SUMMARY

• The longest timeframe for studies evaluating the safety and efficacy of CAPLYTA in patients are 12-months (schizophrenia) and 6-months (for bipolar disorder and major depressive disorder).
• Schizophrenia (12-month): Correll et al (2020)¹, Satlin et al (2019)^2,3, and Vanover et al (2019)³ conducted a 12-month, open-label, long-term study to evaluate the safety and effectiveness of CAPLYTA 42 mg in patients with stable symptoms of schizophrenia.
  • CAPLYTA was well tolerated, led to a reduction in mean body weight from standard of care antipsychotic baseline, and showed a favorable cardiometabolic and endocrine safety profile. There were no clinically relevant changes in extrapyramidal symptoms (EPS).³ Treatment-emergent adverse events (TEAEs) reported in ≥5% of patients were weight decrease, dry mouth, headache, and diarrhea.¹ 
  • There was a reduction in Positive and Negative Syndrome Scale (PANSS) Total score and the Calgary Depression Scale for Schizophrenia (CDSS) score from baseline. PANSS and Clinical Global Impressions Scale (CGI-S) scores were stable or improved.³ Outcomes were more prominent in patients with moderate to severe depression symptoms at baseline (CDSS >6) than in the overall population.²
• Bipolar Disorder (6-month): Tohen et al (2025)⁴ conducted a 6-month OLE of a phase 3, 6-week, double-blind, placebo-controlled study to examine the long-term safety and tolerability of CAPLYTA 42 mg in patients with major depressive episodes (MDEs) associated with bipolar I or bipolar II disorder.
  • Overall, CAPLYTA was well tolerated, and there were no notable changes in EPS scores or cardiometabolic parameters.
  • There were improvements from baseline to day 175 (nominal P<0.0001) in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score, Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) Total score, CGI-BP-S depression subscore, and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) percent score.
• Major Depressive Disorder (6-month): Earley et al (2025)⁵ conducted a 6-month, phase 3, OLE study that examined the long-term safety and antidepressant effects of CAPLYTA 42 mg adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who had completed a phase 3, 6-week, double-blind, placebo-controlled study (study 501⁶ or 502⁷).
  • TEAEs, mostly mild or moderate in severity, were reported in 67.7% of patients, whereas serious adverse events (AEs) were reported in 1.0% of patients. There were no notable changes in EPS or metabolic parameters.
  • There was a clinically meaningful improvement in MADRS Total score: 79.5% of patients had a response, whereas 65.4% of patients had remission.

BACKGROUND

CAPLYTA is an atypical antipsychotic indicated for the 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 major depressive disorder in adults, as adjunctive therapy to antidepressants.⁸ The efficacy and safety of lumateperone have been demonstrated in phase 2⁹ and 3^6,7,10-12 studies. However, data on the long-term use of lumateperone are limited.

CLINICAL DATA

Schizophrenia

Correll et al (2020)¹ conducted an interim analysis of an open-label, long-term study to evaluate the safety and effectiveness of CAPLYTA in patients with stable symptoms of schizophrenia. Of the 602 patients who received CAPLYTA 42 mg for 12 months, 107 patients who completed 1 year of treatment were included in the interim analysis.

Results

Safety

• Weight decrease, dry mouth, headache, and diarrhea were TEAEs reported in ≥5% of patients. Most AEs were of mild or moderate severity.
• Most metabolic parameters, the mean prolactin level, the mean body weight, and mean body mass index (BMI) decreased from standard of care (SOC) baseline.
• CAPLYTA was associated with a low risk of EPS.

Efficacy

• The PANSS Total score decreased significantly from baseline, and PANSS score improvement continued throughout the study.
• In patients with a CDSS score of >5 (moderate to severe depression symptoms) at baseline, the mean CDSS score decreased from 7.4 at baseline to 3.1 on day 300.
  • By day 75, 60% of patients experienced 50% improvement from baseline, and this response rate was sustained through day 300.
  • The magnitude of CDSS improvement was similar regardless of the concurrent ADT.

Satlin et al (2019)² conducted an additional analysis of an open-label, long-term study to evaluate the safety and effectiveness of CAPLYTA in patients with stable symptoms of schizophrenia. Of the 602 patients with stable schizophrenia who were switched from standard of care antipsychotics to CAPLYTA 42 mg for up to 12 months, 239 patients who completed 1 year of treatment were included in the analysis.

Results

Safety

• Weight decrease, dry mouth, diarrhea, and headache were TEAEs reported in ≥5% of patients. Most TEAEs were of mild or moderate severity. The mean body weight showed a notable improvement on day 368; refer to Table: TEAEs and Changes in Body Weight.
• Mean cholesterol (total and low-density lipoprotein), prolactin levels, waist circumference, and BMI decreased from SOC baseline.
• CAPLYTA was associated with a low risk of EPS.

