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INFOMATION:
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
Schizophrenia
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.
Other
Evidence does not support the use of atypical antipsychotics including olanzapine in eating disorders.
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, delusional parasitosis, post-traumatic stress disorder); 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. It has also been used for Tourette syndrome and stuttering.
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 advice was being widely ignored by British doctors.
Adverse effects
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.
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).
- Somnolence (dose-dependent). Tends to produce a moderate amount of sedation, less than clozapine and chlorpromazine but more than aripiprazole, amisulpride, paliperidone and sertindole and approximately that of quetiapine and risperidone.
- 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.
- Hypertriglyceridaemia (elevated blood triglycerides)
- Hypercholesterolaemia (elevated blood cholesterol levels)
- 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)
- Dizziness
- 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)
- Accidental injury
- Insomnia
- Orthostatic hypotension (a drop in blood pressure that occurs upon standing up)
- Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment. ALT & AST are liver enzymes which are often tested for as a measure of liver function.
- Dyspepsia (indigestion)
- Erectile dysfunction. This is most likely the result of hyperprolactinaemia.
- Decreased libido. This is most likely the result of hyperprolactinaemia.
- Rash
- Asthenia (weakness)
- Fatigue
- Oedema the accumulation of fluid in the tissues of the body leading to swelling
- Akathisia An inner sense of restlessness that presents itself with the inability to stay still.
- Parkinsonism (tremor, muscle rigidity, reduced ability to move and being unstable on one's feet.
- Dyskinesia Abnormal, involuntary, repetitive and pointless movements.
Uncommon (0.1-1% incidence)
- Leukopaenia a comparatively low white blood cell (the cells that defend the body from foreign invaders) count.
- Neutropaenia a reduced neutrophil (the white blood cells that kill bacteria) count.
- Bradycardia (low heart rate)
- QTc interval prolongation (an abnormality in the electrical cycle of the heart)
- Photosensitivity reaction
- Alopecia (hair loss)
- Urinary incontinence
- Urinary retention, the inability to urinate.
- Amenorrhea the cessation of menses (a woman's menstrual cycles). This is a complication of hyperprolactinaemia.
- Breast enlargement (in either sex). This is a complication of hyperprolactinaemia.
- Galactorrhoea (expulsion of milk from the breasts that's unrelated to pregnancy or lactation. Most likely the result of hyperprolactinaemia)
- High creatine phosphokinase (an abnormal laboratory finding)
- Increased total bilirubin (a by product of the breakdown of haem - a part of blood cells that is used to carry oxygen. In most people this is an indication of impaired liver function)
Rare (0.01-0.1% incidence)
- Hepatitis (swelling of the liver)
- Rash
- Seizures
Very rare (<0.01% incidence)
- Agranulocytosis, a potentially fatal drop in white blood cell count, basically an exaggerated form of leukopaenia.
- Thrombocytopaenia. A drop in blood platelet counts which are involved in blood clotting.
- Thromboembolism (blood clots; including pulmonary embolism and deep vein thrombosis)
- Rhabdomyolysis (breakdown of muscle tissue leading to the release of myoglobin into the bloodstream which in turn damages the kidneys)
- Alkaline phosphatase increased (an abnormal laboratory parameter)
- Priapism (a painful and enduring erection)
- Urinary hesitation
- 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 coma
- 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.
- Sudden cardiac death
- Anaphylactic reaction a potentially life-threatening allergic reaction.
Paradoxical effects
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.
Metabolic effects
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 to 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.
Pregnancy/Lactation
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.
Animal toxicology
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.
Discontinuation
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 suggest the withdrawal process itself may be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients.
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 2000 mg. 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. Olanzapine is considered moderately toxic in overdose; more toxic than quetiapine, aripiprazole and the SSRIs and less toxic than the MAOIs and TCAs.
Pharmacology
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. 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.
Receptor Ki (nM) Biologic action and notes 5-HT1A 2282 Antagonist 5-HT1B 585 ? 5-HT1D 1061 ? 5-HT1E 2209 ? 5-HT2A 2.4 Inverse agonist. May underlie the "atypicality" of the newer antipsychotics like olanzapine. May contribute to sedating effects. 5-HT2B 11.9 Inverse agonist/antagonist. 5-HT2C 10.2 Inverse agonist. May underlie the appetite-stimulating effects of olanzapine. 5-HT3 202 Antagonist. Possibly responsible, at least in part, for its antiemetic action. 5-HT5A 1212 ? 5-HT6 8.07 Antagonist 5-HT7 105.2 Antagonist α1A 112 Antagonist. Likely responsible for the orthostatic hypotension seen with its use. α1B 263 Antagonist. α2A 315 Antagonist. α2B 81.8 Antagonist α2C 28.9 Antagonist. M1 26 Antagonist. Likely the chief receptor responsible for the anticholinergic effects seen with olanzapine's use. M2 63.5 Antagonist. M3 52.67 Antagonist. Possible role in type 2 diabetes side-effects M4 17.33 Antagonist. M5 7.5 Antagonist. D1 70.33 Antagonist. D2 34.23 Antagonist. Likely responsible for the therapeutic effects of olanzapine against the positive symptoms of schizophrenia. D2Long 31 Antagonist. D2Short 28.77 Antagonist. D3 47 Antagonist. D4 14.33 Antagonist. D5 82 Antagonist. H1 2.19 Inverse agonist. Likely responsible for the sedative effects of olanzapine. H2 44 Antagonist. H4 >10000 Antagonist.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 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.
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 also binds weakly to the GABA-A, beta-adrenergic and benzodiazepine (BZD) receptors.
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