SUMMARY

Major Depressive Disorder

• Durgam et al (2025)¹ conducted a phase 3 trial in patients with major depressive disorder (MDD) who had an inadequate response to ADT (Study 501). The mean changes (standard error [SE]) in lipid parameters from baseline to the end of treatment in the CAPLYTA 42 mg+antidepressant therapy (ADT) group were as follows: total cholesterol, -10.3 (2.08) mg/dL; low-density lipoprotein (LDL) cholesterol,
  -9.4 (1.91) mg/dL; high-density lipoprotein (HDL) cholesterol, -0.4 (0.77) mg/dL; and triglycerides, -4.7 (5.13) mg/dL.
• Durgam et al (2025)² conducted a phase 3 trial in patients with MDD who had an inadequate response to ADT (Study 502). The mean changes (standard deviation [SD]) in lipid parameters from baseline to the end of treatment in the CAPLYTA 42 mg+ADT group were as follows: total cholesterol, -9.3 (35.41) mg/dL; LDL cholesterol,
  -9.4 (31.76) mg/dL; HDL cholesterol, -0.9 (10.57) mg/dL; and triglycerides,
  -2 (97.27) mg/dL.
• Earley et al (2025)³ presented a 26-week open-label extension (OLE) study in adult patients with MDD (Study 503). The mean changes (SD) in lipid parameters from baseline to the end of treatment in the CAPLYTA 42 mg+ADT group were as follows: total cholesterol, -8.2 (32.3) mg/dL; LDL cholesterol, -9.6 (30.42) mg/dL; HDL cholesterol, 0.1 (11.79) mg/dL; and triglycerides, -0.2 (84.26) mg/dL.
• Earley et al (2026)⁴ conducted a pooled analysis of two phase 3 trials (Study 501 and Study 502) in patients with MDD who had an inadequate response to ADT. The mean changes (SD) in lipid parameters from baseline to the end of treatment in the CAPLYTA 42 mg+ADT group were as follows: total cholesterol, -9.8 (33.32) mg/dL; LDL cholesterol, -9.4 (30.21) mg/dL; HDL cholesterol, -0.6 (11.08) mg/dL; and triglycerides, -3.4 (87.36) mg/dL.

Bipolar Disorder

• Correll et al (2026)⁵ conducted a phase 3 study in patients on monotherapy for major depressive episodes (MDEs) associated with bipolar I or bipolar II disorder (Study 401 Part A). The mean changes (SE) in lipid parameters from baseline to Day 43 for the CAPLYTA 42 mg group were as follows: total cholesterol, -4.97 (1.86) mg/dL; LDL cholesterol, -5.21 (1.57) mg/dL; HDL cholesterol, 0.62 (0.76) mg/dL; and triglycerides, 2.92 (4.18) mg/dL.
• Tohen et al (2026)⁶ presented results from a 6-month OLE of a phase 3 study (Study 401 Part B) wherein, the mean changes (SE) in lipid parameters from baseline to Day 175 for the CAPLYTA 42 mg group were as follows: total cholesterol,
  -2.5 (2.12) mg/dL; LDL cholesterol, -5.8 (1.9) mg/dL; HDL cholesterol, 1.4 (0.82) mg/dL; and triglycerides, 2.3 (4.49) mg/dL.
• Suppes et al (2023)⁷ conducted a phase 3 trial in patients with MDEs associated with bipolar I or bipolar II disorder (Study 402). The mean changes (SD) in lipid parameters from baseline to the end of treatment in the CAPLYTA 42 mg group were as follows: total cholesterol, -6.5 (32.2) mg/dL; LDL cholesterol, -5.9 (27) mg/dL; HDL cholesterol, -0.6 (11.9) mg/dL; and triglycerides, -1.6 (57.9) mg/dL.
• Davis et al (2021)⁸ presented results from a pooled analysis of two phase 3 trials (Studies 401 and 404). The mean changes in lipid parameters from baseline to the last on-treatment measurement in the CAPLYTA 42 mg group were as follows: total cholesterol, -0.6 mg/dL; LDL cholesterol, -0.7 mg/dL; HDL cholesterol, 0.4 mg/dL; and triglycerides, -1.4 mg/dL.

