CAPLYTA - Effect on Mania in Bipolar Disorder

SUMMARY

• Cutler et al (2026)¹ conducted a phase 3 study (Study 451) of patients with bipolar I disorder with or without mixed features. In the CAPLYTA 42 mg group, least square mean difference (LSMD) of YMRS total score vs placebo group was -4.8 from baseline to day 22; P<0.0001.
• Durgam et al (2025)² conducted a phase 3 trial of patients with major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features (Study 403). CAPLYTA 42 mg improved the Young Mania Rating Scale (YMRS) total score from baseline to day 43 vs placebo (P<0.05). No cases of mania or hypomania were reported in the combined study population.
• Across 2 post hoc analyses of Study 403 (Yatham et al [2026]³; Durgam et al [2025]⁴), CAPLYTA 42 mg was associated with fewer cases of mild or moderate mania (defined as YMRS total score >12), a lower incidence of worsening mania (defined as ≥50% YMRS total score increase), and reductions in YMRS total scores, alongside higher composite response rates (≥50% reduction in Montgomery-Åsberg Depression Rating Scale [MADRS] and YMRS total scores) vs placebo in the bipolar depression population.^3,4
• In a phase 3 trial by Suppes et al (2023)⁵ evaluating CAPLYTA as adjunctive treatment to lithium or valproate in patients with MDEs associated with bipolar I or bipolar II disorder (Study 402), the mean change in the YMRS total score from baseline to day 43 indicated no increase in mania symptoms.^5,6
  • 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).⁵ 
• Calabrese et al (2021)⁷ conducted a phase 3 trial of patients with MDEs associated with bipolar I or bipolar II disorder (Study 404); the mean change in the YMRS total score from baseline to day 43 indicated no increase in mania symptoms.
  • 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 a post hoc analysis of Study 404 (McIntyre et al [2023]⁸), the YMRS total score decreased numerically over time; a significant decrease was observed on day 29 with CAPLYTA 42 mg vs placebo (P<0.05) among patients with mixed features. 
  • Among patients with mixed features, the rate of TEAEs of mania was 1.4% in the CAPLYTA 42 mg group vs 2.4% in the placebo group. All mania cases were of moderate severity.
• Tohen et al (2026)⁹ conducted a 6-month open-label safety study (Study 401-Part B) in which, CAPLYTA 42 mg demonstrated no worsening of mania symptoms, with no increase in the YMRS total score at EOT, 1 mild event of treatment-emergent mania and no hypomania events.
• In a pooled analysis of Studies 401, 402, and 404 by Tohen et al (2022)¹⁰, 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 total score of 4-16² or ≤12^5,7 in order to be included. The YMRS total score was monitored throughout each trial for emergence of manic symptoms. TEAEs of mania and hypomania were also recorded during the clinical trials.^2,5,7 

CLINICAL DATA

Cutler et al (2026)¹ conducted a phase 3, randomized, double-blind, placebo-controlled study (Study 451) that evaluated the efficacy and safety of CAPLYTA for treatment of manic episodes with or without mixed features in patients with bipolar I disorder. Patients were randomized (1:1) to receive CAPLYTA 42 mg (n=177), or placebo (n=177) for 3 weeks; this was followed by a 1-week safety follow-up period.

• The primary endpoint was change in YMRS total score from baseline (day 1, pre randomization) to Week 3 (day 22).
• Of 354 treated patients, 327 (92.4%) completed treatment and were included in the safety and ITT populations
• At baseline, 58.8% of patients reported ≥5 lifetime manic episodes, and 15.3% had DSM-5 mixed features.
• Mean baseline YMRS total scores were 33.2 in the CAPLYTA 42 mg group and 32.1 in the placebo group, indicating severe mania in both groups.
• The CAPLYTA 42 mg group demonstrated statistically significant improvement compared to the placebo group as indicated by the LSMD in the YMRS total score from baseline to day 22.
  • In the CAPLYTA 42 mg group, LSMD of YMRS total score vs placebo group was -4.8 (95%CI, -6.31 to -3.28); effect size, -0.69; P<0.0001.
• The YMRS total score response rates (≥50% decrease in YMRS total score from baseline at day 22) were 45.8% and 20.9% in CAPLYTA 42 mg group and placebo group, respectively (OR, 3.1 [95% CI, 1.94-4.95]; P<0.0001; number needed to treat [NNT], 4).
• The YMRS total score remission rates (YMRS total score ≤12 at day 22) were 30.5% and 16.4% in CAPLYTA 42 mg group and placebo group, respectively (OR, 2.41 [95% CI, 1.43-4.05]; P=0.0009; NNT, 7.1).
• Adverse events reported in ≥5% of patients receiving CAPLYTA 42 mg and at ≥2-fold the incidence of placebo were dry mouth (7.9% vs 3.4%) and nausea (7.9% vs 2.3%).
• Two severe adverse events (SAEs) and 1 death were reported in the CAPLYTA 42 mg group.
  • The death was considered by the investigator to be likely multifactorial and not directly related to CAPLYTA 42 mg treatment; the same patient also experienced rhabdomyolysis, which resolved before death.
  • The other SAE was bipolar disorder.

