muscarinic receptors, has been studied in GAD. In one controlled study, hydroxyzine was superior to placebo following 1 week of treatment, and this difference was maintained over a 4-week trial (Ferreri and Hantouche 1998). In a larger controlled multicenter trial, hydroxyzine was compared with buspirone over 4 weeks (Lader and Scotto 1998). Changes in the Ham-A from baseline to day 28 indicated that hydroxyzine was superior to placebo, with no difference observed between buspirone and placebo. Of note, both hydroxyzine and buspirone were more efficacious than placebo on the secondary outcomes. Llorca et al. (2002) found that hydroxyzine 50 mg/day was superior to placebo and comparable to bromazepam in a 12-week trial.

Other Drugs The

2

calcium channel antagonist pregabalin was superior to placebo in four studies of GAD (Feltner

et al. 2003; Pande et al. 2003; Pohl et al. 2005; Rickels et al. 2005). Efficacy was noted early in treatment, but the ability of this drug to successfully treat some of the comorbid disorders found with GAD is unknown. The GABA reuptake inhibitor tiagabine failed to separate from placebo on key measures in one multicenter trial (Pollack et al. 2005). Evidence for antipsychotic monotherapy in GAD is limited. An open-label trial suggested benefit for ziprasidone (Snyderman et al. 2005). Flupenthixol is approved for the use of depression in some countries but is also widely used to treat GAD-like states. One controlled study showed that flupenthixol was superior to amitriptyline, clotiazepam, and placebo among subjects with refractory GAD (Wurthmann et al. 1995). Sulpiride is also used in similar situations (Bruscky et al. 1974; Chen et al. 1994). Use of antipsychotic drugs carries some concern about their tolerability and safety profile. Riluzole, a presynaptic glutamate release inhibitor, has shown promise in a small open-label study at a daily dose of 100 mg (Mathew et al. 2005). Complementary treatments, such as homeopathy and the herbal remedy kava kava, are ineffective in GAD (Bonne et al. 2003; Connor and Davidson 2002).

A meta-analysis of GAD studies by Hidalgo et al. (2007) showed that the effect sizes (in diminishing order from strongest to weakest) for each drug or drug group versus placebo were as follows: pregabalin, 0.50; hydroxyzine, 0.45; venlafaxine XR, 0.42; benzodiazepines, 0.38; SSRIs, 0.36; buspirone, 0.17; and homeopathy and herbal treatment, –0.31. Drugs that have been approved in the United States for treating GAD or historical forerunners of the disorder include a large number of benzodiazepines, buspirone, paroxetine IR, escitalopram, venlafaxine XR, and duloxetine. There is also convincing evidence in favor of efficacy for CBT in GAD, with sustained benefit over 2 years of follow-up. These findings have been well reviewed by Swinson et al. (2006). There are no clinically informative studies to compare, or combine, CBT and pharmacotherapy in GAD, but on pragmatic grounds, one may consider their combination in patients who have shown only a partial response to a thorough course of either CBT or medication alone.

POSTTRAUMATIC STRESS DISORDER PTSD is a chronic and disabling disorder, with a lifetime prevalence of about 7% (Kessler et al. 2005a). The direct and indirect consequences of the disorder inflict an enormous burden on society, leading PTSD to be the primary cost driver in the annual $42 billion cost of anxiety disorders in the late 1990s (P. E. Greenberg et al. 1999). Treatment of PTSD should target a range of presenting features. Clearly, effective therapy needs to reduce the core symptoms of the disorder. Treatment also should focus on improving resilience and coping with daily stress, improving quality of life, and reducing comorbidity and disability. For some, medication may serve to help seal over the distress and pain of the event and allow a return to normal daily activities. For others, medication may help them to engage in a treatment plan that involves uncovering the distress and allows for resolution of the traumatic experience. Instruments that have been widely used in trials of pharmacotherapy comprise the DSM-IV criteria– linked Clinician-Administered PTSD Scale (CAPS; Weathers et al. 2001) and the more globally oriented Short PTSD Rating Instrument (SPRINT; Connor and Davidson 2001). Self-rating scales include the Davidson Trauma Scale (DTS; Davidson et al. 1997a), a 17-item, two-part assessment of the major DSM-IV symptoms of PTSD, and the SPRINT, which also has been validated as a self-rating. Most studies to date have evaluated monotherapy, but a growing number are examining augmentation approaches.

Antidepressants The TCAs and MAOIs were among the first pharmacological agents studied in controlled trials of PTSD. More recently, findings from several controlled multicenter trials have shown efficacy for the SSRI and SNRI drugs. With the documented antidepressant and anxiolytic effects of these noradrenergic and serotonergic agents, and the high rates of comorbid depression in PTSD (Kessler et al. 1995), antidepressants would seem like a logical choice for treatment of PTSD.

Tricyclic Antidepressants Positive evidence for the efficacy of TCAs has been found in two controlled trials involving male combat veterans with PTSD defined by DSM-III criteria. In one study, 46 World War II and Vietnam War veterans were given amitriptyline (50–300 mg/day) or placebo for 8 weeks. Greater improvement was noted with amitriptyline than with placebo; 50% of those receiving amitriptyline showed much or very much global improvement, compared with 17% of those receiving placebo (Davidson et al. 1990). A second study examined imipramine (50–300 mg/day) and placebo in 60 veterans of the Vietnam era. Greater reduction in symptoms was noted in subjects receiving imipramine, with a 25% reduction in Impact of Event Scale (IES; Horowitz et al. 1979) score from

baseline for imipramine compared with 5% for placebo. Global improvement also was superior with imipramine (65%) compared with placebo (28%) (Kosten et al. 1991). Together, these studies showed that TCAs are more effective than placebo in the short-term treatment of PTSD in male combat veterans.

Monoamine Oxidase Inhibitors In a study of male combat veterans, Kosten et al. (1991) compared phenelzine (15–75 mg/day) with placebo and found a 45% decrease in IES score from baseline for phenelzine, compared with a 5% decrease for placebo, but no improvement was noted in depressive symptoms with either treatment. The RIMA brofaromine has been assessed in two controlled trials of PTSD: a U.S. sample composed predominantly of combat veterans (n = 114) (Baker et al. 1995) and a civilian European sample with few veterans (n = 68) (Katz et al. 1994). The U.S. study failed to show a difference between the treatments. Findings from the European study also were mixed, depending on the measure used to assess change. Finally, the RIMA moclobemide was assessed in 20 subjects with PTSD meeting DSM-III-R (American Psychiatric Association 1987) criteria (Neal et al. 1997). Following 12 weeks of treatment, 11 subjects no longer met the full PTSD criteria, providing a signal that the drug might be effective in PTSD.

Selective Serotonin Reuptake Inhibitors Three controlled trials support the efficacy of fluoxetine in PTSD. In these studies, fluoxetine was administered at dosages of 20–80 mg/day for 5–12 weeks in samples including both civilians and combat veterans with PTSD meeting DSM-III-R (Connor et al. 1999; van der Kolk et al. 1994) or DSM-IV (Martenyi et al. 2002a) criteria. Significant differences were observed in favor of fluoxetine, as measured by changes in clinician-rated structured interviews from baseline to the end of treatment. In the study by Connor et al. (1999), fluoxetine also was associated with a significant improvement in resilience, as measured by a reduction in stress vulnerability, and in disability. Martenyi et al. (2002a) showed that at a mean dosage of 57 mg/day, fluoxetine was associated with significant reduction in PTSD symptoms from baseline as early as week 6 and at week 12, in a sample predominantly made up of male combat veterans. Two studies of maintenance therapy with fluoxetine over a period of 1 year have shown reductions in the rate of relapse, as compared with placebo substitution (Davidson et al. 2005; Martenyi et al. 2002b). Two studies have shown efficacy for sertraline in PTSD (Brady et al. 2000; Davidson et al. 2001). At a mean dosage of approximately 150 mg/day, sertraline was more effective than placebo in reducing overall PTSD symptoms and avoidance; symptoms of arousal improved with sertraline in one study (Brady et al. 2000; Davidson et al. 2001), but no differences were noted in intrusive symptoms. Based on a response definition of a greater than 30% reduction in CAPS (Blake et al. 1995) score from baseline and a CGI score of 1 or 2 (much or very much improvement), response rates for sertraline ranged from 53% to 60%, compared with 32%–38% for placebo. A pooled analysis of these data showed the broad-spectrum effect of the drug, particularly on psychological symptoms of the disorder, with an early modulation of anger at 1 week preceding improvement in other symptoms (Davidson et al. 2002). This finding is of particular interest, given that angry temperament can be associated with impulsivity and violence and a greater risk for cardiac events (Williams et al. 2001), as well as increased heart rate and blood pressure, in PTSD (Beckham et al. 2002). Other short-term studies of sertraline in PTSD have been negative (Brady et al. 2005; Davidson et al. 2006b; Friedman et al. 2007) or inconclusive (Zohar et al. 2002). Continued treatment with sertraline over 9 months was associated with sustained improvement in more than 90% of the subjects (Londborg et al. 2001). In those with more severe PTSD who did not improve with acute treatment over 12 weeks, more than 50% were likely to respond with continued

treatment (Londborg et al. 2001). Over 15 months of treatment, improvement was sustained, with relapse rates of 5% with sertraline and 26% with placebo, thereby suggesting that the drug provides prophylactic protection against relapse (Davidson et al. 2001). Sertraline is also effective in improving quality of life and reducing functional impairment, with rapid improvement noted with acute treatment and more than 55% of patients functioning at levels within 10% of the general population. These gains are maintained with long-term treatment, and continued improvement can be noted, whereas treatment discontinuation is more likely to lead to deteriorating function, although not to levels observed prior to treatment (Rapaport et al. 2002). The efficacy of paroxetine in PTSD has been shown in two 12-week controlled multicenter trials, including flexible-dose (n = 307; paroxetine 20–50 mg) (Tucker et al. 2001) and fixed-dose (n = 451; paroxetine 20 or 40 mg) (Marshall et al. 2001) regimens. Compared with placebo, paroxetine produced significant improvement in overall PTSD symptomatology, individual symptom clusters, and functional impairment. Response rates ranged from 54% to 62% for paroxetine compared with 37% to 40% for placebo. Findings from two open-label studies of fluvoxamine, at dosages of 100–250 mg/day, have been reported, including those from an 8-week study in civilians (n = 15) and a 10-week study in combat veterans (n = 10) (Davidson et al. 1998; Marmar et al. 1996), in which the drug was effective in treating symptoms of PTSD. Treatment with fluvoxamine (mean = 194 mg/day) also has been associated with significant improvement in autonomic reactivity, with reductions in heart rate and blood pressure on exposure to trauma cues to levels that are indistinguishable from those of control subjects without PTSD (Tucker et al. 2000). These findings are encouraging, but larger controlled trials are needed to determine the efficacy of the drug in PTSD. Two large multicenter studies have established efficacy for venlafaxine XR up to 300 mg per day, in one case for as long as 6 months. Rates of remission exceeded 50% in the longer-term trial, and resilience was significantly improved in one of the two studies (Davidson et al. 2006a, 2006b). In summary, the SSRIs are efficacious in the treatment of PTSD, with two drugs, paroxetine IR and sertraline, approved for treatment of PTSD. SSRIs and SNRIs show a broad spectrum of activity, with significant reduction in some symptoms as early as 1–2 weeks after treatment initiation. SSRI and SNRI drugs not only improve symptoms with acute treatment but also result in sustained and continued improvement, and in some cases remission, with long-term treatment up to 15 months. These drugs are generally well tolerated, although some adverse effects (e.g., sexual dysfunction, sleep disturbances, and weight gain) may lead to treatment discontinuation.

Other Antidepressants Results of one 8-week controlled trial of mirtazapine in 29 outpatients with PTSD have been reported. A clinician-rated global assessment found response rates to mirtazapine of 65% compared with response rates to placebo of 20%, with significant improvement on several measures of PTSD as well as general anxiety (Davidson et al. 2003). Six open-label studies of nefazodone in civilians and combat veterans with PTSD have been reported (Hidalgo et al. 1999). Treatment with nefazodone (50–600 mg/day) over 6–12 weeks was associated with significant reduction in severity of overall PTSD, as well as in each of the symptom clusters. Of particular note was improvement in sleep, which is often disrupted in PTSD, and these problems are frequently exacerbated by treatment with SSRIs. Davis et al. (2004) have demonstrated superior efficacy for the drug, relative to placebo, in combat veterans.

Anxiolytics Benzodiazepines are often prescribed to treat acute anxiety in the aftermath of a trauma. However, findings have been disappointing. An open-label study of alprazolam and clonazepam in 13

outpatients with PTSD found reduced hyperarousal symptoms but no change in intrusion or avoidance/numbing (Gelpin et al. 1996). In a crossover design, subjects received 5 weeks of treatment with either alprazolam or placebo followed by 5 weeks of the alternative therapy (Braun et al. 1990). Minimal improvement was observed in anxiety symptoms overall, with no improvement in the core symptoms of PTSD. Clonazepam 2 mg was not different from placebo in controlling nightmares in a 2-week single-blind crossover study, where the test drug was added to preexisting treatment (Cates et al. 2004). Thus, the evidence does not yet support the use of benzodiazepines in PTSD, even though they appear to be widely used (Mellman et al. 2003). Their position in managing PTSD thus remains unclear.

Anticonvulsants In the 1980s, Lipper et al. (1986) proposed that the pathophysiology of PTSD may involve sensitization and kindling processes and, to this end, that anticonvulsants might be of therapeutic benefit. In testing this hypothesis, these investigators found that 7 of 10 (70%) Vietnam War veterans who received open-label carbamazepine (600–1,000 mg/day) for 5 weeks had "moderate" or "very much" improvement with treatment, particularly in symptoms of intrusion and hyperarousal. Three subsequent open-label studies have been performed, including two with sodium valproate in combat veterans (R. D. Clark et al. 1999; Fesler 1991) and a study of adjunctive topiramate in a civilian PTSD sample (Berlant and van Kammen 2002). The treatments showed somewhat different effects, with sodium valproate (250–2,000 mg/day) improving symptoms of arousal and intrusion in one study (Fesler 1991) and arousal and avoidance in the other (R. D. Clark et al. 1999), whereas topiramate (15.5–500 mg/day) was most effective in reducing symptoms of intrusion, particularly nightmares and flashbacks (Berlant and van Kammen 2002). The largest placebo-controlled trial of an anticonvulsant to date found no difference between tiagabine, dosed up to 16 mg per day, and placebo in 232 patients in a 12-week multicenter trial (Davidson et al. 2007). In a small placebocontrolled trial of lamotrigine (200–500 mg per day) in 15 outpatients (Hertzberg et al. 1999), a response rate of 50% was noted with lamotrigine, compared with a placebo response rate of 25%.

Other Treatments Antipsychotics One placebo-controlled monotherapy trial of olanzapine has been published (Butterfield et al. 2001), in which 15 subjects were randomized 2:1 to treatment with olanzapine (up to 20 mg/day) or placebo. No differences were observed between the treatments, although olanzapine was associated with greater weight gain. It is difficult to interpret these findings in this small sample, especially given the high placebo response rate (60%). Other reports of antipsychotics are based on augmentation therapy in SSRI partial responders. Four placebo-controlled studies, mainly as augmentation, have found superior efficacy for low-dose risperidone (Bartzokis et al. 2005; Hamner et al. 2003; Monnelly et al. 2003; Reich et al. 2004) and olanzapine (M. B. Stein et al. 2002). In the Monnelly study, particular benefit was noted for irritability and in the Hamner study, psychotic symptoms were relieved. These antipsychotic studies in aggregate comprised 155 patients.

Prazosin and Guanfacine Raskind et al. (2003) reported encouraging results for intractable PTSD-related nightmares in a placebo-controlled crossover study of prazosin, an

1-adrenergic

antagonist, at doses of up to 10

mg/day. The investigators have confirmed their initial findings in a second and larger placebocontrolled, double-blind augmentation trial conducted in combat veterans, using doses of up to 15 mg daily; benefits were most apparent on nightmares and sleep quality, but the drug also produced greater global improvement (Raskind et al. 2007). One possible mechanism of action may lie in the ability of prazosin to reduce the output of corticotropin-releasing hormone. Suppression of nightmare-

generating non–rapid eye movement stage 1 sleep may be another explanation for this intriguing finding. Standing in contrast is a negative placebo-controlled study of the

2-adrenergic

agonist

guanfacine in patients who, unlike those in the prazosin studies, were not preselected for having troublesome nightmares (Neylan et al. 2006).

Other Drugs Given the prevalence of comorbid depression with PTSD and the effectiveness of triiodothyronine (T3) augmentation in some individuals with treatment-refractory depression, it is possible that T3 augmentation also may be of benefit in PTSD. Five subjects with PTSD currently taking an SSRI were treated with open-label T3 (25 g/day) for 8 weeks (Agid et al. 2001). Improvement was noted as early as 2 weeks, and by the end of treatment, four of the five subjects showed at least partial improvement in depressive symptoms and hyperarousal. The mechanism for these effects is unknown, and further controlled studies of this augmentation strategy are therefore needed. Cyproheptadine, an antihistaminic drug, was no more effective than placebo for nightmares over 2 weeks in a series of 69 combat veterans with PTSD (Jacobs-Rebhun et al. 2000). The naturally occurring compound inositol was ineffective in a small placebo-controlled trial (Kaplan et al. 1996).

ACUTE STRESS DISORDER AND THE IMMEDIATE AFTERMATH OF TRAUMA Acute stress disorder (ASD) is characterized by the development of a constellation of symptoms shortly after a traumatic event and includes symptoms of dissociation and intrusive recollections, avoidance, and hyperarousal. These symptoms persist for 2–28 days following the trauma and cause significant distress and/or impairment. If the condition persists beyond 1 month, the individual usually qualifies for a diagnosis of PTSD. ASD was first included in the diagnostic nosology in DSM-IV, and little is known about the pharmacotherapy of this disorder. As noted earlier, it has been suggested that early intervention for trauma survivors might help to alter the course of PTSD, and this would imply early identification and treatment of those with or at risk for ASD. The effects of open-label treatment with risperidone have been reported in four inpatient survivors of physical trauma with ASD; this drug showed possible benefit in flashback symptoms (Eidelman et al. 2000). A controlled pilot study assessed the effects of low-dose imipramine compared with choral hydrate in 25 pediatric burn patients with ASD (Robert et al. 1999a). After 1 week of treatment, 38% of the subjects responded to treatment with placebo, compared with 83% to imipramine, with an earlier report noting reduction in intrusion and hyperarousal symptoms (Robert et al. 1999b). Another study evaluated the effects of

-adrenergic blockade in reducing subsequent PTSD following acute

trauma (Pitman et al. 2002). Within 6 hours of the trauma, subjects were treated with either propranolol (n = 18; 40 mg qid) or placebo (n = 23) for 10 days, followed by a 9-day taper period. One month after the trauma, PTSD was noted in 30% of the placebo group compared with 10% of the propranolol group. At 3-month follow-up, physiological arousal was assessed using personal scriptdriven imagery of the event, and 43% of the placebo group were physiological responders compared with 0% of the propranolol group. Although the dropout rate was higher with propranolol (7 of 18; 39%) than with placebo (3 of 23; 13%), these findings suggest that acute treatment with -adrenergic-blocking agents may be effective in preventing the later development of PTSD, but further studies are needed. In one study of temazepam versus placebo for ASD or subthreshold PTSD, coupled with at least moderate sleep disturbance, there was no advantage for the drug, either during treatment or at follow-up 6 weeks posttrauma (Mellman et al. 2002). Two promising studies have found greater long-term benefit for short-term hydrocortisone versus placebo in high-risk subjects recovering from septic shock and from cardiac surgery (Schelling et al. 2006). In subpopulations with critical illness–related corticosteroid insufficiency, this might be an attractive treatment approach for preventing PTSD. One limitation of the authors' work, however, has been the absence of baseline PTSD ratings before administration of hydrocortisone.

CBT has been extensively studied in PTSD and shows efficacy in most cases (Bisson and Andrew 2005). Exposure is regarded as the key therapeutic principle in the numerous variants of CBT. Modest preservation of gains is found at long-term follow-up (Bradley et al. 2005), but much pathology remains. For this reason, it is unfortunate that there are almost no trials, either long or short term, combining CBT with drugs. Shortened forms of CBT appear to be effective for acute PTSD-like states, with persistence of gain at 4-year follow-up (Bryant et al. 1998, 2003).

CONCLUSION Twenty years ago, few would have thought that one class of drugs, the SSRIs, which were all introduced initially for depression, would have established primacy in five of the six major anxiety disorder categories. Their position is based on solid category 1 randomized, controlled trial evidence, and they are now first-line drugs for treatment of these disorders. To the extent that studies have been conducted, SSRIs also offer some protection against relapse. However, they are not 100% successful, they carry some limiting side effects, and they may require supplementation with, or substitution by, drugs from other categories. We have reviewed what is known about these other drugs and expect further progress in the pharmacotherapy of anxiety, with both established drugs and novel categories (e.g., corticotropin-releasing hormone antagonist). Among many unexplored areas, we need to know more about the treatment of resistant anxiety disorders and comorbid anxiety disorder and the comparative efficacy, or contribution, of pharmacotherapy and psychosocial treatment in anxiety. The rationale for using drugs rests, in part, on the broad-based evidence that vulnerability to each of the anxiety disorders includes shared and/or unique genetic risk factors, which usually coexist with environmental factors in respect of explaining variance. High trait neuroticism is a genetic risk factor for internalizing disorders as a whole and for comorbidity among the anxiety disorders and depression (Hettema et al. 2006). A diagnostically nonspecific genetic vulnerability may underlie fear proneness and amygdalar hyperreactivity (Hariri et al. 2005). Family and twin studies, as well as other types of studies, support genetic risk factors for generalized anxiety, panic disorder, phobias, and OCD (Hettema et al. 2001; Westenberg et al. 2007) and social anxiety disorder (Mathew and Ho 2007), for which some candidate genes are beginning to emerge. For PTSD, the evidence suggests a role for unique and shared genetic effects (Chantarujikapong et al. 2001; True et al. 1993), including common genetic liability for PTSD and major depression (Koenen et al. 2008). While detailed consideration of genetics goes beyond the scope of this chapter, it is of considerable interest to note the findings of M. B. Stein et al. (2006) and Denys et al. (2007), for example, that drug response in social anxiety disorder and OCD, respectively, may be related to genetic polymorphisms. These exciting findings may herald a time when we can more effectively individualize pharmacotherapy for anxiety.

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Carl Salzman, Pierre N. Tariot: Chapter 57. Treatment of Agitation and Aggression in the Elderly, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.434758. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 57. Treatment of Agitation and Aggression in the Elderly TREATMENT OF AGITATION AND AGGRESSION IN THE ELDERLY: INTRODUCTION Severe agitation—restlessness, wandering, or screaming—may accompany late-life psychosis or dementia, with particularly high prevalence rates in nursing homes. Aggression and assaultiveness may also occur as a consequence of the delusions or hallucinations of late-life psychosis from dementia, depression, or a combination of these factors. Behavioral and psychiatric symptoms develop in as many as 60% of community-dwelling dementia patients (Lyketsos et al. 2000; Ryu et al. 2005; Tractenberg et al. 2003; Wragg and Jeste 1988). The lifetime risk of behavioral complications of dementia approaches 100% (Lyketsos et al. 2000). Rates of physical aggression range from 11% to 46% among community-dwelling dementia patients and from 31% to 42% among patients in institutional settings (Billig et al. 1991; Brodaty et al. 2003; Cohen-Mansfield et al. 1995; Peabody et al. 1987; Wragg and Jeste 1988; Zimmer et al. 1984). The etiology of agitation and aggression in late-life psychosis or dementia is unknown, although environmental and biological factors, such as drug toxicity, medical illness, pain, frustration, loneliness, reduced sensory input, new surroundings, diminished nutritional status, and altered central nervous system (CNS) function, alone or in combination, may play important roles (Mintzer and Brawman-Mintzer 1996). In recent years, researchers and clinicians have begun to categorize disruptive behavioral syndromes according to associated etiology, as agitation and aggression of 1) psychosis, 2) dementia with psychosis, and 3) nonpsychotic dementia (Jeste et al. 2006). At present, there are no specific diagnostic categories of "psychosis with dementia" or "dementia-related agitation," so that all treatments are "off label." Psychotic and nonpsychotic patients have been mixed together in clinical trials, which may have confused the outcomes and clinical recommendations. A distinct category of "psychosis of Alzheimer's disease and related dementia" may improve research into late-life agitation and aggression (Jeste and Finkel 2000). No drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of persisting psychosis, agitation, or aggression associated with dementia. Nevertheless, despite only modest benefits and frequent warnings about adverse effects and inappropriate use, antipsychotic drugs continue to be used as first-line agents. An increasing number of other medication classes, including anticonvulsants, antidepressants, and cognitive enhancers, are also being used as second-line choices for management of agitation and aggression in dementia that cannot be managed without medication (Docherty et al. 1998; Jeste et al. 2008; Kindermann et al. 2002; Raivio et al. 2007; Salzman 2000; Salzman and Tune 2001; Salzman et al. 2008; Small et al. 1997).

ANTIPSYCHOTIC TREATMENT First-Generation (Conventional, Typical) Antipsychotics Before the second-generation (atypical) antipsychotics, with their superior side-effect profiles, became available, first-generation antipsychotics (FGAs; sometimes called conventional or typical antipsychotics), especially haloperidol, were the mainstay of treatment of late-life agitation. Extrapyramidal side effects (EPS), however, are common with haloperidol, especially in the elderly,

limiting its usefulness. Tardive dyskinesia, a late-appearing EPS, develops more rapidly and at lower antipsychotic doses in elderly patients than in younger ones (Caligiuri et al. 1999; Jeste et al. 1999; Karson et al. 1990; Lieberman et al. 1984; Saltz et al. 1989). Tardive dyskinesia is also more common in patients with evidence of cortical atrophy and in dementia patients (Sweet and Pollock 1992). When antipsychotics are discontinued, tardive dyskinesia symptoms are less likely to disappear in older patients than in younger adults (Smith and Baldessarini 1980; Yassa et al. 1984), although the symptoms may not increase in severity (Yassa et al. 1992). These concerns regarding tardive dyskinesia and other EPS have contributed to the switch in clinical preference for the newer antipsychotic drugs.

Second-Generation Antipsychotics Second-generation antipsychotics (SGAs; sometimes called atypical antipsychotics) have replaced conventional antipsychotics as the first-choice treatment for agitation and aggression in the elderly. As a class, these newer antipsychotics carry a lower risk of EPS and tardive dyskinesia. Although pharmacokinetic data are not available for all of the newer SGAs, studies of risperidone indicate that clearance of risperidone and its 9-hydroxy metabolite does not decline with age, whereas clearance of quetiapine is reduced with increasing age (Jaskiw et al. 2004; Maxwell et al. 2002). SGAs are as effective as FGAs for treating agitation and aggression, with or without associated psychosis (Ballard and Waite 2006; Sink et al. 2005). Ballard and Waite (2006), for example, found a significant improvement in aggression with risperidone and olanzapine compared with placebo and a significant improvement in dementia-associated psychosis among risperidone-treated patients. These observations have been supported by numerous other studies. Katz et al. (1999) reported the superiority of risperidone compared with placebo for the treatment of agitation in Alzheimer's disease. Street et al. (2000) reported that olanzapine was superior to placebo for agitation associated with Alzheimer's disease. Meehan et al. (2002) studied acute treatment of agitation with intramuscular olanzapine in 272 inpatients or nursing home residents with Alzheimer's disease and/or vascular dementia. Patients were given up to three injections of olanzapine (2.5 mg or 5.0 mg), lorazepam (1.0 mg or 0.5 mg), or placebo and assessed within a 24-hour period. Olanzapine was found to be superior to placebo in treating agitation at 2 hours and 24 hours. Adverse events were not significantly different between groups. Aripiprazole was also reported to be superior to placebo for treatment of psychosis of Alzheimer's disease in outpatients (Laks et al. 2006). Not all studies of SGAs have reported positive results, however. In a placebo-controlled multicenter trial comparing quetiapine and haloperidol versus placebo for psychosis associated with dementia, Tariot et al. (2006) reported no benefit of either active treatment, with one secondary measure of agitation suggesting benefit. This led to a subsequent placebo-controlled multicenter trial of quetiapine at fixed dosages (100 mg/day and 200 mg/day), which found overall superiority for quetiapine compared with placebo in the management of agitation (Zhong et al. 2006, 2007). Ballard and Waite (2006) conducted a placebo-controlled trial of quetiapine versus rivastigmine in which no benefit of either treatment was observed on behavioral outcomes; cognition worsened in the quetiapine group, a worrisome result that has not been seen in any other study of quetiapine. The Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer's Disease (CATIE-AD) addressed the relative effectiveness of commonly used atypical antipsychotics (Schneider et al. 2006). Outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to treatment with olanzapine (mean dosage mg/day), risperidone (mean dosage

5 mg/day), quetiapine (mean dosage

50

1 mg/day), or placebo. No conventional antipsychotic was

included in the study because of concerns about tardive dyskinesia. The primary measure of effectiveness was time to all-cause discontinuation; secondary measures addressed time to discontinuation due to lack of efficacy, significant safety concerns, or death, as well as improvement in Clinical Global Impression Scale Change scores. There was no significant difference among the

drugs in the primary outcomes, although time to discontinuation due to lack of efficacy was longer with olanzapine and risperidone versus quetiapine or placebo. Conversely, time to discontinuation due to adverse events or drug intolerability was longer for all active treatments than for placebo. The CATIE-AD trial, therefore, confirmed the modest efficacy of atypical antipsychotic drugs as a class. Meta-analytic reviews also suggest that the overall efficacy of SGAs for treatment of agitation and aggression is modest, as is the difference between active drug and placebo. Overall response rates in CATIE-AD ranged from 48% to 65% with active treatment versus 30%–48% with placebo, showing an incremental treatment benefit of about 18% for active drug over placebo (Schneider et al. 2006). Studies comparing SGAs with FGAs have reported significantly greater efficacy for second-generation agents than for first-generation ones (Suh et al. 2004), and in all studies, the FGAs were associated with more EPS than the SGAs (Chan et al. 2001; De Deyn et al. 1999; Suh et al. 2004). The CATIE-AD study, lacking an FGA arm, could not add to these observations.

Side Effects of Antipsychotic Drugs In addition to modest efficacy, reports of serious side effects other than EPS and tardive dyskinesia have raised concerns regarding the use of antipsychotics as first-line treatments for agitation or aggression, with or without psychosis, in elderly populations. An initial report indicating an increased risk of cerebrovascular adverse events (CVAEs; e.g., stroke, transient ischemic attack [TIA], death) in male nursing home residents older than 85 years who were treated with risperidone (Wooltorton 2002) led to further investigation. Similar suggestive evidence was reported for olanzapine and ultimately for other SGAs (Kryzhanovskaya et al. 2006; Percudani et al. 2005; Wooltorton 2004). Taken together, these observations of increased CVAEs in elderly individuals receiving SGAs stimulated an examination of all studies, which supported concerns regarding a possible increased risk of CVAEs when either of these drugs is given to elderly patients with dementia. Data from 11 olanzapine or risperidone studies collectively suggested that 2.2% of drug-treated subjects experienced CVAEs, compared with 0.8% of placebo-treated subjects. The combined relative risk was 2.7. Ballard and Waite (2006) concluded that despite the modest efficacy of these drugs, the significance of the adverse events dictates that "neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is marked risk or severe distress." In 2003, the FDA issued a black box warning regarding a possible increased risk of CVAEs associated with use of atypical antipsychotics in older adults with dementia. The warning was eventually extended to include aripiprazole, olanzapine, and risperidone. The death rate in clinical trials was 3.5% with SGAs versus 2.3% with placebo, leading the FDA to impose a black box warning for all SGAs. Studies examining large public databases (Ballard and Waite 2006; Schneider et al. 2006) have found similar rates of death among elderly people receiving FGAs (Schneeweiss et al. 2007; Wang et al. 2005). The FDA warning has generated considerable controversy. Some researchers, examining the data on which the FDA's warning was based, have become concerned that methodological faults in many of the studies may have compromised the meta-analyses and led to an overly harsh interpretation of the data and an unwarranted concern for safety. Some studies failed to find an increase in death rate or incidence of CVAEs. For example, Herrmann et al. (2004), as well as Haupt et al. (2006) and Gill et al. (2005), found no significant increase in the risk of ischemic stroke with either FGAs or SGAs or among those receiving SGAs compared with FGAs. The American College of Neuropsychopharmacology has issued a White Paper (Jeste et al. 2008) concluding that further research data are needed to clarify the ongoing significance, if any, of increased development of CVAEs. An expert consensus conference held in 2006 (Salzman et al. 2008) essentially made the same point. Most recently, a retrospective study of 254 very frail patients with dementia (mean age = 86 years)

from seven nursing homes and two hospitals in Finland found that neither SGAs nor FGAs increased mortality (the use of SGAs actually should lower the risk of mortality) (Raivio et al. 2007). Clinicians currently struggle with a difficult treatment dilemma when confronted with an elderly patient with dementia who is possibly psychotic and whose behavior is characterized by extreme agitation and/or aggression that cannot be controlled without medications. The essential conclusion of the CATIE-AD study, and a sensible statement about the role of antipsychotics (Jeste et al. 2008; Salzman et al. 2008; Sink et al. 2005), was that on average, patients receive modest benefit without being harmed: these are the patients for whom continued therapy is rational. The following clinical conclusions appear to be warranted at this time: 1. Recognizing that the use of antipsychotic drugs to treat agitation or aggression is "off label," clinicians must be certain that the behavior cannot be managed nonpharmacologically and that the severity of the disruptive behavior warrants the selection of this class of drugs. If an FGA such as haloperidol is selected, doses should be kept low to minimize the likelihood of developing EPS. 2. SGAs are still preferred to FGAs because of the lower likelihood of EPS and tardive dyskinesia. 3. Clinicians should confer with the patient's family or significant others regarding the use of these drugs and should attempt to obtain some form of informed consent, balancing the possible risk of using these medications against the likelihood of worsening behavior and clinical status without such treatment. 4. Clinicians should follow these patients closely for early warning signs of a CVAE.

NON-ANTIPSYCHOTIC TREATMENT A growing body of clinical experience, research, and anecdotal reports suggests that agents such as trazodone, anticonvulsants (mood stabilizers), buspirone, serotonergic antidepressants, and cognitive enhancers may help manage a variety of agitated behaviors refractory to more conventional treatment. These drugs, however, are ineffective in treating symptoms of psychosis.

Benzodiazepines Although benzodiazepines are quite widely used in this population, there have been no studies of benzodiazepine treatment of agitation or aggression in nearly a decade. Most of the older studies were not placebo controlled, but they nonetheless suggested that on average, agitation could be reduced with short-term benzodiazepine therapy (Loy et al. 1999). For example, Coccaro et al. (1990) compared oxazepam (10–60 mg/day) with low-dose haloperidol in patients with mixed dementia diagnoses. Five percent of patients in the benzodiazepine group improved, compared with 24% of those in the haloperidol group, a difference that was not statistically significant, perhaps because of the small sample size. Christensen and Benfield (1998) compared alprazolam (0.5 mg twice daily) with haloperidol (0.6 mg/day) in a crossover study. Adverse events were not significantly different between groups. The dosages of both agents used in this study were probably too low to expect an effect, and none was seen. Meehan et al. (2002) noted that intramuscular lorazepam 1.0 mg or 0.5 mg was superior to placebo at 2 hours but not at 24 hours. Possible side effects of benzodiazepines given to elderly individuals include ataxia, falls, confusion, anterograde amnesia, sedation, light-headedness, and tolerance and withdrawal syndromes (Patel and Tariot 1995). This profile, along with the scant evidence of efficacy, suggests that use of benzodiazepines for agitation should be time limited or on an as-needed basis, with chronic use only for those patients in whom other agents have proven ineffective. Drugs with simpler metabolisms and relatively short half-lives, such as lorazepam, are always preferred.

Anticonvulsants (Mood Stabilizers) Although Chambers et al. (1982) reported no benefit of carbamazepine in a crossover study in 19 patients with agitation, most subsequent studies suggest that anticonvulsants are modestly helpful for controlling agitation and aggression in elderly individuals with dementia. In a placebo-controlled

crossover study in 25 agitated dementia patients, Tariot et al. (1994) reported improvement with carbamazepine. This was supported by a confirmatory parallel-group study of 51 patients in which the mean daily dosage was 300 mg (Tariot et al. 1998). Carbamazepine was well tolerated in both studies; sedation and ataxia were the most common side effects (Tariot et al. 1998, 2002). Another small (n = 21) placebo-controlled study of carbamazepine (400 mg/day) reported modest benefit. Adverse events were reported as mild (Olin et al. 2001). Despite these preliminary findings, there is a relative dearth of evidence of efficacy from controlled clinical trials. Given the high risk of drug–drug interactions with carbamazepine and the frequent side effects seen in other populations (including rashes, sedation, hematological abnormalities, hepatic dysfunction, and altered electrolytes), carbamazepine should not be considered a first-choice treatment in this population. Valproic acid, and its enteric-coated derivative divalproex sodium, has been the subject of a number of case reports or case series in patients with dementia and agitation, in which about two-thirds of patients with dementia and agitation have been described as clinically improved. The first randomized, placebo-controlled, parallel-group study of valproate was conducted as a precursor to a larger multicenter trial (Porsteinsson et al. 2001); a secondary measure of agitation showed improvement that was also seen in an open-label extension (Porsteinsson et al. 2003). Side effects seen with valproate included sedation, gastrointestinal distress, and ataxia, as well as the expected decrease in average platelet count (about 20,000/mm3). A small placebo-controlled crossover study of valproate used for aggressive behavior found no benefit on primary measures of aggression (Sival et al. 2002). There were no drug–placebo differences in rates or types of adverse events. A 6-week randomized, placebo-controlled multicenter study of divalproex sodium in 172 nursing home residents with dementia and agitation who also met criteria for secondary mania used a target dosage of 10 mg/kg/day for 10 days (Tariot et al. 2001b). There was a high dropout rate (n = 100 completers), with 19 divalproex sodium–treated patients (22%) and 3 placebo-treated patients (4%) withdrawing from the study because of adverse events, primarily somnolence (typically occurring at daily dosages 15 mg/kg).There were no significant drug–placebo differences in change in manic features, although a significant drug effect on agitation was seen. Sedation occurred in 36% of the drug group versus 20% of the placebo group, and mild thrombocytopenia occurred in 7% of the drug group versus none of the placebo-treated patients. There were no other significant drug–placebo differences in adverse effects. The results from this trial were used to amend prescribing information by cautioning against the use of similar high doses and/or titration rates in the elderly. The largest (n = 153) placebocontrolled trial prospectively addressing agitation, conducted by the Alzheimer's Disease Cooperative Study, found no benefit from divalproex (Tariot et al. 2005). In a comprehensive review, Sink et al. (2005) likewise failed to find benefit for divalproex, and they noted mixed results regarding the efficacy of carbamazepine in patients with dementia. A Cochrane review of valproate for agitation in dementia (Lonergan et al. 2004) concluded that low-dose valproate was ineffective and that high-dose valproate was associated with an unacceptable rate of adverse effects. There are no placebo-controlled studies of lamotrigine, gabapentin, or topiramate in the treatment of behavioral symptoms in dementia. Despite the absence of controlled studies, however, anticonvulsants are used in clinical practice when other drug treatments fail or are poorly tolerated. The greatest amount of clinical data are available for gabapentin, with almost all reports noting improvement in a majority (but not all) of the subjects. Dosages used ranged from 200 to 1,200 mg/day (Alkhalil et al. 2004; Goldenberg et al. 1998; Herrmann et al. 2000; Moretti et al. 2003; Roane et al. 2000). A review of case reports described worsening of behavior in Lewy body dementia patients who received gabapentin (Rossi et al. 2002). A small retrospective review of topiramate found that agent modestly helpful for aggressive behavior in dementia (Fhager et al. 2003). A single letter to the editor reported the usefulness of lamotrigine for the treatment of aggression in dementia (Devarajan and Dursun 2000). In an effort to develop more innovative clinical trial designs, as well as to address the public health

significance of psychopathology in Alzheimer's disease, the Alzheimer's Disease Cooperative Study organized the first multicenter trial addressing secondary prevention of psychopathology in Alzheimer's disease (Tariot et al. 2002). This multicenter study is examining whether valproate therapy can delay, attenuate, or prevent the emergence of agitation or psychosis in patients lacking these features at baseline. The design incorporates traditional measures of illness progression as secondary outcomes, based on the potential for neuroprotective effects of chronic administration, and may contribute to improved understanding of mechanisms of action of valproate therapy via use of biological markers selected for their relevance to mechanism of action as well as pathobiology of Alzheimer's disease. The study has completed enrollment and will end in early 2009.

Serotonergic Drugs Sink et al. (2005) found little overall evidence of efficacy for antidepressants in the treatment of neuropsychiatric symptoms other than depression. However, because depression, including irritability, is commonly seen in people with dementia, serotonergic antidepressants are often used in their treatment. The antidepressant drug trazodone has been reported to be effective in treating agitation and severely disruptive behavior (Greenwald et al. 1986; Nair et al. 1973; Pinner and Rich 1988; Simpson and Foster 1986; Tingle 1986), although these studies did not distinguish between psychotic and nonpsychotic patients. Extensive clinical experience suggests that trazodone is effective at dosages of 50–200 mg/day, with few side effects other than sedation. The mechanism of trazodone's effect is unknown. There have been two double-blind, controlled studies of trazodone in the treatment of dementia-associated agitation. The first was a brief crossover study in only 28 patients, comparing trazodone at a mean dosage of 220 mg/day with haloperidol at a mean dosage of 2.5 mg/day (Sultzer et al. 1997). Agitation improved equally in both drug groups, with better tolerability seen in the trazodone group. The Alzheimer's Disease Cooperative Study reported negative results for all active treatments in a multicenter outpatient study contrasting trazodone, haloperidol, placebo, and caregiver training (Teri et al. 2000). Although there is negative as well as positive evidence of trazodone's efficacy, clinical experience suggests that trazodone is often extremely helpful as an add-on medication when antipsychotics or other drugs alone cannot control disruptive behavior. Priapism is a rare side effect of trazodone in elderly men. Selective serotonin reuptake inhibitor (SSRI) antidepressants may also have modest antiagitation properties in elderly patients with dementia (Burke et al. 1997; Swartz et al. 1997). Citalopram (Kim et al. 2000; Pollock et al. 2002) and sertraline (Kaplan 1998), in particular, have demonstrated efficacy. In a double-blind study, citalopram was found to be effective, and superior to perphenzine, in treating behavioral disturbances in hospitalized elderly patients with dementia (Pollock et al. 2002). Sertraline in combination with a cognitive-enhancing medication (donepezil) was reported to decrease agitation, although a fulminant chemical hepatitis developed in one patient, necessitating discontinuation (Verrico et al. 2000). In contrast to these positive reports, Olafsson et al. (1992) failed to show the effectiveness of fluvoxamine in the treatment of behavioral disruption in elderly patients with dementia. One review suggested that when antipsychotics cannot be used, SSRIs should be considered first-line treatment (Burke et al. 1997), especially for verbal aggression (Ramadan et al. 2000). Further research of the antiagitation properties of the SSRIs is essential, however, because these antidepressants also tend to be activating and may actually increase agitation, especially in the late stages of a dementing illness. Buspirone, a nonbenzodiazepine antianxiety agent with effects at serotonin receptors, was reported to be effective in controlling disruptive behavior in older patients in one study (Colenda 1988) but not in another (Strauss 1988). No randomized, placebo-controlled, double-blind studies of buspirone have been conducted, and available studies were small in size. There is insufficient evidence to inform about dosing, titration, safety, tolerability, and efficacy. A small (n = 20) single-blind, placebo-

controlled trial reported improvement on measures of aggression, but only 60% of the 20 subjects completed that study (Levy et al. 1994). In a crossover study (n = 10) comparing buspirone with trazodone, Lawlor (1994) found no relative benefit of buspirone. Cantillon et al. (1996) compared buspirone 15 mg/day versus haloperidol 1.3 mg/day in a nursing home population with Alzheimer's disease (n = 26); they reported no significant benefit of either drug. Even when buspirone is effective, disruptive behavior may not decrease for 1 or 2 weeks at full therapeutic doses. Side effects are modest, although one elderly patient with dementia experienced oral dyskinesia that persisted for at least 4 months after symptom onset (Strauss 1988). An occasional patient may become more agitated. Research studies have not yet compared buspirone's effect with that of placebo or other drugs for treating agitation. The average total daily dosage range is 20–80 mg in divided doses.

Beta-Blockers -Blockers, given at low dosages (10–100 mg/day), have been used to reduce agitated and assaultive behavior in elderly patients (Greendyke et al. 1984; Petrie and Ban 1981; Sky and Grossberg 1994). Not all studies of

-blockers have yielded positive findings, however (Risse and Barnes 1986; Weiler et

al. 1988). Most evidence is derived from older reports in patients with nonspecific diagnoses (Tariot et al. 1995). Shankle et al. (1995) reported decreased aggression in 8 of 12 patients treated with low doses of propranolol (30–80 mg/day). Side effects of note include bradycardia, hypotension, worsening of congestive heart failure, and asthma.

-Blockers should be used only sparingly for this

purpose. Furthermore, these drugs can be given only to those elderly patients without cardiovascular disease and chronic obstructive pulmonary disease (particularly asthma). Typical side effects include sedation, orthostatic hypotension, and decreased cardiac output.

Hormones There are no rigorous studies of either estrogenic or antiandrogenic approaches, although roughly a dozen published anecdotes exist (Rosenquist et al. 2000). The available evidence suggests occasional benefit for hormonal agents, but this is unproven. A single case report (Kyomen et al. 1991) noted that estrogen (diethylstilbestrol 1 mg/day or conjugated estrogen 0.625 mg/day) reduced the number of incidents of physical aggression, but not of verbal aggression or physical or verbal repetitive behaviors, in elderly male patients with dementia. Medroxyprogesterone has been reported to rapidly and safely treat sexual acting-out behavior in elderly men with dementia (Cooper 1987).

Cognitive-Enhancing Drugs Cholinergic Agents As summarized by Cummings (2000), there is increasing evidence that cholinergic agents, especially cholinesterase inhibitors, may have modest behavioral benefits in some patients with dementia. However, most data come from multicenter studies primarily addressing cognitive or global outcomes, using behavioral measures as secondary outcomes. A prospective clinical trial of metrifonate versus placebo found modest average reductions in neuropsychiatric symptoms, as assessed with the Neuropsychiatric Inventory (NPI), in the drug group versus the placebo group (Morris et al. 1998). A retrospective analysis of two 26-week double-blind, placebo-controlled multicenter trials of metrifonate found a behavioral effect size of 15%, with significant improvement observed on measures of agitation/aggression and aberrant motor behavior as well as hallucinations, dysphoria, and apathy (Cummings et al. 2001; Raskind and Risse 1986). In a 5-month study of galantamine, Tariot et al. (2000) showed reduced symptoms of cognitive and attentional dysfunction on drug versus placebo in outpatients who generally lacked psychopathology at baseline. In a placebo-controlled trial of donepezil in nursing home residents with probable Alzheimer's disease complicated by behavioral symptoms, there was no evidence of improved

behavior on a global measure, although a secondary analysis showed some evidence of reduced agitation (Tariot et al. 2001a). Another study of donepezil in mild to moderate Alzheimer's disease found overall improvement, with modest improvement in behavioral symptoms (Holmes et al. 2004). A subsequent study, however, failed to find improvement in behavioral symptoms with rivastigmine (Ballard and Waite 2006). There appears to be no reliable evidence for the therapeutic effect of this drug on psychosis or behavioral symptoms of dementia and related behavioral disruption. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have each been reported to reduce restlessness in a small number of elderly individuals with Lewy body dementia (Herrmann et al. 2004; Maclean et al. 2001; Skjerve and Nygaard 2000).

