Olanzapine

Olanzapine From Wikipedia, the free encyclopedia

Olanzapine

Systematic (IUPAC) (IUPAC) name 2-Methyl-4-(4-methyl-1-piperazinyl)-10 H -thieno[2,3-thieno[2,3-b][1,5]benzodiazepine

Clinical data

Trade names

Zyprexa (oriinator), many eneri!" [1]

AHFS//Drugsc!m Monoraph AHFS

"edlinePlus

a#01213

#icense data

&' *lanzapine $% &'

Pregnancy categ!ry

$ +

$% + (i" not r.led o.t)

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oral, intram."!.lar 

administrati!n #egal status #egal status $ %4 (/re"!ription only)

+ ℞-only

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$ /*M (/re"!ription only)

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P&armac!'inetic data i!aaila*ility

[2]

Pr!tein *inding

3[3]

"eta*!lism

6epati! (dire!t l.!.ronidation and +7/12 mediated oxidation)

i!l!gical &al%+li%e 33 ho.r", 518 ho.r" (elderly) [3] ,-creti!n

$rine (59  a" .n!haned dr.), :ae!e" (30) [3][4]

Identi%iers CAS .um*er

13253-0#-1

ATC c!de

 05603 (;6*)

Pu*C&em

+term symptom redction, response rate, negative symptoms, depression, cognitive fnction, discontination de to poor efficacy, and long>term relapse, bt not in positive symptoms or on the =linical Blobal Impressions score. In contrast, pooled second generation antipsychotics shoed speriority to first generation antipsychotics only against the discontination, negative symptoms (ith a mch larger effect seen among indstry> compared to government>sponsored stdies), and cognition scores. &lan"apine cased less e3trapyramidal side effects, less akathisia, bt cased significantly more eight gain, serm cholesterol increase, and triglyceride increase than haloperidol.#*:% ! -1*- revie conclded that among *1 atypical antipsychotics, only clo"apine, olan"apine, and risperidone ere better than first generation antipsychotics.#*6% ! -1** revie conclded that neither first> nor second generation antipsychotics prodce clinically meaningfl changes in =linical Blobal Impression scores bt fond that olan"apine and amislpride prodce

larger effects on the ;!?SS and 5; containing monoo3ygenase system are involved in olan"apine o3idation. =G;-D8 mediated o3idation appears to be a minor metabolic pathay in vivo. 0he U.S. Food and Drg  !dministration re'ires all atypical antipsychotics to inclde a arning abot the risk of developing hyperglycemia and diabetes, both of hich are factors in the metabolic syndrome. 0hese effects may be related to the drgsH ability to indce eight gain, althogh there are some reports of metabolic changes in the absence of eight gain, #::%#:6%Stdies have indicated that olan"apine carries a greater risk of casing and e3acerbating diabetes than another commonly prescribed atypical antipsychotic, indced metabolic side effects. 0here are some case reports of olan"apine>indced diabetic ketoacidosis.#6*% &lan"apine may decrease inslin sensitivity,#6-%#6:% thogh one :>eek stdy seems to refte this.#66% It may also increase triglyceride levels.#:8% Despite eight gain, a large mlti>center randomi"ed ?ational Institte of 9ental @ealth stdy fond that olan"apine as better at controlling symptoms becase patients ere more likely to remain on olan"apine than the other drgs.#6$% &ne small, open>label, non>randomi"ed stdy sggests that taking olan"apine by orally dissolving tablets may indce less eight gain, #68% bt this has not been sbstantiated in a blinded e3perimental setting.

Pregnancy and lactation #edit% &lan"apine is associated ith the highest placental e3posre of any atypical antipsychotic. #67%  Despite this the available evidence sggests it is safe dring pregnancy, althogh the evidence is insfficiently strong to say anything ith a high degree of confidence. #67% &lan"apine is associated ith eight gain hich according to recent stdies may pt olan"apine>treated patientsH offspring at a heightened risk for neral tbe defects (e.g. spina bifida).#6% #6+%  5reastfeeding in omen taking olan"apine is advised against de to the fact that olan"apine is secreted in breast milk ith one stdy finding that the e3posre to the infant (in mg per kg of body eight, that is) is abot *. that to the mother.#:%

Animal toxicology#edit% &lan"apine has demonstrated carcinogenic effects in mltiple stdies hen e3posed chronically to female mice and rats, bt not male mice and rats. 0he tmors fond ere in either the liver or mammary glands of the animals.#$1%

Discontination#edit% 0he 5ritish ?ational Formlary recommends a gradal ithdraal hen discontining anti> psychotic treatment to avoid acte ithdraal syndrome or rapid relapse. #$*% De to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervos system, ithdraal symptoms can occr dring abrpt or over>rapid redction in dosage. @oever, despite increasing demand for safe and effective antipsychotic ithdraal protocols or dose>redction schedles, no specific gidelines ith proven safety and efficacy are crrently available. Spport grops sch as the Icars ;roect, and other online forms provide resorces and social spport for those attempting to discontine antipsychotics and other psychiatric medications.#$-% Withdraal symptoms reported to occr after discontination of antipsychotics inclde nasea, vomiting, lightheadedness, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, nervosness, di""iness, headache, e3cessive non>stop crying, and an3iety.#$:%#$6% Some have arged additional somatic and psychiatric symptoms associated ith dopaminergic hypersensitivity, inclding dyskinesia and acte psychosis, are common featres of 

ithdraal in individals treated ith neroleptics. #$$%#$8%#$7%#$% 0hs, some sggest the ithdraal process itself may be schi"o>mimetic, prodcing schi"ophrenia>like symptoms even in previosly healthy patients.#$+%

