Olanzapine (originally branded Zyprexa ) is an antipsychotic drug used to treat schizophrenia and bipolar disorder. Usually classified with atypical antipsychotics, newer antipsychotic generations. It appears to have slightly greater effectiveness in treating schizophrenia (especially negative symptoms) and lower risk of causing motion impairment than typical antipsychotics. Olanzapine, however, has a higher risk of causing metabolic side effects such as weight gain and type 2 diabetes than typical antipsychotics.
Olanzapine is believed to work by blocking, or antagonists, dopamine receptors D 2 , its effect with most antipsychotics. Like most other atypical antipsychotics, olanzapine also strongly contradicts the 5-HT 2A receptor, which can partially support its reduced tendency to cause motion impairment.
Olanzapine was first patented in 1971. This drug became generic in 2011. Zyprexa's sales in 2008 were $ 2.2 billion in the US, and $ 4.7 billion worldwide.
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Medical use
Schizophrenia
First-line psychiatric treatment for schizophrenia is an antipsychotic drug; olanzapine is one such drug. Olanzapine appears to be effective in reducing the symptoms of schizophrenia, treating acute exacerbations, and treating early onset schizophrenia. However, the usefulness of maintenance therapy is difficult to determine because more than half of the people in the trial stop before the six-week completion date. Treatment with olanzapine (such as clozapine) can lead to weight gain and elevated levels of glucose and cholesterol when compared to most second-generation antipsychotic drugs used to treat schizophrenia.
Comparison
The National Institute for Health and Nursing Excellence, the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry have shown that there is little difference in effectiveness between antipsychotics in relapse prevention, and recommends that specific antipsychotic options be selected on the basis of people's preference and profile of adverse events. The US Agency for Health Quality and Quality concludes that olanzapine is no different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but is superior to the treatment of negative symptoms and depression. When trials only enroll patients who are resistant to treatment excluded from the analysis, olanzapine is superior to the overall assessment.
In the 2013 comparison of 15 antipsychotic drugs in schizophrenia, olanzapine was ranked third in success. It is 5% more effective than risperidone (4), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (1). The 2013 first episode review of schizophrenia concluded that olanzapine is superior to haloperidol in providing lower rates of stopping, and in the reduction of short-term symptoms, response rates, negative symptoms, depression, cognitive function, cessation of poor efficacy, and long-term relapse, but not in positive symptoms or on the Clinical Global Impressions score. In contrast, a combination of second-generation antipsychotics demonstrated superiority to first-generation antipsychotics only to cessation, negative symptoms (with far greater effects seen among industry than government-sponsored studies), and cognition scores. Olanzapine causes fewer extrapyramidal side effects, less akatisia, but causes significant weight gain, increased serum cholesterol, and elevated triglycerides than haloperidol. A 2012 review concluded that among the 10 atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first-generation antipsychotics. A 2011 review concluded that neither the first and second generation antipsychotics resulted in a clinically significant change in the Clinical Global Impression score but found that olanzapine and amisulpride produced a greater effect on PANSS and BPRS batteries than the other five second-generation antipsychotics or first-generation antipsychotic groups. A systematic review of Cochrane 2010 found that olanzapine may have little advantage in its effectiveness when compared with aripiprazole, quetiapine, risperidone and ziprasidone. No difference in effectiveness was detected when comparing olanzapine with amisulpride and clozapine.
The meta-analysis 9 out of 9 published trials had a minimum duration of 6 months and a median duration of 52 weeks concluded that olanzapine, quetiapine, and risperidone had a better effect on cognitive function than amisulpride and haloperidol.
Bipolar disorder
Olanzapine was recommended by the National Institute of Health and Nursing Excellence as first-line therapy for the treatment of acute mania in bipolar disorder. The other recommended first line is haloperidol, quetiapine and risperidone. Recommended in combination with fluoxetine as first-line therapy for acute bipolar depression; and as second-line treatment by itself for treatment of bipolar disorder treatments.
Network for Mood and Anxiety Treatments (CANMAT) recommends olanzapine as a first-line treatment of bipolar disorder and olanzapine combination with fluoxetine as second-line treatment for bipolar depression.
The 2014 meta-analysis concluded that olanzapine plus fluoxetine was the most effective of the nine treatments for bipolar depression included in the analysis.
Other uses
The evidence does not support the use of atypical antipsychotics, including olanzapine, in eating disorders.
Olanzapine has not been rigorously evaluated in generalized anxiety disorder, panic disorder, delusional parasitosis, or post-traumatic stress disorder. Olanzapine is no less effective than lithium or valproate and is more effective than placebo in treating bipolar disorder. It has also been used for Tourette's syndrome and stuttering.
