Esketamine Use and Attempted Suicide or Intentional Self-Harm Among Individuals with Treatment-Resistant Depression: A Retrospective Cohort Study.
You Wang, Alexandra S Storaci, G Caleb Alexander, Jason B Gibbons
Drug safety September 2, 2026 DOI: 10.1007/s40264-026-01722-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Retrospective cohort study Longitudinal Peer reviewed |
|---|---|
| Sample size | 23,140 |
| Population | Adults with treatment-resistant depression initiating esketamine and matched controls from a U.S. administrative claims database |
| Intervention | Esketamine |
| Duration | Follow-up continued through month 18 |
| Topics | Depression Esketamine |
| Key findings | Current esketamine exposure was not associated with a statistically distinguishable difference in recorded nonfatal, medically attended suicide attempt or intentional self-harm (HR 1.017, 95% CI 0.670-1.544, p=0.938). The confidence interval remained compatible with both clinically meaningful benefit and harm. |
Abstract
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. 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. 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. 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). 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.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cites 17
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II) The International Journal of Neuropsychopharmacology August 26, 2020
- Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study Neuropsychopharmacology May 12, 2023
- Long-term safety of ketamine and esketamine in treatment of depression Expert Opinion on Drug Safety April 13, 2022
- Comparative Effectiveness of Intravenous Ketamine and Intranasal Esketamine in Clinical Practice Among Patients With Treatment-Refractory Depression: An Observational Study. The Journal of Clinical Psychiatry February 1, 2023
and 12 more in the library