Olanzapine (Zyprexa): Uses, Dosage, Metabolic Risks, and What to Expect

Olanzapine (brand name: Zyprexa) is a atypical antipsychotic (second-generation). Olanzapine blocks dopamine D2, serotonin 5-HT2A and 5-HT2C, histamine H1, muscarinic M1-M5, and alpha-1 adrenergic receptors. Its broad receptor profile makes it highly effective but also accounts for its significant side effect burden. The strong 5-HT2C and H1 antagonism drives its weight gain (the most of any atypical antipsychotic). It is structurally similar to clozapine and shares many of its benefits and risks, minus the agranulocytosis.

• Schizophrenia
• Bipolar I Disorder (acute manic or mixed episodes, maintenance)
• Bipolar Depression (in combination with fluoxetine as Symbyax)
• Treatment-resistant depression (with fluoxetine)

Common off-label uses:

• Acute agitation (IM formulation)
• Anorexia nervosa (weight restoration)
• Chemotherapy-induced nausea
• PTSD
• Borderline personality disorder

Schizophrenia: 5-10 mg/day, target 10-20 mg. Bipolar mania: 10-15 mg/day. With fluoxetine for bipolar depression: 6-12 mg olanzapine + 25-50 mg fluoxetine. IM for acute agitation: 5-10 mg. Long-acting injectable (Zyprexa Relprevv): 150-405 mg every 2-4 weeks (requires 3-hour post-injection observation for post-injection delirium/sedation syndrome).

Sedative effects immediate. Antipsychotic effects begin within 1 week, full effect 2-4 weeks. Antimanic effects within days.

• Weight gain (average 5-10 kg in first year — the highest of any atypical antipsychotic)
• Sedation and somnolence
• Metabolic syndrome (diabetes, dyslipidemia)
• Increased appetite
• Dry mouth
• Constipation
• Orthostatic hypotension
• Elevated prolactin (moderate)

• Diabetes mellitus (including diabetic ketoacidosis — can occur within weeks)
• Severe weight gain and metabolic syndrome
• Post-injection delirium/sedation syndrome (with long-acting injectable — REMS program required)
• Tardive dyskinesia
• Neuroleptic malignant syndrome
• Increased mortality in elderly with dementia (black box warning)
• Hepatotoxicity (rare)

CYP1A2 substrate — smoking decreases levels significantly (smokers need higher doses; dose reduction needed if quitting). Fluvoxamine increases levels. Carbamazepine decreases levels. Additive sedation with CNS depressants. Avoid with IM benzodiazepines (respiratory depression risk).

Category C. May increase risk of gestational diabetes. Third-trimester use may cause extrapyramidal symptoms in newborns.

Taper gradually to avoid rebound psychosis, insomnia, and withdrawal symptoms. Cholinergic rebound (nausea, diarrhea, diaphoresis) can occur due to muscarinic receptor supersensitivity.