SUMMARY

• A pooled analysis of 3 randomized, double-blind, placebo-controlled studies assessed the safety and tolerability of CAPLYTA 42 mg in the treatment of schizophrenia.¹ 
  • Based on a narrow standard Medical Dictionary for Regulatory Activities (MedDRA) query, the rates of extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) with CAPLYTA, placebo, and risperidone were 3%, 3.2%, and 6.3%, respectively.¹
  • The mean change in EPS from the baseline value to the last on-treatment value in patients receiving CAPLYTA, risperidone, and placebo, respectively, was 0.1, 0.1, and 0 for the Simpson-Angus Scale (SAS) score; -0.1, 0.1, and 0 for the Barnes Akathisia Rating Scale (BARS) Total score; and 0.1, 0.1, and 0 for the Abnormal Involuntary Movement Scale (AIMS) score.²
• A 6-week, open-label (OL), switching study assessed the short-term safety and tolerability of CAPLYTA 42 mg in outpatients with stable schizophrenia who had transitioned from a prior antipsychotic therapy.³
  • TEAEs related to EPS were reported in 1% of the population, and akathisia was reported in 1 patient (0.3%).
• A 4-week, phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of CAPLYTA in patients with schizophrenia.⁴
  • No EPS-related TEAEs occurred in ≥5% of patients in any group.
• A 2-week, OL, positron emission tomography (PET) study evaluated the dopamine D₂ receptor occupancy (D₂RO) at plasma steady state with CAPLYTA 42 mg daily in the morning after at least a 2-week washout period from standard-of-care antipsychotics in patients with schizophrenia.⁵
  • There were no adverse event reports of akathisia or other EPS.
• A 6-week, phase 3, randomized, double-blind, placebo-controlled, outpatient, multicenter study assessed the efficacy and safety of CAPLYTA in patients with major depressive episodes (MDEs) associated with bipolar I or bipolar II disorder.⁶
  • Based on a narrow standard MedDRA query, the only EPS-related TEAEs were 2 cases of akathisia: n=1 each in the CAPLYTA 28 mg and placebo groups.
• A 6-month, open-label extension (OLE) of a phase 3 study assessed the long-term safety and tolerability of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder.⁷
  • Based on a broad standard MedDRA query, EPS-related TEAEs were reported in 5 patients (3.9%), with akathisia and tremor reported in 2 patients each (1.6%) and musculoskeletal stiffness reported in 1 patient (0.8%).
• A 6-week, phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of CAPLYTA (28 or 42 mg) as adjunctive treatment to lithium or valproate in patients with MDEs associated with bipolar I or bipolar II disorder.⁸
  • Based on a broad standard MedDRA query, EPS-related TEAEs reported with CAPLYTA 42 mg, CAPLYTA 28 mg, and placebo were 4%, 2.8%, and 2.3%, respectively.
  • Mean changes in EPS from baseline to the end of treatment in patients receiving CAPLYTA 42 mg, CAPLYTA 28 mg, and placebo, respectively, were 0, 0, and 0 for the SAS score; 0, -0.1, and -0.1 for the BARS score; and 0, 0, and 0 for the AIMS score.⁹
• A 6-week, phase 3, randomized, double-blind, placebo-controlled, multinational study evaluated the efficacy and safety of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder.¹⁰
  • No significant changes from baseline were reported in either group for BARS score, AIMS score, or SAS score.
• A study analyzed the incidence of EPS across short- and long-term studies of CAPLYTA 42 mg in patients with bipolar depression.¹¹
  • In the short-term studies, EPS-related TEAEs reported were mild dyskinesia with CAPLYTA monotherapy (n=1; 0.3%), mild akathisia with adjunctive CAPLYTA (n=1; 0.6%), and severe akathisia with placebo in monotherapy trials (n=1; 0.3%).
  • In the long-term population, the EPS-related TEAE of akathisia (mild and moderate severity) was reported in 2 patients (1.6%).
• A 6-week, randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of CAPLYTA 42 mg in patients with MDEs associated with major depressive disorder (MDD) or bipolar depression with mixed features.¹²
  • Based on a narrow standard MedDRA query, the only EPS-related TEAE was mild akathisia reported in 1 patient with MDD in the CAPLYTA 42 mg group.
  • Based on a broad standard MedDRA query, the incidence of EPS-related TEAEs in the combined MDD/bipolar depression population was 8 (4.2%) and 2 (1.0%) in the CAPLYTA 42 mg and placebo groups, respectively.
• A 6-week, phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study assessed the efficacy and safety of CAPLYTA 42 mg adjunctive to antidepressant therapy (ADT) in patients with MDD who had an inadequate response to ADT.¹³
  • Based on a broad standard MedDRA query, EPS-related TEAEs reported with CAPLYTA+ADT and placebo+ADT were 6.2% and 2.9%, respectively.
  • Mean changes in EPS from baseline to the end of treatment in patients receiving CAPLYTA+ADT and placebo+ADT, respectively, were 0.0 and 0.0 for the SAS Total score, 0.0 and 0.0 for the BARS Total score, and 0.0 and 0.0 for the AIMS Total score.¹⁴
• A 6-week, phase 3, randomized, double-blind, placebo-controlled, multicenter, international study evaluated the efficacy and safety of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had an inadequate response to ADT.¹⁵
  • Based on a broad standard MedDRA query, EPS-related TEAEs reported with CAPLYTA+ADT and placebo+ADT were 5.4% and 0.4%, respectively.
  • Mean changes in EPS from baseline in patients receiving CAPLYTA and placebo, respectively, were 0.0 and 0.0 for the SAS Total score, 0.0 and -0.1 for the BARS Total score, and 0.0 and 0.0 for the AIMS Total score.
• A 26-week, OL study evaluated the long-term safety and tolerability of CAPLYTA 42 mg as adjunctive therapy to ADT in adult patients with MDD who had completed study 501 or 502.¹⁶
  • EPS-related TEAEs were reported in 5 patients (0.6%) and 31 patients (3.8%) based on narrow and broad standard MedDRA queries, respectively.
  • Minimal changes were noted in postbaseline EPS scores.
• A pooled analysis of studies 501 and 502 evaluated the safety and tolerability of CAPLYTA 42 mg adjunctive to ADT in patients with MDD with inadequate ADT response.¹⁷
  • No notable changes in EPS, as assessed by the AIMS, BARS, and SAS, were reported.

