OLANZEPINE

Olanzapine

Title: Olanzapine

CAS Registry Number: 132539-06-1

CAS Name: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine

Manufacturers’ Codes: LY-170053

Trademarks: Zyprexa (Lilly)

Molecular Formula: C17H20N4S

Molecular Weight: 312.43

Percent Composition: C 65.35%, H 6.45%, N 17.93%, S 10.26%

Literature References: Serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. Prepn: J. K. Chakrabarti et al., EP 454436; eidem, US 5229382 (1991, 1993 both to Lilly). Comparative pharmacology: N. A. Moore et al., Curr. Opin. Invest. Drugs 2, 281 (1993). HPLC determn in human plasma: J. T. Catlow et al., J. Chromatogr. B 668, 85 (1995). Clinical evaluation in schizophrenia: D. S. Baldwin, S. A. Montgomery, Int. Clin. Psychopharmacol. 10, 239 (1995); in mania of bipolar disorder: M. Tohen et al., Am. J. Psychiatry 156, 702 (1999). Review of pharmacology and clinical experience: B. C. Lund, P. J. Perry, Expert Opin. Pharmacother. 1, 305-323 (2000).

Properties: Crystals from acetonitrile, mp 195°. Practically insol in water.

Melting point: mp 195°

Therap-Cat: Antipsychotic.

Keywords: Antipsychotic; Other Tricyclics; Serotonin-Dopamine Antagonist.

Olanzapine (sold under the brand names Zyprexa, Zypadhera and Lanzek or in combination with fluoxetine, Symbyax) is anatypical antipsychotic. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder.^[4]

Olanzapine is structurally similar to clozapine and quetiapine, but is classified as a thienobenzodiazepine. The olanzapine formulations are manufactured and marketed by the pharmaceutical company Eli Lilly and Company; the drug went generic in 2011. Sales of Zyprexa in 2008 were $2.2B in the US, and $4.7B worldwide.^[5]

Medical uses

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication which includes olanzapine.^[6] A Cochrane reviewfound that the usefulness for maintenance therapy; however, is difficult to determine as more than half of people in trials quit before the six week completion date.^[7]

Zyprexa (olanzapine) 10 mg tablets (AU)

Olanzapine has a higher affinity for 5-HT_2A serotonin receptors than D₂ dopamine receptors, which is a common property of all atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride. Olanzapine also had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study.^[60] P-glycoprotein transports a number of drugs across a number of different biological membranes including the blood-brain barrier, which could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein.^[61]

Receptor	K_i(nM)^[62]	Biologic action and notes^[63]
5-HT_1A	2282	Antagonist
5-HT_1B	585	?
5-HT_1D	1061	?
5-HT_1E	2209	?
5-HT_2A	2.4	Inverse agonist. May underlie the “atypicality” of the newer antipsychotics like olanzapine. May contribute to sedating effects.
5-HT_2B	11.9	Inverse agonist/antagonist.
5-HT_2C	10.2	Inverse agonist. May underlie the appetite-stimulating effects of olanzapine.
5-HT₃	202	Antagonist. Possibly responsible, at least in part, for its antiemetic action.
5-HT_5A	1212	?
5-HT₆	8.07	Antagonist
5-HT₇	105.2	Antagonist
α_1A	112	Antagonist. Likely responsible for the orthostatic hypotension seen with its use.^[63]
α_1B	263	Antagonist.
α_2A	315	Antagonist.
α_2B	81.8	Antagonist
α_2C	28.9	Antagonist.
M₁	26	Antagonist. Likely the chief receptor responsible for the anticholinergic effects seen with olanzapine’s use.^[63]
M₂	63.5	Antagonist.
M₃	52.67	Antagonist. Possible role in type 2 diabetes side-effects ^[64]
M₄	17.33	Antagonist.
M₅	7.5	Antagonist.
D₁	70.33	Antagonist.
D₂	3.00	Antagonist. Likely responsible for the therapeutic effects of olanzapine against the positive symptoms of schizophrenia.^[63]
D_2Long	31	Antagonist.
D_2Short	28.77	Antagonist.
D₃	47	Antagonist.
D₄	14.33	Antagonist.
D₅	82	Antagonist.
H₁	2.19	Inverse agonist. Likely responsible for the sedative effects of olanzapine.^[63]
H₂	44	Antagonist.
H₄	>10000	Antagonist.

