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.
A target trial simulation using real-world data suggests that esketamine, when added to standard antidepressant treatment, maintains effectiveness and safety over a sustained period for people with major depressive disorder. The analysis, designed to mimic a randomized trial, found that patients receiving esketamine showed continued improvement in depressive symptoms without unexpected safety concerns. The findings support the long-term use of esketamine as a treatment option for major depressive disorder.