|Systematic (IUPAC) name|
|Legal status||℞ Prescription only|
|Metabolism||Hepatic (direct glucuronidation and CYP mediated oxidation)|
|Excretion||urine 57%, feces 30%|
|Melt. point||195 °C (383 °F)|
|Solubility in water||Practically insoluble in water mg/mL (20 °C)|
| (what is this?)
Olanzapine (trade name Zyprexa or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder. Olanzapine is structurally similar to clozapine, 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 alone, and $4.7B in total.
Medical uses 
The benefits of olanzapine in schizophrenia is difficult to determine as more than half of people in trials quit before the six week completion date. In light of this the positive effects of olanzapine appear equivalent to typical antipsychotics with less extrapyramidal side effects but greater weight again. When compared to other atypical antipsychotic there is tentative data that olanzapine may be a bit more effective however it produced more weight gain and other metabolic problems.
Case-reports, open-label, and small pilot studies suggest efficacy of olanzapine for the treatment of some anxiety spectrum disorders (e.g. generalized anxiety disorder, panic disorder, delusional parasitosis, post-traumatic stress disorder); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use. Other common off-label uses of olanzapine include as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette syndrome and stuttering.
Citing an increased risk of stroke, in 2004 the Committee on the Safety of Medicines (CSM) in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis. However, a BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.
Adverse effects 
|This section's factual accuracy is disputed. (April 2013)|
||This article may contain original research. (September 2009)|
||This section needs additional citations for verification. (April 2013)|
As with all neuroleptic drugs, olanzapine can cause the (sometimes) irreversible movement disorder tardive dyskinesia. This is especially a concern with long term usage, and symptoms of tardive dyskinesia should be monitored carefully by the prescribing physician. Another concern is the rare, but life-threatening, neuroleptic malignant syndrome.
Other recognised side effects may include:
- akathisia; inability to remain still (restlessness)
- anhedonia (may result from the breakdown in the brain's reward system, involving the neurotransmitter dopamine)
- excruciating fatigue
- dry mouth
- red eye
- urinary retention
- orthostatic hypotension
- heart failure, heart attack, or stroke
- weight gain
- increased appetite
- runny nose
- impaired judgment, thinking, and motor skills
- impaired spatial orientation
- impaired responses to senses
- trouble swallowing
- dental problems and discoloration of teeth
- missed periods
- problems with keeping body temperature regulated
- apathy, lack of emotion
- Endocrine side effects have included hyperprolactinemia, hyperglycemia, and diabetes mellitus
- Brain zaps (may result from the blockade of serotonin receptors, since SSRI discontinuation can cause brain zaps and vertigo too)
- Auditory Hallucinations
Paradoxical effects 
While olanzapine is used therapeutically to treat serious mental illness, occasionally it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, with the drug causing unusual changes in personality, thoughts or behavior; hallucinations, and suicidal ideation have also been linked to olanzapine use.
Metabolic effects 
The U.S. Food and Drug Administration requires all atypical antipsychotics to include a warning about the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs' ability to induce weight gain, although there are some reports of metabolic changes in the absence of weight gain, Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, Risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures. The effect is dose dependent in humans and animal models of olanzapine-induced metabolic side-effects. Olanzapine may directly affect adipocyte function, promoting fat deposition. There are some case reports of olanzapine-induced diabetic ketoacidosis. Olanzapine may decrease insulin sensitivity, though one 3-week study seems to refute this. It may also increase triglyceride levels.
Recent studies have established that:
- olanzapine and clozapine disturb the metabolism by making the body take preferentially its energy from fat (instead of privileging carbohydrates). Thus, levels of carbohydrates remaining high, the body would develop insulin resistance (reduction of insulin sensitivity).
- olanzapine promotes fat accumulation : due to disturbances in fat metabolism, rodents become fatter (but don't have their weight increasing at first). Being fatter, they do less exercise, burning less fat and gaining weight.
- olanzapine may cause body weight gain and hyperphagia by altering appetite signaling in the brain and periphery
- olanzapine may induce hyperglycaemia leading to diabetes side-effects by altering insulin secretion from the pancreatic beta cell through blockade of the muscarinic M3 receptor
Despite weight gain, a large multi-center randomized National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs. One small, open-label, non-randomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.
Olanzapine in is the pregnancy category C. Pregnancy category C means: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. Olanzapine can cross the placenta and is excreted in mothers' milk. Potential benefits to the mother may outweigh the risks to the foetus / infant, therefore as per the Prescribing Information from the packet insert: Patients should be advised to notify their doctor if they become pregnant or intend to become pregnant during treatment with olanzapine.
