CAPLYTA - Use in the Treatment of Bipolar Depression and Major Depressive Disorder with Mixed Features

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 in patients with major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features.
  • CAPLYTA showed improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to day 43 compared to placebo.
    • In the combined MDD with mixed features and bipolar depression with mixed features group, the least squares (LS) mean change from baseline for CAPLYTA 42 mg was -18.1 vs -12.4 for placebo, with LS mean difference of -5.7 (95% confidence interval [CI]: -7.60 to -3.84; effect size [ES]=-0.64; P<0.000).^1,2
  • CAPLYTA also showed improvement in the Clinical Global Impression-Severity
    (CGI-S) score from baseline to day 43 compared to placebo.
    • In the combined MDD with mixed features and bipolar depression with mixed features group, the LS mean change from baseline for CAPLYTA 42 mg was -1.8 vs -1.2 for placebo, with LS mean difference of -0.6 (95% CI: -0.81 to -0.39; ES=-0.59; P<0.0001).^1,2
  • In the combined MDD and bipolar depression population, the treatment-emergent adverse event (TEAE) rate was 54.2% for CAPLYTA 42 mg vs 37.3% for placebo. Specifically, among patients with MDD, the TEAE rate was 51.1% for CAPLYTA 42 mg vs 32.3% for placebo; in patients with bipolar depression, the TEAE rate was 57.0% for CAPLYTA 42 mg vs 42.0% for placebo.¹
• In multiple post hoc analyses of Study 403, CAPLYTA 42 mg 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 or bipolar depression with mixed features.^3-6

PRODUCT LABELING

CAPLYTA is an atypical antipsychotic indicated for: treatment of schizophrenia in adults; treatment of 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 in patients with MDEs associated with MDD or bipolar depression with mixed features.

• Key inclusion criteria were:
  • Meeting 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 between 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; 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; see Table: Change in MADRS Total Score and CGI-S Score at Day 43 (Modified Intent-to-Treat Population).

• In the combined MDD and bipolar depression population, the TEAE rate was 54.2% for CAPLYTA 42 mg vs 37.3% for placebo. Specifically, among patients with MDD, the TEAE rate was 51.1% for CAPLYTA 42 mg vs 32.3% for placebo; in patients with bipolar depression, the TEAE rate was 57.0% for CAPLYTA 42 mg vs 42.0% for placebo.¹
• In the combined MDD and bipolar depression population, rate of discontinuation due to adverse events was 4.7% for CAPLYTA 42 mg vs 1.6% for placebo. Specifically, among patients with MDD, the rate of discontinuation was 2.2% for CAPLYTA 42 mg vs 1.1% for placebo; in patients with bipolar depression, the rate of discontinuation was 7.0% for CAPLYTA 42 mg vs 2.0% for placebo.¹
• In the combined MDD and bipolar depression population, the most common TEAEs (occurring in ≥5% of the CAPLYTA 42 mg group and more than twice that of placebo) were somnolence (CAPLYTA 42 mg, 12.5%; placebo, 1.6%), dizziness (CAPLYTA 42 mg, 12.0%; placebo, 2.1%), and nausea (CAPLYTA 42 mg, 9.9%; placebo, 1.6%). Specifically, among patients with MDD, the most common TEAEs were somnolence (CAPLYTA 42 mg, 12.0%; placebo, 1.1%), dizziness (CAPLYTA 42 mg, 12.0%; placebo, 4.3%), and nausea (CAPLYTA 42 mg, 10.9%; placebo, 1.1%); in patients with bipolar depression, the most common TEAEs were somnolence (CAPLYTA 42 mg, 13.0%; placebo, 2.0%), dizziness (CAPLYTA 42 mg, 12.0%; placebo, 0%), nausea (CAPLYTA 42 mg, 9.0%; placebo, 2.0%), dry mouth (CAPLYTA 42 mg, 5.0%; placebo, 2.0%), and fatigue (CAPLYTA 42 mg, 5.0%; placebo, 1.0%).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 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 54.3% of patients with bipolar depression (CAPLYTA 42 mg: n=56; placebo: n=52); and 73.9% of patients with MDD (CAPLYTA 42 mg: n=67; placebo: n=69).
• CAPLYTA 42 mg showed a greater decrease in MADRS and CGI-S scores from baseline to day 43 compared to placebo in patients with anxious distress.
  • MADRS total score: least squares mean difference (LSMD), -6.1 (95% CI: -8.52 to 3.71; ES: -0.67) in the combined MDD/bipolar depression population; LSMD, -6.8 (95% CI: -9.82 to -3.77; ES: -0.79) in the MDD population; and LSMD, -5.5 (95% CI: -9.34 to -1.62; ES: -0.59) in the bipolar depression population.
  • CGI-S score: LSMD, -0.5 (95% CI: -0.78 to -0.26; ES: -0.54) in the combined MDD/bipolar depression population; LSMD, -0.6 (95% CI: -0.98 to -0.30; ES: -0.66) in the MDD population; and LSMD, -0.4 (95% CI: -0.82 to 0.05; ES: -0.48) in the bipolar depression population.
  • MADRS single-item scores for inner tension improved from baseline at day 43 across all 3 populations.

