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CAPLYTA®

(lumateperone)

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CAPLYTA® (lumateperone)
Medical Information

CAPLYTA - Onset of Action in Major Depressive Disorder

Last Updated: 05/06/2026

SUMMARY

  • CAPLYTA is not approved for the treatment of major depressive disorder (MDD) as monotherapy.
  • In two phase 3, placebo-controlled studies assessing the efficacy and safety of CAPLYTA adjunctive to antidepressant therapy (ADT) in patients with MDD who had an inadequate response to ADT:1,2
    • Study 501 (N=485): CAPLYTA 42 mg adjunctive to ADT was associated with an improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score as early as day 8 and continued till day 43 (end of treatment). The least squares mean difference (LSMD) vs placebo at day 43 was -4.9 (95% confidence interval [CI], -6.38 to -3.44; P<0.0001).
    • Study 502 (N=480): Patients treated with CAPLYTA 42 mg+ADT experienced an improvement in the MADRS Total score as early as day 15 and persisted through day 43 (LSMD vs placebo at day 43, -4.5; 95% CI, -6.03 to -3.02; P<0.0001).
  • In a 26-week, open-label extension (OLE) study assessing the efficacy and safety of CAPLYTA adjunctive to ADT in patients with MDD who had completed Study 501 or Study 502 (N=809), CAPLYTA 42 mg adjunctive to ADT was associated with a decrease in MADRS total score starting by day 8 of the pooled double blind treatment period and continued through week 26 of the open label treatment (mean±standard deviation [SD] change in the MADRS Total score from open-label baseline to week 26, -9.1±8.98).3,4

CLINICAL DATA

Phase 3 Studies

Durgam et al (2025)1 conducted a phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study to assess the efficacy and safety of CAPLYTA adjunctive to ADT in patients with MDD who had an inadequate response to ADT (N=485). Patients were randomized (1:1) to receive either CAPLYTA 42 mg (n=242) or placebo (n=243) as adjunctive treatment to ADT for 6 weeks; this was followed by a 1-week safety follow up period (see Figure: Study Design for Study 501).

Study Design for Study 5011,5

Abbreviations: ADT, antidepressant therapy; CGI-S, Clinical Global Impression Scale-Severity; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th edition; ET, early termination; GAD-7, Generalized Anxiety Disorder-7; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; MDE, major depressive episode; QIDS-SR-16, Quick Inventory of Depressive Symptomatology-Self Report-16 item.
aEligible patients who completed 6 weeks of double-blind treatment and provided informed consent to rollover into the open-label safety study would not have entered the safety follow-up period.

The primary endpoint was change in the MADRS Total score from baseline to day 43. As shown in Figure: Least-Squares Mean Change in MADRS Total Score Over Time (501 Study), there was a statistically significant change from baseline to day 43 in the MADRS Total score in patients treated with CAPLYTA 42 mg+ADT (n=239) vs placebo+ADT (n=242; LSMD, -4.9; 95% CI, -6.38 to -3.44; P<0.0001). Patients treated with CAPLYTA had clinically meaningful improvements in depression symptoms and disease severity by day 8 and persisted throughout the study.

Least-Squares Mean Change in MADRS Total Score Over Time (501 Study)1 

Abbreviations: ADT, antidepressant therapy; LS, least squares; LSMD, least squares mean difference; MADRS, Montgomery-Ǻsberg Depression Rating Scale.
aP<0.001, bP<0.0001. LSMD vs placebo. *Weekly time points prior to 6 weeks were not adjusted for multiple comparisons. Therefore, the p-values displayed are nominal, and statistical significance has not been established.
Adapted from: Durgam S, Earley WR, Kozauer SG, et al. Lumateperone as adjunctive therapy in patients with major depressive disorder: results from a randomized, double-blind, phase 3 trial. J Clin Psychiatry. 2025;86(4):25m15848.

Durgam et al (2025)2 conducted a phase 3, randomized, double-blind, placebo-controlled, multicenter, international study to evaluate the efficacy and safety of CAPLYTA adjunctive to ADT in patients with MDD who had an inadequate response to ADT (N=480). Patients were randomized (1:1) to receive either CAPLYTA 42 mg (n=242) or placebo (n=238) as adjunctive treatment to ADT for 6 weeks; this was followed by a 1-week safety follow-up period (see Figure: Study Design for Study 502).

