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(lumateperone)

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CAPLYTA® (lumateperone)

Medical Information

CAPLYTA - Onset of Action in Major Depressive Disorder

Last Updated: 11/06/2025

SUMMARY  

  • CAPLYTA is not approved for the treatment of major depressive disorder (MDD) as monotherapy.
  • Durgam et al (2025)1 conducted a phase 3, 6-week, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study to assess the efficacy and safety of CAPLYTA 42 mg adjunctive to antidepressant therapy (ADT) in patients with MDD who had an inadequate response to ADT (N=485).
    • There was a statistically significant change from baseline to day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total score in patients treated with CAPLYTA 42 mg+ADT vs placebo+ADT. The least squares mean difference (LSMD) vs placebo was -4.9 (95% confidence interval [CI], -6.38 to -3.44; P<0.0001).
  • A phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, international study evaluated the efficacy and safety of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had an inadequate response to ADT (N=480).2
    • Patients treated with CAPLYTA 42 mg+ADT experienced an improvement in the MADRS Total score as early as day 8 (LSMD vs placebo, -0.7; 95% CI, -1.49 to 0.00; P=0.0504).
  • Earley et al (2025)3,4 conducted a 26-week, open-label extension (OLE), multicenter, international study that evaluated the long-term safety and tolerability of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had completed Study 501 or 502 (N=809).
    • Patients demonstrated improvement in depression symptoms throughout the OLE period.3,4 The mean±standard deviation (SD) change in the MADRS Total score from open-label baseline to week 26 was -9.1±8.98.3

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

A diagram of a graph AI-generated content may be incorrect.

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). The MADRS response (≥50% decrease in MADRS Total score from baseline) and remission (MADRS Total score ≤10) rates on day 43 were significantly greater with CAPLYTA 42 mg+ADT than placebo+ADT (response rate: odds ratio [95% CI], 2.6 [1.78-3.89] [P<0.0001]; remission rate: odds ratio [95% CI], 2.2 [1.40-3.56] [P<0.001]). Among patients with MDD and anxious distress, those receiving CAPLYTA+ADT (n=109) showed significant improvement in the MADRS Total score at day 43 compared to placebo+ADT (n=98; LSMD, -6.8; 95% CI, -9.0 to -4.51; P<0.0001).

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

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

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.
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.

A phase 3, randomized, double-blind, placebo-controlled, multicenter, international study evaluated 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).2

Study Design for Study 5022

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), patients treated with CAPLYTA 42 mg+ADT experienced an improvement in the MADRS score as early as day 8 (LSMD vs placebo, -0.7; 95% CI, -1.49 to 0.00; P=0.0504). A statistically significant improvement in the MADRS Total score was achieved beginning at day 15 (LSMD vs placebo, -1.1; 95% CI, -2.22 to -0.06; P=0.0384) and was maintained through day 43 (LSMD vs placebo, -4.5; 95% CI, -6.03 to -3.02; P<0.0001).

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

A graph of a graph with red dots AI-generated content may be incorrect.

Abbreviations: ADT, antidepressant therapy; LS, least squares; MADRS, Montgomery-Ǻsberg Depression Rating Scale.
aP<0.05, bP<0.0001.
Adapted from: Data on File. CAPLYTA. Clinical Study Report of Study 502. Intra-Cellular Therapies, Inc; 2024.

OLE Study

Earley et al (2025)3,4 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. The mean±SD change in the MADRS Total score from open-label baseline to week 26 was -9.1±8.98.3 The MADRS response (≥50% decrease from baseline in MADRS Total score) and remission (MADRS Total score ≤10) rates at week 26 were 79.5% and 65.4%, respectively.4

Mean Change in MADRS Total Score Over Time (Study 503)4

A graph of a graph AI-generated content may be incorrect.

Abbreviations: ADT, antidepressant therapy; DB, double-blind; EOLTP, end of long-term treatment period; MADRS, Montgomery-Ǻsberg Depression Rating Scale; OLE, open-label extension.
Adapted from: Earley WR, Durgam S, Kozauer SG, et al. Long-term adjunctive lumateperone treatment in major depressive disorder: results from a six-month open-label extension study. Poster presented at: American Psychiatric Association (APA) 2025 Annual Meeting; May 17-21, 2025; Los Angeles, CA.

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT® (and/or other resources, including internal/external databases) was conducted on 08 September 2025.

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 Data on File. CAPLYTA. Clinical Study Report of Study 502. Intra-Cellular Therapies, Inc; 2024.  
3 Data on File. CAPLYTA. Final Clinical Study Report of Study 503. Intra-Cellular Therapies, Inc; 2025.  
4 Earley WR, Durgam S, Kozauer SG, et al. Long-term adjunctive lumateperone treatment in major depressive disorder: results from a six-month open-label extension study. Poster presented at: American Psychiatric Association (APA) Annual Meeting; May 17-21, 2025; Los Angeles, CA.  
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.