Olanzapine

From Wikipedia, the free encyclopedia - View original article

Olanzapine
Olanzapine.svg
Olanzapine3Dan2.gif
Systematic (IUPAC) name
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
Clinical data
Trade namesLanzek, Zypadhera, Zyprexa
AHFS/Drugs.commonograph
MedlinePlusa601213
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
Routesoral, intramuscular
Pharmacokinetic data
Bioavailability87%[1]
Protein binding93%[2]
MetabolismHepatic (direct glucuronidation and CYP1A2 mediated oxidation)
Half-life33 hours, 51.8 hours (elderly)[2]
ExcretionUrine (57%; 7% as unchanged drug), faeces (30%)[2][3]
Identifiers
CAS number132539-06-1 YesY
ATC codeN05AH03
PubChemCID 4585
IUPHAR ligand47
DrugBankDB00334
ChemSpider10442212 YesY
UNIIN7U69T4SZR YesY
KEGGD00454 YesY
ChEBICHEBI:7735 N
ChEMBLCHEMBL715 YesY
Chemical data
FormulaC17H20N4S 
Mol. mass312.439
Physical data
Melt. point195 °C (383 °F)
Solubility in waterPractically insoluble in water mg/mL (20 °C)
 N (what is this?)  (verify)
 
Jump to: navigation, search
Olanzapine
Olanzapine.svg
Olanzapine3Dan2.gif
Systematic (IUPAC) name
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
Clinical data
Trade namesLanzek, Zypadhera, Zyprexa
AHFS/Drugs.commonograph
MedlinePlusa601213
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
Routesoral, intramuscular
Pharmacokinetic data
Bioavailability87%[1]
Protein binding93%[2]
MetabolismHepatic (direct glucuronidation and CYP1A2 mediated oxidation)
Half-life33 hours, 51.8 hours (elderly)[2]
ExcretionUrine (57%; 7% as unchanged drug), faeces (30%)[2][3]
Identifiers
CAS number132539-06-1 YesY
ATC codeN05AH03
PubChemCID 4585
IUPHAR ligand47
DrugBankDB00334
ChemSpider10442212 YesY
UNIIN7U69T4SZR YesY
KEGGD00454 YesY
ChEBICHEBI:7735 N
ChEMBLCHEMBL715 YesY
Chemical data
FormulaC17H20N4S 
Mol. mass312.439
Physical data
Melt. point195 °C (383 °F)
Solubility in waterPractically insoluble in water mg/mL (20 °C)
 N (what is this?)  (verify)

Olanzapine (sold under the brand names Zyprexa, Zypadhera and Lanzek 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.[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 alone, and $4.7B in total.[5]

Medical uses[edit]

Schizophrenia[edit]

The benefits of olanzapine in schizophrenia are difficult to determine as more than half of people in trials quit before the six week completion date.[6] In light of this, the positive effects of olanzapine appear equivalent to typical antipsychotics with fewer extrapyramidal side effects but greater weight gain.[6] When compared to other atypical antipsychotics, the available data suggests that olanzapine may be slightly more effective (although amisulpride and clozapine do appear to be slightly more effective[7]); however, it produced more weight gain and other metabolic problems.[7][8]

Other[edit]

Evidence does not support the use of atypical antipsychotics including olanzapine in eating disorders.[9]

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,[10] panic disorder,[11] delusional parasitosis,[12] post-traumatic stress disorder);[13] however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use. Olanzapine is no less effective than lithium or valproate, and more effective than placebo in treating bipolar disorder.[14] It has also been used for Tourette syndrome and stuttering.[15]

Elderly[edit]

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.[16] However, a BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.[17]

Adverse effects[edit]

The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangements in the blood lipid and blood sugar profiles (see section Metabolic effects). A recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APD compared with a SMD of 0.74[7] Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine[18] but may include tremors and muscle rigidity.

By incidence[edit]

Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce non-trivial hyperglycemia in patients with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the body's natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.[2][19][20][21][3]

Very common (>10% incidence)[edit]

Common (1-10% incidence)[edit]

Uncommon (0.1-1% incidence)[edit]

Rare (0.01-0.1% incidence)[edit]

Very rare (<0.01% incidence)[edit]

Paradoxical effects[edit]

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.[25]

Metabolic effects[edit]

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

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.[38] One small, open-label, non-randomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain,[39] but this has not been substantiated in a blinded experimental setting.