CLINICAL DATA

Schizophrenia

Kane et al (2021)¹ conducted a pooled analysis of 3 randomized, double-blind, placebo-controlled studies (studies 005, 301, and 302) to assess the safety and tolerability of CAPLYTA 42 mg in the treatment of schizophrenia (CAPLYTA 42 mg, n=406; risperidone 4 mg, n=255; placebo, n=412). Patients were treated with CAPLYTA once daily for 4 weeks in studies 005 and 301 and for 6 weeks in study 302. Safety was assessed at baseline, weekly (while on treatment), and at the end of the study.

• Based on a narrow standard MedDRA query, rates of EPS-related TEAEs with CAPLYTA, placebo, and risperidone were 3%, 3.2%, and 6.3%, respectively.
  • EPS-related TEAEs reported in the CAPLYTA 42 mg group were akathisia (n=8; 2%), dystonia (n=2; 0.5%), and tardive dyskinesia (n=2; 0.5%).² 
• Mean changes in EPS from baseline to the last on-treatment value in patients receiving CAPLYTA, risperidone, and placebo, respectively, were 0.1, 0.1, and 0 for the SAS score; -0.1, 0.1, and 0 for the BARS Total score; and 0.1, 0.1, and 0 for the AIMS score.

Correll et al (2021)³ conducted a 6-week, OL, switching study to assess the short-term safety and tolerability of CAPLYTA 42 mg in outpatients with stable schizophrenia who had transitioned from a prior antipsychotic therapy (N=301). The study included a 2-week safety follow-up period during which the patients were switched back to previous or another approved antipsychotic.

• TEAEs related to EPS were reported in 1% of the population, and akathisia was reported in 1 patient (0.3%).
• Mean (standard deviation) changes from baseline to day 42 in BARS Total, BARS Global, AIMS Total, and SAS Total scores are summarized in Table: Changes in EPS Assessment Scales.¹⁸ 

Correll et al (2020)⁴ conducted a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of CAPLYTA in patients with schizophrenia. Patients were randomized (1:1:1) to receive CAPLYTA 42 mg (n=150), CAPLYTA 28 mg (n=150), or placebo (n=149) for 4 weeks. Approximately 2 weeks after the last dose of study medication, a follow-up safety assessment was performed.

