Glossary / Lexicon

Deutsch: Olanzapin / Español: olanzapina / Português: olanzapina / Français: olanzapine / Italiano: olanzapina

The term olanzapine refers to a second-generation (atypical) antipsychotic medication primarily used to treat mental health conditions such as schizophrenia and bipolar disorder. Developed in the 1990s, it acts by modulating neurotransmitter activity in the brain, particularly dopamine and serotonin, to stabilize mood and perception. Its pharmacological profile has made it a cornerstone in psychiatric therapy, though its use is carefully monitored due to potential side effects.

General Description

Olanzapine is a thienobenzodiazepine derivative classified as an atypical antipsychotic, meaning it exhibits a lower propensity for extrapyramidal side effects (e.g., parkinsonism, dystonia) compared to first-generation (typical) antipsychotics. Its mechanism of action involves antagonism at multiple receptor sites, including dopamine D₂, serotonin 5-HT_2A, muscarinic M₁, histamine H₁, and adrenergic α₁ receptors. This broad receptor affinity contributes to its efficacy in managing positive symptoms (e.g., hallucinations, delusions) and negative symptoms (e.g., apathy, social withdrawal) of schizophrenia, as well as acute manic or mixed episodes in bipolar I disorder.

The drug is available in oral formulations (tablets, orally disintegrating tablets) and as a long-acting injectable (olanzapine pamoate) for maintenance therapy. Its pharmacokinetic properties include high oral bioavailability (≈60%), extensive hepatic metabolism via CYP1A2 and CYP2D6 enzymes, and a half-life of approximately 30 hours, allowing for once-daily dosing. Plasma protein binding is high (≈93%), primarily to albumin and α₁-acid glycoprotein. Due to its lipophilic nature, olanzapine readily crosses the blood-brain barrier, achieving therapeutic concentrations in the central nervous system.

Clinical guidelines, such as those from the National Institute for Health and Care Excellence (NICE), recommend olanzapine as a first-line treatment for schizophrenia and bipolar disorder, often preferred for its balanced efficacy in symptom control and relatively lower risk of tardive dyskinesia. However, its use is associated with significant metabolic side effects, including weight gain, dyslipidemia, and increased risk of type 2 diabetes mellitus, necessitating regular monitoring of metabolic parameters (e.g., fasting glucose, lipid profiles, waist circumference).

Pharmacological Profile

Olanzapine's receptor affinity profile distinguishes it from other antipsychotics. Its high affinity for 5-HT_2A receptors (vs. D₂) is hypothesized to underlie its "atypical" classification, as this ratio correlates with reduced extrapyramidal symptoms (EPS). Additionally, its antagonism at histamine H₁ receptors contributes to sedative effects, while muscarinic M₁ blockade may cause anticholinergic side effects (e.g., dry mouth, constipation, urinary retention). The drug's moderate affinity for α₁-adrenergic receptors can lead to orthostatic hypotension, particularly during dose titration.

Unlike clozapine, another thienobenzodiazepine, olanzapine does not require mandatory blood monitoring for agranulocytosis, though rare cases of blood dyscrasias have been reported. Its metabolic side effects are attributed to interactions with hypothalamic pathways regulating appetite (e.g., via 5-HT_2C and H₁ receptor blockade), leading to increased food intake and altered glucose metabolism. Genetic polymorphisms in CYP1A2 (e.g., *1F allele) can influence olanzapine clearance, with smokers (who induce CYP1A2) potentially requiring higher doses to achieve therapeutic effects.

Application Area

• Schizophrenia: Approved for the treatment of acute and maintenance phases, olanzapine reduces psychotic symptoms (e.g., auditory hallucinations, paranoid delusions) and improves cognitive function. It is often used in combination with psychosocial interventions for long-term management.
• Bipolar I Disorder: Effective in managing acute manic or mixed episodes, either as monotherapy or adjunctive therapy with mood stabilizers (e.g., lithium, valproate). It is also approved for maintenance treatment to delay recurrence of mood episodes.
• Treatment-Resistant Depression: In combination with fluoxetine (as olanzapine/fluoxetine combination), it is indicated for depressive episodes in bipolar disorder and treatment-resistant major depressive disorder (MDD), though this use is limited by metabolic risks.
• Off-Label Uses: Occasionally prescribed for anxiety disorders (e.g., generalized anxiety disorder, PTSD), agitation in dementia (though black-box warnings exist for increased mortality in elderly patients), and adjunctive therapy in obsessive-compulsive disorder (OCD).