Pregnancy/Lactation[edit]

Olanzapine is associated with the highest placental exposure of any atypical antipsychotic.[23] Despite this the available evidence suggests it is safe during pregnancy, although the evidence is insufficient strong to say anything with a high degree of confidence.[23] Olanzapine is associated with weight gain which according to recent studies may put olanzapine-treated patients' offspring at a heightened risk for neural tube defects (e.g. spina bifida).[40][41] Breastfeeding in women taking olanzapine is advised against due to the fact that olanzapine is secreted in breast milk with one study finding that the exposure to the infant (in mg per kg of body weight, that is) is about 1.8% that to the mother.[2]

Animal toxicology[edit]

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 total brain volume and weight decreases (8-11%) were detected. Higher losses in specific regions of the brain did reach statistical significance, eg/ The mean gray matter volume of the frontal lobes was significantly reduced(15.2%) compared to controls[42] In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss,[43] There was a 5% loss in the number of neurons that was not statistically significant. An earlier primate study, conducted by Selemon et al. in 1999,[44] 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.[45]

Discontinuation[edit]

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[46] 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.[47] 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.[48][49] Some have argued additional somatic and psychiatric symptoms associated with dopaminergic hypersensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics.[50][51][52][53] Thus, some suggest the withdrawal process itself may be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients.[54]

Overdose[edit]

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 2000 mg.[55] 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.[55] Olanzapine is considered moderately toxic in overdose; more toxic than quetiapine, aripiprazole and the SSRIs and less toxic than the MAOIs and TCAs.[23]

Pharmacology[edit]

Zyprexa (olanzapine) 10 mg tablets (AU)

Olanzapine has a higher affinity for 5-HT2A 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.[56] 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.[57]

ReceptorKi (nM)[58]Biologic action and notes[22]
5-HT1A2282Antagonist
5-HT1B585 ?
5-HT1D1061 ?
5-HT1E2209 ?
5-HT2A2.4Inverse agonist. May underlie the "atypicality" of the newer antipsychotics like olanzapine. May contribute to sedating effects.
5-HT2B11.9Inverse agonist/antagonist.
5-HT2C10.2Inverse agonist. May underlie the appetite-stimulating effects of olanzapine.
5-HT3202Antagonist. Possibly responsible, at least in part, for its antiemetic action.
5-HT5A1212 ?
5-HT68.07Antagonist
5-HT7105.2Antagonist
α1A112Antagonist. Likely responsible for the orthostatic hypotension seen with its use.[22]
α1B263Antagonist.
α2A315Antagonist.
α2B81.8Antagonist
α2C28.9Antagonist.
M126Antagonist. Likely the chief receptor responsible for the anticholinergic effects seen with olanzapine's use.[22]
M263.5Antagonist.
M352.67Antagonist. Possible role in type 2 diabetes side-effects [59]
M417.33Antagonist.
M57.5Antagonist.
D170.33Antagonist.
D234.23Antagonist. Likely responsible for the therapeutic effects of olanzapine against the positive symptoms of schizophrenia.[22]
D2Long31Antagonist.
D2Short28.77Antagonist.
D347Antagonist.
D414.33Antagonist.
D582Antagonist.
H12.19Inverse agonist. Likely responsible for the sedative effects of olanzapine.[22]
H244Antagonist.
H4>10000Antagonist.

Olanzapine is a potent antagonist of the muscarinic M3 receptor,[60] which may underlie its diabetogenic side effects.[59][61] Additionally olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.[62] 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 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. 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.[63]

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.[64]

Olanzapine also binds weakly to the GABA-A, beta-adrenergic and benzodiazepine (BZD) receptors.[18]

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.[18] 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 FDA for:

Controversy, 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.[72] 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.[73] Although Lilly had evidence that it is not effective for dementia, Zyprexa was marketed for elderly Alzheimer's patients.[74] The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.[75]

According to the New York Times, "Eli Lilly has engaged in a decade-long effort to play down the health risks of Zyprexa according to hundreds of internal Lilly documents and e-mail messages among top company managers",[76] most of which had been disclosed as the result of the lawsuits by individuals who had taken the drug, though other documents had been stolen.[77] 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".[77] Temporary injunctions required those who had received the documents to return them and to remove them from websites.[78] 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.[77] On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order.[79] The documents given to The New York Times by Jim Gottstein show that 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. 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.[80] 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."[80]

