Zyprexa (Olanzapine)
olanzapine · also available as Zyprexa Zydis (ODT), Zyprexa Relprevv (LAI), Symbyax (olanzapine/fluoxetine)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Schizophrenia | Adults; adolescents 13–17 | Monotherapy | FDA Approved |
| Bipolar I — manic or mixed episodes | Adults; adolescents 13–17 | Monotherapy or adjunct to lithium/valproate | FDA Approved |
| Bipolar I — maintenance | Adults | Monotherapy | FDA Approved |
| Acute agitation (IM) — schizophrenia / bipolar I mania | Adults | Monotherapy | FDA Approved |
| Bipolar I depression (with fluoxetine) | Adults; children/adolescents 10–17 | Combination (olanzapine + fluoxetine) | FDA Approved |
| Treatment-resistant depression (with fluoxetine) | Adults | Combination (olanzapine + fluoxetine) | FDA Approved |
Olanzapine is among the most broadly indicated atypical antipsychotics, with FDA approvals spanning schizophrenia, bipolar mania (monotherapy and adjunctive), bipolar maintenance, acute agitation (IM formulation), and in combination with fluoxetine for both bipolar depression and treatment-resistant depression (the combination is marketed as Symbyax). Olanzapine has the highest metabolic liability among common atypical antipsychotics, with substantial risks of weight gain, hyperglycaemia, and dyslipidaemia. The PI specifically advises clinicians to consider prescribing other drugs first in adolescents due to this increased metabolic risk.
Chemotherapy-induced nausea (breakthrough): Low-dose olanzapine (5–10 mg) added to standard antiemetic regimens has RCT support; included in NCCN and ASCO antiemetic guidelines. Evidence quality: High.
Anorexia nervosa: Small RCTs suggest modest benefit for weight gain; limited evidence for psychological symptoms. Evidence quality: Low.
Delirium: Used in clinical practice; limited RCT data; APA guidelines suggest cautious use. Evidence quality: Low.
Dosing
Oral — Adult Indications
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Schizophrenia — adults | 5–10 mg QD | 10 mg/day (target) | 20 mg/day | Efficacy demonstrated at 10–15 mg/day; doses above 10 mg not shown to be more efficacious; adjust in 5 mg increments at ≥1-week intervals Steady state reached in ~1 week |
| Bipolar mania — adults (monotherapy) | 10 or 15 mg QD | 5–20 mg/day | 20 mg/day | Adjust in 5 mg increments at ≥24-hour intervals; efficacy range 5–20 mg |
| Bipolar mania — adults (adjunct to Li/VPA) | 10 mg QD | 5–20 mg/day | 20 mg/day | Given concurrently with lithium or valproate; long-term adjunctive efficacy not systematically evaluated |
| Bipolar I depression (with fluoxetine) | OLZ 5 mg + FLX 20 mg QD (evening) | OLZ 5–12.5 mg + FLX 20–50 mg | OLZ 18 mg + FLX 75 mg | Olanzapine monotherapy is NOT indicated for bipolar depression; must be combined with fluoxetine |
| Treatment-resistant depression (with fluoxetine) | OLZ 5 mg + FLX 20 mg QD (evening) | OLZ 5–20 mg + FLX 20–50 mg | OLZ 18 mg + FLX 75 mg | TRD defined as failure of ≥2 adequate antidepressant trials; olanzapine monotherapy is NOT indicated for TRD |
IM — Acute Agitation (Adults)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute agitation — schizophrenia or bipolar I mania | 10 mg IM | Up to 10 mg per subsequent injection | 30 mg/day total IM | 5 or 7.5 mg if clinically warranted; subsequent doses 2–4 h apart; assess orthostatic hypotension before each re-dose Do NOT combine IM olanzapine with IM benzodiazepines — risk of respiratory depression and death. Do NOT use IV |
Paediatric & Special Populations
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Schizophrenia — adolescents 13–17 | 2.5–5 mg QD | 10 mg/day (target) | 20 mg/day | Adjust in 2.5–5 mg increments; mean modal dose in trials was 12.5 mg; consider other drugs first due to higher metabolic risk in adolescents |
| Bipolar mania — adolescents 13–17 | 2.5–5 mg QD | 10 mg/day (target) | 20 mg/day | Mean modal dose in trials was 10.7 mg; same metabolic caution as schizophrenia |
| Debilitated / elderly / non-smoking females ≥65 | 5 mg QD | Titrate per response | Per indication | Slower metabolism in this population; increased sensitivity to orthostatic hypotension |
| IM — geriatric patients | 5 mg IM | Per response | Assess before re-dosing | 2.5 mg if debilitated or hypotension-prone; assess orthostatic BP before any re-dose |
Tobacco smoking induces CYP1A2, increasing olanzapine clearance by approximately 23%. Patients who smoke may require higher doses to achieve therapeutic levels. Conversely, if a patient stops smoking (e.g., during hospitalisation), olanzapine levels can rise significantly and dose reduction may be needed. This interaction applies to tobacco smoke specifically (polycyclic aromatic hydrocarbons), not to nicotine itself — nicotine replacement therapy does not affect CYP1A2.
