olanzapine

General Information

Olanzapine (brand Zyprexa) is a second-generation antipsychotic (SGA) with broad efficacy across schizophrenia and bipolar disorder but notable metabolic adverse effects.

This profile focuses on adult and adolescent schizophrenia, bipolar I mania/mixed states, and bipolar depression in combination (Symbyax), while noting depot (Relprevv) REMS requirements.

The compare tool can help contrast metabolic risk, EPS profiles, and sedation when collaborating on antipsychotic selection.

The olanzapine evidence feed can support review, and long-acting injectable discussions can be routed through the LAI navigator when evaluating depot therapy.

Despite metabolic liabilities, olanzapine is favored for severe agitation, treatment-resistant schizophrenia, and sedation needs; weight gain, dyslipidemia, and glucose dysregulation make structured metabolic monitoring standard to reduce metabolic syndrome risk.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Olanzapine antagonizes dopamine D1–D4 and serotonin 5-HT2A/5-HT2C receptors, moderating psychotic symptoms while influencing mood and cognition.

High affinity for histamine H1 and muscarinic receptors contributes to sedation and metabolic effects.

• Antagonist at dopamine D2/D3, serotonin 5-HT2A/5-HT2C/5-HT6, histamine H1, and muscarinic M1 receptors.
• Antagonist at adrenergic α1 receptors.

Metabolism and Pharmacokinetics

• Oral bioavailability ~60%; Tmax 5–8 hours (oral) and 15–45 minutes (IM).
• Approximately 93% protein bound with large volume of distribution (~10–20 L/kg).
• Metabolized via CYP1A2 (major) and CYP2D6 with glucuronidation; smoking reduces plasma levels via CYP1A2 induction.
• Half-life ~30 hours in non-smokers and ~21 hours in smokers; prolonged in hepatic impairment and elderly.
• Eliminated ~57% in urine and ~30% in feces as metabolites; <7% excreted unchanged.

Dosing and Administration

• Schizophrenia (adults): initiate 5–10 mg once daily; titrate by 5 mg increments at ≥24-hour intervals to 10–20 mg/day (max 20 mg).
• Schizophrenia (adolescents): start 2.5–5 mg/day; titrate to 5–20 mg/day.
• Bipolar I mania/mixed: 10–15 mg once daily; IM 10 mg for agitation up to 3 doses/24 h.
• Maintenance: continue effective dose; adjust 5–20 mg/day; depot dosing per REMS protocol.
• Dose adjustments: lower doses with CYP1A2 inhibitors (fluvoxamine); smokers may require higher doses; caution in hepatic impairment.

Monitoring & Labs

• Metabolic monitoring (weight/BMI, waist circumference, blood pressure, fasting glucose/A1c, lipids) at baseline and periodically (early and then ongoing) because weight and glycemic changes can occur quickly.
• Appetite changes, sedation, and falls risk—reassess driving and occupational safety after dose changes and when other CNS depressants are added.
• Smoking status and CYP1A2 modulators; reduce dose when smoking stops and reassess if smoking restarts or if CYP1A2 inhibitors are introduced.
• AIMS/EPS monitoring at routine intervals, especially in older adults and at higher doses (EPS risk is lower than FGAs but not zero).
• For depot olanzapine pamoate, adhere to REMS observation and PDSS counseling requirements, including post-injection monitoring and “no driving” instructions on injection day.

Olanzapine’s monitoring burden is primarily metabolic; documenting early lifestyle counseling and follow-up supports both clinical outcomes and coverage decisions.

Adverse Effects

Interactions

• CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) elevate levels—reduce dose and monitor for sedation/metabolic issues.
• CYP1A2 inducers (smoking, carbamazepine, omeprazole) lower exposure—may require dose increases.
• CYP2D6 inhibitors (fluoxetine, paroxetine) modestly increase levels; monitor tolerability.
• Additive CNS depression with alcohol, benzodiazepines, opioids.
• Antagonizes dopamine agonists (levodopa); avoid in Parkinson’s disease if possible.

Other Useful Information

• Implement lifestyle interventions (diet, exercise) early to mitigate weight gain.
• Smoking cessation increases plasma levels—reassess dosing if tobacco use changes.
• Consider prophylactic bowel regimen in patients prone to constipation.
• Depot therapy requires REMS participation due to PDSS risk; use the LAI navigator for interval and overlap planning.
• Baseline and periodic metabolic labs (weight, fasting lipids/glucose, A1c) are essential.
• In bipolar maintenance, pair olanzapine with psychosocial supports, monitor for metabolic syndrome and mania/hypomania, and use the bipolar disorder hub to standardise follow-up.

References

1. ZYPREXA prescribing information — DailyMed (2025)
2. ZYPREXA RELPREVV prescribing information
3. Allison1999 Antipsychotic Weight Gain
4. Metabolic AND Endocrine Adverse Effects OF Second Generation Antipsychotics: A Systematic Review — CNS Drugs (2011)
5. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia — The New England Journal of Medicine (2005)