olanzapine

**Class:** Thienobenzodiazepine, second-generation (atypical) antipsychotic. Related to clozapine structurally and in receptor profile.

**Mechanism of action:** - Antagonist at serotonin 5-HT2A and dopamine D2 receptors (mesolimbic D2 blockade reduces positive symptoms; 5-HT2A blockade increases dopamine in the nigrostriatal and mesocortical pathways, which lowers EPS and may help negative symptoms). - Also blocks H1 (sedation, weight gain), M1 muscarinic (anticholinergic effects: dry mouth, constipation, urinary retention, blurred vision), and α1 adrenergic receptors (orthostatic hypotension). - Has some 5-HT2C antagonism, which is thought to contribute to appetite increase and weight gain.

**Indications:** - Schizophrenia (acute and maintenance) - Acute manic or mixed episodes of bipolar I disorder, and maintenance therapy - Treatment-resistant depression, combined with fluoxetine (Symbyax) - Acute agitation (IM formulation) - Off-label: anorexia nervosa (weight restoration), chemotherapy-induced nausea and vomiting, Tourette syndrome, delirium - Combined with samidorphan (Lybalvi) to blunt weight gain

**Adverse effects (high-yield):** - **Metabolic syndrome:** marked weight gain, hyperglycemia/type 2 diabetes, dyslipidemia. Olanzapine and clozapine carry the highest metabolic risk among the atypicals. Monitor weight/BMI, waist circumference, fasting glucose or HbA1c, lipids, and blood pressure. - Sedation, anticholinergic effects, orthostatic hypotension - Lower risk of EPS and tardive dyskinesia than first-generation agents (but not zero) - Mild prolactin elevation (less than risperidone) - QT prolongation (modest) - Neuroleptic malignant syndrome (rare, but possible with all antipsychotics) - Boxed warning: increased mortality in elderly patients with dementia-related psychosis. The Symbyax (olanzapine/fluoxetine) label also carries the antidepressant suicidality warning. - IM olanzapine plus parenteral benzodiazepines: avoid co-administration because of risk of excessive sedation and cardiorespiratory depression. - Olanzapine pamoate long-acting injection: post-injection delirium/sedation syndrome (PDSS) requires observation after each injection.

**Pharmacokinetics:** Hepatic metabolism, mainly CYP1A2 (also glucuronidation). Smoking induces CYP1A2 and lowers olanzapine levels. Fluvoxamine and ciprofloxacin inhibit CYP1A2 and raise levels. Half-life is about 30 hours, allowing once-daily dosing.

**Board pearls:** - Weight gain plus sedation in an atypical antipsychotic question → olanzapine (or clozapine). - Clozapine is the one atypical that causes agranulocytosis and seizures. Olanzapine does not require ANC monitoring. - Risperidone/paliperidone cause the most hyperprolactinemia among atypicals. - Ziprasidone has the most QT prolongation concern, while aripiprazole (a partial D2 agonist) and ziprasidone have the lowest metabolic risk. - Olanzapine is first-line for acute agitation when oral/IM options are needed. It has also been used for treating anorexia nervosa given its weight-promoting effect. - Mnemonic: "Olanzapine = Obesity" (also "Olanzapine and Clozapine → fat and sugar").