Chemistry[edit]

Olanzapine can be prepared starting from malononitrile and propionaldehyde:[81]

Olanzapine synthesis.png

Research[edit]

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.[82]

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 Healthand 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.[83] 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.[84]

References[edit]

  1. ^ Burton, Michael E.; Shaw, Leslie M.; Schentag, Jerome J.; Evans, William E. (May 1, 2005). Applied Pharmacokinetics & Pharmacodynamics: Principles of Therapeutic Drug Monitoring (4th ed.). Lippincott Williams & Wilkins. p. 815. ISBN 978-0-7817-4431-7. 
  2. ^ a b c d e "PRODUCT INFORMATION OLANZAPINE SANDOZ® 2.5mg/5mg/7.5mg/10mg/15mg/20mg FILM-COATED TABLETS" (PDF). TGA eBusiness Services. Sandoz Pty Ltd. 8 June 2012. Retrieved 26 November 2013. 
  3. ^ a b "Zyprexa, Zyprexa Relprevv (olanzapine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 26 November 2013. 
  4. ^ a b c "Olanzapine Prescribing Information" (PDF). Eli Lilly and Company. 2009-03-19. Retrieved 2009-09-06. 
  5. ^ "Lilly 2008 Annual Report" (PDF). Lilly. 2009. Retrieved 2009-08-06. 
  6. ^ a b Duggan L, Fenton M, Dardennes RM, El-Dosoky A, Indran S (2005). "Olanzapine for schizophrenia". In Duggan, Lorna. Cochrane Database of Systematic Reviews (2): CD001359. doi:10.1002/14651858.CD001359.pub2. PMID 10796640. 
  7. ^ a b c d Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet [Internet]. 2013 Jun 27 [cited 2013 Sep 19];382(9896) 951–62. Available from:http://www.sciencedirect.com/science/article/pii/S0140673613607333
  8. ^ Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, Kissling W, Leucht S (2010). "Olanzapine versus other atypical antipsychotics for schizophrenia". In Komossa, Katja. Cochrane Database of Systematic Reviews (3): CD006654. doi:10.1002/14651858.CD006654.pub2. PMID 20238348. 
  9. ^ Off-Label Use of Atypical Antipsychotics: An Update. 2011. PMID 22132426. 
  10. ^ 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". Biological Psychiatry 59 (3): 211–5. doi:10.1016/j.biopsych.2005.07.005. PMID 16139813. 
  11. ^ 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 (2006). "Olanzapine Augmentation in Treatment-Resistant Panic Disorder". Journal of Clinical Psychopharmacology 26 (1): 45–9. doi:10.1097/01.jcp.0000195108.01898.17. PMID 16415705. 
  12. ^ Meehan WJ, Badreshia S, Mackley CL (2006). "Successful Treatment of Delusions of Parasitosis with Olanzapine". Archives of Dermatology 142 (3): 352–5. doi:10.1001/archderm.142.3.352. PMID 16549712. 
  13. ^ Jakovljević M, Sagud M, Mihaljević-Peles A (2003). "Olanzapine in the treatment-resistant, combat-related PTSD – a series of case reports". Acta Psychiatrica Scandinavica 107 (5): 394–6; discussion 396. doi:10.1034/j.1600-0447.2003.00065.x. PMID 12752037. 
  14. ^ Review of olanzapine in the management of bipolar disorders Neuropsychiatr Dis Treat. 2007 October; 3(5): 579–587.
  15. ^ Scott, Lisa (Winter 2006). "Genetic and Neurological Factors in Stuttering". Stuttering Foundation of America. 
  16. ^ "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." 
  17. ^ "Doctors 'ignoring drugs warning'". BBC News. 17 June 2008. Retrieved 2008-06-22. 
  18. ^ a b c Lexi-Comp Inc. (2010) Lexi-Comp Drug Information Handbook 19th North American Ed. Hudson, OH: Lexi-Comp Inc. ISBN 978-1-59195-278-7.
  19. ^ Stöllberger, C., Lutz, W. and Finsterer, J. (2009), Heat-related side-effects of neurological and non-neurological medication may increase heatwave fatalities. European Journal of Neurology, 16: 879–882.
