Olanzapine (Zyprexa)
SGA • Last reviewed 2025-09-23
General information
Olanzapine (brand name Zyprexa) is an atypical second-generation antipsychotic approved for schizophrenia, acute manic or mixed episodes associated with bipolar I disorder (monotherapy or adjunct to lithium/valproate), maintenance treatment of bipolar I disorder (monotherapy or with lithium/valproate), and in combination with fluoxetine for treatment-resistant depression and bipolar depression. The first FDA approval dates to 1996; oral generics have been available since 2011. Long-acting injectable formulations (olanzapine pamoate depot, marketed separately) provide maintenance options but require post-injection monitoring for delirium/sedation syndrome.
Oral dosage forms include tablets (2.5, 5, 7.5, 10, 15, 20 mg), orally disintegrating tablets (5, 10, 15, 20 mg), and an intramuscular injection (10 mg vial) for acute agitation. Schizophrenia and bipolar mania typically start at 5–10 mg once daily (or BID for IM use), titrating to 10–20 mg/day based on response. Bipolar maintenance often uses 5–20 mg/day; combination therapy with fluoxetine for bipolar depression begins at olanzapine 6 mg + fluoxetine 25 mg at bedtime. Pediatric schizophrenia (≥13 years) and bipolar I mania (≥13 years) start at 2.5–5 mg/day, targeting 10–20 mg/day. Olanzapine may be taken with or without food. Routine therapeutic drug monitoring is not standard, but plasma concentrations 20–80 ng/mL may correlate with response and can guide dosing when adherence or interactions are concerns.
Olanzapine exhibits high affinity for multiple receptors: serotonin 5-HT2A/2C, 5-HT6, 5-HT3, dopamine D1–D4, histamine H1, adrenergic α1, and muscarinic M1–M5. Its 5-HT2A/D2 antagonism supports antipsychotic efficacy with low EPS liability, while strong H1 and 5-HT2C antagonism contribute to weight gain and metabolic derangements. Muscarinic antagonism underlies anticholinergic effects (dry mouth, constipation), and α1 blockade can cause orthostatic hypotension. Minimal D2 receptor occupancy above ~80% reduces hyperprolactinemia compared with typical antipsychotics.
Olanzapine is well absorbed with peak plasma concentrations in ~5–8 hours; bioavailability is ~60% due to first-pass metabolism. It is extensively distributed (volume of distribution ~10–20 L/kg) and ~93% plasma protein bound. Hepatic metabolism occurs primarily via CYP1A2 and to a lesser extent CYP2D6, resulting in N-desmethyl and 2-hydroxymethyl metabolites (largely inactive). Smoking induces CYP1A2, reducing olanzapine exposure; conversely, inhibitors (fluvoxamine) significantly increase levels. The elimination half-life averages 30 hours (range 21–54 h) in adults, shorter in smokers (17 h) and longer in elderly or hepatic impairment. Approximately 57% of the dose is excreted in urine and 30% in feces, mostly as metabolites.
Dosing & administration
Schizophrenia (adults): start 5–10 mg once daily; increase by 5 mg increments to 10–20 mg/day based on response.
Schizophrenia (adolescents ≥13): start 2.5–5 mg/day; titrate to 10–20 mg/day with weekly adjustments.
Bipolar I mania (monotherapy): initiate 10–15 mg once daily; adjust within 5–20 mg/day.
Bipolar maintenance: continue 5–20 mg/day monotherapy or in combination with lithium/valproate.
Bipolar depression (with fluoxetine): start olanzapine 6 mg + fluoxetine 25 mg at bedtime; range 6–12 mg olanzapine with 25–50 mg fluoxetine.
Acute agitation (IM): 10 mg IM; may repeat every 2 hours up to 30 mg/24 h (transition to oral ASAP).
Smoking, CYP1A2 inhibitors, or hepatic impairment necessitate dose adjustments; reduce dose in elderly or when coadministered with fluvoxamine.
Dose ranges by indication
- Schizophrenia (adult)
- 5–20 mg/day; initial 5–10 mg once daily.
- Schizophrenia (≥13 years)
- 2.5–20 mg/day; increase by 2.5–5 mg increments weekly.
- Bipolar I mania (monotherapy)
- 10–20 mg/day (start 10–15 mg).
- Bipolar I maintenance
- 5–20 mg/day (monotherapy or with lithium/valproate).
- Bipolar depression (OFC)
- Olanzapine 6–12 mg + fluoxetine 25–50 mg at bedtime.
- Smoking or CYP1A2 induction
- May require higher doses; monitor clinical response and levels.
Mechanism of action
Olanzapine’s antipsychotic and mood-stabilizing effects result from broad antagonism across serotonin (5-HT2A/2C/6), dopamine (D1–D4), adrenergic α1, histamine H1, and muscarinic receptors. Balanced 5-HT2A/D2 antagonism reduces EPS while controlling psychotic symptoms.
Strong 5-HT2C and H1 antagonism contributes to weight gain and metabolic effects; muscarinic blockade causes anticholinergic side effects. Partial agonism at some 5-HT1A receptors has been suggested but is less clinically significant.