Memantine Memantine, a noncompetitive inhibitor of N-methyl-D-aspartate (NMDA) receptors approved by the FDA for treatment of moderate to severe Alzheimer's disease, has been examined in several multicenter trials, none addressing behavior as a primary objective. A placebo-controlled study of memantine 10 mg/day in patients with severe dementia showed no benefit on the single behavior item that was used (Winblad and Poritis 1999). A subsequent placebo-controlled study of memantine 20 mg/day also did not find significant behavioral benefit (Reisberg et al. 2003). However, a study in which memantine or placebo was administered to patients already receiving donepezil found significant benefit from memantine on behavior (Cummings et al. 2006a, 2006b; Tariot et al. 2004). In a meta-analysis, Sink et al. (2005) found that cholinesterase inhibitors had a small but statistically significant benefit for behavioral symptoms, whereas memantine had no significant benefit. Trinh et al. (2003) also reported slight overall benefit from cholinesterase inhibitors in patients with mild to moderate Alzheimer's disease. More recently, modest behavioral benefits of memantine have been reported (Swanberg 2007; Winblad and Poritis 1999; Winblad et al. 2007), including data from unpublished trials. Memantine added to donepezil also has been shown to have modest benefit for behavioral disruption in Alzheimer's disease (Tariot et al. 2004). More research is needed on the use of these drugs for treatment of dementia-associated agitation.

CONCLUSION Good clinical care of the agitated and/or aggressive elderly patient with dementia requires careful appraisal of factors that may be contributing to the disruptive behavior. Special attention should be paid to recent changes in medical status, treatment with nonpsychiatric medications, and alterations in the environment (Jeste et al. 2008; Salzman et al. 2008). When psychiatric medications become necessary, clinicians now may choose among several classes of psychotropic agents: antipsychotic drugs, mood stabilizers, and serotonergic antidepressants. Available data would suggest that antipsychotic agents are still the first-choice class of drugs, especially for the most severely agitated and aggressive elderly person. This class of drugs, however, carries a potential increased risk of side effects, including extrapyramidal symptoms, cerebrovascular events (including stroke), and possibly premature death. Clinicians must endeavor to use these medications carefully, therefore, monitoring patients closely and informing family members (or significant responsible individuals) of these risks. Initial doses should be modest, with careful dose increments, following the geriatric maxim "Start low and go slow." Other recommended classes of psychotropic drug treatment, in order of preference, are mood stabilizers, serotonergic antidepressants, and cognitive enhancers. These medications are less reliably effective but lack the side effects of antipsychotic drugs. Clinical choice depends on the physical health, prior drug response, and vulnerability to side effects of the elderly individual. Future research will continue to elucidate the risks versus benefits of different classes of psychotropic drugs while also developing nonpharmacological approaches for the treatment of the common yet serious disruptive behavioral problems associated with dementia.

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Charles P. O'Brien, Charles A. Dackis: Chapter 58. Treatment of Substance-Related Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.434964. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 58. Treatment of Substance-Related Disorders TREATMENT OF SUBSTANCE-RELATED DISORDERS: INTRODUCTION Drugs that produce substance use disorders all activate the brain reward system, but each class of drugs activates the system by a different pharmacological mechanism. Thus, this chapter is organized according to pharmacological class. The emphasis is on pharmacotherapy, but all treatment using medications should be accompanied by counseling or psychotherapy according to the patient's needs. Medication combines very well with psychotherapy, including self-help groups such as Alcoholics Anonymous (AA). The majority of patients also have an additional mental disorder (besides the addictive disorder) such as depression, anxiety, or bipolar disorder. These comorbidities require specific treatment including medication and psychotherapy. The best treatments for addiction complicated by additional psychiatric disorders are delivered in an integrated fashion, preferably from the same therapist. All psychiatrists should be able to manage substance use disorders, especially those that co-occur with other psychiatric diagnoses.

ALCOHOL The 12-month prevalence of alcohol use disorders in the United States in the most recent epidemiological survey was 7.35%, and combined with other drug use disorders the total was more than 8.4% (Compton et al. 2007). Alcohol is the number one substance chosen by both adults and teenagers. The annual loss of life for all causes, but often through accidents, is over $185 billion per year. In a 2005 survey among twelfth-grade students, 53% had used alcohol in the past 30 days and 34% had been drunk during the same period (Johnston 2006). As with all substance use disorders, the best treatments involve a combination of psychotherapy and pharmacotherapy. A variety of medications have been used at the important stages of alcohol use disorder treatment. The first stage is detoxification, which means clearing of the alcohol from the body. After detoxification, the relapse prevention stage should be continued for months or even years.

Alcohol Detoxification Detoxification involves the clearing of alcohol from the body and the readjustment of all systems to functioning in the absence of alcohol. The alcohol withdrawal syndrome at the mild end may include only headache and irritability, but about 5% of alcoholic patients have severe withdrawal symptoms manifested by tremulousness, tachycardia, rapid respiration, and even seizures. The presence of malnutrition, electrolyte imbalance, or infection increases the possibility of cardiovascular collapse. Significant progress has been made in establishing safe and effective medications for alcohol withdrawal. Pharmacotherapy with a benzodiazepine is the treatment of choice for the prevention and treatment of the signs and symptoms of alcohol withdrawal. Many patients, however, detoxify from alcohol dependence without specific treatment or medications. It is difficult to determine accurately which persons require medication for alcohol withdrawal. Clinicians should learn to use a formal alcohol withdrawal scale such as the Clinical Institute Withdrawal Assessment (CIWA AD; Sellers et al. 2000) in order to rate the severity of withdrawal and the response to medication. Patients in good physical condition with uncomplicated mild to moderate alcohol withdrawal symptoms usually can be treated as outpatients.

A typical outpatient regimen requires the patient to attend the clinic daily for 5–10 days to receive clinical evaluations, multiple vitamins, and gradually decreasing benzodiazepine pharmacotherapy. A typical medication dosing regimen involves giving enough benzodiazepine on the first day of treatment to relieve withdrawal symptoms. The dose should be adjusted if withdrawal symptoms increase or if the patient complains of excessive sedation. Over the next 5–7 days, the dose of benzodiazepine is tapered to zero. Most clinicians use longer-acting benzodiazepines such as clonazepam, chlordiazepoxide, or diazepam. The usual starting dose of medication on the first day is 25–50 mg of chlordiazepoxide or 10 mg of diazepam given every 6 hours. In an outpatient setting, oxazepam may be particularly useful because it is associated with less abuse and does not require hepatic biotransformation, an important consideration for alcoholics with liver disease. The diagnosis of delirium tremens is given to patients who have marked confusion and severe agitation in addition to the usual alcohol withdrawal symptoms. It is important to remember that there is a risk of mortality approaching 5% in patients with severe alcohol withdrawal symptoms. Patients who have medically complicated or severe alcohol withdrawal must be treated in a hospital. Benzodiazepines usually will be sufficient to calm agitated patients; however, some patients may require intravenous medication to control extreme agitation.

Relapse Prevention All patients should be engaged in long-term outpatient care after detoxification. Referral to an AA group is often very useful, but this should not be expected to replace a case manager or therapist. A multipronged approach involving AA, counseling, and medication has the best chance of being successful. Three different kinds of medication have received U.S. Food and Drug Administration (FDA) approval.

Disulfiram In 1951, disulfiram (Antabuse) became the first medication to be approved by the FDA for the treatment of alcohol dependence other than detoxification. Disulfiram inhibits a key enzyme, aldehyde dehydrogenase, involved in breakdown of ethyl alcohol. After drinking, the alcohol–disulfiram reaction produces excess blood levels of acetaldehyde, which is toxic in that it produces facial flushing, tachycardia, hypotension, nausea and vomiting, and physical discomfort. The usual maintenance dosage of disulfiram is 250 mg/day. There have been only a few randomized, controlled trials of disulfiram, and these trials have had mixed results for drug efficacy (Peachy and Naranjo 1984). The most comprehensive trial was the Veterans Administration (VA) Cooperative Study of disulfiram treatment of alcoholism. This study was conducted with male veterans and found no differences between disulfiram, 250 mg/day and 1 mg/day (an ineffective dose), and placebo groups in total abstinence, time to first drink, employment, or social stability. Among patients who drank, those in the 250-mg disulfiram group reported significantly fewer drinking days (Fuller et al. 1986). The main problem with disulfiram is that frequently patients stop taking it and relapse to drinking (Goodwin 1992). Disulfiram is most effective when it is used in a clinical setting that emphasizes abstinence and offers a mechanism to ensure that the medication is taken. Drug compliance may be successfully ensured either by giving the medication at 3- to 4-day intervals in the physician's office or at the treatment center or by having a spouse or family member administer it.

Naltrexone Naltrexone is a specific opiate receptor antagonist developed for the treatment of heroin addiction. In animal models of alcohol drinking, it was found to reduce the self-administration of alcohol. Beginning in 1983, it was tested as an adjunctive therapy for alcoholism and was found to prevent relapse in some, but not all, patients (Volpicelli et al. 1990, 1992).

After replication of these findings by other researchers (O'Malley et al. 1992), naltrexone was approved by the FDA for use in alcoholism. The first use of naltrexone was to test the hypothesis that at least a part of the reward from alcohol is mediated by the endogenous opioid system. Studies in animal models and in humans have supported that hypothesis (Volpicelli et al. 1995). There have also been reports of reduction in alcohol craving (O'Malley et al. 2002). Alcoholics in treatment get no adverse effects if they drink alcohol while on naltrexone, but they frequently report that it is no longer rewarding. In 2006, the FDA approved an extended-release depot version of naltrexone that is effective with only one injection per month. This is a major treatment advance because the requirement of daily dosing of the oral form led to poor adherence and more relapse. Of course, opioid peptides may not be the only brain system involved in alcohol reinforcement. Norepinephrine, dopamine, serotonin, and -aminobutyric acid (GABA) may also be involved in alcohol craving and consumption. Medications aimed at these neurotransmitters are currently in development.

Acamprosate Another FDA-approved pharmacotherapy for alcohol dependence is acamprosate, whose chemical name is calcium acetyl homotaurinate. Structurally, acamprosate is similar to the amino acid taurine and has been shown to have several actions on the GABA–N-methyl-D-aspartate (NMDA) complex. Acamprosate has been reported to be a safe and effective treatment for alcoholism in several controlled studies. In 1985, Lhuintre et al. published the results of a double-blind study in which 85 subjects, described as severely alcoholic, were randomly assigned to 3 months of treatment with either acamprosate or placebo. Seventy subjects completed the trial, and of these, 20 of 33 (61%) acamprosate-treated subjects and 12 of 37 (32%) placebo-treated subjects were abstinent during the study. Positive results were reported for two subsequent placebo-controlled trials (Lhuintre et al. 1990; Paille et al. 1995) in which the total number of abstinent days was higher for acamprosatetreated subjects compared with placebo-treated subjects. In 1996, the reports of two German doubleblind, placebo-controlled studies were published. In the first trial, Sass et al. (1996) studied 272 subjects randomly assigned to a year of treatment with either acamprosate or placebo and evaluated for an additional 12 months following the discontinuation of study medication. Compared with placebo-treated subjects, the subjects who received acamprosate had a significantly lower dropout rate, a greater number of days before their first drink, and a greater number of days of total abstinence during the study. The second study, which had a similar design, involved 455 subjects and was conducted by Whitworth et al. (1996). The results of this trial were that acamprosate was superior to placebo with respect to the number of dropouts, relapse rate, and total days of abstinence. Interestingly, 18% of the acamprosate-treated subjects, compared with 7% of the placebo-treated subjects, remained continuously abstinent a year after discontinuation of study medication. Subsequently, acamprosate was studied in a multiclinic trial in the United States (Mason and Ownby 2000) and in a large National Institutes of Health–sponsored trial comparing acamprosate, naltrexone, and placebo (Anton et al. 2006). Although acamprosate trials in the United States have not been positive, the clear results of the European trials were sufficient to merit FDA approval in 2004.

Alcoholism With Other Coexisting Mental Disorders Depression commonly occurs in alcoholic individuals. The above anticraving medications can be used in combination with all antidepressants, including monoamine oxidase inhibitors (MAOIs), if they are otherwise indicated. Antidepressants alone have not been found to be consistently useful in reducing drinking, but in depressed persons with alcoholism, they are effective in improving mood and overall well-being.

NICOTINE According to the 2000 National Household Survey, an estimated 65.5 million Americans, or 29% of the

population, reported current use of tobacco. Most tobacco users, 55.7 million, smoked cigarettes, whereas the remainder smoked cigars and pipes or used smokeless tobacco (Substance Abuse and Mental Health Services Administration 2001). Tobacco accounts for approximately 400,000 deaths per year. Since the mid-1960s, the incidence of smoking in the United States has progressively decreased by about 1% per year (Substance Abuse and Mental Health Services Administration 2001). This remarkable change in tobacco use is a consequence of the realization by society that tobacco-related mortality and morbidity are entirely preventable. Most of these smokers have symptoms that meet the DSM-IV-TR (American Psychiatric Association 2000) criteria for the substance use disorder nicotine dependence. The behavioral aspects of nicotine dependence are similar to those for alcohol and opiate dependence, as well as the production of tolerance and physical dependence. In about 80% of smokers (Gross and Stitzer 1989), nicotine abstinence leads to well-described withdrawal signs and symptoms (Hughes and Hatsukami 1986). Pharmacotherapy in the form of nicotine replacement has been a key element in reducing withdrawal symptoms and initiating smoking cessation. More recently, nonnicotine medications that can be used in combination with nicotine replacement have become available.

Nicotine Replacement Nicotine replacement can be obtained over the counter in the form of gum, patch, or nasal spray. Nicotine replacement reduces irritability and withdrawal symptoms such as sleep disturbance, difficulty concentrating, and restlessness. Transdermal nicotine is initially administered in 15- to 21-mg patches for 4–12 weeks, followed by lower-dose patches for up to another 8 weeks. Transdermal nicotine also has excellent documentation for its ability to decrease the severity of withdrawal symptoms and also to decrease craving for tobacco (Daughton et al. 1991; Tonnesen et al. 1991). Neither gum nor transdermal nicotine has any long-term effect in preventing weight gain after cessation of smoking. Both nicotine preparations provide a significant advantage over placebo in smoking cessation. Stitzer (1991) reviewed seven double-blind, placebo-controlled smoking cessation trials in which nicotine gum was used. Abstinence rates at 4–6 weeks were 73% for nicotine gum compared with 49% for placebo gum. Most of the transdermal nicotine double-blind studies were reviewed by Palmer et al. (1992), who found that quit rates at 4–6 weeks were 39%–71% for transdermal nicotine compared with 13%–41% for the placebo patches. The FDA approved nicotine gum in 1981 and transdermal nicotine in 1991 as prescription medications, and in 1996 both were approved for over-the-counter (nonprescription) use. Beyond the initiation of abstinence, nicotine preparations are associated with a progressive relapse to smoking. After 1 year, abstinence rates are about 25% for the nicotine gum and patch compared with 12% for placebo (Benowitz 1993). The nasal spray and the inhaler are preparations that provide rapid-release forms of nicotine. The potential advantage of these rapid-release preparations is that they closely simulate smoking by providing a rapid plasma concentration and oral and sensory stimulation. The results from the initial trials for the nasal spray (Schneider et al. 1995; Sutherland et al. 1992) and the inhaler (Tonnesen et al. 1993) are similar to those for the gum and patch.

Nonnicotine Pharmacotherapies Bupropion, a monocyclic antidepressant that has noradrenergic and dopaminergic effects, was approved by the FDA as a pharmacotherapeutic agent for smoking cessation. Bupropion reduces craving for nicotine, but the mechanism by which this occurs is not well understood. The results from several studies indicate that the bupropion anticraving effect is related to its action on central nervous system dopamine (Covey et al. 2000). In an initial double-blind trial (Ferry et al. 1992) in which 42 men were randomly assigned to 12 weeks of treatment with bupropion 300 mg/day or placebo, the results showed significantly longer continuous abstinence for bupropion-treated subjects at the end of

treatment, as well as 6 and 12 months after treatment. Hurt et al. (1997) conducted a study that clearly established the efficacy of bupropion as pharmacotherapy for nicotine dependence. The trial involved 615 nondepressed subjects (50% female) who were randomized to either bupropion 300 mg/day or placebo for an 8-week medication phase. At 1 year, the smoking cessation rate was 23% for the bupropion group compared with 12% for the placebo group. Jorenby et al. (1999) reported on a multisite smoking study with 893 subjects in which placebo, bupropion, nicotine patch, and bupropion plus nicotine patch were compared for efficacy as pharmacotherapy for nicotine dependence. The 12-month abstinence rates were 15.5% for placebo, 16.4% for nicotine patch, 30.3% for bupropion, and 35.5% for bupropion plus nicotine patch. Bupropion, alone or in combination with the nicotine patch, was superior to the nicotine patch or placebo. Bupropion has also been found to be useful in adolescent smokers, a time of great vulnerability to addiction (Killen et al. 2006). Varenicline is the newest medication that was approved in 2006 by the FDA as an aid to smoking cessation. It is an

4,

2 nicotinic acetylcholine receptor partial agonist. Laboratory data suggest that

this receptor is involved in the reinforcing effects of nicotine through activation of the brain reward system. Varenicline was tested against bupropion and placebo in two identical multisite studies. In one study (Gonzales and Weiss 1998) of 1,025 smokers, those randomized to varenicline had significantly greater abstinence rates (44%) at 12 weeks than placebo- or bupropion-treated patients. Continuous abstinence to 52 weeks was 29.1% for varenicline, 16.1% for bupropion, and 8.4% for placebo. In the second study (Jorenby et al. 2006), the varenicline group also had significantly greater abstinence rates than the placebo or bupropion groups by week 12, and the rates of continuous abstinence to 52 weeks were 23% for varenicline, 14.6% for bupropion, and 10.3% for placebo. Thus, the clinician has three pharmacotherapy options to aid in smoking cessation, along with a behavioral treatment program.

Smoking and Psychiatric Disorders The incidence of smoking in persons who abuse alcohol, stimulants, and opiates is about 90%; however, compared with the other two groups, alcoholic patients smoke the most cigarettes (Burling and Ziff 1988). Many of those who work with psychiatric patients have observed that cigarette smoking is extremely common among patients with schizophrenia. Research not only supports this observation but also clearly shows the extraordinarily high rate of smoking in schizophrenic inpatients and outpatients. Goff et al. (1992) studied schizophrenic outpatients and found that 74% smoked, compared with a national average of less than 30%. Between 80% and 90% of a group of institutionalized schizophrenic patients were found to smoke (Matherson and O'Shea 1984). There is no known reason for the high rate of nicotine use by schizophrenic patients. Some have speculated that the dopamine-augmenting effect of nicotine may counterbalance a relative dopamine deficiency that exists in schizophrenic patients (Glassman 1993). However, nicotine-induced changes in other neurotransmitters (e.g., serotonin) (Benwell and Balfour 1982) may help to explain why so many schizophrenic patients smoke. Also, there is speculation that nicotine ameliorates the cognitive deficits in schizophrenia (Sacco et al. 2005). Further research is needed to understand nicotine's involvement in the pathophysiology of schizophrenia. It is not unreasonable to expect that future antipsychotics not only will ameliorate psychiatric symptoms but also may decrease nicotine dependence in schizophrenic patients. Glassman et al. (1988) conducted pioneering research establishing the link between major depression and cigarette smoking. Based on data from the Epidemiologic Catchment Area (ECA) survey (Regier et al. 1984), they found that 76% of persons with a lifetime history of major depression "had ever smoked" compared with 52% of persons without a depression history. Similarly, the incidence of depression was 6.6% in smokers compared with 2.9% in nonsmokers, and smokers with a history of depression had a low rate of cessation. These findings have been replicated by several investigators,

and the association between depression and smoking is well supported. Another observation is that depressive symptoms appear during smoking cessation in persons with a history of depression (Covey et al. 1990). These researchers also found that alcoholism had the highest association with smoking. Smoking rates among persons with anxiety disorders are at least twice those of persons without a psychiatric diagnosis. It is unclear what role smoking plays in psychopathology of these disorders. There is some information supporting smoking in these populations as a maladaptive coping strategy (Revell et al. 1985). Future research on smoking in these targeted psychiatric populations may indicate the most efficient treatment approaches for patients who suffer from a combination of nicotine dependence and another psychiatric disorder. Ignoring the nicotine addiction in psychiatric patients, however, is no longer considered acceptable practice.

BENZODIAZEPINES AND OTHER SEDATIVES The benzodiazepines have largely replaced older sedative-hypnotic agents, such as barbiturates and meprobamate, in clinical use. To a great extent, the benzodiazepines are popular because they are safe in overdose situations and because, when first marketed, they were thought to have no (or almost no) abuse potential. Clinical experience and scientific study have since shown that although the benzodiazepines, as a class of drugs, are certainly safer in isolated overdose situations than the older agents, physiological dependence is possible and occurs with long-term use, even at therapeutic doses. These findings have touched off a controversy that has yet to be settled. Most patients who are, in fact, physiologically dependent on benzodiazepines do not increase the dose of medication above the physician's prescription or in any other way abuse the prescribed medication. However, if the benzodiazepine were to be abruptly discontinued, the patient would, in all probability, experience a withdrawal abstinence syndrome that could be extremely severe (O'Brien 2005). For instance, abrupt discontinuation of high therapeutic doses of alprazolam has frequently been reported to cause seizures. Thus, any patient receiving a benzodiazepine for a significant length of time, that is, longer than 3–6 months, should be slowly tapered off his or her medication; this does not preclude the possibility of reemergence of the patient's anxiety symptoms, which may necessitate continued use of the medication. The fact that patients become physiologically dependent on therapeutic doses of benzodiazepines has led some people in the field to equate any use of benzodiazepines in any patient for long-term treatment with abuse of the drug. This is undoubtedly an overstatement of the abuse of these agents. Significant abuse of benzodiazepines does, in fact, occur but is usually seen in patients abusing other drugs also, not in patients who are carefully monitored and are stable taking therapeutically indicated benzodiazepines. In general, patients who abuse only benzodiazepines are rare; benzodiazepine abuse in combination with abuse of other drugs is much more common. Alcoholic patients will not infrequently abuse benzodiazepines if the opportunity presents, and patients who abuse cocaine and opioids are also likely to use benzodiazepines concomitantly. Studies in alcoholic patients admitted for detoxification have shown that the rate of benzodiazepine use among these patients is between 28% and 41%, as determined by urinalysis (Crane et al. 1988; Ogborne and Kapur 1987; Soyka et al. 1989); generally only about one-third of the patients with a positive urine test result for benzodiazepines admitted to using the drugs. A variety of studies from Europe have examined benzodiazepine use in patients who use illicit opioids and have found that up to 90% of patients use benzodiazepines to some extent, although most patients deny that they use benzodiazepines or state that they use them to mitigate insomnia or anxiety or to reduce withdrawal symptoms. Methadone-maintained patients often use benzodiazepines, but generally on a sporadic basis. Magura

et al. (1987) showed that 40% of patients in four methadone programs in New York had urine test results that were positive for benzodiazepines, whereas studies in England showed rates of benzodiazepine-positive urine test results of 54% (Lipsedge and Cook 1987) and 59% (Beary et al. 1987) in methadone-maintained patients. In patients who use benzodiazepines in conjunction with other drugs, the issues of abuse and physiological dependence take on a much different meaning than in stable patients taking long-term prescribed benzodiazepines. If these patients use or abuse more than one substance, the use or abuse of benzodiazepines can seriously interfere with drug abuse treatment for other substances; for example, the patient may be discharged from his or her methadone maintenance program for having urine test results that are consistently positive for illicit benzodiazepines. These patients require detoxification from benzodiazepines, with either a benzodiazepine or a phenobarbital taper; evaluation for underlying psychiatric disorders such as generalized anxiety or panic disorder; and relapse prevention techniques for benzodiazepine abuse.

COCAINE Cocaine abuse in the United States reached epidemic status in the early 1980s. Over the next decade, cocaine use initially decreased and then stabilized. In 2000, an estimated 1.2 million Americans age 12 years and older were current cocaine users. The estimated number of current crack users in 2000 was 265,000 (Substance Abuse and Mental Health Services Administration 2001). According to data from the 2000 Drug Abuse Warning Network (DAWN) Report, cocaine was the illicit substance most frequently associated with hospital emergencies (Substance Abuse and Mental Health Services Administration 2001). In 2000, the rate of cocaine mentions was 71 per 100,000 population. This rate has remained essentially the same since 1994. The selection of potential pharmacotherapies has been based on the current understanding of the neurochemical changes that result from chronic stimulant use (see Chapter 49, "Neurobiology of Substance Abuse and Addiction"). Cocaine administration results in increased levels of dopamine in the region of the nucleus accumbens in rats, which is an important part of the brain reward pathways. Cocaine and other abused substances that increase nucleus accumbens dopamine also decrease the threshold for brain stimulation reward (Kornetsky and Porrino 1992) and increase the threshold during cocaine withdrawal after chronic cocaine (Koob et al. 2004). A large number of human imaging and animal model studies demonstrate that chronic cocaine exposure dysregulates dopamine function in reward-related brain regions (Dackis and O'Brien 2003). Pharmacotherapy for cocaine dependence must be considered separately from pharmacotherapy used to treat complications involved in cocaine abuse such as depression and psychotic reactions. Gawin and Kleber (1986) initially described a three-phase cocaine withdrawal syndrome consisting of crash, withdrawal, and extinction. Although this description of cocaine withdrawal found quick acceptance by many clinicians, it was not observed to be valid in several inpatient trials (Miller et al. 1993; Satel et al. 1991; Weddington et al. 1990). In these trials, only mild abstinence symptoms, including depression, anxiety, fatigue, and impaired concentration, were found; the symptoms declined in a linear fashion over the course of 1–2 weeks (Satel et al. 1991; Weddington et al. 1990). However, despite the fact that cocaine withdrawal is not considered to be medically significant, cocaine withdrawal symptom severity is important because of its predictive value. Kampman et al. (2004b) used an instrument called the Cocaine Selective Severity Assessment to measure cocaine withdrawal symptom severity. They found that cocaine withdrawal symptom severity at the start of treatment predicted outcome in several trials. Severe cocaine withdrawal may result from cocaine-induced neuroadaptations and may identify patients with more persistent hedonic dysregulation (Dackis 2005). Over the past three decades, many agents have been tested and demonstrated to be ineffective as treatments for cocaine dependence. It is noteworthy that dopamine antagonists actually destabilize cocaine-addicted individuals (Grabowski et al. 2000; Kampman et al. 2003), perhaps by exacerbating

cocaine-induced dopamine dysregulation. Conversely, the dopamine-enhancing agents disulfiram and modafinil promoted abstinence in controlled trials (Carroll et al. 2004; Dackis et al. 2005). Modafinil also blunted cocaine-induced euphoria in three controlled human laboratory studies (Dackis et al. 2003; Myrick et al. 2004; Hart et al. 2006) and is under current investigation in three large clinical trials. Advances in the neurobiology of cocaine dependence have guided medication development by identifying neuronal mechanisms associated with specific aspects of cocaine dependence, such as euphoria, withdrawal, and cue-induced craving (Dackis 2005). While dopamine-enhancing agents may reverse neuroadaptations that interfere with the attainment of abstinence, GABA-enhancing agents may prevent relapse in abstinent patients by dampening cue-induced craving, which is a persistent clinical phenomenon that leads directly to recidivism. Topirimate, a GABA-enhancing agent, may promote abstinence by dampening cue-induced craving (Kampman et al. 2004a). Similarly, modafinil and vaccines that reduce cocaine's entry into the brain may promote abstinence by blocking cocaine-induced euphoria (Sofuoglu and Kosten 2005). The lack of success in identifying an effective medication for treating cocaine dependence has not dampened scientific enthusiasm or impeded further research. On the contrary, there is renewed interest in studying various methods of altering the physiological effects of cocaine. One promising type of relapse prevention pharmacotherapy is not a medicine but a vaccine capable of stimulating the production of cocaine-specific antibodies. Several cocaine vaccines are under development. One of these vaccines, called TACD, works by stimulating the production of cocaine-specific antibodies that bind to cocaine molecules and prevent them from crossing the blood–brain barrier. Because cocaine is inhibited from entering the brain, its euphoric and reinforcing effects are reduced. Cocaine itself is too small a molecule to provoke an immune response, so the vaccine attaches a large protein molecule to a cocaine molecule, thus allowing the immune system to recognize cocaine and produce antibodies against it. TACD can stimulate the production of cocaine-specific antibodies in rats and mice, and the vaccine is effective in reducing cocaine self-administration in rodent models (Fox et al. 1996; Kantak et al. 2000). TACD was administered to 34 former cocaine users in a Phase I trial. The vaccine was well tolerated, and dose-related levels of anticocaine antibodies were detected (Kosten et al. 2002; Martell et al. 2005).

METHAMPHETAMINE In recent years, methamphetamine abuse has become a severe problem, especially in Hawaii and western continental United States. Methamphetamine is a stimulant that possesses stronger dopamine augmentation than cocaine and for a longer duration. While cocaine temporarily blocks dopamine reuptake at synapses, amphetamines also reverse the transporter, thus releasing even more of the neurotransmitter into synapses. Amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate, and diethylpropion all produce behavioral activation similar to that of cocaine. Intravenous or smoked methamphetamine produces an abuse/dependence syndrome similar to that of cocaine, but paranoid psychosis appears to be more common with amphetamine abuse. A different picture arises when oral stimulants are prescribed in a weight reduction program. These drugs do reduce appetite, with accompanying weight loss, on a short-term basis, but the effects diminish over time as tolerance develops. In rodents, there is a rebound of appetite and weight gain when amphetamine use is stopped. In obese humans, weight loss after amphetamine treatment is usually temporary. Anorectic medications, therefore, are not considered to be a treatment for obesity by themselves but rather a short-term adjunct to behavioral treatment programs. Drug abuse manifested by drug-seeking behavior occurs in only a small proportion of patients given stimulants to facilitate weight reduction. No medication has yet achieved FDA approval for the treatment of methamphetamine addiction, but several that have received positive reports in cocaine addiction treatment such as modafinil are

currently in clinical trials for methamphetamine (Ling et al. 2006).

OPIOIDS Pharmacotherapy for opioid dependence has a long history, in part because "heroinism" was one of the first recognized drug problems in the United States and because therapeutically used congeners of the drug of abuse, heroin, were readily available. Later studies have shown only limited success with nonpharmacological treatment.

Detoxification From Opioid Dependence The classical method of opioid detoxification was, and remains, short-term substitution therapy. The medication traditionally used has been methadone, at a sufficient dose to suppress signs and symptoms of heroin withdrawal; the methadone is then tapered over a period ranging from 1 week to 6 months. The idea behind a rapid (i.e., 1- to 2-week) detoxification regimen is to achieve total opioid abstinence quickly so that treatment can be continued in a drug-free setting. Detoxification usually can be accomplished in 4–7 days in an inpatient setting, whereas more time is often required in the outpatient setting to minimize patient discomfort. Most practitioners consider 21 days sufficient for short-term outpatient detoxification. However, many patients have very chaotic lives when presenting for treatment and require a period of stabilization before they can hope to maintain a drug-free lifestyle. There is no evidence that more rapid detoxification leads to better long-term outcomes. As discussed below, the regulations for opioid treatment facilities require that patients be dependent on opioids for at least 1 year before they may be admitted to methadone maintenance. The 6-month stabilization/detoxification regimen allows these patients to work on the most acute personal and employment problems while they are stabilized at a relatively low dosage (30–40 mg/day) of methadone and then are detoxified from methadone to continue treatment in a drug-free setting. Unfortunately, the relapse rate after detoxification and drug-free counseling is very high, and long-term maintenance on medication is usually necessary. The partial opiate agonist buprenorphine received FDA approval in 2002 for the treatment of opioid withdrawal and for maintenance. A major change in the U.S. approach to addiction treatment occurred with passage of a law in 2000 that allows physicians who have a special federal certification to prescribe buprenorphine in their office rather than limiting access, as is the case with methadone. Buprenorphine has been studied for efficacy in suppressing withdrawal signs and symptoms. In outpatient trials, Bickel et al. (1988) showed that buprenorphine was as effective as methadone in a 10-week double-blind trial (4 weeks on medication taper followed by 6 weeks of placebo). In an open trial, Kosten and Kleber (1988) compared three doses of buprenorphine and found that 4 mg, administered sublingually, was superior to 2 or 8 mg in suppressing signs and symptoms of withdrawal, although illicit opiates were present in the urine of approximately equal numbers of patients in both the 2-mg and the 4-mg dose groups. There has always been concern about substitution detoxification on the basis that the physician is prolonging the problem by prescribing an addictive medication, even with a tapering regimen. Many of the symptoms of opioid withdrawal (e.g., diaphoresis, hyperactivity, and irritability) appear to be mediated by overactivity in the sympathetic nervous system. This led Gold et al. (1978, 1980) to attempt to depress this overactivity and thereby ameliorate the withdrawal abstinence syndrome by using adrenergic agents that have no abuse potential. Clonidine, an

-adrenergic agonist with

inhibitory action primarily at an autoreceptor in the locus coeruleus, was effective in inpatient populations in decreasing the signs and symptoms of opioid withdrawal. Outpatient detoxification with clonidine has not been as successful as inpatient treatment. Inpatient studies reported an 80%–90% success rate, whereas outpatient studies reported success rates as low as 31% in detoxifying patients from methadone and 36% in detoxifying patients from heroin. The problems identified in outpatient clonidine detoxification include 1) access to heroin and other opioids, 2) lethargy, 3) insomnia, 4)

dizziness, and 5) oversedation. The last four adverse effects were noted in inpatient populations during detoxification with clonidine but were easily managed in the hospital setting. Because the side effects of clonidine were unacceptable to many patients, other

-adrenergic agonists

have been investigated for use in detoxifying opioid-dependent patients. Lofexidine is widely used for this purpose in the United Kingdom and is in clinical trials in the United States (Gerra et al. 2001). Ultrarapid detoxification under general anesthesia has been used in some settings with claims of a painless and rapid method to attain the opiate-free state. A randomized comparison of this procedure with a standard buprenorphine detoxification was conducted, and the results showed no advantage for the ultrarapid procedure (Collins et al. 2005). The major hurdle for the treatment of opiate addiction is prevention of relapse, and the method or duration of the detoxification makes no difference.

Maintenance Treatment of Opioid Dependence Methadone maintenance has been the mainstay of the pharmacotherapy for opioid dependence since its introduction by Dole and Nyswander (1965). Since the 1970s, levo- -acetylmethadol (LAAM), a long-acting congener of methadone, has been used experimentally for maintenance treatment. It was approved by the FDA for this purpose in 1993 but was later withdrawn from the U.S. market by the pharmaceutical company because of concerns about possible cardiac arrhythmias. With the availability of buprenorphine in 2002, there are again two options for agonist maintenance treatment: methadone and buprenorphine.

Methadone As discussed earlier in this chapter, methadone has been used for both short- and long-term detoxification from opioids. Methadone maintenance, however, is designed to support patients with opioid dependence for months or years while the patient engages in counseling and other therapy to change his or her lifestyle. Experience with methadone encompassing approximately 1.5 million person-years strongly showed methadone to be safe and effective (Gerstein 1992). Furthermore, this experience has shown that although patients on methadone maintenance show physiological signs of opioid tolerance, there are minimal side effects, and patients' general health and nutritional status improve. This approach to the treatment of opioid dependence has been controversial since its beginning. Physicians and other treatment professionals who consider addiction to be a brain disease have little or no problem treating patients with an active drug for long periods of time, especially in light of repeated treatment failures in the absence of active medication therapy. However, many people view methadone maintenance as simply substituting a legal drug for an illegal one and refuse to accept any outcome other than total abstinence from all drugs. These people point to long-term follow-up studies of methadone maintenance patients (see Maddux and Desmond 1992) that show that only 10%–20% of the patients are completely abstinent (defined as not being enrolled in methadone maintenance and not using illicit opioids) 5 years after discharge from the maintenance program. However, long-term follow-up studies of patients discharged from drug-free treatment programs show that only 10%–19% of opioid-dependent patients are abstinent at 3- or 5-year time points (see Maddux and Desmond 1992) when the same definition is used. The DSM course specifier "on agonist therapy" applies to those patients who do well on methadone or buprenorphine while continuing the medication and do not use illegal drugs. Outcome studies conducted with patients in maintenance treatment consistently show that these patients have marked improvement in various measures. Investigators have shown up to an 85% decrease in criminal behavior, measured by self-report or arrest records. Employment among maintenance patients ranges from 40% to 80%. Gerstein (1992) quoted a Swedish study published in

1984 showing the results over 5 years in 34 patients who applied for treatment to the only methadone clinic in Sweden at the time. The 34 patients were randomly assigned to either methadone maintenance or outpatient drug-free therapy; the patients in drug-free treatment could not apply for methadone for a minimum of 24 months after being accepted into the study. After 2 years, 71% of the methadone patients were doing well, compared with 6% of the patients admitted to drug-free treatment. After 5 years, 13 of 17 (76%) patients remained on methadone and were free of illicit drugs, whereas 4 of 17 (24%) patients had been discharged from treatment for continued drug use. Of the 17 drug-free treatment patients, 9 (53%) had subsequently been switched to methadone treatment, were free of illicit drug use, and were "socially productive." Of the remaining 8 patients, 5 (63%) were dead (allegedly from overdose), 2 (25%) were in prison, and 1 (13%) was drug free. Furthermore, although previous generations of drug abusers had hepatitis B, endocarditis, and other infections, in this age when injection drug use and concomitant sharing of needles and syringes place a patient at risk for HIV infection, the medical consequences of heroin dependence must be taken into account when determining appropriate therapy for a patient. These issues are currently being studied by a variety of methods, but the overall clinical impression of increased general health in methadone maintenance patients is very strong. Additionally, Metzger et al. (1993) undertook a study of HIV seroconversion rates in opioid-dependent subjects. In this study, 152 subjects were in methadone maintenance treatment and 103 subjects were out of treatment. At baseline, 12% of the subjects were HIV positive (10% of in-treatment and 16% of out-of-treatment subjects); follow-up of HIV-negative subjects over 18 months showed conversion rates of 3.5% for in-treatment subjects and 22% for those remaining out of treatment. These data suggest that although transmission of HIV still occurs, opioid-abusing injection drug users in methadone maintenance programs have a significantly lower likelihood of becoming infected than do patients who are not in treatment. Methadone maintenance programs in the United States are accredited by agencies such as Joint Commission on Accreditation of Healthcare Organizations, approved under regulations by the Center for Substance Abuse Treatment (CSAT) in the Substance Abuse and Mental Health Services Administration (SAMHSA) of the Department of Health and Human Services and the Drug Enforcement Agency (DEA). A program must be accredited and its physicians licensed for a methadone maintenance program in order to prescribe or dispense more than a 2-week supply of any opioid to a patient known or suspected to be dependent on opioids. Most clinics treat ambulatory outpatients and are open 6–7 days per week, requiring patients to come into the clinic daily to receive medication unless and until a patient has "earned" privileges (take-home medication) by compliance with the clinic rules and abstinence from illicit substances. For a person to be eligible for methadone maintenance, he or she must be at least 18 years old (or have consent of the legal guardian) and must be physiologically dependent on heroin or other opioids for at least 1 year. The treatment regulations define a 1-year history of addiction to mean that the patient was addicted to an opioid narcotic at some time at least 1 year before admission and was addicted, either continuously or episodically, for most of the year immediately before admission to the methadone maintenance program. A physician must document evidence of current physiological dependence on opioids before a patient can be admitted to the program; such evidence may be a precipitated abstinence syndrome in response to a naloxone challenge or, more commonly, signs and symptoms of opioid withdrawal, evidence of intravenous injections, or evidence of medical complications of intravenous injections. Exceptions to these requirements are patients who have recently been in penal or chronic care, previously treated patients, or pregnant patients; in these cases, patients need not show evidence of current physiological dependence, but the physician must justify their enrollment in methadone maintenance. A person younger than 18 years must have documented evidence of at least two attempts at short-term detoxification or drug-free treatment (the episodes must be separated by at least 1 week) and have the consent of his or her parent or legal guardian. Dosage of methadone is an important variable and should be adjusted according to the level of

physical dependence. A careful study of performance of methadone programs showed continued heroin use among low-dose patients. Among patients receiving at least 71 mg/day of methadone, no heroin use was detected, whereas patients receiving 46 mg/day of methadone or lower were five times more likely to use heroin than those receiving higher doses (Ball and Ross 1991). Furthermore, McLellan et al. (1993) showed, in a comparison of three levels of treatment services in which all patients received at least 60 mg/day of methadone, that "enhanced methadone services" patients (methadone plus counseling and on-site medical/psychiatric, employment, and family therapy) had fewer positive urine test results for illicit substances than did patients in the "standard services" (methadone plus counseling) group or the "minimum services" (methadone alone) group. The standard services group did significantly better in treatment than did the minimum services group, and in fact, 69% of the minimum services group required transfer to a standard program 12 weeks into the study because of unremitting use of opioids or other illicit drugs. Yet another issue that has engendered a great deal of controversy is the treatment of opioid dependence in pregnant women. Those who are philosophically opposed to methadone treatment would advocate that any woman using illicit opioids (heroin) or enrolled in methadone maintenance who became pregnant should be detoxified. It is currently estimated that up to 3% of infants born each year have had intrauterine exposure to opioids. Because many women with substance abuse problems fear all organizations, including medical ones, they frequently have little or no prenatal care, exposing themselves and their babies to the complications of unsupervised pregnancy in addition to the severe stressor of maternal addiction. The complications and treatment of maternal opioid addiction and the effects on the fetus and neonate have been discussed by Finnegan (1991) and Finnegan and Kandall (1992). For the purposes of this chapter, it should be noted that current evidence shows that pregnant women who wish to be detoxified from opioids (either heroin or methadone) should not be detoxified before gestational week 14 because of the potential risk of inducing abortion or after gestational week 32 because of possible withdrawal-induced fetal stress (see Finnegan 1991). Most clinicians dealing with pregnant opioid-dependent patients advocate methadone maintenance at a dose of methadone that maintains homeostasis and eliminates opioid craving; this dose must be individualized for each patient and managed in concert with the obstetrician.

Buprenorphine Buprenorphine is a partial agonist of

opioid–type receptor and is a clinically effective analgesic agent

with an estimated potency of 25–40 times that of morphine (Cowan et al. 1977). Buprenorphine was approved by the FDA for the treatment of opiate addiction in 2002 in addition to its use as an analgesic agent. Human pharmacology studies have shown buprenorphine to be 25–30 times as potent as morphine in producing pupillary constriction, but buprenorphine was less effective in producing morphinelike subjective effects (Jasinski et al. 1978). Furthermore, these studies showed that the physiological and subjective effects of morphine (15–120 mg) were significantly attenuated when morphine was administered 3 hours after buprenorphine in patients maintained on 8 mg/day of buprenorphine; the physiological and subjective effects of 30 mg of morphine also were tested at 29.5 hours after the last dose of chronically administered buprenorphine and were again significantly attenuated. Studies in opiate-abusing patients have shown that buprenorphine can be administered sublingually rather than subcutaneously, the route most commonly used for analgesic effect, with only a moderate decrease in potency, 1.0 mg subcutaneously being equal to 1.5 mg sublingually (Jasinski et al. 1989). Early clinical trials with opioid-dependent patients found that patients would tolerate the sublingual route, that the dose of buprenorphine could be rapidly escalated to effective doses without significant side effects or toxicity (Johnson et al. 1989), and that detoxification from heroin dependence using buprenorphine was as effective as using methadone (Bickel et al. 1988) or clonidine (Kosten and

Kleber 1988). Johnson et al. (1992) compared buprenorphine (8 mg/day sublingually) and methadone (20 mg/day or 60 mg/day) in a 25-week maintenance study and found that buprenorphine was as effective as 60 mg/day of methadone in reducing illicit opioid use and keeping patients in treatment. Both buprenorphine and methadone 60 mg/day were superior to methadone 20 mg/day in this study. A multicenter study compared sublingual doses of 1 mg of buprenorphine with 8 mg of buprenorphine in more than 700 patients. The 8-mg dose was significantly better than the 1-mg dose on outcome measures of opiate-free urine tests and retention in treatment (Ling et al. 1998). Results from a review of the controlled studies suggest that buprenorphine is as effective as moderate dosages of methadone (e.g., 60 mg/day), although it is not clear whether it can be as effective as higher methadone dosages (80–100 mg/day) in patients requiring higher dosages for maintenance therapy. A Swedish randomized trial of buprenorphine/naloxone combination versus standard methadone treatment reported equal results as measured by opiate-free urines and improvement on the Addiction Severity Index (Kakko et al. 2007). Both detoxification and maintenance studies have shown that the abrupt discontinuation of buprenorphine in a blind fashion causes only very minor elevations in withdrawal scores on any withdrawal scale (Bickel et al. 1988; Fudala et al. 1990; Jasinski et al. 1978; Johnson et al. 1989; Kosten and Kleber 1988). Because the issue of take-home medication is likely to arise in any opiate maintenance program and because methadone take-home medication has the potential for being diverted to illegal channels, the option of every-other-day buprenorphine dosing has been explored. After 19 heroin-dependent patients were stabilized on buprenorphine, 8 mg/day, for 2 weeks, 9 patients continued to receive buprenorphine daily while the other 10 patients, in a blind fashion, received alternate-day buprenorphine doses, 8 mg/dose, for 4 weeks. Patients reported some dysphoria on days on which they received placebos, and it was also noted that pupils were less constricted on placebo days in the patients on alternate-day therapy, but patients tolerated the 48-hour dosing interval without significant signs or symptoms of opiate withdrawal abstinence (Fudala et al. 1990). This leaves open the possibility of alternate-day medication in the treatment setting, eliminating the need for take-home medication. Buprenorphine is currently marketed in 4:1 combinations with naloxone (buprenorphine/naloxone sublingual tablets of 2 mg/0.5 mg and 8 mg/2 mg). The goal is to reduce abuse of prescribed buprenorphine by injection instead of sublingual dosage. Mendelson et al. (1999) showed that buprenorphine-to-naloxone combination ratios of 2:1 and 4:1 might be useful in treating opiate dependence by causing significant opiate withdrawal symptoms when the combination is taken intravenously. A multicenter clinical trial compared the efficacy of a sublingual tablet of buprenorphine/naloxone, in a 4:1 ratio, with that of placebo and a buprenorphine mono sublingual tablet. The results showed that both the buprenorphine/naloxone combination and the buprenorphine mono tablets were significantly more effective than placebo in reducing illicit opioid use, reducing opioid craving, and improving global functioning. No difference was noted between the efficacy of the combination and the mono products, and the combination product was as acceptable to the subjects as was the mono product (Fudala et al. 1999). Because the buprenorphine/naloxone combination is now widely prescribed throughout the United States, a monitoring program has been in place since 2002 to detect signs of street use of the medication. Thus far, nonprescribed use is minimal, and careful interviews have found that it is most often used to self-treat withdrawal symptoms but not to get high (C. R. Schuster, C. E. Johanson, T. Cicero, C. O'Brien, S. Schnoll, J. Anthony, C. Boyd, R. Schottenfeld, and M. Ensminger, "Surveillance Report—Subutex/Suboxone (July 1–September 30, 2007)," personal communication, December 24, 2007).

Drug Addiction Treatment Act of 2000 The Drug Addiction Treatment Act of 2000 (DATA) allows for the use of opioid medications in the office-based treatment of opioid dependence, provided that both the medication and the physician

meet the criteria set forth by the act. The medication must be approved by the FDA for the treatment of opioid dependence and be scheduled in C-III, C-IV, or C-V; medications in Schedule C-II, such as methadone, are not included in the act. The physician must be a "qualified" physician and have an addendum to his or her DEA license to prescribe medications under DATA 2000. Qualifying physicians under this law, however, will be able to more effectively treat opioid dependence in their offices, without referring patients to opioid treatment clinics. The only medications currently available that meet the requirements of DATA are buprenorphine and buprenorphine/naloxone combinations.

