SUMMARY

• Patients evaluated in three phase 3 clinical studies of CAPLYTA (Study 501, Study 502, and Study 503) as adjunctive therapy for major depressive disorder (MDD) continued their prior antidepressants during the study.^1-3 
  • The background antidepressants included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or bupropion.  
  • The most commonly used antidepressants were citalopram/escitalopram, sertraline, and venlafaxine/desvenlafaxine.^4-6 
• Patients evaluated in clinical studies of CAPLYTA for the treatment of bipolar depression and schizophrenia were required to stop any prior antidepressant use.^7-14 

PRODUCT LABELING

Indication

CAPLYTA is an atypical antipsychotic indicated for: treatment of schizophrenia in adults; treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate; and adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults.¹⁵ 

Drug Interactions

Although no clinically significant drug interactions with adjunctive SSRIs/SNRIs in MDD were observed in CAPLYTA clinical trials, CAPLYTA’s moderate serotonin transporter (SERT) activity may increase the risk of serotonin reuptake inhibitor (SRI)-associated adverse reactions (e.g., serotonin syndrome, hyponatremia).¹⁵ 

Geriatric Use

The use of SRIs has been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction. The concomitant use of CAPLYTA with an SRI may increase this risk.¹⁵ 

CLINICAL DATA

Major Depressive Disorder

Durgam et al (2025)¹ conducted a 6-week, randomized, double-blind, placebo-controlled, phase 3 study (Study 501, N=485) to assess the efficacy and safety of CAPLYTA 42 mg adjunctive to antidepressant therapy (ADT) in patients with MDD who had an inadequate response to 1 or 2 courses of ADT (defined as <50% improvement with ≥6 weeks of treatment). Eligible patients were 18 to 65 years with moderate to severe depression. Pertinent exclusion criteria included patients with a significant risk of suicidal behavior or lifetime history of treatment resistance to ≥3 approved treatments. Background ADT during the double-blind treatment period are listed in Table: Background ADT in Study 501 (Safety Population).

Durgam et al (2025)² conducted a 6-week, randomized, double-blind, placebo-controlled, international, phase 3 study (Study 502, N=480) to evaluate the efficacy and safety of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had an inadequate response to ADT. The inclusion and exclusion criteria were the same as Study 501. Background ADT during the double-blind treatment period are listed in Table: Background ADT in Study 502 (Safety Population).

Earley et al (2025)³ ​presented a 26-week, open-label study (Study 503, N=812) that evaluated the long-term safety and tolerability of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had completed Study 501 or 502. Background ADT during the open-label extension study are listed in Table: Background ADT in Study 503 (Safety Population).

Bipolar Depression

Correll et al (2025)⁷ and Calabrese et al (2021)⁸ conducted phase 3, randomized, double-blind, placebo-controlled studies (Study 401, N=554; and Study 404, N=381; respectively) to assess the efficacy and safety of CAPLYTA in adult patients with major depressive episodes (MDEs) associated with bipolar I or bipolar II disorder. To be eligible for either study, patients had to stop their current antidepressant or other psychotropic treatment.

Suppes et al (2023)⁹ conducted a phase 3, randomized, double-blind, placebo-controlled study (Study 402, N=529) to assess the efficacy and safety of CAPLYTA adjunctive to lithium or valproate in adult patients with MDEs associated with bipolar I or bipolar II disorder. Patients included in the study were required to stop their current antidepressant or other psychotropic treatment other than lithium or valproate.

Major Depressive Disorder or Bipolar Depression With Mixed Features

Durgam et al (2025)¹⁰ conducted a randomized, double-blind, placebo-controlled, multicenter study (N=388) to assess the efficacy and safety of CAPLYTA to treat MDEs associated with MDD or bipolar (I or II) disorder in adult patients with mixed features. Patients included in the study were required to stop their current antidepressant or other psychotropic treatment.¹³ 

Schizophrenia

Correll et al (2020)¹¹ and Lieberman et al (2016)¹² conducted randomized, double-blind, placebo-controlled studies (Study 301, N=450; and Study 005, N=335; respectively) to assess the efficacy and safety of CAPLYTA in adult patients with schizophrenia. Patients included in the study were required to stop any prior psychotropic treatment.^12,14 

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 December 2025.