Efficacy

• There was a significant reduction in PANSS Total score from SOC baseline to day 368.
  • The mean change from baseline in PANSS score in the overall population was -4.0 (95% confidence interval [CI], -5.8 to -2.1; P<0.001).
  • The day 368 mean difference in the PANSS score in patients with moderate to severe depression symptoms at baseline (CDSS score >6) was -11.6 (95% CI, -20.2 to
    -3.0; P=0.01).
• There was a significant reduction in CDSS score from baseline to day 368.
  • The mean change from baseline in the CDSS score in the overall population was -0.6 (95% CI, -1.1 to -0.1; P=0.01).
  • In patients with moderate to severe depression symptoms at baseline, the mean CDSS score improved from 7.9 at baseline to 2.0 at day 368 (P<0.001).

Vanover et al (2019)³ conducted a 12-month open-label study to evaluate the long-term safety and tolerability of CAPLYTA in patients with stable symptoms of schizophrenia. All patients (N=603) received CAPLYTA 42 mg for up to 12 months.

Results

Safety

• CAPLYTA was well tolerated.
• There was a reduction in mean body weight from standard of care antipsychotic baseline and a favorable cardiometabolic and endocrine safety profile.
• There were no clinically relevant changes in EPS.

Efficacy

• Schizophrenia symptoms were stable or improved (assessed using PANSS and CGI-S).

Bipolar Disorder

Tohen et al (2025)⁴ conducted a 6-month OLE of a phase 3, 6-week, double-blind, placebo-controlled study to examine the long-term safety and tolerability of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder. Patients had completed the double-blind, randomized, placebo-controlled period of study 401, which consisted of 6 weeks of CAPLYTA 28 mg, CAPLYTA 42 mg, or placebo. A total of 127 patients received CAPLYTA 42 mg once daily for up to 175 days. The mean (standard deviation) CAPLYTA exposure was 127 (64.4) days.

Results

Safety

• During the study, 57.5% of patients experienced ≥1 TEAE (mostly mild to moderate), and 42.5% of patients experienced a drug-related TEAE; refer to Table: TEAEs and Changes in EPS Scales.
  • Headache, dry mouth, dizziness, and nausea were the most frequently reported TEAEs (≥10%).
  • Five patients (3.9%) experienced EPS-related TEAEs (akathisia, n=2; tremor, n=2; and musculoskeletal stiffness, n=1).
  • One patient had a TEAE of mania; however, there were no reports of hypomania.
• Overall, CAPLYTA was well tolerated; there were no notable changes in cardiometabolic parameters, and there were no electrocardiogram (ECG)-related TEAEs.

Efficacy

• There were improvements from baseline to day 175 (nominal P<0.0001) in MADRS Total score (mean change, -8.9), CGI-BP-S Total score (mean change, -2.3), CGI-BP-S depression subscore (mean change, -1.3), and Q-LES-Q-SF percent score (mean change, 9.0); refer to Figure: Mean Change From Baseline Based on Observed Cases in (a) MADRS Total Score, (b) CGI-BP-S Total Score, and (c) Q-LES-Q-SF Percent Score.

MDD, Adjunctive Therapy to Antidepressants

Earley et al (2025)⁵ conducted a 6-month, phase, 3 OLE study that examined the long-term safety and antidepressant effects of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had completed a phase 3, 6-week, double-blind, placebo-controlled study (study 501⁶ or 502⁷). Patients (N=809) received CAPLYTA 42 mg once daily for 26 weeks.

Results

Safety

• During the study, 67.7% of patients experienced ≥1 TEAE (mostly mild or moderate in severity), and 36.1% of patients experienced a drug-related TEAE; refer to Table: Adverse Events.
  • Headache, dizziness, dry mouth, nausea, somnolence, diarrhea, and nasopharyngitis were the most commonly reported TEAEs (≥5%).
  • There were no serious AEs related to suicidal behavior or suicidality during the study.

• There were no notable changes in cardiometabolic parameters or body morphology; refer to Table: Mean Change in Body Morphology, Cardiometabolic Parameters, and Prolactin From Baseline to End of Treatment During the OLE.

• There were no notable changes in EPS (assessed using clinician-rated scales).

Efficacy

• Improvement in depression symptoms in studies 501 and 502 continued into the OLE; refer to Figure: Assessment of Depression Symptoms: (A) Mean Change From Baseline in MADRS Total Score and (B) MADRS Response and Remission Rates.
  • There was a clinically meaningful improvement in depressive symptoms as assessed by MADRS: 79.5% of patients had a response, whereas 65.4% of patients had remission.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 8 September 2025.