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Olanzapine

Clinical data
Pregnancy category	C
Routes of administration	oral, intramuscular
ATC code	N05AH03 (WHO)
Legal status
Legal status	US: WARNING In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	87%
Metabolism	Hepatic (direct glucuronidation and CYP mediated oxidation)
Elimination half-life	21–54 hours
Excretion	urine 57%, feces 30%
Identifiers
IUPAC name 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thienobenzodiazepine
CAS Number	132539-06-1
PubChem CID	4585
IUPHAR/BPS	47
DrugBank	DB00334
ChemSpider	10442212
UNII	N7U69T4SZR
KEGG	D00454
ChEMBL	ChEMBL715
CompTox Dashboard (EPA)	DTXSID9023388
ECHA InfoCard	100.125.320
Chemical and physical data
Formula	C17H20N4S
Molar mass	312.439 g·mol
3D model (JSmol)	Interactive image
Melting point	195 °C (383 °F)
Solubility in water	Practically insoluble in water mg/mL (20 °C)
SMILES CN1CCN(CC1)C/2=N/c4ccccc4Nc3sc(C)cc\23
InChI InChI=1S/C17H20N4S/c1-12-11-13-16(21-9-7-20(2)8-10-21)18-14-5-3-4-6-15(14)19-17(13)22-12/h3-6,11,19H,7-10H2,1-2H3 Key:KVWDHTXUZHCGIO-UHFFFAOYSA-N
(verify)

Olanzapine (trade names Zyprexa, Zalasta, Zolafren, Olzapin, Oferta, Zypadhera or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the 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, whose patent for olanzapine proper expires in 2011 (in October 2009 a Canadian judge ruled that the 1991 patent was invalid). Sales of Zyprexa in 2008 were $2.2B in the US alone, and $4.7B in total.

Indications and Usage

• 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

Known FDA approvals are as follows:

• approved for the treatment of the manifestations of psychotic disorders on September 6, 1996

• approved in combination with fluoxetine for the treatment of depressive episodes associated with Bipolar disorder on December 24, 2003

• approved for the long-term treatment of bipolar I disorder on January 14, 2004

• approved in combination with fluoxetine for treatment of resistant depression on March 19, 2009.

Off-label uses

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, post-traumatic stress disorder); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa) and as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette syndrome and stuttering. Olanzapine is also used in many addiction clinics as a sleep aid (usually 2.5–5 mg) due to its low abuse profile and zero addictive properties.

Prevention of psychosis

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 for schizophrenia. The study examined 60 patients with prodromal schizophrenia, 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 had a lower risk of progressing to psychosis, although the difference did not reach statistical significance. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.

Use in elderly

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.

Dosage and administration

Olanzapine is available as a tablet in strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg. It also comes as an orally disintegrating wafer (known as Zydis), which dissolves on the tongue, in strengths of 5 mg, 10 mg, 15 mg and 20 mg. It is also available as a 10 mg vial for a rapid-acting intramuscular injection for short-term acute use.

Dose may be adjusted depending on the patient's response to the drug. The dose also will depend on certain medical problems the person may have. It is generally recommended to be taken once daily before bed as it is highly sedating. However, sedation tends to diminish as treatment is pursued.

Pharmacology

Olanzapine has a higher affinity for 5-HT₂ serotonin receptors than D₂ dopamine receptors. Other affinities are (K_i, nM):

• dopamine D₁: 31
• dopamine D₂: 11
• serotonin 5-HT_2A: 4
• serotonin 5-HT_2C: 11
• muscarinic M₁: 1.9
• adrenergic alpha₁: 19

Like most atypical antipsychotics, compared to the older typical ones, olanzapine has a lower affinity for histamine, cholinergic muscarinic and alpha adrenergic receptors. Olanzapine also exhibits weak affinity for GABA_A, BZD receptor site which may contribute slightly to its sedating properties. The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism at serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia, and with therapeutic effects. Antagonizing H₁ histamine receptors causes sedation and may cause weight gain, although antagonistic actions at 5-HT_2C receptors have also been implicated in weight gain.