Animal toxicology 
In a placebo-compared study of six Macaque monkeys receiving doses of olanzapine resulting in drug levels comparable to those seen in subjects with schizophrenia treated with these medications for between 17 and 27 months, significant brain volume and weight decreases (8-11%) were detected. In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss, There was a 5% loss in the number of neurons. Even though this was not statistically significant it is highly clinically significant and in line with the loss found in the brains of patients diagnosed with schizophrenia (see the references in Konopaske et al. 2008 above). This study however was contradicted by an earlier primate study, conducted by Selemon et al. in 1999, which found that at therapeutic dosages, olanzapine increased glial counts in monkeys. To date, the effect of olanzapine on glia remains an open question.
Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumors found were in either the liver or mammary glands of the animals.
The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. However, despite increasing demand for safe and effective antipsychotic withdrawal protocols or dose-reduction schedules, no specific guidelines with proven safety and efficacy are currently available. Support groups such as The Icarus Project, and other online forums provide resources and social support for those attempting to discontinue antipsychotics and other psychiatric medications. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, nervousness, dizziness, headache, excessive non-stop crying and anxiety. Some have argued that additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics. This has led some to suggest that the withdrawal process might itself be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients.
Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 1500 mg. There is no known specific antidote for olanzapine overdose, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case. Prescription should be kept in small quantity to reduce risk of overdose as acute bipolar disorder and schizophrenic patients can be at a high risk of suicide (Eli Lilly 2010)
Olanzapine has a higher affinity for 5-HT2 serotonin receptors than D2 dopamine receptors. Affinities are (Ki, nM). Olanzapine binds as an antagonist/inverse agonist at the following receptors:
- dopamine D1: 70
- dopamine D2: 31
- dopamine D3: 11
- dopamine D4: 18
- serotonin 5-HT1A: 2300
- serotonin 5-HT2A: 3.7
- serotonin 5-HT2B: 8.2
- serotonin 5-HT2C: 10
- serotonin 5-HT3: 57
- serotonin 5-HT6: 5
- serotonin 5-HT7: 7.1
- muscarinic M1: 2.5
- muscarinic M2: 18-96
- muscarinic M3: 25-132
- muscarinic M4: 13-32
- muscarinic M5: 48
- adrenergic α1A: 110
- adrenergic α2A: 310
- histamine H1: 2.2
Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetes side-effects. Additionally olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. 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, and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic 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. Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation. Olanzapine may display an antiemetic effect due to its blockade of several receptors (specifically acetylcholine, dopamine, histamine, and serotonin 5-HT3) within the chemoreceptor trigger zone.
Olanzapine is metabolized by the cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be increased or decreased by agents that induce (e.g. cigarette smoke) or inhibit (e.g. fluvoxamine or ciprofloxacin) CYP1A2 activity, respectively.
Society and culture 
Regulatory status 
FDA approved for:
- Treatment - in combination with fluoxetine - of depressive episodes associated with bipolar disorder (December 2003).
- 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 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 
- Short term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).
- 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).
Controversy, lawsuits and settlements 
In 2002, British and Japanese regulatory agencies warned that Zyprexa may be linked to diabetes, but even after the FDA issued a similar warning in 2003, Lilly did not publicly disclose their own findings. Eli Lilly agreed on January 4, 2007 to pay up to $500 million to settle 18,000 lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa. On January 15, 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. Although Lilly had evidence that it is not effective for dementia, Zyprexa was marketed for elderly Alzheimer's patients. The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.
"Eli Lilly has engaged in a decade-long effort to play down the health risks of Zyprexa, its best-selling medication for schizophrenia, according to hundreds of internal Lilly documents and e-mail messages among top company managers", most of which had been disclosed as the result of lawsuits by individuals who had taken the drug, though other documents had been stolen. Eli Lilly filed a protection order to stop the dissemination of some of them about Zyprexa which also the judge believed to be confidential and "not generally appropriate for public consumption". Temporary injunctions required those who had received the documents to return them and to remove from websites. 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. These health risks include an increased risk for diabetes through Zyprexa's links to obesity and its tendency to raise blood sugar. Zyprexa was Lilly’s top-selling drug, with sales of $4.2 billion in 2011.
The documents, given to The New York Times by Jim Gottstein, show that Lilly executives kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes. The Times of London also reported that as early as October 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales. 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."