Olanzapine is a potent antagonist of the muscarinic M₃ receptor,^[65] which may underlie its diabetogenic side effects.^[64]^[66] Additionally, olanzapine also exhibits a relatively low affinity for serotonin 5-HT₁, GABA_A, beta-adrenergic receptors, and benzodiazepine binding sites.^[67] ^[27]

The mode of action of olanzapine’s antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia(TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated withanticholinergic side effects such as dry mouth and constipation, in addition it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, however it offers no protection against the development of tardive dyskinesia. In common with other second generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its high affinity for the D₁ receptor over the D₂ receptor.^[68]

Antagonizing H₁ histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT_2C and dopamine D₂ receptors have also been associated with weight gain and appetite stimulation.^[69]

Dosage forms[edit]

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 milligrams. Zyprexa (and generic olanzapine) is available as an orally-disintegrating “wafer” which rapidly dissolves in saliva. It is also available in 10 milligram vials for intramuscular injection.^[4]

Metabolism[edit]

Olanzapine is metabolized by the cytochrome P450 system; principally by isozyme 1A2 and to a lesser extent by 2D6. By these mechanisms more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect.^[27] Drugs or agents that increase the activity of CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of Olanzapine; conversely, drugs which inhibit 1A2 activity (examples: Ciprofloxacin, Fluvoxamine) may reduce Olanzapine clearance.^[4]

Society and culture[edit]

Regulatory status[edit]

Olanzapine is approved by the Food and Drug Administration (FDA) for:

Treatment — in combination with fluoxetine — of depressive episodes associated with bipolar disorder (December 2003).^[70]

Long-term treatment of bipolar I disorder (January 2004).^[71]^[72]

Treatment — in combination with fluoxetine — of resistant depression (March 2009).^[73]

Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate)
Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults
Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults ^[74]

Treatment of the manifestations of psychotic disorders (September 1996^[75]—March 2000).^[76]

Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000).^[76]

Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).^[76]

Maintaining treatment response in schizophrenic patients who had been stable for approximately eight weeks and were then followed for a period of up to eight months (November 2000).^[76]

Controversy, prosecution, lawsuits and settlements[edit]

Eli Lilly has faced many lawsuits by from people who claimed they developed diabetes or other diseases after taking Zyprexa. In 2006, Lilly paid $700 million to settle 8,000 of these lawsuits.^[77] In 2007, Eli Lilly agreed to pay up to $500 million to settle 18,000 more lawsuits.^{[citation needed]}

In 2009 Eli Lilly pled guilty to a criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion.^[78]^[79]

A New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzpine’s side effects.^[80] The company denied these allegations and stated that the article had been based on cherry picked documents. Most of the documents were disclosed as the result of lawsuits by individuals who had taken the drug, though other documents had been stolen.^[81] Eli Lilly filed a protection order to stop the dissemination of some of the documents which the judge believed to be confidential and “not generally appropriate for public consumption”.^[81] Temporary injunctions required those who had received the documents to return them and to remove them from websites.^[82] Judge Jack B. Weinstein issued a permanent judgement against further dissemination of the documents and requiring their return by a number of parties named by Lilly.^[81] On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation‘s motion to stay his order.^[83] The documents given to The New York Times by Jim Gottstein show that senior Lilly executives may have kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes.^{[citation needed]} The Times of London also reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a “top threat” to Zyprexa sales.^[84] On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board he belonged to was “quite impressed by the magnitude of weight gain on olanzapine and implications for glucose.”^[84]

Research[

Olanzapine has been investigated for use as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV). A 2007 study demonstrated its successful potential for this use, achieving a complete response in the acute prevention of nausea and vomiting in 100% of patients treated with moderately and highly-emetogenic chemotherapy, when used in combination with palonosetron and dexamethasone.^[85]

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education (PRIME) study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk forschizophrenia. The study examined 60 patients with prodromalschizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo.^[86] In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.^[87]

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Jump up^ treatment resistant depression defined as major depressive disorder in adult patients who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode
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