SUMMARY

• Durgam et al (2025)¹ conducted a 6-week, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of CAPLYTA in patients with major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features.
  • CAPLYTA (n=193) improved the Young Mania Rating Scale (YMRS) total score from baseline to day 43 vs placebo (n=195; P<0.05).
  • No cases of mania or hypomania were reported in the combined study population.
• Suppes et al (2023)² conducted a 6-week, phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of CAPLYTA as adjunctive treatment to lithium or valproate in patients with MDEs associated with bipolar I or bipolar II disorder.
  • No increase in mania symptoms was observed in the CAPLYTA 28 mg group (n=176) or the CAPLYTA 42 mg group (n=177), as indicated by the mean change in the YMRS score from baseline to day 43.^2,3 
  • One treatment-emergent adverse event (TEAE) of mania was reported in a patient treated with CAPLYTA 42 mg and valproate; 1 TEAE of hypomania was reported in a patient who received placebo and valproate (n=175 in the placebo group).² 
• Calabrese et al (2021)⁴ conducted a 6-week, phase 3, randomized, double-blind, placebo-controlled, multinational study to evaluate the efficacy and safety of CAPLYTA in patients with MDEs associated with bipolar I or bipolar II disorder.
  • No increase in mania symptoms was observed in the CAPLYTA 42 mg (n=188) or placebo (n=189) group, as indicated by the mean change in the YMRS score from baseline to day 43.
  • Mania was reported in 1.1% of patients in the CAPLYTA group vs 2.1% of patients in the placebo group. Hypomania was reported in 0.5% of patients in each group.
• McIntyre et al (2023)⁵ conducted a post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study (Study 404) to evaluate the efficacy of CAPLYTA in patients with MDE associated with bipolar I or bipolar II disorder with or without mixed features (N=376).
  • Among patients with mixed features (CAPLYTA, n=73; placebo, n=83), the YMRS score decreased numerically over time; a significant decrease was observed on day 29 with CAPLYTA vs placebo (P<0.05).
  • Among patients with mixed features, the rate of TEAEs of mania was 1.4% in the CAPLYTA group vs 2.4% in the placebo group. All mania cases were of moderate severity.
• Tohen et al (2022)⁶ conducted an analysis to evaluate the incidence of mania and hypomania in patients with MDE associated with bipolar depression who were treated with CAPLYTA across short- and long-term studies.
  • The mean change in the YMRS total score from baseline to day 43 was comparable between the CAPLYTA and placebo groups.
  • In the pooled monotherapy groups, TEAEs of mania or hypomania with mild or moderate severity were reported in 6 patients in the CAPLYTA group (n=372) vs 5 patients in the placebo group (n=374).

BACKGROUND

In phase 3, placebo-controlled studies in patients with bipolar depression, patients were required to have a YMRS score of 4-16¹ or ≤12^2,4 in order to be included. The YMRS score was monitored throughout each trial for emergence of manic symptoms. TEAEs of mania and hypomania were also recorded during the clinical trials.^1,2,4 

CLINICAL DATA

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

• During the study, CAPLYTA improved the YMRS total score from baseline to day 43 vs placebo; see Table: Change in the Young Mania Rating Scale Total 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 vs 37.3% for placebo. Specifically, among patients with MDD, the TEAE rate was 51.1% for CAPLYTA vs 32.3% for placebo; in patients with bipolar depression, the TEAE rate was 57.0% for CAPLYTA vs 42.0% for placebo. No cases of mania or hypomania were reported in the combined study population.

Suppes et al (2023)² conducted a phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of CAPLYTA as adjunctive treatment to lithium or valproate in patients with MDEs associated with bipolar I or bipolar II disorder. Patients were randomized (1:1:1) to receive CAPLYTA 28 mg (n=176), CAPLYTA 42 mg (n=177), or placebo (n=175) for 6 weeks; this was followed by a 2-week safety follow-up period.

