Esketamine Use and Attempted Suicide or Intentional Self-Harm Among Individuals with Treatment-Resistant Depression: A Retrospective Cohort Study.

BACKGROUND: Treatment-resistant depression (TRD) is associated with elevated suicide risk, but real-world evidence on whether esketamine reduces suicide attempts and intentional self-harm remains limited. OBJECTIVE: The aim was to estimate whether current esketamine exposure was associated with a higher or lower risk of recorded nonfatal, medically attended suicide attempt or intentional self-harm among adults with TRD using a large, real-world administrative claims database. METHODS: We conducted a retrospective cohort study using a nationwide, multipayer administrative claims database from January 2015 through June 2025. Among 1,574,657 adults eligible for matching, patients initiating esketamine after TRD were matched to up to three controls using risk-set propensity score matching. A marginal structural model combined a baseline esketamine treatment probability weight accrued from TRD to index with longitudinal inverse probability of treatment weights. Follow-up continued through month 18. RESULTS: The final cohort of complete 3:1 matched sets included 23,140 patients, comprising 5785 treated patients and 17,355 controls, who contributed 295,137 patient-months. Current esketamine exposure was not associated with a statistically distinguishable difference in recorded nonfatal, medically attended suicide attempt or intentional self-harm. The hazard ratio (HR) was 1.017, the 95% confidence interval (CI) was 0.670-1.544, and p = 0.938. In the within-treated analysis, the pooled current-exposure HR was 0.718 (95% CI 0.456-1.130; p = 0.152). In the secondary full-cohort analysis, the estimate per additional cumulative exposed calendar month was 1.039 (95% CI 0.999-1.081; p = 0.057) and the carryover joint test was nonsignificant (p = 0.893). CONCLUSIONS: Current esketamine exposure was not associated with a statistically distinguishable difference in recorded nonfatal, medically attended suicide attempt or intentional self-harm. The CI remained compatible with clinically meaningful benefit and harm.