Durgam et al (2025)² 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. 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 patients with bipolar depression, the TEAE rate was 57% for CAPLYTA vs 42% for placebo. No cases of mania or hypomania were reported in the combined study population.

Yatham et al (2026)³ conducted a post hoc analysis of Study 403 to assess the effect of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder with or without mixed features.

• In the bipolar depression population, CAPLYTA 42 mg was associated with a lower incidence of worsening mania (≥50% increase in the YMRS total score) vs placebo: CAPLYTA 42 mg, n=3 (3%); placebo, n=5 (5.1%).

Durgam et al (2025)⁴ conducted a post hoc analysis of Study 403 to evaluate the efficacy of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder with or without mixed features.

• LS mean change in the YMRS total score from baseline to day 43 in the bipolar depression population was -5.6 and -4 in the CAPLYTA 42 mg and placebo groups, respectively.
• CAPLYTA 42 mg group had a greater response (defined as ≥50% decrease in MADRS total score and ≥50% decrease in YMRS total score from baseline to end of treatment [EOT]) vs placebo in the individual bipolar depression population.
  • Bipolar depression population: CAPLYTA 42 mg (n=100), 48%; placebo (n=99), 31% (OR, 2.1; 95% CI, 1.15-3.72)
• During the study, a higher proportion of patients receiving CAPLYTA 42 mg had remission (defined as composite MADRS total score and YMRS total score) vs placebo in the bipolar depression population; see Table: Composite MADRS and YMRS Total Score Remission Rates at EOT (Modified Intent-to-Treat Population).

Suppes et al (2023)⁵ conducted a phase 3, randomized, double-blind, placebo-controlled, multicenter study (Study 402) 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 lumateperone 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 the CAPLYTA 42 mg or lumateperone 28 mg group, as indicated by the mean change in the YMRS total score from baseline to day 43.^5,6 
  • In the lumateperone 28 mg group, the mean ± standard deviation (SD) YMRS total score decreased by -1.4±2.87 on day 43 from baseline (3.4±1.97).
  • In the CAPLYTA 42 mg group, the mean ± SD YMRS total score decreased by
    -1.7±2.8 on day 43 from baseline (3.5±2.26).
  • In the placebo group, the mean ± SD YMRS total score decreased by -1.4±2.91 on day 43 from baseline (3.5±2.43).
• The rate of TEAEs in the lumateperone 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.⁵

Calabrese et al (2021)⁷ conducted a phase 3, randomized, double-blind, placebo-controlled, multinational study (Study 404) 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 total score from baseline to day 43 (CAPLYTA 42 mg, -1.4; placebo, -0.9).
• At any point during the study, 2.1% of patients in the CAPLYTA 42 mg group vs 2.7% of patients in the placebo group had a YMRS total score of ≥15.
• Mania was reported in 1.1% of patients in the CAPLYTA 42 mg 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 42 mg group, 1 serious TEAE of mania led to treatment discontinuation.

McIntyre et al (2023)⁸ 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 total score ≥4 and ≤12) or without mixed features (YMRS total score <4).

• Among patients with mixed features (CAPLYTA 42 mg, n=73; placebo, n=83), the YMRS total score decreased numerically over time, with a significant decrease noted on day 29 with CAPLYTA 42 mg vs placebo (P<0.05).
• Among patients without mixed features (CAPLYTA 42 mg, n=115; placebo, n=105), the YMRS total score remained stable over time, except for a significant reduction observed on day 43 with CAPLYTA 42 mg vs placebo (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 42 mg 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 42 mg 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 42 mg group vs 1.2% of patients (mild severity) in the placebo group.

Tohen et al (2026)⁹ conducted a 6-month OLE following a 6-week, phase 3, randomized, double-blind, placebo-controlled study (Study 401 Part B) to evaluate the long-term safety of CAPLYTA 42 mg in patients with MDEs associated with bipolar depression. Of 127 patients included in OLE, 40 received lumateperone 28 mg, 43 received CAPLYTA 42 mg, and 44 received placebo during the randomized part of the study. All patients received CAPLYTA 42 mg during the OLE period regardless of the treatment administered in Study 401 Part A.

• No worsening of mania symptoms was observed in the CAPLYTA 42 mg group, as indicated by the mean change of -0.1 in the YMRS total score from baseline (7.2) to EOT.
• During the study, 1 mild TEAE of mania was reported with no hypomania events.
• One patient (0.8%) discontinued treatment due to a TEAE of mania.

Tohen et al (2022)¹⁰ 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 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 to 0.1; P=0.1).
• 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 total score from baseline to EOT 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 10 June 2026.