Specific population
Pregnancy and lactation
Olanzapine is associated with the highest placental exposure of any atypical antipsychotic. Nevertheless, the available evidence suggests it is safe during pregnancy, although the evidence is not strong enough to say anything with a high level of confidence. Olanzapine is associated with weight gain which, according to recent studies, may place offspring of patients treated with olanzapine at high risk for neural tube defects (eg spina bifida). Breastfeeding in women taking olanzapine is recommended due to the fact that olanzapine secreted in breast milk with one study found that infant exposure (in mg per kg body weight, ie) was about 1.8% for the mother.
In elderly
Citing an increased risk of stroke, in 2004 the Committee on Drug Safety (CSM) in the United Kingdom issued a warning that olanzapine and risperidone, both atypical antipsychotic drugs, should not be given to elderly patients with dementia. In the US, olanzapine comes with a black box warning to increase the 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 suggestion was being ignored by British doctors. Evidence suggests that elderly people are more likely to gain weight in olanzapine compared with aripiprazole and risperidone.
Maps Olanzapine
Adverse effects
The main side effect of olanzapine is weight gain, which may be very deep in some cases and/or associated with disorders in blood lipids and blood sugar profiles (see the metabolic effects section). A recent meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest tendency to cause weight gain from 15 APDs compared with SMD 0.74. The extrapyramidal side effects, though potentially serious, are rare. rare of olanzapine but may include tremors and muscle stiffness.
Some patient groups have a high risk of side effects from olanzapine and antipsychotics in general. Olanzapine can produce high blood sugar non-trivial in people with diabetes mellitus. Similarly, parents are at a greater risk of falling and unintentional injury. Young men seem to be at high risk for dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, can interfere with the body's natural thermoregulation system, allowing travel to dangerous levels when the situation (heat exposure, strenuous exercise) occurs.
Other side effects include galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction (impotence).
Paradoxical Effects
Olanzapine is used therapeutically to treat serious mental illness. Sometimes, it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, mind, or behavior; hallucinations and excessive thoughts of suicide are also associated with the use of olanzapine.
Metabolic effects
Direct glucuronidation and oxidation mediated cytochrome P450 is the main metabolic pathway for olanzapine. In vitro studies have shown that CYPs 1A2 and 2D6 and flavin-containing monooxygenase systems are involved in olanzapine oxidation. CYP2D6-mediated oxidation appears to be a minor metabolic pathway in vivo. The US Food and Drug Administration requires all atypical antipsychotics to include warnings about the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. This effect may be related to the drug's ability to induce weight gain, although there are reports of metabolic changes in the absence of weight gain. Studies have shown that olanzapine carries a greater risk of causing and exacerbating diabetes than any other commonly prescribed atypical antipsychotic, Risperidone. Of all atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on different sizes. The effect depends on the dose in humans and animal models of olanzapine-induced metabolic side-effects. There are several cases of olanzapine-induced diabetic ketoacidosis. Olanzapine may decrease insulin sensitivity, although a 3-week study seems to contradict this. It can also increase triglyceride levels.
Despite weight gain, a multi-centered National Institute of Mental Health study found that olanzapine is better at controlling symptoms because patients are more likely to continue to use olanzapine than with other drugs. One small, open-label, non-randomized study showed that taking olanzapine by oral dissolving tablets can lose weight, but this is not proven in a blinded experimental setting.
Animal toxicology
Olanzapine has shown a carcinogenic effect in some studies when exposed chronically to female and rat rats, but not in rats and rats. The tumors found are in the liver or animal milk glands.
Termination
The British National Formulary recommends gradual withdrawal when stopping anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Due to changes in compensation in dopamine, serotonin, adrenergic and histamine receptors in the central nervous system, withdrawal symptoms may occur during sudden or over-rapid dose reduction. However, despite an increase in demand for safe and effective antipsychotic withdrawal protocols or dose-reduction schedules, no specific guidelines with proven safety and efficacy are currently available. Supporting groups such as the Icarus Project, and other online forums provide resources and social support for those seeking to stop antipsychotics and other psychiatric drugs. Reported withdrawal symptoms occur after antipsychotic stops include nausea, vomiting, light headache, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety. Some have suggested additional somatic and psychiatric symptoms associated with dopaminergic hypersensitivity, including dyskinesia and acute psychosis, are a common feature of withdrawal in individuals treated with neuroleptics. Thus, some suggest the withdrawal process itself may be schizo-mimetic, producing symptoms similar to schizophrenia even in previously healthy patients.
