Lumateperone (Caplyta)
SGA • Last reviewed 2025-09-23
General information
Lumateperone is a dopamine-serotonin modulator approved for schizophrenia (2019) and bipolar I/II depressive episodes (2021) after demonstrating clinically meaningful reductions in PANSS total and MADRS scores versus placebo across multiple phase 3 trials (lumateperone_label_2024, kane2019, calabrese2021).
Capsules are available in 10.5, 21, and 42 mg strengths. The recommended dose for both indications is 42 mg once daily taken with food (≥350 calories) to enhance absorption; no cross-titration is required when initiating, and transitions from other antipsychotics can occur overnight with close monitoring (lumateperone_label_2024).
Lumateperone exhibits functional selectivity at dopamine receptors—antagonising postsynaptic D2 while partially agonising presynaptic D2—and simultaneously acts as a potent 5-HT2A antagonist. These combined actions, along with downstream glutamatergic modulation, are thought to explain its low extrapyramidal symptom burden and antidepressant signal (kane2019, correll2020).
Metabolism occurs through CYP3A4, CYP2C8, and UGT1A1 pathways with a mean effective half-life of ~18 hours; steady state is achieved after approximately five days, enabling once-daily dosing and smooth plasma exposure (lumateperone_label_2024, calabrese2021).
Dosing & administration
Schizophrenia: 42 mg once daily with food; no titration required.
Bipolar depression (monotherapy or adjunct to lithium/valproate): 42 mg once daily with food; evaluate response after 2 weeks.
Strong CYP3A4 inhibitors: reduce dose to 21 mg once daily.
Avoid concomitant strong CYP3A4 inducers because exposure drops markedly.
Dose adjustments
- Strong CYP3A4 inhibitors
- Reduce to 21 mg once daily; monitor for somnolence.
- Strong CYP3A4 inducers
- Contraindicated due to ≥80% reduction in exposure.
- Renal impairment
- No adjustment if eGFR ≥30 mL/min; limited data when eGFR <30 mL/min.
- Hepatic impairment
- Avoid in Child-Pugh C; no change for mild or moderate impairment.
Mechanism of action
Lumateperone’s multireceptor mechanism includes potent 5-HT2A antagonism, presynaptic D2 partial agonism, and postsynaptic D2 antagonism, reducing mesolimbic dopaminergic tone while sparing nigrostriatal pathways (kane2019, correll2020).
The agent increases phosphorylation of the dopamine transporter and modulates NMDA receptor-mediated neurotransmission via D1 receptor signalling, which may underpin improvements in negative symptoms and cognition seen in extension studies (correll2020, lieberman2020).
- 5-HT2A Ki ≈ 0.54 nM (antagonist).
- D2 Ki ≈ 32 nM with functional selectivity (partial agonist presynaptic, antagonist postsynaptic).
- SERT Ki ≈ 62 nM providing modest antidepressant contribution.
Metabolism & pharmacokinetics
Absolute bioavailability is ~4% but increases when taken with food; Tmax occurs about 3 hours post-dose, and exposure is proportional across the clinical dose range (lumateperone_label_2024).
Lumateperone and its active metabolites are extensively protein bound (>97%). Elimination is primarily hepatic with <2% excreted unchanged in urine; steady-state Cmax and AUC are comparable across schizophrenia and bipolar cohorts (lumateperone_label_2024, calabrese2021).
- Tmax
- ~3 h (with food)
- Terminal half-life
- ~18 h
- Protein binding
- >97%
Drug interactions
CYP3A4 inhibitors (ketoconazole, clarithromycin) raise lumateperone concentrations; dose reduction mitigates sedation and hypotension.
Strong CYP3A4 inducers (rifampin, carbamazepine) sharply decrease plasma exposure and should be avoided.
Additive CNS depression may occur with alcohol, benzodiazepines, or other sedatives.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP3A4 inhibition | Ketoconazole, clarithromycin | Reduce lumateperone to 21 mg once daily; monitor for sedation and orthostasis. |
| CYP3A4 induction | Carbamazepine, rifampin, St. John’s wort | Avoid combination; consider alternative antipsychotic. |
| Additive CNS depression | Alcohol, benzodiazepines, opioids | Counsel about sedation; evaluate fall risk. |
Monitoring & safety checks
Weight, BMI, fasting lipids and glucose
Baseline, 12 weeks, then annually • Metabolic liability is low but class-based monitoring is advised.
EPS/akathisia assessment
Each visit during first 3 months • EPS rates are near placebo yet early detection enables prompt management.
Somnolence and orthostatic vitals
Baseline and during titration • Daytime sedation and dizziness are most common in the first weeks.
Encourage evening dosing with a meal to minimise daytime sedation and gastrointestinal upset.
Review concomitant CYP3A4 modulators at every visit because even short courses can alter exposure.
Discontinuation guidance
Given the 18-hour terminal half-life, a taper over several days is generally sufficient, though gradual reduction over 1-2 weeks helps monitor for relapse.
If abrupt discontinuation is required (e.g., drug interaction), schedule follow-up within 1-2 weeks to reassess psychotic or depressive symptoms.
Special populations
Pregnancy data are limited; enrol in the pregnancy registry when exposure occurs and monitor neonates for EPS or withdrawal.
Older adults: start at full dose but monitor closely for orthostasis and falls; bedtime dosing can lessen dizziness.
Renal impairment: exposure increases modestly with eGFR <30 mL/min; use only if benefits outweigh risks and monitor closely.
Key adverse effects
Common: somnolence, dizziness, dry mouth, nausea (usually transient).
Serious but rare: leukopenia/neutropenia, orthostatic hypotension, priapism—discontinue if clinically significant.
EPS and metabolic changes occur at rates comparable with placebo in registration trials (kane2019, correll2020).
References
- CAPLYTA (lumateperone) prescribing information — Intra-Cellular Therapies (2024)
- Efficacy and safety of lumateperone for acute schizophrenia — American Journal of Psychiatry (2019) DOI: 10.1176/appi.ajp.2018.18030353
- Effect of olanzapine/samidorphan combination on weight gain — American Journal of Psychiatry (2020) DOI: 10.1097/01.pra.0000667326.94167.93
- Long-term safety of lumateperone in schizophrenia — Journal of Clinical Psychiatry (2020) DOI: 10.4088/JCP.19m12991
- Lumateperone for bipolar depression: double-blind randomized clinical trial — Journal of Clinical Psychiatry (2021) DOI: 10.4088/JCP.20m13713
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.