O!erdose#edit% Symptoms of an overdose inclde tachycardia, agitation, dysarthria, decreased consciosness and coma. Death has been reported after an acte overdose of 6$1 mg, bt also srvival after an acte overdose of -111 mg.#81% 0here is no knon specific antidote for olan"apine overdose, and even physicians are recommended to call a certified poison control center  for information on the treatment of sch a case.#81% &lan"apine is considered moderately to3ic in overdoseC more to3ic than 'etiapine, aripipra"ole and the SS@0-! serotonin receptors than D- dopamine receptors, hich is a common property of all atypical antipsychotics, aside from the ben"amide antipsychotics sch as amislpride. &lan"apine also had the highest affinity of any second>generation antipsychotic toards the ;>glycoprotein in one in vitro stdy.#8*% ;>glycoprotein transports a nmber of drgs across a nmber of different biological membranes inclding the blood>brain barrier , hich cold mean that less brain e3posre to olan"apine reslts from this interaction ith the ;>glycoprotein.#8-% $ecept! r

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@0*, B!5! !, beta>adrenergic receptors, and ben"odia"epine binding sites.#-%#8% 0he mode of action of olan"apineHs antipsychotic activity is nknon. It may involve antagonism of dopamine and serotonin receptors. !ntagonism of dopamine receptors is associated ith e3trapyramidal effects sch as tardive dyskinesia(0D), and ith therapetic effects.  !ntagonism of mscarinic acetylcholine receptors is associated ith anticholinergic side effects sch as dry moth and constipation, in addition it may sppress or redce the emergence of e3trapyramidal effects for the dration of treatment, hoever it offers no protection against the development of tardive dyskinesia. In common ith other second generation (atypical)

antipsychotics, olan"apine poses a relatively lo risk of e3trapyramidal side effects inclding 0D, de to its high affinity for the D* receptor over the D- receptor .#8+%  !ntagoni"ing @* histamine receptors cases sedation and may case eight gain, althogh antagonistic actions at serotonin $>@0 -= and dopamine D- receptors have also been associated ith eight gain and appetite stimlation. #71%

Metabolism #edit% &lan"apine is metaboli"ed by the cytochrome ;6$1 systemC principally by iso"yme *!- and to a lesser e3tent by -D8. 5y these mechanisms more than 61 of the oral dose, on average, is removed by the hepatic first>pass effect.#-% Drgs or agents that increase the activity of =G;*!-, notably tobacco smoke, may significantly increase hepatic first>pass clearance of &lan"apineC conversely, drgs hich inhibit *!- activity (e3amplesJ =iproflo3acin, Flvo3amine) may redce &lan"apine clearance.#

%$Society and culture#edit% "eglatory stats #edit% &lan"apine is approved in the U.S.!. by the Food and Drg !dministration (FD!) forJ •

0reatment K in combination ith flo3etine K of depressive episodes associated ith bipolar disorder  (December -11:).#7*% /ong>term treatment of bipolar I disorder  (anary -116).#7-%#7:%

•

•

•

•

•

/ong>term treatment K in combination ith flo3etine K of resistant depression (9arch -11+).#76% &ral formlationJ acte and maintenance treatment of schi"ophrenia in adlts, acte treatment of manic or mi3ed episodes associated ith bipolar I disorder (monotherapy and in combination ith lithim or sodim valproate) Intramsclar formlationJ acte agitation associated ith schi"ophrenia and bipolar I mania in adlts &ral formlation combined ith flo3etineJ treatment of acte depressive episodes associated ith bipolar I disorder in adlts, or treatment of acte, resistant depression in adlts#7$% 0reatment of the manifestations of psychotic disorders (September *++8 #78%K9arch -111).

•

#77%

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•

•

Short>term treatment of acte manic episodes associated ith bipolar I disorder  (9arch -111).#77% Short>term treatment of schi"ophrenia instead of the management of the manifestations of psychotic disorders (9arch -111).#77% 9aintaining treatment response in schi"ophrenic patients ho had been stable for appro3imately eight eeks and ere then folloed for a period of p to eight months (?ovember -111).#77%

Contro!ersy# prosection# la$sits and settlements #edit%

li /illy has faced many lasits from people ho claimed they developed diabetes or other diseases after taking 2ypre3a. In -118, /illy paid 4711 million to settle ,111 of these lasits. #7%  In -117, li /illy agreed to pay p to 4$11 million to settle *,111 more lasits. #7+% In -11+, li /illy pleaded gilty to a criminal misdemeanor charge of illegally marketing 2ypre3a for off>label se and agreed to pay 4*.6 billion. #1%#*%  ! ?e Gork 0imes article based on leaked company docments conclded that the company had engaged in a deliberate effort to donplay olan"apineHs side effects. #-% 0he company denied these allegations and stated that the article had been based on cherry picked docments. 9ost of the docments ere disclosed as the reslt of lasits by individals ho had taken the drg, thogh other docments had been stolen.#:% li /illy filed a protection order to stop the dissemination of some of the docments hich the dge believed to be confidential and Lnot generally appropriate for pblic consmptionL.#:% 0emporary innctions re'ired those ho had received the docments to retrn them and to remove them from ebsites.#6% dge ack 5. Weinstein issed a permanent  dgement against frther dissemination of the docm ents and re'iring their retrn by a nmber of parties named by /illy.#:% &n anary , -117, dge ack 5. Weinstein refsed the lectronic Frontier FondationHs motion to stay his order .#$% 0he docments given to 0he ?e Gork 0imes by im Bottstein sho that senior /illy e3ectives may have kept important information from doctors abot 2ypre3aMs links to obesity and its tendency to raise blood sgar K both knon risk factors for diabetes. The Times of /ondon also reported that as early as *++, /illy considered the risk of drg>indced obesity to be a Ltop threatL to 2ypre3a sales. #8% &n &ctober +, -111, senior /illy research physician