Lurasidone

Indications

• Schizophrenia in adults and in adolescents ages 13-17, both for acute episodes and for continued maintenance treatment.
• Depressive episodes associated with bipolar I disorder as monotherapy in adults and in pediatric patients ages 10-17.
• Bipolar I depression in adults as adjunctive therapy with lithium or valproate when monotherapy is insufficient.
• Frequently chosen when metabolic risk, obesity, diabetes, or dyslipidemia makes olanzapine or quetiapine unattractive.
• Off-label uses include augmentation in unipolar depression with mixed features and maintenance treatment of bipolar I disorder.

Mechanism of action

• High-affinity antagonist at dopamine D2 and serotonin 5-HT2A receptors, giving antipsychotic efficacy with moderate extrapyramidal liability.
• Potent 5-HT7 antagonism is a distinguishing feature, linked in preclinical work to antidepressant and procognitive effects.
• Partial agonism at 5-HT1A contributes to mood and anxiety benefit and may soften striatal dopamine blockade.
• Essentially no histamine H1 or muscarinic affinity, which explains minimal weight gain, low sedation, and no anticholinergic burden.
• Modest alpha-2C antagonism may add to antidepressant action, while low alpha-1 affinity limits orthostatic hypotension.

Pharmacokinetics

• Bioavailability roughly doubles when taken with a meal of at least 350 calories, and fasting administration is a common cause of failure.
• Metabolized almost entirely by CYP3A4, which makes it contraindicated with strong inhibitors and strong inducers of that enzyme.
• Terminal half-life is about 18 hours, supporting once-daily dosing with steady state reached in roughly 7 days.
• Two active metabolites contribute modestly to effect, and about 9 percent of the dose is recovered in urine.
• Exposure rises with renal and hepatic impairment, so both carry explicit dose caps rather than simple caution statements.

Dosing

• Schizophrenia in adults: start 40 mg once daily with food, with a usual range of 40-160 mg/day and no initial titration required.
• Bipolar depression in adults: start 20 mg once daily with food and titrate as needed, with a labeled maximum of 120 mg/day.
• Adolescents with schizophrenia start at 40 mg/day with a maximum of 80 mg/day; pediatric bipolar depression starts at 20 mg with the same cap.
• With a moderate CYP3A4 inhibitor such as diltiazem, start at 20 mg/day and do not exceed 80 mg/day.
• Renal impairment with clearance under 50 mL/min and moderate hepatic impairment both cap the dose at 80 mg/day; severe hepatic caps at 40 mg/day.
• Taper gradually when discontinuing, and remember that a switch away from lurasidone often unmasks weight or sedation from the new agent.

Adverse effects

• Akathisia and parkinsonism are the leading adverse effects and are clearly dose related, appearing more often above 80 mg/day.
• Somnolence, nausea, and agitation are common early, and taking the dose in the evening with supper mitigates both sedation and nausea.
• Weight and metabolic effects are among the lowest in the class, with mean weight change near 1 kg and neutral lipid and glucose effects.
• Prolactin elevation is small but real, larger in women and adolescents than in adult men, and occasionally causes menstrual change.
• Serious risks are those of the class: neuroleptic malignant syndrome, tardive dyskinesia, and rare severe cutaneous reactions.

Monitoring

• Weight, BMI, blood pressure, fasting glucose or A1c, and lipids at baseline, at 12 weeks, and then annually, as for any antipsychotic.
• Assess for akathisia and parkinsonism at every early visit, since these are the effects most likely to end treatment.
• Serum creatinine and hepatic panel at baseline to determine whether the 80 mg or 40 mg dose ceiling applies.
• Verify at each visit that doses are taken with a meal of at least 350 calories, and consider this first when response is poor.
• AIMS at baseline and every 6-12 months, plus prolactin testing when menstrual or sexual symptoms emerge.

Interactions

• Contraindicated with strong CYP3A4 inhibitors including ketoconazole, itraconazole, clarithromycin, ritonavir, and voriconazole.
• Contraindicated with strong CYP3A4 inducers including rifampin, carbamazepine, phenytoin, and St. John's wort.
• Moderate inhibitors such as diltiazem, verapamil, erythromycin, and fluconazole require the reduced 80 mg/day ceiling.
• Grapefruit juice should be avoided because it inhibits intestinal CYP3A4 and unpredictably raises exposure.
• Additive sedation with opioids, benzodiazepines, and alcohol, but minimal QT effect compared with ziprasidone or iloperidone.

Special populations

• Third-trimester exposure risks neonatal extrapyramidal and withdrawal symptoms; pregnancy data are more limited than for older agents.
• Lactation data are sparse, so monitor breastfed infants for sedation and poor feeding and consider better-characterized alternatives.
• Approved from age 10 for bipolar depression and 13 for schizophrenia, with a lower maximum dose than adults in both indications.
• Older adults tolerate it relatively well given low anticholinergic and orthostatic effects, but the dementia mortality warning still applies.
• Dose ceilings of 80 mg/day apply in moderate to severe renal impairment and moderate hepatic impairment, and 40 mg/day in severe hepatic disease.

Clinical pearls

• Give it with supper: under 350 calories, exposure falls by half and the drug looks ineffective.
• Strong CYP3A4 inhibitors and inducers are contraindications, not cautions; check the med list first.
• Akathisia at higher doses is the usual failure mode, not weight gain.