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. In light of this, the positive effects of olanzapine appear equivalent to typical antipsychotics with fewer extrapyramidal side effects but greater weight gain. 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); however, it produced more weight gain and other metabolic problems.
Evidence does not support the use of atypical antipsychotics including olanzapine in eating disorders.
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 advice was being widely ignored by British doctors.
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 Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine but may include tremors and muscle rigidity.
Adverse effects by incidence
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.
Very common (>10% incidence)
Weight gain (dose-dependent). Weight gain of over 7% of a person's initial body weight prior to treatment is in this category of very common too with some estimates of its incidence putting it at around 40.6%. This AE is most likely the result of its potent 5-HT2C receptor and H1 receptor blockade (or more specifically inverse agonism).
Hyperprolactinemia elevated blood levels of the hormone, prolactin. Prolactin is one of the hormones that plays a key role in lactation. Long-term uncontrolled hyperprolactinaemia can lead to bone demineralisation (osteoporosis) and an increased risk of fractures (breaks). It tends to produce hyperolactinaemia less often than risperidone, paliperidone and the typical antipsychotics but more often than quetiapine and clozapine.
Hyperglycaemia (elevated blood glucose levels). This may be the result of olanzapine's inhibitory effects on the M3 receptor which regulates the release of insulin from the pancreas.
Common (1-10% incidence)
Extrapyramidal symptoms (EPS) (dose-dependent). Tends to produce less extrapyramidal side effects than typical antipsychotics but more extrapyramidal side effects than sertindole, clozapine and quetiapine.
Mild and transient constipation and xerostomia (dry mouth)
Weight gain of over 15% of one's initial body weight. Is reported to occur in approximately 7.1% of patients.
Glucosuria (glucose in the urine. This is a consequence of hyperglycaemia)
Pancreatitis, swelling of the pancreas which supplies the body with insulin.
Neuroleptic malignant syndrome a potentially fatal complication of antipsychotic drug treatment. Presents with hyperthermia, tremor, tachycardia (high heart rate), mental status change (e.g. confusion), etc.
Jaundice, which is basically when the body's ability to clear a by product (called bilirubin) of the breakdown of an essential component of the blood called haem, is impaired leading to yellow discolouration of the skin, eyes and mucous membranes.
Diabetic ketoacidosis. Type II diabetes mellitus is basically where the body cannot effectively utilise sugars to produce energy due to the fact that its cells have become unresponsive to the hormone, insulin, which allows cells to utilise sugars for energy. This in turn forces the body to burn fats for energy and fats require conversion to ketone bodies in order to be utilised by the cells of the body as an energy source. The ketone bodies are acidic hence when the body is entirely reliant on these ketone bodies for energy the levels in the blood reaches a point where it overwhelms the body's natural mechanisms to keep blood pH (a measure of acidity) within a safe range, leading to the blood becoming acidic which is potentially damaging to the tissues of the body due to the ability of acidic environments to denature the proteins of the body.
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.
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, 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. The effect is dose dependent in humans and animal models of olanzapine-induced metabolic side effects. 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.
Recent studies have established that:
olanzapine and clozapine disturb normal metabolism by forcing the body to preferentially derive its energy from fat (instead of privileging carbohydrates). Thus forcing levels of carbohydrates to remain high which, in turn, would cause the body would develop insulin resistance (reduction of insulin sensitivity).
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.
olanzapine may cause body weight gain and hyperphagia by altering appetite signaling in the brain and periphery
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
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 suggests that taking olanzapine by orally dissolving tablets may induce less weight gain,but this has not been substantiated in a blinded experimental setting.
Olanzapine is associated with the highest placental exposure of any atypical antipsychotic. 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. 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). 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.
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 In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss, There was a 5% loss in the number of neurons. Even though this was not statistically significant it is highly clinically significant and in line with the loss found in the brains of patients diagnosed with schizophrenia (see the references in Konopaske et al. 2008 above). 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.
The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. 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. 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. 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. Thus, some to suggest the withdrawal process itself may be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients.
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. There is no known specific antidote for olanzapine overdose, and even physicians are recommended to call a certified poison control centre for information on the treatment of such a case. Olanzapine is considered moderately toxic in overdose; more toxic than quetiapine, aripiprazole and the SSRIs and less toxic than the MAOIs and TCAs.
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 onein vitro study. 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.
Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetogenic side effects. Additionally olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism of dopamine andserotoninreceptors. 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.
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.
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.
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. 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.
Treatment — in combination with fluoxetine — of resistant depression (March 2009).
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 sodium valproate)
Intramuscular formulation: 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 
Treatment of the manifestations of psychotic disorders (September 1996—March 2000).
Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).
Maintaining treatment response in schizophrenic patients who had been stable for approximately eight weeks and were then followed for a period of up to eight months (November 2000).
Controversy, lawsuits and settlements
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. In 2007, Eli Lilly agreed to pay up to $500 million to settle 18,000 more lawsuits.
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. 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.
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", 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. 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". Temporary injunctions required those who had received the documents to return them and to remove them from websites. 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. On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order. 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. 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."
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 forschizophrenia. 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. In this study, patients receiving olanzapine did not have a significantlylower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.
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