Risk of manic switch and suicidal outcomes in bipolar depression treated with esketamine: A one-year retrospective cohort study of 2126 patients.
Tingting Liu, Jheng-Yan Wu, Po-Yu Huang, Wan-Lin Cheng, C. Lai
European Neuropsychopharmacology August 6, 2025 DOI: 10.1016/j.euroneuro.2025.07.006 via Semantic Scholar
Summary
Esketamine, when added to a mood stabilizer, is associated with a lower risk of suicide-related events in adults with bipolar depression and does not increase the risk of manic switch. In a matched analysis of 2,126 patients, those receiving esketamine had a significantly lower hazard of suicide-related outcomes across intervals from 1–7 days (HR = 0.439) through 1–365 days (HR = 0.754). The risk of manic switch was also lower at 1–180 days (HR = 0.643) and 1–365 days (HR = 0.673). Suicide risk reduction was consistent across age, sex, and racial subgroups, while the lower manic switch risk was significant only in female patients at longer intervals.
Study at a glance
| Characteristics | Retrospective cohort study Peer reviewed |
|---|---|
| Sample size | 2,126 |
| Population | Adults with bipolar depression treated with esketamine plus a mood stabilizer |
| Keywords | Medicine |
| Citations | 6 |
| Key finding | Esketamine plus a mood stabilizer was associated with a significantly lower risk of suicide-related events across all time intervals and a lower risk of manic switch at longer intervals, with no increased risk of manic switch overall. |
Abstract
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.