Schizophrenia

• Correll et al (2021)⁹ conducted a phase 3 trial in patients with stable schizophrenia (Study 303, part A). Decreases from previous antipsychotics baseline were observed after week 1 of CAPLYTA 42 mg treatment in total cholesterol and LDL cholesterol, which were sustained for the rest of the treatment period.
• Cutler et al (2022)¹⁰ presented the results of a post-hoc analysis of Study 303. Across all groups that switched from other antipsychotics to CAPLYTA 42 mg, decreases in total cholesterol and LDL cholesterol were observed from baseline to Day 42, with the greatest decreases observed in the olanzapine group.
• Correll et al (2026)¹¹ conducted a 1-year open-label study (Study 303, Part B) in patients with stable schizophrenia. The mean changes (SD) in lipid parameters from baseline to Day 368 in the CAPLYTA 42 mg group were as follows: total cholesterol,
  -10.8 (27.56) mg/dL; HDL cholesterol, -0.3 (10.75) mg/dL; LDL cholesterol, -9.1 (24.95) mg/dL; and triglycerides, -8.2 (57.31) mg/dL.¹²
• Correll et al (2020)¹³ conducted a phase 3 trial in patients with schizophrenia (Study 301). The mean changes (SD) in lipid parameters from baseline to Day 28 in the CAPLYTA 42 mg group were as follows: total cholesterol, -0.12 (0.66) mmol/L; LDL cholesterol, -0.02 (0.58) mmol/L; HDL cholesterol, -0.09 (0.24) mmol/L; and triglycerides, -0.04 (0.47) mmol/L.¹⁴
• Durgam et al (2025)¹⁵ presented the results of a phase 3 withdrawal study for the prevention of relapse in patients with schizophrenia (Study 304). The mean changes (SD) in lipid parameters from baseline to Day 28 in the CAPLYTA 42 mg group were as follows: total cholesterol, -6.1 (37.32) mg/dL; HDL cholesterol, 2 (12.26) mg/dL; LDL cholesterol, -4.8 (35.06) mg/dL; and triglycerides, -11 (83.88) mg/dL.
• Lieberman et al (2016)¹⁶ conducted a phase 2 trial in patients with schizophrenia (Study 005). The mean changes (SD) in lipid parameters from baseline to Day 28 in the CAPLYTA 42 mg group were as follows: total cholesterol, -0.04 (0.71) mmol/L; LDL cholesterol, 0.06 (0.6) mmol/L; HDL cholesterol, -0.08 (0.28) mmol/L; and triglycerides, 0.01 (0.42) mmol/L.¹⁷
• Kane et al (2021)¹⁸ performed a pooled analysis of 3 trials (Studies 005, 301, and 302) wherein, triglycerides decreased in patients receiving CAPLYTA but increased in those receiving placebo. Additionally, CAPLYTA treatment led to similar mean changes in total cholesterol and LDL cholesterol levels as placebo.

PRODUCT LABELING

Metabolic Changes

Antipsychotic drugs have been reported to have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain.¹⁹

Dyslipidemia

Antipsychotics have been reported to have caused adverse alterations in lipids. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment.¹⁹

CLINICAL DATA

MDD, Adjunctive Therapy to Antidepressants

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 ADT in patients with MDD who had an inadequate response to ADT (Study 501).

• 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.
• Changes in lipid parameters at end of treatment were not clinically significant and were generally similar between the treatment groups; see Table: Changes in Lipid Parameters at End of Treatment (Safety Population).