• No EPS-related TEAEs occurred in ≥5% of patients in any group; see Table: Incidence of EPS-Related TEAEs.

Vanover et al (2019)⁵ conducted a 2-week, OL, PET study to evaluate the D₂RO at plasma steady state with CAPLYTA 42 mg daily in the morning after at least a 2-week washout period from standard-of-care antipsychotics in patients with schizophrenia (N=10).

• There were no adverse event reports of akathisia or other EPS.

Bipolar Disorder

Correll et al (2025)⁶ conducted a 6-week, phase 3, randomized, double-blind, placebo-controlled, outpatient, multicenter study to assess the efficacy and safety of CAPLYTA in patients with MDEs associated with bipolar I or bipolar II disorder. Patients were randomized (1:1:1) to receive CAPLYTA 42 mg (n=185), CAPLYTA 28 mg (n=183), or placebo (n=186); the final safety follow-up visit was scheduled approximately 2 weeks after the last dose of study medication.

• Based on a narrow standard MedDRA query, the only EPS-related TEAEs were 2 cases of akathisia: n=1 each in the CAPLYTA 28 mg and placebo groups.
• Based on a broad standard MedDRA query, the number of patients with EPS-related TEAEs in the CAPLYTA 42 mg, CAPLYTA 28 mg, and placebo groups were 2 (1.1%), 6 (3.3%), and 2 (1.1%), respectively.
• Changes in EPS-related scale scores are summarized in Table: Changes in EPS-Related Scale Scores from Baseline to EOT.

Tohen et al (2025)⁷ conducted a 6-month OLE of a phase 3 study assessing the long-term safety and tolerability of CAPLYTA 42 mg in patients with MDEs associated with bipolar I or bipolar II disorder (N=127).

• Based on a broad standard MedDRA query, EPS-related TEAEs were reported in 5 patients (3.9%), with akathisia and tremor reported in 2 patients each (1.6%) and musculoskeletal stiffness reported in 1 patient (0.8%).
• Mean (standard error) changes from baseline to day 175 or end of treatment were -0.1 (0.05) for the SAS Total score, -0.0 (0.05) for the BARS Total score, and -0.0 (0.01) for the AIMS Total score (N=116).

Suppes et al (2023)⁸ conducted a 6-week, phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of CAPLYTA (28 or 42 mg) as adjunctive treatment to lithium or valproate in patients with MDEs associated with bipolar I or bipolar II disorder (CAPLYTA 42 mg, n=177; CAPLYTA 28 mg, n=176; placebo, n=176). In addition to weekly safety assessments, a safety assessment was also performed ~2 weeks after the last study dose.

• Based on a broad standard MedDRA query, EPS-related TEAEs reported with CAPLYTA 42 mg, CAPLYTA 28 mg, and placebo were 4%, 2.8%, and 2.3%, respectively.
  • According to a narrow standard MedDRA query, the only EPS-related TEAE was mild akathisia, reported in 1 patient (0.6%) in each CAPLYTA group.
• Mean changes in EPS from baseline to the end of treatment in patients receiving CAPLYTA 42 mg, CAPLYTA 28 mg, and placebo, respectively, were 0, 0, and 0 for the SAS score; 0, -0.1, and -0.1 for the BARS score; and 0, 0, and 0 for the AIMS score.⁹ 

Calabrese et al (2021)¹⁰ conducted a phase 3, randomized, double-blind, placebo-controlled, multinational study to evaluate 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) to receive either CAPLYTA 42 mg (n=188) or placebo (n=189) for 6 weeks; the final safety follow-up visit occurred approximately 2 weeks after the last dose of study medication.

• No significant changes from baseline were reported in either group for BARS score, AIMS score, or SAS score.
• One case of mild dyskinesia (0.5%) in the CAPLYTA 42 mg group was the only EPS-related TEAE, which started on day 43 and was deemed related to CAPLYTA treatment.

Escher et al (2022)¹¹ presented the results of an analysis of the incidence of EPS across short- and long-term studies of CAPLYTA 42 mg in patients with bipolar depression. The short-term safety population comprised 746 patients from pooled monotherapy studies (CAPLYTA 42 mg, n=372; placebo, n=374) and 352 patients from adjunctive therapy with lithium or valproate studies (adjunctive CAPLYTA 42 mg, n=177; adjunctive placebo, n=175), and the long-term OLE safety population comprised 127 patients.