Relapse Prevention As has been noted earlier in this chapter, various methods of detoxifying patients from opioids have been developed, from substitution and rapidly tapering the dose of opioid to long-term methadone maintenance and a very gradual methadone taper. These methodologies are, by and large, unsuccessful in achieving permanent opioid abstinence in patients. It has long been thought that both conditioned reactivity to drug-associated cues (O'Brien et al. 1977; Wikler 1973) and protracted withdrawal symptoms (Martin and Jasinski 1969) contribute to the high rate of opioid relapse. The use of a blocking dose of a pure opioid antagonist would allow the patient to extinguish the conditioned responses to opioids by blocking the positive reinforcing effects of the illicit drugs. Naltrexone was shown to be orally effective in blocking the subjective effects of morphine for up to 24 hours (Martin et al. 1973). Patients using naltrexone maintenance for relapse prevention need to be carefully screened because they must be opioid free at the start of naltrexone administration. Many practitioners administer a naloxone challenge, which must be negative, before starting naltrexone. Naltrexone is usually administered either daily (50 mg) or three times weekly (100 mg, 100 mg, and 150 mg). Although naltrexone is pharmacologically able to block the reinforcing effects of opioids, the patient must take the medication in order for it to be effective. Many opioid-addicted patients have very little motivation to remain abstinent. Fram et al. (1989) reported that of 300 inner-city patients offered naltrexone, only 15 (5%) agreed to take the medication, and 2 months later, only 3 patients were still taking naltrexone. However, patients with better-identified motivation, among them groups of recovering professionals (e.g., physicians, attorneys) and federal probationers who face loss of license to practice a profession or legal consequences, have significantly better success with naltrexone. A group of federal probationers with a history of opiate addiction were randomly assigned to either naltrexone or treatment as usual. The group receiving naltrexone had significantly fewer opiatepositive urines, and most importantly, the reincarceration rate of the naltrexone group was half that of the control group at 6 months. In 2006, a depot formulation was approved by the FDA for the treatment of alcoholism (Garbutt et al. 2005). Approval for opiate addiction was not requested, but laboratory studies showed the medication to be effective for 30–40 days in blocking usual doses of injected opiates (Bigelow et al. 2006). A clinical trial of another formulation of depot naltrexone, not yet FDA approved, was found to be effective in a placebo-controlled clinical trial (Comer et al. 2006). Thus, the marketed depot version of naltrexone is yet another option for long-term relapse prevention in patients detoxified from opiate addiction.

HALLUCINOGENS The use and abuse of hallucinogens wax and wane much more than the use of some other drugs, such as alcohol and opioids. The major drugs of abuse that fall into this classification are cannabis and related compounds, lysergic acid diethylamide (LSD) and other indolealkylamines (psilocybin), phencyclidine (PCP) and its congeners, and hallucinogenic amphetamine congeners such as methylenedioxymethamphetamine (MDMA, "ecstasy"). Cannabis has a relatively constant rate of use, but its use alone usually does not cause the user to seek medical attention. That has changed somewhat in recent years, as will be described below. LSD (and related compounds) use has changed from the pattern set in the 1960s, when users lived together communally and the lifestyle of the group

frequently revolved around the psychedelic experience. Today, LSD use occurs in isolated groups, polysubstance abusers, and adolescents and young adults who frequent "rave" clubs. Most users of LSD and related compounds are not seen in emergency departments, but occasionally patients experiencing acute adverse reactions to these drugs are brought to medical attention. The most frequent adverse effects of LSD and related compounds are acute panic reactions. Most acute panic reactions, the "bad trips," do not require any intervention other than a calm atmosphere and reassurance, but occasionally a patient will be seen who benefits from a low dose of a benzodiazepine to decrease the anxiety associated with the experience. Likewise, intoxication with MDMA rarely requires more than reassurance or, occasionally, acute benzodiazepine administration, again to enable the patient to deal with the anxiety associated with an adverse experience. However, more recently, as MDMA use has become more popular, particularly in dance or "rave" club situations, more serious effects have been noted. These effects include things such as grinding of the teeth, causing dental problems, as well as more significant medical complications, most notably severe dehydration. It is not known whether the combination of alcohol and MDMA increases the risk of dehydration, but the combination is a frequent occurrence. PCP intoxication, however, can have serious psychiatric and medical complications. An acute psychotic state can be produced by very low doses of PCP, but behavioral disinhibition, frequently accompanied by anxiety, rage, aggression, and panic rather than by the core psychotic effects, necessitates treatment in most cases in which treatment is mandated. There is no convincing evidence of the superiority of either benzodiazepines or neuroleptics in treating the acute reaction to PCP. Benzodiazepines are frequently used because they have a rapid onset of action and because they can be titrated intravenously. If a neuroleptic is to be used, haloperidol is the most commonly used agent because many other neuroleptics have significant interaction with the anticholinergic properties of PCP itself. There is a paucity of information on chronic use of PCP and on treatment, if indicated, of the chronic user.

MARIJUANA Marijuana is mentioned as an hallucinogen, but its use is so common that it deserves special consideration. The cannabis plant has been cultivated for centuries both for the production of hemp fiber and for its presumed medicinal and psychoactive properties. The smoke from burning cannabis contains many chemicals, including 61 different cannabinoids that have been identified. One of these, delta-9-tetrahydrocannabinol ( -9-THC), produces almost all of the characteristic pharmacological effects of smoked marijuana (Iversen 2000). The pharmacological effects of

-9-THC vary according

to the dose, route of administration, experience of the user, vulnerability to psychoactive effects, and setting of use. Intoxication with marijuana produces changes in mood, perception, and motivation, but the effect sought after by most users is the "high" and "mellowing out." This is described as different from the stimulant high and the opiate high. The effects vary with dose, but the typical marijuana smoker experiences a high that lasts about 2 hours. Some users progress to daily use, which is associated with true dependence (addiction) as well as low motivation and possibly increased risk for schizophrenia (Ferdinand et al. 2005). Rates of marijuana consumption in adults 18 years and older held relatively steady at 4% of respondents in 2002. However, rates of marijuana-related disorders—discrete conditions defined according to criteria established by the American Psychiatric Association—increased from 1.2% to 1.5% of respondents, or from 30.2% overall to 35.6% among marijuana smokers (Compton et al. 2007). In 2007, the National Survey Results on Drug Use estimated that 31.7% of twelfth grade students used marijuana during 2007 (Figure 58–1). FIGURE 58–1. Percentages of youths ages 12–17 years reporting past-year marijuana use, by age group: 2000.

Source. Reprinted from Substance Abuse and Mental Health Services Administration: 2000 National Household Survey on Drug Abuse Report: Marijuana Use Among Youth. Substance Abuse and Mental Health Services Administration, July 2002. Used with permission. Marijuana is one of the four major substances of abuse; the others are alcohol, cocaine, and heroin. According to the 2000 DAWN report, marijuana had one of the highest emergency department drug mentions, at 39 per 100,000. From 1994 to 2000, marijuana mentions increased from 17 to 39, or by 141% (Substance Abuse and Mental Health Services Administration 2002). After alcohol use disorders, marijuana abuse had the second highest rate of treatment, with 700,000 persons (Substance Abuse and Mental Health Services Administration 2001). The usual treatment interventions for marijuana abuse include drug monitoring, individual and group psychotherapy, and education (Hubbard et al. 1999). No pharmacotherapy is available for marijuana abuse. This may soon change, given the recent remarkable discoveries concerning cannabinoids. There has been an explosive growth of marijuana research. Key to this have been the discoveries of cannabinoid receptors and endocannabinoids (naturally occurring cannabis substances) in humans. The neurobehavioral and genetic aspects of cannabinoids are the focus of numerous ongoing studies (see review by Onaivi 2006). The recent scientific discoveries are significant first steps in understanding the mechanisms by which cannabinoids cause physiological effects. Marijuana has been proposed for several medical indications, including nausea associated with cancer chemotherapy, glaucoma, and wasting disorders. Also, the discovery of cannabinoid receptors opens the opportunity for the development of specific agonists and antagonists at these receptors that may have important medical value.

SELF-HELP GROUPS Self-help groups—such as Alcoholics Anonymous, Narcotics Anonymous, and Cocaine Anonymous—that are based on a 12-Step method of recovery can be a valuable source of support for the recovering patient. These groups are a fellowship of recovering people interested in helping themselves and others lead drug-free lives. The groups are very good for reminding people of the adverse consequences of relapse and of the benefits of abstinence. Many recovering people feel that it

is easier and more relevant to hear about some aspects of recovery from another recovering person. Patients can attend meetings as frequently as necessary and can learn more effective management of leisure time. A sponsor, a person in the group with a prolonged time in a drug-free lifestyle, can provide a good role model for a person in recovery, in addition to providing support and encouragement. Self-help groups are also available to non-drug-abusing family members to help them understand the addictive process and how family member dynamics can affect the drug-abusing or recovering family member.

CONCLUSION Addictive disorders can be caused by a variety of drugs that activate the reward system. The common clinical feature of all addictions is loss of control over drug use so that recurrent compulsive drug taking occurs. Treatment, as with other chronic disorders, is generally effective for at least the short term, but relapses are always possible and even likely. Randomized, controlled clinical trials have demonstrated that the combination of antiaddiction medications and psychotherapy provides the best treatment for addictive disorders.

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W. Stewart Agras: Chapter 59. Treatment of Eating Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.435224. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 59. Treatment of Eating Disorders TREATMENT OF EATING DISORDERS: INTRODUCTION Eating disorders are seen frequently in the clinic, reflecting a combined prevalence in women for anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED) of about 3.5% for the full disorder and 6% if subthreshold disorders are included (Hudson et al. 2007). Males are affected less frequently; about 10% of all cases of AN and BN are in males, with the proportion rising to about 30% for BED in clinical samples. Because much comorbid psychopathology is associated with each of these disorders, including current major depression in about 25% of cases, the treatment plan must take any such disorders into account. Two forms of treatment, psychopharmacological and psychotherapeutic, are effective in the treatment of BN and BED, and possibly in AN. Hence, determining how to sequence or combine treatment modalities is an important issue.

HISTORICAL BACKGROUND Case histories of starvation, binge eating, and purging have been documented, mostly as rare curiosities, for centuries. The histories of saintly women in the thirteenth to fifteenth centuries who had all the symptoms of AN, including self-induced vomiting, are particularly well documented both in their own writings and in the accounts of others. For these women, starvation was in the service of their religious beliefs (Bynum 1987). Cases of BN were rarely seen in the clinic until their relatively sudden increase throughout the Western world in the late 1970s (Garner et al. 1985). This apparent increase in the prevalence of BN has been attributed to increasing societal pressures on women to maintain a thin body shape. Hence, the motivation for excessive dieting may vary according to the cultural pressures of the times. Research into the psychopathology and treatment of the eating disorders was relatively slow to develop as compared with such research in depression and the anxiety disorders. This was probably because of the low prevalence of AN and the relatively recent increase in the number of cases of BN. Moreover, BED was only recently recognized as a syndrome, although there is now a large body of literature on the condition. Despite this slow start, sufficient controlled treatment trials are now available to provide guidance to the clinician. This is particularly true for BN, for which psychopharmacological and psychotherapeutic studies began at the same time. Because of the similarity between BN and BED, treatments successful for BN were then applied to BED with some success.

BULIMIA NERVOSA BN has its onset in late adolescence or early adult life, with a prodromal period characterized by dissatisfaction with body shape and a fear of becoming overweight, followed by dietary restriction and weight loss. Sooner or later, periods of dietary restriction are followed by episodes of binge eating experienced as a loss of control over dietary intake. This, in turn, further aggravates dissatisfaction with body shape and fears of weight gain. Ultimately, the bulimic patient discovers purging, usually in the form of self-induced vomiting, with or without laxative or diuretic use, excessive exercise, or (less commonly) fasting; and in rare cases in the form of chewing food and spitting it out. DSM-IV-TR (American Psychiatric Association 2000) distinguishes two forms of BN: purging and nonpurging types, the latter characterized by the use of exercise or fasting rather than other compensatory behaviors. The implications of this classification for treatment are unknown. Medical complications of BN are relatively rare; the most serious are potassium depletion and dental caries. Other complications include salivary gland enlargement and exercise injuries. Comorbid psychopathology includes major depression; anxiety disorders, including obsessive-compulsive disorder, social phobia, and panic disorder; alcoholism; and personality disorders, particularly those in the Cluster B spectrum.

Assessment Assessment should begin with a history of the development of disordered eating, including the psychosocial factors involved in its development. Areas that should be explored include binge eating, purging methods, exercise, and concerns about weight and shape. Eating binges comprise two features: a feeling of loss of control over eating and the eating of a large amount of food. Loss of control appears to be facilitated by the experience of negative affect often deriving from faulty interpersonal interactions (Agras and Apple 2007; Agras and Telch 1998). An objective binge involves eating an amount of food equivalent to an intake of two or more meals. Such binges are required to meet criteria for the diagnosis. Subjective binges consist of a feeling of loss of control but eating less than the required amount for an objective binge. These binges are often quite small and may involve eating a "forbidden" food. The most

common method of purging is self-initiated vomiting. It is important to inquire about the use of ipecac to facilitate vomiting because of its toxic cardiovascular effects. The next most frequent method of purging is the use of laxatives. Diuretics also may be used, but less frequently than laxatives. Chewing food and spitting it out and the use of enemas as purgative methods are occasionally seen. Exercise is also used frequently in an attempt to control weight and shape. It is important to distinguish such exercise from normal exercise patterns. The most common distinguishing feature is an exercise regimen that results in exhaustion or that is compulsively adhered to and that would cause anxiety if it were omitted from the daily routine. In addition to the history, an electrolyte panel is needed, particularly to check potassium levels, which are low and require correcting in about 5% of individuals with BN. A hematocrit is also useful because anemia may be present. Serum amylase levels also may be elevated. If the patient is not receiving regular dental care, then a referral for such care should be considered because of the erosion of dental enamel and periodontal disease that frequently accompany bulimia. Finally, the assessment should document both past and present comorbid psychiatric disorders because these conditions may have to be taken into account in planning treatment. For example, current major depression may interfere with the patient's ability to adhere to treatment and should be treated together with the eating disorder.

Pharmacological Treatment Antidepressants The use of antidepressants in the treatment of BN was sparked by the observation that depression is often a comorbid feature of the disorder (Pope and Hudson 1982). In 1982, two groups of researchers conducted small-scale uncontrolled studies indicating that both tricyclic antidepressants and monoamine oxidase inhibitors reduced binge eating and purging (Pope and Hudson 1982; Walsh et al. 1982). These observations were followed by a series of double-blind, placebo-controlled studies confirming the utility of antidepressants in treating BN, at least in the short term. A wide range of antidepressant drugs have been found effective, including imipramine (Agras et al. 1987; Mitchell et al. 1990; Pope et al. 1983), desipramine (Agras et al. 1991; Barlow et al. 1988; Blouin et al. 1989; Hughes et al. 1986), phenelzine (Walsh et al. 1988), brofaromine (Kennedy et al. 1993), trazodone (Pope et al. 1989), fluoxetine (Fluoxetine Bulimia Nervosa Collaborative Study Group 1992), fluvoxamine (Milano et al. 2005), and citalopram (Leombruni et al. 2006). Fluoxetine is the only medication approved by the U.S. Food and Drug Administration for the treatment of BN. In these studies, the median rate of decrease in binge eating and purging was 69%, the median recovery rate was 32%, and the mean dropout rate was 23%. In one study involving 77 BN patients (Walsh et al. 2006b) that examined the rate of decline in bulimic symptoms with desipramine, the authors found that those unlikely to respond to the antidepressant could be reliably identified after 2 weeks of treatment. Antidepressants are prescribed for BN at the same dosages used for treating depression, with the exception of fluoxetine, for which a dosage of 60 mg/day was found to be more effective than 20 mg/day in reducing binge eating and purging in a placebo-controlled trial involving 387 bulimic women (Fluoxetine Bulimia Nervosa Collaborative Study Group 1992). One problem with medication given at times other than bedtime is that a significant amount may be purged through subsequent vomiting. Side effects and reasons for discontinuation of the various medications are similar to those observed in the treatment of depression. However, a study of bupropion found that a higherthan-expected proportion of patients developed grand mal seizures (Horne et al. 1988). The authors concluded that bupropion should not be used for the treatment of BN. Overall, most antidepressants appear effective for the short-term treatment of BN, with little difference between them (Bacaltchuk and Hay 2003). An interesting recent study involving 47 patients with BN (Monteleone et al. 2005) examined the association of the 5-HTTLPR serotonin transporter genotype with antidepressant response, finding that those with the long form had a tenfold higher likelihood of attaining remission with a selective serotonin reuptake inhibitor (SSRI). As the authors pointed out, these results, if replicated, could allow therapists to prescribe SSRIs to those patients with BN who would be most likely to respond to these agents. Less is known about the long-term effectiveness of medication. Three small-scale uncontrolled studies found that about one-third of the patients continuing antidepressant medication over periods of 6 months to 2 years relapsed (Pope et al. 1985; Pyle et al. 1990; Walsh et al. 1991). In a larger-scale examination of this issue, 147 women with BN who had decreased their vomiting by at least 50% while taking 60 mg of fluoxetine over an 8-week period were randomly allocated to continue medication or to be switched to placebo (Romano et al. 2002). A survival analysis found that the group receiving active medication experienced a longer time to relapse (or dropout) than did the placebo group. However, it should be noted that at the 3-month assessment, 55% of the fluoxetine group and 78% of the placebo group had either relapsed or dropped out of the study. At the 12-month follow-up, 83% of the fluoxetine group and 92% of the placebo group had experienced a relapse. The authors suggest that given these results, a multimodal

approach to the treatment of BN, including cognitive-behavioral therapy (CBT), should be considered. To date, only one study has compared different lengths of antidepressant treatment, in this case with desipramine. Patients with BN treated for 16 weeks relapsed to pretreatment levels of binge eating when medication was withdrawn. On the other hand, those treated for 24 weeks maintained remission after withdrawal and at 1-year follow-up (Agras et al. 1991, 1994a). This study suggests that patients who respond to antidepressant treatment should be given a minimum trial of 6 months on medication. For the most part, however, controlled studies of antidepressants are of relatively short duration, as is the assessment of bulimic symptoms. Both of these factors may somewhat exaggerate the clinical efficacy of these medications.

Other Medications Although considerable evidence from controlled trials indicates that most antidepressants are useful in the treatment of BN, few controlled studies of other pharmacological agents have appeared in the literature. However, topiramate (an anticonvulsant drug) has been evaluated in two controlled trials. In the first of these studies, patients meeting criteria for DSM-IV-TR bulimia nervosa were allocated at random to treatment with either topiramate (n = 35) or placebo (n = 34) over a 10-week period (Hoopes et al. 2003). Twenty-two (63%) of those in the topiramate group completed the trial, and topiramate was statistically superior in reducing binge eating and purging, and 22% of completers were recovered at the end of treatment. In the second study (Nickel et al. 2005), 30 patients with BN were randomly allocated to either topiramate or placebo. Topiramate was statistically superior to placebo in reducing binge eating and purging; however, no data on remission or recovery were reported. Although no direct comparison between topiramate and an antidepressant has been made, the data so far suggest that topiramate is about as effective as the antidepressants in the treatment of BN.

Combined Treatment CBT for BN was developed in parallel with the use of antidepressants. CBT in either individual or group format has been shown to be more effective in reducing binge eating and/or purging than placebo (Mitchell et al. 1990), supportive psychotherapy plus self-monitoring of eating behavior (Agras et al. 1989), stress management (Laessle et al. 1991), behavior therapy (Fairburn et al. 1993), and psychodynamic forms of psychotherapy (Garner et al. 1993; Walsh et al. 1997). The existence of two different and effective treatments, antidepressant medications and CBT, naturally led to the question of whether the combined treatments would be more effective than either treatment alone. The first study of this question used a randomized 2 x 2 design with four experimental groups: 1) imipramine combined with group psychosocial treatment, 2) imipramine with no psychosocial treatment, 3) placebo combined with group psychosocial treatment, and 4) placebo with no psychosocial treatment (Mitchell et al. 1990). Treatment was preceded by a single-blind placebo washout phase. One hundred and seventy-one women with BN entered treatment, which lasted for 10 weeks. The psychosocial treatment was an intensive group variant of CBT, with 5 daily sessions in the first week and 22 treatment sessions overall. The mean daily dosage of imipramine was 217 mg for the psychosocial treatment group and 266 mg for the group receiving medication alone. As might be expected, the dropout rate was significantly higher for those receiving medication (34%) compared with those taking placebo (15%). Imipramine was superior to placebo; however, CBT, with a remission rate of 51%, was superior to imipramine, with a remission rate of 16%, and combining the two treatments did not result in any additional advantage in reducing binge eating and purging. The combined treatment was, however, significantly superior to CBT in reducing depression. In the second study (Agras et al. 1991, 1994a), 71 participants were randomly allocated to one of three groups: 1) desipramine (mean daily dosage = 168 mg), 2) CBT, and 3) combined treatment. Half of the desipramine participants were withdrawn from medication at 16 weeks and the remainder at 24 weeks. CBT lasted for 24 weeks. Eighteen percent of the participants stopped taking desipramine before the end of treatment, compared with a treatment dropout of 4.3% of those participants receiving CBT. CBT, with a 48% remission rate, was significantly superior to desipramine, with a 33% remission rate, in reducing the frequency of binge eating and purging, and the combined treatment was no more effective than CBT alone. At 1-year follow-up of 61 of the original 71 patients, 77% of the combined treatment group were abstinent, compared with 54% of those receiving CBT alone (Agras et al. 1994a). This difference was not statistically significant. However, receiving desipramine alone for 24 weeks was the most cost-effective approach in terms of the cost of treatment per recovered patient at 1-year follow-up (Koran et al. 1995). Another study involving 120 women with BN used a more sophisticated medication regimen consisting of desipramine followed by fluoxetine if the first medication was either ineffective or poorly tolerated (Walsh et al. 1997). It is important to note that the two-medication combination was used by two-thirds of the patients assigned to active medication, suggesting that a two-medication combination is closer to clinical reality than the use of a single medication. This study used a five-cell design: CBT combined with placebo or active medication, psychodynamically oriented therapy combined with placebo or active medication, and medication alone. CBT (plus placebo) was more

effective than psychodynamic therapy (plus placebo) in reducing both binge eating and purging. The average dosage of desipramine was 188 mg/day and of fluoxetine was 55 mg/day. Forty-three percent of the patients receiving medication dropped out of the study, compared with 32% of those receiving psychotherapy. Patients receiving active medication (in combination with psychological treatments) reduced binge eating significantly more than did those receiving placebo. Finally, antidepressant medication combined with CBT was superior to medication alone in reducing purging frequency. Of those receiving CBT plus medication, 50% were in remission, compared with 25% of those receiving medication alone. These findings suggest that the combination of CBT plus antidepressant medication may be the most effective approach to the treatment of BN. A meta-analysis confirmed this impression (Bacaltchuk et al. 2000).

Treatment After Psychotherapy Failure In a small-scale double-blind, randomized, controlled trial, participants who had failed to respond to either CBT or interpersonal therapy in a multisite trial were randomly allocated to either fluoxetine 60 mg/day or placebo (Walsh et al. 2000). Twenty-three participants entered the study with a median of 22 binges and 30 purges over a 4-week period. Of those receiving fluoxetine, 38% were abstinent (over a 4-week period) at the end of treatment compared with none in the placebo group. This finding suggests that fluoxetine may be useful for those who do not respond to psychological treatments.

Comprehensive Treatment Patients with BN are best treated as outpatients, unless there are either medical or psychiatric reasons for hospitalization (e.g., an intercurrent physical illness or a comorbid psychiatric disorder requiring hospitalization, such as major depression with suicidality). One reason that outpatient treatment is useful for the BN patient is that gains made in the hospital may not carry over to the patient's natural environment, where more complex food stimuli and greater stress are present than in the hospital. The research evidence to date suggests that the combination of antidepressant medication and CBT is likely to be somewhat more effective than either therapy alone. Because CBT is more effective than antidepressant medication, having fewer dropouts than medication, in the ideal case, this should be the first therapy offered to the patient. However, CBT is not always available, and in such circumstances, medication will be the only choice. In addition, patient preferences for one or another treatment should be taken into account. The flow chart in Figure 59–1 presents an algorithm as guidance to the overall treatment of BN. The first decision to make is whether the patient has current major depression, which is seen in approximately 25% of bulimic patients presenting for treatment. Because depressive symptoms can interfere with the conduct of CBT for BN, antidepressant medication should precede CBT in such patients. When the patient has sufficiently recovered from depression, the eating disorder should be reevaluated. If the patient has not recovered from the eating disorder, then CBT should be added. FIGURE 59–1. Flow chart depicting different treatment sequences for bulimia nervosa (BN).

CBT = cognitive-behavioral therapy. As shown in Figure 59–1, after 4 weeks (six sessions) of therapy, if the reduction in purging with CBT is less than 70%, an antidepressant should be added. This algorithm is based on the findings of a multisite study involving 194 women with BN, which found that the initial treatment response to CBT predicted outcome reasonably well (Agras et al. 2000). Those reducing purging less than 70% after 4 weeks of treatment were more likely to be nonresponders. If there is an inadequate response to antidepressant treatment or a relapse, an alternative antidepressant should be used. For those who complete CBT with insufficient improvement, despite having reduced their purging at session 6, then an antidepressant should be advised.

BINGE-EATING DISORDER Although the association between binge eating and obesity has been noted from time to time in case reports in the literature, it was not until the upsurge of research into the psychopathology and treatment of BN that systematic attention was paid to BED. The principal features of BED are episodes of binge eating at a frequency of at least 2 days a week for 6 months, marked distress caused by binge eating, and binge eating that does not occur during the course of BN or AN. Purging does not occur in this condition, although about 10% of the patients with BED have a history of BN.

Between 1% and 2% of women in the general population meet criteria for BED (Bruce and Agras 1992). In clinical populations, the ratio of women to men with BED is approximately 3:2, the highest rate for men for any eating disorder. Although obesity is not a requirement for the diagnosis of BED, there is a substantial overlap between BED and obesity. Studies have shown that about one-quarter of obese subjects have symptoms that meet criteria for BED and that the prevalence of binge eating increases as body mass index increases (Marcus et al. 1985; Spitzer et al. 1993; Telch et al. 1988). Because binge eating often precedes the onset of becoming overweight, binge eating may be a risk factor for obesity and the multiple health problems associated with being overweight. Moreover, the syndrome is associated with comorbid psychopathology similar to that of BN and causes much distress; hence, it is an entity deserving of treatment in its own right. One study that compared individuals with BED with weight-matched non-binge-eating obese individuals found that subjects with BED were significantly more likely to receive diagnoses of major depression (51%), panic disorder (9%), and borderline personality disorder (9%) than were those without BED (Yanovski et al. 1992).

Pharmacological Treatment Antidepressants Double-blind, placebo-controlled studies suggest that antidepressants are at least as useful in the treatment of BED as in BN. Early placebo-controlled studies found desipramine to be effective in reducing binge eating, with an abstinence rate of 60% (McCann and Agras 1990). Studies of SSRIs suggest moderate efficacy for fluoxetine, sertraline, and citalopram (Appolinario and McElroy 2004; McElroy et al. 2000). Other studies have found no effect for fluoxetine on binge eating (Devlin et al. 2005; Grilo et al. 2005b). These conflicting results may be due to the relatively high placebo response observed in some studies. There has also been considerable variability in weight losses experienced by patients with BED treated with antidepressants, from essentially no weight loss to several pounds. Although the McCann and Agras (1990) study found that antidepressants reduced binge eating, patients who stopped binge eating did not lose weight. In another controlled study, 108 overweight women with BED received 3 months of CBT, followed by 6 months of weight-loss treatment combined with desipramine. No additive effect of desipramine on binge eating was found; however, women in the medication group lost significantly more weight (4.8 kg) than those in the comparison group (Agras et al. 1994b). The serotonin–norepinephrine reuptake inhibitor sibutramine (15 mg/day) and the selective norepinephrine reuptake inhibitor reboxetine (8 mg/day) also appeared to be useful in the treatment of BED in open-label studies (Shapira et al. 2000; Silveira et al. 2005). Weight losses were relatively large with both of these medications. A placebo-controlled study of sibutramine in 60 obese women with BED confirmed these early studies (Appolinario et al. 2003), with 52% achieving abstinence from binge eating compared with 32% in the placebo group. Weight losses were 7.4 kg for the sibutramine group compared with a small increase in weight for the placebo group.

Other Medications Anticonvulsants such as topiramate and zonisamide also appear useful in the treatment of BED (McElroy et al. 2006). A multisite study in which more than 400 participants with BED were allocated at random to either topiramate or placebo provided further evidence of the efficacy of topiramate (McElroy et al. 2007). The median dosage of topiramate was 300 mg/day. Dropouts were equivalent between groups (29% topiramate; 30% placebo). Fifty-eight percent of those in the topiramate group and 29% in the placebo group were in remission at the end of the study period. The mean weight loss was 4.5 kg in the topiramate group versus a small gain in the placebo group. The most common side effects specific to topiramate were paresthesia and difficulty concentrating. Hence, topiramate leads to a reasonable rate of remission combined with substantial weight loss. Finally, a placebo-controlled study comprising 50 overweight participants with BED compared orlistat (120 mg three times daily) with placebo, both groups receiving an abbreviated form of CBT (Grilo et al. 2005a). At the end of treatment, 64% of those in the orlistat group and 36% of those in the placebo group were in remission. The proportions achieving at least a 5% weight loss were 36% for orlistat and 8% for placebo. However, after discontinuation of both treatments, there was no difference in abstinence rates between groups (52% in both groups).

Comprehensive Treatment BED presents three problems to the clinician: binge eating, overweight, and comorbid psychopathology, particularly depression. Hence, a comprehensive treatment should address all of these problems. There are few direct comparisons of psychotherapy and medication, and the situation is further complicated by the larger placebo responses found in BED as compared with BN, probably accounting for the lack of efficacy of pharmacological agents in some studies. For patients who prefer to try medication, it appears on present evidence that sertraline and topiramate are the most effective in terms of reducing both binge eating and weight. Less is known about medications that may add to the

effects of psychotherapies such as CBT and interpersonal therapy, both of which are associated with substantial reductions in binge eating that appear to be well maintained, although weight losses are small. Hence, it appears reasonable to augment psychotherapy with either sertraline or another SSRI, topiramate, or orlistat.

ANOREXIA NERVOSA AN is a relatively rare disorder characterized by marked weight loss (at least 15% below ideal body weight), intense fear of gaining weight, disturbance in the experience of body shape (i.e., feeling fat in the face of marked weight loss), and (in females) amenorrhea. It is the most lethal psychiatric disorder. Follow-up studies document an aggregate mortality rate of about 5.6% per decade; about half of these deaths are a result of suicide, and the remainder are largely due to cardiovascular instability (Casiero and Fishman 2006). Because of the chronicity of the condition, it has become apparent that identification and treatment of the disorder early in its course are essential. A specific family therapy for adolescents that aims to help parents take charge of their child's eating appears to be successful in both the short and the long term, with about 70% of adolescent patients with anorexia recovered both at the end of treatment and at follow-up (Lock et al. 2005, 2006). Most patients with anorexia can be treated as outpatients. However, treatment can be difficult because of the patient's reluctance to gain weight. Weight should be monitored at every outpatient visit, and it is important that weight be measured in a hospital gown to prevent the use of lead weights to which some patients with anorexia resort. Other methods of inflating weight are less easy to detect, such as drinking large quantities of water before being weighed. Indications for hospitalization include weight less than 75% of ideal body weight for age and height, heart rate below 40 beats/minute, blood pressure below 90/60 mm Hg, potassium levels below 3 mEq/L, temperature below 97°F, and very rapid weight loss. In addition, because of the associated psychopathology in this disorder, the usual indications for hospitalization for severe psychopathology should be followed. Because the disorder is rare, it is difficult in any one center to acquire an adequate sample size for a study in a reasonable time; thus, satisfactory randomized, double-blind medication trials are difficult to accomplish. Moreover, medication trials should be long enough and use optimal medication dosages to adequately show effects in this chronic relapsing disorder. Unfortunately, few trials meet these criteria; many are of short duration, use inadequate dosages of medication, or have been carried out in inpatients.

Pharmacological Treatment Most studies of antipsychotic agents in the treatment of AN, including chlorpromazine, pimozide, and sulpiride, showed no evidence of efficacy (Dally and Sargant 1960; Vandereycken 1984; Vandereycken and Pierloot 1982). Recent case reports, however, suggest that risperidone may lead to weight gains (Newman-Toker 2000). The effects of olanzapine were studied in 34 patients with anorexia nervosa receiving day care treatment who were allocated to active drug or placebo. The mean dosage of olanzapine was 6.61 mg/day. Those allocated to olanzapine recovered more quickly than those on placebo and gained about 0.6 kg more than those on placebo. Obsessive thinking was also decreased in those receiving olanzapine, but there were no other differences in psychopathology between groups (Bissada et al. 2008). Further studies with larger sample sizes are needed. Moreover, the clinical impression is that olanzapine is not well accepted by patients with AN. An important study found that fluoxetine was not effective in hospitalized patients with AN (Attia et al. 1998). In this study, 31 women hospitalized with AN participated in a 7-week randomized, double-blind trial of fluoxetine at a mean dosage of 56 mg/day. Four patients in each group terminated the trial early. Although all patients in the study showed improvement, no significant differences were seen between active medication and placebo. In addition, there was no apparent effect of medication on depression or obsessional symptoms. This study suggested that fluoxetine had no effect over and above that of an inpatient program and adds to the consistent failure to show a beneficial effect of antidepressant medication during the period of weight regain. Despite the findings of an earlier small-scale outpatient study (Kaye et al. 2001), a more recent study of 93 adult outpatients found no benefit of fluoxetine in either promoting weight maintenance or prolonging time to relapse in a double-blind, placebo-controlled trial (Walsh et al. 2006a). As is usual in this population, there was a large proportion of dropouts or early terminations from treatment (51% of fluoxetine-treated and 63% of placebo-treated patients). A fairly high proportion of patients were dissatisfied with treatment. The very high dropout rates make a statistical comparison between groups difficult because of the large amount of data being carried forward in an intent-to-treat analysis. Nonetheless, the only difference between groups was a statistical advantage for fluoxetine in reducing anxiety levels. Given the findings that fluoxetine confers no benefit for adult patients with AN either during the weight gain period in hospital or during outpatient treatment, one must conclude that the use of fluoxetine is not indicated in the treatment of AN except for the treatment of comorbid psychopathology. At this point, however, there have been no satisfactory

studies of SSRIs in adolescents with AN, and such studies would appear warranted given the high priority for treatment early in the course of AN.

CONCLUSION The place of psychopharmacological agents in the treatment of BN has been well worked out. Treatment with sequential trials of different antidepressants should result in abstinence rates of about 40%. The addition of CBT enhances the effectiveness of antidepressants. It is becoming clear that agents such as topiramate and similar anticonvulsants are useful in the treatment of BED, with the added advantage of facilitating substantial weight loss in the overweight patient. In the case of AN, there is little evidence that pharmacological agents are helpful in either inpatient or outpatient treatment of the adult patient, except to treat comorbid psychiatric disorders. There is insufficient information regarding adolescent anorexia to provide guidance regarding the use of medication at this point.

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Martin Reite: Chapter 60. Treatment of Insomnia, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.442061. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 60. Treatment of Insomnia TREATMENT OF INSOMNIA: INTRODUCTION Our conceptualization of insomnia has undergone a dramatic shift during the past few years, from an annoying but not particularly serious symptom to the recognition that 1) sleep loss from any cause has serious consequences, 2) chronic insomnia and the impaired sleep it represents are highly comorbid with (or indeed may cause) many other medical and psychiatric disorders, and 3) chronic insomnia in some cases may represent a separate medical disorder in itself, with an independent neurobiological basis. It has been suggested that certain chronic insomnias be considered on a par with depression as a serious disorder with a tendency toward chronicity whose treatment needs independent assessment and possibly long-term management (Jindal et al. 2004). This increase in complexity is in part offset by improved treatment options, both pharmacological and nonpharmacological. This chapter will review these areas in what we hope is a clinically useful manner.

MORBIDITY OF INSOMNIA AND CONSEQUENCES OF SLEEP LOSS The 2005 National Institutes of Health (NIH) Consensus Conference on Chronic Insomnia in Adults estimated that 30% of the general population has symptoms or complaints consistent with insomnia (http://consensus.nih.gov/2005/2005InsomniaSOS026html.htm). The symptoms of insomnia may include complaints of not being able to get to sleep, not being able to stay asleep, waking too early, or sleep that is not refreshing—and often a combination of the foregoing. Individuals with insomnia report diminished quality of life, including impaired concentration and memory, decreased ability to accomplish daily tasks, decreased ability to accomplish daily tasks, and decreased ability to enjoy interpersonal relationships (Ancoli-Israel and Roth 1999). Untreated insomnia is associated with increases in new-onset anxiety and depression, increased daytime sleepiness, and increased healthrelated concerns (Richardson 2000), as well as increased use of health-related services (Novak et al. 2004). Patients with primary insomnia demonstrate impaired memory consolidation during sleep (Backhaus et al. 2006), and recent evidence suggests they may have diminished hippocampal volumes (Riemann et al. 2007). New data on the effects of sleep loss in otherwise healthy adults affirm the importance of adequate sleep. Going without sleep for 17–21 hours, not uncommon in many occupations and life situations, may lead to psychomotor performance decrements similar to those seen with legal alcohol intoxication (Dawson and Reid 1997), which may not be apparent to the individual concerned. Going without sleep for a single night following a hepatitis A immunization may lead to a 50% reduction in hepatitis A antibody formation a month later (Lange et al. 2003). Relatively mild sleep loss may result in significant decline in cognitive performance, and sleep restriction to 4 hours per night for 2 nights in healthy males has been shown to decrease leptin and increase ghrelin production, with potentially adverse effects on the potential to develop obesity (Spiegel et al. 2004). Both short-term total and partial sleep deprivation have been shown to increase C reactive protein levels in otherwise healthy adults (Meier-Ewert et al. 2004). Although an insomnia complaint is not isomorphic with sleep deprivation, individuals with insomnia have been shown to get less sleep and therefore are at greater risk for the adverse events accompanying sleep deprivation. Data are emerging suggesting a relationship between sleep loss and the development of both insulin resistance and the individual

components of the metabolic syndrome (Wolk and Somers 2007), an issue of special concern in an American population thought to be generally mildly sleep deprived and in which obesity and type 2 diabetes are serious public health issues. We now recognize that the insomnia complaint may reflect dysfunction of several underlying neurobiological systems supporting sleep, including the homeostatic Process S and circadian Process C systems, as well as influences from comorbid medical and/or psychiatric conditions and the effects of environmental stress and poor sleep habits. Quite often, several of these factors interact to produce the insomnia-based symptom complex that patients present with, a circumstance that serves to highlight the importance of accurate and comprehensive differential diagnosis of an insomnia complaint before embarking on treatment. This chapter advances the position that most patients with insomnia complaints can be helped if sufficient attention is paid to accurate differential diagnosis, with recognition and appropriate treatment of their underlying pathologies contributing to their complaints.

SLEEP ARCHITECTURE Sleep architecture refers to the characteristic scalp electroencephalogram (EEG) patterns that characterize the different waking and sleep states (wakefulness, rapid eye movement [REM] sleep) and non-REM sleep stages (1 through 4). EEG rhythms are defined primarily by their frequency in cycles per second (termed Hertz [Hz]), with the major frequency bands being delta (4 to 20 Hz). Sometimes 12- to 14-Hz "sleep spindle" activity is termed sigma activity. Wakefulness is normally accompanied by what is termed a "low-voltage, fast" scalp-recorded EEG, with frequencies usually greater than 8 Hz and amplitudes in the vicinity of 50 V or less. The most prominent EEG rhythm of quiet, relaxed wakefulness is the so-called alpha rhythm, seen over the top and back of the head (visual receptive regions) when the eyes are closed. Alpha rhythm consists of rhythmical 8- to 12-Hz activity, usually about 50 V in amplitude. The transition from wakefulness to sleep—normally Stage 1 non-REM sleep—is indicated by the appearance in the EEG of slower 5- to 7-Hz theta activity of generally low voltage. The subject is not responsive at this point but can be easily aroused. Stage 1 sleep usually constitutes only about 5%–7% of total sleep time. After a few minutes, the typical subject transitions into Stage 2 sleep, characterized by further slowing of the EEG and the appearance of sleep spindles and K complexes. Spindles are short (usually 75 mV) slow (50% slow delta activity. Stage 3 and Stage 4 sleep are often grouped together and termed delta sleep or slow-wave sleep (SWS). Stage 3 and 4 sleep constitute about 20%–25% of sleep time in adults, but that percentage is higher in adolescents and lower in healthy elderly individuals as well as in many pathological conditions, including depression, schizophrenia, and many insomnia disorders. Older individuals may have slow-wave delta activity, but it is not of sufficient amplitude (75 V) to be formally scored as Stage 3 or 4. After the typical adult has been asleep (in non-REM sleep) for about 90 minutes, the EEG transitions to a lower-voltage, faster pattern. The subject remains asleep, but the eyes can now be seen rapidly moving beneath the closed lids. Consequently, this stage of sleep is called rapid eye movement or REM sleep. If awakened during this stage, the subject will often report dreaming. The time from sleep

onset (i.e., Stage 1) to the onset of the first REM period is termed REM latency, which has diagnostic implications. In some psychiatric disorders (e.g., major affective disorders, schizophrenia, and eating disorders), and occasionally in narcolepsy, REM latency is shorter than normal. REM latency tends to decrease with advancing age, but, as a rule of thumb, nocturnal REM latency of less than 60 minutes in an adult should be considered unusually short and might suggest a major affective disorder. REM sleep usually constitutes about 20% of total sleep time in adults. Until very recently, conventional EEG sleep scoring was still largely based on the sleep atlas of Rechtschaffen and Kales (1968), which dates from the time that sleep records were recorded on paper EEG machines, usually run at a speed of 10–30 mm/second, and included only those EEG frequencies easily visible to the naked eye (very low [50 Hz] frequencies were usually not recorded). We can probably expect some significant revisions in scoring techniques in the near future based on availability of computerized EEG recording and analytical techniques. Altered sleep morphology not captured by conventional scoring includes the presence of "cyclic alternating patterns" that appear during sleep and may be associated with daytime fatigue (Guilleminault et al. 2006), computer quantification of slow-wave activity indexing sleep drive and/or quality (Armitage et al. 2007), and the presence of very-high-frequency (gamma-band) EEG activity (Perlis et al. 2001a, 2001b). Such issues have begun to be addressed in "The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specification," recently published by the American Academy of Sleep Medicine (2007).

SLEEP PHYSIOLOGY AS IT RELATES TO INSOMNIA It is necessary to have a basic understanding of the neurobiological mechanisms underlying sleep if we are to understand insomnia. Perhaps the most basic issue is that there are fundamentally two quite different types of sleep, non-REM and REM, each with its own neuroanatomy, physiology, function, developmental course across the life span, and pathologies. These differences are summarized in Table 60–1. TABLE 60–1. Characteristics of non-REM and REM sleep

Neuroanatomy Physiology

Non-REM sleep

REM sleep

Basal forebrain, VLPO neurons

Pontine tegmentum

HR, RR, BP, BT, EMG

↕HR, ↕RR, ↕BP, poikilothermic, EMG

Control mechanism

Process S and Process C

Independent pontine oscillator

Developmental course

Appears during first year,

across life span

adolescence, then stabilizes in adulthood

Function

Neurometabolic restoration, synaptic pruning

in early

High at birth, decreases by age 6 years to adult levels Early mammalian brain development

Pathologies Note.

= increased;

Insomnia, parasomnias, hypersomnias = decreased;

Nightmares, RBD, narcolepsy

= very greatly decreased; ↕ = highly variable.

BP = blood pressure; BT = body temperature; EMG = electromyograph; HR = heart rate; REM = rapid eye movement; RBD = REM sleep behavior disorder; RR = respiratory rate; VLPO = ventrolateral preoptic area. At any single point in time, the brain will usually be in only a single "state"—that is, either awake, in non-REM sleep, or in REM sleep. Admixtures of state, however, are possible and usually present as unusual sleep pathologies. For example, "sleep paralysis" and cataplexy are admixtures of REM sleep and awake. Sleepwalking is an admixture of partial (motor—not conscious) arousal and non-REM sleep. The major indicator of what state we are in is the type of EEG patterns and related physiological

and behavioral activity present at the moment. A second basic issue is that we usually conceptualize sleep as reflecting the balance of two fundamental processes—Process S, a homeostatic process in which the tendency to go into non-REM sleep is increased by previous time awake, and Process C, a circadian arousal process that tends to offset Process S so that we don't go to sleep until we are ready to—that is, when 1) Process S has built up and 2) the Process C arousal tendency begins to decrease. These different types of sleep and control processes should become clearer as we outline them in the following sections.

Wakefulness, Non-REM Sleep, and the Biology of Process S The neuronal systems that regulate our daily cycle of sleep and wakefulness, while quite complex, are becoming better defined. Discovery of the ascending reticular activating system (ARAS), a wakefulness-promoting neurophysiological circuit that originates in the lower and more central parts of the brain, was based in part on von Economo's observations of brain pathology in individuals who died of the epidemic of sleeping sickness or encephalitis lethargica that was seen in Europe and the United States in the early twentieth century. Mediated through two major pathways, one to the thalamus and a second more direct one to the hypothalamus and cortex, these cell groups when active promote wakefulness. The ARAS depends significantly on acetylcholine and monoamines, as well as other neuropeptide neurotransmitter systems. A second set of competing systems located primarily in hypothalamic and contiguous regions, and emphasizing neuronal activity in the ventrolateral preoptic (VLPO) region of the hypothalamus, promotes non-REM or slow-wave sleep and inhibits wakefulness. These neuronal systems depend significantly on the inhibitory neurotransmitters galanin and -aminobutyric acid (GABA) (which most hypnotics are thought to modulate). Cells in the VLPO system appear to be activated by a buildup of adenosine secondary to duration of preceding wakefulness (Basheer et al. 2004). The longer a person has been awake, the more likely it is that sleep will be triggered, and the adenosine antagonist caffeine tends to prolong wakefulness. Although the ARAS and the VLPO system are competing (increased activity in one decreases activity in the other), normally only one system at a time is predominant, for as a rule we are either awake or asleep and spend relatively little time in intermediate (and biologically less useful states) states. This suggests from an engineering view a type of biological flip-flop switch. Recent research indicates that such a switch may indeed exist, mediated by the lateral hypothalamic neuropeptides orexin and hypocretin, serving the function of a stabilizing system to keep the brain in either a wakeful or sleep state and preventing rapid oscillation from one state to the other (Saper et al. 2005). The role of orexin in modulating the sleep–wake system is not yet well understood, although preliminary animal studies suggest orexin antagonists induce sleep in animals and humans (Brisbare-Roch et al. 2007).

The REM State REM sleep constitutes the third major physiological state (wakefulness and slow-wave sleep being the others), with neuronal generating and control systems essentially independent of wakefulness and non-REM or slow-wave sleep. The REM state is uniquely different from either wakefulness or slow-wave sleep, may include elements of both, yet may be independent of both. Brain stem neuronal systems that have independent oscillation frequencies appear to account for the periodic generation of the REM state in all mammals, including humans. These systems largely reside in the pontine tegmentum and may constitute a separate component of the ARAS. The periods of these independent oscillations appear to be a function of body size, being approximately 2 hours in elephants, 90 minutes in humans, 60 minutes in Old World monkeys, 30 minutes in cats, 12 minutes in rats, and 6 minutes in mice. Cholinergic systems appear involved in activating REM states, and

monoamines in suppressing them. Agents that increase acetylcholine (ACh) activity, such as the acetylcholinesterase inhibitor physostigmine, increase REM sleep, and agents that increase monoamine activity, such as monoamine oxidase–inhibiting antidepressants, decrease REM sleep. It has recently been suggested that a type of neurophysiological toggle switch also exists for controlling transitions into and out of the REM state, consisting of mutually inhibitory neuronal populations that are GABA-ergic in nature, with independent pathways mediating EEG and atonia effects (Lu et al. 2006). This switch is thought to be subsidiary to the putative wake–sleep toggle switch, preventing transitions into REM during wakefulness, absent pathologies such as narcolepsy, which is thought to involve a weakened wake side of the wake–sleep switch due to loss of orexin neurons. Such a model would help explain a number of disorders in which impaired REM regulation is seen.

