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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 misdemeanor charge of illegally marketing Zyprexa for off-label use, and agreed to pay $1.4 billion.<ref>[http://www.msnbc.msn.com/id/28677805/ MSN.com] Lilly settles Zyprexa suit for $1.42 billion. The Associated Press, January 15, 2009</ref> Although Lilly had evidence that it is not effective for [[dementia]], Zyprexa was marketed for elderly [[Alzheimer's disease|Alzheimer's]] patients.<ref>{{cite news|author=Cronin Fisk, Martha, Lopatto, Elizabeth and Feeley, Jef|title=Lilly Sold Drug for Dementia Knowing It Didn’t Help, Files Show|url=http://www.bloomberg.com/apps/news?pid=20601109&sid=aTLcF3zT1Pdo|date=June 1, 2009|publisher=Bloomberg L.P.|accessdate=2009-09-03}}</ref> The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.<ref>{{cite news|author=Berenson, Alex|title=Drug Files Show Maker Promoted Unapproved Use |url=http://www.nytimes.com/2006/12/18/business/18drug.ht|date=December 18, 2006|publisher=The New York Times|accessdate=2009-09-03}}</ref>


==Medical uses==
==Medical uses==

Revision as of 16:29, 6 July 2012

Olanzapine
Clinical data
Trade namesZyprexa
AHFS/Drugs.comMonograph
MedlinePlusa601213
Pregnancy
category
  • C
Routes of
administration		oral, intramuscular
ATC code
Legal status
Legal status
  • US: WARNING[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability87% [2]
MetabolismHepatic (direct glucuronidation and CYP mediated oxidation)
Elimination half-life21–54 hours
Excretionurine 57%, feces 30%
Identifiers
  • 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.125.320 Edit this at Wikidata
Chemical and physical data
FormulaC17H20N4S
Molar mass312.439 g·mol−1
3D model (JSmol)
Melting point195 °C (383 °F)
Solubility in waterPractically insoluble in water mg/mL (20 °C)
  • CN1CCN(CC1)C/2=N/c4ccccc4Nc3sc(C)cc\23
  • 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 checkY
  • Key:KVWDHTXUZHCGIO-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Olanzapine (trade name Zyprexa or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder.[3] 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.[4]

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 misdemeanor charge of illegally marketing Zyprexa for off-label use, and agreed to pay $1.4 billion.[5] Although Lilly had evidence that it is not effective for dementia, Zyprexa was marketed for elderly Alzheimer's patients.[6] The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.[7]

Medical uses

  • 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 like Zyprexa IntraMuscular: 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 [8]

Known FDA approvals are as follows:

  • approved for the treatment of the manifestations of psychotic disorders on September 6, 1996[9]
  • approved in combination with fluoxetine for the treatment of depressive episodes associated with Bipolar disorder on December 24, 2003[10]
  • approved for the long-term treatment of bipolar I disorder on January 14, 2004[11]
  • approved in combination with fluoxetine for treatment of resistant depression on March 19, 2009.[12]

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,[13] panic disorder,[14] delusional parasitosis,[15] post-traumatic stress disorder);[16] 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.[17]

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.[18] 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.[19]

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.[20] However, a BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.[21]

Investigatory Uses

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.[22]

Adverse effects

As with all neuroleptic drugs, olanzapine can cause the (sometimes) irreversible movement disorder tardive dyskinesia, and the rare, but life-threatening, neuroleptic malignant syndrome. Some also associate all antipsychotics with permanent brain damage.[23]

Other recognised side effects may include:

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,[26][27] 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.[28][29][30][31] The effect is dose dependent in humans[32] and animal models of olanzapine-induced metabolic side-effects.[33] Olanzapine may directly affect adipocyte function, promoting fat deposition.[34] There are some case reports of olanzapine-induced diabetic ketoacidosis.[35] Olanzapine may decrease insulin sensitivity,[36][37] though one 3-week study seems to refute this.[38] It may also increase triglyceride levels.[29]

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).[39]
  • 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.[40]
  • that olanzapine may cause body weight gain and hyperphagia by altering appetite signaling in the brain and periphery[41]
  • that 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[42]

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.[43] One small, open-label, non-randomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain,[44] but this has not been substantiated in a blinded experimental setting.

Animal toxicology

In a placebo-compared study of six Macaque monkeys receiving doses of olanzapine higher than those given to humans, for between 17 and 27 months, a significant brain volume and weight decreases (8-11%) were detected.[45] In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss,[46] There was no change in the number of neurons. 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.[47]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[48] 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. Some have suggested using the Ashton Manual http://www.benzo.org.uk/manual/, originally developed for benzodiazapine withdrawal. Support groups such as The Icarus Project http://theicarusproject.net/HarmReductionGuideComingOffPsychDrugs, 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, orthostasis, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety.[49][50] 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.[51][52][53][54] This has led some to suggest that the withdrawal process might itself be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well the public.[55] Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.[citation needed]

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.[56] 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.[56] 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)

Pharmacology

Zyprexa (olanzapine) 10 mg tablets (AU)

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[57]:

  • dopamine D1: 31
  • dopamine D2: 11
  • dopamine D4: 27
  • serotonin 5-HT2A: 4
  • serotonin 5-HT2C: 11
  • serotonin 5-HT3: 57
  • muscarinic M1: 26
  • adrenergic alpha1: 19
  • histamine H1: 7

Olanzapine is a potent antagonist of the muscarinic M3 receptor,[58] which may underlie its diabetes side-effects.[59] Additionally olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.[60][61] 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.[62] 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.

Metabolism

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.