• In the short-term studies, EPS-related TEAEs reported were mild dyskinesia with CAPLYTA monotherapy (n=1; 0.3%), mild akathisia with adjunctive CAPLYTA (n=1; 0.6%), and severe akathisia with placebo in monotherapy trials (n=1; 0.3%).
• Mean changes from baseline in the AIMS, BARS, and SAS scores were similar across groups for both monotherapy and adjunctive therapy studies.
• In the long-term population, the EPS-related TEAE of akathisia (mild and moderate severity) was reported in 2 patients (1.6%).

Major Depressive Disorder or Bipolar Depression with Mixed Features

Durgam et al (2025)¹² conducted a 6-week, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of CAPLYTA 42 mg 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.

• Based on a narrow standard MedDRA query, the only EPS-related TEAE was mild akathisia reported in 1 patient with MDD in the CAPLYTA 42 mg group.
• Based on a broad standard MedDRA query, the incidence of EPS-related TEAEs in the combined MDD/bipolar depression population was 8 (4.2%) and 2 (1.0%) in the CAPLYTA 42 mg and placebo groups, respectively.
• No meaningful changes from baseline were reported in either group for BARS score, AIMS score, or SAS score; see Table: Mean Change in EPS-Related Scales at EOT (Safety Population).

Major Depressive Disorder

Durgam et al (2025)¹³ conducted a phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study to assess the efficacy and safety of CAPLYTA adjunctive to ADT in patients with MDD who had an inadequate response to ADT (CAPLYTA 42 mg, n=242; placebo, n=243). CAPLYTA was administered once daily for 6 weeks; this was followed by a 1-week safety follow-up period.

• Based on a broad standard MedDRA query, EPS-related TEAEs reported with CAPLYTA+ADT and placebo+ADT were 6.2% and 2.9%, respectively.
  • Tremor was reported in 12 patients in the CAPLYTA+ADT group and 1 patient in the placebo+ADT group.
• Mean changes in EPS from baseline to the end of treatment in patients receiving CAPLYTA+ADT and placebo+ADT, respectively, were 0.0 and 0.0 for the SAS Total score, 0.0 and 0.0 for the BARS Total score, and 0.0 and 0.0 for the AIMS Total score.¹⁴  

A phase 3, randomized, double-blind, placebo-controlled, multicenter, international study evaluated the efficacy and safety of CAPLYTA adjunctive to ADT in patients with MDD who had an inadequate response to ADT (CAPLYTA 42 mg, n=242; placebo, n=238). CAPLYTA was administered once daily for 6 weeks; this was followed by a 1-week safety follow-up period.¹⁵

• Based on a broad standard MedDRA query, EPS-related TEAEs reported with CAPLYTA+ADT and placebo+ADT were 5.4% and 0.4%, respectively.
• Mean changes in EPS from baseline in patients receiving CAPLYTA and placebo, respectively, were 0.0 and 0.0 for the SAS Total score, 0.0 and -0.1 for the BARS Total score, and 0.0 and 0.0 for the AIMS Total score.

A 26-week, OL study evaluated the long-term safety and tolerability of CAPLYTA 42 mg as adjunctive therapy to ADT in adult patients with MDD (N=809) who had completed study 501 or 502.¹⁶ 

• EPS-related TEAEs were reported in 5 patients (0.6%) and 31 patients (3.8%) based on narrow and broad standard MedDRA queries, respectively.
• Minimal changes were noted in postbaseline EPS scores at the end of the OL treatment period.
• The incidence of EPS-related TEAEs and changes in postbaseline EPS scores are summarized in Table: Incidence of EPS-related TEAEs and Changes from Baseline to the End of the OLTP in EPS Scores (Safety Population, Final Analysis).

Kozauer et al (2024)¹⁷ presented a pooled analysis of studies 501 and 502 that evaluated the safety and tolerability of CAPLYTA 42 mg adjunctive to ADT in patients with MDD with inadequate ADT response. The pooled safety population included 964 patients (CAPLYTA+ADT, n=483; placebo+ADT, n=481).

• No notable changes in EPS, as assessed by the AIMS, BARS, and SAS, were reported.
• Changes in EPS, as assessed by the AIMS, BARS, and SAS, as well as EPS-related TEAEs, are summarized in Table: Extrapyramidal Symptoms.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 15 September 2025.