Overdose
Overdose symptoms include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survives after an acute overdose of 2000 mg. Death generally occurs with olanzapine plasma concentrations greater than 1000 ng/mL post-mortem, with concentrations up to 5200 ng/mL recorded (although this may be a confounding by dead tissue, which can release olanzapine into the blood after death). There is no specific antidote for olanzapine overdose, and even doctors are recommended to contact a certified poison control center for information on such case care. Olanzapine is considered to be quite toxic in overdose, more toxic than quetiapine, aripiprazole, and SSRI and less toxic than MAOIs and TCAs.
Interactions
Drugs or agents that increase the activity of the CYP1A2 enzyme, especially tobacco smoke, can significantly improve the first gastric cleansing of olanzapine; on the contrary, drugs that inhibit CYP1A2 activity (eg, ciprofloxacin, fluvoxamine) can reduce olanzapine expenditure. Carbamazepine, a known enzyme inducer, has reduced the olanzapine concentration/dose ratio by 33% compared to olanzapine alone. Another enzyme induser, ritonavir, has also been shown to decrease body exposure to olanzapine, due to the induction of the CYP1A2 enzyme and the 5'-diphospho-glucuronosyltransferase (UGT) uridine. Probenecid increases total exposure (area under the curve, or AUC) and maximum plasma concentration (C max ) olanzapine. Although olanzapine metabolism includes a small metabolic pathway of CYP2D6, the presence of CYP2D6 fluoxetine inhibitors has no clinically significant effect on olanzapine's clearance.
Pharmacology
Pharmacodynamics
Olanzapine has a higher affinity for the 5-HT serotonin receptor 2A than the dopamine receptor D 2 , which is a common trait of most atypical antipsychotics, aside from benzamide antipsychotics such as amisulpride joint with non-benzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone and perospirone.
Olanzapine has the highest affinity of second-generation antipsychotics against P-glycoprotein in one in vitro study . P-glycoproteins carry a myriad of drugs in different biological membranes (found in many body systems) including blood-brain barrier (semi-permeable membrane that filters blood content before it reaches the brain); P-GP inhibition may mean that less brain exposure to olanzapine results from this interaction with P-glycoprotein. Large amounts of food and drugs commonly encountered inhibit P-GP, and it is common enough for pharmaceuticals to become P-GP substrates, or to inhibit its action; both the P-GP substrate and inhibitor effectively increase the permeability of the cerebral blood barrier to the P-GP substrate and subsequently increase the central activity of the substrate while reducing local effects on GI channels. The mediation of olanzapine in the central nervous system by P-GP means that any substance or other drug interacting with P-GP increases the risk of toxic accumulation of both olanzapine and other drugs.
Olanzapine is a powerful muscarinic receptor antagonist M 3, which may underlie its diabetogenic side effects. In addition, olanzapine also showed a relatively low affinity for serotonin 5-HT 1 , GABA A , beta-adrenergic receptors, and benzodiazepine binding sites.
The workings of olanzapine antipsychotic activity are unknown. This may involve the antagonism of dopamine receptors and serotonin. The antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. The receptor antagonism of acetylcholine muscarinic receptors is associated with anticholinergic side effects such as dry mouth and constipation, otherwise it can suppress or reduce the appearance of extrapyramidal effects for the duration of treatment, but does not offer protection against the development of tardive dyskinesia. Similar to other second-generation antipsychotics (atypical), olanzapine has a relatively low risk of extrapyramidal side-effects including TD, because of its high affinity for D 1 receptor above D 2 receptors.
Histamine receptor antagonization H 1 causes sedation and may lead to weight gain, although antagonistic action on 5-HT serotonin recipes 2C and dopamine D 2 is also associated with weight gain and appetite stimulation.
Pharmacokinetics
Metabolism
Olanzapine is metabolized by the P450 cytochrome system; mainly by isozyme 1A2 and to a lesser extent by 2D6. With this mechanism more than 40% of oral doses, on average, are removed by a hepatic first-pass effect. Clearance of olanzapine appears to vary by sex; women have about 25% less permission than men. Cleansing of olanzapine also varies by race; in an identifiable African-American individual or Black, olanzapine clearance is 26% higher. There seems to be no difference in permissions between individuals who identify as Caucasian, Chinese, or Japanese. Routine pharmacokinetic monitoring of plasma olanzapine levels is generally unwarranted, despite unusual circumstances (eg drug-drug interactions) or the desire to determine whether a patient is taking their medication or can not ask for its use.