• No increase in mania symptoms was observed in either CAPLYTA group, as indicated by the mean change in the YMRS score from baseline to day 43.^2,3 
  • In the CAPLYTA 28 mg group, the mean±standard deviation (SD) YMRS score was decreased by -1.4±2.87 at day 43 from baseline (3.4±1.97).
  • In the CAPLYTA 42 mg group, the mean±SD YMRS score was decreased by -1.7±2.80 at day 43 from baseline (3.5±2.26).
  • In the placebo group, the mean±SD YMRS score was decreased by -1.4±2.91 at day 43 from baseline (3.5±2.43).
• The rate of TEAEs in the CAPLYTA 28 mg, CAPLYTA 42 mg, and placebo groups was 45.5%, 49.7%, and 44.6%, respectively. One TEAE of mania was reported in a patient treated with CAPLYTA 42 mg and valproate; 1 TEAE of hypomania was reported in a patient treated with placebo and valproate.²

Calabrese et al (2021)⁴ conducted a phase 3, randomized, double-blind, placebo-controlled, multinational study to evaluate the efficacy and safety of CAPLYTA in patients with MDEs associated with bipolar I or bipolar II disorder. Patients were randomized (1:1) to receive either CAPLYTA 42 mg (n=188) or placebo (n=189) for 6 weeks; this was followed by a 2-week safety follow-up period.

• No increase in mania symptoms was observed in either group, as indicated by the mean change in the YMRS score from baseline to day 43 (CAPLYTA, -1.4; placebo, -0.9).
• At any point during the study, 2.1% of patients in the CAPLYTA group vs 2.7% of patients in the placebo group had a YMRS score of ≥15.
• Mania was reported in 1.1% of patients in the CAPLYTA group vs 2.1% of patients in the placebo group. Hypomania was reported in 0.5% of patients in each group.
• In each group, a TEAE of mania led to treatment discontinuation in 1.1% of patients. In the CAPLYTA group, 1 serious TEAE of mania led to treatment discontinuation.

McIntyre et al (2023)⁵ conducted a post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study (Study 404) to evaluate the efficacy of CAPLYTA in 376 patients with MDE associated with bipolar I or bipolar II disorder with mixed features (YMRS score ≥4 and ≤12) or without mixed features (YMRS score <4).

• Among patients with mixed features (CAPLYTA, n=73; placebo, n=83), the YMRS score decreased numerically over time, with a significant decrease noted on day 29 with CAPLYTA vs placebo (P<0.05).
• Among patients without mixed features (CAPLYTA, n=115; placebo, n=105), the YMRS score remained stable over time, except for a significant reduction observed on day 43 with CAPLYTA vs placebo (least squares mean difference [LSMD], -0.8; 95% confidence interval [CI], -1.43 to -0.07; effect size, -0.32; P<0.05).
• Among patients with mixed features, the rate of TEAEs of mania was 1.4% in the CAPLYTA group vs 2.4% in the placebo group. Among patients without mixed features, the rate of TEAEs of mania was 0.9% in the CAPLYTA group vs 1.9% in the placebo group. All mania cases were of moderate severity.
• Among patients with mixed features, hypomania was reported in 1.4% of patients (moderate severity) in the CAPLYTA group vs 1.2% of patients (mild severity) in the placebo group.

Tohen et al (2022)⁶ conducted an analysis to evaluate the incidence of mania and hypomania in patients with MDE associated with bipolar depression who were treated with CAPLYTA across short- and long-term studies. Data were pooled from the following 3 studies: Study 401 and Study 404 (short-term, 6-week, placebo-controlled studies of CAPLYTA 42 mg monotherapy); Study 402 (phase 3, placebo-controlled study of CAPLYTA 42 mg adjunctive treatment with lithium or valproate); and a 6-month, open-label extension (OLE) period of Study 401.

• In the intent-to-treat population of the monotherapy studies, the mean change in the YMRS total score from baseline to day 43 was comparable between CAPLYTA (n=354) and placebo (n=365) (LSMD, -0.5; 95% CI, -1.0 to 0.1; P=0.10).
• Similarly, in the adjunctive treatment study, the mean change in the YMRS total score from baseline to day 43 was comparable between CAPLYTA (n=174) and placebo (n=174; LSMD, -0.2; 95% CI, -0.8 to 0.4; P=0.56).
• In the safety population of the pooled monotherapy groups, TEAEs of mania or hypomania of mild or moderate severity were reported in 6 patients (1.6%) in the CAPLYTA group (n=372) vs 5 patients (1.3%) in the placebo group (n=374).
• In the adjunctive therapy group, 1 patient each in the CAPLYTA (n=177) and placebo (n=175) groups reported mania or hypomania. In the CAPLYTA monotherapy group, 1 patient reported a serious TEAE of mania.
• In the OLE safety population (N=127), 1 patient reported a TEAE of mild mania in the CAPLYTA group. The mean change in the YMRS score from baseline to the end of treatment was -0.5 (95% CI, -1.7 to 0.6; P=0.37).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 August 2025.