Pharmacology
Mechanism of Action
Olanzapine is a thienobenzodiazepine derivative with broad receptor binding affinity. It antagonises dopamine D1, D2, D3, and D4 receptors, serotonin 5-HT2A, 5-HT2C, 5-HT3, and 5-HT6 receptors, histamine H1 receptors, adrenergic alpha-1 receptors, and multiple muscarinic receptor subtypes (M1–M5). Its antipsychotic efficacy is attributed primarily to combined D2 and 5-HT2A antagonism, while its broad receptor profile accounts for both its clinical versatility and its prominent side effect burden. The strong H1 and muscarinic antagonism is responsible for its significant sedative and appetite-stimulating effects, driving the weight gain and metabolic syndrome that distinguish olanzapine from less metabolically active agents. Olanzapine shows lower propensity for acute extrapyramidal symptoms compared to first-generation antipsychotics, consistent with the rapid D2 dissociation and 5-HT2A/D2 ratio characteristic of atypical agents.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed orally; Tmax ~6 h (oral), 15–45 min (IM); bioavailability ~60% due to 40% first-pass metabolism; food does not affect absorption; ODT and tablet are bioequivalent | Once-daily dosing is appropriate; IM provides rapid absorption for acute agitation; can be taken without regard to meals |
| Distribution | Vd ~1000 L; 93% plasma protein binding (albumin and alpha-1 acid glycoprotein) | Extensive tissue distribution; high protein binding but clinically significant displacement interactions are uncommon |
| Metabolism | Extensively hepatic: direct glucuronidation via UGT1A4 (10-N-glucuronide, major metabolite); oxidation via CYP1A2 (4′-N-desmethylolanzapine); FMO3 (N-oxide); minor CYP2D6. All metabolites are pharmacologically inactive | CYP1A2 is the key drug interaction pathway: smoking induces it (lower levels), fluvoxamine inhibits it (higher levels), carbamazepine induces it. CYP2D6 poor metabolisers do not require adjustment. Olanzapine does not inhibit CYP enzymes |
| Elimination | t½ 21–54 h (mean ~30 h); 57% urine, 30% feces (as metabolites); only 7% excreted unchanged in urine; steady state in ~1 week; linear pharmacokinetics | Long half-life permits once-daily dosing; smoking status, gender (females clear more slowly), and age affect clearance; no renal dose adjustment needed |
Side Effects
Olanzapine has the highest metabolic burden among commonly used atypical antipsychotics. Data below are from short-term placebo-controlled adult monotherapy trials in the FDA PI and the CATIE trial, supplemented by adolescent trial data.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Weight gain | 22–29% (≥7% gain in adults); 89% in adolescents long-term | Adults: mean 2.6–3.0 kg in short-term trials; CATIE: mean 0.9 kg/month (highest among all comparators). Adolescents: mean 4.6 kg (6 wk schiz) and 11.2 kg long-term (201 days). 55% of adolescents gain ≥15% baseline weight with extended use (FDA PI) |
| Somnolence / sedation | 20–35% | Driven by H1 antagonism; dose-related; usually improves with continued treatment; administer at bedtime |
| Increased appetite | 12–24% | H1 and 5-HT2C mechanisms; greater in adolescents; major contributor to weight gain trajectory |
| Dry mouth | 9–22% | Anticholinergic effect via muscarinic M1/M3 antagonism; counsel on dental hygiene |
| Constipation | 9–11% | Muscarinic antagonism; monitor in elderly; may be severe with concurrent anticholinergics |
| Dizziness | 11–18% | Related to alpha-1 antagonism and orthostatic hypotension; most prominent during initiation |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Orthostatic hypotension | 3–5% | Alpha-1 blockade; syncope reported rarely; use caution with IM dosing (max 3 doses can cause substantial orthostasis) |
| Akathisia | 3–5% | Less than with risperidone; may respond to dose reduction or propranolol |
| Tremor | 4–6% | EPS risk lower than typical antipsychotics but not negligible at higher doses |
| Hyperprolactinaemia | Variable; dose-dependent | Less persistent elevation than risperidone; may not cause clinical symptoms in all cases; monitor if galactorrhoea or amenorrhoea develops |
| Personality disorder (behavioural changes) | ≥5% (schizophrenia trials) | PI-listed term capturing various behavioural changes; may require clinical assessment to distinguish from illness |
| Asthenia / fatigue | 5–15% | More prominent in bipolar mania trials; distinct from sedation |