Lilly told its sales representatives to play down in conversations with doctors their own published data, which has shown that 30 percent of patients taking Zyprexa gain 22 pounds or more after a year on the drug. Another study showed 16% of Zyprexa patients gained at least 30 kg (66 pounds) in one year, and some patients have reported gaining 100 pounds or more. Between 1995 to 2004, Lilly was concerned that Zyprexa’s sales would be hurt if the company was more forthright about the fact that the drug might cause unmanageable weight gain or diabetes. In 2002, British and Japanese regulatory agencies warned that Zyprexa may be linked to diabetes, but even after the FDA issued a similar warning in 2003, Lilly did not publicly disclose their own findings.
In 2006, Lilly paid $700 million to settle 8,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. On January 4, 2007, Eli Lilly agreed to pay up to $500 million to settle 18,000 similar lawsuits, or - including earlier settlements - at least $1.2 billion to 28,500 people. At least 1,200 suits were still pending. About 20 million people worldwide have taken Zyprexa since its introduction in 1996. On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order. Subsequently, in May 2007, the Zyprexa price in Germany was increased by 18 percent .
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-emetogenicchemotherapy, when used in combination with palonosetron and dexamethasone.
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 theNational Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. 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. 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.
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- Forbes.com[dead link]
- 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
- "NDA 20-592" (PDF). Food and Drug Administration. 1996-09-06. Retrieved 2009-09-06.
- "Eli Lilly and Company Agrees to Pay $1.415 Billion to Resolve Allegations of Off-label Promotion of Zyprexa". U.S. Justice Department. 2009-01-15. Retrieved 2012-07-09.
- MSN.com Lilly settles Zyprexa suit for $1.42 billion. The Associated Press, January 15, 2009
- Cronin Fisk, Martha, Lopatto, Elizabeth and Feeley, Jef (June 1, 2009). "Lilly Sold Drug for Dementia Knowing It Didn’t Help, Files Show". Bloomberg L.P. Retrieved 2009-09-03.
- Berenson, Alex (December 18, 2006). "Drug Files Show Maker Promoted Unapproved Use". The New York Times. Retrieved 2009-09-03.
- The New York Times December 17, 2006
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- Eli Lilly was Concerned by Zyprexa Side-Effects from 1998, The Times (London), January 23, 2007
- NYtimes.com Mother Wonders if Psychosis Drug Helped Kill Son, New York Times, January 4, 2007
- NYtimes.com Lilly to Pay Up to $500 Million to Settle Claims. The New York Times, January 4, 2007
- Press Releases: January, 2007 | Electronic Frontier Foundation
- Frontal21.ZDF.de, Tödliche Nebenwirkungen? - Umstrittenes Medikament bringt satte Gewinne
- YouTube.com, Zyprexa - Umstrittenes Medikament bringt satte Gewinne
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- "A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study.". PubMed Journal Article. Support Care Cancer. 2007. Retrieved 2011-09-02. "For the first cycle of chemotherapy, the complete response (no emesis, no rescue) for the acute period (24 h post-chemotherapy) was 100%, the delayed period (days 2-5 post-chemotherapy) 75%, and the overall period (0 120 h post-chemotherapy) 75% in 8 patients receiving HEC and was 97, 75, and 72% in 32 patients receiving MEC. Patients with no nausea for the acute period was 100%, the delayed period 50%, and the overall period 50% in 8 patients receiving HEC and was 100, 78, and 78% in 32 patients receiving MEC."
- McGlashan, T.H.; et al. (1 May 2003). "The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design". Schizophrenia Research (Amsterdam: Elsevier) 61 (1): 7–18. doi:10.1016/S0920-9964(02)00439-5. PMID 12648731.
- McGlashan, Thomas H.; et al. (May 2006). "Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis". American Journal of Psychiatry (Arlington, VA: American Psychiatric Association) 163 (5): 790–99. doi:10.1176/appi.ajp.163.5.790. PMID 16648318. Retrieved 2007-12-03.
Manufacturer site 
Consumer information 
- MedLibrary.org - 'Information on Zyprexa and How to Use It, Precautions and Other Medications to Avoid While Taking, MedLibrary
- NIH.gov - 'Olanzapine (Systemic)' Drug Information, MedlinePlus
- Esoteric Drugs Olanzapine - Esoteric Drugs Olanzapine, ilaç tr
- nytyimes.com - Lilly Settles With 18,000 Over Zyprexa, Alex Berenson, New York Times (December 17, 2006)