Process C: Circadian Physiology and Sleep A second major neurobiological system controlling the timing of sleep is termed Process C (for circadian). Like most living organisms, humans have prominent daily, or circadian, biological rhythms, which have important implications for normal sleep regulation and sleep disorders. The body's major circadian oscillator is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN can oscillate independently, and animal studies suggest that separate genes control the phase, period, and amplitude of its oscillations. Recent studies have linked specific human circadian clock genes to circadian-based sleep disorders (Hamet and Tremblay 2006). The SCN controls many biological rhythms, including those of body temperature, various hormones, and the sleep–wake cycle, or perhaps more precisely the circadian alerting tendency, which is here termed Process C. This rhythm appears coupled to the temperature rhythm, with higher body temperatures being associated with an increased tendency to wakefulness, and vice versa. The normal sleep–wake rhythm is a 24-hour rhythm that is usually synchronized to the circadian temperature and cortisol rhythm. The sleep–wake rhythm may become desynchronized when the sleep–wake schedule is abruptly changed (as occurs with a rapid time zone shift), during which the circadian oscillator initially remains on its original schedule. This desynchrony between the attempted sleep–wake schedule in the new time zone and the underlying circadian rhythm is one cause of "jet lag." Human subjects who live in caves or other dimly lit, time cue–free environments will typically adopt a sleep–wake rhythm of approximately 24.2 hours (Czeisler et al. 1999). This suggests that the normal free-running circadian period is slightly longer than 24 hours and must be "phase advanced" about 12 minutes each day to stay in synchrony with the 24-hour rhythm of the sun. Overall, it appears easier to phase-delay than to phase-advance the body's rhythms, since a phase delay is going in the "direction" of a free-running rhythm. This has practical implications in the adaptation to a new time zone. A phase delay, as in East-to-West travel (with a later bedtime), is generally easier and more quickly adjusted to than a phase advance, such as when going West to East (with an earlier bedtime). Light is a major synchronizer of circadian rhythms, and it has become apparent that, as in most other organisms, circadian rhythms in humans can be reset by appropriately timed exposure to bright light (Czeisler et al. 1986). Recent evidence suggests that short-wavelength light (shifted toward the blue end of the spectrum; wavelength ~460 nm) is more effective at modulating the activity of the SCN compared to longer-wavelength light (Lockley et al. 2006). The phase–response curve (PRC) plots how the timing of light exposure affects circadian rhythm timing. The human PRC suggests that exposure to bright light immediately before or shortly after onset of the sleep period (i.e., typically in the late evening) will tend to delay the circadian system, whereas exposure late in the sleep period, shortly before or after awakening (i.e., early morning), will tend to advance the circadian system. Light sensitivity may be related to the time of the lowest body temperature (the "nadir" of the body

temperature circadian rhythm), with light exposure just prior to the body temperature nadir phase delaying the circadian rhythms and light exposure just after the nadir phase advancing the circadian rhythms. The human PRC provides useful information for timing the use of bright-light exposure as a therapeutic modality for treatment of jet lag or circadian rhythm disorders resulting from shift work. The hormone melatonin, secreted by the pineal gland at night, appears to influence circadian rhythms. Its secretion is regulated by light information relayed to the pineal gland from the SCN. Melatonin secretion can be blocked by exposure to bright light during normally dark times. There is emerging evidence that melatonin can be used to reset the circadian system, to treat circadian rhythm disorders, and possibly to treat jet lag and work shift change (Brzezinski 1997), although it generally does not work well as a hypnotic agent. Although the therapeutic use of melatonin is receiving considerable media attention, it has been classified as a food supplement and is available over the counter. The take-away point here is that both Process S and Process C have specific biological underpinnings, and pathologies in either or both can result in disturbed sleep and complaints of insomnia. Part of the differential diagnosis of insomnia is attempting to separate the two systems in terms of their independent contribution to the complaint, as this impacts treatment.

Functions of Sleep Sleep is a function of the brain and is thought to support proper brain function. Emerging data clearly suggest sleep has a major role in both memory consolidation and brain (synaptic) plasticity (Walker and Stickgold 2006). Sleep spindle activity has been related specifically to improved memory recall performance (Clemens et al. 2005; Schabus et al. 2004), and very localized increases in very slow delta activity during sleep has been related to performance improvement in sleep-dependent learning of motor tasks, supporting its role in synaptic "pruning and tuning" (Huber et al. 2004). Sleep is likely intimately related to regulation of overall energy metabolism as well, as suggested by the effect of mild sleep restriction on changes in leptin (decreases) and ghrelin (increases) production (Spiegel et al. 2004). Both sleep restriction and excessive sleep have been reported as risk factors in the development of insulin resistance and type 2 diabetes (Yaggi et al. 2006), and it has been postulated that chronic sleep loss may be a risk factor for obesity and insulin resistance, as well as type 2 diabetes (Chaput et al. 2008; Gangwisch et al. 2007; Spiegel et al. 2005). The role of REM sleep in adult animals remains to be clearly defined, but its role in the development of the immature mammalian brain seems apparent, specific mechanisms notwithstanding. Human newborns have about 50% REM sleep, and human premature infants 80%. Newborn infants of altricial mammals like rats and cats have greater percentages of REM sleep than adult animals, while newborn infants of precocial animals like guinea pigs have lower adultlike levels of REM sleep at birth. It has been suggested that the periodic ascending brain activation associated with REM sleep may be important in developing species-appropriate neuronal pathways in the developing brain. Its role in adult animals has been postulated as involving learning and memory functions, but studies to date are inconclusive in this regard.

THE INSOMNIA COMPLAINT The duration of an insomnia complaint has a major impact on its differential diagnosis and treatment. Transient and short-term insomnias are usually stress- or environmentally related, and the cause is obvious. Although they rarely come to the attention of health care providers, their treatment is also generally straightforward, and they should, as a rule, be treated when found to prevent them from becoming more chronic. The chronic insomnia complaint requires a more systematic differential diagnosis procedure, also fortunately usually fairly straightforward. We first consider the transient and short-term complaint and then move on to a discussion of the chronic insomnia complaint.

Transient and Short-Term Insomnias Transient (several days) and short-term (several weeks) insomnias are quite common. Most individuals experience short-term trouble with sleep latency or sleep maintenance at times of stress, excitement, or anticipation; during an illness; after going to high altitudes; or accompanying sleep time changes (e.g., shift work, jet lag). Such problems rarely come to the attention of the clinician in the early stages, although, of course, clinicians will experience these problems themselves. Symptoms of insomnias can nonetheless be decreased, and daytime functioning improved, if certain guidelines are followed. Stress-related insomnia, or temporary trouble sleeping in response to excitement or worry (e.g., anticipating a trip or a forthcoming interview or examination), may appropriately be treated with a night or two of a short-half-life hypnotic agent (e.g., zolpidem 5 or 10 mg at bedtime). This medication need not necessarily be taken in anticipation of trouble sleeping; it can be placed at the bedside and taken only after the patient has been unable to fall asleep for 30–60 minutes, because it has a rapid onset and relatively short duration of action. Awakening in the middle of the night with inability to fall asleep again can be treated with zaleplon 10 mg (half-life approximately 1 hour), as long as at least 4 hours are still available for sleep. Short-term insomnias are due to more serious and prolonged stressful situations and may last up to several weeks. The concern is that, if not treated, a conditioned or learned insomnia may develop in response to concerns about not being able to go to sleep that can result in a more chronic insomnia. The appropriate treatment of transient and short-term insomnia not only improves daytime performance but also may prevent the insomnia from developing into a chronic problem. There is no reason that responsible patients who know they are susceptible to transient insomnia in relation to predictable stressful events cannot have a hypnotic agent available to use prophylactically. Bereavement is often associated with a short-term insomnia, which has been reported to respond favorably to sedative tricyclic agents (Pasternak et al. 1991).

Altitude-Related Insomnia Altitude-related insomnia may occur when individuals rapidly travel to higher altitudes, such as skiing and mountain climbing trips. High-altitude insomnia results primarily from periodic breathing with increases in sleep-related central apneas and hypopneas, which can be diminished by several days' administration of acetazolamide (125 mg once or twice a day). Acetazolamide also appears to decrease risk of developing altitude sickness. A short-acting hypnotic may also be useful for several nights. It has been demonstrated that both zaleplon (10 g) and zolpidem (10 mg) improve sleep quality at altitude without adverse effects on respiration, attention, alertness, or mood (Beaumont et al. 2007). Altitude-related insomnia normally improves spontaneously after several days, at least at altitudes below 15,000 feet. Altitude-related sleep problems can also be seen in infants but normally resolve spontaneously without specific treatment after the first night (Yaron et al. 2004).

Shift Work– and Jet Lag–Related Insomnia Attempts to sleep at times substantially different from what one is accustomed to, commonly associated with long-distance travel (jet lag) or shift work, often result in disrupted sleep and insomnia complaints. In both cases sleep is being attempted when the Process C system may be in the high arousal state, and wakefulness may be necessary when the Process C is in the low arousal state. In both shift work– and jet lag–related insomnia, there can be significant problems with both sleep and wakefulness. Shift work is the more serious of the two since it is often prolonged and is known to be associated with health and performance impairments. More than 6 million Americans work night shifts on a regular or rotating basis, and shift work sleep disorder is common in this group, with increased incidence of gastrointestinal and cardiovascular disorders and impaired family and social functioning, as well as an

increased risk of accidents (Schwartz and Roth 2006). When working shifts is necessary, efforts must be made to preserve sleep as much as possible as well as to maintain wakefulness during the work period. Such efforts can be both pharmacological and behavioral. Modafinil (200 mg) has been shown to help maintain wakefulness during work hours, but because it has a relatively long half-life (~12–15 hours), it should be taken early so as not to interfere with later sleep. The use of hypnotics to improve sleep during the sleep period must be considered in terms of the risk–benefit ratio. Bright light early during the work period, with protection from bright light late in the work period and on the way home in the morning, can help with subsequent sleep (Schwartz and Roth 2006). Jet lag also involves travel-related rapid time zone changes such that waking activities are required during the circadian sleep time and sleep is required during the circadian wake time. Symptoms are due both to this circadian desynchrony and sleep loss. Paying proper attention to light exposure following transoceanic travel and remembering that initially the circadian system responds to light as though it is still on the time zone one departed from can facilitate rapid entrainment to the new light–dark schedule. Protection of sleep with short-acting hypnotic agents during the new sleep periods for the first few nights can be helpful, as is appropriate supplemental melatonin administration (Cardinali et al. 2006).

Chronic Insomnia Chronic insomnia is of greater concern than short-term insomnia, as it is both common (the National Sleep Foundation estimates that 10%–15% of adults experience chronic insomnia) and results in substantial adverse effects on health, quality of life, and overall function, as reviewed by Krystal (2007). Chronic insomnia in adults is a risk factor for the development of anxiety and depression (Neckelmann et al. 2007; Richardson 2000). Chronic insomnia in adolescents is a risk factor for development of early adult depression and substance abuse (Roane and Taylor 2008). Chronic insomnia should be viewed not just as a sleep problem but also as a problem affecting the individual 24 hours a day.

DIFFERENTIAL DIAGNOSIS OF THE CHRONIC INSOMNIA COMPLAINT: A SIX-STEP DECISION PROCESS The differential diagnosis and effective treatment of chronic insomnia can challenge the most skilled clinician. With chronic insomnias, unlike transient and short-term insomnias, the primary cause is rarely immediately apparent, and the likelihood of more than one cause is high. Accurate diagnosis is important because different causes of insomnia can present in a similar fashion, and the appropriate treatment for one may aggravate another. Failure to systematically pursue a complete differential diagnosis may yield misdiagnoses, treatment failures, and dissatisfied patients. Most patients with chronic insomnia present with a straightforward complaint of insomnia; however, it is important to realize that a substantial disturbance in nocturnal sleep can present as complaints of chronic fatigue, impaired daytime performance, and excessive daytime sleepiness (EDS), which raises the question of a possible excessive sleep disorder. A careful history should identify such patients so that a more appropriate inquiry into nocturnal sleep habits and patterns can be undertaken. Similarly, a large variety of medical and psychiatric disorders (and sometimes their treatments) are accompanied by insomnia complaints. First in order in any patient is a detailed sleep history, which will include the type of insomnia problem (sleep onset, sleep maintenance, early awakening), when it began (childhood, recently, at time of major stress or life event), when it occurs (every night, weeknights only, at times of stress), what has been done when and by whom, previous response to treatment, how the insomnia affects daytime functioning, and similar issues. Family history is important since there are substantial genetic contributions both to basic sleep control mechanisms and to sleep pathologies (Hamet and Tremblay 2006). Development of atypical sleep-related habits counter to those of good sleep hygiene should be inquired about. A sleep diary kept for 1–2 weeks may be helpful in establishing the type, perceived

severity, and periodicity of the insomnia. For this group of insomnias, the clinician should first establish that the patient has a true insomnia and is not just a typical short sleeper. Short sleepers, although not common, do exist and may get along fine on 4–5 hours of sleep a night. They do not complain of EDS or fatigue, and usually they have no sleep complaints. Their families, however, see the patient up until midnight and then out of bed again at 4:00 A.M. and assume that he or she has a sleep problem and convince him or her to seek professional help. Such individuals need no specific treatment, although an explanation is helpful for family members. It is also important to decide whether the insomnia reflects a problem with non-REM or slow-wave sleep (more often) or REM sleep (less often). REM sleep–related insomnia complaints can result from frequent awakenings from frightening dreams or nightmares or from REM sleep behavior disorder (RBD). RBD is most often seen in older males and results from failure of proper skeletal muscle inhibition during REM such that patients can act out their dreams, often resulting in very disturbed sleep. Memory of dream content during the episode suggests RBD, which can be confirmed by polysomnography (Schenck and Mahowald 2005). With this information on hand, the differential diagnosis is facilitated by a systematic approach such as that outlined in the schematic decision tree in Figure 60–1. FIGURE 60–1. Differential diagnosis decision tree for chronic insomnia.

Note. SMSS = sleep state misperception syndrome.

Step 1—Medical Conditions Affecting Sleep Medical conditions, as well as the pharmacological treatments of medical conditions, can result in insomnia complaints. The endocrinopathies are notorious for being associated with sleep-related

complaints, as are conditions associated with chronic pain, breathing difficulties, cardiac arrhythmias, arthritis, renal failure, and central nervous system (CNS) disorders, especially the dementias. Evaluation may include a complete medical history and, if appropriate, a physical examination with relevant laboratory tests. Keep in mind the fact that the incidence of medical disorders accompanied by sleep complaints increases with age. Some of the more common medical disorders associated with impaired sleep are listed in Table 60–2. TABLE 60–2. Medical conditions commonly associated with impaired sleep Cardiovascular disorders Angina Congestive heart failure Ischemic heart disease Pulmonary disorders Chronic obstructive pulmonary disease Cystic fibrosis Asthma Sleep apnea Dyspnea from any cause Neurological disorders Dementias Parkinson's disease Central nervous system degenerative disorders Traumatic brain injury Central nervous system neoplasms Endocrinological disorders Hyperthyroidism Hypothyroidism Cushing's syndrome Addison's disease Gastrointestinal disorders Gastroesophageal reflux Peptic ulcer disease Genitourinary disorders Nocturia Renal failure Immunological and rheumatic disorders Rheumatoid arthritis

Osteoarthritis Fibromyalgia Pain and fever from any cause Metabolic disorders such as diabetes Sleep-related breathing disorders are frequently associated with insomnia complaints. Obstructive and mixed apneas are usually accompanied by other symptoms, such as snoring, excessive daytime sleepiness, and possibly cognitive problems. Central apnea is an occasional, albeit uncommon, cause of chronic insomnia, especially in older patients and at higher altitudes. The clinician should inquire whether the patient has had any subjective sense of trouble getting his or her breath or feeling like his or her breathing is interfered with, especially during the transition from wakefulness to sleep. Also ask the bed partner whether the patient has irregular breathing or pauses in his or her breathing during sleep. Snoring may be another clue (although it is more likely related to an obstructive component). Frequent apneas cause sleep fragmentation, which results in insomnia complaints and often complaints of increased daytime sleepiness (Bonnet and Arand 1997). Central sleep apnea is frequently associated with medical and neurological disorders (Thalhofer and Dorow 1997), but it may also occur in otherwise healthy individuals. It is more frequently encountered in older individuals (Ancoli-Israel et al. 1997). Both oxygen and continuous positive airway pressure (CPAP) can be used in the treatment of central apnea in patients with medical disorders (Franklin et al. 1997; Granton et al. 1996). The pharmacological treatment of central sleep apnea is less than optimal. Therapeutic options might include protriptyline (5–20 mg at bedtime), fluoxetine (10–20 mg/day), or theophylline (300–600 mg/day) (Ancoli-Israel et al. 1997), although their efficacy has yet to be clearly established in well-controlled studies. Also, a number of prescription drugs may result in insomnia complaints (prescription drug use also tends to increase with age). Commonly used medications that can produce insomnia complaints in some patients are listed in Table 60–3. TABLE 60–3. Commonly used drugs with insomnia as a side effect -Blockers Corticosteriods Adrenocorticotropic hormone Monoamine oxidase inhibitors Phenytoin Calcium channel blockers -Methyldopa Bronchodilators Stimulating tricyclics Stimulants Some selective serotonin reuptake inhibitors Thyroid hormones Oral contraceptives Antimetabolites Some decongestants

Thiazides No specific sleep abnormalities are usually associated with most medical disorders other than usually a decrease in total sleep, an increase in awakenings, and perhaps decreases in REM sleep. Fibromyalgia and chronic fatigue syndrome are very frequently associated with sleep complaints. On occasion, fibromyalgia is associated with an alpha–delta type of sleep abnormality, in which alpha frequency activity is accentuated in the slow-wave-sleep background, with a complaint of nonrestorative sleep. This pattern suggests a state of CNS hyperarousal. Sleep complaints are very common in chronic fatigue syndrome and can include insomnia, hypersomnia, nonrestorative sleep, and sleeping at the wrong time of the 24-hour period (circadian rhythm abnormalities). Conventional polysomnographic findings are generally nonspecific and include decreased sleep efficiency, decreased slow-wave sleep, increased sleep latency, and alpha–delta sleep EEG patterns (VanHoof et al. 2007). Chronic fatigue–related disturbances in regulation of underlying sleep control mechanisms are supported by several studies. One recent study found an increase in the cyclic alternating pattern in polysomnograms of chronic fatigue patients complaining of nonrestorative sleep (Guilleminault et al. 2006), and there is also evidence of decreased sleep drive (Process S) in chronic fatigue syndrome (Armitage et al. 2007). Treatment of insomnia associated with medical conditions involves first isolating and appropriately treating the medical condition and then, if the insomnia complaint persists, evaluating the possibility of a separate additional sleep disorder. Conditioned insomnia can complicate insomnia complaints in this population, and it must be separately addressed (as outlined below). Similarly, it is quite possible for a patient with primary insomnia also to have a medical condition that further disrupts sleep. A study by Rybarczyk et al. (2005) indicated that cognitive-behavioral therapy (CBT) may be effective in older patients with insomnia comorbid with other medical conditions, such as osteoarthritis, coronary artery disease, or pulmonary disease, suggesting that CBT should be considered in these conditions. Insomnia associated with acute medical conditions is appropriately treated with short-half-life hypnotic agents (e.g., zolpidem 5–10 mg, triazolam 0.125–0.25 mg, or eszopiclone 2–3 mg at bedtime) if no other contraindication to their use exists. Insomnia complaints associated with fibromyalgia and chronic fatigue syndrome are frequently resistant to treatment, although small doses of amitriptyline (10–50 mg at bedtime) or cyclobenzaprine (10 mg three times a day) have been reported to be helpful, and occasionally zolpidem (5–10 mg) will help with the associated insomnia complaints. Scharf et al. (2003) reported that treatment with sodium oxybate (Zyrem) improved both sleep abnormalities and symptoms of pain and fatigue in patients with fibromyalgia. Edinger et al. (2005) found that CBT was effective in treating sleep complaints in patients with fibromyalgia. Modafinil has been reported to decrease daytime fatigue and sleepiness in fibromyalgia patients, but its impact on sleep has not yet been reported (Schaller and Behar 2001). If a medical disorder is suspected of causing or contributing to the sleep complaint, a change of or alterations in treatment that might improve sleep should be considered. It is important, however, to remember that the differential diagnosis of a chronic insomnia complaint does not stop here—the remainder of the differential diagnosis should be completed. Dementing illnesses such as Alzheimer's disease are often associated with severe insomnia complaints that are quite disruptive to patients and families and often are the factors precipitating institutional care. Disease-associated neuropathological changes in the sleep and circadian rhythm control centers in the hypothalamus and SCN may contribute to these symptoms. Patients with Alzheimer's disease demonstrate phase-delayed body temperature and activity rhythms, with delayed sleep onset, increased nocturnal activity, and fragmented sleep, likely related to disease-associated SCN lesions. Some evidence suggests that a melatonin deficiency may be present in some patients with Alzheimer's disease (Liu et al. 1999). Sleep is also disturbed in dementia with Lewy bodies (DLB), which has been

found in up to 20% of dementia cases referred to autopsy (McKeith 2000); this disturbance is often in the realm of increased motor activity suggestive of an REM behavior disorder (Boeve et al. 1998; Ferman et al. 1999). Clearly, then, sleep and activity abnormalities associated with dementia may result from very different pathophysiologies and thus might respond to different treatments. Until such specific treatments can be based on specific pathophysiology, we should adhere to optimal environmental circadian principles (quiet, dark nocturnal environment; bright, socially stimulating daytime environment). Possible supplementation with evening melatonin and additional morning bright light may prove useful, in addition to the appropriate use of sedative-hypnotic agents, with the proviso that CNS lesions may significantly impact the response to hypnotic agents. There is evidence that behavioral treatment methods may benefit some Alzheimer's patients (McCurry et al. 2004).

Step 2—Psychiatric Disorders The presence of significant anxiety, dysphoric or cyclic mood, or frank depression with sleep complaints should alert the clinician to a possible psychiatric-related insomnia. Nocturnal panic attacks can result in insomnia complaints, even in individuals who do not have typical panic episodes during the day. Accordingly, the clinician should pay special attention to evidence of nocturnal arousals accompanied by autonomic symptoms such as tachycardia, rapid breathing, and the sense of anxiety or fearfulness. Insomnias related to psychiatric causes usually covary with the degree of psychiatric symptoms. The fear of not being able to get to sleep seen in patients with conditioned insomnia ("I can't turn off my thoughts") sometimes can be difficult to distinguish from anxiety, but treatments may differ (e.g., CBT for conditioned insomnia, anxiolytics for anxiety). Psychiatric disorders, especially disorders associated with anxiety or depression, frequently include insomnia as an associated symptom. Chronic anxiety is not infrequently associated with sleep-onset insomnia or sleep-maintenance insomnia, whereas depression is not infrequently associated with early-morning awakening. These associations are not specific enough to be diagnostic, however, and a systematic psychiatric evaluation is necessary. Many depressive disorders appear to be accompanied by shortened REM latency, increased REM density during the first REM period of the night, and deficient slow-wave sleep. To date, however, such findings are not sufficiently specific to merit the cost of a polysomnogram. Antidepressant agents, although effective for the patient's depression, may have significantly different effects on sleep—a possibility that is useful to bear in mind. Table 60–4 shows sleep-related effects of the major antidepressant groups. TABLE 60–4. Overview of the effects of antidepressants on sleep Drug

Continuity

SWS

REM sleep

Sedation

TCAs Amitriptyline (Elavil)

++++

Doxepin (Sinequan)

++++

Imipramine (Tofranil)

++

Nortriptyline (Pamelor)

++

Desipramine (Norpramin)

+

Clomipramine (Anafranil)

±

MAOIs Phenelzine (Nardil)

Drug

Continuity

SWS

REM sleep

Sedation

Tranylcypromine (Parnate) SSRIs Fluoxetine (Prozac)

±

Paroxetine* (Paxil)

±

Sertraline (Zoloft) Citalopram (Celexa) +

Fluvoxamine (Luvox) Others Bupropion (Wellbutrin) Venlafaxine (Effexor)

++

Trazodone (Desyrel)

++++

Mirtazapine (Remeron)

++++

Duloxetine (Cymbalta) Note.

= increased;

= decreased;

= no change; + = slight effect; ++ = small effect; +++ = moderate

effect; ++++ = great effect; ± = no significant effect. EEG = electroencephalogram; MAOIs = monoamine oxidase inhibitors; REM = rapid eye movement; SSRIs = selective serotonin reuptake inhibitors; SWS = slow-wave sleep; TCAs = tricyclic antidepressants. *When taken at bedtime, paroxetine potentially decreases sleep continuity less than other SSRIs. Source. Adapted from Winoker A, Reynolds C: "Overview of Effects of Antidepressant Therapies on Sleep." Primary Psychiatry 1:22–27, 1994. Used with permission. The choice of an antidepressant agent for a specific patient, all other things being equal, might well take into account the type of accompanying sleep complaint and the therapeutic effect on sleep desired. Typically, resolution of the depression will be accompanied by reduction in the sleep complaints. If, for a patient already complaining of insomnia, an antidepressant with a known high incidence of insomnia side effects is chosen, it may be useful to augment it with a hypnotic agent early in the course of treatment. Treatment of insomnia associated with anxiety can incorporate a benzodiazepine with sedativehypnotic properties with a sufficient bedtime dose to augment sleep. Many antianxiety agents, such as sedative tricyclics, have sedative-hypnotic properties as well, which facilitate the management of the insomnia component. Panic attacks can occasionally arise exclusively from sleep (Rosenfeld and Furman 1994); treatment in such cases should probably follow conventional panic attack treatment strategies. Mirtazapine, an antidepressant with antianxiety properties (Anttila and Leinonen 2001), may be helpful in the management of some cases of anxiety with insomnia. Bipolar disorder may be accompanied by prominent sleep disruption. Manic and hypomanic episodes may be accompanied by marked decreases in sleep, although not necessarily insomnia complaints. Sedative antidepressants have been shown to increase the risk of a shift to mania in treating insomnia complaints in bipolar depressed patients (Saiz-Ruiz et al. 1994), and the use of other hypnotic agents would therefore be more advisable in these patients. Milder cyclic mood disorders also may have associated insomnia complaints, which can be mistaken for a primary insomnia or a conditioned arousal insofar as the patients find it difficult to turn off their thinking at sleep onset or after awakening during the night. If these patients are questioned carefully, evidence of a cyclic mood

component will suggest that treatment with a mood stabilizer might be appropriate for the chronic insomnia complaint in these patients. Posttraumatic stress disorder (PTSD) is a psychiatric disorder in which sleep disturbances are a hallmark. Patients with PTSD may exhibit increased sleep latency, decreased sleep efficiency, recurrent traumatic dreams, and evidence of increased REM density (Mellman et al. 1997), as well as evidence of impaired skeletal muscle inhibition during REM sleep (Ross et al. 1994). Chronic nightmares in PTSD have been successfully treated with CBT (Davis and Wright 2007). Recent reviews suggest that a variety of medications may be useful for insomnia problems associated with PTSD, including the atypical antipsychotic olanzapine and the 1-adrenoreceptor antagonist prazosin, and possibly serotonin 2 (5-HT2) receptor antagonists (van Liempt et al. 2006), and residual insomnia in PTSD patients has been treated with CBT (Deviva et al. 2005). Overall, however, satisfactory treatment of sleep problems in PTSD remains elusive.

Step 3—Substance Misuse A careful drug history will help to identify those patients who have used sedatives or hypnotics, including alcohol, nightly for many months to years in order to fall asleep and who have developed a chronic insomnia secondary to substance misuse. Similarly, a history of stimulant use or other inappropriate drug use may result in a sleep disorder. A history of chronic or excessive drug or alcohol use recounted by the patient or, equally important, by a family member or friend suggests that further workup in this area is required. Psychotropic dependence—the perceived need to "take a pill" to diminish anxiety about potentially not being able to sleep—is not always easy to distinguish from physical dependence—the actual need for the physiological effects of medication in order to maintain sleep. Alcohol remains a significant problem, as do stimulants and other drugs of abuse. Alcohol-dependent sleep disorder occurs in those who habitually "self-medicate" with alcohol to induce sleep. Alcohol does tend to decrease sleep latency and wakefulness during the first 3–4 hours of sleep. It also suppresses REM sleep and leads to REM rebound (with the possibility of vivid dreams or nightmares), with fragmented sleep during the latter part of the night. Treatment includes withdrawal of alcohol, with long-term abstinence as the goal. When necessary, sedation can be provided by judicious use of antihistamines (e.g., diphenhydramine [25–50 mg] or cyproheptadine [4–24 mg]). Chronic use of stimulants leads to prolonged sleeplessness, and their withdrawal is followed by a period of hypersomnolence. A chronic insomnia complaint is often seen in long-term stimulant abusers even when they are not actively abusing the agents. Treatment is similar to that of alcohol-induced sleep disorder. Antikindling agents such as carbamazepine (100–600 mg/day) or divalproex (250–1,500 mg/day) may help when CNS hyperarousal/kindling is evident, as is sometimes seen in postcocaine panic disorder in polysubstance abusers. Habituation to benzodiazepine agents does not usually result in insomnia unless they are too rapidly withdrawn, in which case the withdrawal syndrome may include insomnia. Doses should be tapered by one therapeutic dose per week. In all cases of substance abuse sleep disorders, the insomnia complaint should emphasize behavioral treatment strategies to the fullest extent possible because psychoactive agents have already proved to be a problem.

Step 4—Circadian Rhythm Disorders Circadian rhythm disorders often present as sleep complaints. The most common is the delayed sleep phase syndrome (DSPS), which presents as sleep-onset insomnia. Typically, individuals with DSPS cannot get to sleep until 3:00–4:00 A.M. If they can then sleep until 10:00 A.M. or noon the next day, they can do fine, indicating that they may have no trouble initiating or maintaining sleep, but if they

are required to arise early to get to school or work, they complain of insomnia, and they are, of course, sleep deprived. Individuals with DSPS typically sleep in on weekends to recoup lost sleep. They often have already tried hypnotics, which are generally ineffective other than in inducing drowsiness, and their complaints are usually long-standing. DSPS typically appears in adolescence or early adulthood, and it is frequently familial. Often first-degree relatives have a history of similar sleep patterns. In DSPS patients, evidence indicates that temperature rhythms and sleep rhythms are delayed and that possibly sleep persists for a longer time following the body temperature low point, suggesting that these patients may continue to sleep through the period when bright light would be most effective in phase-advancing their circadian system (Ozaki et al. 1988). Melatonin rhythms also may be phase-delayed in DSPS (Shibui et al. 1999). Other forms of circadian rhythm disorders presenting as sleep complaints include advanced sleep phase syndrome (ASPS) and non-24-hour sleep–wake syndrome, also known as hypernychthemeral syndrome (Richardson and Malin 1996). ASPS is accompanied by retiring very early in the evening and correspondingly arising very early in the morning, a schedule that sometimes mimics that of terminal insomnia. Patients with the hypernychthemeral syndrome experience a failure of the circadian clock to entrain normally to the 24-hour day, and they sometimes experience a free-running 25-hour rhythm. This disorder is especially prevalent in blind persons, for whom light is unable to synchronize the circadian system. Some blind persons, however, are sensitive to light as an entrainer of the circadian system so long as the retina and retinohypothalamic tract are functioning normally. Treatment of circadian rhythm–based sleep disorders now most often includes both bright light and melatonin. Early-morning bright-light exposure administered after the body temperature low point, with restriction of light exposure in the evening, has been found to be effective for phase-advancing the circadian system in DSPS (Regestein and Pavlova 1995; Rosenthal et al. 1990). Evening bright-light treatment has been found to be effective in phase-delaying the circadian system and in effectively treating ASPS (Chesson et al. 1999). Melatonin has also been used successfully in the treatment of DSPS (Dahlitz et al. 1991; Lamberg 1996; Szeinberg et al. 2006), and a case report indicated its successful use in entraining the circadian system in a blind, mentally retarded child who was unresponsive to bright light (Lapierre and Dumont 1995). Melatonin is also effective in synchronizing the free-running circadian rhythm in blind persons (Lewy et al. 2006).

Step 5—Movement Disorders: Restless Legs Syndrome and Periodic Leg Movements in Sleep Restless legs syndrome (RLS) is not a true sleep disorder but rather a movement disorder that interferers with sleep. RLS is characterized by uncomfortable sensations in the calves at sleep onset that require that the patient get up and "walk them out." RLS symptoms are often maximal between the hours of 10 P.M. and 2 A.M., thus interfering with sleep. Severe untreated cases can be associated with significant sleep impairment and even skeletal injury (Kuzniar and Silber 2007). RLS is increased in pregnancy, iron deficiency, renal disease, and diabetic neuropathy. There are genetic contributions to RLS, and several candidate gene loci have been identified (Winkelmann et al. 2007). While its pathophysiology remains unclear, some evidence suggests that RLS is associated with increased intracortical excitability that can be reversed by the dopamine D2 receptor agonist cabergoline (Nardone et al. 2006). Treatment for RLS should take into account severity, and division of patients into three groups has been suggested: 1) those with intermittent RLS symptoms, 2) those with daily RLS symptoms, and 3) those with symptoms refractory to common treatments. Both behavioral and pharmacological strategies should be employed, and treatment algorithms are available (Hening 2007). Dopamine agonists have been used for treatment of RLS. Carbidopa or levodopa was used initially but frequently led to augmentation, or worsening of symptoms, with time. Ropinirole 0.5–6 mg/day in divided doses,

and pramipexole 0.125–0.75 mg have been shown to be effective in treating RLS. Gabapentin 300–1,200 mg has also been found helpful (Happe et al. 2003) Because iron deficiency can be a cause of RLS, iron supplementation can often be helpful, especially if serum ferritin levels are below 45 g/L (O'Keeffe 2005). Some evidence suggests a deficiency of iron transport into the CNS in RLS (Connor et al. 2003), and the use of intravenous iron has been reported to be helpful in severe cases but is not yet an approved treatment modality. Periodic leg movements in sleep (PLMS; formerly termed nocturnal myoclonus) consist of periodic leg jerks occurring during sleep. Physiologically they appear to consist of extensions of the great toe and dorsiflexion of the ankle, knee, and hip, and they may represent the release of Babinski-type reflexes due to enhanced spinal cord excitability during light sleep. Associated muscle contractions are usually short (0.5–1.0 second) in duration and periodic (every 20–40 seconds), with recurrent episodes. They may be associated with EEG arousals or with cyclic-alternating-pattern discharges in the EEG. There is disagreement as to whether PLMS constitutes a form of sleep pathology that should be evaluated for treatment (Hogl 2007) or a normal variant with little clinical significance and not requiring treatment (except perhaps for the bed partner experiencing the kicking activity) (Mahowald 2007). In any case, dopaminergic agents as used for RLS are the treatments of choice, but the issue remains unresolved, and individual cases should be evaluated in the context of the latest medical literature.

Step 6—Conditioned Insomnia, Primary Insomnia, and Sleep State Misperception Syndrome Group Finally, after the foregoing causes have been ruled out, a persistent chronic insomnia complaint likely falls into what we term the conditioned insomnia/primary insomnia/sleep state misperception syndrome category. This group has often been characterized as "psychophysiological insomnia" (American Academy of Sleep Medicine 2005), a term recently resurrected in the latest International Classification of Sleep Disorders (ICSD) that, while likely correct in that insomnia has both psychological and physiological components, is not of great help in separating independent causes that may respond to separate treatments. Primary insomnia is a DSM-IV-TR (American Psychiatric Association 2000) diagnostic with emerging information on the pathophysiology underlying its apparent chronic physiological hyperarousal. Conditioned insomnia is, as the name suggests, a "learned insomnia" in which a susceptible individual, after having trouble sleeping for a few nights, becomes fearful, with accompanying hyperarousal, about the very thought of going to bed or even going into the bedroom. The sleep state misperception syndrome is an interesting if still poorly understood condition that can be initially confusing, for these individuals appear unable to recognize that they have been asleep. These three types (as used here) of chronic insomnia tend to have a commonality of treatment approaches, which will likely continue to be the case until we have more data on their specific independent pathophysiologies. From a statistical and epidemiological standpoint, this category, in combination with the psychiatric causes of poor sleep, represents overall the largest group of the chronic insomnias. We believe it useful to attempt to separate the members of this category, even though they respond to the same treatment approaches. We will consider these three syndromes independently, first defining each as best we can and then discussing the common differential diagnosis and treatments options.

Conditioned Insomnia The presenting symptoms for conditioned insomnia are as follows: Insomnia complaint, in a susceptible individual, beginning at a time of stress but persisting after the resolution of the stress Fear of going to bed because of the difficulty getting to sleep Racing thoughts when finally lying down and trying to sleep (must be differentiated from anxiety and mood dysregulation)

May not be present in alternative sleep environment (couch, sleep lab, another home) Conditioned insomnia is a learned arousal state. Typically beginning at a time of stress in susceptible individuals (those with a history of fragile or easily interrupted sleep), a few nights of trouble getting to sleep or staying asleep lead to development of a fear of going to bed because of concern that sleep again will be difficult to initiate or maintain. This fear is associated with increased cognitive and physiological arousal, and soon a vicious cycle is established in which merely going into the bedroom to prepare for sleep results in a conditioned arousal response sufficient to interfere with sleep. More specifically, these individuals develop a "conditioned arousal" to the normal sleep environment. The conditioned arousal can continue long after resolution of the initial stress, and the resulting insomnia complaint can be quite chronic. Such individuals may be able to sleep on the living room couch, because they are conditioned to arouse only in their own bedroom. They may be able to nap during the day, and often sleep well on vacation or in a new environment. They may also sleep normally in the sleep lab, which is a new environment in which they may not experience conditioned arousal. Thus, a normal polysomnogram does not mean that the patient does not experience insomnia at home. Frequently, such individuals complain of not being able to turn off their thoughts at bedtime and recognize that they become fearful and aroused at the thought of going to bed. The differential diagnosis includes anxiety disorders and racing thoughts associated with a mildly hypomanic state, such as may accompany bipolar II disorder. Not surprisingly, conditioned arousal can co-occur with and complicate other causes (e.g., medical, psychiatric) of insomnia, having developed in response to the sleep difficulties associated with those disorders.

Primary Insomnia The presenting symptoms for primary insomnia are as follows: Complaint of chronic insomnia 1 month or more in duration (sometimes years), that may wax and wane in intensity and appears independent of stressful or life events. Little evidence of fear about going to bed or complaints of racing thoughts. Other causes of chronic insomnia have been ruled out, or if present appropriately treated. DSM-IV-TR criteria for primary insomnia are listed in Table 60–5. TABLE 60–5. DSM-IV-TR diagnostic criteria for primary insomnia A. The predominant complaint is difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least 1 month. B. The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or a parasomnia. D. The disturbance does not occur exclusively during the course of another mental disorder (e.g., major depressive disorder, generalized anxiety disorder, a delirium). E. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition. Recent evidence suggests a state of hyperarousal may accompany and possibly be a cause of primary insomnia. These patients evidence increases in brain metabolism using positron emission tomography (PET) neuroimaging both while awake and during sleep compared with normally sleeping control subjects (Nofzinger et al. 2004), and evidence of increased metabolism during NREM sleep using single photon emission computed tomography (SPECT) imaging (Smith et al. 2002). They also evidence increased fast-EEG activity during sleep (Merica et al. 1998; Perlis et al 2001a, 2001b). There may be genetic contributions, although specifics remain to be determined (Heath et al. 1990).

The important point is that this may be a bona fide medical disorder requiring long-term management, including possibly long-term medication for sleep.

Sleep State Misperception Syndrome Sleep state misperception syndrome (SSMS), a somewhat confusing term and a still poorly understood condition, characterizes individuals who may go to sleep, spend time asleep, and awaken, and yet not be aware of having slept. If sleep lab studies are performed to investigate the chronic insomnia complaint, findings may appear normal. However, despite evidence of normal or near-normal sleep, SSMS patients may still have symptoms seen in other patients with chronic insomnia, such as disturbed daytime vigilance (Sugerman et al. 1985). Interestingly, a "reverse sleep state misperception syndrome" has also been reported, in which a patient reported having slept normally while objectively awake (Attarian et al. 2004). Physiological studies are sparse. One study reported evidence of increased basal metabolic rate in patients with SSMS compared with control subjects, but not as high as in psychophysiological insomnia (Bonnet and Arand 1997), and there is evidence of possible sleep EEG differences (increased faster rhythms) in SSMS (Edinger and Krystal 2003). The extent to which sleep misperception may constitute a clinically meaningful subtype of chronic insomnia remains to be determined. Because the syndrome has yet to be objectively defined and requires objective evidence of lack of awareness of being in a state of EEG-defined sleep, the issue of etiology remains moot, although the usual suspects (genetics, impaired arousal regulation (cause), conditioning or learning, stress responses) come to mind.

Differential Diagnosis for the Conditioned Arousal, Primary Insomnia, and Sleep State Misperception Syndrome Group Since other causes having already been eliminated, the major differential in the case of conditioned insomnia, sleep state misperception, and primary insomnia rests upon history, symptoms, and perhaps a polysomnogram (may be helpful in SSMS). An important aspect of conditioned insomnia is that it frequently complicates insomnias resulting from other causes, and requires independent assessment and treatment. In conditioned insomnia, the history will often disclose a stressful event as initiating the insomnia, which continues after the event resolves. In conditioned insomnia, sleep complaints tend to be fixed over time, but they may covary with the degree of daytime stress. These patients often tend to be tense or "wired" individuals; thus, some individuals may be more prone than others to the development of psychophysiological insomnia. Sleep-onset insomnia does not always characterize this disorder. Some patients may be able to fall asleep rather easily, but then they may have several hours of wakefulness later in the night, again unable to turn off their thoughts. Primary insomnia tends to be more chronic without clear cut stressful initiating events. The separation of primary insomnia from chronic mild anxiety is sometimes difficult. SSMS patients may complain of getting absolutely no sleep at all—which of course is unlikely. The DSM-IV-TR criteria for primary insomnia need to be met. SSMS may not be suggested until a laboratory study (actigraphy or polysomnography) suggests a dissociation between subjective complaints and objective findings.

SLEEP LABORATORY STUDIES Are sleep laboratory studies useful in any of the insomnias? In most cases—no. An all-night sleep study or polysomnogram may be indicated in chronic insomnia patients who are suspected of having either PLMS possibly causing insomnia or a SRBD, where identification and quantification is useful. Some conditioned insomnia patients may have less trouble sleeping in the laboratory environment than at home, which results in more normal-appearing polysomnographic findings. Thus, the presence of a relatively normal polysomnogram result in the laboratory does not exclude the possibility of real

sleep difficulties in the patient's regular sleep environment. A polysomnogram can be helpful in the case of SSMS, where the findings may be within normal limits even though the patient believes he or she has obtained little or no sleep. It is questionable, however, whether the cost–benefit ratio merits a polysomnogram in the latter cases, unless there are other reasons for the study (e.g., treatment nonresponsiveness). Conventional polysomnography is designed primarily to quantify respiratory and related physiology as well as muscle activity, but it does not typically sample brain activity with sufficient temporal and spatial resolution to provide useful information about other insomnia conditions. A polysomnogram in insomnia typically shows evidence of increased sleep latency, more frequent awakenings, and lowerthan-normal total sleep and sleep efficiency, but the patient has already told you that. Functional neuroimaging studies (high-density EEG or magnetoencephalography, PET, SPECT) are research tools of potential value in better understanding disturbances in brain function underlying insomnia complaints, but they are not yet of routine diagnostic utility for most insomnia patients. Actigraphy, providing an objective measure of minute-to-minute activity over several days or weeks, may be helpful in suggesting a circadian rhythm disorder and sometimes SSMS, but while activity measures often correlate well with polysomnogram-determined sleep measures, actigraphy alone has not yet been shown to be accurate for diagnosis (Littner et al. 2003).

TREATMENT OF CHRONIC INSOMNIA It is very important to realize that more than one cause of chronic insomnia may be present—in fact, it might be stated that comorbidity is the rule, not the exception. A patient may, for example, have a medical cause and a psychiatric cause in addition to PLMS or another movement disorder–related insomnia, and may then go on to develop a "conditioned" component. Patients who are depressed with comorbid insomnia may also have a primary insomnia disorder. Thus a complete differential diagnosis should be done for each patient, which should not stop when the first likely cause is identified. Similarly, treatments should be designed to cover all appropriate causes. The question of whether all appropriate treatments should be initiated together rather than waiting to see if the first treatment modality works alone before adding another is an important issue with no clear answer. Starting several at once risks overtreatment, whereas starting only one modality to see if it works before starting the others can mean delay in obtaining relief, furthering the belief that the insomnia is intractable and possibly even leading to the development or aggravation of a conditioned component. In the absence of firm rules, good clinical judgment and a good understanding of the patient are paramount.

Combined Treatment Approach for Chronic Insomnia Recent years have seen major advances in both pharmacological and nonpharmacological (behavioral) treatments for insomnia (Erman 2005). These treatments will often be supplementary to the treatments designed specifically for medical, psychiatric, and other comorbidities, which may also be concurrent. As a general rule, a combined approach—utilizing both behavioral and pharmacological components—is preferable, recognizing that behavioral components may not always be available. The mainstay of nonpharmacological behavioral treatments is CBT, which has been well documented as an effective strategy. Additional behavioral treatments include improved sleep hygiene, biofeedback, sleep restriction, progressive relaxation, and various meditation techniques. From the pharmacological standpoint, recent years have seen the development of a series of new nonbenzodiazepine hypnotic agents that are both more effective and less troublesome than the older benzodiazepine agents.

Nonpharmacological Treatments for Chronic Insomnia Cognitive-Behavioral Therapy

CBT for chronic insomnia has proved effective in a number of recent studies (Morin 2004; Smith and Perlis 2006). CBT has three components—education, behavioral modification, and cognitive therapy (Morin 2004). The literature on CBT as an effective treatment for insomnia is extensive and compelling and was nicely reviewed by Morin (2004). Smith and Perlis (2006) outline its use as a first-line treatment for chronic insomnia, including insomnia comorbid with medical and psychiatric disorders. One recent study using CBT in the treatment of insomnia associated with breast cancer suggested improvement in both sleep and immunological function resulting from CBT (Savard et al. 2003). Two issues of concern are which patients are optimally suited (or not well suited) for CBT (Smith and Perlis 2006) and whether therapists trained in CBT are available. Recent reports indicate that CBT need not be a long-term and complex treatment program; indeed, a very brief two-session form of CBT has recently been described that can be effective in primary care settings (Edinger and Sampson 2003). Perlis et al. (2005) has published a manualized step-by-step cognitive-behavioral treatment program for insomnia that clinicians should be able to implement effectively.

Sleep Hygiene Sleep hygiene should be emphasized in the treatment of any chronic insomnia, including psychophysiological insomnia. Principles of good sleep hygiene are summarized in Table 60–6. TABLE 60–6. Sleep hygiene Regular sleep time

Establishing a regular sleep–wake schedule is very important, especially a regular time to awaken in the morning, with no more than 1-hour deviation from day to day, including weekends. Arousal time is perhaps the most important synchronizer of circadian rhythms. Awakening at 6:00 A.M. on weekdays to go to work and then sleeping until noon on weekends should be discouraged.

Proper sleep

Sleep interruptions should be minimized. The bedroom should be cool, dark, and quiet. The

environment

clinician needs to inquire specifically about noise, because patients may habituate to a noisy sleep environment and may not remember the noise, even though it continues to disrupt their sleep pattern. Patients who have convinced themselves that they can sleep only with the radio or television on should be discouraged from this practice. Attention to the radio or television may prevent their minds from wandering, or may keep them from beginning to worry about other matters, and thus assist with sleep latency, but the continuing noise will be a disruptive factor during the course of the night. Clock radios that automatically turn off may be useful.

Wind-down time

Time to wind down before sleep is important. The clinician should advise patients to stop work at least 30 minutes before sleep-onset time and to change their activities to something different and non-stressful, such as reading or listening to music.

Stimulus control

This procedure, an important component of sleep hygiene, involves removing from the bedroom all stimuli that are not associated with sleep. The bedroom should be used for sleep and, of course, sexual activity (which is often conducive to sleep). Activities such as eating, drinking, arguing, discussing the day's problems, and paying bills should be done elsewhere, because their associated arousal may interfere with sleep onset.

Avoidance of

Caffeine is quite disruptive of nocturnal sleep in many patients, and it has a long half-life.

poorly timed

Thus, caffeine consumption should be limited to the forenoon and in some individuals not

alcohol and

be continued after noon. A glass of wine or beer in the evening may help some individuals

caffeine

relax, but regularly having several drinks before bedtime for the express purpose of using the alcohol as a sedative should be discouraged. Alcohol in large doses can substantially disrupt and fragment sleep. Cigarette smoking may produce or aggravate insomnia in some patients.