Durgam et al (2025) conducted a phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, international study that evaluated the efficacy and safety of CAPLYTA 42 mg as adjunctive therapy to ADT in patients with MDD who had an inadequate response to ADT (Study 502).²

• Patients were randomized (1:1) to receive either CAPLYTA 42 mg+ADT (n=242) or placebo+ADT (n=238) for 6 weeks; this was followed by a 1-week safety follow-up period.
• Changes in lipid parameters at end of treatment were not clinically relevant and were generally similar between the treatment groups; see Table: Changes in Lipid Parameters at End of Treatment.

Earley et al (2025)³ presented a 26-week OLE study (Study 503) that evaluated the long-term safety and tolerability of CAPLYTA 42 mg+ADT as adjunctive therapy to ADT in adult patients with MDD who had completed Study 501 or Study 502.

• Patients (N=809) were administered CAPLYTA 42 mg once daily in the evening for 26 weeks.
• Changes in lipid parameters at end of treatment were minimal; see Table: Changes in Lipid Parameters.

Earley et al (2026)⁴ conducted a pooled analysis of Study 501 and Study 502 that evaluated the pooled safety and tolerability of CAPLYTA adjunctive to ADT in patients with MDD with an inadequate response to ADT.

• The pooled safety population included 964 patients: CAPLYTA 42 mg+ADT, n=483; placebo+ADT, n=481.
• Changes in lipid parameters at end of treatment were minimal; see Table: Changes in Lipid Parameters at End of Treatment (Safety Population)

Bipolar Depression

Correll et al (2026)⁵ conducted a phase 3, 6-week, randomized, double-blind, placebo-controlled study (Study 401 Part A) that assessed the efficacy and safety of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder.

• Patients were randomized (1:1:1) to receive lumateperone 28 mg (n=180), CAPLYTA 42 mg (n=184), or placebo (n=185; n values were based on safety population) once daily for 6 weeks.

No notable changes were reported in lipid parameters, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides from baseline to Day 43; see Table: Changes in Lipid Parameters from Baseline.

Tohen et al (2026)⁶ presented results from a 6-month OLE of a phase 3 study (Study 401 Part B) that assessed the long-term safety and tolerability of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder.

• Eligible patients (N=127) received CAPLYTA 42 mg/day for 175 days.
• No notable changes were reported in lipid parameters, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides; see Table: Changes in Lipid Parameters.

Suppes et al (2023)⁷ 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 (Study 402).

• Patients were randomized (1:1:1) to receive lumateperone 28 mg (n=176), CAPLYTA 42 mg (n=177), or placebo (n=176) for 6 weeks; this was followed by a 2-week safety follow-up period.
• No notable changes were reported at end of treatment in lipid parameters, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides; see Table: Changes in Lipid Parameters at End of Treatment.

Davis et al (2021)⁸ presented results of a pooled analysis of two phase 3, randomized, double-blind, placebo-controlled, 6-week trials (ie, Studies 401 and 404) to assess the metabolic profile of CAPLYTA 42 mg monotherapy in the treatment of patients with bipolar depression.

• The combined safety population from the 2 studies comprised 746 patients (CAPLYTA 42 mg, n=372; placebo, n=374).
• Mean changes from baseline to last on-treatment measure in lipid parameters were similar between the treatment groups; see Table: Changes in Lipid Parameters from Baseline to the Last On-treatment Measurement.

Schizophrenia

Correll et al (2021)⁹ conducted a 6-week, open-label, outpatient, antipsychotic switch study to evaluate the efficacy and safety of CAPLYTA 42 mg in patients with stable schizophrenia (Study 303, Part A).

• The safety population comprised 301 patients who had received at least 1 dose of CAPLYTA 42 mg.
• Decreases from baseline while receiving previous antipsychotics were observed after week 1 of CAPLYTA treatment in total cholesterol and LDL cholesterol; these decreases were sustained for the rest of the treatment period.

Cutler et al (2022)¹⁰ presented the results of a post-hoc analysis of Study 303 that evaluated the safety, tolerability, and efficacy of CAPLYTA 42 mg in patients stratified by previous antipsychotics and switched to CAPLYTA 42 mg for 6 weeks.