Metabolism

Olanzapine is metabolized by the cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be decreased or increased by agents that induce (e.g. cigarette smoke) or inhibit (e.g. fluvoxamine or ciprofloxacin) CYP1A2 activity respectively.

Side effects, adverse reactions

This article possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (September 2009) (Learn how and when to remove this message)

As with all neuroleptic drugs, olanzapine can cause tardive dyskinesia and rare, but life-threatening, neuroleptic malignant syndrome. Similarly to other antipsychotics prolonged use is often associated with permanent brain damage.

Other recognised side effects may include:

• akathisia; inability to remain still (restlessness)
• dry mouth
• dizziness
• irritability
• sedation
• insomnia
• constipation
• urinary retention
• orthostatic hypotension
• weight gain
• increased appetite
• runny nose
• impaired judgment, thinking, and motor skills
• impaired spatial orientation
• impaired responses to senses
• seizures
• 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 Shivers
• Auditory Hallucinations

Metabolic effects

The 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 not dose dependent. 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).
• that 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.

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 suggest that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.

Animal Toxicology

In a placebo-compared study of six Macaque monkeys receiving olanzapine between 17 and 27 months, a 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, with the neurons spared but positioned more closely compared to the controls. However according to this study the neurons do not seem to be completely spared. The gray matter shrinking found was 14.6%, but the neuron density increase was only 10.2% which corresponds to approximately a loss of 5% of the neurons.

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.

Overdose

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. Perscription should be kept in small quantity to reduce risk overdose as acute bipolar disorder and schizophrenic patients can be at a high risk of suicide(Eli Lilly 2010)

Controversy, lawsuits and settlements

According to a New York Times article published on December 17, 2006, "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. These had been sent to a number of journalists by a lawyer advocate for individuals with a psychiatric diagnosis opposed to forced psychiatric treatment. Eli Lilly filed a protection order to stop the dissemination of certain Eli Lilly documents about Zyprexa which they, and the judge, believed to be confidential and "not generally appropriate for public consumption". Temporary injunctions required those who had been received the documents to return them and that the documents be removed from websites which had posted them. In his final judgement, Judge 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 is Lilly’s top-selling drug, with sales of $4.2 billion last year.

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 obtained copies of the documents and reported that as early as October 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales. In another document, dated 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’s own published data, which it told its sales representatives to play down in conversations with doctors, 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. But 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, according to the documents, which cover the period 1995 to 2004. In 2006, Lilly paid $700 million to settle 18,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. Thousands more suits are still pending.

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. Including earlier settlements over Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who claim they were injured by the drug. At least 1,200 suits are still pending, the company said. 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.

On January 15, 2009 Eli Lilly plead guilty to a 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.

In order to make up for the costs for settling the lawsuits and shrinking sales figures for Zyprexa in the U.S.A. the company increased the prices for this medication in Germany in May 2007 by 18 percent.

