SUMMARY

• Low sodium (<130 mEq/L) was a chemistry laboratory parameter that was evaluated as a potentially clinically significant (PCS) criteria in CAPLYTA clinical trials. Safety assessments also included treatment-emergent adverse events (TEAEs) for hyponatremia.^1-14 
• In 3 clinical trials for major depressive disorder (MDD), PCS low sodium was reported in 0.5-1.3% of patients treated with CAPLYTA+antidepressant therapy (ADT).^1-6 All decreases in sodium were transient and normalized with continued administration.¹⁵ There was 1 TEAE for hyponatremia reported in the open-label study (study 503). This TEAE was related to study drug, mild in severity, and resolved with continued administration.
• In 3 clinical trials for bipolar depression, PCS low sodium was reported in 0-2.3% of patients treated with CAPLYTA. There were no TEAEs for hyponatremia reported.^7-12 
• In a pooled analysis of 3 randomized, double-blind, placebo-controlled studies (studies 005, 301, and 302) looking at the safety and efficacy of CAPLYTA in schizophrenia, there were no reports of PCS low sodium in patients who received CAPLYTA 42 mg and no TEAEs for hyponatremia.^13,14
• There were no reports of syndrome of inappropriate antidiuretic hormone (SIADH) adverse events in CAPLYTA clinical trials across all indications (adjunctive major depressive disorder, bipolar I or II disorder, and schizophrenia).

PRODUCT LABELING

Geriatric Use

The use of serotonin reuptake inhibitors (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.¹⁶ 

CLINICAL DATA

Major Depressive Disorder

Study 501

Durgam et al (2025)​¹ conducted a 6-week, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose, phase 3 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 (CAPLYTA+ADT, n=241; placebo+ADT, n=243). In patients with available non-PCS baseline values and at least 1 postbaseline assessment (N₁), 3 patients (1.3%) receiving CAPLYTA+ADT (N₁=230) and no patients receiving placebo+ADT met the criteria for PCS low sodium.⁴

Study 502

Durgam et al (2025)² conducted a 6-week, randomized, double-blind, placebo-controlled, multicenter, international, phase 3 study to evaluate the efficacy and safety of CAPLYTA 42 mg adjunctive to ADT in patients with MDD who had an inadequate response to ADT (CAPLYTA+ADT, n=242; placebo+ADT, n=238). The number of patients who met the PCS criteria for low sodium was 1 patient (0.5%) receiving CAPLYTA+ADT (N₁=211) and 0 patients receiving placebo+ADT.⁵

Pooled Safety Analysis (Study 501 and Study 502)

In a pooled safety analysis, all decreases in sodium found in study 501 and study 502 were transient and normalized at subsequent laboratory assessment with continued drug administration. No TEAEs for hyponatremia were reported.¹⁵ 

Study 503

Earley et al (2025)⁶ ​presented a 26-week, open-label (OL) study 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 (N=809). The incidence of patients who met the PCS criteria for low sodium and received CAPLYTA+ADT was 0.5% (n=4/N₁=777) during the open-label treatment period (OLTP). One patient treated with CAPLYTA (N=809) had a TEAE of hyponatremia.³ The TEAE was related to study drug, mild in severity, and resolved with continued administration during the OLTP.¹⁵ 

Bipolar Depression

Study 401

Tohen et al (2025)⁷ reported the results of a 6-month OLE period of a phase 3 study that assessed the long-term safety of CAPLYTA 42 mg in patients with major depressive episodes (MDEs) associated with bipolar I or bipolar II disorder (N=127). CAPLYTA was administered once daily for up to 175 days; this was followed by a 2-week safety follow-up period. There were no reports of low sodium or TEAEs for hyponatremia in the open-label follow-up period.⁸ 

Study 402

Suppes et al (2023)⁹ conducted a phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of lumateperone adjunctive to lithium or valproate in patients with MDEs associated with bipolar I or bipolar II disorder (CAPLYTA 42 mg, n=177; lumateperone 28 mg, n=176; placebo, n=175). CAPLYTA was administered once daily for 6 weeks. Safety was assessed weekly and approximately 2 weeks after the last study dose. In patients who were reported to not have a markedly abnormal value at baseline and had at least 1 postbaseline value (N₁), PCS low sodium was reported in 4 patients (2.3%) receiving CAPLYTA 42 mg (N₁=173), 1 patient (0.6%) receiving lumateperone 28 mg (N₁=172), and 2 patients (1.2%) receiving placebo (N₁=173).¹⁰ There were no TEAEs for hyponatremia reported.

Study 404

Calabrese et al (2021)¹¹ conducted a phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of CAPLYTA 42 mg for the treatment of major depressive episodes associated with bipolar I and bipolar II disorders (CAPLYTA, n=188; placebo, n=189). Safety was assessed weekly and approximately 2 weeks after the last study dose. PCS low sodium was reported in 1 (0.5%) patient receiving CAPLYTA (N₁=187) and 1 (0.5%) patient receiving placebo (N₁=188).¹² There were no TEAEs for hyponatremia reported.

Schizophrenia

Pooled Safety Analysis (Study 005, Study 301, and Study 302)

Kane et al (2021)¹⁴ conducted a pooled analysis of 3 randomized, double-blind, placebo-controlled studies to assess the efficacy, safety, and tolerability of CAPLYTA 42 mg in patients with schizophrenia (CAPLYTA 42 mg, N=406; placebo, N=412; risperidone 4 mg, N=255). Patients were treated with CAPLYTA 42 mg once daily for 4 weeks in studies 005 and 301 and for 6 weeks in study 302. Safety was assessed at baseline, weekly on-treatment, and at the end of the study. Low sodium was not reported in patients who received CAPLYTA 42 mg and there were no TEAEs for hyponatremia.¹³ 

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 October 2025.