Society and culture
Regulatory status
Olanzapine is approved in the US by the Food and Drug Administration (FDA) to:
- Treatment - in combination with fluoxetine - depressive episodes associated with bipolar disorder (December 2003).
- Long-term bipolar I treatment (January 2004).
- Long-term treatment - in combination with fluoxetine - depression resistant (March 2009).
- Oral formulations: acute care and maintenance of schizophrenia in adults, acute treatment of manic episodes or mixtures 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 formulations combined with fluoxetine: treatment of acute episodes of depression associated with bipolar I disorder in adults, or treatment of adult resistant depression in adults
- Treatment of manifestations of psychotic disorders (September 1996 - March 2000).
- Short-term treatment of acute episodes of mania associated with bipolar I disorder (March 2000).
- Short-term treatment of schizophrenia rather than management of psychotic disorder manifestations (March 2000).
- Maintain a treatment response in a stable schizophrenic patient for approximately eight weeks and then followed for a period of up to eight months (November 2000).
Controversy and litigation
Eli Lilly has faced many lawsuits from people who claim they have diabetes or other diseases after taking Zyprexa, as well as by various government entities, insurance companies, and others. Lilly produced a large number of documents as part of this phase of litigation discovery, which began in 2004; the documents were kept secret by the judge and placed under the seal, and then they themselves became the subject of litigation.
In 2006, Lilly paid $ 700 million to complete about 8,000 of these lawsuits, and in early 2007 Lilly completed about 18,000 clothes for $ 500 million, which made Lilly pay the total to complete the drug-related suit up to $ 1, 2 billion.
The New York Times article in December 2006 based on leaked company documents concluded that the company had made deliberate attempts to downplay the side effects of olanzapine. The Company denies these allegations and states that the article is based on cherry-picked documents. The documents were given to the Times by Jim Gottstein, a lawyer representing a mentally ill patient, who obtained it from a doctor, David Egilman, who served as an expert consultant in the case. In 2007 Lilly filed a protective order to stop the spread of several documents, to which Judge Jack B. Weinstein of the Brooklyn District Court of Brooklyn was given, and criticized the New York Times reporter Gottstein and Egilman in the verdict. The Times London also received the document and reported that in early 1998, Lilly considered the risk of drug-induced obesity to be a "major threat" to Zyprexa sales. On October 9, 2000, senior research expert Lilly Robert Baker noted that his academic advisory board "was greatly impressed by the enormous weight gain in olanzapine and the implications for glucose."
Lilly threatened Egilman with a charge of criminal defamation of the documents he was taking and gave to reporters; in September 2007 he agreed to pay Lilly $ 100,000 in return for the company's approval to impose the threat of allegations.
In September 2008, Judge Weinstein issued an order to publish Lilly's internal documents about the drug in different clothing brought by insurance companies, pensions, and other payers.
In March 2008, Lilly settled the lawsuit with the state of Alaska and in October 2008, Lilly agreed to pay $ 62 million to 32 states and the District of Columbia to settle the lawsuit filed under state consumer protection laws.
In 2009, Eli Lilly pleaded guilty to allegations of federal US federal penalty infringement from Zyprexa's illegal marketing for off-label use and agreed to pay $ 1.4 billion.
Trade name
Olanzapine is generic and is available under many trade names around the world.
Dosage form
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-dissolved "wafer" that rapidly dissolves in saliva. It is also available in 10 milligrams of vial for intramuscular injection.
Research
Olanzapine has been studied for use as an antiemetic, especially to control chemotherapy-induced nausea and vomiting (CINV). A 2007 study showed a successful potential for this use, achieving a complete response in the prevention of acute nausea and vomiting in 100% of patients treated with moderate and highly-emetogenic chemotherapy, when used in combination with palonosetron and dexamethasone.
Olanzapine has been considered part of the initial psychotic approach to schizophrenia. The Risk Identification, Management and Education Prevention Study (PRIME), funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine may prevent the onset of psychosis in people at high risk for schizophrenia. The study investigated 60 patients with prodromal schizophrenia, who were estimated to be 36-54% of the developing schizophrenia within a year, and treated half with olanzapine and half with placebo. In this study, patients receiving olanzapine had no significantly lower risk to develop into psychosis. Olanzapine is effective for treating prodromal symptoms, but is associated with significant body weight.
References
External links
- Zyprexa.com - Zyprexa's official website from Eli Lilly and Company
- Inserting the Zyprexa package
- Berenson, Alex (December 17, 2006). "Lilly Settle With 18,000 More Than Zyprexa". The New York Times . Ã,
Source of the article : Wikipedia
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