| Peripheral oedema | 3–5% | May be related to metabolic effects or alpha-1 blockade |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Metabolic syndrome (hyperglycaemia, dyslipidaemia) | Fasting glucose normal→high: 2.2% (≤12 wk), 12.8% (≥48 wk); borderline→high: 17.4% (≤12 wk), 26.0% (≥48 wk) | Weeks; worsens with duration | Fasting glucose and lipids at baseline, 12 weeks, then periodically; DKA and hyperosmolar coma reported including fatalities; olanzapine has the greatest association with glucose abnormalities among atypical antipsychotics (FDA PI) |
| Neuroleptic malignant syndrome | Rare | Any time | Immediate discontinuation; supportive care; monitor CK, renal function, temperature |
| Tardive dyskinesia | Low; risk increases with duration and dose | Months to years | May be irreversible; reassess need for continued treatment periodically; VMAT2 inhibitors available for treatment |
| DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) | Rare (FDA safety communication 2016); median onset ~2 months | Weeks to months | Stop olanzapine immediately if fever + rash + eosinophilia or organ involvement; may be fatal; do not rechallenge |
| Cerebrovascular events in elderly with dementia | Significantly higher than placebo in dementia trials; mortality 3.5% vs 1.5% | During treatment | Olanzapine is NOT approved for dementia-related psychosis; boxed warning applies |
| Agranulocytosis / neutropenia | Rare | First few months | Monitor CBC if pre-existing low WBC or history of drug-induced leukopenia; discontinue at first sign of clinically significant WBC decline |
Olanzapine carries the highest metabolic liability among commonly prescribed atypical antipsychotics. The FDA PI states explicitly that “olanzapine appears to have a greater association [with glucose abnormalities] than some other atypical antipsychotics.” In CATIE, olanzapine-treated patients gained a mean of 0.9 kg per month (the highest among all comparators), had the greatest increases in glycosylated haemoglobin, cholesterol, and triglycerides, and the highest metabolic discontinuation rate (9% vs 1–4%). Adolescents are even more vulnerable: 89% gained ≥7% body weight and mean long-term gain was 11.2 kg. The metabolic risk persists even at low doses used off-label for insomnia or anxiety. All patients require baseline and ongoing metabolic monitoring regardless of indication or dose.
Drug Interactions
Olanzapine is metabolised primarily by CYP1A2 and glucuronidation (UGT1A4). Unlike quetiapine, CYP3A4 plays a minimal role. Olanzapine does not inhibit any major CYP isoforms and does not affect levels of lithium, valproate, or warfarin. The most clinically important interactions involve CYP1A2 modulation (smoking, fluvoxamine, carbamazepine) and pharmacodynamic additive effects.
Monitoring
- Weight / BMI / WaistBaseline, monthly ×3, then quarterly
RoutineOlanzapine has the highest weight gain liability. Adolescents: 89% gain ≥7% body weight long-term. Monitor weight against expected growth in paediatric patients. Dietary and exercise counselling at initiation. - Fasting Glucose / HbA1cBaseline, 12 weeks, then periodically
RoutineFasting glucose normal→≥126: 2.2% (short-term), 12.8% (long-term). DKA and hyperosmolar coma reported including deaths. More frequent monitoring if diabetes risk factors present. - Fasting Lipid PanelBaseline, 12 weeks, then periodically
RoutineCATIE: olanzapine caused greatest cholesterol and triglyceride increases among comparators. Adolescents: mean total cholesterol increased 12.9 mg/dL, triglycerides 28.4 mg/dL in short-term trials. - Blood PressureBaseline and during titration
RoutineOrthostatic measurements during initial dose period. For IM dosing, assess orthostatic BP before every subsequent injection. - CBCBaseline; frequent if pre-existing low WBC
Trigger-basedAgranulocytosis reported; discontinue if clinically significant WBC decline without other cause. - Hepatic EnzymesBaseline and periodically
Trigger-basedTransaminase elevations >3× ULN observed; hepatitis and cholestatic liver injury reported postmarketing. Monitor if symptoms of hepatotoxicity arise. - Abnormal MovementsEvery visit
RoutineScreen for tardive dyskinesia using AIMS. Low EPS incidence but risk increases with duration. - ProlactinIf clinical symptoms arise
Trigger-basedDose-dependent elevations; may not persist with chronic use. Check if galactorrhoea, amenorrhoea, sexual dysfunction, or gynaecomastia develops.
