CAPLYTA - Use in Major Depressive Disorder as Monotherapy

SUMMARY

• Durgam et al (2025)¹ conducted a 6-week, randomized, double-blind, placebo-controlled, multicenter study (Study 403) to evaluate the efficacy and safety of CAPLYTA 42 mg monotherapy in patients with major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features.
  • In the MDD group, the least squares (LS) mean change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score for CAPLYTA 42 mg vs placebo was -18.2 vs -12.2, with LS mean difference of
    -5.9 (95% confidence interval [CI]: -8.61 to -3.29; effect size [ES]=-0.67; P<0.0001).^1,2
  • In the MDD group, the LS mean change from baseline to day 43 in the Clinical Global Impression-Severity (CGI-S) score for CAPLYTA 42 mg vs placebo was -1.7 vs -1.1, with LS mean difference of -0.6 (95% CI: -0.89 to -0.27; ES=-0.57; P=0.0003).^1,2
  • In the MDD population, the treatment-emergent adverse event (TEAE) rate was 51.1% for CAPLYTA 42 mg vs 32.3% for placebo.¹
• In multiple post hoc analyses of Study 403 (Bhagwagar et al [2025]³, Durgam et al [2025]⁴, Durgam et al [2025]⁵, Yatham et al [2026]⁶), CAPLYTA 42 mg monotherapy had decreases in MADRS total scores, CGI-S scores, and MADRS individual item scores from baseline to day 43 compared to placebo in patients with MDEs associated with MDD.^3-6

PRODUCT LABELING

CAPLYTA is an atypical antipsychotic indicated for treatment of schizophrenia in adults, depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate, and adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults.⁷

CLINICAL DATA

Durgam et al (2025)¹ conducted a randomized, double-blind, placebo-controlled, multicenter study (Study 403) to evaluate the efficacy and safety of CAPLYTA monotherapy in patients with MDEs associated with MDD or bipolar depression with mixed features.

• Key inclusion criteria were:
  • Met the Diagnostic and Statistical Manual of Mental Disorders, 5^th Edition
    (DSM-5) criteria for mixed features
  • A Young Mania Rating Scale (YMRS) total score of ≥4 and ≤16
  • A MADRS total score ≥24
  • A CGI-S score ≥4
• Patients were randomly assigned (1:1) to receive either CAPLYTA 42 mg (n=193) or placebo (n=195) for 6 weeks, once daily; this was followed by a 2-week safety follow-up period.
• The primary efficacy endpoint was the change in MADRS total score from baseline to day 43, and the key secondary efficacy endpoint was the change in CGI-S score from baseline to day 43.
• During the study, CAPLYTA 42 mg showed improvement in both MADRS total score and CGI-S score from baseline to day 43 vs placebo in the MDD population; see Table: Change in MADRS Total Score and CGI-S Score at Day 43 (Modified Intent-to-Treat Population).

• In the MDD population, the TEAE rate in the CAPLYTA 42 mg group (n=92) vs placebo group (n=93) was 51.1% vs 32.3%.¹
• In the MDD population, the rate of discontinuation in the CAPLYTA 42 mg group vs placebo group was 2.2% vs 1.1%.¹
• In the MDD population, the most common TEAEs were somnolence (CAPLYTA 42 mg, 12%; placebo, 1.1%), dizziness (CAPLYTA 42 mg, 12%; placebo, 4.3%), and nausea (CAPLYTA 42 mg, 10.9%; placebo, 1.1%).¹

Post hoc Analyses

Bhagwagar et al (2025)³ conducted a post hoc analysis of a randomized, double-blind, placebo-controlled, multicenter study (Study 403) to investigate the efficacy of CAPLYTA 42 mg monotherapy in patients with MDD/bipolar depression with mixed features and anxious distress.

• From the 383 patients in the mITT MDD or BPD with mixed features population, 63.7% had anxious distress (CAPLYTA 42 mg [n=123]; placebo [n=121]).
  • Anxious distress was present in 73.9% of patients with MDD (CAPLYTA 42 mg: n=67; placebo: n=69).
• CAPLYTA 42 mg showed a decrease in MADRS and CGI-S scores from baseline to day 43 compared to placebo in patients with anxious distress in the MDD population.
  • MADRS total score: least squares mean difference (LSMD), -6.8 (95% CI: -9.82 to
    -3.77; ES: -0.79).
  • CGI-S score: LSMD, -0.6 (95% CI: -0.98 to -0.3; ES: -0.66).
  • MADRS single-item scores for inner tension improved from baseline at day 43.

Durgam et al (2025)⁴ conducted a post hoc analysis of Study 403 to investigate the efficacy of CAPLYTA 42 mg monotherapy in improving anhedonia in patients with MDD/bipolar depression with mixed features.

• In the mITT population, patients in the CAPLYTA 42 mg group showed a decrease in MADRS anhedonia scores from baseline to day 43 compared those in the placebo group in the MDD population (CAPLYTA 42 mg [n=92] vs placebo [n=92]).
  • MADRS anhedonia factor score: LSMD vs placebo was -3.4 (ES: -0.63).
• All MADRS items comprising the anhedonia factor score improved with CAPLYTA 42 mg vs placebo at day 43. Improvements were reported in the following individual items for MDD population: apparent sadness, reported sadness, lassitude, concentration difficulties, and inability to feel

Durgam et al (2025)⁵ conducted a post hoc analysis of Study 403 to define and measure response and remission based on reductions in both MADRS and YMRS scores in patients with MDEs with mixed features associated with MDD/bipolar depression.

• Based on the mITT MDD population, the CAPLYTA 42 mg group had a decrease in MADRS total scores at day 43 compared to the placebo group (CAPLYTA 42 mg [n=92] vs placebo [n=92]).
• In the MDD population, CAPLYTA 42 mg improved both response (defined as decrease in ≥50% MADRS total score and ≥50% YMRS total score from baseline to end of treatment [EOT]) and remission (MADRS total score ≤10 and YMRS ≤6)¹ at day 43 compared to placebo.
  • The response rate (CAPLYTA 42 mg vs placebo) was 58% vs 35% (NNT, 5; OR, 2.5 [95% CI: 1.39-4.57]).
  • For results related to remission rates for MDD population, please see Table: Remission Rates in mITT Population at the End of Treatment.

Yatham et al (2026)⁶ conducted a post hoc analysis of Study 403 to assess the effect of CAPLYTA 42 mg on MADRS single-item scores in patients with MDD/bipolar depression with mixed features.

• In the mITT MDD population, the CAPLYTA 42 mg group showed a decrease in most MADRS items from baseline to day 43 compared to placebo (CAPLYTA 42 mg [n=92] vs placebo [n=92]).
• Changes observed in individual MADRS items in the MDD population were as follows:
  • CAPLYTA 42 mg (vs placebo) showed a greater decrease in 8 out of 10 MADRS items. The largest placebo-adjusted improvements were reported in apparent sadness (LSMD, -0.9; ES: -0.74), reported sadness (LSMD, -0.9; ES: -0.71), and reduced sleep (LSMD, -0.9; ES: -0.64).
• Shifts in MADRS item scores from ≥4 at baseline to ≤2 at EOT in the MDD population were as follows: reported sadness, apparent sadness, inner tension, reduced sleep, and inability to feel.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 22 June 2026.