lumateperone

General Information

Lumateperone (Caplyta; lumateperone tosylate) is a serotonin–dopamine activity modulator approved for adults with schizophrenia, depressive episodes associated with bipolar I or II disorder, and adjunctive treatment of major depressive disorder.

Its mechanism integrates 5-HT2A antagonism, presynaptic D2 partial agonism, postsynaptic D2 antagonism, and modest serotonin reuptake inhibition, delivering antipsychotic plus antidepressant effects with comparatively low EPS and metabolic burden.

It is dispensed as a fixed 42 mg once-daily capsule without titration, offering placebo-like EPS rates and minimal metabolic change—useful when weight gain, prolactin elevation, or EPS with other SGAs limit therapy.

Because it lacks antimanic efficacy, bipolar care plans often pair lumateperone with mood stabilizers or antipsychotics that cover manic/hypomanic relapse prevention when needed; follow-up and safety checklists can be coordinated through the bipolar disorder hub.

The compare tool can help weigh sedation, metabolic trade-offs, and dose logistics, and the lumateperone evidence feed can support review of recent studies when considering switching or augmentation strategies.

Adoption is rising for patients needing a low-metabolic-burden option without titration. Insurance coverage, somnolence, and CYP3A4 interaction constraints remain practical barriers; medication lists are typically reviewed for interactions before initiation.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Exerts potent 5-HT2A antagonism with presynaptic dopamine D2 partial agonism/postsynaptic antagonism, tempering mesolimbic activity while preserving low striatal occupancy.

Indirect enhancement of NMDA-mediated glutamatergic signaling and modest serotonin transporter inhibition may contribute to antidepressant effects observed in bipolar depression trials.

• Antagonist at serotonin 5-HT2A receptors.
• Partial agonist at serotonin 5-HT1A receptors.
• Presynaptic D2 partial agonist/postsynaptic antagonist with limited striatal engagement.
• Low affinity for histamine H1, adrenergic α1, and muscarinic receptors, reducing sedation, orthostasis, and anticholinergic burden.

Metabolism and Pharmacokinetics

• Oral bioavailability ~4%; peak concentrations achieved 1–1.5 hours post-dose. Food increases exposure by ~13% but is not clinically meaningful.
• Highly protein bound (~97%) with a distribution volume near 4.1 L/kg.
• Metabolized predominantly via CYP3A4 with minor CYP2C8 and UGT contributions; active metabolites (e.g., ITI-214, ITI-263) contribute to clinical effect.
• Parent half-life averages 13 hours; active metabolites persist 18–37 hours, enabling once-daily dosing.
• Elimination occurs primarily via feces (~58%) and urine (~33%) as metabolites.

Dosing and Administration

• Schizophrenia, bipolar depression, and adjunctive major depressive disorder: 42 mg orally once daily with or without food; no titration required.
• Maximum recommended dose: 42 mg once daily.
• Reduce to 21 mg once daily when co-administered with moderate CYP3A4 inhibitors (e.g., fluconazole, diltiazem); avoid strong CYP3A4 inhibitors or inducers.
• Limit to 21 mg/day in moderate hepatic impairment; contraindicated in severe hepatic impairment. Use cautiously in severe renal impairment (CrCl <30 mL/min).
• If a dose is missed and remembered within 12 hours, take it immediately; otherwise skip and resume the next scheduled dose—do not double up.

Adverse Effects

Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, itraconazole) markedly increase exposure and are contraindicated.
• Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John’s wort) substantially reduce exposure and are contraindicated.
• Moderate CYP3A4 inhibitors warrant dose reduction to 21 mg/day with close monitoring.
• Grapefruit/grapefruit juice is typically avoided due to CYP3A4 inhibition potential.
• Additive CNS depression occurs with alcohol, benzodiazepines, opioids, or other sedatives—driving and machinery precautions are commonly discussed.

Other Useful Information

• Fixed once-daily dosing can aid adherence; pharmacy coverage and prior authorization are often reviewed early.
• Routine metabolic labs and blood pressure monitoring are typically continued despite favorable averages to maintain SGA safety standards.
• Sedation, cognition, and fall risk are often reassessed within the first few weeks; evening dosing can minimize daytime somnolence.
• Complementary antimanic therapy (e.g., lithium, valproate, or another SGA) is typically maintained or added when lumateperone treats bipolar depression, because it does not prevent manic relapse.
• Education for patients/caregivers often covers hypersensitivity symptoms (swelling, difficulty breathing) that warrant emergency care.
• New prescriptions and over-the-counter products are typically reviewed with the prescribing team due to CYP3A4 sensitivity.

References

1. CAPLYTA (lumateperone) prescribing information — DailyMed (2025)
2. Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial — JAMA Psychiatry (2020)
3. Lumateperone FOR THE Treatment OF Bipolar Depression: Results From A Randomized, Double Blind, Placebo Controlled Trial — The Journal of Clinical Psychiatry (2021)
4. Lumateperone AS Adjunctive Therapy IN Patients With Major Depressive Disorder: Results From A Randomized, Double Blind, Phase 3 Trial. — Journal of Clinical Psychiatry (2025)
5. Adjunctive Lumateperone IN Patients With Major Depressive Disorder: Results From A Randomized, Double Blind, Phase 3 Trial. — American Journal of Psychiatry (2025)
6. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia — American Psychiatric Association (2020)Guidelineschizophreniaclinical