Pharmacology

Olanzapine is structurally similar to clozapine, and 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.The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism at serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia, and with therapeutic effects. Antagonizing H₁ histamine receptors causes sedation and may cause weight gain, although antagonistic actions at 5-HT_2C receptors have also been implicated in weight gain.

Dosing and administration

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

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

Pharmacokinetics

Olanzapine displays linear kinetics. Its elimination half-life ranges from 21 to 54 hours. Steady state plasma concentrations are achieved in about a week. Olanzapine undergoes extensive first pass metabolism and bioavailability is not affected by food.

In cases of acute agitiation, olanzapine can also be administered by intramuscular injection in doses up to 10 milligrams. Olanzapine injection should not be given by the intravenous route, and should not be co-administered with benzodiazepines.

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.

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:

• akathisia
• amblyopia
• dry mouth
• dizziness
• sedation
• insomnia
• 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

Weight gain

Of the atypical antipsychotics, olanzapine and clozapine are the most likely to induce weight gain.^[4] The effect is more pronounced if high doses of olanzapine are used.^[5] Smaller amounts of weight gain are induced by risperidone and quetiapine. Ziprasidone and aripiprazole are considered to be weight neutral antipsychotics.

Recently the Food and Drug Administration (FDA) required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with these drugs. 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, and recent (2007) evidence suggests that olanzapine may directly affect adipocyte function, promoting fat deposition. There are some case reports of olanzapine-induced diabetic ketoacidosis.^[6] There are data that suggest that olanzapine can decrease insulin sensitivity.^[7], though there are other studies that seem to refute this^[8]

Triglyceride levels rose from 99 to 166 in one year with olanzapine, in the CAFE ("Comparison of Atypicals for First-Episode Psychosis") study.^{[citation needed]} Of the three drugs administered in that study, "olanzapine was associated with the greatest increases in body weight and related measures."^[9] In the same study, where the median patient age was 23, 46% of male patients on Zyprexa had a waist size of 40" or greater after one year,^{[citation needed]} and "80% gained 7% or more over their baseline weight compared with 57.6% of those receiving risperidone and 50% of those receiving quetiapine."^[10] Impaired glucose metabolism, high triglycerides, and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease.

The results of a large, random-design study funded by NIH's National Institute of Mental Health (NIMH) were published in September 2005. The 18-month study, which involved 1,400 participants at 57 sites around the country, found that "patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those participants taking the other drugs."^[11] However, the study also found that olanzapine helped more patients control symptoms for significantly longer than the other drugs. Specifically, after 18 months, the researchers found, "64 percent of the patients taking olanzapine had stopped, while at least 74 percent had quit each of the other medications."^[12]

Data from a small, open-label, non-randomized study seem to suggest that taking olanzapine by orally dissolving tablets may not be associated with the same degree of weight gain as conventional tablet formulations;^[13] however this has not been substantiated in a blinded experimental setting.

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,^[14] panic disorder,^[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's syndrome and stuttering.

Olanzapine has been marketed for dementia by Eli Lilly though it has never been shown to help with the symptoms of dementia. According to internal documents obtained by the New York Times, Lilly instructed its sales representatives to suggest that physicians prescribe Zyprexa to older patients with symptoms of dementia. One such document states "dementia should be first message" for primary care doctors, since they "do not treat bipolar" or schizophrenia, but "do treat dementia". Three months after its launch, Lilly's Zyprexa campaign, called "Viva Zyprexa", led to 49,000 new prescriptions. In 2002, the company changed the name of the primary care campaign to "Zyprexa Limitless" and began to focus on people with mild bipolar disorder who had previously been diagnosed as depressed, despite the fact that Zyprexa has been FDA approved only for the treatment of mania in bipolar disorder, not depression.^[17]

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.^[18]

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.^[19] 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.^[19]

Note and References