  20. ^ "OLANZAPINE (olanzapine) tablet OLANZAPINE (olanzapine) tablet, orally disintegrating [Prasco Laboratories]". DailyMed. Prasco Laboratories. September 2013. Retrieved 26 November 2013. 
  21. ^ "Olanzapine 10 mg tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Aurobindo Pharma - Milpharm Ltd. 17 May 2013. Retrieved 26 November 2013. 
  22. ^ a b c d e f g Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8. 
  23. ^ a b c d Taylor, D. The Maudsley prescribing guidelines in psychiatry. Wiley-Blackwell. 
  24. ^ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  25. ^ Cerner Multum Incorporated (27 September 2011). "Olanzapine". Drugs.com. 
  26. ^ Ramankutty G (2002). "Olanzapine-induced destabilization of diabetes in the absence of weight gain". Acta Psychiatrica Scandinavica 105 (3): 235–6; discussion 236–7. doi:10.1034/j.1600-0447.2002.2c257a.x. PMID 11939979. 
  27. ^ Lambert MT, Copeland LA, Sampson N, Duffy SA (2006). "New-onset type-2 diabetes associated with atypical antipsychotic medications". Progress in Neuro-Psychopharmacology and Biological Psychiatry 30 (5): 919–23. doi:10.1016/j.pnpbp.2006.02.007. PMID 16581171. 
  28. ^ Moyer, Paula (Oct 25, 2005). "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, Goldstein D, Pashdag J, Mintz J, Marder SR (1999). "Novel Antipsychotics". The Journal of Clinical Psychiatry 60 (6): 358–63. doi:10.4088/JCP.v60n0602. PMID 10401912. 
  31. ^ "NIMH study to guide treatment choices for schizophrenia" (Press release). National Institute of Mental Health. 19 September 2005. Retrieved 2006-12-18. 
  32. ^ McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, Sweitzer D, Olexy C, Weiden P, Strakowski SD (2007). "Efficacy and Tolerability of Olanzapine, Quetiapine, and Risperidone in the Treatment of Early Psychosis: A Randomized, Double-Blind 52-Week Comparison". American Journal of Psychiatry 164 (7): 1050–60. doi:10.1176/appi.ajp.164.7.1050. PMID 17606657. 
  33. ^ Nemeroff CB (1997). "Dosing the antipsychotic medication olanzapine". The Journal of Clinical Psychiatry 58 (Suppl 10): 45–9. PMID 9265916. 
  34. ^ Fulbright, A. R.; Breedlove, K. T. (2006). "Complete Resolution of Olanzapine-Induced Diabetic Ketoacidosis". Journal of Pharmacy Practice 19 (4): 255–8. doi:10.1177/0897190006294180. 
  35. ^ Chiu CC, Chen CH, Chen BY, Yu SH, Lu ML (2010). "The time-dependent change of insulin secretion in schizophrenic patients treated with olanzapine". Progress in Neuro-Psychopharmacology and Biological Psychiatry 34 (6): 866–70. doi:10.1016/j.pnpbp.2010.04.003. PMID 20394794. 
  36. ^ Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, Lackner E, Joukhadar C, Müller M, Kasper S (2007). "Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers". Neuropsychopharmacology 33 (7): 1633–41. doi:10.1038/sj.npp.1301541. PMID 17712347. 
  37. ^ Sowell M, Mukhopadhyay N, Cavazzoni P, Carlson C, Mudaliar S, Chinnapongse S, Ray A, Davis T, Breier A, Henry RR, Dananberg J (2003). "Evaluation of Insulin Sensitivity in Healthy Volunteers Treated with Olanzapine, Risperidone, or Placebo: A Prospective, Randomized Study Using the Two-Step Hyperinsulinemic, Euglycemic Clamp". Journal of Clinical Endocrinology & Metabolism 88 (12): 5875–80. doi:10.1210/jc.2002-021884. PMID 14671184. 
  38. ^ Carey, Benedict (September 20, 2005). "Little Difference Found in Schizophrenia Drugs". The New York Times. Retrieved 2007-12-03. 
  39. ^ 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 175 (3): 389–90. doi:10.1007/s00213-004-1951-2. PMID 15322727. 