Contraindications & Cautions
Absolute Contraindications
- None with olanzapine monotherapy per FDA PI
- When used with fluoxetine, refer to Symbyax contraindications (concurrent MAOI use, pimozide, thioridazine)
Relative Contraindications (Specialist Input Recommended)
- Dementia-related psychosis in elderly — boxed warning; increased mortality (3.5% vs 1.5% placebo) and cerebrovascular events
- Uncontrolled diabetes / metabolic syndrome — olanzapine has the greatest metabolic risk; consider lower-liability alternatives
- History of DRESS or severe hypersensitivity to olanzapine — FDA safety communication (2016) highlights risk; do not rechallenge
Use with Caution
- Narrow-angle glaucoma / prostatic hypertrophy / paralytic ileus history — muscarinic antagonism may exacerbate these conditions
- Seizure history — seizures reported; use cautiously with conditions lowering threshold
- Hepatic impairment — consider starting dose of 5 mg; no formal dose reduction required by PI
- Debilitated patients / elderly non-smoking females — slower metabolism; start at 5 mg
- Concurrent IM benzodiazepine use — do not give IM olanzapine within 1 hour of IM benzodiazepine; risk of fatal cardiorespiratory depression
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. In olanzapine-specific trials, the mortality rate was 3.5% in olanzapine-treated patients versus 1.5% in placebo-treated patients. Cerebrovascular adverse events including stroke and TIA, some fatal, were also significantly more frequent with olanzapine in dementia trials. Olanzapine is not approved for dementia-related psychosis.
Patient Counselling
Purpose of Therapy
Olanzapine is prescribed to manage symptoms of schizophrenia, bipolar disorder (including manic episodes and, in combination with fluoxetine, depressive episodes), and in some cases treatment-resistant depression. It works by balancing chemical messengers in the brain that affect mood, thinking, and behaviour. It is taken once daily and can be taken with or without food.
How to Take
Take olanzapine at the same time each day, usually at bedtime to manage daytime drowsiness. It can be taken with or without food. The orally disintegrating tablet (Zydis) should be placed on the tongue with dry hands and allowed to dissolve — it can be swallowed with or without water. Do not push the tablet through the foil. Do not stop olanzapine suddenly without discussing with your prescriber.
Sources
- ZYPREXA (olanzapine) tablets, orally disintegrating tablets, intramuscular injection. Full Prescribing Information. Eli Lilly and Company. FDA LabelPrimary regulatory source for all olanzapine dosing, adverse reaction data, metabolic tables, contraindications, and warnings.
- FDA Drug Safety Communication: FDA warns about rare but serious allergic reactions with the mental health drug olanzapine (Zyprexa). September 2016. FDA Safety CommunicationSafety alert adding DRESS syndrome to olanzapine warnings based on 23 postmarketing cases.
- Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia (CATIE). N Engl J Med. 2005;353(12):1209–1223. DOILandmark CATIE trial: olanzapine had longest time to discontinuation but highest metabolic burden; mean weight gain 0.9 kg/month; metabolic discontinuation rate 9% vs 1–4% for comparators.
- Tohen M, Greil W, Calabrese JR, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry. 2005;162(7):1281–1290. DOI12-month maintenance trial comparing olanzapine with lithium in bipolar I disorder.
- Tohen M, Vieta E, Calabrese JR, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079–1088. DOIKey trial establishing olanzapine-fluoxetine combination efficacy for bipolar depression; olanzapine monotherapy was inferior.
- Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375(2):134–142. DOIPivotal RCT demonstrating olanzapine 10 mg added to standard antiemetics significantly reduces CINV; basis for ASCO/NCCN guideline inclusion.
- Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97–170. DOIRecommends olanzapine as first-line for acute mania monotherapy; second-line for bipolar depression (with fluoxetine) due to metabolic risk.
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia, Third Edition. Am J Psychiatry. 2021;178(supplement). DOIAPA guideline supporting atypical antipsychotic monotherapy for schizophrenia with metabolic monitoring recommendations.
- Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996;14(2):87–96. DOIDefinitive receptor binding study characterising olanzapine’s affinity at D1-D4, 5-HT2A/2C/3/6, H1, M1-M5, and alpha-1 receptors.
- Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet. 1999;37(3):177–193. DOIComprehensive PK review establishing absorption, distribution, CYP1A2-mediated metabolism, and covariate effects (smoking, gender, age).
- Mauri MC, Paletta S, Di Pace C, et al. Clinical pharmacokinetics of atypical antipsychotics: an update. Clin Pharmacokinet. 2018;57(12):1493–1528. DOIUpdated PK review covering olanzapine interactions, smoking effects, and therapeutic drug monitoring recommendations.
- De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2012;8(2):114–126. DOIAuthoritative review of metabolic risk hierarchy among antipsychotics, positioning olanzapine and clozapine as highest risk.