Olanzapine

Olanzapine - What is Olanzapine?

Olanzapine (trade names Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, Rexapin or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder.

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.

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 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.

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.

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: acute treatment of depressive episodes associated with Bipolar I Disorder in adults, or acute treatment of treatment 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 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 warning was being widely ignored by doctors.

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Olanzapine Pharmacology

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.

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.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Olanzapine" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.

Olanzapine 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 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. "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. 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. 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."

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.

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Olanzapine Side Effects

As with all neuroleptic drugs, olanzapine can cause tardive dyskinesia and rare, but life-threatening, neuroleptic malignant syndrome.

Other recognised side effects may include:

  • Aggressiveness
  • akathisia inability to remain still
  • dry mouth
  • dizziness
  • irritability
  • sedation
  • insomnia
  • constipation
  • urinary retention
  • orthostatic hypotension
  • weight gain (90% of users experience weight gain ) (see below)
  • increased appetite
  • runny nose
  • low blood pressure
  • impaired judgment, thinking, and motor skills
  • impaired spatial orientation
  • impaired responses to senses
  • seizure
  • 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
  • Hyperprolactinemia causing sexual dysfunction, menstrual irregularities, and osteoporosis

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. 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. 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 studies

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 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.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Olanzapine" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.