Controversy, lawsuits and settlements

According to a New York Times article published on December 17, 2006,[63] "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.[64] 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".[64] Temporary injunctions required those who had received the documents to return them and that the documents be removed from websites which had posted them.[65] 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.[64] 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.[66] 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."[66]

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.[67]

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.[68] On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order.[69]

On January 15, 2009 Eli Lilly pled guilty to a misdemeanor charge of illegally marketing Zyprexa for off-label use, and agreed to pay $1.4 billion.[70] Although Lilly had evidence that it is not effective for dementia, Zyprexa was marketed for elderly Alzheimer's patients.[71] The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.[72]

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. [73][74] In Canada a class action lawsuit was settled in Ontario, Quebec and British Columbia.

Chemistry

Olanzapine can be prepared starting from malononitrile and propionaldehyde:[75]

See also

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.
  2. ^ Burton, Michael E.; Shaw, Leslie M.; Schentag, Jerome J.; Evans, William E. (May 1, 2005). Applied Pharmacokinetics & Pharmacodynamics: Principles of Therapeutic Drug Monitoring. Lippincott Williams & Wilkins; Fourth Edition edition. p. 815. ISBN 978-0-7817-4431-7. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help)
  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. ^ "Lilly 2008 Annual Report" (PDF). Lilly. 2009. Retrieved 2009-08-06.
  5. ^ MSN.com Lilly settles Zyprexa suit for $1.42 billion. The Associated Press, January 15, 2009
  6. ^ 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)
  7. ^ Berenson, Alex (December 18, 2006). "Drug Files Show Maker Promoted Unapproved Use". The New York Times. Retrieved 2009-09-03.
  8. ^ 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
  9. ^ "NDA 20-592" (PDF). Food and Drug Administration. 1996-09-06. Retrieved 2009-09-06.
  10. ^ "NDA 21-520" (PDF). Food and Drug Administration. 2003-12-24. Retrieved 2009-09-06.
  11. ^ "NDA 20-592 / S-019" (PDF). Food and Drug Administration. 2004-01-14. Retrieved 2009-09-06.
  12. ^ Forbes.com
  13. ^ 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)
  14. ^ Sepede G, De Berardis D, Gambi F, Campanella D, La Rovere R, D'Amico M, Cicconetti A, Penna L, Peca S, Carano A, Mancini E, Salerno RM, Ferro FM. (2003). "Olanzapine augmentation in treatment-resistant panic disorder: a 12-week, fixed-dose, open-label trial". J Clin Psychopharmacol. 107 (5): 394–6. PMID 16415705.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Meehan, W.J.; Badreshia, S.; Mackley, C.L. (2006-03). "Successful treatment of delusions of parasitosis with olanzapine". Arch Dermatol. 142 (3): 352–355. doi:10.1001/archderm.142.3.352. PMID 16549712. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Jakovljević M, Sagud M, Mihaljević-Peles A. (2006). "Olanzapine in the treatment-resistant, combat-related PTSD—a series of case reports". Acta Psychiatrica Scandinavica. 26 (1): 45–9. doi:10.1111/j.1600-0447.1951.tb10961.x. PMID 12752037.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Stuttering Foundation of America - A look at genetic and neurological correlates of stuttering
  18. ^ 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)
  19. ^ 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)
  20. ^ "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.
  21. ^ "Doctors 'ignoring drugs warning'". BBC News. 17 June 2008. Retrieved 2008-06-22. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  22. ^ "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.
  23. ^ Breggin, P (2007). Brain disabling treatments in psychiatry. Springer Publishing Compan. p. 320. ISBN 0-8261-2934-X. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help)
  24. ^ Makkos Z, Csonka A (2006). "[Akathisia in the course of olanzapine treatment]". Neuropsychopharmacol Hung (in Hungarian). 8 (4): 215–7. PMID 17211056. {{cite journal}}: Unknown parameter |month= ignored (help)
  25. ^ Olanzapine Side Effects - drugs.com
  26. ^ Ramankutty, G (2002). "Olanzapine-induced destabilization of diabetes in the absence of weight gain". Acta Psychiatrica Scandinavica. 105 (3): 235–236. doi:10.1034/j.1600-0447.2002.2c257a.x.
  27. ^ Lambert, MT (2006). "New-onset type-2 diabetes associated with atypical antipsychotic medications". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 30 (5): 919–923. doi:10.1016/j.pnpbp.2006.02.007. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  28. ^ Moyer, Paula (2005-10-25). "CAFE Study Shows Varying Benefits Among Atypical Antipsychotics". Medscape Medical News. WebMD. Retrieved 2007-12-03.
  29. ^ a b 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 [ body mass index ], 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).
  30. ^ Wirshing DA, Wirshing WC, Kysar L, Berisford MA (1999). "Novel antipsychotics: comparison of weight gain liabilities". Journal of Clinical Psychology. 60: 358–63. PMID 10401912.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  33. ^ Weston-Green, KL (2011). "Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats". Behavioural Brain Research. 217 (2): 337–46. doi:10.1016/j.bbr.2010.10.039. PMID 21056063. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  34. ^ 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)
  35. ^ 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.
  36. ^ Chiu CC, Chen CH, Chen BY, Yu SH, Lu ML (2010). "The time-dependent change of insulin secretion in schizophrenic patients treated with olanzapine". Prog. Neuropsychopharmacol. Biol. Psychiatry. 34 (6): 866–70. doi:10.1016/j.pnpbp.2010.04.003. PMID 20394794. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  37. ^ 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}}: CS1 maint: multiple names: authors list (link)
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