Late-night

A bedtime snack such as a glass of milk, a cookie, a banana, or a similar high-tryptophan

high-tryptophan

food may help promote sleep onset in some patients.

snack Regular exercise

Periods of exercise for 20–30 minutes at least 3–4 days a week should be encouraged. Improved aerobic fitness has been shown experimentally to promote slow-wave sleep. Exercise should not occur within 3 hours of bedtime, however, because the autonomic arousal accompanying the exercise may serve to delay sleep onset.

Biofeedback Biofeedback treatment that directly teaches patients how to control autonomic functioning may be a useful therapeutic strategy (Hauri et al. 1982). Biofeedback may serve the dual function of enhancing a sense of self-control and reducing autonomic arousal. Although electromyography (EMG) and skin temperature biofeedback systems are perhaps the most commonly available forms, EEG biofeedback has been shown to be useful in some cases of chronic insomnia (Cortoos et al. 2006).

Sleep Restriction Some patients with chronic insomnia (especially elderly patients) spend greater and greater amounts of time in bed achieving less and less sleep, such that they may be in bed 10 hours or more and sleep only 6 hours. Sleep tends to spread out among the hours spent in bed, and this process further fragments nocturnal sleep. The principle of sleep restriction is to decrease substantially the time spent in bed so that sleep will consolidate to that time (Spielman et al. 1987). Restricting time available for sleep results in enhanced consolidation (which has important benefits in terms of improving actual and perceived sleep quality) and an improved subjective sense of self-control over sleep habits. The steps involved include the following: 1. Have the patient maintain a sleep diary for at least 5 nights. This diary should include a) time to bed at night, b) estimated time of sleep onset, c) number and estimated time of awakenings during the night, d) time of final awakening in the morning, and e) time out of bed. From this 5-night sleep diary data, calculate the mean value for estimated total sleep time (TST) and percentage sleep efficiency: TST divided by total time in bed. 2. Set the beginning total time in bed to equal the mean TST. For example, if the patient's estimate of his or her TST per night averaged over 5 nights is 5½ hours, set the time in bed to no more than 5½ hours, perhaps having the patient go to bed at 12:30 A.M. and get up again at 6:00 A.M. This restriction will result in increased daytime sleepiness the first several days, so the patient may need encouragement to continue with the program. 3. Instruct the patient to call in, usually to an answering machine, every morning while in the program and report his or her sleep data for the previous night, including time to bed, time of awakenings during sleep, time of final awakening, and time out of bed. 4. Calculate TST and sleep efficiency for each night. When mean sleep efficiency for 5 consecutive nights reaches 85% or better, increase time in bed by 15 minutes, by allowing the patient to go to bed 15 minutes earlier. If mean sleep efficiency declines to less than 85%, decrease time in bed by 15 minutes (but not within the first 10 days of treatment). Naps outside the prescribed time in bed are not allowed. 5. Repeat the above procedure until the patient is maintaining a sleep efficiency of 85% or better and obtaining what he or she considers to be a subjectively adequate amount of nocturnal sleep. Sleep restriction results in some unavoidable sleepiness at the beginning of the regimen, and not all patients can complete this treatment. However, those who can have a substantial chance of improving their sleep efficiency and achieving greater satisfaction with their sleep.

Pharmacological Treatment Options for Chronic Insomnia

The use of hypnotic agents in the treatment of insomnia has a long and checkered history. Early sedative-hypnotic agents such as the barbiturates, and then agents such as Noludar, Placidyl, Quaalude, and Doriden, with their potential lethality, disruption of sleep morphology, and addiction and/or habit-forming tendencies, gave the word "hypnotic" a bad reputation, to a considerable extent well deserved at the time. Such agents no longer have a place in the routine treatment of insomnia. Although chloral hydrate (500–1,000 mg) is still available for hypnotic use, it is associated with increased addiction potential and has a relatively limited range between effective and lethal dose; thus, it might best be reserved for occasional use when indicated for other reasons. Mendelson and Jain (1995) suggested that the ideal hypnotic would have a therapeutic profile characterized by rapid sleep induction and no residual effects (including memory effects). Its pharmacokinetic profile would include rapid absorption and optimal half-life, as well as specific receptor binding and lack of active metabolites. Its pharmacodynamic profile would include lack of tolerance or physical dependence and no CNS or respiratory depression. Although the ideal hypnotic agent has yet to be developed, hypnotic agents are being systematically improved with respect to most of the foregoing issues. When the benzodiazepines came on the scene in the latter part of the twentieth century, with their prominent and useful sedative, hypnotic, anxiolytic, and anticonvulsant effects, safety was improved, but habituation, tolerance, and altered sleep morphology (decreased SWS) were side effects of concern. Because these agents activate the multiple benzodiazepine receptors in the brain and enhance CNS GABAergic inhibition, they have a role in insomnia related to anxiety, where their anxiolytic and GABAergic hypnotic effects are useful. Benzodiazepine agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of insomnia are listed in Table 60–7. TABLE 60–7. Benzodiazepine agents for treatment of insomnia Drug

Half-life (hours) Absorption Typical dose (mg) Active metabolite

Triazolam (Halcion)

2–5

Fast

2.5–10

No

Temazepam (Restoril) 8–12

Moderate

7.5–30

No

Estazolam (ProSom)

12–20

Moderate

1–2

Minimal

Quazepam (Doral)

50–200

Fast

7.5–15

Yes

Flurazepam (Dalmane) 50–200

Fast

15–30

Yes

The benzodiazepine compounds differ substantially in terms of half-life, and the clinician can choose the agent with a half-life most appropriate for the clinical situation. A long-half-life hypnotic such as flurazepam (15–30 mg) or quazepam (7.5–15.0 mg) might be appropriate for an anxious patient in whom daytime anxiolytic effects are helpful if the interference with psychomotor performance is acceptable and tolerable and if both patient and physician realize that considerable buildup in blood level can be expected. Patients with difficulty sleeping through the night might benefit from intermediate-half-life agents such as temazepam (15–30 mg) or estazolam (1–2 mg). Patients who must be alert in the morning without residual daytime sedation would best be managed with a shorthalf-life agent such as triazolam (0.125–0.25 mg). Many other benzodiazepines have been used for insomnia because of their sedative-hypnotic properties, but current thinking suggests that these agents might best be reserved for those patients who have significant anxiety or who have perhaps not responded to newer hypnotic agents. Several new nonbenzodiazepine hypnotic agents have been developed that appear to act on the omega1 benzodiazepine receptor but carry less potential for the problems that may accompany benzodiazepine use, such as habituation, tolerance, and altered sleep patterns. These newer nonbenzodiazepine agents generally have in common demonstrated efficacy in treating insomnia, differing primarily in half-life and effective duration of action (Table 60–8).

TABLE 60–8. Nonbenzodiazepine agents for treatment of insomnia Drug

Half-life (hours) Absorption Typical dose (mg) Active metabolite

Zaleplon (Sonata)

1–1.5

Fast

5–20

No

Ramelteon (Rozerem)

1–2.6

Fast

4–8

Yes

Zolpidem (Ambien)

1.5–2.6

Fast

2.5–10

No

Zolpidem ER (Ambien CR) 2.8

Fast

6.12–12.5

No

Eszopiclone (Lunesta)

Fast

7.5–15

Yes

6

Zolpidem is an imidazopyridine agent active at the omega1 benzodiazepine receptor but without the same degree of potential for tolerance or rebound seen with the benzodiazepines. Zolpidem has shown no evidence of rebound insomnia after being used at 10 mg/day for up to 35 days (Monti et al. 1994; Scharf et al. 1994; Ware et al. 2007). An extended-release (XR) form of zolpidem is available that extends duration of action about 1.5 hours. Its use over a 6-month period is associated with minimal residual and rebound effects (Owen 2006a). Zaleplon is a nonbenzodiazepine pyrazolopyrimidine sedative-hypnotic agent that also acts as a benzodiazepine receptor agonist. With a short half-life of about 1.5 hours, this agent can be administered during middle-of-the-night awakenings as long as the patient has 4 hours of possible sleep time remaining (Zammit et al. 2006). Its short duration of action provides a somewhat more favorable safety profile for adult and elderly patients (Israel and Kramer 2002). Eszopiclone is a nonbenzodiazepine cyclopyrrolone agent with rapid absorption and a half-life of about 6 hours. Eszopiclone is extensively metabolized by oxidation and demethylation, and the cytochrome P450 (CYP) isozymes CYP3A4 are involved, thus agents that induce or inhibit these enzymes may influence the metabolism of eszopiclone. Some individual report a bitter taste as a side effect (Najib 2006). As a group, these agents appear to be relatively safe and effective for insomnia complaints, differing primarily in regard to half-life. With this increased safety and resulting increased worldwide use has come potentially significant problems associated with their inappropriate use or misuse, most often involving either 1) routine prescription without adequate preliminary differential diagnosis (the clinician's problem), and/or 2) taking the medication at an inappropriate time such as before having retired to bed (most often the patient's problem), resulting in inappropriate and potentially dangerous drug-induced waking behaviors. This is an issue related to proper differential diagnosis and proper treatment planning and monitoring, which needs to be addressed by improved education (still unfortunately often relatively sparse in medical school curricula). The 2005 NIH Consensus Conference on Chronic Insomnia in Adults recommended that these newer nonbenzodiazepine hypnotic agents be considered as the first-line treatment for insomnia rather than the traditional benzodiazepines. While not significantly altering sleep morphology, these agents do not specifically increase SWS, an attribute thought to be possibly desirable based on the role of SWS in memory function. Additional recently developed agents include the melatonin MT1 and MT2 receptor agonist ramelteon, approved for use in insomnia with no long-term-use restrictions (Owen 2006b). Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the suprachiasmatic nucleus (Pandi-Perumal et al. 2007). It was shown to be effective for treatment of primary insomnia in elderly adults at a dose of 4 mg or 8 mg, with no evidence of adverse next-day effects (Roth et al. 2007b). Several agents that are not yet formally approved for the treatment of insomnia have been found to selectively increase SWS. Sodium oxybate, a sedative-hypnotic agent that has been shown to increase SWS, is currently FDA approved only for use in treating narcolepsy. Its potential for abuse and limited

availability are issues of concern. Tiagabine, a GABA reuptake inhibitor that increases synaptic GABA through selective inhibition of the GABA transporter type 1 (GAT-1), has been shown to increase SWS in a dose-dependent fashion in primary insomnia at doses up to 8 mg (Walsh et al. 2006). Gaboxadol, a selective extrasynaptic GABAA agonist, has been demonstrated to increase SWS at a dose of 15 mg (Deacon et al. 2007) and to improve sleep in a phase-advance model of insomnia (Walsh et al. 2007a). Lankford et al. (2008) reported results of two randomized, placebo-controlled studies of the use of gaboxidal over a 30-night period in both young adult and elderly patient with primary insomnia. Subjects treated with gaboxidal demonstrated enhancement of PSG-measured sleep maintenance and SWS as well as improvement in subjective sleep measures. The unique extrasynaptic mechanism of action of gaboxadol involves a GABAA receptor well represented in the thalamus, suggesting a quite different mechanism of action than most other GABA agents (Wafford and Ebert 2006). The FDA has recommended limitations on quantities and duration of use for many hypnotic agents, although several recently approved agents (e.g., eszopiclone, zolpidem ER, ramelteon) have no such limitations. There are a number of other sedative agents, many of them among the tricyclic antidepressant arsenal, that have been used for insomnia, including amitriptyline, nortriptyline, trimipramine, and doxepin (which are generally antihistaminic). Trazodone is also frequently prescribed. While clearly indicated when insomnia complicates depression, their general use for insomnia has neither FDA approval nor solid scientific backing. Special caution should be used in patients with increased risk factors such as cardiac conduction defects, glaucoma, or seizure disorders. Similar considerations exist for sedating atypical antipsychotic agents, which while often quite useful for insomnia complaints, should remain in the domain of patients experiencing cognitive symptoms suggestive of possible thought disorder. That being said, the author has had patients with chronic insomnia nonresponsive to usual hypnotic agents that does respond well to very low bedtime doses of sedative tricyclics such as nortriptyline. It should be noted that a recent placebo-controlled study has found doxepin doses of 1, 3, and 6 mg to be effective for treatment of primary insomnia, demonstrating improvement of both PSG-determined and patient-reported sleep measures. Presumably at this dose the drug is acting primarily as an H1 selective antagonist (Roth et al. 2007a). FDA approval for doxepin in this dose range for insomnia is pending. Over-the-counter sleep agents and various herbal remedies found in health food stores have generally not been evaluated for hypnotic efficacy in well-controlled double-blind studies. Although some have modest sedative effects, consumers should be cautious, especially as concerns regular or excessive use of such agents. The future may see the use of orexin-modulating agents in insomnia. Orexins are involved in sleep–wake stabilization and are deficient in narcolepsy, which is accompanied by excessive sleepiness. An orexin antagonist has been shown to induce sleep in both animals and humans, but is not yet available for clinical use (Brisbare-Roch et al. 2007).

Long-Term Use of Hypnotic Agents for Chronic Insomnia The long-term use of hypnotic agents employed in the treatment of chronic insomnia is a topic of considerable concern. Short-term intermittent use is often recommended and remains a good overall principle. If a specific etiology, such as a medical or psychiatric disorder, can be identified and treated, the insomnia may resolve. Many, although not all, circadian rhythm disorders can be effectively managed with bright-light or melatonin treatment. Many patients with primary insomnia, however, may require long-term pharmacological management. In a recent study, long-term (6-month) treatment of chronic primary insomnia with eszopiclone 3 mg led to enhanced quality of life, reduced work limitations, and improved patient satisfaction with sleep without evidence of rebound insomnia following medication discontinuation (Walsh et al. 2007b). Several similar placebo-

controlled studies reported that 12.5 mg zolpidem ER administered 3–7 nights per week over a 6-month period resulted in improved daytime concentration and work performance as well as improved satisfaction with nocturnal sleep (Erman et al. 2008; Krystal et al. 2008). The use of the lowest dose of the most innocuous but most effective agent is a good rule. Unnecessary withholding of treatment should be avoided, however. Considering the known adverse effects of chronic sleep loss, in the context of the current availability of relatively safe and effective hypnotic agents, there would appear to be no reason to withhold or to limit treatment in those patients for whom a comprehensive and thorough diagnostic evaluation has established the presence of a primary insomnia disorder that would benefit from long-term treatment. The cost–benefit ratio of chronic pharmacological treatment must be carefully evaluated on an individual patient basis. Given the demonstrated effectiveness of CBT, it seems any patients being considered for long-term hypnotic treatment should at least be given the option of trying CBT to see if it might decrease the need for hypnotic use. The following three general rules might be useful to keep in mind when considering the long-term use of hypnotics: 1. Use the lowest effective dose and the shortest clinically indicated duration of use. 2. Do not put a patient on long-term hypnotic use for a chronic insomnia condition without including at the very least a good trial of behavioral treatment for insomnia. 3. Do not hesitate to prescribe long-term use of one of the newer and safer hypnotic agents when clinically indicated for an appropriately evaluated chronic insomnia condition (including but not limited to primary insomnia).

INSOMNIA IN THE ELDERLY Up to 50% of older Americans report chronic difficulties with their sleep (Foley et al. 1995), and similar numbers have been reported from other cultures. In addition to resulting dissatisfaction with sleep and aspects of daytime performance, those with sleep complaints use health services to a greater extent (Novak et al. 2004). While the differential diagnosis and treatment strategies are similar in elderly individuals, there are both physiological and behavioral aspects of aging that impact sleep that require emphasis.

Normal Aging and Sleep Control Mechanisms CNS changes associated with aging may adversely impact both Process S and Process C sleep control systems. There is evidence that the number of non-REM-promoting VLPO neurons in the hypothalamus decreases with age, beginning about after age 50 years, with the decrease being more pronounced in women than men (Hofman and Swaab 1989). By age 85 years, there may be a loss of 50% of VLPO neurons. To the extent that these VLPO neurons support the integrity of non-REM sleep, or Process S, this cell loss could be related to the increase in insomnia complaints in the elderly, especially women (Ancoli-Israel and Ayalon 2006). Additionally, the nocturnal production of melatonin decreases with age, significantly so by age 60 years, which may lead to impairment in the Process C circadian arousal control system (Cardinali et al. 2006). The possible impact of such changes should be taken into account in evaluating sleep complaints in the elderly—the use of hypnotics and/or melatonin supplementation may be especially useful (Haimov et al. 1995). Those medical and psychiatric conditions adversely impacting sleep and sometimes comorbid with insomnia increase in frequency in the elderly, and specific sleep disorders, such as RLS, sleep apnea, and REM sleep behavior disorder, also increase in incidence with age. The comorbidity of insomnia and sleep-related breathing disorders in the elderly is associated with significant impairment (Gooneratne et al. 2006). Elderly people frequently take a variety of medications that, for a variety of reasons, may either interact or act differently in the elderly person and result in altered sleep patterns or sleep behavior.

Adverse Sleep Habits and Environments in the Elderly Even the healthy elderly may live a lifestyle of restricted interests and decreased mental and physical activities, which can contribute to poorer sleep. Process S appears to be stimulated by the amount and intensity of the preceding day's mental and physical activity, and reductions in such can be expected to adversely impact Process S. Maintenance of a sleep-healthy lifestyle with vigorous mental and physical as well as social activities can certainly help here. The impact of exercise on sleep is still somewhat unclear (Driver and Taylor 2000; Kubitz et al. 1996); however, the role of improved aerobic fitness in health and well-being generally is well established. The less healthy elderly, who may reside in more restrictive environments or nursing homes, are at special risk, not only because of the foregoing but because of the adverse impact of factors such as irregular schedules, excessive nocturnal lighting, noise, and other issues adversely affecting sleep. Efforts should be made to modify and improve the living and sleeping environment before routinely moving to pharmacological interventions such as sedative-hypnotic agents.

Treatment of Insomnia in Elderly Patients Strict attention to good sleep hygiene is important, including not spending excessive time in bed and improving aerobic fitness if possible. Excessive use of caffeine, including that contained in over-thecounter analgesics, should be curtailed. Bright-light treatment has been useful in treating sleep disorders, including morning bright light for certain cases of sleep-onset insomnia (possibly caused by a mild circadian phase delay), in elderly patients. Evening bright light has been found to be effective in sleep-maintenance insomnia in healthy elderly subjects (Campbell et al. 1995). It should be kept in mind that elderly individuals may be less responsive to bright light and therefore might require a greater duration or intensity of treatment (Duffy et al. 2007). Use of pharmacological agents must be tempered by the awareness that half-lives may be extended, that risk of multiple drug interactions may be increased, and that lower-than-usual doses may be adequate. Zaleplon, because of its short half-life, may be a relatively safe agent in the elderly, and indiplon (15 mg), a nonbenzodiazepine hypnotic active at the benzodiazepine alpha1 subunit, was shown to improve sleep in elderly patients with primary insomnia during a 2-week treatment period with no significant side effects (Lydiard et al. 2006). Indiplon could potentially be released as a hypnotic in the near future. Some have suggested that use of hypnotics in elderly patients should be very conservative, with an emphasis on nonpharmacological strategies (Bain 2006; Sivertsen and Nordhus 2007) and CBT, which has been shown to be effective in elderly patients with insomnia. While concerns have been expressed about a relationship between hypnotic use and falls in the elderly, a recent study found that insomnia, but not hypnotic use, was associated with a greater risk of subsequent falls (Avidan et al. 2005). Considering the cognitive difficulties experienced by many elderly individuals possibly related to sleep impairment, a recent study demonstrating improved cognitive function in an animal model of genetically induced impaired sleep following treatment with a benzodiazepine to help improve sleep might be important (Pallier et al. 2007). It has yet to be determined whether nonpharmacological treatment of insomnia is as effective as pharmacological in reversing the adverse cognitive effects of insomnia.

CONCLUSION It is gratifying that the available treatment strategies for insomnia have improved coincidentally with our recognition of the importance of protecting sleep and treating insomnia in recent years. We are still left with an unclear understanding of the basic pathophysiology of many insomnia-related

syndromes, however, and until our knowledge base improves, we must depend on systematic differential diagnosis and treatment planning using the information available. Fortunately, with this approach, most patients with insomnia complaints can be significantly helped.

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Daphne Simeon, Eric Hollander: Chapter 61. Treatment of Personality Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.424865. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 61. Treatment of Personality Disorders WHAT DOES MEDICATION CHANGE IN TREATING PERSONALITY? Personality disorders are some of the more challenging psychiatric conditions and have traditionally been viewed by many clinicians as more difficult to treat than numerous Axis I conditions, often requiring investment in more lengthy treatments that involve a variety of modalities and approaches. It is also common to attain lesser and more modest degrees of success in treating personality disorders, with a recognition, however, that even partial modifications in people's dysfunctional interpersonal relationships, coping mechanisms, and symptomatology can bring about notably better adaptations. Psychotherapy continues to be the treatment foundation for all personality disorders, and psychotherapy studies of personality disorders on the whole find that patients with these disorders improve with treatment, with large treatment effects—two to four times greater than the improvement found in the control conditions (Perry and Bond 2000). In more recent years, the traditional psychodynamic therapy approaches have become enriched with more eclectic possibilities and structured therapies, such as dialectical-behavioral therapy for borderline personality disorder (BPD) (Linehan 1993) and various other cognitive psychotherapies (Tyrer and Davidson 2000). Although medications continue to be an adjunct to the treatment of personality disorders, and research medication treatment trials in personality disorders continue to be much fewer than those available in Axis I disorders, medications undoubtedly can play a useful role in the treatment of personality disorders, at least in some disorders and for some patients. The main indications for using medications in treating personality disorders are periods of decompensation, crises, and hospitalizations; the longer-term management of symptom clusters that are maladaptive and may be responsive to medication; and the reappearance or worsening of comorbid Axis I conditions. Frameworks have been previously described conceptualizing the medication treatment of personality disorders (Coccaro 1993; Gabbard 2000; Kapfhammer and Hippius 1998). Such frameworks must address several interesting questions. Can medication treat the underlying personality disorder per se or simply some of its symptomatic manifestations? Is medication effective at targeting Axis II symptom clusters that lie on a dimensional continuum and are subclinical variants of Axis I conditions? Can medication, in addition, treat unique symptomatology that may be more temperament related and less Axis I bound? Reflecting on these questions necessitates a brief overview of the foundations of personality, as well as an overview of the kinds of changes over time that medication treatment studies of personality disorders examine and the methodological issues involved.

Overview of Personality Personality can be broadly conceptualized as an admixture of temperament, which is strongly determined by genetics, and character, which is mainly environmentally shaped. Evidence from population twin studies indicates that personality disorders have a heritable component that presumably is attributable largely to temperament (Coolidge et al. 2001; Torgersen et al. 2000), with heritability estimates ranging from approximately 0.30 to 0.80, depending on the personality disorder. Additionally, symptom clusters within a personality disorder may have distinct heritabilities. For example, there is evidence in BPD that affective and impulsive traits show independent familial

transmission (Silverman et al. 1991). One of the more widely used temperament models in the mainstream psychiatric literature is Cloninger's psychobiological model of personality, which delineates four basic and independent temperaments—novelty seeking, harm avoidance, reward dependence, and persistence—which contribute about 50% to the formation of personality (Cloninger et al. 1993). It was initially postulated that there was a single neurochemical axis underlying each temperament: dopamine for novelty seeking, serotonin for harm avoidance, and norepinephrine for reward dependence. However, recent genetic studies have not lent support to this simplistic conceptualization but have rather begun to suggest that each temperament dimension may be more complexly determined by several neurochemical systems and specific receptor types (Comings et al. 2000). In addition, we do not yet have behavioral genetic studies confirming the genetic nature of temperament and the nongenetic nature of character, and thus this traditional dichotomy must not be taken for granted (Cravchik and Goldman 2000). Conversely, when character is being reflected on, other aspects of the personality are evoked, those presumed to be shaped by early parental influences, other environmental effects, trauma, and life stressors, leading to intrapsychic structure or organization characterized by particular self-representations, mechanisms for regulating self-cohesion and self-esteem, internalized object relations, defensive styles, and predominant cognitive schemata. The widely held assumption is that these constituents of character are not predominantly biologically driven and, therefore, are not highly amenable to medication treatment. Although the clinical wisdom of this outlook is largely taken for granted, some caution is called for. The degree to which aspects of character are biologically determined is a largely unexplored area, notable for the absence of studies rather than the presence of negative studies. This is due, at least in part, to the complexity of character concepts, which makes them more difficult to operationalize and study than simple symptoms, as well as the traditional divergence and absence of collaboration between psychodynamic and phenomenologically or biologically oriented scientists. On a second note of caution, the assumption that if something is strongly biologically driven, it will respond better to pharmacotherapy, and if it is more environmentally determined, it will be more amenable to psychotherapy, is partially a fallacy. Genetically, high cholesterol can be partly treated with appropriate diet. In strongly biologically driven disorders such as obsessive-compulsive disorder (OCD), pharmacotherapy and cognitive-behavioral therapy can have comparable therapeutic efficacy and are accompanied by similar brain activity changes (for details, see Baxter et al. 1992; Schwartz et al. 1996).

Medication and Personality Disorders Unfortunately, aspects of character organization, and measures of these, traditionally have been excluded from pharmacological trials in treating personality disorders; thus, again we are faced with an absence of studies rather than negative studies. In one small study that partially addressed this question (Mullen et al. 1999), defense mechanisms as measured by the Defense Style Questionnaire and personality organization as measured by the Inventory of Personality Organization were assessed before and after treatment of major depression. Compared with the nonresponders, the responders showed a significant reduction in the use of primitive defenses. Personality organization did not change, but this was assessed in only a small subgroup of patients. It does make sense that treating symptoms such as affective and impulse dysregulation could have a notable effect on self-perception, self-esteem, and relationships with others and thus could positively affect character, even if not modifying its core. Indeed, several treatment studies of Axis I disorders found a decrease in comorbid Axis II disorders after treatment of the target disorder, and this finding may in part reflect some shift in character structure when gross symptomatology is stabilized (Baer et al. 1992; Noyes et al. 1991). Furthermore, some evidence indicates that patterns of relationships between the more "biologically driven" temperament traits and the more "experience driven"

character traits may exist within a given personality disorder. For example, in BPD, the trait of affective instability has been found to be associated with the defenses of splitting, projection, acting out, passive aggression, undoing, and autistic fantasy, whereas the trait of impulsive aggression was positively associated with the defense of acting out and negatively associated with the defenses of suppression and reaction formation (Koenigsberg et al. 2001). Another caveat in the biological versus nonbiological conceptualization of personality disorders is that some are typically viewed, with some supporting evidence, as more biologically driven than others, possibly lying on a continuum with biologically well-characterized Axis I disorders (Siever et al. 1991). The main biologically driven personality disorders are schizotypal personality disorder, which can be conceptualized as a schizophrenia spectrum disorder with supporting familial and biological data; BPD, which can be viewed as a mood spectrum disorder; and avoidant personality disorder, which may lie on a continuum with social phobia. Gitlin (1993) described three conceptual frameworks for the pharmacotherapy of personality. The first is categorical, proposing that the medications treat the disorder itself as a whole. This model may be more plausible when one is considering the aforementioned more strongly biologically driven personality disorders. Although it is compelling to speculate that medications may treat more than the manifest symptoms of personality, as we just described, evidence for this is lacking, and we hope that it will be addressed by future study designs. The second framework is dimensional, most supported by the literature to date, and the one adopted in this chapter. It proposes that pharmacotherapy targets core trait vulnerabilities, manifested as symptom clusters, that may cut across the various personality disorders or may even represent Axis I subclinical variants. The major four such dimensions that are consistently cited in the literature are cognitive–perceptual, impulsivity–aggression, mood instability–lability, and anxiety–behavioral inhibition (see Siever and Davis 1991; Soloff 1990). The various personality disorders thus present with various admixtures of these trait symptom clusters (these are described further in the sections detailing the pharmacological treatment of each disorder). The third conceptual model speculates that in treating Axis II personality disorders with medication, efficacy results from the treatment of Axis I disorders that may be masked or distorted by the prominent personality features. For example, individuals with avoidant personality disorder may in fact have a very chronic and pervasive generalized type of social phobia that is being interpreted as personality pathology. This model, in our view, has become less useful in recent times as both clinicians and researchers have become more educated and adept in diagnosing on both axes and reflecting on their interactions. Another important area in critically assessing the medication treatment trials of personality disorders is an awareness of the significant methodological challenges that face this field (Coccaro 1993; Gitlin 1993). A historical issue relates to the fact that the classification of personality disorders changed dramatically with the advent of DSM-III-R in 1987 (American Psychiatric Association 1987); therefore, treatment trials prior to that time can be extrapolated to only currently defined disorders. Fortunately, at least from a research point of view, DSM-IV (American Psychiatric Association 1994) did not introduce much change in classifying Axis II disorders. Pharmacological treatment studies of personality disorders have assessed to varying degrees the comorbid Axis I or Axis II disorders that may be affecting treatment outcome. Also, personality disorders, particularly those of Cluster B, can notoriously differ in how they manifest at differing points in time. For example, BPD patients can be much more or less symptomatic, depending on a variety of environmental factors. Therefore, the traditional 8- to 12-week trial design that establishes a very-short-term baseline and then measures short-term change to an arbitrary endpoint may not be as ideally suited for studying Axis II as it is for Axis I disorders. Trials that use a more broadly defined

baseline, or examine more long-term change across multiple time points, might be more suited to studying Axis II disorders. Finally, the choice of instruments used to measure Axis II change is critical. Traditionally, these are directly borrowed from Axis I studies, such as the Hamilton Rating Scale for Depression and the Hamilton Anxiety Scale. However, other types of scales measuring less tightly Axis I bound symptoms and concepts such as mood intensity, mood lability, parasuicidal tendencies, aggressive outbursts, and subtle cognitive distortions may be better suited to accurately track Axis II symptomatology. A good example is the Overt Aggression Scale (Coccaro et al. 1991; Yudofsky et al. 1986), which measures and quantifies various types of verbally and physically aggressive behaviors against the self, objects, and others. It is currently widely used in Axis II treatment trials and had no good analog prior to its conception, exemplifying the dimensional approach to personality disorder pathology. Just as important, symptom scales are typically used in Axis II treatment studies rather than measures of character such as defenses, self-concept, personality organization, and interpersonal relationships. Character measures have been pervasively absent from trials to date, and we hope that they will become more prevalent in future studies.

Overview of the Chapter In this chapter, we review the existing medication trials for the treatment of personality disorders. The chapter is organized by personality disorder clusters, beginning with Cluster B, which has by far the largest number of studies, and followed by Clusters A and C, in which the much fewer existing studies partly overlap with those in Cluster B. We take this pragmatic approach in presenting the treatment studies because the large majority of them selected subjects by personality disorder diagnosis as the major inclusion criterion, although in reviewing these studies, it is always useful to keep in mind the target symptom dimensional approach. Following these sections, the chapter ends with a section on Axis I comorbidity, in which three pertinent questions are addressed: 1) How does the presence of Axis II comorbidity affect the likelihood of medication treatment for Axis I conditions? 2) What is the compliance rate with such treatment? and 3) What is the likelihood of this treatment being efficacious?

PHARMACOTHERAPY FOR CLUSTER B PERSONALITY DISORDERS By far the most extensive literature on pharmacological treatment of Cluster B, or any Axis II disorders for that matter, refers to BPD. The symptom clusters typically targeted in this condition, although varying from trial to trial and in instruments used, are dysregulated impulsivity and aggression, affective lability and hyperreactivity, cognitive-perceptual disorganization, anxiety, and dissociation. Dysregulation of impulses and affective instability are widely viewed as the hallmark symptoms of BPD. The remaining symptom clusters are examined less systematically in BPD studies—for example, when there is a focus on psychotic spectrum or trauma spectrum pathology.

Summary of Medication Trials Conventional Antipsychotics Cognitive-perceptual symptoms, such as paranoia, perceptual aberrations, and subtle thought disorder, although not figuring as prominently in the diagnosis of Cluster B as in Cluster A personality disorders, are definitely present in at least a subgroup of BPD patients, especially under periods of stress and decompensation. The presence of such target symptoms, more prominent in the older BPD trials that included schizotypal subgroups of patients, was the impetus for the early neuroleptic trials. Studies from the late 1970s and early 1980s began to report some efficacy of low-dose neuroleptics in treating BPD, although these studies were not placebo controlled (Brinkley et al. 1979; Leone 1982). Serban and Siegel (1984) reported on a large trial of 52 outpatients with personality disorders (46

completers: 16 with BPD, 14 with schizotypal personality disorder, 16 with both) treated for 12 weeks in a randomized, double-blind design with thiothixene 9.4 mg/day or haloperidol 3 mg/day (mean dosages). Of the total subjects, 84% showed moderate to marked improvement. The main symptoms that improved were cognitive disturbance, derealization, ideas of reference, anxiety, depression, self-esteem, and social functioning, suggesting that medicating target symptoms may have a wide-reaching effect. Outcome did not vary by borderline or schizotypal diagnosis. In another study (Montgomery and Montgomery 1982), patients with personality disorders, mostly borderline, presenting acutely with a suicide attempt and with histories of at least two prior attempts were treated with a low-dose depot neuroleptic (flupenthixol 20 mg every 4 weeks) or placebo. The neuroleptic was highly effective in reducing suicide attempts at 4–6 months of treatment. Shortly after and for the next decade, several placebo-controlled, randomized trials were published examining conventional antipsychotics in the treatment of BPD and comparing these agents with other classes of medications such as antidepressants, mood stabilizers, and benzodiazepines. Goldberg et al. (1986) studied 50 outpatients (17 with BPD, 13 with schizotypal personality disorder, 20 with both) with a bias toward psychotic presentation: at least one psychotic symptom was required for inclusion. Subjects were treated for 12 weeks with thiothixene (average dosage = 9 mg/day) or placebo. Thiothixene was significantly better than placebo in treating psychosis (especially for greater symptom severity at baseline), obsessive-compulsive symptoms, and phobic anxiety, but not depression. The results suggested narrow efficacy, because total scores for borderline pathology, schizotypal pathology, and global assessment did not change. When the results were analyzed by diagnosis, the pure BPD subgroup showed the smallest medication effect, implying that neuroleptics may have target specificity for psychotic spectrum symptoms. Another study, however, suggested that low-dose neuroleptics have a more global effect in treating BPD (Soloff et al. 1986, 1989). Ninety acutely hospitalized inpatients (35 with BPD, 4 with schizotypal personality disorder, 51 with both) were treated for 5 weeks with haloperidol (average dosage = 5 mg/day), amitriptyline (average dosage = 150 mg/day), or placebo. Haloperidol was found to have a broad-spectrum effect in symptom domains, including schizotypal, affective, and impulsivebehavioral, and was superior to amitriptyline in all areas with the exception of a comparable weak antidepressant effect. As in the Goldberg et al. (1986) study, more severe psychotic spectrum symptoms predicted a better response to haloperidol, although overall improvement was still modest. However, these results were not replicated by the same investigator group in a subsequent large study with a very similar design, consisting of 108 consecutively admitted inpatients (42 with BPD, 66 with BPD and schizotypal personality disorder) treated for 5 weeks with haloperidol, the monoamine oxidase inhibitor (MAOI) phenelzine, or placebo (Soloff et al. 1993). This study failed to replicate efficacy for haloperidol (average dosage = 4 mg/day), with the exception of some measures of overt hostile or aggressive behavior. The investigators attributed this discrepancy to the presence of more severely ill psychotic spectrum patients in the earlier studies and suggested that in less impaired BPD populations, low-dose neuroleptics had little to contribute and were poorly tolerated in terms of side effects. The above acute treatment study was extended into a 16-week outpatient continuation trial with 54 continuing participants (Cornelius et al. 1993), which again yielded essentially negative results. Haloperidol was effective only in treating irritability, and two-thirds of the subjects dropped out. Another frequently cited medication trial in BPD is a double-blind, placebo-controlled comparison of the typical antipsychotic trifluoperazine (average dosage = 8 mg/day), the benzodiazepine anxiolytic alprazolam (average dosage = 5 mg/day), the anticonvulsant and mood stabilizer carbamazepine (average dosage = 820 mg/day), and the MAOI tranylcypromine (average dosage = 40 mg/day) (Cowdry and Gardner 1988). This study found very modest effects for neuroleptic treatment. Trifluoperazine was only associated with a trend toward lessened behavioral dyscontrol, whereas

alprazolam led to paradoxical disinhibition and worsening of severe behavioral dyscontrol. Psychotic-like symptoms were not assessed. Conventional antipsychotic studies in BPD are summarized in Table 61–1. TABLE 61–1. Summary of medication treatment trials with antipsychotics in borderline personality disorder (BPD) Study

Subjects

Antipsychotic(s)

Other agent(s)

Duration Outcome

30 BPD

Depot flupenthixol

Placebo

4–6

Typical antipsychotics Montgomery and

Decreased suicide attempts

months

Montgomery 1982 Serban and

16 BPD, 14

Siegel 1984

SPD, 16 both haloperidol

Thiothixene,

Goldberg et al.

17 BPD, 13

1986

SPD, 20 both

Soloff et al.

35 BPD, 4

1986, 1989

SPD, 51 both

Cowdry and

16 BPD

—

12 weeks Improvement on multiple domains

Thiothixene

Placebo

12 weeks Decreased psychosis, anxiety

Haloperidol

Amitriptyline,

5 weeks

General improvement

Alprazolam,

6-week

Minimal decrease in behavioral

carbamazepine,

crossover dyscontrol; psychoticism not

placebo Trifluoperazine

Gardner 1988

tranylcypromine,

measured

placebo Soloff et al.

42 BPD, 66

1993

BPD and SPD

Haloperidol

Phenelzine,

5 weeks

Largely ineffective

placebo

Cornelius et al.

Continuation

16-week

1993

of above

extension

study Atypical antipsychotics Frankenburg

15

and Zanarini

refractory

1993

BPD

Schulz et al.

BPD

Clozapine

—

2–9

33% overall improvement

months

Risperidone

Placebo

8 weeks

1998

Modest improvement, no better than placebo

Schulz et al.

11 BPD (7

1999

also SPD)

Zanarini and

28 BPD

Olanzapine

—

8 weeks

General modest to moderate improvement

Olanzapine

Placebo

6 months Decreased anger, paranoia,

Frankenburg

anxiety, interpersonal

2001

sensitivity

Rocca et al.

15 BPD with

2002

marked aggression

Risperidone

—

8 weeks

Decreased aggression, improved global functioning

Study

Subjects

Antipsychotic(s)

Other agent(s)

Duration Outcome

Villeneuve and

23 BPD

Quetiapine

—

12 weeks Improved impulsivity, other

Lemelin 2005 Bellino et al.

measures, and global function 14 BPD

Quetiapine

—

2006 Perrella et al.

impulsiveness/aggressiveness 29 BPD

Quetiapine

—

2007 Schulz et al.

12 weeks Improvement especially for

12 weeks Improvement especially in aggression and low mood

314 BPD

2007

Olanzapine 2.5–20

Placebo

mg/day

12 weeks No difference in overall symptom improvement between groups

Zanarini et al. 2007

451 BPD

Low-dose

Placebo

12 weeks Greater overall improvement

olanzapine

on moderate-dose olanzapine

(2.5mg/day),

compared with two other

moderate-dose

groups

olanzapine (5–10 mg/day) Note. SPD = schizotypal personality disorder.

Atypical Antipsychotics The question of efficacy of atypical antipsychotics in BPD has received growing attention (see Table 61–1), and earlier smaller trials have now been followed by larger studies. An open trial of clozapine in 15 severely disturbed patients with refractory BPD and pronounced psychotic symptoms reported an overall 33% improvement during a 2- to 9-month treatment (Frankenburg and Zanarini 1993). Given the weekly monitoring and the common compliance difficulties of BPD patients, this antipsychotic is clearly not the optimal choice for the average patient. A case report noted partial to good response to aripiprazole treatment in 2 out of 3 patients (Mobascher et al. 2006). A small 8-week placebo-controlled risperidone trial in BPD reported similar modest symptomatic improvement in the two treatment groups (Schulz et al. 1998). An open-label trial of risperidone in 15 BPD outpatients with prominent histories of aggressive behavior and no current major Axis I disorders, using a final mean dosage of 3.3 mg/day, reported a marked reduction in aggression, along with a reduction in depressive symptoms and improved global functioning (Rocca et al. 2002). To date, there are three published quetiapine treatment trials in BPD, all open-label. In one 12-week trial in 23 outpatients, at a mean dosage of 250 mg/day, impulsivity significantly improved, as did most other outcome measures and global functioning (Villeneuve and Lemelin 2005). Another 12-week trial in 14 outpatients employed an average dosage of about 300 mg/day and reported significant improvement in various symptom domains, particularly impulsiveness/aggressiveness (Bellino et al. 2006). The third open trial followed 29 outpatients for 12 weeks, at a higher average dosage of 540 mg/day, and reported a highly significant improvement in a number of BPD features, including aggression and low mood; transient thrombocytopenia occurred in 2 patients (Perrella et al. 2007). Finally, a case report described a marked improvement in severe self-mutilation in two BPD patients treated with quetiapine (Hilger et al. 2003). An 8-week open trial examined the efficacy of olanzapine (average dosage = 8 mg/day) in 11 BPD outpatients with comorbid dysthymia, 7 of whom also had schizotypal personality disorder, and reported moderate significant improvement in all symptom domains (Schulz et al. 1999). In a small controlled olanzapine trial of 28 women with BPD (Zanarini and Frankenburg 2001), longer duration of treatment was undertaken for 6 months, a time frame more reflective of clinical reality, at a mean end

dose of 5.3 mg/day. Olanzapine was found to be significantly better than placebo in decreasing anxiety, paranoia, anger/hostility, and interpersonal sensitivity, but not depression. More recently, two much larger randomized, controlled multicenter trials have yielded mixed findings on the efficacy of olanzapine in treating BPD. One 12-week study used flexibly dosed olanzapine (range 2.5–20 mg/day) versus placebo in 314 outpatient participants with moderate disorder severity, and although both treatment groups significantly improved during treatment, there was no difference in overall change between the two groups (P = 0.66), with response rates of 65% for olanzapine and 54% for placebo group (Schulz et al. 2007). The second 12-week study of 451 BPD participants was overall similar in design and illness severity but differed in using two fixed dosages of olanzapine, low (2.5 mg/day) and moderate (5–10 mg/day), versus placebo (Zanarini et al. 2007). Treatment with the higher olanzapine dose resulted in significantly greater overall improvement than the lower dose (P = 0.018) and the placebo (P = 0.006), with response rates of 74%, 60%, and 58%, respectively. Furthermore, both olanzapine-treated groups showed significantly greater improvement on irritability, suicidality, and family life functioning relative to placebo. Adverse events more common on olanzapine included somnolence and weight gain (3.2 kilograms for the higher dose).

Antidepressants Tricyclic antidepressants (TCAs) have a limited role in treating BPD (Soloff et al. 1986, 1989). The few MAOI trials that have been conducted have yielded mixed results. Soloff et al. (1993) and Cornelius et al. (1993) found that phenelzine had only modest efficacy in BPD and was superior to placebo only against anger and hostility, but not in measures of depression, atypical depression, psychoticism, impulsivity, or global borderline severity. The investigators speculated that the short duration of treatment, the use of suboptimal phenelzine dosing (average dosage = 60 mg/day), and the fact that the atypical depression characteristics known to be responsive to MAOIs were not highly prominent in the patient samples may have contributed to these studies' failure to show efficacy for phenelzine. In contrast, a crossover placebo-controlled study of four classes of medications in BPD (Cowdry and Gardner 1988) found that the MAOI tranylcypromine was significantly superior to placebo, according to both clinicians and patients, in global ratings and in most domains that were measured, including depression, anxiety, anger, rejection sensitivity, impulsivity, and suicidality. This finding was more in accordance with an earlier report of phenelzine efficacy in BPD patients, all of whom had concurrent atypical depression (Parsons et al. 1989). Regardless of efficacy, both TCAs and MAOIs pose serious overdose and dangerous adverse effect risks that are of particular concern in this unstable, impulsive population. Investigations of newer antidepressants in treating BPD appear more promising. Preliminary reports in small open trials first suggested that the selective serotonin reuptake inhibitor (SSRI) fluoxetine at dosages ranging from 20 to 60 mg/day might be beneficial in treating depression and impulsive aggression in BPD (Coccaro et al. 1990; Cornelius et al. 1991; Norden 1989). A larger open trial (Markovitz et al. 1991) involved 22 patients with BPD or schizotypal personality disorder treated for 12 weeks with high-dose fluoxetine (80 mg/day). There was a 74% decline in self-mutilation, as well as an overall improvement in depressive symptoms, obsessive-compulsive symptoms, anxiety, interpersonal sensitivity, psychoticism, and paranoia. In a comparable open trial by the same group (Markovitz 1995), 23 BPD patients were treated openly for an initial 12-week period with sertraline 200 mg/day, and about half showed improvement in self-injurious behavior, anxiety, depression, and suicidality. Of note, half of the responders had previously failed to respond to fluoxetine, underlining the usefulness of trying more than one SSRI in this population, given the variability of responses across SSRIs. The trial was continued to a 1-year duration, and dosages in nonresponders were increased to more than 300 mg/day. By the completion of the study, on average, depression had decreased by 56% and self-injurious episodes had decreased by 93%. In another small open trial of sertraline in nine patients with personality disorders, dosages of 100–200 mg/day resulted in a decrease of impulsive

aggression over 8 weeks (Kavoussi et al. 1994). Subsequently, three controlled trials of SSRIs in borderline spectrum patients have been described. In a small double-blind trial, 17 BPD patients were randomly assigned to high-dose fluoxetine (80 mg/day) or placebo for 14 weeks. A statistically significant improvement was seen in the fluoxetine group, compared with placebo, on all measures used, including global symptomatology, anxiety, and depression (Markovitz 1995). A larger study randomly assigned 27 patients with borderline disorder or traits, at the milder end of the severity spectrum and without current major depression, to fluoxetine (average dosage = 40 mg/day) or placebo (Salzman et al. 1995). The main finding after 12 weeks of treatment was a significantly greater decrease in anger and depression with fluoxetine, despite a pronounced placebo response. Finally, in the largest trial reported (Coccaro and Kavoussi 1997), the effects of fluoxetine were investigated over a 12-week period in 40 subjects with personality disorder with marked impulsive aggression as the major entry criterion and without current major depression. About half of the subjects met Cluster B criteria (one-third of the total had BPD), 40% met Cluster C criteria, and 28% met Cluster A criteria. Compared with placebo, fluoxetine at dosages of 20–60 mg/day led to a consistent and significant decrease in aggression and irritability and in global improvement apparent by the second month of treatment, and this effect was irrespective of changes in depression or anxiety. In addition to SSRIs, newer antidepressants have been tried in BPD. In an open trial of the serotonin– norepinephrine reuptake inhibitor (SNRI) venlafaxine, 45 subjects were entered and 39 completed a 12-week treatment with an average dosage of 315 mg/day (Markovitz and Wagner 1995). A highly significant overall reduction of 41% occurred on a scale of global symptomatology. Of the 7 patients who were self-injurious at baseline, only 2 remained self-injurious at the end of treatment. Although the study was not placebo controlled, this was a fairly large trial, and the results appear promising. Studies of antidepressant treatment in BPD are summarized in Table 61–2. TABLE 61–2. Summary of medication treatment trials with antidepressants in borderline personality disorder (BPD) Study

Subjects

Soloff et al. 35 BPD, 4 SPD, 51

Antidepressant(s) Other agent(s)

Duration

Amitriptyline

5 weeks

1986, 1989 both Soloff et al. 42 BPD, 66 BPD 1993

Haloperidol, placebo

Phenelzine

and SPD

Haloperidol,

Minimally effective and only for depression

5 weeks

placebo

Modest efficacy, better than placebo

Cornelius

Continuation of

16-week

et al. 1993

above study

extension

Cowdry

16 BPD

Only for hostility/anger

Alprazolam,

6-week

Decreased depression,

and

carbamazepine,

crossover

anxiety, anger, rejection

Gardner

trifluoperazine,

sensitivity, impulsivity,

1988

placebo

suicidality

Markovitz

22 BPD or SPD

Tranylcypromine

Outcome

Fluoxetine

—

12 weeks

et al. 1991

Marked decline in self-mutilation, depression, anxiety, interpersonal sensitivity, paranoia

Markovitz 1995

23 BPD

Sertraline

—

12 weeks

Half of subjects showed improvement in self-injury, anxiety, depression, suicidality

Study

Subjects

Antidepressant(s) Other agent(s)

Continuation of

Duration 1 year

above study Kavoussi et 9 personality al. 1994

Outcome Decline in depression 56%, self-injury 93%

Sertraline

—

8 weeks

disorder with

Decreased impulsive aggression

impulsive aggression Markovitz

17 BPD

Fluoxetine

Placebo

14 weeks

1995 Salzman et 27 BPD or BPD al. 1995

Global improvement on all measures

Fluoxetine

Placebo

12 weeks

traits

Decreased anger, depression

Coccaro

40 impulsive-

and

aggressive

aggression and irritability

Kavoussi

personality disorder

irrespective of changes in

1997

(one-third BPD), no

anxiety/depression

Fluoxetine

Placebo

12 weeks

Marked decrease in

major depression Markovitz

45 BPD

Venlafaxine

and

—

12 weeks

40% global improvement, less self-injury

Wagner 1995 Note. SPD = schizotypal personality disorder.

