Olanzapine

Indications

• Schizophrenia in adults and adolescents ages 13-17, including maintenance treatment, with a long-acting injectable available for adults.
• Acute manic or mixed episodes of bipolar I disorder in adults and adolescents ages 13-17, as monotherapy or as adjunct to lithium or valproate.
• Maintenance monotherapy for bipolar I disorder in adults, where relapse prevention data are among the strongest in the class.
• Combined with fluoxetine for bipolar I depression in patients age 10 and older and for treatment-resistant depression in adults.
• Intramuscular olanzapine is approved for acute agitation in schizophrenia and bipolar I mania, and is used off-label for chemotherapy-induced nausea.

Mechanism of action

• Antagonist at dopamine D2 and serotonin 5-HT2A receptors with a moderate D2 occupancy window that yields efficacy with limited extrapyramidal risk.
• Very high histamine H1 affinity produces sedation and powerful appetite stimulation, the main driver of its weight gain.
• Potent 5-HT2C antagonism further increases appetite and, with H1 blockade, explains the largest metabolic burden in routine practice.
• Substantial muscarinic blockade gives dry mouth, constipation, and low extrapyramidal symptoms, but also cognitive dulling in older adults.
• Alpha-1 antagonism contributes to orthostatic hypotension, most apparent with the intramuscular formulation and rapid titration.

Pharmacokinetics

• Well absorbed orally, unaffected by food, with an orally disintegrating form useful when adherence or covert nonadherence is in question.
• Cleared by direct UGT1A4 glucuronidation and by CYP1A2 oxidation, with CYP2D6 playing only a minor role.
• Half-life averages about 30 hours with a range of 21-54 hours, allowing once-daily dosing and reaching steady state in about a week.
• Smoking induces CYP1A2 and lowers levels, so smokers often need higher doses and levels rise sharply when a patient quits or is hospitalized.
• Women and older adults clear the drug more slowly, and clearance is about 30 percent lower in nonsmoking women than in smoking men.

Dosing

• Schizophrenia in adults: start 5-10 mg/day PO once daily, target 10 mg/day after about one week, with a labeled maximum of 20 mg/day.
• Bipolar mania: start 10-15 mg/day as monotherapy or 10 mg/day when combined with lithium or valproate, adjusting by 5 mg no faster than daily.
• Adolescents start at 2.5-5 mg/day with a 10 mg/day target, since they gain weight faster and more than adults at any given dose.
• Intramuscular olanzapine for agitation is 10 mg, repeatable at 2 and 6 hours, with a total daily maximum of 30 mg across all routes.
• Zyprexa Relprevv is 150-300 mg IM every 2 weeks or 405 mg every 4 weeks, and requires 3 hours of post-injection observation.
• Start at 5 mg/day in debilitated patients, hepatic impairment, or older adults, and taper gradually to avoid cholinergic rebound.

Adverse effects

• Weight gain is the defining problem, averaging 5-7 kg in the first months and continuing for a year or more, with high rates of clinically significant gain.
• Fasting glucose, triglycerides, and total cholesterol rise substantially, and new-onset diabetes and diabetic ketoacidosis are reported.
• Sedation, dizziness, dry mouth, constipation, and orthostatic hypotension are common and reflect H1, muscarinic, and alpha-1 blockade.
• Extrapyramidal symptoms and prolactin elevation are modest compared with risperidone, and akathisia is much less common than with aripiprazole.
• Neuroleptic malignant syndrome, seizures, and severe drug reaction with eosinophilia and systemic symptoms are rare but serious.
• Post-injection delirium and sedation syndrome occurs in about 0.07 percent of Relprevv injections and mandates supervised observation.

Monitoring

• Weight and BMI at baseline, every visit for 3 months, then quarterly; a rise above 5 percent of body weight warrants a change in plan.
• Fasting glucose or A1c and a lipid panel at baseline, at 12 weeks, and at least annually, with earlier repeat in anyone gaining weight.
• Blood pressure at baseline and after dose changes, and orthostatic vitals when using the intramuscular formulation.
• Consider metformin coverage early rather than late in patients gaining weight who cannot switch off olanzapine.
• Track smoking status, since starting or stopping cigarettes changes CYP1A2 induction and shifts olanzapine levels markedly.

Interactions

• Fluvoxamine is a strong CYP1A2 inhibitor and can nearly double olanzapine levels, often requiring a dose reduction.
• Carbamazepine and cigarette smoke induce CYP1A2 and reduce olanzapine exposure by roughly half in heavy smokers.
• Parenteral benzodiazepines given with intramuscular olanzapine have caused fatal respiratory depression, so separate the administrations.
• Additive sedation, orthostasis, and anticholinergic load with opioids, benzodiazepines, alcohol, and antihistamines.
• Olanzapine antagonizes levodopa and dopamine agonists and is a poor choice for psychosis in Parkinson disease.

Special populations

• One of the better characterized antipsychotics in pregnancy, though third-trimester exposure risks neonatal extrapyramidal and withdrawal signs.
• Relative infant dose in lactation is around 1 percent; breastfeeding is generally acceptable with monitoring for infant sedation.
• Approved from age 13, but adolescents show greater weight gain, sedation, and lipid elevation, so it is rarely a first-line pediatric choice.
• In older adults start at 2.5-5 mg/day and expect anticholinergic and orthostatic effects; it is not approved for dementia-related psychosis.
• No renal adjustment is needed; in hepatic impairment start low, and monitor transaminases when they are already elevated.

Clinical pearls

• Reserve it for patients who need efficacy above all, and plan metabolic protection from day one.
• Smoking cessation can raise olanzapine levels enough to cause new sedation and extrapyramidal signs.
• IM olanzapine plus IM benzodiazepine has caused fatal respiratory depression; do not stack them.