Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label in cancer patients for treatment of chemotherapy-induced nausea and vomiting[8] and as an appetite stimulant.[9] For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.
Common side effects include feeling tired, dizziness, constipation, dry mouth, and restlessness. Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, diabetes mellitus, seizures, and tardive dyskinesia. In older people with dementia, its use increases the risk of death. Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth. Although its mechanism of action is not entirely clear, it is known to block dopamine and serotonin receptors.
Olanzapine was patented in 1991 and approved for medical use in the United States in 1996.[10][11] It is available as a generic medication.[10] In 2023, it was the 167th most commonly prescribed medication in the United States, with more than 3million prescriptions.[12][13] It is on the World Health Organization's List of Essential Medicines.[14]
Medical uses
It is approved by the FDA for the following indications:
In the United Kingdom and Australia, it is approved for schizophrenia, moderate to severe manic episodes, alone, or in combination with lithium or valproate and the short-term treatment of acute manic episodes associated with bipolar I disorder.[19]
Olanzapine is also used off-label for the treatment of chemotherapy-induced nausea and vomiting.[8]
- schizophrenia.
- acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder.
- adjunct to lithium or valproate in the treatment of manic or mixed episodes associated with bipolar I disorder.
- combination olanzapine/fluoxetine (Symbyax) for the treatment of depressive episodes of bipolar I disorder and for treatment-resistant depression.[15]
Adverse effects
The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in blood-lipid and blood-sugar profiles (see section metabolic effects). A 2013 meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APDs compared with an SMD of 0.74.[21] Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine,[38] but may include tremors and muscle rigidity.
Although olanzapine causes an early dose-related rise in prolactin, this is less frequent and less marked than that seen with haloperidol, and is usually transient. A rise in prolactin is seen in about half of patients on olanzapine compared to over 90% of those taking risperidone, and enduring increases were less frequent in those taking olanzapine.[39]
It is not recommended to be used by IM injection in acute myocardial infarction, bradycardia, recent heart surgery, severe low blood pressure, sick sinus syndrome, and unstable angina.[40]
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.[66] Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death). No specific antidote for olanzapine overdose is known, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case.[66] Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs, and less toxic than the monoamine oxidase inhibitors and tricyclic antidepressants.[32]
Interactions
Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance.[67] Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ratio of olanzapine by 33% compared to olanzapine alone. Another enzyme inducer, ritonavir, has also been shown to decrease the body's exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5'-diphospho-glucuronosyltransferase (UGT). Probenecid increases the total exposure (area under the curve) and maximum plasma concentration of olanzapine. Although olanzapine's metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapine's clearance.
Olanzapine has been used as a hallucinogen antidote to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).[68][69]
Pharmacology
Pharmacodynamics
Olanzapine was first discovered while searching for a chemical analog of clozapine that would not require hematological monitoring. Investigation on a series of thiophene isosteres on 1 of the phenyl rings in clozapine, a thienobenzodiazepine analog (olanzapine) was discovered.[88]
Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone.
In one study D2 receptor occupancy was 60% with low-dose olanzapine (5 mg/day) and occupancy with high dose at 83% (20 mg/day).[89] In the usual clinical dose range of 10–20 mg/day, D2 receptor occupancy varied from 71% to 80%.[90]
Chemical synthesis
The preparation of olanzapine was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s. In the final two steps, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was reduced with stannous chloride in ethanol to give the substituted thienobenzodiazepine ring system, and this was treated with methylpiperazine in a mixture of dimethyl sulfoxide and toluene as solvent to produce the drug.[105]
- Olanzapine synthesis.svg
Society and culture
Legal status
Olanzapine is approved by the US FDA for:
The drug became generic in 2011. Sales of Zyprexa in 2008 were $2.2 billion in the US and $4.7 billion worldwide.[113]
Research
Olanzapine may be useful in promoting weight gain in underweight adult outpatients with anorexia nervosa. However, no improvement in psychological symptoms was noted.[127] It has also been shown to be helpful in the management of cancer-related anorexia.[9]
Olanzapine has been shown to help address a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and has since been used in the treatment of a range of mood and anxiety disorders.[128] Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder.[129] It has also been used for Tourette syndrome and stuttering.[130]
External links
References
- Anvisa. RDC Nº 784 – Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial Diário Oficial da União, 31 March 2023, retrieved 16 August 2023^
- Zyprexa- olanzapine tablet; Zyprexa Zydis- olanzapine tablet, orally disintegrating; Zyprexa intramuscular- olanzapine injection, powder, for solution DailyMed, 13 December 2023, retrieved 17 October 2024^
- Zyprexa EPAR