Mood Stabilizers Mood stabilizers also have emerged as highly promising in treating BPD. The literature on lithium is unfortunately limited to older studies but looks promising. Most studies examined the effects of lithium on aggression in mentally retarded or violent inmate populations and reported some efficacy (reviewed by Wickham and Reed 1987). More directly relevant to BPD, an older study had first documented the efficacy of lithium in treating mood lability (other symptoms were not measured) in a 6-week placebo-controlled trial of 21 subjects with "emotionally unstable character disorder" (Rifkin et al. 1972). Description of the characteristics of this disorder, such as mood swings, overreactivity, impulsivity, and chronic maladaptive behaviors, clearly overlaps with current BPD criteria, although these patients may have had a bipolar variant. Finally, a single small controlled study examined lithium in subjects meeting clear BPD criteria (Links et al. 1990). Seventeen subjects received 6 weeks each of lithium, the TCA desipramine, and placebo in a randomized crossover design, and 10 completed at least two medication trials. Neither medication was better than placebo for depressive symptoms, but lithium resulted in a significant decrease in anger and suicidality according to clinician, but not patient, perception. A larger study is clearly warranted but has not been done. Anticonvulsants are used more widely than lithium in treating BPD. Cowdry and Gardner (1988) found that carbamazepine led to a dramatic and highly significant decrease in behavioral dyscontrol but had much more modest effects on mood, and patients subjectively did not feel better while taking it. This was a 6-week double-blind, placebo-controlled crossover design, comparing alprazolam (average dosage = 5 mg/day), carbamazepine (average dosage = 820 mg/day), trifluoperazine (average dosage = 8 mg/day), and tranylcypromine (average dosage = 40 mg/day) (Cowdry and Gardner 1988). Subjects were 16 female outpatients with BPD, with additional inclusion criteria of presence of prominent behavioral dyscontrol and absence of current major depression. However, another carbamazepine study, involving 20 inpatients with BPD without concurrent depression or concomitant

medications, yielded negative results (De La Fuenta and Lotstra 1994). After 4 weeks of treatment at standard therapeutic drug levels, carbamazepine was no better than placebo in treating depression, behavioral dyscontrol, or global symptomatology. More recently, anticonvulsant trials have focused on valproate and, to a lesser extent, on the newer anticonvulsants. In one open trial, 11 patients with BPD were treated openly with valproate for 8 weeks, attaining blood levels of 50–100 g/mL, and 8 patients completed the trial (Stein et al. 1995). Half of the completers were rated as overall responders, with significant decreases in depression, anxiety, anger, impulsivity, rejection sensitivity, and irritability. The trial was summarized as modestly helpful, and larger controlled studies were called for to establish valproate efficacy in BPD. In another open-label trial, 20 BPD patients were treated for 12 weeks with extended-release valproate, leading to significant overall improvement and decline in irritability and aggression (Simeon et al. 2007). In another small but placebo-controlled trial, 16 outpatients with BPD were treated for 10 weeks with valproate or placebo (Hollander et al. 2001). Global improvement was significant by two measures in patients treated with valproate, but the small sample size and dropout rate precluded statistically significant findings. In another controlled valproate study, efficacy was examined in 30 women with comorbid BPD and bipolar II disorder over 6 months of treatment (Frankenburg and Zanarini 2002). Valproate at an average dosage of 850 mg/day (with blood levels ranging between 50 and 100 g/mL) was well tolerated and resulted in significant improvement in interpersonal sensitivity, hostility/anger, and aggression compared with placebo. More importantly, there is now a large placebo-controlled multicenter trial of valproate focusing on the treatment of impulsive aggression in Cluster B personality disorders (Hollander et al. 2003). Ninety-one outpatients selected for the presence of prominent impulsive aggression and absence of bipolar I disorder or current major depression were randomly assigned to 12 weeks of treatment with placebo or valproate, at an average end dosage of 1,400 mg/day with an end mean blood level of 66 g/mL. About 10% were taking concomitant stable doses of antidepressants, and there was an approximately equal dropout rate of almost half of the subjects in each group. Valproate was well tolerated overall, with 17% of the subjects discontinuing for valproate-related adverse events. The main finding of the study was a significant decrease in impulsive aggression in the last month of treatment, reflected in significantly greater than placebo declines in overall aggression, including verbal assault, assault against objects, and assault against others, and in overall irritability. When the BPD subgroup of the above study was examined separately (Hollander et al. 2005), it was found that divalproex was indeed superior to placebo in reducing impulsive aggression in this subgroup. Divalproex-treated patients responded better as a function of higher baseline trait impulsivity symptoms and state aggression symptoms. These two effects appeared to be independent of one another, while baseline affective instability did not influence differential treatment response. With respect to the newer anticonvulsants, there is a report of a small open trial of lamotrigine, 75–300 mg/day, while concomitant psychotropic medications were tapered off, in eight patients with BPD without concurrent major depression (Pinto and Akiskal 1998). Two subjects were discontinued secondary to adverse events or noncompliance, and three did not respond. The remaining three were described as robust responders, with a marked increase in their overall level of functioning; a cessation of impulsive behaviors such as promiscuity, substance abuse, and suicidality; and maintenance of response at 1-year follow-up. We can probably expect further trials of new anticonvulsants in BPD. Medication trials of mood stabilizers in BPD are summarized in Table 61–3. TABLE 61–3. Summary of medication treatment trials with mood stabilizers in borderline personality disorder (BPD) Study

Subjects

Mood stabilizer(s)

Other agent(s)

Duration

Outcome

Study

Subjects

Mood

Other agent(s)

Duration

Outcome

Placebo

6 weeks

Decreased mood lability

stabilizer(s) Rifkin et al.

21 emotionally

1972

unstable

Lithium

character disorder Cowdry and

16 BPD

Carbamazepine

Gardner 1988

Trifluoperazine,

6-week

Marked decrease in

tranylcypromine,

crossover

behavioral dyscontrol

alprazolam, placebo Links et al.

17 BPD

Lithium

Desipramine, placebo

1990 De La Fuenta

20 BPD without

and Lotstra

depression

Carbamazepine

Placebo

6-week

Decreased anger and

crossover

suicidality

4 weeks

No effect for depression, behavioral dyscontrol,

1994 Stein et al.

global symptoms 11 BPD

Valproate

—

8 weeks

1995

Modest benefit, half responders, less depression, anxiety, anger, impulsivity, rejection sensitivity

Pinto and

8 BPD without

Akiskal 1998

depression

Lamotrigine

—

1 year

Two discontinued; three robust global responders with decreased impulsivity and suicidality

Frankenburg

30 BPD

Valproate

Placebo

6 months

Significant improvement

and Zanarini

in hostility, anger,

2002

aggression, interpersonal sensitivity

Hollander et

91 impulsive-

al. 2003

aggressive

Valproate

Placebo

12 weeks

Significant decrease in impulsive aggression

Cluster B Simeon et al.

20 BPD

2007

Valproate

—

extended release

12 weeks

Overall improvement, decreased irritability and aggression

Other Medications Another class of medications for which very limited data exist on treating BPD is the opioid antagonists. A more extensive literature supports the efficacy of naltrexone in treating impulsive addictive behaviors such as alcoholism and gambling, and therefore naltrexone would be a consideration in borderline patients with these types of problems. An open trial of naltrexone at daily dosages of 100–400 mg in 15 women with BPD found that it led to a significant decrease in dissociative symptoms and flashbacks over a course of treatment of at least 2 weeks (Bohus et al. 1999).

Conclusions and Treatment Guidelines In conclusion, several open and controlled pharmacological treatment trials of BPD have been conducted. Interpretation of the findings is somewhat complicated by the diversity of patient

presentations at treatment entry, including inpatient or outpatient status; overall severity of baseline pathology; presence of comorbid personality disorders; presence or absence of major depression, including atypical symptoms; emphasis on varying symptomatology, such as psychoticism or impulsive aggression; and use of a wide range of change measures. In addition, some of the core features of the disorder, such as identity diffusion, interpersonal vicissitudes, and primitive defensive structure, were never examined, and thus the assumption that these features are less medication responsive has not been empirically proven. As mentioned earlier, it is not unreasonable to assume that stabilization and alleviation of dysregulated affect, cognition, and impulses could have a beneficial effect on "deeper" aspects of character structure. Furthermore, concomitant psychotherapy is rarely mentioned as an exclusion criterion in the BPD medication trials, and clinical knowledge of these populations makes it reasonable to assume that it must have commonly co-occurred, even if of a general exploratory and supportive nature and not specifically geared to the structured treatment of the condition. We therefore cannot underestimate the potential influence of general placebo effects and concomitant therapies in many of these studies, and medications continue to be viewed as adjuvant features of treating patients with Cluster B disorders. Notwithstanding, it is reasonable to conclude that three classes of medications emerge as the most useful in treating BPD: serotonin reuptake inhibitors, mood stabilizers, and atypical antipsychotics. Fluoxetine, valproate, and olanzapine are the three best-studied medications to date regarding efficacy. Comparison trials of these three classes of medications, including combination strategies, have not been reported and would be of great interest in the future. Dosing guidelines are also not entirely clear because most trials aim to minimize possible undertreatment and tend to use relatively high dosages. Therefore, SSRIs may be efficacious at lower dosages than the 60 or 80 mg/day fluoxetine target dosages that have been studied. There are also no guidelines for targeted blood levels of valproate in treating BPD, although a recent large trial reported efficacy at a mean endpoint blood level of 66 g/mL (Hollander et al. 2003). For olanzapine, it appears that moderate doses are more effective than low doses (Zanarini et al. 2007). In clinical settings, it makes sense to start with lower doses because these are generally better tolerated and gradually increase the dosage while carefully monitoring response to increasing dose. Symptoms of the disorder are often chronic and by their nature considerably fluctuating; thus, the effect of each medication and dose can be more reliably assessed over longer rather than shorter durations. With respect to specific target symptoms, certain algorithms can be extrapolated from the existent trials and have been proposed on the basis of the types of symptoms that are most prevalent in each patient and the degree of response to the various medication pathways (American Psychiatric Association 2001; Soloff 1998). These algorithms give useful practical guidance, although they tend to become quickly outdated with findings of new trials. On the basis of the existent algorithms in the literature and modifying them according to the results of the latest medication trials, we propose a medication treatment approach outline for BPD as summarized in Table 61–4. TABLE 61–4. Psychopharmacological treatment guidelines for borderline personality disorder If most prominent symptoms are depression, interpersonal sensitivity, and impulsivity and aggression 1. Start with selective serotonin reuptake inhibitor (SSRI) (or related antidepressant). 2. If good response, maintain. If partial response, add mood stabilizer. If no response, switch to mood stabilizer. 3. If significant residual anger, anxiety, dyscontrol, add atypical antipsychotic.

If most prominent symptoms are mood lability, impulsivity and aggression, and family history of bipolar spectrum 1. Start with mood stabilizer (valproate; carbamazepine or lithium as alternatives). 2. If good response, maintain. If partial response, add mood stabilizer. If no response, switch to mood stabilizer. 3. If significant residual anger, anxiety, dyscontrol, add atypical antipsychotic. If most prominent symptoms are paranoia, psychoticism, hostility, and overwhelming anxiety 1. Start with atypical antipsychotic (olanzapine and risperidone most studied). 2. If good response, maintain. If partial response, add SSRI or mood stabilizer. If no response and minimal mood symptoms, switch to typical antipsychotic. Almost all Cluster B personality disorder trials have focused primarily on BPD. Although some of these trials, as individually mentioned in the overview above, included mixed samples of Cluster B participants, they did not present separate analyses for non-BPD diagnoses. Therefore, the general principle to follow in treating these other disorders would be to target symptom clusters with medications as per the guidelines developed above for BPD. In general, narcissistic and histrionic personality disorders are not characterized by the severe degree of either mood lability or impulse dyscontrol encountered in BPD, but in individuals in whom such features are more prominent or problematic, medication trials can be attempted. With regard to antisocial personality disorder, the general treatment guideline is that individuals who meet full criteria for the disorder are generally treatment noncompliant and nonresponsive. Very few pharmacological studies have been done in patients with antisocial personality disorder (Coccaro 1993), and those closest to showing at least temporary benefits are some of the earlier lithium studies that reported decreased impulsiveaggressive behavior in prison inmates (Wickham and Reed 1987). More recently, a report on four antisocial personality disorder inpatients in a maximum-security facility found decreases in impulsivity, hostility, aggressiveness, irritability, and rage reactions with quetiapine treatment at dosages of 600–800 mg/day (Walker et al. 2003). Generally, borderline patients who have some antisocial traits are more responsive to medication treatment than purely antisocial patients. Recent studies with the mood stabilizer valproate suggest that subjects with antisocial personality disorder are less responsive to the pharmacotherapy than are subjects with other Cluster B personality disorders (Hollander et al. 2003). It also has been found that borderline patients are significantly more likely than antisocial personality disorder patients to have received adequate medication trials, including anxiolytics and antidepressants (Zanarini et al. 1988).

PHARMACOTHERAPY FOR CLUSTER A PERSONALITY DISORDERS Cluster A personality disorders are characterized by cognitive distortions, perceptual distortions, mild thought disorder, constricted affectivity, and interpersonal mistrust and distance. Schizotypal personality disorder is the prime example of all these symptom clusters, whereas in paranoid and schizoid personality disorders, the cognitive-perceptual and thought disorder disturbances are not prominent. Cluster A symptoms are reminiscent of both the positive and the negative symptoms of schizophrenia, and dopaminergic dysregulation has been postulated to underlie them (Siever and Davis 1991). Schizotypal personality disorder is by far the most extensively investigated disorder of the cluster in terms of biological underpinnings (Siever 1985; Siever et al. 1990), relation to Axis I as a schizophrenia spectrum disorder (Asarnow et al. 2001; Kendler et al. 1994), and pharmacological treatment trials. All the treatment trials to date, however, have included subjects typically with BPD or

with mixed personality disorders. They have been presented already in the Cluster B section, and we summarize them again here with respect to schizotypy findings. We are not aware of any medication trials examining specifically paranoid or schizoid personality disorder. Serban and Siegel (1984) treated a sample of patients, one-third of whom had schizotypal personality disorder and one-third of whom had schizotypal personality disorder and BPD, with either thiothixene or haloperidol, without placebo, and found marked improvement in psychotic spectrum symptoms. Goldberg et al. (1986) treated a similar sample with thiothixene or placebo and found a significant improvement in psychotic symptoms with thiothixene that was more pronounced in the patients with the schizotypal rather than the borderline diagnosis. Soloff et al. (1986, 1989), in a sample containing a sizable proportion of combined schizotypal personality disorder and BPD patients, found significantly better efficacy for haloperidol compared with placebo for schizotypal symptoms but were not able to replicate this finding in a subsequent haloperidol trial with similar diagnoses (Soloff et al. 1993). They speculated that their failure to replicate might have been because the later trial included a less disturbed group of subjects with less prominent psychotic symptoms. With regard to the treatment of schizotypy with atypical antipsychotics, Schulz et al. (1999) reported improvement in psychotic symptoms in a small group of patients who received olanzapine, most of whom had schizotypal personality disorder that was comorbid with BPD. There is one published randomized, placebo-controlled trial of an atypical antipsychotic focusing exclusively on schizotypal personality disorder, which found risperidone to be significantly more efficacious than placebo (Koenigsberg et al. 2002). In this 9-week study in 25 schizotypal personality disorder patients, with low incidence of comorbid depression or BPD, low-dose risperidone was used, titrated up from 0.25 to 2 mg/day. Active medication resulted in a significantly greater decrease in negative and positive symptoms compared to placebo, and side effects were generally well tolerated. With regard to the effect of antidepressants on schizotypal personality disorder, Markovitz et al. (1991) conducted an open trial of fluoxetine in patients with BPD and schizotypal personality disorder (proportions of each unspecified) and reported improvement in psychoticism and paranoia, among numerous other symptoms. Although the results were not analyzed with respect to diagnosis, it is notable that no worsening of psychotic spectrum symptoms was found. This finding is difficult to interpret in that improved paranoia could be consequent to better affective regulation in subjects with prominent borderline traits. Of note, an older trial reported increased hostility and paranoia in a subgroup of patients treated with the TCA amitriptyline (Soloff et al. 1986, 1989). Finally, a large trial of fluoxetine that found significant benefits for impulsive aggression across Axis II disorders (Coccaro and Kavoussi 1997) included 28% Cluster A subjects, but results did not focus on psychotic spectrum symptoms and were not presented separately by cluster. In summary, the limited trials of Cluster A disorders suggest, not surprisingly, that the medications of choice are conventional antipsychotics. Given the probable need for long-term treatment of the chronic, stable psychotic spectrum symptoms in these populations, the better safety profile of atypical antipsychotics with regard to tardive dyskinesia suggests that they should be tried first, although more data exist in the literature to date examining conventional neuroleptics. Finally, in subjects with mixed traits and prominent additional affective or impulsive symptoms, SSRIs appear to cause no worsening of psychosis and may be of some adjuvant benefit.

PHARMACOTHERAPY FOR CLUSTER C PERSONALITY DISORDERS Anxiety and behavioral inhibition are the main symptoms that characterize individuals with Cluster C personality disorders, although the focus of the anxiety varies across disorders. It centers on social interaction in avoidant personality disorder, need for control of uncertainty in obsessive-compulsive personality disorder, and conflicts surrounding autonomy in dependent personality disorder. The medication trials in these disorders are very limited to date and are summarized below. In addition,

limited indirect information and insights can be gauged from studies either of related Axis I disorders or of personality traits or dimensions that are characteristic of the Cluster C personality disorders. Avoidant personality disorder has received the most attention in terms of pharmacological treatment of the Cluster C disorders because it is often viewed as lying on a continuum with Axis I social phobia. Clinically, it can be difficult to distinguish pervasive, generalized social phobia of long-standing duration from avoidant personality disorder. The latter tends to be characterized by deeper interpersonal difficulties, impairments in interpersonal skills, and a very small number of close relationships, which is often not the case even in very socially phobic individuals (Turner et al. 1986). Numerous studies have convincingly shown the efficacy of MAOIs and SSRIs in social phobia, including its generalized subtype. Although, unfortunately, these studies did not report on the presence or change in avoidant personality, they do suggest that these medications may be worth trying in treating the Axis II variant. Indeed, a few open trials and case reports have reported promising findings. Deltito and Perugi (1986) reported the case of a man with pervasive social phobia and avoidant personality disorder who responded well to phenelzine 45 mg/day, with an overall improvement in his social adjustment. Subsequently, another four cases were described of individuals with avoidant personality disorder who responded to MAOIs or fluoxetine, showing increased social confidence and well-being (Deltito and Stam 1989). Liebowitz et al. (1988) also described a sizable proportion of generalized social phobia patients who also met avoidant personality disorder criteria and showed substantial overall gain in social and occupational functioning when they were given phenelzine. However, in all these reports, most, if not all, avoidant subjects had comorbid social phobia, and the criteria used to differentiate the two conditions and their medication response were not clearly defined. In a more systematic approach, Reich et al. (1989) openly treated 14 patients with DSM-III-R social phobia with alprazolam for 8 weeks at a mean daily dosage of 3 mg and specifically measured treatment response in nine avoidant personality traits based on the DSM-III-R diagnostic criteria for avoidant personality disorder. Six of the nine avoidant traits showed significant improvement during treatment, correlating with a change in subjective anxiety and disability. Further pharmacological studies with precise dissection of social phobia from avoidant personality would be of great interest. There is hardly any literature on the pharmacological treatment of obsessive-compulsive personality disorder. Although Axis I OCD is well known to respond to serotonin reuptake inhibitors, and the older psychodynamic literature merged the two conditions as obsessional neurosis, recent studies dispute the notion that the Axis I and II variants are related. The older literature suggested the presence of definite obsessional traits in as many as two-thirds of patients with OCD, but structured personality assessments were not used. In more recent standardized evaluations, only a minority of patients with OCD had DSM-III-R obsessive-compulsive personality disorder, but other personality disorders such as avoidant or dependent were more common (Thomsen and Mikkelsen 1993). In addition, personality disorders may be more common in the presence of longer OCD duration, suggesting that they could be secondary to the Axis I disorder, and criteria for personality disorders may no longer be met after successful treatment of the OCD (Baer et al. 1990, 1992). However, a recent study presented evidence in favor of a familial spectrum of OCD and obsessive-compulsive personality disorder (Samuels et al. 2000). Regardless, no medication trials have examined this personality disorder per se, and SSRI trials in severe obsessive-compulsive personality disorder would be of some interest. One report from the early 1990s claimed that major depression in the presence of comorbid compulsive personality disorder showed better response to serotonin reuptake inhibitors than that in the absence of comorbid compulsive personality (Ansseau et al. 1991). However, this finding has not been replicated, and methodological issues have been raised, including the validity of the distinction between preexisting obsessional personality and depression-related obsessional states (Pollitt and

Tyrer 1992). We are also not aware of studies examining the pharmacological treatment of dependent personality disorder. It has been reported in the presence of comorbid Axis I panic disorder, in particular, that the initial rate of dependent personality traits was to a large extent state related and waned with the treatment of panic over a 3-year period (Noyes et al. 1991). Finally, one study examined change in core symptoms of Cluster C disorders, as measured by personality inventories in the absence of categorical Axis II assessment, in patients treated pharmacologically for Axis I disorders (Brody et al. 2000). In 37 patients treated with SSRIs for major depression or OCD, an increase in social dominance and a decrease in social hostility were found, irrespective of treatment response for Axis I, supporting the notion that serotonin reuptake inhibitors may be useful to treat avoidant personality traits. Similarly, a decrease in harm avoidance was found with treatment, which was greater in the Axis I treatment responders, again supporting the notion that serotonin reuptake inhibitors may be useful in treating obsessive-compulsive and dependent personality traits. More pharmacological studies using this dimensional approach to symptom change would be of interest in Cluster C personality disorders.

TREATMENT ISSUES IN THE PRESENCE OF AXIS I COMORBIDITY This section focuses not on the direct treatment of Axis II disorders but rather on the widely asked question of whether the presence of Axis II disorders affects the likelihood of, compliance in, or success of treating major Axis I disorders, primarily depression and anxiety. The literature in this area often shows contradictory results, and lore blends with evidence-based reality. Here we summarize the major empirical findings against the background of a widely espoused belief, not necessarily substantiated by fact, that the presence of personality disorders generally impedes the recognition and successful treatment of Axis I disorders. A community survey, conducted as part of a 1981 epidemiological study that used DSM-III (American Psychiatric Association 1980) diagnostic criteria, examined the association between Axis I and II disorders and the need for and likelihood of treatment (Samuels et al. 1994). Among subjects with any Axis I disorder, 87% of those with personality disorders were in need of treatment compared with 46% of those without, a highly significant difference. Furthermore, 18% of the subjects with personality disorders were actually receiving treatment compared with 6% of the subjects without. In essence, then, although those with comorbid personality disorders were proportionately more likely to be receiving some type of psychiatric treatment if in need of it, about 80% of the total individuals with personality disorders who were deemed as needing treatment were not receiving it. The literature is most extensive for depressive disorders. Earlier studies from the 1980s reported that depressed patients with personality disorders were less likely to receive medication treatment (Black et al. 1988; Charney et al. 1981) or received it for shorter periods (Pfohl et al. 1987) than did those without personality disorders. However, Downs et al. (1992) found that patients with Axis II comorbidity were not less likely to receive medications. Based on chart review, they were actually likely to receive greater numbers of medications, especially if they had BPD, than patients without personality disorder. In regard to the question of compliance, patients with major depression who dropped out of controlled medication trials were characterized by a significantly higher prevalence of "image distorting" defense mechanisms, such as projective identification, splitting, omnipotence, and idealization/devaluation (Mullen et al. 1999). Two review studies have examined the impact of Axis II disorders on the efficacy of pharmacotherapy in depressed patients. A descriptive review study (Mulder 2002) examined more than 50 relevant trials and concluded that better-designed treatment trials were least supportive of an adverse effect of personality pathology on depression outcome. A negative impact of personality on depression treatment was most consistently found for high neuroticism scores, whereas Cloninger's personality

dimensions bore no consistent relation to depression outcome. Similarly, when personality disorders were measured by categorical diagnostic instruments, results among the various studies were quite inconsistent, and the best-designed studies that used structured diagnostic interviews and randomized, controlled designs showed the least effect. A more recent meta-analytic review study (Kool et al. 2005) reported similar findings. When all randomized, controlled trials in adult ambulatory patients with major depression and comorbid personality disorders were examined according to strict methodological criteria, the difference in depression remission rates between the groups with and without Axis II disorders was a mere 3%, a difference neither statistically significant nor clinically pertinent. However, another study reported that acute response of major depressive disorder to electroconvulsive therapy (ECT) was poorer in patients with comorbid BPD than in patients with other or no personality disorders, a finding not accounted for by age, gender, or medication-resistance status (Feske et al. 2004). Addressing a somewhat different question, a recent 11-year prospective study examined whether the presence of Axis II comorbidity increases the likelihood of major depression recurrence or relapse and found that it did (Khan et al. 2007). In a sample of 168 outpatients receiving long-term treatment with an SSRI, Cluster A, B, and C dimensional personality traits were highly inversely correlated with duration of stability without mood disorder. Similar findings were reported when Axis II pathology was examined categorically; patients without personality disorders remained in remission from depression almost twice as long as did patients with at least one personality disorder. Less literature exists examining the relation between the treatment of Axis I bipolar disorder and the presence of Axis II personality disorder. A study of 200 bipolar I and II disorder patients examining various factors affecting medication compliance found that personality disorder comorbidity was the factor most strongly associated with poor compliance (Colom et al. 2000). About one-quarter of the subjects had at least one comorbid Axis II disorder, and of these, 17% were assessed as having good compliance, 37% medium compliance, and 44% poor compliance. Fewer studies have examined the relation between Axis II comorbidity and treatment of Axis I anxiety disorders. A recent report claims to be the first one to examine the amount of psychiatric treatment received in anxiety disorder patients as a function of comorbid personality disorder (Phillips et al. 2001). This large study examined several hundred anxious patients with a variety of Axis I diagnoses: panic disorder, generalized anxiety disorder, social phobia, OCD, posttraumatic stress disorder, and agoraphobia. Despite minor discrepancies between the two time-point assessments (1991 and 1996), the findings were fairly consistent: similar percentages of anxious subjects with and without personality disorders received medication treatment. If medicated, those with personality disorders, and especially those with BPD, were likely to be receiving a greater number of medications, specifically heterocyclic antidepressants. Thus, these investigators found no evidence for medication undertreatment of patients with Axis II comorbidity. They proposed, in reviewing trends in the pertinent literature, that influential biological studies and medication trials of Axis II disorders from the late 1980s and the early 1990s may have led toward a more favorable shift in medicating patients with personality disorders who previously may have been more likely to be assessed as needing only psychotherapy.

CONCLUSION In this chapter, we reviewed the pharmacological treatment of personality disorders, providing a conceptual framework, highlighting methodological limitations, and summarizing treatment trials to date. Almost all of these trials focused on symptom clusters, such as psychoticism, impulsivity, hostility/aggression, mood instability, and anxiety/inhibition. Trials were largely limited to BPD, although from some trials, additional conclusions can be drawn about other personality disorders in mixed-group study designs or by extrapolation of comparable symptom clusters. It is becoming increasingly established that medication treatment can play a very important role, albeit adjunctive to

psychotherapy, in the treatment of personality disorders. Even if benefits are more modest than those encountered with medication treatment of some Axis I conditions, they can still make a significant contribution to symptom reduction, functional improvement, and overall adaptation. Continued medication trials of Axis II disorders that also focus on broader dimensions of personality, including aspects of character, are eagerly awaited.

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Margaret B. Weigel, David C. Purselle, Barbara D'Orio, Steven J. Garlow: Chapter 62. Treatment of Psychiatric Emergencies, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.425634. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 62. Treatment of Psychiatric Emergencies TREATMENT OF PSYCHIATRIC EMERGENCIES: INTRODUCTION Psychiatric emergencies occur in many different situations in both clinical and nonclinical settings. While often managed in specialized psychiatric emergency and crisis stabilization units, psychiatric emergencies may also surface in other settings, such as general medical/surgical units and outpatient clinics, general emergency departments, and other nonclinical settings. The resources and personnel available in a facility will significantly affect the thoroughness of the evaluation, options for short-term stabilization, and ultimate disposition of the patient. A fully staffed, freestanding psychiatric emergency room will provide more options for patient care than will an ambulatory clinic or a general emergency medicine department. The effective practice of emergency psychiatry requires a broad range of clinical skills, including elements of psychosomatic psychiatry, behavioral neurology, psychopharmacology, individual and family psychotherapy, and addiction psychiatry. In addition, a basic knowledge of forensic and legal issues is essential. With recent large-scale changes in mental health care delivery, including the deinstitutionalization of the mentally ill and the elimination and downsizing of inpatient mental health facilities with an emphasis on cost containment, the role of an emergency psychiatrist in the mental health field has expanded dramatically. These changes impact not only specialized psychiatric facilities but also general emergency room departments. According to one study that used the National Hospital Ambulatory Medical Care Survey (NHAMCS), from 1992 until 2001 there were 53 million mental health–related general emergency room visits. This represented an increase from 4.9% to 6.3% of all emergency room visits across the decade (Larkin et al. 2005). Decision making in psychiatric emergencies involves gathering objective data from the medical history and mental status examination, the same process as in other fields of medicine. But in emergent situations, this assessment may occur without the luxury of time to develop a comprehensive differential diagnosis. Patients with emergent behavioral and psychiatric syndromes are often unable or unwilling to provide accurate historical details; therefore, the clinician must rely on collateral sources of information, including friends, family, and previous treatment providers. One consequence of this process of data collection is that absolute patient confidentiality, the standard of care in other clinical settings, is more tenuous. In the context of a psychiatric emergency, the need to acquire critical information supersedes the individual's right to privacy. In emergent situations, resources such as medical records, friends, and relatives may provide critical data for diagnosis and treatment. And depending on the patient's condition, it may not be possible to obtain his or her consent to acquire this information. This is one situation in which it is appropriate to stretch the boundaries of confidentiality in order to provide the best clinical care. The focus is on obtaining components of history while not disclosing protected information. There are other circumstances in which there is a mandated breach of confidentiality, which includes a patient's risk of harm to self or others, and the knowledge of child and elder abuse. Requirements vary by jurisdiction. Another consequence of the need to make diagnostic and treatment decisions with limited information is that these decisions should be conservative. For example, care must be taken not to rashly make a diagnosis such as schizophrenia in response to the presence of psychotic symptoms when the data do

not justify this conclusion. A 1-year study of diagnostic stability suggested that 38.7% of psychiatric emergency room patients were given a different discharge diagnosis from the inpatient service (Woo et al. 2006). Use of "rule out," "provisional," and "not otherwise specified (NOS)" qualifiers helps ensure that a patient does not receive an incorrect diagnosis that may cause additional problems in the future (American Psychiatric Association 2000). The setting in which the patient is evaluated will have a significant effect on the diagnostic formulation. A patient evaluated in a crisis stabilization facility with a 24- to 48-hour secure observation unit should receive a more definitive diagnosis than one evaluated in an emergency medicine department in a general hospital that is not equipped or staffed for long-term psychiatric observation. Following the principles of Hippocrates, the emphasis is to make treatment decisions in the best interests of the patient while balancing the need to prevent further harm. The ultimate goals are to provide adequate treatment of the underlying pathology based on a careful but succinct evaluation of the patient and to provide this treatment in the least restrictive environment while maintaining the safety of patient, clinician, and staff. Psychiatric emergencies can be divided into those that do not call for pharmacological intervention, those that may require adjunctive pharmacological intervention, and those that usually demand pharmacological intervention. The remainder of this chapter is divided along these lines.

NONPHARMACOLOGICAL PSYCHIATRIC EMERGENCIES Situations that require emergent psychiatric intervention but not psychopharmacological treatment include evaluation of need for hospitalization, assessment of suicide or homicide risk, determination of ability to care for self, and requirements to notify third parties to ensure safety of the patient or others (Table 62–1). Emergency psychiatrists are in a unique position of having to make predictions about patients' future behavior (e.g., suicide, homicide) and (to the best of their abilities) take appropriate preemptive action to prevent these outcomes. The focus is on the welfare of the patient and the safety of others with whom the psychiatrist has no therapeutic relationship. All states have civil commitment laws that allow for the involuntary hospitalization of persons who by virtue of a mental illness may be considered an imminent risk to themselves or others. Typically, these laws allow for commitments of 48–72 hours in secure receiving facilities for assessment and stabilization. Involuntary hospitalization beyond this holding period for observation and treatment generally involves some form of judicial review. TABLE 62–1. Psychiatric emergencies that do not require pharmacological intervention Emergency

Intervention

Suicidal state

Risk assessment Decision to admit

Homicidal state

Establish or rule out presence of psychiatric disorder Risk assessment Decision to admit Tarasoff notification

Grave disability, unable to care for self

Patient identification (if wandered from caregivers) Medical evaluation Decision to admit

Child, elder, spouse abuse

Notify/report to law enforcement and other agencies Referral to safe shelters

Need for Hospitalization The decision to hospitalize a psychiatric patient is dependent on several factors, but the welfare of the

patient is of the greatest importance. There should be clear, definable treatment objectives for hospitalization, and the facility in which the patient is hospitalized should be able to meet these needs. Beyond consideration of the patient's welfare, other factors can contribute to the decision of whether to hospitalize a patient (R. I. Simon 1998). These include availability of psychiatric hospital beds and admission authorization by third-party payers. A decrease in funding of mental health services has resulted in a decrease in available inpatient resources. Thus, the clinician must balance the availability of resources with the needs of individual patients. And while third-party payers may limit the ability to admit a patient to a hospital, the onus of providing appropriate care ultimately falls on the clinician. Once the decision is made to hospitalize a patient, every effort should be made to have this occur on a voluntary basis. This is the first step in establishing therapeutic rapport with patients. The indiscriminate use of involuntary commitments can set up the perception of an adversarial relationship between patients and treatment providers (Olofsson and Jacobson 2001). Patients with chronic, persisting mental illnesses will most likely require multiple hospitalizations in the course of their illness. Avoiding experiences that elicit the perception of being "locked up" against one's will is one way of facilitating the long-term care of the mentally ill patient.

Suicidal State Suicide is the eleventh leading cause of death in the United States across all age groups. As a public health issue, suicide continues to be a major problem, with a population rate around 11 deaths per 100,000, which has remained invariant over the past four decades. But there are several recent studies that suggest a slight decrease in U.S. suicide rates since selective serotonin reuptake inhibitors (SSRIs) have been introduced. Historically, one of the truly vexing problems in psychiatry is the lack of effect of specific psychiatric treatments on the suicide rate. Several studies have failed to find any association between the availability of psychiatric treatment resources and the suicide rate (Garlow et al. 2002; Lewis et al. 1994). Predicting imminent suicide in any individual patient is difficult and can provoke significant anxiety in the clinician (Pokorny 1983, 1993). Completed suicide is a rare event, but it has profound effects on both the surviving family members and friends of the victim and the physician and treatment staff (Gitlin 1999; Hendin et al. 2000). There are also potential legal ramifications of a patient's committing suicide if he or she has been in recent contact with psychiatrists and other mental health providers (R. I. Simon 2000). Recently, a relationship between antidepressant use and suicidal behaviors has been reported in the media and psychiatric literature. The impetus for this focus was the addition of a black box warning by the U.S. Food and Drug Administration (FDA) on the potential increased risk of suicidal ideation in children, adolescents, and young adults treated with SSRIs. Of note, within the study population from which the original warning was issued, there were no completed suicides. This warning stirred a debate on the risk versus the potential beneficial effects of treatment with this class of medications. Subsequent analysis of the FDA database using a standardized algorithm for assessing suicidal events, termed the Columbia Classification Algorithm of Suicide Assessment (C-CASA), suggests that misclassification of suicidal events may have led to an overestimation of true risk (Posner et al. 2007). Observational studies have shown that treatment, specifically the use of SSRIs, has a protective effect on emergent suicidal behavior (Gibbons et al. 2005, 2007; G. E. Simon and Savarino 2007). Additional research has shown the highest number of suicide attempts in the month before treatment, suggesting that suicidal behavior is often a precipitant for seeking treatment rather than a consequence of antidepressant use (G. E. Simon and Savarino 2007). This particular study compared patients entering psychotherapy to those receiving antidepressant medication, and there was no difference in the rates of suicide-related behaviors in either treatment group, strongly suggesting that suicidality is a reflection of the underlying disease and not of the treatment. One way of solving this conundrum is to use toxicological analysis to determine the presence of antidepressants in suicide

victims. One study of more than 5,000 adult suicides found most had not taken antidepressants immediately prior to death, despite being diagnosed as being depressed (Isacsson et al. 1997). Similar results were found in adolescent populations (Isacsson et al. 2005). With the addition of the black box warning and the subsequent publicity, utilization of antidepressants in the pediatric and adolescent populations has fallen, with a coincident increase in suicide-related behaviors (Nemeroff et al. 2007). In summary, despite claims to the contrary, the evidence suggests that antidepressant medications exert a protective effect on suicide risk. The relationship between suicidal ideation, attempted suicide, and completed suicide is complex (Moscicki 1997). No direct relation exists between any one of these states and the others. In one population-based study of completed suicides, 56% of the individuals were successful on the first attempt (Isometsa and Lonnqvist 1998). In another comprehensive study of completed suicides, 75% had no contact with mental health providers in the year prior to death (Appleby et al. 1999). One ominous finding in this study was that 16% of the suicides occurred while the victims were inpatients in psychiatric wards, and 24% occurred within 3 months after discharge from psychiatric facilities. In a 10-year follow-up study of patients admitted to the hospital for a medically serious suicide attempt, 25% of the cohort made a second attempt, and 12% eventually died by suicide, with the highest rate of completed suicides occurring in the 2 years following the index admission (Isometsa and Lonnqvist 1998). The expression of suicidal ideation and a history of previous suicide attempts appear to identify a large group of at-risk patients, but only a small percentage of these patients go on to complete suicide. Understanding which patients will go on to complete suicide involves a comprehensive assessment of suicide risk factors. Suicide risk is estimated by assessing both acute and chronic risk factors (Table 62–2), which include patient characteristics, nature of suicidal behavior, availability of a high-lethality means, and level of and access to psychosocial support systems (e.g., family, friends, community) (R. C. Hall et al. 1999; R. I. Simon and Gutheil 2002). This is an example of a psychiatric emergency in which acquiring reliable and accurate past and collateral history is essential, which may lead to some breach of patient confidentiality. Acute risk factors are most predictive of emergent suicidality and should carry the most weight in the decision to hospitalize a patient (Fawcett et al. 1991). TABLE 62–2. Acute and chronic risk factors for suicide Acute

Chronic

Increasing anxiety/frank panic attacks

Gender (male:female = 4:1)

Psychic turmoil

Age (18–24 years; >65 years)

Global insomnia

Chronic illness

Mood-congruent nihilistic delusions

Race (white:nonwhite = 2:1)

Profound hopelessness

Presence of a mental illness

Recent discharge from a psychiatric hospital Substance abuse/dependence Substance intoxication

Access to high-lethality means

Access to high-lethality means

Previous suicide attempts

Previous suicide attempts

Family history of suicide

Acute Risk Factors Acute risk factors are much more predictive of emergent suicidality than chronic risk factors. Acute risk factors include increasing anxiety and frank panic attacks, psychic turmoil, global insomnia, mood-congruent nihilistic delusions, profound hopelessness, and recent discharge from a psychiatric hospital (Busch et al. 2003; Fawcett 1992; Fawcett et al. 1991). Patients who are experiencing the

first three of these symptoms should be viewed as being at particularly high risk regardless of whether they verbalize suicidal ideation. In terms of recent psychiatric hospitalization, the 3-month period following discharge poses a significant period of vulnerability, with one population study indicating 7.8% of the suicide victims completed suicide within 1 month of discharge (Deisenhammer et al. 2007). Active substance intoxication is another acute risk factor. Recent alcohol consumption plays a role in 25%–50% of all suicides, and the consumption of both alcohol and cocaine may be particularly dangerous (Cornelius et al. 1998). Alcohol intoxication is related to higher rates of completed suicide, while cocaine intoxication is related to higher rates of suicidal ideation (Garlow 2002; Garlow et al. 2003). In this comprehensive series of suicide victims, 40% had alcohol or cocaine detected at the time of autopsy, indicating that the substance was consumed within 48 hours of death (Garlow 2002). Fully 21% of these suicide victims had blood alcohol levels above the legal limit for intoxication (0.08 g/mL). Cocaine intoxication doubles the risk of suicide in white teenagers compared with African American teenagers (Garlow et al. 2007). Previous suicide attempts are known precursors for completed suicide; thus, nonlethal suicide attempts are acute risk factors (Deisenhammer et al. 2007; Isometsa and Lonnqvist 1998; Tejedor et al. 1999). The risk for completion is notably higher in the time period following a suicide attempt (Conwell et al. 1996). Consideration should be given to the actual lethality of the attempt; the patient's perception of that lethality; efforts made by the patient to ensure detection or nondetection; calls for help by the patient to medical or law enforcement agencies; contacts to friends or family during the attempt; and use of a firearm. All of these factors illuminate the actual suicidal intent of a patient. A person who took a lethal overdose in a secluded location with no contact to others and who was discovered by accident represents a much higher risk than a person who took a sublethal overdose in a witnessed situation or who immediately called someone to report the overdose or ask for help. Access to firearms must always be determined in a suicide attempt and in someone who appears to be at high risk (Conwell et al. 2002; Miller et al. 2002; Romero and Wintemute 2002). Other behaviors that should be noted include giving away possessions, placing financial and legal affairs in order, and showing extreme social withdrawal or severing previous interpersonal relationships. Reliable assessment of these behaviors requires collateral history from individuals close to the patient.

Chronic Risk Factors Chronic risk factors for suicide set the background on which acute risk factors are evaluated. They are derived from population-based analyses of suicides and often are not amenable to any therapeutic intervention, since they are primarily demographic characteristics of people who have died by suicide (Kessler et al. 1999; Moscicki 1997). Males complete suicide four times more often than females do, but females attempt suicide three times more often than males. Males tend to choose more lethal and violent means of suicide than do females. Among males, firearms are the most commonly used (57.6%) method of suicide (National Center for Injury and Prevention and Control 2005). Individuals age 65 years and older constitute 13% of the population but account for 19% of the suicides, making older age a significant chronic risk factor. The suicide rate for white men older than 85 years is 65 deaths per 100,000 population. A coincident risk factor is chronic illness, especially if it was diagnosed in the previous year. Another at-risk group is teenagers and young adults between the ages of 18 and 24 years, in whom suicide is the third leading cause of death. Whites complete suicide two times more often than nonwhites, with white males accounting for 73% of the suicides in 1998 (National Center for Injury Prevention and Control 2002). The suicide rates for Native Americans are 1.5 times the national average. Suicide rates for specific ethnic groups change with the age and gender of the individual, so blanket statements of risk are not necessarily accurate.

In one study, African American males constituted the largest group, numerically and statistically, of teenage suicide victims but accounted for only 26% of victims from all age groups. In this same data set, African American females accounted for only 3% of all suicides, with only one occurring in an individual older than 45 years (Garlow et al. 2005). Approximately 90%–95% of suicide victims have a major psychiatric illness, of which approximately half have a mood disorder (Angst et al. 2002; Fawcett 1992; Harris and Barraclough 1997). Male bipolar patients are at higher risk, especially those at an earlier phase of the illness, those who are currently in a depressed state, and those with comorbid substance abuse (Simpson and Jamison 1999). Patients with alcohol and other substance use disorders have higher rates of completed suicide than the national average, with alcoholic patients having a suicide rate twice the national average (Fowler et al. 1986). For alcoholic patients, comorbid depression and recent interpersonal loss increase risk (Murphy and Wetzel 1990; Murphy et al. 1992). A family history of suicide increases suicide risk independent of a family history of mental illness (Qin et al. 2002, 2003). Patients with personality disorders often express ongoing suicidal ideation; as a result, suicidality becomes embedded in their sense of self (Soloff et al. 1994). This can manifest as repeated acts of parasuicidal or gestural self-injurious behavior, such as cutting and sublethal overdoses. These patients can be very difficult to manage and can put a great deal of strain on the mental health services delivery system. A consistently applied treatment plan, restrained responses on the part of clinicians and staff (minimizing countertransference behaviors), and use of secure 24-hour patient observation areas can be particularly useful in managing these patients. The goal is to allow patients to deescalate and calm down so that they can ultimately be discharged back into their ongoing outpatient treatment regimens (Maltsberger and Buie 1974).

Protective Factors In formulating a suicide risk assessment, it is important to note protective factors in addition to the presence or absence of acute and chronic risk factors. One study of depressed patients without a history of suicide attempts found that the following served as protective factors: an expression of more responsibility toward family, more fear of social disapproval, more moral objections to suicide, greater coping skills, and greater fear of suicide (Malone et al. 2000). Social connectivity also serves a protective role for depressed patients, as first described by Emile Durkheim (1951). Having close familial relationships, living with another person (family or friend), and having dependent children are all protective factors. Being involved in cultural groups such as organized religion and having moral objections to suicide are associated with lower rates of suicide (Dervic et al. 2004, 2006). Generating a comprehensive suicide risk assessment involves organizing and balancing risk with protective factors. Clear documentation of these risk/protective factors, steps taken toward intervention, and associated clinical reasoning are essential. A basic statement indicating competency should also be included. In the case of a chronically suicidal patient, clearly documenting this pattern and obtaining a second opinion to corroborate the treatment plan and objectives may be beneficial.

Management of Suicidal Patients Ensuring safety is the first and most important step in managing a potentially suicidal patient. This can best be accomplished through admission to a secure patient holding area. If no such facility is available, close observation of the patient by a staff member is another option. In this circumstance, moving the patient to a more secure location is the first treatment goal. Patients who are considered to be particularly high risk may require close observation even after they have been admitted to a secure unit. It is important to note that in one study of inpatient suicides on whom information on precaution status was available, 42% were on 15-minute checks or were observed within 15 minutes of the suicide. Furthermore, 9% of this group was on one-to-one observation at the time of suicide (Busch et al. 2003). Staff assigned to monitor patients should be given specific instructions regarding their role

and responsibilities. Furthermore, there should be guidelines for how to manage attempts toward self-injurious behaviors. Use of extended observation areas can be useful in clarifying the clinical picture while the patient is maintained in safe surroundings. Patients who are intoxicated and expressing suicidal ideation can be allowed to sober up prior to a more definitive assessment. In one psychiatric emergency setting, cocaine use, but not ethanol use, was associated with suicidal ideation, although the mood state was usually transient, resolving in 48–72 hours (Garlow et al. 2003). The decision to hospitalize a potentially suicidal patient should take into account both acute and chronic risk factors; specific treatment needs of the patient; availability of other treatment options, including partial hospitalization, day treatment, and crisis group home settings; and social support network for the patient. No-harm contracts between patients and clinicians are not useful in making treatment decisions with suicidal patients (Kroll 2000; R. I. Simon 1999). Of psychiatric inpatients who committed suicide, 50% had made such no-harm contracts, and 67% had denied suicidal ideation on the day of the suicide (R. I. Simon 1999). Focusing on the acute behavioral state of the patient (anxiety, agitation, and insomnia), the presence of chronic risk factors, and access to high-lethality means (firearms) is much more relevant to making the decision to hospitalize the patient. Patients who are not hospitalized require close follow-up, including a detailed treatment plan, an identified treatment provider, and instructions for the patient and family members on what to do in case of symptom worsening. For individuals not hospitalized and for those recently discharged from the hospital, interventions should be made to improve the safety of the patient's living environment. Individuals with access to high-lethality means should be advised to remove these items from the home. Firearms and medications lethal in overdose should be neither in the home nor readily accessible. Family members and friends may be consulted to assist with the removal of these items from the patients' possession (Mann et al. 2005).