The multi-receptor profile underpins efficacy in mood disorders and treatment-resistant depression when combined with fluoxetine (OFC).
- Antagonist at 5-HT2A/2C, D2, D4, H1, α1, and muscarinic receptors.
- Low propensity for EPS due to 5-HT2A:D2 blockade ratio.
- High risk of metabolic syndrome linked to H1 and 5-HT2C antagonism.
Metabolism & pharmacokinetics
Oral olanzapine reaches peak plasma concentrations in 5–8 hours; food has minimal effect on absorption. The drug is highly lipophilic and extensively distributed.
Metabolism occurs via CYP1A2 (primary) and CYP2D6 (secondary) to inactive metabolites. Smoking induces CYP1A2, reducing exposure by ~30–40%; conversely, fluvoxamine markedly increases plasma levels.
The elimination half-life averages 30 hours in non-smokers and 21 hours in smokers; elderly patients may exhibit half-lives up to 50 hours. Renal impairment has minimal effect, but hepatic impairment increases plasma concentrations—use lower starting doses.
- Time to peak concentration (Tmax)
- 5–8 hours
- Elimination half-life
- ~30 h (non-smokers); ~21 h (smokers); up to 54 h (elderly)
- Protein binding
- ~93%
- Metabolism
- CYP1A2 (major), CYP2D6 (minor)
Drug interactions
Strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) can double olanzapine levels—reduce dose by at least 50% and monitor for sedation/EPS.
Smoking or CYP1A2 inducers (carbamazepine, tobacco) decrease exposure; dose increases may be necessary.
CNS depressants (alcohol, benzodiazepines) can cause additive sedation and respiratory depression.
Olanzapine may antagonize levodopa/dopamine agonists; monitor Parkinson’s symptoms.
Combination with parenteral benzodiazepines requires caution (respiratory depression reported); separate administration by ≥1 hour when possible.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP1A2 inhibition | Fluvoxamine, ciprofloxacin | Reduce olanzapine dose by 50% and monitor. |
| CYP1A2 induction | Smoking, carbamazepine | Consider dose increase when smoking; monitor levels if available. |
| CNS depression | Benzodiazepines, alcohol, opioids | Advise caution; monitor for sedation/hypotension. |
| Dopaminergic antagonism | Levodopa, dopamine agonists | Monitor for reduced efficacy; adjust therapy. |
| QT prolongation | Antiarrhythmics, other QT-prolonging agents | ECG monitoring in high-risk patients. |
Monitoring & safety checks
Weight/BMI and waist circumference
Baseline, 4 weeks, 8 weeks, 12 weeks, then quarterly • Olanzapine carries high risk for weight gain.
Fasting lipids & glucose/A1c
Baseline, 3 months, then annually • Monitor for dyslipidemia and glucose abnormalities.
Blood pressure
Baseline and periodically • Orthostatic hypotension can occur via α1 blockade.
EPS / tardive dyskinesia screening
Each visit during titration; periodically thereafter • Lower EPS risk than FGAs but still possible.
Liver function tests
Baseline and periodically if clinically indicated • Rare transaminase elevations/hepatitis reported.
Initiate lifestyle interventions (diet, exercise) at treatment onset to mitigate metabolic effects.
Monitor for sedation, anticholinergic effects, and ensure adequate bowel regimen if needed.
Discontinuation guidance
Taper gradually over 1–2 weeks to minimize rebound insomnia, agitation, or relapse. Monitor for cholinergic rebound (insomnia, anxiety) given muscarinic antagonism.
When transitioning to or from long-acting injectables (olanzapine pamoate), account for prolonged exposure and post-injection monitoring requirements.
Special populations
Smoking: induces CYP1A2, lowering exposure; dose increments or monitoring may be required if smoking status changes.
Hepatic impairment: start at 5 mg/day and titrate cautiously; hepatic dysfunction increases half-life and exposure.
Renal impairment: minimal effect; no adjustment typically necessary.
Elderly: increased half-life and sensitivity to hypotension and sedation; use low starting doses (2.5–5 mg/day).
Pregnancy/Lactation: limited controlled data; neonates exposed in third trimester should be observed for EPS or withdrawal.
Key adverse effects
Very common: weight gain, increased appetite, somnolence, dry mouth, constipation, dizziness.
Metabolic: hyperglycemia/new-onset diabetes, dyslipidemia; monitor closely especially in at-risk populations.
Serious: neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, seizures (dose-related), elevation of liver enzymes.
LAI availability
Clozapine does not have an FDA-approved long-acting injectable formulation. Related LAI options for the treatment class are listed below.
References
- ZYPREXA (olanzapine) Prescribing Information — Eli Lilly and Company (2024)
- Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018) DOI: 10.1007/s00213-017-4813-7
- Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a network meta-analysis — The Lancet (2017) DOI: 10.1016/S0140-6736(17)32455-2
- Metabolic considerations in the use of antipsychotic medications: a review — CNS Drugs (2005) DOI: 10.1007/s40263-005-0078-4
- Effects of smoking on olanzapine plasma concentrations — Psychoneuroendocrinology (2019) DOI: 10.1016/j.psyneuen.2019.104357
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.