Well Known Examples

• Zyprexa® (Eli Lilly): The original brand-name formulation of olanzapine, available in multiple dosages (2.5 mg to 20 mg tablets) and as an intramuscular injection (Zyprexa Relprevv®) for long-acting therapy.
• Symbyax® (Eli Lilly): A fixed-dose combination of olanzapine and fluoxetine (a selective serotonin reuptake inhibitor, SSRI) approved for bipolar depression and treatment-resistant MDD.
• Generic Formulations: Widely available globally under various generic names (e.g., Olanzapine Teva, Olanzapine Mylan), increasing accessibility and reducing treatment costs.

Risks and Challenges

• Metabolic Syndrome: Olanzapine is associated with a higher risk of weight gain (average 4–10 kg over 10 weeks), insulin resistance, and dyslipidemia compared to other antipsychotics (e.g., aripiprazole, ziprasidone). The American Diabetes Association (ADA) recommends baseline and quarterly metabolic screening for patients on olanzapine.
• Extrapyramidal Symptoms (EPS): Though less common than with typical antipsychotics, olanzapine can still cause EPS, particularly at higher doses (>20 mg/day). Akathisia (restlessness) and parkinsonism (tremor, rigidity) may require dose adjustment or adjunctive anticholinergic therapy.
• Sedation and Cognitive Impairment: Histamine H₁ antagonism contributes to daytime somnolence, which can impair driving or operating machinery. Cognitive dulling (e.g., slowed processing speed) may also occur, affecting occupational functioning.
• Withdrawal and Discontinuation Syndrome: Abrupt cessation may lead to rebound psychosis, insomnia, nausea, or diaphoresis. Tapering over 4–8 weeks is recommended to minimize withdrawal effects.
• Black-Box Warnings:
  • Increased mortality in elderly patients with dementia-related psychosis (FDA warning).
  • Risk of suicidal thoughts in adolescents and young adults (particularly in depressive disorders).

Similar Terms

• Clozapine: Another thienobenzodiazepine antipsychotic with superior efficacy in treatment-resistant schizophrenia but reserved for refractory cases due to the risk of agranulocytosis (requires weekly blood monitoring).
• Quetiapine: An atypical antipsychotic with a receptor profile similar to olanzapine (high 5-HT_2A/D₂ affinity) but with a shorter half-life (≈7 hours) and lower metabolic liability. Used for schizophrenia, bipolar disorder, and adjunctive depression therapy.
• Risperidone: A benzisoxazole antipsychotic with higher D₂ affinity than olanzapine, leading to a greater risk of EPS but lower metabolic side effects. Approved for schizophrenia, bipolar mania, and irritability in autism.
• Antipsychotic Polypharmacy: The concurrent use of multiple antipsychotics (e.g., olanzapine + aripiprazole), which is generally discouraged due to increased side effects but sometimes employed in treatment-resistant cases under specialist supervision.

Summary

Olanzapine is a versatile atypical antipsychotic widely used for schizophrenia, bipolar disorder, and treatment-resistant depression due to its balanced receptor affinity and efficacy in managing both positive and negative symptoms. While its metabolic side effects—particularly weight gain and insulin resistance—pose significant challenges, its clinical benefits often outweigh these risks when monitored appropriately. The availability of generic formulations has improved accessibility, though careful dose titration and regular metabolic screening are essential to mitigate adverse outcomes. As with all antipsychotics, olanzapine should be prescribed as part of a comprehensive treatment plan that includes psychosocial support and lifestyle interventions to optimize long-term outcomes.

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