Homicidal State Establishment of a psychiatric diagnosis is the first step in developing a management plan for a patient expressing homicidal ideation. Whereas suicide most often occurs in the context of a mental illness, homicide and homicidal behaviors often do not. There is a relation between sadness and other negative affective states and suicide, but there is no correlation between these mood states and homicidal or violent acts (Apter et al. 1991). Nonetheless, a patient may develop homicidal ideation in the context of a psychotic disorder, particularly disorders that include firmly held paranoid, persecutory, or erotomanic delusions. If such delusional beliefs are driving the expression of homicidal ideation, involuntary hospitalization would be the appropriate course of action. Expressions of anger, hostility, rage, and violent intent occur in many interpersonal situations and conflicts in which the perpetrator is not afflicted with a psychiatric disorder. In these cases, once a determination has been made that the individual is not psychotic or delusional or expressing homicidal ideation on the basis of some other psychiatric disorder, appropriate interventions are in the domain of law enforcement agencies and not psychiatrists. Such an individual would not benefit from a psychiatric hospitalization but would instead divert scarce resources away from patients who truly would benefit from such an intervention. If a patient who is expressing homicidal ideation is not admitted to a psychiatric facility, the clinician must give very careful consideration to the need to notify the intended victim and law enforcement agencies based on the principles set forth in Tarasoff v. Regents of the University of California (1976; R. I. Simon 1998; Walcott et al. 2001). This case established a precedent for mental health workers to breach confidentiality to notify an intended victim and law enforcement agencies if they are aware of a patient's plan to harm that victim. Clinicians should consider making a Tarasoff notification to the intended victim any time a patient who has expressed homicidal ideation is discharged, regardless of

whether that patient has a psychiatric diagnosis. Adoption of the principles set forth in the Tarasoff ruling varies by state; therefore, awareness of and adherence to the particular laws within one's own jurisdiction are essential. Predicting which individuals may act on homicidal ideation is very difficult (Resnick and Scott 2000). Factors that contribute to this assessment are the specificity of the plan, identity of the victim, access to high-lethality means (firearms), capacity of the patient to persist in the plan, and proximity of the perpetrator to the intended victim (Borum and Reddy 2001). Even with a careful history, assessment, and appropriate intervention, preventing an adverse outcome may not be possible. In the Tarasoff case, the police determined that the perpetrator was not a threat when they interviewed him, but he eventually carried out the lethal act 3 months later.

Grave Disability and Inability to Care for Self Another condition for which involuntary commitment laws exist is for patients who by virtue of a mental illness are unable to care for themselves; some states also include "as a result of substance abuse disorders" under this heading (K. T. Hall and Appelbaum 2002). The consideration is whether the patient cannot provide adequately for basic needs, shelter, food, and medical attention because of a mental illness. Common manifestations of this situation include when the patient with a psychotic disorder is living on the streets, without regular or adequate nutrition, and is possibly neglecting ongoing medical conditions. This situation is not the same as that in which a person is homeless because of some other occurrence or circumstance, because homelessness does not in itself constitute grave disability. Another common situation that falls under this heading is when a patient with dementia or other profound cognitive impairments has wandered away from his or her caregivers. In this case, effort should be focused on establishing the identity of the individual and returning him or her to the appropriate facility. If this is a new-onset cognitive impairment, the patient should be hospitalized for definitive evaluation and diagnosis.

Notification of Third Parties As noted earlier, the principles set forth by the Tarasoff ruling in California encourage clinicians to act in the best interests of the intended victim, with notification of the intended victim and law enforcement agencies in the case of expressed homicidal ideation. As in the case of assessment of suicidal and homicidal risk, this may result in a breach of patient confidentiality. This places a unique burden on psychiatrists—to predict future behavior of a patient and to assume responsibility for the welfare of another person with whom the psychiatrist does not have a therapeutic relationship. Another circumstance that requires breach of patient confidentiality is notification of authorities in cases of suspected child abuse and neglect. All states have statutes that require clinicians of all disciplines to notify the appropriate agency in the case of suspected child abuse. Many states also have laws for reporting elder abuse and abuse of other vulnerable individuals. Specifics of these laws vary with each jurisdiction.

PSYCHIATRIC EMERGENCIES REQUIRING MINIMAL OR ADJUNCTIVE PHARMACOLOGICAL INTERVENTION Psychiatric emergencies requiring minimal or adjunctive pharmacological intervention occur in many different situations, although many share a common thread of developing in response to some discrete, identifiable stressor (Table 62–3). The practice of crisis intervention psychiatry involves identifying the root cause or stressor of the presenting syndrome and developing a focused treatment plan. The principal therapeutic goals are to alleviate short-term distress, rapidly return the patient to his or her previous level of functioning, and prevent the development of a more serious long-term syndrome. The judicious use of psychopharmacological agents, in concert with psychotherapeutic, psychosocial, and family system interventions, can be particularly effective in these emergencies.

TABLE 62–3. Psychiatric emergencies requiring minimal or adjunctive pharmacological intervention Emergency Adjustment disorder or acute grief

Intervention Diagnostic/psychosocial assessment Psychotherapy Social and family system intervention Short course of sedative-hypnotic Short course of benzodiazepine Selective serotonin reuptake inhibitor

Rape, assault, or trauma

Medical evaluation and treatment Law enforcement Psychotherapy Short course of sedative-hypnotic Short course of benzodiazepine Insult-specific psychotherapy Rape counseling Spousal abuse counseling Violence victim counseling

Borderline personality disorder

Controlled environment/deescalation Structured psychotherapies Low-dose neuroleptics

Panic disorder

Medical evaluation Short course of benzodiazepine Treatment referral

Some conditions in this category require a more thorough diagnostic evaluation and long-term pharmacological management, but in the short term, these agents may or may not be required. Examples of this situation are new-onset panic disorder, dissociative states, catatonia, mania, and conversion disorders. Any of these conditions occurring in a previously well individual, with no history of mental illness, require comprehensive medical evaluation and diagnosis. The long-term management of patients with panic disorder, mania, or psychotic disorders will undoubtedly involve psychopharmacological agents, but these agents may not be required in the immediate setting, depending on the severity of the presenting behavioral syndrome.

Adjustment Disorder Adjustment disorders are defined as the maladaptive response to an identifiable psychosocial stressor within 3 months of onset of the stressor, with the symptoms having persisted for no more than 6 months (American Psychiatric Association 2000). The common clinical manifestations of adjustment disorders encountered in psychiatric emergency settings are patients experiencing a mixture of anxiety, depressive, and neurovegetative symptoms in response to some external stressor or crisis. DSM-IV-TR (American Psychiatric Association 2000) nosology provides subtype designations for characterization of the predominant symptoms of the adjustment disorder: with depressed mood, with anxiety, with mixed anxiety and depressed mood, with disturbance of conduct, and with mixed disturbance of emotions and conduct. The potential stressors are myriad, including death of a family member or friend, job loss, diagnosis of a serious medical condition, divorce and other disturbances of family function, financial hardship, and many other circumstances.

The principal interventions for adjustment disorders are psychotherapeutic, educational, and psychosocial. Most crises have a natural time course and resolution. Feelings of distress in response to many of these insults are innate and expected. Psychoeducational interventions are aimed at helping the patient realize that the syndrome is self-limited and expectable in response to the stressor. Often, these patients have a sleep disturbance, so the short-term use of a soporific (diphenhydramine 25–50 mg, hydroxyzine 25 mg, trazodone 50–100 mg, mirtazapine 7.5–15.0 mg), a sedative-hypnotic (zolpidem 5–10 mg, zaleplon 5–10 mg, eszopiclone 2–3 mg, ramelteon 8 mg), or a benzodiazepine (lorazepam 1–2 mg, diazepam 5 mg) could be considered to assist in reestablishing a normal sleep–wake cycle. If daytime anxiety symptoms are particularly severe and debilitating, daytime use of a benzodiazepine may be considered, but this must be done cautiously, because there is no evidence indicating that the early use of such agents prevents the eventual development of more serious disorders such as posttraumatic stress disorder (PTSD) (Gelpin et al. 1996). The goal of any of these interventions is to assist the patient to return to his or her previous functional level as rapidly as possible. Bereavement falls into this category and can be on the severe end of the spectrum, especially with the loss of a spouse or child. Because many reactions to such losses are culture-bound, a patient's response to a loss must be evaluated against the background of culturally normative behavior. In normal grief reactions, additional therapeutic focus should be on the involvement of family, friends, religious and spiritual figures, and other members of the patient's community. Bereavement can be distinguished from a major depressive episode on the basis of several criteria. The presence of suicidal ideation, excessive guilt, prominent psychomotor retardation, hallucinations, preoccupation with worthlessness, or symptoms that last for longer than 2 months are not consistent with a diagnosis of uncomplicated bereavement. Further evaluation and more intensive interventions are necessary in these cases.

Acute Trauma Patients who have been exposed to an acute psychological trauma are at risk for developing acute stress disorder (ASD) or PTSD. The DSM-IV-TR definition of traumatic events includes direct personal experience of an event that involves actual or threatened death, injury, or threat to one's physical integrity or witnessing such an event or learning about such an event happening to a family member or close associate. Most people who experience such traumas do not go on to develop any psychiatric disorder, but a significant minority, up to 30%, will develop PTSD. One theoretical formulation of PTSD is the failure of the normal recovery process after experiencing a trauma (Foa et al. 1989). Psychological debriefing has become one of the standard interventions after traumatic events (Mitchell 1983). A trained moderator conducts the debriefing with the goal of encouraging the expression of thoughts and feelings about an event shortly after it has occurred. This type of intervention is commonly offered to both the victims of a trauma and the care providers (e.g., police officers, firefighters, emergency medical technicians) that were involved. Evidence shows that the timing of the debriefing is critical and that this might not be the ideal posttraumatic intervention in all situations (Campfield and Hills 2001; Greenberg 2001). An evolving approach to immediate trauma intervention is to assess the risk of a patient developing PTSD and educate the patient about normal reactions to trauma and potential symptoms of PTSD. Theoretical frameworks suggest that adrenergic activation during times of stress contribute to the solidification of memories in the hippocampus. Attempts have been made to test this theory by administering a -adrenergic antagonist within 6 hours of the traumatic event to assess whether blocking this receptor may lead to a decreased intensity and imprinting of the stored memory. Results of such investigations are promising but warrant the need for further investigation (Pitman et al. 2002; Vaiva et al. 2003). Treatment referrals should be made to appropriate providers in the event that a patient develops

symptoms of ASD or PTSD over time. Behavioral indicators of risk of developing PTSD include heightened levels of arousal and coping via disengagement after a traumatic event (Mellman et al. 2001). Personalization of the traumatic event, especially thoughts that one might die, is another risk factor. The typical time course for posttraumatic reactions to resolve is on the order of 4 weeks. During this time, it is extremely common for all trauma victims to experience some of the symptoms of PTSD. One of the main early therapeutic goals should be to educate patients about this time course and to encourage them to return to treatment if these symptoms persist past 4 weeks or become particularly debilitating. Referral to trauma-specific psychotherapies (rape crisis, violent crime, survivor groups) can be helpful to victims of these specific insults. The role of the emergency psychiatrist in the face of a national disaster was assessed following the attacks on the United States on September 11, 2001. In the wake of the terrorist attacks on 9/11, studies have assessed access to mental health care. Some early reports suggested that 44% of Americans reported "substantial symptoms" of psychological distress following the attacks (Schuster et al. 2001). Another study suggests that the residents of the communities that were directly affected by the attacks were significantly distressed by the events, while U.S. communities as a whole did not experience an increase in emergent mental health–related complaints (Catalano et al. 2004). In the wake of a national disaster, the emergency psychiatrist should be prepared to deal with traumarelated symptoms of stress. Medication recommendations are the same as for adjustment disorders. Two SSRIs, sertraline and paroxetine, have a U.S. Food and Drug Administration (FDA)–approved indication for treatment of PTSD symptoms once the full-blown syndrome has developed. Other SSRIs may share a similar pharmacological profile and subsequent clinical utility. Whether the early use of SSRIs after a trauma prevents the development of PTSD is an open question. One study using animal models suggested that immediate postexposure administration of an SSRI (in this case, sertraline) reduced anxiety-like and avoidant behavior, decreased hyperarousal responses, and diminished the overall incidence of extreme (PTSD-like) behavioral responses, compared with a delayed treatment (7 days posttrauma) regimen and with saline controls (Matar et al. 2006). Other studies have evaluated the use of brief cognitive-behavioral therapy for patients with acute PTSD. One such study indicated accelerated rates of recovery in patients who received this intervention, although it did not influence the long-term outcome (Sijbrandij et al. 2007). The use of benzodiazepines is controversial in the context of acute trauma. While these medications may be useful in decreasing overall levels of anxiety, there is no clinical evidence supporting their use as prophylaxis against the development of PTSD. The Consensus Statement on PTSD from the International Consensus Group on Depression and Anxiety discouraged the use of benzodiazepines secondary to limited efficacy, concern for tolerance and withdrawal, and the possibility of "impairment of learning" (Ballenger et al. 2000, 2004). In general, these agents should be considered to have a secondary or augmentation role in the treatment of PTSD. If the decision is made to use these medications, long-half-life agents, such as clonazepam and diazepam, minimize the risk of withdrawal or rebound anxiety (Davidson 2004). If PTSD symptoms persist after 4 weeks or become increasingly debilitating 2–3 weeks after a traumatic event, consideration should be given to use of an SSRI. In addition to SSRIs, recent studies suggest a role for a novel psychotherapeutic treatment, eye movement desensitization and reprocessing (EMDR), in the treatment of adult trauma survivors. In one study, 75.0% of adult-onset versus 33.3% of child-onset PTSD subjects receiving EMDR achieved asymptomatic end-state functioning, compared with none in the SSRI group (van der Kolk et al. 2007).

Conditions That Require Medical Evaluation With any acute change in mental status or sudden-onset change in behavior in a previously well

individual, organic causes must be considered first, before it is assumed that the symptoms are a manifestation of a previously undiagnosed psychiatric disorder (Frame and Kercher 1991; R. C. Hall et al. 1978, 1981). This is especially true when the syndrome occurs outside of the usual age-based window of vulnerability. For example, new-onset psychotic symptoms in a patient older than 40 years or mania in a patient older than 50 years should be considered to be due to a medical condition until proven otherwise. Other psychiatric disorders do not have as clearly defined windows of vulnerability as schizophrenia and bipolar disorder, but should on initial presentation be suspected as due to a medical condition.

Panic Disorder A patient presenting for the very first time with dyspnea, tachycardia, diaphoresis, chest pain, and light-headedness should receive a thorough medical evaluation before being assigned a diagnosis of panic disorder. Many different conditions can present with some or all of these symptoms, including unstable angina and myocardial infarction, hypoglycemia, anemia, pulmonary embolism, asthma, obstructive pulmonary disease, gastroesophageal reflux disease, irritable bowel disease, hyperparathyroidism, hyperthyroidism, pheochromocytoma, Huntington's disease, Parkinson's disease, seizure disorder, and autoimmune disorders, such as systemic lupus erythematosus (Roy-Byrne et al. 2006). Only after these medical conditions have been ruled out should a diagnosis of panic disorder be entertained. During the initial attack, use of a benzodiazepine may be helpful to make the patient more comfortable, but care should be taken not to mask symptoms of a more serious underlying condition. Current FDA-approved medications for panic disorder include alprazolam (a benzodiazepine), sertraline and paroxetine (SSRIs), and venlafaxine (serotonin–norepinephrine reuptake inhibitor). SSRIs tend to be utilized first line because of their general tolerability, lack of potential for dependence/misuse, and safety profile (Katon 2006). Currently, the gold standard of clinical practice in the definitive long-term management of panic disorder is the use of SSRIs in concert with cognitive-behavioral therapy.

Dissociative Episodes Amnestic and acute confusional states should always be considered to be due to a medical or neurological condition until proven otherwise. Amnestic symptoms are common after head injury, during cerebrovascular accidents and transient ischemic accidents, in postictal states, with brain tumors, in intentional and unintentional intoxications, and in many other medical conditions. Another important diagnostic consideration is of a delirium, which could have any number of medical or metabolic causes. Establishing the correct diagnosis in this type of patient is facilitated by extended observation, with repeated assessments. This allows for detection of the fluctuating levels of consciousness and awareness common in delirium and of the temporal evolution of the amnestic symptoms. Unobtrusive observation of these patients also allows for assessment of purposeful, deliberate, and organized behaviors, which usually are observed in patients with psychogenic or factitious amnestic conditions but often are not seen in those with an organic condition.

Catatonia Catatonia is a syndrome of motor dysregulation characterized by the presence of at least two of the following symptoms for more than 24 hours: mutism, immobility, negativism, posturing, staring, rigidity, stereotypy, mannerisms, echophenomena, perseveration, and automatic obedience (Fink and Taylor 2006; Taylor and Fink 2003). Catatonia can be diagnosed in 7%–15% of psychiatric patients in acute inpatient services and emergency room settings (Fink and Taylor 2006). Although commonly classified as a psychotic spectrum disorder, catatonia is more frequently associated with mania, melancholia, and psychotic depression than it is with schizophrenia. If a patient has not had documented previous episodes of catatonia in conjunction with one of these psychiatric disorders, a medical cause should be sought vigorously. Episodes of catatonic behavior can occur in a variety of

neurological and medical conditions, including metabolic encephalopathies, viral encephalitis, cerebrovascular accidents, epileptic episodes, hypercalcemia, and adverse medication (neuroleptic) and drug (phencyclidine [PCP]) side effects. These conditions should be ruled out before a psychiatric diagnosis is made. Although no established standard of care exists for the treatment of catatonia, acceptable treatment options include high-dose intravenous barbiturates (e.g., amobarbital) and benzodiazepines (e.g., lorazepam), as well as electroconvulsive therapy (ECT) (Fink 2001; Rosebush et al. 1990). However, definitive treatment is based on the underlying diagnosis.

Mania and Psychosis New-onset mania and psychosis should always be approached as potentially due to a medical condition. The clinical context will guide the urgency of the medical evaluation. New-onset psychotic symptoms in a 40-year-old and new-onset mania in a 50-year-old should prompt an urgent medical evaluation. Such symptoms appearing in an adolescent or a young adult should still be evaluated medically, although not with the same urgency as in the older adult. These symptoms can be caused by brain tumors, cerebrovascular accidents, autoimmune disorders, multiple sclerosis, and hyperthyroidism. Many medications, including exogenously administered steroids and stimulants, as well as illicit drugs can provoke manic and psychotic symptoms. Therefore, a thorough physical examination and a urine drug screen are essential components of the diagnostic workup.

Conversion Disorder Conversion disorder is a diagnosis of exclusion. Accordingly, new-onset neurological symptoms, including nonepileptic seizures, nonanatomical movement disorders, paresthesias, paresis, and amnestic syndromes, should be thoroughly evaluated before being attributed to a psychogenic cause. Management of conversion symptoms includes a complete medical assessment and reassurance that the symptoms will resolve with time. In one case report describing treatment of a patient with acute conversion disorder, use of intravenous lorazepam in combination with hypnosis led to a full recovery (Stevens 1990). Long-term management involves both physical rehabilitation and treatment of the underlying psychological conflict or distress. Family therapy can be a useful tool, given that family dynamics are often an essential part of the psychosomatic response to stress (Hurwitz 2004). Similar treatment strategies can be used for the treatment of somatization disorder.

PSYCHIATRIC EMERGENCIES THAT USUALLY REQUIRE PHARMACOLOGICAL INTERVENTION Management of severe behavioral emergencies usually requires psychopharmacological intervention prior to definitive diagnosis (Table 62–4). Many psychiatric patients will have episodes of disorganized, disinhibited, agitated, aggressive, or violent behavior. These behavioral states can occur in patients who are psychotic, manic, or intoxicated as well as in those who have organic syndromes such as dementia or delirium. Patients who are experiencing severe medication side effects or adverse events also require pharmacological intervention, as do patients with substance use disorders in withdrawal states. TABLE 62–4. Psychiatric emergencies that *usually* require pharmacological intervention Emergency

Intervention

Assaultive, aggressive, or violent behavior

Calm, controlled staff Adequate staff/"show of force" Seclusion/stimulus minimization Physical restraint

Primary psychotic or mood disorder

Medication: Lorazepam

Emergency

Intervention Haloperidol Atypical antipsychotics Definitive diagnosis and treatment plan

Delirium

Diagnose delirium vs. other disorder Definitive medical diagnosis Treat underlying cause Intravenous (iv) or intramuscular (im) haloperidol

Ethanol or sedative-hypnotic withdrawal

Benzodiazepine to stabilize withdrawal symptoms Controlled taper under supervision Refer to chemical dependency treatment

Alcohol withdrawal delirium

Medical intensive care Supportive measures Benzodiazepine taper

Medication side effects Neuroleptic-induced dystonia

Acute: Diphenhydramine 25–50 mg iv Maintenance: Diphenhydramine 25–100 mg qd, or Benztropine 0.5–4.0 mg qd, or Trihexyphenidyl 2–10 mg qd

Neuroleptic-induced akathisia

Lower antipsychotic dose Propranolol 10 mg two to three times daily Benzodiazepine

Neuroleptic malignant syndrome

Discontinue offending agent Medical intensive care/support: Cooling Hydration Anticoagulation Medical intensive care/support: Cooling Hydration Anticoagulation Dantrolene Benzodiazepine Electroconvulsive therapy

Emergency Anticholinergic delirium

Intervention Discontinue offending agent(s) Supportive measures

Hypertensive crisis

Management of blood pressure Supportive measures

Serotonin syndrome

Discontinue offending agent Medical supportive measures/intensive care Benzodiazepine

Priapism

Discontinue offending agent Medical supportive measures Urology evaluation if condition does not resolve

Selective serotonin reuptake inhibitor discontinuation

Reassurance; restart medications

syndrome

Assaultive, Aggressive, or Violent Behavior Assaultive, aggressive, and violent behaviors can have many different etiologies, including psychotic or delusional ideation secondary to a primary psychotic or mood disorder, substance intoxication, acute confusional states associated with dementia and delirium, rage attacks in patients with personality disorders, and deliberate, volitional acts by antisocial individuals. The most important chronic risk factor for predicting violent behavior is a history of such behavior. Acute risk factors include over- or undercontrolled behavior. The former refers to a patient with decreased psychomotor activity, tension, anger, and paranoia, whereas the latter refers to a patient who is agitated, intrusive, and verbally provocative. Intoxication is an independent acute risk factor that can potentiate violent behaviors in patients with many different diagnoses. The initial diagnostic effort should be to globally assess the behavioral state causing the aggressive behaviors, because this will affect subsequent treatment decisions. Concurrently, the focus should be to maintain a safe environment for the patient, other patients, and the staff. A well-trained staff of an adequate number in an appropriately designed facility is the best preventive strategy for minimizing violent episodes. Staff members who are trained to respond in a calm, deliberate, and nonthreatening manner help to establish an atmosphere of order and control. Preventing a violent act from occurring is preferable to responding to a violent act after it has occurred; thus, ongoing assessment of patients is essential, as is the proactive use of sedating medications. It is better to have a patient take a medication voluntarily and orally before his or her behavior has escalated than to be required to involuntarily medicate the patient after a crisis has occurred. This cooperation of care is the first step in establishing a therapeutic alliance, which in turn can further mitigate the risk of escalation. There are several options in the acute management of the agitated patient. Orally available agents include several benzodiazepines and atypical antipsychotics. Lorazepam in 2-mg doses given every 45–60 minutes usually will sedate most patients by the second dose. Other alternatives are 15–20 mg of olanzapine, 4–6 mg of risperidone, or 5 mg of haloperidol in a single oral dose. The decision of which agent to use is based on the underlying diagnosis. If a patient with a known diagnosis of schizophrenia or bipolar disorder appears to be experiencing a psychotic or manic decompensation, then an atypical antipsychotic should be used. If the diagnosis is not known or is unclear, then lorazepam is a better choice. This is especially true given that acute intoxication with some agents—for example, anticholinergics like diphenhydramine—may be worsened by the addition of atypical antipsychotics. Lorazepam is also most appropriate for patients who are violent as a result of intoxication with drugs or alcohol.

The administration of oral medications is preferred over the use of parenteral medications when the agitated patient is willing to accept such an intervention. Research has suggested that clinicians may overutilize intramuscular injections out of ease of treatment. One study in a Geneva, Switzerland, psychiatric emergency service evaluated the rates of involuntary injections in patients being observed for psychomotor agitation. The results supported the theory of overutilization, as there was a 27% reduction in involuntary injections during a 3-month observation of treatment (Damsa et al. 2006). Given these findings, efforts should be made to encourage voluntary administration of medications if possible. New alternatives to the established pill or tablet formulation of second-generation antipsychotics exist and demonstrate positive results in comparative trials. Risperidone M-Tab, Zyprexa Zydis, and Abilify disc melt are currently available rapidly dissolving forms of their parent agents. Risperidone is also available in an oral concentrate solution. These formulations exhibit benefit over the traditional pill formulation in patients who may "cheek," or store the administered medication in their cheek, and dispose of it prior to consumption (Allen et al. 2001, 2005). These formulations display similar pharmacokinetics compared with the traditional pill formulation. When staff attempts to redirect an actively or imminently violent patient fail, quick and decisive action must be taken. The most direct means to ensure safety of the patient and all others in the immediate area is seclusion and restraint. Adequate numbers of well-trained staff are required to accomplish this rapidly and with minimal chance of injury to the patient and staff. Staff should be trained to manage the situation assertively while maintaining professionalism—that is, not acting in a manner that is punitive or reactive to the patient's behavior. Patients who are restrained also should receive medication, usually via the intramuscular or intravenous route. However, because establishment of intravenous access in a combative patient is often very difficult and is potentially dangerous to the patient and staff, intramuscular is usually the preferred route. Involuntary administration of psychotropic medications is allowed in emergencies that are considered life-threatening, although rather wide variation exists in the legal definition of life-threatening emergencies and in the practice of administering involuntary medication. Clinicians should be well informed on the local definitions and regulations regarding involuntary administration of psychotropic medication. Accurate and timely documentation of the need for restraint and involuntary medication administration is essential. Currently, six medications are suitable for intravenous or intramuscular administration in behavioral emergencies. These are lorazepam, diazepam, haloperidol, and injectable preparations of three atypical antipsychotics—olanzapine, ziprasidone, and aripiprazole. Lorazepam is the most useful and should be the mainstay for controlling behavioral emergencies (Battaglia et al. 1997; Foster et al. 1997; Salzman et al. 1991). Lorazepam is rapidly absorbed from intramuscular injections, has a rapid onset of action, has a short half-life, and is anxiolytic as well as sedating. Patients who are being combative generally are experiencing high levels of fear or anxiety, so the anxiolytic properties of lorazepam are an additional advantage. Intramuscular diazepam can be absorbed erratically and thus is not particularly useful. Haloperidol should be reserved for patients who are clearly psychotic, with the expectation that they will receive long-term treatment with an antipsychotic agent. A sufficiently large dose should be given with the first injection in a behavioral emergency to ensure rapid onset of sedation and to minimize the need for a second or third injection. Lorazepam should be administered in 2-mg doses that can be repeated at 45 minutes if the initial dose is not sufficient. Very rarely will any additional injections be required after a second 2-mg dose of lorazepam. The initial haloperidol injection should be 2.5–5.0 mg and should not be repeated for at least 2 hours. Sufficient time must be given for the medication to be absorbed and for maximal sedation to occur. Under no circumstances should a patient receive more than 5 mg of haloperidol in a single injection or more than two injections (10 mg) in 24 hours, which can provoke a severe dystonic reaction. To prevent

dystonia, 1 mg of benztropine should be included with intramuscular haloperidol. Alternatively, 25 mg of diphenhydramine may be added to prevent dystonia while providing additional sedation via its antihistaminergic mechanism of action. The combination of lorazepam and haloperidol in a ratio of 2 mg of lorazepam to 5 mg of haloperidol is often used to provide adequate sedation and anxiolysis while treating the underlying psychosis. However, unless the patient is obviously psychotic and the plan is for long-term antipsychotic treatment, this combination should be avoided. On the other hand, benztropine is not needed if lorazepam has been given with haloperidol. The injectable atypical antipsychotics should be reserved for patients who will be given an oral atypical agent after the immediate emergency has resolved. Intramuscular ziprasidone was approved in 2002, and it has been studied in patients with schizophrenia who were psychotic and agitated and is currently indicated for the treatment of these conditions (Daniel et al. 2001; Lesem et al. 2001). In these clinical trials, patients received an initial injection of 10 mg, followed by injections of 5–20 mg every 4–6 hours, for a maximum dose of 80 mg in 24 hours. At the end of 3 days of intramuscular treatment, these patients were converted to the oral preparation of ziprasidone. The intramuscular ziprasidone package insert (Geodon 2008) recommends doses of 10–20 mg, with 10-mg doses repeatable at 2-hour intervals and 20-mg doses at 4-hour intervals. The maximum recommended intramuscular dose in 24 hours is 40 mg. Studies of intramuscular ziprasidone in the treatment of acute agitation note overall efficacy in reducing agitation while relieving anxiety. Intramuscular ziprasidone appears to have a low incidence of extrapyramidal side effects compared with intramuscular haloperidol (Brook et al. 2000). Results from one naturalistic study suggest that the use of intramuscular ziprasidone may reduce time in restraints for agitated patients compared with treatment with a conventional agent (Preval et al. 2005). One drawback of the intramuscular ziprasidone preparation is that it has to be reconstituted with sterile water immediately prior to administration. Injectable olanzapine has been studied for use in agitated patients with schizophrenia, bipolar mania, and dementia (Breier et al. 2002; Meehan et al. 2001, 2002; Wright et al. 2001). In the schizophrenia trials, patients received up to three individual injections of 2.5–10.0 mg in 24 hours, with the higher doses producing more significant and sustained reduction of agitation. In the bipolar trials, patients received up to three injections of 5 or 10 mg of olanzapine in 24 hours, with significant reduction in agitated behaviors. In the dementia trial, agitated patients received up to three olanzapine injections of 2.5 or 5 mg in 24 hours, with significant reduction in agitation. A recent review of the literature by Tulloch and Zed (2004) concluded that injectable olanzapine was superior to placebo in all study populations and to intramuscular lorazepam in patients with bipolar affective disorder. However, this review further concluded that injectable olanzapine did not differ significantly from intramuscular haloperidol or lorazepam in the management of agitation associated with schizophrenia/schizoaffective disorder or dementia. It is relevant to note that olanzapine is FDA approved for the treatment of schizophrenia and bipolar mania, but not agitation associated with dementia. Injectable aripiprazole was FDA approved for the treatment of agitation in patients with schizophrenia and bipolar mania in 2006. With a unique mechanism of action as a dopamine partial agonist, aripiprazole presents a new treatment approach in the management of acute agitation. Efficacy studies demonstrate injectable aripiprazole at a dose of 9.75 mg is superior to placebo and comparable to injectable olanzapine. Injectable aripiprazole demonstrated tolerability and symptom reduction without oversedation (Trans-Johnson et al. 2007). One benefit of this formulation is that it is packaged in a 9.75 mg/1.3 mL ready-to-use single vial.

Schizophrenia Atypical antipsychotics represent the current standard of care for the treatment of acute agitation in patients with schizophrenia (American Psychiatric Association 2004). With proven efficacy in

comparison with haloperidol and improved tolerability, these agents represent the first-line treatment in the agitated psychotic patient (Aleman and Kahn 2001; Currier and Trenton 2002; Yildiz et al. 2003). The only patients in whom this is not the case are those who have been stable long term (5 or more years) while taking a typical antipsychotic. The optimal intervention in a patient with schizophrenia who is experiencing an acute exacerbation is to rapidly initiate treatment with an atypical antipsychotic. In this regard, risperidone and olanzapine are the most useful agents, because both can be initiated at a high therapeutic dose (15–20 mg for olanzapine; 4–6 mg for risperidone) and can be given in multiple oral doses (two or three doses) over a period of 24 hours. Both of these medications, as well as aripiprazole, are available in an orally disintegrating formulation if compliance is in question. However, if compliance is a concern, then one must assess the utility of oral medications in general, and consider an intramuscular medication. In a patient who is too disorganized or combative to take medication orally, intramuscular administration is the only viable route. Currently, haloperidol, ziprasidone, olanzapine, and aripiprazole are available as injectable preparations. In a patient who is psychotic and agitated, the coadministration of a benzodiazepine during the first few days of treatment can be particularly effective in controlling behavior while the antipsychotic response develops. Studies suggest that this combination may reduce the total antipsychotic dose and potentially result in fewer adverse antipsychotic effects (Salzman et al. 1991; Yildiz et al. 2003). One caveat to this choice of treatment is the recent attention surrounding an increased risk of sedation and cardiorespiratory depression in patients treated with intramuscular olanzapine and intramuscular lorazepam, leading to a warning in the prescribing information provided by Eli Lilly, the manufacturer of olanzapine (Zyprexa 2005).

Bipolar Disorder Although behavioral emergencies can occur during both manic and depressive mood states, they tend to occur more often during mania. The goal of managing these patients is the establishment of a long-term definitive treatment regimen, which means initiating treatment with a mood-stabilizing agent such as lithium (10–20 mg/kg) or valproic acid (20–30 mg/kg) as soon as possible. Prior to initiating either of these two agents, a serum pregnancy test should be obtained and documented as negative, since both agents are teratogenic. Patients should be monitored for signs and symptoms of adverse side effects and toxicity. Both lithium and valproic acid require time to reach a therapeutic blood level and may take up to 14 days to become fully effective. Until steady state is established, behavioral control can be achieved with oral or intramuscular lorazepam or another benzodiazepine on an as-needed basis or with an atypical antipsychotic such as olanzapine, risperidone, ziprasidone, quetiapine, or aripiprazole, all of which are FDA approved for the treatment of acute bipolar mania. Olanzapine, risperidone, and quetiapine have the advantage of being sedating, which can be useful in an emergency room–type setting. In fact, atypical agents may be preferable to benzodiazepines in the management of acute bipolar mania according to recent studies. A recent review of the literature indicated that intramuscular olanzapine was superior to lorazepam monotherapy in the treatment of agitated manic patients (Tulloch and Zed 2004). Focusing on the long-term treatment goals is of the essence. If the long-term plans do not include an antipsychotic, then lorazepam or another benzodiazepine should be used for short-term behavioral control. If, however, it is known that the patient will require both a mood stabilizer and an antipsychotic for long-term management, then the antipsychotic should be substituted for the benzodiazepine. Another treatment option in both manic and depressed bipolar patients is ECT. With a rapid onset of action and known efficacy, especially in terms of short-term stabilization, this is a viable treatment option. This could be considered a treatment of choice in patients who are pregnant. Unfortunately, many facilities are not equipped to provide this treatment, and there are legal issues around obtaining informed consent to administer ECT emergently.

Substance Intoxication

Violent and combative behavior by intoxicated patients is a very common occurrence in psychiatric and medical emergency departments. Alcohol, cocaine, and PCP are the main culprits, but methamphetamines, -hydroxybutyrate, and hallucinogens also can lead to violent behavior. Ethanol intoxication is a very common cause of violent behavior in many settings. The appropriate interventions are physical restraint and sedation with a benzodiazepine, in conjunction with haloperidol if the agitation is significant, to allow the patient to become sober while serving as a seizure prophylaxis. Once a patient's blood alcohol level is below the legal limit for intoxication, a more definitive evaluation can be carried out, focusing on presence of an underlying psychiatric diagnosis or other treatment needs. Follow-up options include referral to substance abuse treatment, involuntary commitment if allowed in that jurisdiction, admission to a dual-diagnosis unit or program, or discharge. Prolonged cocaine use can lead to development of both mood and psychotic syndromes. Transient paranoid states are very common in cocaine users, as are frank delusions and hallucinations. Agitated, paranoid states accompanying cocaine intoxication can lead to significant violent behavior. Interventions are as described previously, including seclusion and restraint, use of intramuscular lorazepam, and possibly use of an antipsychotic if the patient is frankly psychotic. When the patient is no longer intoxicated, the presence of underlying psychopathology can be assessed. Disposition is as described for alcohol: admission to a dual-diagnosis program if the patient has another psychiatric disorder, referral to chemical dependency treatment, or discharge. PCP intoxication can be particularly provocative of agitated, combative, and violent behavior. Fortunately (or unfortunately), PCP use tends to occur in localized geographical regions and not in others. In areas where PCP use is common, intoxicated persons are common in emergency facilities. PCP intoxication can present with frank psychotic symptoms, agitation, disorientation, and disorganized behavior. Violent outbursts can be sudden, unprovoked, and unexpected. Patients in the throes of PCP intoxication can be very insensitive to pain, so they are prone to continue to fight even if seriously injured. Adequate numbers of well-trained staff are essential when dealing with patients who have been using PCP. The expectation should be that these patients will require seclusion and restraint. Restraint rooms should be dark and quiet so as to minimize stimulation. Intramuscular lorazepam should be used to sedate the patient, and he or she should be allowed to become fully sober before definitive assessment. The half-life of PCP is 20 hours, so these behavioral states can persist for several days before fully resolving. Methamphetamine, hallucinogens, -hydroxybutyrate, and cannabis can cause agitated, disorganized, and even violent behavior. Methamphetamine in particular can have behavioral consequences very similar to those of cocaine. Because of the long half-life of methamphetamine compared with cocaine, this drug can be particularly provocative of frank paranoid and psychotic symptoms. Like PCP use, methamphetamine use tends to be limited to certain geographical regions and not others. From 1991 to 1994, methamphetamine-related emergency cases tripled nationwide, making it a growing clinical phenomenon (Centers for Disease Control and Prevention 1995). Presenting symptoms often include agitation, hallucinations, suicidal ideation, and chest pain (Derlet et al. 1989). Distinguishing stimulant intoxication from other clinical diagnoses can be challenging given the symptom overlap. Generally, stimulant-induced psychosis tends to be distinguishable from primary psychotic disorders by the absence of a thought disorder and a prominence of visual hallucinations (Harris and Batki 2000). However, given the potential for comorbidity, a positive drug screen does not completely discount the diagnosis of a mood or psychotic disorder. Treatment should focus on maintaining the patient's safety while awaiting the drug's metabolism and dissipation from the patient's system. A more complete diagnostic workup can be completed once the patient is no longer intoxicated.

Delirium Patients with delirium can become disorganized, agitated, and combative. Delirium is defined as a state of a disturbed level of consciousness with a change in cognition or with perceptual disturbances, during which the symptoms occurs rapidly and tend to fluctuate with time. Delirium may be due to a general medical condition, substance intoxication or withdrawal, or secondary to multiple etiologies (American Psychiatric Association 2000). Delirium is a medical emergency and carries a very high burden of morbidity and mortality. The definitive treatment of delirium requires diagnosing the underlying cause and taking corrective action toward that particular pathology. Interventions aimed at controlling behavior include soft or leather restraints, environmental modification including frequent reorientation of the patient, and use of intravenous haloperidol. Behavioral control is essential so that the patient does not further injure him- or herself or interfere with treatment and to protect staff and other patients. The first intravenous dose of haloperidol should be 2.5 mg. If the patient is still agitated after 2 hours, the dose should be increased to 5 mg. This dose can be repeated in another 2 hours if the patient continues to be agitated. Once the patient is stabilized, a routine neuroleptic regimen should be initiated, dividing the total dose into two or four regular doses. The neuroleptic can be decreased and discontinued as the delirium clears. Benzodiazepines are generally contraindicated in cases of delirium, because they can exacerbate behavioral dysregulation and potentiate the altered level of consciousness.

Dementia Patients with dementia can become agitated, combative, or psychotic for many different reasons. The most common cause for this is a delirium overlying the dementia. Delirium in these patients can be caused by side effects from medications; infectious processes, which can appear quite minimal or clinically insignificant; and metabolic disturbances from many medical causes. Definitive diagnosis and treatment of the underlying disorder are essential to achieving adequate long-term resolution. Patients with dementia who are not delirious can become agitated as a result of confusion or psychosis inherent in the dementing pathology. In these cases, the best interventions are nonpharmacological, including environmental modification, behavior modification, and supportive measures. Aggressive behavior in patients with dementia can be treated pharmacologically, in the short term with lorazepam or low-dose neuroleptics and in the long term with low-dose neuroleptics, the anticonvulsants carbamazepine or valproic acid, propranolol, serotonin reuptake inhibitors, or buspirone. As is the case in all geriatric medicine, low doses and slow titration schedules are the appropriate course. Recent data suggest an increased mortality risk associated with the administration of neuroleptics in the management of dementia-related psychosis (Schneider et al. 2005). It is important to note that second-generation antipsychotics are not approved for the treatment of dementia-related psychosis and that a black box warning has been placed on the prescribing information of these agents in this population regarding an increase risk of cerebrovascular events and adverse events that are infectious in nature.

Substance Withdrawal States Alcohol and Sedative-Hypnotics Alcohol and sedative-hypnotic withdrawal can result in a frank delirium that is life-threatening (Marco and Kelen 1990; Olmedo and Hoffman 2000). The acute signs of early alcohol, sedative-hypnotic, and benzodiazepine withdrawal are similar and include autonomic instability, tremulousness, diaphoresis, and gastrointestinal disturbances. Autonomic signs include tachycardia, hypertension, and hyperthermia. Treatment of this withdrawal state is best accomplished with a long-half-life benzodiazepine. Use of long-half-life agents such as diazepam or chlordiazepoxide prevents peaks and troughs in blood levels, thereby leading to a smoother taper. During the first 24 hours, vital signs should be taken at 2- to 4-hour intervals and additional benzodiazepine given if vital signs are still

elevated. After 24 hours, the total dose should be added up and given as four divided doses, which are then decreased 10%–20% per day. In patients with significant liver disease, lorazepam or oxazepam should be used in preference to other benzodiazepines because their metabolism is not as dependent on hepatic function. It is important to consider concomitant medications, since

-blockers prescribed

for a general medical condition may mask the autonomic signs of withdrawal. Alcohol withdrawal delirium (delirium tremens) is a life-threatening medical condition (Erwin et al. 1998). This syndrome has a very high mortality rate—up to 35% of untreated patients and as high as 5%–15% in optimally treated patients. The delirium usually develops 48–72 hours after discontinuation of alcohol or sedative-hypnotics, peaks around day 4, and can persist for 2 weeks. The symptoms include autonomic instability, fever, disorientation, perceptual disturbances and hallucinations, agitation, and confusion. Patients with delirium tremens should be treated in a medical intensive care unit. These patients typically require physical restraint and vigorous supportive measures. Intravenous haloperidol can be used to control agitation and psychosis, but by the time a patient develops delirium tremens, benzodiazepines are not particularly useful. Wernicke-Korsakoff syndrome is another consequence of long-term alcohol use. Wernicke encephalopathy is the symptom complex of ophthalmoplegia, ataxia, and an acute confusional state. Wernicke-Korsakoff syndrome is diagnosed if persistent learning and memory deficits are additionally present. Alcoholic patients should receive three daily 100-mg doses of thiamine via the intramuscular route from the day of presentation, followed by three daily oral doses to prevent development of this syndrome. Patients should receive the first intramuscular dose before oral or intravenous administration of a carbohydrate load in order to prevent rapid thiamine depletion and emergent development of Wernicke-Korsakoff syndrome. Patients should also be given folic acid and magnesium replacement supplementation, because nutritional deficiencies are common in alcohol-dependent patients. Another potentially emergent situation is a patient presenting with an alcohol–disulfiram reaction. Disulfiram (Antabuse) blocks alcohol dehydrogenase, leading to a buildup of acetaldehyde. Subsequent consumption of alcohol produces unpleasant symptoms, including headache, flushing, nausea, and vomiting, creating an aversive reaction to alcohol consumption. No treatment for these mild symptoms is necessary. Serious symptoms such as arrhythmias and respiratory depression can occur and should be treated immediately with supportive measures.

Opiates Opiate withdrawal can be exceedingly uncomfortable for the patient but, unlike alcohol and sedativehypnotic withdrawal, is generally not life-threatening. Accordingly, the goal of opiate withdrawal treatment is relief of pain and suffering. Symptoms of opiate withdrawal include dysphoria, anxiety, irritability, craving, mydriasis, piloerection, diaphoresis, nausea, vomiting, diarrhea, rhinorrhea, lacrimation, insomnia, fever, and hypertension. Onset of this syndrome depends on the half-life of the drug used and with heroin is usually 6–8 hours after the last use. The syndrome can last 2–5 days, depending on the individual patient. Most of the symptoms are attributable to upregulation of 2-adrenergic

receptors; as a result,

2

agonists such as clonidine are very useful. Clonidine in doses of

0.1–0.3 mg every 3 hours, up to 0.8 mg/day, can be given to suppress signs of opiate withdrawal (Ahmadi-Abhari et al. 2001; Akhondzadeh et al. 2000; Charney et al. 1981; Gossop 1988). A major side effect of this regimen is hypotension, so the regimen must be carried out in a medically supervised setting. Clonidine should be avoided in patients who are dependent on both opiates and alcohol or a sedative-hypnotic; clonidine may mask the autonomic signs of ethanol withdrawal without actually preventing the emergence of delirium tremens. Another approach to opiate withdrawal is to substitute a long-half-life agent such as methadone at a dose of 30–80 mg and then taper off this agent at a rate of 10%–20% per day. This is best

accomplished in a "cocktail" that keeps the patient "blind" to the daily dose. This type of detoxification regimen is recommended in patients who are dually addicted to opiates and ethanol or sedativehypnotics. A long-half-life opiate and long-half-life benzodiazepine are used to detoxify both dependencies.

Psychotropic Medication Side Effects Antipsychotics Several adverse events can occur in patients taking typical antipsychotics and to a lesser degree in patients taking atypical antipsychotics. Dystonic reactions are characterized by extreme muscle contraction and rigidity in a patient with stable vital signs and a clear sensorium. These occur most frequently with high-potency, first-generation antipsychotics (Moleman et al. 1982; Schillevoort et al. 2001). Young males are particularly susceptible to dystonic reactions. Most dystonic reactions are extremely uncomfortable and frightening to the patient. Treatment of these reactions is typically 1–2 mg of benztropine via the oral or intramuscular route. An alternative is diphenhydramine in doses of 25–50 mg via the oral or intramuscular route. Dystonias that include the eyes, the so-called oculogyric crises, are particularly frightening, as are dystonias that cause laryngeal spasms, which can compromise the airway. These reactions should be treated with 50 mg of intravenous diphenhydramine, which provides rapid relief. Maintenance treatment of 1–2 mg of benztropine twice a day or 25–50 mg of diphenhydramine twice a day should be initiated after the acute reaction has resolved (Keepers et al. 1983). Akathisia is a syndrome characterized by internal restlessness, often perceived as the need to be in motion. This leads to increased psychomotor activity, including pacing, rocking, leg tapping and bouncing, and moving frequently between sitting and standing. The patient may complain of feeling anxious, irritable, or that his or her "skin is crawling." Treatment providers may interpret the anxiety, irritability, and increased motor activity common to patients with akathisia as worsening of psychotic symptoms, resulting in increased administration of antipsychotics. This further provokes the akathisia and consequently worsens the behavioral state. Lowering the dose of the antipsychotic or switching to an atypical antipsychotic are treatment options; the atypical drugs cause akathisia at lower rates compared with typical agents. Propranolol in doses of 10 mg two or three times a day is an effective treatment for akathisia. Neuroleptic malignant syndrome (NMS) is a potentially fatal delirium that develops in some patients in response to antipsychotic agents (Susman 2001). The diagnosis is made on the triad of symptoms of altered level of consciousness, muscular rigidity (often described as lead-pipe rigidity), and autonomic instability. The autonomic instability includes hyperthermia, tachycardia, labile blood pressure, diaphoresis, incontinence, and occasional dysphagia and bowel obstruction. Associated findings include elevated creatine phosphokinase (CPK), elevated white blood cell count, and metabolic acidosis. Later complications include rhabdomyolysis and renal failure. The main interventions in NMS are discontinuation of the offending agent and provision of general supportive measures, including cooling, rehydration, intensive nursing care, and anticoagulation. A few drugs have been used to treat NMS, including benzodiazepines, bromocriptine (15 mg/day), dantrolene (100–300 mg/day), and amantadine (200 mg/day). ECT also has been used to treat NMS. The atypical antipsychotic clozapine can cause catastrophic agranulocytosis in up to 1% of patients treated. This usually occurs within 6 weeks to 6 months of initiating therapy with clozapine. As a result, a surveillance program has been put in place so that all patients taking clozapine have weekly blood counts for the first 6 months of therapy, then every other week for 6 months, followed by monthly counts for the duration of treatment. A white blood cell count of less than 3,500/mm3 or a granulocyte count of less than 1,500/mm3 warrants discontinuation of the medication. Other signs of

impending marrow failure are fever, flulike symptoms, and sore throat. Discontinuation of the clozapine, supportive measures, and treatment of specific infections if identified are the main interventions for agranulocytosis, and in life-threatening cases, growth factors (filgrastim [Neupogen]) can be used.

