Olanzapine

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Indications and Usage br 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 br intramuscular formulation acute agitation associated with Schizophrenia and Bipolar I Mania in adults br oral formulation combined with fluoxetine acute treatment of depressive episodes associated with Bipolar I Disorder in adults or acute treatment of treatment resistant depression in adults br Known FDA approvals are as follows br approved for the treatment of the manifestations of psychotic disorders on September 6 1996 br approved in combination with fluoxetine for the treatment of depressive episodes associated with Bipolar disorder on December 24 2003 br approved for the long term treatment of bipolar I disorder on January 14 2004 br approved in combination with fluoxetine for treatment resistant depression on March 19 2009 br Off label uses br 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 citation needed Olanzapine is also used in many addiction clinics as a sleep aid usually 2 55 160 mg due to its low abuse profile and zero addictive properties br Prevention of psychosis br 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 3654 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 br Use in elderly br 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 warning was being widely ignored by doctors br Dosage and administration br Olanzapine is available as a tablet in strengths of 2 5 160 mg 5 160 mg 7 5 160 mg 10 160 mg 15 160 mg and 20 160 mg It also comes as an orally disintegrating wafer known as Zydis which dissolves on the tongue in strengths of 5 160 mg 10 160 mg 15 160 mg and 20 160 mg It is also available as a 10 mg vial for a rapid acting intramuscular injection for short term acute use br Dose may be adjusted depending on the person 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 br Pharmacology br Olanzapine is structurally similar to clozapine but is classified as a thienobenzodiazepine Olanzapine has a higher affinity for 5 HT2 serotonin receptors than D2 dopamine receptors br 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 GABAA 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 HT2C receptors have also been implicated in weight gain br Metabolism br 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 br Side effects adverse reactions br As with all neuroleptic drugs olanzapine can cause tardive dyskinesia and rare but life threatening neuroleptic malignant syndrome br Other recognised side effects may include br Aggressiveness citation needed br akathisia inability to remain still br dry mouth br dizziness br irritability br sedation br insomnia br urinary retention br orthostatic hypotension br weight gain 90 of users experience weight gain citation needed see below br increased appetite br runny nose br low blood pressure br impaired judgment thinking and motor skills br impaired spatial orientation br impaired responses to senses br seizure br trouble swallowing br dental problems and discoloration of teeth br missed periods br problems with keeping body temperature regulated br apathy lack of emotion br Metabolic effects br 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 citation needed 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 dubious discuss 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 br 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 br Animal studies br 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 clarification needed However according to this study the neurons does not seem to be completeley 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 br Overdose br Symptoms of an overdose include tachycardia agitation dysarthria decreased consciousness and coma Death has been reported after an acute overdose of 450 160 mg but also survival after an acute overdose of 1500 160 mg There is no specific known 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 br Controversy lawsuits and settlements br Further information Eli Lilly Controversy br 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 against the company though some 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 top selling drug with sales of 4 2 billion last year br The documents given to The New York Times by Jim Gottstein show that Lilly executives kept important information from doctors about Zyprexa 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 br Lilly 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 30 160 kg 66 pounds in one year and some patients have reported gaining 100 pounds or more But Lilly was concerned that Zyprexa 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 8 000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa Thousands more suits are still pending br 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 br 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 br 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 br 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 br See also br Antipsychotics br Eli Lilly and Company br Notes and references br Burton Michael E Shaw Leslie M Schentag Jerome J Evans William E May 1 2005 Applied Pharmacokinetics amp Pharmacodynamics Principles of Therapeutic Drug Monitoring Lippincott Williams amp Wilkins Fourth Edition edition pp 160 815 ISBN 978 0781744317 160 br Olanzapine Prescribing Information PDF Eli Lilly and Company 2009 03 19 http pi lilly com us zyprexa pi pdf Retrieved 2009 09 06 160 br Pharmalot com br Lilly 2008 Annual Report PDF Lilly 2009 http files shareholder com downloads LLY 696621960x0x296463 611E167A 61C9 4C03 8866 ACF5FA7C8953 English PDF Retrieved 2009 08 06 160 br 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 br NDA 20 592 PDF Food and Drug Administration 1996 09 06 http www accessdata fda gov drugsatfda_docs nda 96 020592_Original_Approval_Pkg 20 pdf Retrieved 2009 09 06 160 br NDA 21 520 PDF Food and Drug Administration 2003 12 24 http www accessdata fda gov drugsatfda_docs appletter 2003 21520ltr pdf Retrieved 2009 09 06 160 br NDA 20 592 S 019 PDF Food and Drug Administration 2004 01 14 http www accessdata fda gov drugsatfda_docs appletter 2004 20592se1 019ltr pdf Retrieved 2009 09 06 160 br Forbes com br 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 Psy

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