Study Design for Study 5022,6

A graph with red and black rectangular lines AI-generated content may be incorrect.

Abbreviations: ADT, antidepressant therapy; CGI-S, Clinical Global Impression Scale-Severity; CSFQ-14, Changes in Sexual Functioning Questionnaire-14-item; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th edition; ET, early termination; GAD-7, Generalized Anxiety Disorder-7; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; MDE, major depressive episode; QIDS-SR-16, Quick Inventory of Depressive Symptomatology-Self Report-16 item.
aEligible patients who completed 6 weeks of double-blind treatment and provided informed consent to rollover into the open-label safety study would not have entered the safety follow-up period.

The primary efficacy endpoint was change in the MADRS Total score from baseline to day 43. As shown in Figure: Mean Change in MADRS Total Score Over Time (Study 502), improvements in the MADRS Total score were achieved by day 15 and were maintained through day 43 (LSMD vs placebo at day 43, -4.5; 95% CI, -6.03 to -3.02; P<0.0001).

Mean Change in MADRS Total Score Over Time (Study 502)2 

Abbreviations: ADT, antidepressant therapy; LS, least squares; MADRS, Montgomery-Ǻsberg Depression Rating Scale.
aP=0.0504, bP<0.05, cP<0.0001. *Weekly time points prior to 6 weeks were not adjusted for multiple comparisons. Therefore, the p-values displayed are nominal, and statistical significance has not been established.
Adapted from: Durgam S, Earley WR, Kozauer SG, et al. Adjunctive lumateperone in patients with major depressive disorder: results from a randomized, double-blind, phase 3 trial. Am J Psychiatry. 2025;182(12):1072-1082.

OLE Study

Durgam et al (2026)3 conducted a 26-week, OLE, multicenter, international study that evaluated the long-term safety and tolerability of CAPLYTA 42 mg as adjunctive therapy to ADT in patients with MDD who had completed Study 501 or 502 (N=809).

The change in depression symptoms from baseline to week 26 was assessed using the MADRS Total score. As shown in Figure: Mean Change in MADRS Total Score Over Time (Study 503), patients demonstrated improvement in depression symptoms throughout the OLE period.3 Decrease in MADRS total score began by day 8 of the pooled double-blind treatment and continued through week 26 of the open-label treatment. The mean±SD change in the MADRS Total score from open-label baseline to week 26 was -9.1±8.98.4 

Mean Change in MADRS Total Score Over Time (Study 503)3

Abbreviations: ADT, antidepressant therapy; DB, double-blind; MADRS, Montgomery-Ǻsberg Depression Rating Scale; OL, open-label.
aIncludes patients who received ≥1 dose in Study 503. DB week 6 visit (day 43) is the same as the OL week 1 visit (day 1). Error bars represent standard error of the mean.
Adapted from: Durgam S, Earley WR, Kozauer SG, et al. Long-term adjunctive lumateperone 42 mg treatment in major depressive disorder: results from a 6-month open-label extension study. Eur Neuropsychopharmacol. 2026;108(2026):112786.

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT® (and/or other resources, including internal/external databases) was conducted on 01 April 2026.

 

References

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1 Durgam S, Earley WR, Kozauer SG, et al. Lumateperone as adjunctive therapy in patients with major depressive disorder: results from a randomized, double-blind, phase 3 trial. J Clin Psychiatry. 2025;86(4):25m15848.  
2 Durgam S, Earley WR, Kozauer SG, et al. Adjunctive lumateperone in patients with major depressive disorder: results from a randomized, double-blind, phase 3 trial. Am J Psychiatry. 2025;182(12):1072-1082.  
3 Durgam S, Earley WR, Kozauer SG, et al. Long-term adjunctive lumateperone 42 mg treatment in major depressive disorder: results from a 6-month open-label extension study. Eur Neuropsychopharmacol. 2026;108:112786.  
4 Data on File. CAPLYTA. Final Clinical Study Report of Study 503. Intra-Cellular Therapies, Inc; 2025.  
5 Durgam S, Earley WR, Kozauer SG, et al. Supplement to: Lumateperone as adjunctive therapy in patients with major depressive disorder: results from a randomized, double-blind, phase 3 trial. J Clin Psychiatry. 2025;86(4):25m15848.  
6 Data on File. CAPLYTA. Clinical Study Report of Study 502. Intra-Cellular Therapies, Inc; 2024.