Durgam et al (2025)⁴ conducted a post hoc analysis of Study 403 to investigate the efficacy of CAPLYTA 42 mg 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 greater decrease in MADRS anhedonia scores from baseline to day 43 compared to patients in the placebo group with combined MDD/bipolar depression (CAPLYTA 42 mg [n=192] vs placebo [n=191]), MDD (CAPLYTA 42 mg [n=92] vs placebo [n=92]), and bipolar depression (CAPLYTA 42 mg [n=100] vs placebo [n=99]).
• MADRS anhedonia factor score: LSMD vs placebo, -3.4 (ES: -0.63) in the combined MDD/bipolar depression population; LSMD vs placebo, -3.4 (ES: -0.63) in the MDD population; and LSMD vs placebo, -3.3 (ES: -0.61) in the bipolar depression population.
• Across all 3 subpopulations, 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 each subpopulation:
  • Combined MDD/bipolar depression: apparent sadness, reported sadness, lassitude, inability to feel, and concentration difficulties
  • MDD: apparent sadness, reported sadness, lassitude, concentration difficulties, and inability to feel
  • Bipolar depression: apparent sadness, reported sadness, lassitude, and inability to feel
• In the combined MDD/bipolar depression population, TEAEs were reported in 54.2% of patients in the CAPLYTA 42 mg group vs 37.3% of patients in the placebo group. Most TEAEs occurring in ≥5% of the CAPLYTA 42 mg group at more than twice that of placebo were mild to moderate in severity.

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 population, the CAPLYTA 42 mg group had a greater decrease in MADRS total scores at day 43 compared to the placebo group in the combined MDD/bipolar depression population (CAPLYTA 42 mg [n=192] vs placebo [n=191]), the MDD population (CAPLYTA 42 mg [n=92] vs placebo [n=92]), and the bipolar depression population (CAPLYTA 42 mg [n=100] vs placebo [n=99]).
• Across all 3 populations, CAPLYTA 42 mg improved both response (defined as decrease in ≥50% MADRS total score and ≥50% YMRS total score from baseline to EOT) and remission (MADRS total score ≤10 or ≤12)¹ at day 43 compared to placebo.
  • Response rate (CAPLYTA 42 mg vs placebo): 53% vs 33% (NNT, 6; OR, 2.3 [95% CI: 1.5-3.47]) in the combined MDD/bipolar depression population, 58% vs 35% (NNT, 5; OR, 2.5 [95% CI: 1.39-4.57]) in the MDD population, and 48% vs 31% (NNT, 6; OR, 2.1 [95% CI: 1-15-3.72]) in the bipolar depression population.
  • For results related to remission rates for all subpopulations, 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 population, CAPLYTA 42 mg showed improvement in most MADRS items from baseline to day 43 compared to placebo in patients with combined MDD/bipolar depression population (CAPLYTA 42 mg [n=192] vs placebo [n=191]), MDD population (CAPLYTA 42 mg [n=92] vs placebo [n=92]), and bipolar depression population (CAPLYTA 42 mg [n=100] vs placebo [n=99]).
• Changes observed in individual MADRS items across subpopulations were as follows:
  • Combined MDD/bipolar depression population: improvement with CAPLYTA 42 mg were observed in all MADRS items except suicidal thoughts. The largest placebo-adjusted improvements were reported in apparent sadness (LSMD, -0.9; ES: -0.68), reduced sleep (LSMD, -0.9; ES: -0.62), and reported sadness (LSMD, -0.8;
    ES: -0.59).
  • MDD population: improvement with CAPLYTA 42 mg were observed in 8 out of 10 MADRS items vs placebo. The largest placebo-adjusted improvements were reported in reported sadness (LSMD, -0.9; ES: -0.71), apparent sadness (LSMD, -0.9;
    ES: -0.74), and reduced sleep (LSMD, -0.9; ES: -0.64).
  • Bipolar depression population: improvement was observed in 8 out of 10 MADRS items with CAPLYTA 42 mg vs placebo. The largest placebo-adjusted improvements were reported for reduced sleep (LSMD, -0.9; ES: -0.6), apparent sadness
    (LSMD, -0.8; ES: -0.63), and inability to feel (LSMD, -0.8; ES: -0.64).
• Shifts in MADRS item scores from ≥4 at baseline to ≤2 at EOT across sub-populations were as follows:
  • Combined MDD/bipolar depression population: reported sadness, apparent sadness, reduced sleep, lassitude, and inability to feel.
  • MDD population: reported sadness, apparent sadness, inner tension, reduced sleep, and inability to feel.
  • Bipolar depression population: 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 17 March 2026.