Chemistry

http://www.google.com/patents/about?id=ZGYeAAAAEBAJ&dq=US+5229382

See also

• Antipsychotics
• Eli Lilly and Company

Notes and references

1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
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3. "Olanzapine Prescribing Information" (PDF). Eli Lilly and Company. 2009-03-19. Retrieved 2009-09-06. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
4. Pharmalot.com
5. "Lilly 2008 Annual Report" (PDF). Lilly. 2009. Retrieved 2009-08-06.
6. 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
7. "NDA 20-592" (PDF). Food and Drug Administration. 1996-09-06. Retrieved 2009-09-06.
8. "NDA 21-520" (PDF). Food and Drug Administration. 2003-12-24. Retrieved 2009-09-06.
9. "NDA 20-592 / S-019" (PDF). Food and Drug Administration. 2004-01-14. Retrieved 2009-09-06.
10. Forbes.com
11. Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA, Mick E, Kinrys G, Oppenheimer J. (2006). "Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study". Biol Psychiatry. 59 (3): 211–5. doi:10.1016/j.biopsych.2005.07.005. PMID 16139813.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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14. Stuttering Foundation of America - A look at genetic and neurological correlates of stuttering
15. "Antiphyscotic used as sleeping pill". Forbes. 0028–0836. Retrieved 2005-12-11.
16. McGlashan, T.H. (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. 61 (1). Amsterdam: Elsevier: 7–18. doi:10.1016/S0920-9964(02)00439-5. PMID 12648731. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
17. McGlashan, Thomas H. (2006). "Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis". American Journal of Psychiatry. 163 (5). Arlington, VA: American Psychiatric Association: 790–99. doi:10.1176/appi.ajp.163.5.790. PMID 16648318. Retrieved 2007-12-03. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
18. "Important Safety Information for Olanzapine". Zyprexa package insert. Eli Lilly & Company. 2007. Archived from the original on 2007-11-23. Retrieved 2007-12-03. Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. ZYPREXA (olanzapine) is not approved for the treatment of elderly patients with dementia-related psychosis.
19. "Doctors 'ignoring drugs warning'". BBC News. 17 June 2008. Retrieved 2008-06-22. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
20. RXlist.com
21. Cancer.gov Definition of Olanzapine - National Cancer Institute
22. Breggin, P (2007). Brain disabling treatments in psychiatry. Springer Publishing Compan. p. 320. ISBN 082612934X. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help)
23. Makkos Z, Csonka A (2006). "". Neuropsychopharmacol Hung (in Hungarian). 8 (4): 215–7. PMID 17211056. {{cite journal}}: Unknown parameter |month= ignored (help)
24. Moyer, Paula (2005-10-25). "CAFE Study Shows Varying Benefits Among Atypical Antipsychotics". Medscape Medical News. WebMD. Retrieved 2007-12-03.
25. ^ AstraZeneca Pharmaceuticals (4 April 2006). "Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First Episode Psychosis: A Randomised Double Blind 52 Week Comparison". AstraZeneca Clinical Trials. AstraZeneca PLC. Archived from the original on 2007-11-13. Retrieved 2007-12-03. At week 12, the olanzapine-treated group had more weight gain, a higher increase in , and a higher proportion of patients with a BMI increase of at least 1 unit compared with the quetiapine and risperidone groups (p<=0.01).
26. Wirshing DA, Wirshing WC, Kysar L, Berisford MA. (1999) Novel antipsychotics: comparison of weight gain liabilities. Journal of Clinical Psychology 60 358-63
27. "NIMH study to guide treatment choices for schizophrenia" (Press release). National Institute of Mental Health. 19 September 2005. Retrieved 2006-12-18.
28. Engl J, Rettenbacher M, Fleischhacker WW, Ebenbichler CF (2007). "Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis". Neuropsychopharmacology. Nov;32(11):2431-2; author reply 2433-4. 32 (11): 2431–2.{{cite journal}}: CS1 maint: multiple names: authors list (link)
29. Fulbright, April R.; Breedlove, K. T. (2006). "Complete Resolution of Olanzapine-Induced Diabetic Ketoacidosis" (abstract). Journal of Pharmacy Practice. 19 (4). Thousand Oaks, CA: SAGE Publications: 255–258. doi:10.1177/0897190006294180. Retrieved 2007-12-02. Olanzapine has been associated with diabetic ketoacidosis and also with weight gain, lipid abnormalities, and the development of type 2 diabetes.
30. Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, Lackner E, Joukhadar C, Müller M, Kasper S., J; Mossaheb, N; Spindelegger, C; Klein, N; Geiss-Granadia, T; Sauermann, R; Lackner, E; Joukhadar, C; Müller, M (2008). "Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers". Neuropsychopharmacology. 33 (7): 1633–41. doi:10.1038/sj.npp.1301541. PMID 17712347. {{cite journal}}: |access-date= requires |url= (help)CS1 maint: multiple names: authors list (link)
31. Sowell, Margaret (August 8, 2003). "Evaluation of Insulin Sensitivity in Healthy Volunteers Treated with Olanzapine, Risperidone, or Placebo: A Prospective, Randomised Study Using the Two-Step Hyperinsulinemic, Euglycemic Clamp". Journal of Clinical Endocrinology & Metabolism. 88 (12). The Endocrine Society: 5875–5880. doi:10.1210/jc.2002-021884. PMID 14671184. Retrieved 2007-12-02. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
32. Albaugh VL; Vary TC; Ilkayeva O; Wener BR; Maresca KP; Joyal JL; Breazeale S; Elich TD; Lang CH (2010). "Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents". Schizophrenia Bulletin. doi:10.1093/schbul/sbq053. PMID 20494946.
33. Albaugh VL; Judson JG; She P; Lang CH; Maresca KP; Joyal JL; Lynch CJ (2010). "Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis". Molecular Psychiatry. doi:10.1038/mp.2010.33. PMC 2892549. PMID 20308992.
34. Carey, Benedict (September 20, 2005). "Little Difference Found in Schizophrenia Drugs". New York Times. The New York Times Company. Retrieved 2007-12-03.
35. de Haan L, van Amelsvoort T, Rosien K, Linszen D (2004). "Weight loss after switching from conventional olanzapine tablets to orally disintegrating olanzapine tablets". Psychopharmacology (Berl). 175 (3): 389–90. doi:10.1007/s00213-004-1951-2. PMID 15322727.{{cite journal}}: CS1 maint: multiple names: authors list (link)
36. Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA (2005). "The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys". Neuropsychopharmacology. 30 (9): 1649–61. doi:10.1038/sj.npp.1300710. PMID 15756305. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
37. Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, Lewis DA (2008). "Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys". Biol. Psychiatry. 63 (8): 759–65. doi:10.1016/j.biopsych.2007.08.018. PMC 2386415. PMID 17945195. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
38. Giovanni Brambilla, Francesca Mattioli, Antonietta Martelli (2009). "Genotoxic and carcinogenic effects of antipsychotics and antidepressants". Toxicology. 261 (3): 77–88. doi:10.1016/j.tox.2009.04.056. PMID 19410629. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
39. ^ "Symbyax (Olanzapine and fluoxetine) drug overdose and contraindication information". RxList: The Internet Drug Index. WebMD. 2007. Retrieved 2007-12-03.
40. The New York Times December 17, 2006
41. ^ U:\Cases\Civil L-Z\In re Zyprexa\Documents Leak\Injunction Memo & Order\FINAL INJUNCTION MEMO 2.13.07.wpd
42. EFF.org
43. ^ Eli Lilly was Concerned by Zyprexa Side-Effects from 1998, The Times (London), January 23, 2007
44. NYtimes.com Mother Wonders if Psychosis Drug Helped Kill Son, New York Times, January 4, 2007
45. NYtimes.com Lilly to Pay Up to $500 Million to Settle Claims. The New York Times, January 4, 2007
46. Press Releases: January, 2007 | Electronic Frontier Foundation
47. MSN.com Lilly settles Zyprexa suit for $1.42 billion. The Associated Press, January 15, 2009
48. 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.{{cite news}}: CS1 maint: multiple names: authors list (link)
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50. Frontal21.ZDF.de, Tödliche Nebenwirkungen? - Umstrittenes Medikament bringt satte Gewinne
51. YouTube.com, Zyprexa - Umstrittenes Medikament bringt satte Gewinne

External links

Manufacturer site

• Zyprexa.com - official Zyprexa brand website from Eli Lilly and Company
• Zyprexa package insert

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

Controversy

• nytyimes.com - Lilly Settles With 18,000 Over Zyprexa, Alex Berenson, New York Times (December 17, 2006)

• Atypical antipsychotics
• Eli Lilly and Company
• Piperazines
• Thienobenzodiazepines