Antidepressants Older-generation antidepressants can cause severe adverse events, whereas the newer agents, especially the SSRIs, are remarkably safe. Adverse events associated with tricyclic antidepressants include anticholinergic delirium, cardiac conduction delays, and seizures. Anticholinergic delirium is more common in elderly and impaired individuals and may be potentiated by concomitant anticholinergic medications. The principal intervention is to decrease or discontinue the offending agent. Furthermore, the coadministration of an SSRI or other drug known to inhibit the cytochrome P450 2D6 enzyme with a tricyclic antidepressant can cause dramatic increases in tricyclic antidepressant blood levels and resultant delirium. This can occur in a patient taking a low dose of the tricyclic antidepressant, and pharmacokinetic interactions must be considered in an emerging delirium in a patient taking what would otherwise be a safe dose of a tricyclic antidepressant. These drugs also can affect cardiac conduction, can lower seizure thresholds, and are lethal in overdose. A hypertensive crisis can occur in a patient who is taking monoamine oxidase inhibitors. This usually happens after ingestion of a large dose of tyramine, which can be found in certain food products or after an interaction with another drug, such as meperidine, other antidepressants, and sympathomimetic agents. Discontinuation of the monoamine oxidase inhibitor and management of the hypertension are the appropriate treatments. Blood pressure control can be achieved with intravenous phentolamine or intramuscular or oral chlorpromazine. Serotonin syndrome is a delirium characterized by altered level of consciousness, autonomic instability, and neuromuscular abnormalities including myoclonus, hyperreflexia, nystagmus, akathisia, and muscle rigidity (Martin 1996; Mason et al. 2000). Several different drugs, usually administered in combination, can cause this adverse event. Drugs reported to provoke serotonin syndrome include SSRIs, tricyclic antidepressants, monoamine oxidase inhibitors, venlafaxine, trazodone, nefazodone, lithium, tryptophan, meperidine, sumatriptan, buspirone, duloxetine, milnacipran, and amphetamines. Discontinuation of the offending agent and general supportive measures are the principal interventions. Unlike in NMS, bromocriptine can worsen the serotonin syndrome. Other drugs useful in treating this condition are benzodiazepines, cyproheptadine, chlorpromazine, methysergide, and propranolol. Although not a life-threatening emergency, SSRI discontinuation syndrome can be very frightening and distressing to patients. This syndrome develops after abrupt discontinuation of a short-half-life SSRI, with paroxetine and venlafaxine the two most common agents. Symptoms include dizziness, malaise, nausea, paresthesias, tremor, ataxia, confusion, myoclonus, anxiety, and vivid dreaming. Symptoms usually develop 48 hours after the last dose, peak around day 4–5, and can last as long as 2 weeks. Interventions include reassuring the patient and restarting the medicine, followed by a very gradual taper. Another approach is to switch to a long-half-life agent such as fluoxetine during the final days of SSRI treatment, which will then result in a more gradual clearing of the drug and a much lower chance of provoking the discontinuation syndrome. Priapism is a rare but potentially serious adverse event that has been associated with psychotropic medications including trazodone. This physiological condition is usually self-limiting. However, a patient with an erection lasting for more than 4 hours warrants an evaluation and treatment by appropriate medical personnel (Montague et al. 2003). Patients should be warned of this rare but serious potential side effect.

CONCLUSION In the modern era, with changes in the mental health care delivery systems and the resultant limitations placed on the utilization of inpatient treatment resources, the emergency psychiatrist will increasingly be called upon to diagnose and initiate definitive treatment of patients with a wide range of psychiatric disorders. Emergency psychiatrists must balance the needs of individual patients with those of the larger community, the health care system, and the third-party payer system with a focus on delivering care that is both efficacious and cost-effective. This will require a broad knowledge base, incorporating elements of all branches of psychiatry, and consideration toward thorough yet expeditious evaluation, diagnosis, and treatment of patients with mental illnesses.

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Karen Dineen Wagner, Steven R. Pliszka: Chapter 63. Treatment of Child and Adolescent Disorders, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.435382. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 63. Treatment of Child and Adolescent Disorders TREATMENT OF CHILD AND ADOLESCENT DISORDERS: INTRODUCTION This chapter focuses on the psychopharmacology of psychiatric disorders in children and adolescents. However, nonpharmacological treatment interventions are also an important component of a child's psychiatric care. Individual psychotherapy, group therapy, and family therapy may improve clinical outcome. Working closely with school personnel is another ingredient in the treatment of a child with a psychiatric disorder. Case management for the child and support for the family are other facets of treatment for children. It is important for clinicians to be aware of the evidence base for the use of psychotropic medications for children and adolescents. In this chapter, data from the literature, with a focus on controlled studies, are presented. On the basis of these findings, clinical recommendations regarding pharmacotherapy for childhood psychiatric disorders are offered. The appendix and tables contain specific information about dosages, monitoring, and adverse effects of psychotropics in children. [Portions of the Attention-Deficit/Hyperactivity Disorder section of this chapter were adapted from Wagner KD: “Management of Treatment Refractory Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.” Psychopharmacology Bulletin 36:130–142, 2002. Used with permission.]

PSYCHOTROPIC MEDICATION FOR CHILDREN AND ADOLESCENTS Attention has been focused on the need for controlled studies to assess the safety and efficacy of psychotropic medication for children and adolescents. Although there has been a substantial increase in the use of psychotropic medications for children (Safer et al. 1996) and for preschoolers (Zito et al. 2000), there is a significant gap between empirical treatment research and clinical practice with these agents (Jensen et al. 1999). The pressing need to expand the empirical basis for the treatment of children has resulted in a substantial increase in National Institute of Mental Health (NIMH)–funded research for clinical trials in children and adolescents with psychiatric disorders (Vitiello 2001). The U.S. Food and Drug Administration Modernization Act (FDAMA) of 1997, which provides a 6-month extension of market exclusivity for selected medications for children, has resulted in a significant increase in the number of industry-sponsored studies of psychotropic medications in youths. Following this act, the U.S. Food and Drug Administration (FDA) issued "Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients" (U.S. Food and Drug Administration 1998), which became effective in April 1999. This rule allows the FDA to require pediatric studies of certain new and marketed drugs, especially those that are likely to be commonly used for children. The information obtained from these studies will allow product labeling to include directions for the safe and effective use of these medications in children. To date, however, there are relatively few FDA-approved psychotropic medications for children and adolescents.

Evaluation Prior to the initiation of psychotropic medication for children and adolescents, it is essential to conduct a comprehensive evaluation to ensure the accuracy of the diagnosis. A thorough history and careful attention to the clinical presentation are central components of the evaluation. The clinician should

interview the child and parents separately so that both may have the opportunity to freely express their concerns. Extended family members, school personnel, and school records are other potential sources of information. Clinicians must be skilled at differential diagnosis of childhood disorders, given that there is a significant overlap of symptoms among these disorders (e.g., bipolar disorder and attentiondeficit/hyperactivity disorder [ADHD]). Knowledge of commonly occurring comorbid disorders is also necessary. Medical conditions, such as seizure disorders and hypothyroidism, should be considered within the differential diagnosis and adequately assessed. Disorder-specific rating scales at baseline and during the course of treatment may be useful in assisting with the measurement of clinical outcome.

Clinical Issues Affecting Response to Pharmacotherapy Whenever a child fails to respond to initial pharmacotherapy, several clinical issues should be addressed before initiating alternative or adjunctive medication, as discussed below.

Diagnostic Accuracy The diagnosis should be reassessed. Often there is symptomatic overlap among disorders that may lead to misdiagnosis. For example, symptoms of excessive energy and distractibility are common features of both ADHD and bipolar disorder. Similarly, irritability and sleep disturbance often occur in children with major depression, bipolar disorder, and posttraumatic stress disorder (PTSD).

Comorbid Disorders Unrecognized comorbid disorders may adversely affect treatment outcome. As an illustration, children with comorbid internalizing disorders have been reported to have lower response rates to methylphenidate than children without comorbidity (Tannock et al. 1995).

Psychosocial Factors Child abuse, domestic violence, family conflict, parental psychopathology, and bullying by peers may lead to symptoms that mimic or exacerbate a preexisting psychiatric disorder. As examples, ostracism by peers may lead to depression in a child, or a parent with depression who has a negative cognitive style may heighten the pessimistic views of a child with depression.

Medication Compliance Some children and adolescents are reluctant to take medication because of such reasons as denial of illness, perceived stigma, and side effects. To increase medication compliance, it is essential that the child or adolescent, as well as the parent, understand the youth's disorder, course of illness, and goals of treatment. It is important for parents to participate in monitoring their child's medication compliance.

Nonpharmacological Treatment Psychotherapy may be a component of treatment, either alone or in conjunction with medication. Specific psychotherapies have been found to be effective in the treatment of some childhood disorders. As examples, cognitive-behavioral therapy (CBT) (Brent et al. 1997) and interpersonal therapy (Mufson and Sills 2006) have demonstrated efficacy in the treatment of adolescents with depression. Similarly, CBT is commonly used for the treatment of childhood anxiety disorders (Roblek and Piacentini 2005). Behavior therapy has led to improvement in symptoms of ADHD for children (Pelham et al. 1998), although stimulants have demonstrated superiority to behavioral treatment (MTA [Multimodal Treatment of ADHD] Cooperative Group 1999). Adjunctive psychoeducation to medication treatment has shown benefit in the treatment of children with bipolar disorder (Fristad et

al. 2003). Social skills training can be a useful component of treatment in autism spectrum disorders (Krasny et al. 2003).

Informed Consent Informed consent is necessary prior to prescribing psychotropic medication to any patient, but it is particularly important in pediatric psychopharmacology because there are few FDA-approved medications and few controlled studies to address safety and efficacy in children. There are five recommended components of informed consent for prescribing psychotropic medications to children and adolescents (Popper 1987). The child's parent(s) and the child/adolescent should be provided with the following information: 1. The purpose (benefits) of the treatment 2. A description of the treatment process 3. An explanation of the risks of the treatment, including risks that would ordinarily be described by the psychiatrist and risks that would be relevant to making the decision 4. A statement of the alternative treatments, including nontreatment 5. A statement that there may be unknown risks of these medications (This is particularly essential for children, because there is a paucity of information on the potential long-term effects of psychotropic medications.)

Evidence Base It is important for clinicians to be aware of the evidence base for medication treatment of each childhood psychiatric disorder. Clinical treatment guidelines generally rely on the strength of the available data in determining first-line agents (Hughes et al. 2007; Kowatch et al. 2005). In most cases, clinicians should select a medication within the group of first-line agents when initiating medication treatment with a child. Additional factors that will dictate medication choice are prior medication history, medical history, side-effect profile of the drug, and adolescent and parent preferences.

MAJOR DEPRESSIVE DISORDER The prevalence of major depression in children and adolescents is estimated to range from 1.8% to 4.6% (Kashani and Sherman 1988; Kroes et al. 2001). DSM-IV-TR (American Psychiatric Association 2000) criteria are used to establish a diagnosis of major depression in children and adolescents. The mean length of an episode of major depression in youth ranges from 8 to 13 months, and relapse rates range from 30% to 70% (Birmaher et al. 2002). There is increasing evidence for the continuity of depression from youth into adulthood (Dunn and Goodyer 2006). Recently, a number of double-blind, placebo-controlled multicenter medication studies for treating major depression in children and adolescents have been reported. In the following subsections, medication groups are discussed in order of largest to smallest evidence base.

Selective Serotonin Reuptake Inhibitors Fluoxetine Fluoxetine is the only selective serotonin reuptake inhibitor (SSRI) medication to have FDA approval for the treatment of major depression in children and adolescents. There have been three positive medication trials. In the first study of fluoxetine, 96 child and adolescent outpatients (ages 8–17 years) with major depression were randomly assigned to fluoxetine (20 mg/day) or placebo for an 8-week trial (Emslie et al. 1997). The fluoxetine group, with 27 youths (56%) much or very much improved, showed statistically significant greater improvement in Clinical Global Impressions (CGI) scores than did the placebo group, with 16 youths (33%) much or very much improved. Remission, which was defined as

a Children's Depression Rating Scale—Revised (CDRS-R; Poznanski et al. 1985) score

28, occurred in

31% of the fluoxetine group and 23% of the placebo group. Medication side effects leading to discontinuation in the study were manic symptoms in 3 patients and severe rash in 1 patient. In a double-blind, placebo-controlled multicenter study of fluoxetine, 219 child and adolescent outpatients (ages 8–17 years) with major depression were randomly assigned to fluoxetine (20 mg/day) or placebo for an 8-week trial (Emslie et al. 2002). The fluoxetine group showed statistically significant greater improvement in depression, as assessed by CDRS-R scores, than did the placebo group. Fifty-two percent of patients treated with fluoxetine were rated as much or very much improved, compared with 37% of patients treated with placebo. Remission rates were 39% in the fluoxetine group and 20% in the placebo group. Headache was the only side effect that was reported more frequently in the group treated with fluoxetine than in the group treated with placebo. Fluoxetine alone, fluoxetine with CBT, CBT alone, and placebo were compared in a multicenter trial of 439 adolescent outpatients with a diagnosis of major depression (Treatment for Adolescents with Depression Study [TADS] Team 2004). Patients were randomly assigned to 12 weeks of fluoxetine (10–40 mg/day), fluoxetine (10–40 mg/day) with CBT, CBT alone, or placebo. Compared with placebo, the combination of fluoxetine with CBT was significantly superior on CDRS-R scores. Combination treatment with fluoxetine and CBT was significantly superior to fluoxetine alone and CBT alone. Fluoxetine monotherapy was superior to CBT. Based on CGI scores of much or very much improved, the response rates were 71% for fluoxetine–CBT combination therapy, 61% for fluoxetine, 43% for CBT, and 35% for placebo. At the end of 12 weeks, only 23% of youths achieved remission (CDRS-R 28). Remission rates were significantly higher in the combination group (37%) than in the fluoxetine (23%), CBT (16%), and placebo (17%) groups (Kennard et al. 2006).

Citalopram There have been two controlled trials of citalopram, one with positive and one with negative results in the treatment of depression in youth. The efficacy of citalopram was demonstrated in a double-blind, placebo-controlled multicenter trial of 174 outpatient children and adolescents (ages 7–17 years) with major depression (Wagner et al. 2004b). Patients were randomly assigned to citalopram (dosage range = 20–40 mg/day; mean daily dose = 23 mg for children, 24 mg for adolescents) or placebo for an 8-week trial. The group treated with citalopram showed statistically significant greater improvement in depression (CDRS-R scores) than did the placebo group. The response rates (CDRS-R score 5% and at least twice that of placebo were dizziness, cough, dyspepsia, and vomiting. A 12-week international placebo-controlled multicenter trial of paroxetine in 286 adolescents with major depression failed to show superiority of paroxetine compared with placebo on change from baseline in MADRS or Schedule for Affective Disorders and Schizophrenia for School-Aged Children —Lifetime version (Kiddie-SADS-L; Kaufman et al. 1997) total scores (Berard et al. 2006).

Sertraline The efficacy of sertraline was assessed in two identical double-blind, placebo-controlled multicenter studies of 376 outpatient children and adolescents with major depression (Wagner et al. 2003a). Patients were randomly assigned to sertraline (dosage range = 50–200 mg per day; mean daily dose = 131 mg) or placebo for a 10-week trial. The group receiving sertraline showed a statistically significant greater improvement in depression (CDRS-R scores) than did the placebo group. Response rates (decrease >40% in baseline CDRS-R scores) were 69% in the group treated with sertraline and 59% in the group treated with placebo. The most common side effects in the group treated with sertraline were headache, nausea, insomnia, upper respiratory tract infection, abdominal pain, and diarrhea. In a 24-week open follow-up of 226 of these patients, continued improvement in depressive symptoms was shown with sertraline treatment. At endpoint, 86% of youths met response criteria (Rynn et al. 2006). Sertraline, CBT, and combined CBT plus medication were compared for the treatment of 73 adolescents with depressive disorders (Melvin et al. 2006). All treatments showed statistically significant improvement on all outcome measures; there were no significant advantages of combined treatment.

Escitalopram There has been one controlled study of escitalopram that failed to demonstrate significant improvement on CDRS-R scores at endpoint between escitalopram and placebo (Wagner et al. 2006a). In this study, 264 children and adolescents were randomly assigned to escitalopram (10–20 mg/day) or placebo for 8 weeks. In a post hoc analysis of adolescent completers, escitalopram showed significantly improved CDRS-R scores compared with placebo. Headache and abdominal pain were the only adverse events reported in more than 10% of the patients in the escitalopram group.

Other Antidepressants Venlafaxine Two double-blind, placebo-controlled multicenter studies have evaluated the efficacy of venlafaxine extended-release (XR) for the treatment of major depression in 165 and 169 child and adolescent outpatients, ages 7–17 years, respectively (Emslie et al. 2007a, 2007b). Patients were randomly assigned to venlafaxine XR (37.5–225 mg/day) for 8-week trials. Both studies were negative on the primary outcome measure of change from baseline to endpoint in the CDRS-R scores. A post hoc analysis of the pooled data showed greater improvement on CDRS-R scores with venlafaxine XR for adolescents than for children. The most common adverse events were anorexia and abdominal pain (Emslie et al. 2007a). In a 6-month open-label follow-up study, it was found that most improvement with venlafaxine XR occurred in the first 6 weeks of treatment. At the end of week 6, mean CDRS-R scores decreased from 60 to 36.3, and to 33.8 at 6 months (Emslie et al. 2007b).

Nefazodone The efficacy of nefazodone was assessed in a double-blind, placebo-controlled multicenter trial of 195 adolescents (ages 12–17 years) with major depression (Rynn et al. 2002). Adolescents were randomly assigned to nefazodone (dosage range = 300–600 mg/day; mean daily dose = 444 mg) for an 8-week trial. The nefazodone group showed greater improvement than the placebo group; however, this difference missed statistical significance (P 50% improvement on the YMRS from baseline to endpoint. Twenty-three patients (58%) discontinued the study; of those, 16 patients had a comorbid diagnosis, including ADHD, conduct disorder, or oppositional defiant disorder (ODD). Headache, nausea, vomiting, diarrhea, and somnolence were the most common side effects. In the previously mentioned active-comparator study of lithium, divalproex, and carbamazepine, the response rate ( 50% reduction in baseline YMRS scores) was 53% for divalproex. The effect size for divalproex was 1.63. The most common side effects of divalproex were nausea and sedation (Kowatch et al. 2000b). The efficacy of divalproex was compared with that of quetiapine in 50 hospitalized adolescents with bipolar I disorder, manic or mixed (DelBello et al. 2006). Twenty-five adolescents were randomly assigned to divalproex (serum level 80–120 g/mL) or quetiapine (400–600 mg/day). There were no significant differences between divalproex and quetiapine across the 28 days of the study. The CGI-BP-I overall response rate (CGI-BP-I overall score

2 at endpoint) was 40%, and the CGI-BP-I

mania response rate was 56% for divalproex, which were significantly lower than the rates for quetiapine. The rate of remission (YMRS 12) for divalproex was 28%.

Carbamazepine In a 6-week active-comparator study of lithium, divalproex, and carbamazepine (Kowatch et al. 2000b), carbamazepine had a response rate (defined as 50% reduction in YMRS from baseline to endpoint) of 38% (vs. 38% for lithium and 53% for divalproex) and an effect size of 1.00 (vs. 1.6 for lithium and 1.63 for divalproex). The most common side effects of carbamazepine were sedation, nausea, dizziness, and rash.

Oxcarbazepine There is one double-blind, placebo-controlled multicenter trial of oxcarbazepine for the treatment of youths with bipolar I disorder, manic or mixed, that failed to show superiority of oxcarbazepine to placebo. One hundred sixteen youths (ages 7–18 years) were randomly assigned to oxcarbazepine (mean dosage = 1,515 mg/day) or placebo for a 7-week trial (Wagner et al. 2006b). There was no

significant difference in YMRS scores at endpoint between the oxcarbazepine and placebo groups. The most common side effects in the oxcarbazepine-treated patients were dizziness, nausea, somnolence, diplopia, fatigue, and rash.

Topiramate A double-blind, randomized, placebo-controlled multicenter study assessing the efficacy of topiramate treatment in children and adolescents with acute mania was designed as a 200-patient study but was terminated after randomizing 56 patients (ages 6–17 years) when adult mania trials failed to show efficacy (DelBello et al. 2005). Patients were titrated to 400 mg/day (mean dosage = 278 mg/day). Over a 4-week period, no significant difference was found between the topiramate and placebo groups. The most common adverse events in the topiramate group included decreased appetite, nausea, diarrhea, paresthesias, and somnolence.

Lamotrigine In a 12-week open-label single-center outpatient study in adolescents diagnosed with bipolar disorder I, depressed or mixed, 23 patients entered, and 13 completed the trial (Swope et al. 2004). The mean dosage of lamotrigine was 241 mg/day. There was improvement on depression and mania ratings at study endpoint. No subjects discontinued for adverse events related to the study drug. Lamotrigine as monotherapy or adjunctive treatment for 20 adolescents with bipolar depression was assessed in an 8-week open-label trial (Chang et al. 2006). The mean dosage of lamotrigine was 132 mg/day. Seven adolescents were also taking other psychotropic medications. The response rate (CGI-I

2) was 84%, and the remission rate (CDRS-R 28 and CGI-S

2) was 58%. The most common

side effects were headache, fatigue, nausea, sweating, and difficulty sleeping. There were no significant rashes during the trial. The use of lamotrigine as adjunctive therapy for treatment-refractory bipolar depression in adolescents was assessed in an open-label study (Kusumakar and Yatham 1997). Twenty-two adolescents whose bipolar depression was refractory to treatment with a combination of divalproex plus another mood stabilizer and antidepressant were treated with lamotrigine added to divalproex for 6 weeks. Sixteen of the adolescents (72%) had a positive response by week 6.

Atypical Antipsychotics Olanzapine There is one reported double-blind, placebo-controlled multicenter study of olanzapine (2.5–20 mg/day) for the treatment of adolescent outpatients with bipolar I disorder, mixed or manic (Tohen et al. 2007). Adolescents were randomly assigned to olanzapine (n = 107) or placebo (n = 54) for 3 weeks. Response rates (defined as 50% decrease in YMRS and a CGI-BP mania score

3) were

significantly greater for the olanzapine group (44.8%) than for the placebo group (18.5%). Remission rates (defined as YMRS C > D)—The FDA is empirically conservative and has access to the greatest

amount of pre- and postmarketing data. Although this rating may be controversial for some medications, medicolegal considerations support this approach. Few or no metabolites—Data from both pregnancy and lactation suggest that drug metabolites, which typically have longer elimination half-lives relative to the parent drug, may achieve higher steady-state levels in both fetal circulation and nursing infant serum. The issue of active versus inactive metabolites is unresolved with respect to teratogenic effects. Fewer side effects and drug interactions—Medications with fewer hypotensive and anticholinergic side effects are preferable. Additionally, the effect on seizure threshold and potential interaction with commonly used obstetrical anesthetic and analgesic agents should be minimized. Concordant data—Medications with conflicting data should be avoided; a clinically comparable alternative should be used, if available. Adherence to this recommendation also should reduce any potential legal liability.

Dosage The goal of treatment during pregnancy and lactation is adequate treatment for syndrome remission. Partial treatment only enhances risk by continuing to expose mother and infant to both illness and medications. The minimum effective dose should be maintained throughout treatment, and the clinician should remain mindful that dosage requirements might change during pregnancy. To minimize the potential for neonatal withdrawal and maternal toxicity after delivery, careful monitoring of side effects and serum concentrations may be indicated. Adjusting the feeding and dose schedule and discarding the peak breast milk concentrations for several agents can minimize exposure of nursing infants.

Communication With Other Physicians It is highly recommended that the psychiatrist discuss the medication and potential interactions with both the patient's obstetrician and, if the patient chooses to nurse, her infant's pediatrician.

Monitoring Exposure of Nursing Infants Most clinical laboratory assays lack the sensitivity necessary to detect the typical serum concentrations of nursing infants, and even detectable infant serum concentrations are uninterpretable; therefore, infant serum monitoring is not routinely indicated for most psychotropic medications. One noteworthy exception is the child who is exhibiting potential medication side effects. A small proportion of breast-feeding children may be metabolic outliers for a particular medication and thus may accumulate especially high serum concentrations. If there is a reasonable index of suspicion that the child's symptoms represent a medication effect, then breast-feeding should be discontinued, regardless of infant serum concentration. Consequently, we recommend checking an infant's serum concentration when the child is suspected to be experiencing a medication side effect. Furthermore, infant serum concentrations and other laboratory studies (e.g., blood counts, electrolytes, hepatic profiles) should be monitored when nursing mothers are taking medications (e.g., certain anticonvulsants) with low therapeutic indices or known systemic toxicities.

CONCLUSION The use of pharmacological therapies during pregnancy and lactation will continue to be a complex clinical endeavor that will certainly generate anxiety among patients and clinicians. There is a propensity in the medical literature and the news media to emphasize adverse outcomes, whereas negative study results seldom garner much attention. This is true for both medication and illness exposures. Consequently, clinicians must practice with access to incomplete information. Thoughtful consideration of "pregnancy potential" in the treatment planning for women of reproductive capacity serves to reduce the consternation precipitated by a positive pregnancy test. By inquiring routinely about birth control during all visits when treating women during the reproductive

years, clinicians can provide a conduit for discussion and treatment planning that aims to reduce risk for mother and child.

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Steven P. Roose, Bruce G. Pollock, D. P. Devanand: Chapter 65. Treatment During Late Life, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.443009. Printed 5/12/2009 from www.psychiatryonline.com Textbook of Psychopharmacology >

Chapter 65. Treatment During Late Life TREATMENT DURING LATE LIFE: INTRODUCTION Adverse events caused by medication have been estimated to be between the fourth and sixth leading cause of death in the United States (Lazarou et al. 1998). The elderly bear the greatest burden of medical illness and are subject to extensive medication regimens; in consequence, they experience more adverse drug events than do other segments of the population. In a large study of ambulatory Medicare enrollees, 38% of adverse drug events were serious, life-threatening, or fatal and 28% were considered preventable (Gurwitz et al. 2005). Moreover, psychotropics are among the most common medications associated with preventable adverse drug events in elderly patients in long-term care settings (Gurwitz et al. 2000).

PHARMACOKINETICS OF PSYCHOTROPIC MEDICATIONS IN THE ELDERLY In general, age-associated pharmacokinetic changes result in higher and more variable drug concentrations. Nonetheless, specific information on the pharmacokinetics of most psychoactive medications is inadequate, particularly with regard to medical subgroups and potential drug interactions. The limited information that does exist for older subjects is largely derived from classical pharmacokinetic modeling (Pollock 2005). For example, with fluoxetine, the only published data on disposition in older subjects are limited to a study of single doses in 11 healthy volunteers (Bergstrom et al. 1988). Traditional pharmacokinetic studies require a large number of plasma drug samples obtained from a small number (i.e., 6–12) of volunteers. Single-dose pharmacokinetic studies usually are not adequate to rule out the possibility of nonlinear kinetics. Moreover, it is difficult to generalize from these studies because of the small numbers, the virtual absence of elderly subjects and those with illness, and the concurrent medication use typical at this age (DeVane and Pollock 1999). It should also be appreciated that age or illness-associated differences in pharmacodynamics are not interpretable in the absence of drug concentration data. Population pharmacokinetics provides a means for addressing heterogeneous drug exposure for elders using minimal sampling methods (Bigos et al. 2006). For example, using this approach, our laboratory analyzed 199 citalopram concentration samples obtained on clinic visits from 109 patients across a wide age range. After correcting for weight effects, a significant relationship between age and clearance was observed, with the clearance of citalopram decreasing from approximately 30 L/hour at 18 years of age to as low as 5 L/hour at 93 years of age (Bies et al. 2004). Similarly, among 171 elders treated with paroxetine, we found that weight, sex, and cytochrome P450 (CYP) 2D6 genotype had significant pharmacokinetic effects (Feng et al. 2006). Although individuals older than 65 years now account for more than one-third of prescription drug expenditures in the United States, they are often excluded from clinical and regulatory trials (Atkin et al. 1999). While regulatory authorities have developed guidelines for pharmaceutical companies regarding new medications that are likely to have significant use in the elderly, the full impact of these guidelines has yet to be realized. In addition, the trials that do include elders rarely include the "oldest old" (i.e., 85+ years), those having multiple comorbidities, or those taking multiple medications. These exclusions raise questions about the generalizability of psychotropic data to the frail elderly. The lack of information on new pharmaceuticals has resulted in an escalating pattern of

recommended dosage decreases for neuropharmacological drugs after there has been clinical experience in older patients (Cross et al. 2002). Age-associated pharmacokinetic differences may be due to changes in absorption, distribution, metabolism, or elimination of a drug (Table 65–1). The multidimensional changes associated with aging are heterogeneous, and only the most superficial generalizations can be made (Lotrich and Pollock 2005; Pollock 1998). TABLE 65–1. Physiological changes in the elderly associated with altered pharmacokinetics Organ system

Change

Pharmacokinetic consequence

Gastrointestinal

Decreased intestinal and splanchnic blood flow

Decreased rate of drug absorption

tract Circulatory

Kidney

Decreased concentration of plasma albumin

Increased or decreased free concentration of

and increased 1-acid glycoprotein

drugs in plasma

Decreased glomerular filtration rate

Decreased renal clearance of active metabolites

Muscle

Decreased lean body mass and increased

Altered volume of distribution of lipid-soluble

adipose tissue

drugs, leading to increased elimination half-life

Liver

Decreased liver size; decreased hepatic blood

Decreased hepatic clearance

flow; minimal effects on cytochrome P450 enzyme activity

Absorption Absorption of nutrients, such as iron, thiamine, and calcium, is often impaired in the elderly. Nonetheless, the rate and extent of passive drug absorption do not appear to be affected by normal aging. Antacids, high-fiber supplements, and cholestyramine may significantly diminish the absorption of medications.

Distribution For most psychotropics that are lipid soluble, the loss of lean body mass with aging will lead to increases in their volumes of distribution, resulting in longer half-lives and drug accumulation. This is because a drug's half-life is directly proportional to its apparent volume of distribution. Conversely, for water-soluble drugs such as lithium and digoxin, volumes of distribution will be diminished in older patients, reducing the margin of safety after acute increases in plasma drug concentration. Reductions in serum albumin with age and possible increases in

1-acid

glycoprotein with illness may

affect the extent of drug bound to plasma proteins. However, it is now recognized that changes in plasma protein binding are of clinical significance only when therapeutic drug monitoring is used to adjust dosing, because total drug concentrations (free + protein bound) are usually reported (Benet and Hoener 2002). Total drug levels may be interpreted as too low if a drug's free fraction is increased by diminished plasma proteins or drug displacement. The use of free drug levels in older patients has been found to be useful for lidocaine, theophylline, phenytoin, and digitoxin. More data regarding the use of therapeutic plasma levels are needed for elders treated with valproate, given its greater risks for thrombocytopenia and hepatotoxicity in the aged (Conley et al. 2001).

Metabolism Available evidence suggests that there is no uniform age-associated decline in liver metabolism by CYP enzymes (Pollock et al. 1992b; Schmucker 2001). Nonetheless, reductions in hepatic mass and

blood flow with aging place greater emphasis on interindividual differences in drug metabolic capacity. These metabolic differences may be either genetic or the result of interactions from multiple medications. Enzyme specificity suggests that inhibition or induction of a given CYP enzyme will affect all drugs metabolized by that specific enzyme (Pollock 1998). CYP2D6 is the enzyme responsible for metabolizing tricyclic antidepressants (TCAs) and venlafaxine as well as several older neuroleptics and risperidone. Among the white population, 5%–10% are genetically poor CYP2D6 metabolizers, which has been shown in older patients to affect nortriptyline doses (Murphy et al. 2001) and the severity of perphenazine-associated adverse effects (Pollock et al. 1995). Concern also has been raised about poor CYP2D6 metabolizers treated with venlafaxine or extensive metabolizers given venlafaxine and concomitant 2D6 inhibitors (Johnson et al. 2006; Lessard et al. 1999, 2001; Whyte et al. 2006). Drugs metabolized by CYP3A4, such as alprazolam, triazolam, sertraline, mirtazapine, and nefazodone, appear to be cleared less well in elderly patients (Barbhaiya et al. 1996; Greenblatt et al. 1991; Ronfeld et al. 1997; Timmer et al. 1996). However, this may be because metabolism of CYP3A4 drugs is typically perfusion limited (i.e., dependent on hepatic blood flow, which is known to decline substantially with age) (Wynne et al. 1990). CYP3A4 makes up 30% of total hepatic CYP and nearly all of drug-metabolizing enzyme in the small bowel, and therefore is substantially responsible for "first-pass" or presystemic drug disposition (Shimada et al. 1994). Minimally, 50% of clinically used medications are at least partly dependent on CYP3A4 for their clearance. Serious toxicity has occurred when the 3A4-mediated clearance of terfenadine, astemizole, cisapride, cerivastatin, midazolam, and triazolam was inhibited (Dresser et al. 2000). CYP3A4 activity may be inhibited by grapefruit juice, protease inhibitors, macrolide antibiotics, and triazole antifungals. Among antidepressants, nefazodone and fluvoxamine are the most potent inhibitors of CYP3A4, followed by fluoxetine, through its demethylated metabolite. The very long half-life of norfluoxetine may result in interactions occurring many weeks after the initiation of fluoxetine treatment. The 3A4 enzyme is also potently induced by other drugs, such as carbamazepine, phenytoin, topiramate, modafinil, barbiturates, steroids, and St. John's wort. CYP3A4 induction will increase the likelihood of therapeutic failure for concurrently prescribed 3A4 substrate drugs. Many CYP3A4 inhibitors (e.g., diltiazem) and inducers (e.g., St. John's wort) also have been found to inhibit or induce the P-glycoprotein drug transporter, amplifying their effects on 3A4 (Yu 1999). CYP1A2 metabolizes clozapine, olanzapine, fluvoxamine, and theophylline and contributes to the demethylation of some tertiary TCAs. This enzyme is induced by cigarette smoking, cruciferous vegetables, and charcoaled meats as well as by medications such as omeprazole and phenobarbital. Estrogen replacement therapy in postmenopausal women has been found to inhibit CYP1A2 metabolism (Pollock et al. 1999). CYP2C9 metabolizes several drugs with a narrow therapeutic index (i.e., phenytoin, tolbutamide, ibuprofen, and warfarin). It is therefore important to recognize that this enzyme may be inhibited by fluvoxamine and fluoxetine. CYP2B6 has been found to metabolize bupropion, and in vitro evidence indicates that fluoxetine, paroxetine, and sertraline may cause inhibition (Hesse et al. 2000).

Excretion The well-established age-associated decline in renal clearance may affect excretion of psychotropic drug metabolites and lithium in older patients. The magnitude of this decline varies greatly among the aged (Pollock et al. 1992b), being exacerbated by concomitant conditions (e.g., diabetes and hypertension) and medications (e.g., nonsteroidal anti-inflammatory drugs). Accumulation of active TCA metabolites in the elderly was previously a subject of concern (Pollock et al. 1992a). Higher concentrations of bupropion and venlafaxine metabolites also have been observed in older patients and those with renal impairment, with uncertain clinical consequences (Sweet et al. 1995; Whyte et al. 2006).

PHARMACODYNAMICS OF PSYCHOTROPIC MEDICATIONS IN THE ELDERLY Interindividual differences in pharmacodynamics become evident when those with similar plasma drug concentrations experience different effects. In general, older patients are more sensitive to adverse effects of psychotropics at lower concentrations (Pollock 1999). Homeostatic mechanisms, such as postural control, water balance, orthostatic circulatory responses, and thermoregulation, are frequently less robust in the aged. This factor may interfere with the ability to physiologically adapt to medication. For example, all psychotropics, including selective serotonin reuptake inhibitors (SSRIs), may increase the risk of falls and hip fractures (Liu et al. 1998). Similarly, the syndrome of inappropriate antidiuretic hormone secretion has been reported as an age-associated adverse effect of all SSRIs and of venlafaxine (see Kirby and Ames 2001). Reductions in dopamine or acetylcholine function with age may increase sensitivity to antipsychotics and SSRIs (which indirectly reduce dopamine outflow) as well as medications with antimuscarinic effects. Even low serum anticholinergic levels may be associated with cognitive impairment in depressed and nondepressed elderly persons (Mulsant et al. 2002; Nebes et al. 2005). Unfortunately, anticholinergic drugs continue to be widely prescribed in older patients, including those with cognitive impairment (Roe et al. 2002). Anticoagulant–antidepressant interactions may be both pharmacokinetic and pharmacodynamic. Fluvoxamine and fluoxetine pose the greatest risk of pharmacokinetic interactions through CYP2C9 inhibition, reducing the clearance of warfarin's active S-enantiomer. However, increased bleeding times with SSRIs alone or in combination with anticoagulants also may be possible as a result of depleting platelets of serotonin and attenuating their aggregation (Pollock et al. 2000b). At present, evidence is limited that genetic differences may influence pharmacodynamics in older patients. Depressed elderly patients with the long–long (LL) serotonin transporter promoter genotype were found to have a more rapid initial response to paroxetine (Pollock et al. 2000a). This is consistent with results obtained with other SSRIs in younger patients (Serretti et al. 2006). Another study in geriatric major depression found that carriers of the short (S) allele experienced more severe adverse events during paroxetine treatment (Murphy et al. 2004). Interestingly, findings in Koreans with late-life depression were in the opposite direction—that is, better responses among carriers of the S allele (Kim et al. 2006). Serotonin transporter polymorphisms also may influence the probability that those with dementia will manifest aggressive or psychotic disturbances (Sweet et al. 2001). Similarly, the serotonin 5-HT2A receptor C102/C102 genotype was found significantly more frequently in Alzheimer's disease patients with psychosis (Nacmias et al. 2001). These intriguing reports reinforce the possibility that serotonergic dysfunction plays a prominent role in the psychiatric symptoms of dementia (Pollock et al. 2002, 2007). Given the extensive use of risperidone in the treatment of late-life psychoses and its potent affinity for the 5-HT2A receptor, it is also of interest that the C102/C102 genotype was found to be associated with a more robust risperidone response in younger patients with acutely exacerbated schizophrenia than in younger patients without this genotype (Lane et al. 2002). This same variation in the 5-HT2A receptor was associated with more side effects and more study discontinuations in geriatric patients treated with paroxetine but not mirtazapine (Murphy et al. 2003). Although findings from these early association studies are tenuous, it is encouraging that attempts are now being made to parse medication response by genotype in older subjects.

ANTIDEPRESSANTS IN THE ELDERLY Treatment of Late-Life Depression The combined prevalence of major depressive disorder and dysthymia in late life is 5%–12% in epidemiological studies; this rate is similar to the rate in the younger adult population. However, the symptom pattern and frequency of specific depressive subtypes appear to be different; older patients

have more somatic symptoms, and both the melancholic and the delusional subtypes of depression increase in frequency in older populations. In addition, some degree of cognitive impairment, whether manifest only concurrently with the depressive episode or as a function of age, is common. As in younger patients, untreated depression in late life causes significant social, vocational, and interpersonal morbidity, and depression in late life is associated with a significant risk of mortality. Comorbid depression adversely affects the course of several disease processes; this has been best documented for ischemic heart disease. Patients with unstable angina, post–myocardial infarction, or congestive heart failure who are depressed have a higher cardiac mortality rate than do medically comparable patients who are not depressed (Musselman et al. 1998). Furthermore, the suicide rate in men (in the United States, specifically white men) increases dramatically after age 60 years and continues to rise significantly as a function of age. Depression in late life probably represents a heterogeneous group of disorders with distinct etiologies; for example, late-onset depression, defined as having a first episode after age 60 years, is associated with brain imaging findings consistent with significant vascular disease (Figiel et al. 1991), and late-life dysthymia in men is associated with low testosterone levels (Seidman and Roose 2000). Thus, late-life depression is not simply an episode of major depression in a patient 70 years old rather than a patient 40 years old.

Studies of Antidepressant Treatment in Older Patients The pharmacological treatment of late-life depression has long been influenced by three widely held clinical beliefs about older patients: 1) they do not respond at the same rate or as robustly as younger patients; 2) they take longer to respond to antidepressant medication, and therefore a 12-week trial is mandatory; and 3) they experience a higher rate of side effects and adverse events. Until recently, there has been a relative paucity of rigorous randomized, controlled trials of antidepressant treatment in late-life depression; consequently, these clinical beliefs have gone untested. However, perhaps stimulated by the prevalence and clinical significance of late-life depression and the need to establish safe and effective treatments, there has been a recent increase in the number of studies of antidepressant treatment for late-life depression (although most are sponsored by the pharmaceutical industry). In addition, analyses of extant data address the issue of optimal duration of treatment. Considering the physiological changes associated with aging and the differences in the phenomenology and possible etiology of depression in late life compared with earlier in life, it is expected that clinical trials of antidepressants in late life will have a unique set of patient moderators and study design mediators that may significantly affect results. Variability in results of randomized, controlled trials of antidepressants in late-life depression may result from heterogeneity in the patient population. Treatment moderators that have been identified as significant for late-life depression include Subtype (e.g., melancholic or atypical) Severity Medical burden Social support Abnormalities on magnetic resonance scans indicating vascular disease Pattern of neurocognitive abnormalities labeled "executive dysfunction" With respect to mediators of treatment response, the standard considerations in study design —namely, randomization, placebo versus comparator control, dosage, duration, and criteria for response and remission—are all important, but specifically the value of placebo-controlled trials versus comparator trials and optimal duration of treatment have been systematically reexamined. Sneed et al. (2008) conducted a meta-analysis of all studies published in peer-reviewed journals from 1985 to 2006 that were randomized, placebo-controlled or comparator (a comparison of two active

conditions) trials of antidepressants for the treatment of late-life depression. The intent of the meta-analysis was to determine whether rates of response to medications in comparator trials are significantly higher than rates of response to comparable medications in placebo-controlled trials—that is, whether study design significantly affects treatment outcome. Sixteen studies (9 comparator trials and 7 placebo-controlled trials) met the rigorous inclusion criteria for the meta-analysis. As hypothesized, antidepressant response rates were significantly higher in the comparator trials compared to placebo-controlled trials; the estimated probability of antidepressant response in a placebo-controlled trial was 46% as compared with 60% in a comparator trial. One possible explanation for the higher response rate to the same medication in a comparator trial is that patient, doctor, and even research rater expectations of response are higher when it is known that the subject is receiving an active medication. Irrespective of the reason that response rates are higher in comparator trials, the results of the study suggest that when clinicians want to make evidence-based treatment decisions and communicate likelihood of response to patients, data from comparator trials may be more appropriate than results of placebo-controlled trials, since comparator trials more closely approximate the clinical situation in that both patient and doctor know that an active medication is being prescribed. Although it would be optimal if the numerous randomized, controlled trials of antidepressant treatment in late-life depression all had comparable patients, the same rigorous study design, and similar data analysis, few (if any) studies are without problems. Thus, the review of specific antidepressants that follows does not attempt to be inclusive of all studies but rather aims to illustrate the effect of medication by reviewing data from the best studies available.

Tricyclic Antidepressants There are scores of randomized, placebo-controlled or comparator (usually an SSRI) trials of TCA treatment for late-life depression. The problem is that most of the placebo-controlled trials involving TCAs were done before the use of plasma-level measurements to ensure optimal TCA treatment. Later randomized, controlled trials that compared TCAs with SSRIs were invariably supported by the pharmaceutical industry, which had no desire to compare their new compound against optimal TCA treatment. Consequently, the preponderance of studies of TCA treatment in late-life depression reported on inadequate doses of the tertiary-amine tricyclics amitriptyline and imipramine. Nonetheless, the results of these studies established that TCAs are an effective treatment for depression in geriatric patients.

Nortriptyline Of the tricyclics, nortriptyline has been found to induce the least orthostatic hypotension and has a documented "therapeutic window" that permits optimal dosing (Roose et al. 1981). Consequently, nortriptyline has emerged as the choice of this class of medications issued to treat late-life depression. However, there are no rigorous placebo-controlled trials of nortriptyline in late-life depression; thus, the relative effectiveness of this medication is inferred from two open trials and three randomized comparator trials. In a study reported by Flint and Rifat (1996), 101 patients meeting DSM-III-R (American Psychiatric Association 1987) criteria for major depressive disorder were treated openly with nortriptyline. The dosing schedule was as follows: all patients achieved a dose of 75 mg by the end of week 1, and then the dose was adjusted if necessary to achieve a plasma level within the therapeutic window of 50–150 ng/mL. The treatment duration was 6 weeks, and the remission criterion was a final Hamilton Rating Scale for Depression (Ham-D; 17-item) score of 10 or less; 60% of the intent-to-treat sample and 75% of the completers met the remission criteria. To establish speed of response, the authors determined the week of treatment that the 61 patients who met criteria for remission at the end of the study first achieved sustained remission. Not surprisingly, at the end of week 1, no patient met the criteria for

remission, and thus the cumulative response rate was 0%. At week 2, 11% of the sample met the remission criteria, and at week 3, 33% met the remission criteria (thus, the cumulative rate at the end of week 3 was 11% + 33%, or 44%). At weeks 4 and 5, 25% and 20%, respectively, met the remission criteria. Thus, the accumulated remission rate at the end of week 5 was 89%. Although it is widely believed that late-life depression patients should have longer treatment trials, specifically 12 weeks, this study found that 89% of the patients who eventually recovered did so by the end of week 5. With respect to tricyclics, it may be that the slower dose escalation often used for older patients, rather than an intrinsic difference in the rapidity of response between young and old, is the critical factor accounting for delayed response. A second open study of a therapeutic plasma level of nortriptyline reported on 42 inpatients (mean age = 70 years) with cardiac disease and melancholic depression who also were treated for 6 weeks (Roose et al. 1994). The remission criterion was a final Ham-D (21-item) score of 8 or less; the intentto-treat remission rate was 67%, the completer remission rate was 82%, and the dropout rate was 19%. Three randomized, controlled trials compared nortriptyline with an SSRI; two studies compared a therapeutic plasma level of nortriptyline with paroxetine, and one study compared flexible-dose nortriptyline with sertraline. Mulsant et al. (2001a) compared nortriptyline with paroxetine in 116 inpatients and outpatients (mean age = 72 years) in a 12-week trial. Patients were considered to be in remission if the final Ham-D (17-item) score was 10 or less; the intent-to-treat remission rate was 57% for the nortriptyline group and 55% for the paroxetine group. The rate of dropout due to side effects in the nortriptyline group was significantly higher than that in the paroxetine group (33% vs. 16%; P = 0.04). A second randomized, controlled trial comparing nortriptyline (targeted to a therapeutic plasma level) with paroxetine is included in this chapter, although technically it should not be considered a geriatric study because the mean age of the patients was 58 years (Nelson et al. 1999). However, it is the only other study comparing a therapeutic plasma level of a tricyclic with an SSRI, and the results are consistent with those of the Mulsant et al. (2001a) study. In this trial, 81 outpatients with ischemic heart disease were treated with medication for 6 weeks. The remission criterion was a final Ham-D (17-item) score of 8 or less; in the intent-to-treat analysis, 63% of the nortriptyline group and 61% of the paroxetine group were remitters. The dropout rate for nortriptyline (35%) was significantly higher than the dropout rate for paroxetine (10%) (P