Risk of manic switch and suicidal outcomes in bipolar depression treated with esketamine: A one-year retrospective cohort study of 2126 patients.

Objective: To evaluate the safety of esketamine in bipolar depression, focusing on suicide-related outcomes and manic switch across timeframe and demographic subgroups.

Methods: This retrospective cohort study was conducted in May 2025 using data from the TriNetX global collaborative network. Adults with bipolar depression treated with esketamine plus a mood stabilizer were propensity score-matched 1:1 to patients who received mood stabilizers alone. The primary outcomes were suicide-related events and manic switches across 1-7, 1-30, 1-90, 1-180, and 1-365 day intervals.

Results: After matching, 2126 patients (mean age, 47.0 years; 63 % female) were included. Esketamine use was associated with significantly lower risk of suicide-related outcomes at 1-7 days (hazard ratio [HR] = 0.439; 95 % CI, 0.256-0.753), 1-30 days (HR = 0.485; 95 % CI, 0.324-0.726), 1-90 days (HR = 0.641; 95 % CI, 0.456-0.901), and 1-365 days (HR = 0.754; 95 % CI, 0.577-0.985). Risk of manic switch was not increased and was significantly lower at 1-180 days (HR = 0.643; 95 % CI, 0.442-0.935) and 1-365 days (HR = 0.673; 95 % CI, 0.477-0.950). Subgroup analyses showed consistent suicide risk reduction across age, sex, and race. Female patients exhibited a significantly lower risk of manic switch at longer intervals, an effect not observed in males.

Conclusions: Our real-world study suggests that esketamine, when used alongside mood stabilizers, is a safe and potentially effective treatment for bipolar depression, demonstrating sustained anti-suicidal benefits without an increased risk of manic switch across both short- and long-term follow-up and across different patient subgroups.