• Overall, 235 out of 301 patients receiving CAPLYTA 42 mg, were previously treated with risperidone/paliperidone (n=95), quetiapine (n=60), aripiprazole/brexipiprazole (n=43), or olanzapine (n=37).
• Across all groups that switched from other antipsychotics to CAPLYTA 42 mg, decreases in total cholesterol and LDL cholesterol were observed from baseline to Day 42, with the greatest decreases observed in the olanzapine group.

Correll et al (2026)¹¹ conducted a 1-year open-label study (Study 303, Part B) that evaluated the long-term safety and effectiveness of CAPLYTA 42 mg in patients with stable schizophrenia.

• In Part B, 602 patients received CAPLYTA 42 mg with a planned treatment duration of up to 1 year.
• Mean changes from baseline to Day 368 in lipid parameters are presented below; see Table: Changes in Lipid Parameters from Baseline to Day 368.

Correll et al (2020)¹³ conducted a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of CAPLYTA in patients with schizophrenia (Study 301).

• Patients were randomized (1:1:1) to receive lumateperone 28 mg (n=150), CAPLYTA 42 mg (n=150), or placebo (n=149; n values are based on safety population) for 4 weeks. A follow-up safety assessment was performed approximately 2 weeks after the last dose of study medication.
• There were no significant mean changes in cholesterol and triglycerides from baseline to Day 28 compared with placebo; see Table: Changes in Lipid Parameters from Baseline to Day 28.

Durgam et al (2025)¹⁵ presented the results of a phase 3, randomized, double-blind, placebo-controlled, withdrawal study to evaluate the efficacy and safety of CAPLYTA 42 mg for the prevention of relapse in patients with schizophrenia (Study 304).

• Following an 18-week open-label period on CAPLYTA 42 mg, stable patients were randomized (1:1) to double-blind treatment with CAPLYTA 42 mg (n=110) or placebo (n=114) for 26 weeks or until relapse.
• There were no notable mean changes in cholesterol and triglycerides from baseline to end of treatment compared with placebo; see Table: Changes in Lipid Parameters from Baseline During Double-Blind Treatment (Safety Population).

Lieberman et al (2016)¹⁶ conducted a phase 2, randomized, double-blind, placebo- and active-controlled, multicenter clinical trial to evaluate the efficacy and safety of CAPLYTA in patients with schizophrenia (Study 005).

• Patients were randomized 1:1:1:1 to receive CAPLYTA 42 mg (n=84), lumateperone 84 mg (n=83), risperidone 4 mg (n=82), or placebo (n=85) for 4 weeks.
• Total cholesterol decreased in patients receiving CAPLYTA 42 mg but increased in those receiving placebo, whereas mean changes from baseline to the Day 28 in LDL cholesterol and HDL cholesterol levels were similar between the CAPLYTA 42 mg and placebo groups; see Table: Changes in lipid parameters from baseline to Day 28

• In post hoc comparisons to risperidone, CAPLYTA 42 mg and lumateperone 84 mg treatment resulted in lower total cholesterol and triglycerides.

Kane et al (2021)¹⁸ performed a pooled analysis of 3 randomized, double-blind, placebo-controlled trials (ie, Studies 005, 301, and 302) to assess the safety and tolerability of CAPLYTA 42 mg in the treatment of schizophrenia.

• The pooled population comprised 1073 patients with acute exacerbation of schizophrenia (CAPLYTA 42 mg [n=406], risperidone 4 mg [n=255], or placebo [n=412]).
• Patients were treated with CAPLYTA for 4 weeks in Studies 005 and 301 and for 6 weeks in Study 302. Additionally, Studies 005 and 302 included risperidone 4 mg as an active control for assay sensitivity.
• Triglycerides decreased in patients receiving CAPLYTA but increased in those receiving placebo, whereas mean changes from baseline to the last on-treatment value in total cholesterol, HDL, and LDL cholesterol levels were similar between the CAPLYTA and placebo groups; see Table: Changes in Lipid Parameters from Baseline to the Last On-treatment Value.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 July 2026.