  40. ^ Rasmussen SA, Chu SY, Kim SY, Schmid CH, Lau J (June 2008). "Maternal obesity and risk of neural tube defects: a metaanalysis". American Journal of Obstetrics & Gynecology 198 (6): 611–619. doi:10.1016/j.ajog.2008.04.021. PMID 18538144. 
  41. ^ McMahon DM, Liu J, Zhang H, Torres ME, Best RG (February 2013). "Maternal obesity, folate intake, and neural tube defects in offspring". Birth Defects Research Part A: Clinical and Molecular Teratology 97 (2): 115–122. doi:10.1002/bdra.23113. PMID 23404872. 
  42. ^ 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. 
  43. ^ 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". Biological Psychiatry 63 (8): 759–65. doi:10.1016/j.biopsych.2007.08.018. PMC 2386415. PMID 17945195. 
  44. ^ Selemon LD, Lidow MS, Goldman-Rakic PS (1999). "Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure". Biological Psychiatry 46 (2): 161–72. doi:10.1016/S0006-3223(99)00113-4. PMID 10418690. 
  45. ^ Brambilla G, Mattioli F, Martelli A (2009). "Genotoxic and carcinogenic effects of antipsychotics and antidepressants". Toxicology 261 (3): 77–88. doi:10.1016/j.tox.2009.04.056. PMID 19410629. 
  46. ^ "4.2.1 Antipsychotic drugs". British National Formulary (57th ed.). London and Chicago: Pharmaceutical Press. March 2009. pp. 221–31. ISBN 978-0-85711-065-7. "Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse." 
  47. ^ "Harm Reduction Guide To Coming Off Psychiatric Drugs & Withdrawal". Icarus Project. April 23, 2008. 
  48. ^ Kim DR, Staab JP (2005). "Quetiapine Discontinuation Syndrome". American Journal of Psychiatry 162 (5): 1020. doi:10.1176/appi.ajp.162.5.1020. PMID 15863814. 
  49. ^ Michaelides C, Thakore-James M, Durso R (2005). "Reversible withdrawal dyskinesia associated with quetiapine". Movement Disorders 20 (6): 769–70. doi:10.1002/mds.20427. PMID 15747370. 
  50. ^ Chouinard G, Jones BD (1980). "Neuroleptic-induced supersensitivity psychosis: Clinical and pharmacologic characteristics". The American Journal of Psychiatry 137 (1): 16–21. PMID 6101522. 
  51. ^ Miller R, Chouinard G (1993). "Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia". Biological Psychiatry 34 (10): 713–38. doi:10.1016/0006-3223(93)90044-E. PMID 7904833. 
  52. ^ Chouinard G, Jones BD, Annable L (1978). "Neuroleptic-induced supersensitivity psychosis". The American Journal of Psychiatry 135 (11): 1409–10. PMID 30291. 
  53. ^ Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Männistö PT, Robinson S, Palmiter RD, Tallerico T (2005). "Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis". Proceedings of the National Academy of Sciences 102 (9): 3513–8. Bibcode:2005PNAS..102.3513S. doi:10.1073/pnas.0409766102. JSTOR 3374957. PMC 548961. PMID 15716360. 
  54. ^ Moncrieff J (2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. 
  55. ^ a b "Symbyax (Olanzapine and fluoxetine) drug overdose and contraindication information". RxList: The Internet Drug Index. WebMD. 2007. Retrieved 2007-12-03. 
  56. ^ Wang JS, Zhu HJ, Markowitz JS, Donovan JL, DeVane CL (September 2006). "Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein". Psychopharmacology (Berl) 187 (4): 415–423. doi:10.1007/s00213-006-0437-9. PMID 16810505. 
  57. ^ Moons T, de Roo M, Claes S, Dom G (August 2011). "Relationship between P-glycoprotein and second-generation antipsychotics". Pharmacogenomics 12 (8): 1193–1211. doi:10.2217/pgs.11.55. PMID 21843066. 
  58. ^ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 26 November 2013. 
  59. ^ a b Weston-Green K, Huang XF, Deng C (10 October 2013). "Second Generation Antipsychotic-Induced Type 2 Diabetes: A Role for the Muscarinic M3 Receptor". CNS Drugs 27: 1069–1080. doi:10.1007/s40263-013-0115-5. PMID 24114586. Retrieved 15 February 2014. 
  60. ^ Johnson DE, Yamazaki H, Ward KM, Schmidt AW, Lebel WS, Treadway JL, Gibbs EM, Zawalich WS, Rollema H (2005). "Inhibitory Effects of Antipsychotics on Carbachol-Enhanced Insulin Secretion from Perifused Rat Islets: Role of Muscarinic Antagonism in Antipsychotic-Induced Diabetes and Hyperglycemia". Diabetes 54 (5): 1552–8. doi:10.2337/diabetes.54.5.1552. PMID 15855345. 
  61. ^ Silvestre JS, Prous J (2005). "Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes". Methods and Findings in Experimental and Clinical Pharmacology 27 (5): 289–304. doi:10.1358/mf.2005.27.5.908643. PMID 16082416. 
  62. ^ "olanzapine". NCI Drug Dictionary. National Cancer Institute. 
  63. ^ Lemke TL, Williams DA (2009) Foye's Medicinal Chemistry, 6th edition. Wolters Kluwer: New Delhi. ISBN 978-81-89960-30-8.
  64. ^ "Medication and Weight Control"
  65. ^ "NDA 21-520" (PDF). Food and Drug Administration. 2003-12-24. Retrieved 2009-09-06. 
  66. ^ "NDA 20-592 / S-019" (PDF). Food and Drug Administration. 2004-01-14. Retrieved 2009-09-06. 
  67. ^ Pillarella J, Higashi A, Alexander GC, Conti R (2012). "Trends in the use of atypical antipsychotics for the treatment of bipolar disorder in the United States, 1998-2009". Psychiatric Services 63 (1): 83–86. doi:10.1176/appi.ps.201100092. PMID 22227765. 
  68. ^ Forbes.com[dead link]
  69. ^ 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
  70. ^ "NDA 20-592" (PDF). Food and Drug Administration. 1996-09-06. Retrieved 2009-09-06. 
  71. ^ a b c d "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. 
  72. ^ Berenson, Alex (January 4, 2007). "Mother Wonders if Psychosis Drug Helped Kill Son". The New York Times. Retrieved May 21, 2013. 
  73. ^ MSN.com Lilly settles Zyprexa suit for $1.42 billion. The Associated Press, January 15, 2009
  74. ^ Fisk, Margaret Cronin; Lopatto, Elizabeth; Feeley, Jef (June 1, 2009). "Lilly Sold Drug for Dementia Knowing It Didn't Help, Files Show". Bloomberg. Retrieved May 21, 2013. 
  75. ^ Berenson, Alex (December 18, 2006). "Drug Files Show Maker Promoted Unapproved Use". The New York Times. Retrieved May 21, 2013. 
  76. ^ Berenson, Alex (December 17, 2006). "Eli Lilly Said to Play Down Risk of Top Pill". The New York Times. Retrieved May 21, 2013. 
  77. ^ a b c L-Z\In re Zyprexa\Documents Leak\Injunction Memo & Order\FINAL INJUNCTION MEMO 2.13.07.wpd
  78. ^ EFF.org
  79. ^ Press Releases: January, 2007 | Electronic Frontier Foundation
  80. ^ a b Eli Lilly was Concerned by Zyprexa Side-Effects from 1998,[dead link] The Times (London), January 23, 2007
  81. ^ US 5229382 
  82. ^ Navari RM, Einhorn LH, Loehrer PJ, Passik SD, Vinson J, McClean J, Chowhan N, Hanna NH, Johnson CS (2007). "A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: A Hoosier oncology group study". Supportive Care in Cancer 15 (11): 1285–91. doi:10.1007/s00520-007-0248-5. PMID 17375339. 
  83. ^ McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller TJ, Woods SW, Hawkins KA, Hoffman R, Lindborg S, Tohen M, Breier A (2003). "The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis". Schizophrenia Research 61 (1): 7–18. doi:10.1016/S0920-9964(02)00439-5. PMID 12648731. 
  84. ^ McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, Hawkins KA, Hoffman RE, Preda A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, Breier A (2006). "Randomized, Double-Blind Trial of Olanzapine Versus Placebo in Patients Prodromally Symptomatic for Psychosis". American Journal of Psychiatry 163 (5): 790–9. doi:10.1176/appi.ajp.163.5.790. PMID 16648318. 

External links[edit]