Comparison of rTMS and esketamine for treatment-resistant depression: A target trial emulation.
Jen-Ping Chen, Chih-Wei Hsu, Yi-Ting Chen, Yi-Ya Fang, Ping-Tao Tseng, Mu-Hong Chen, Yu-Chen Kao, Tien-Wei Hsu, Chih-Sung Liang
Journal of Affective Disorders April 15, 2026 DOI: 10.1016/j.jad.2025.121132 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 3,380 |
| Population | Adults aged 18-65 years with treatment-resistant depression |
| Interventions | repetitive transcranial magnetic stimulation (rTMS) esketamine |
| Duration | First year (with 30-90-day interval analysis) |
| Topics | Depression Esketamine |
| Keywords | Target trial emulation |
| Key findings | rTMS was associated with a lower risk of hospitalization, arrhythmia, and any injury compared to esketamine, while suicide-related outcomes were broadly comparable except for a protective effect of esketamine during the 30-90-day interval and among patients aged 45-65 years. |
Abstract
Repetitive transcranial magnetic stimulation (rTMS) and esketamine are FDA-approved treatments for treatment-resistant depression (TRD), yet head-to-head comparative effectiveness data remain limited. Our study compared the effectiveness and safety profiles of rTMS versus esketamine in adults with TRD. This cohort study used target trial emulation with 1:1 propensity score matching on 50 covariates using de-identified electronic health records from TriNetX US Collaborative Network. Adults aged 18-65 years with TRD who initiated rTMS or esketamine between March 2019 and September 2025 were included. After matching, 1690 patients remained in each cohort. Overall, rTMS was associated with a higher, but not statistically significant, risk of suicide-related outcomes compared to esketamine (reported as hazard ratio with 95 % confidence interval: 1.199, 0.943-1.526), while the 30-90-day interval was statistically significant (1.496, 1.031-2.170). For safety outcomes, rTMS was associated with a lower risk of hospitalization than esketamine (0.746, 0.646-0.861), lower risks of arrhythmia (0.677, 0.485-0.943) and any injury (0.745, 0.627-0.885), which attenuated over longer follow-up. The risk differences of hypertension and seizure were not statistically significant. In subgroup analyses, esketamine's protective association against suicide was more evident among patients aged 45-65 years, whereas the safety advantages of rTMS were particularly evident in males. rTMS was associated with fewer medical complications, suggesting a more favorable overall medical safety profile over the first year. Suicide-related outcomes were broadly comparable overall, although esketamine showed an advantage during the 30-90-day interval and among patients aged 45-65 years, which should be interpreted cautiously.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cites 11
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- 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 Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. American Journal of Psychiatry March 1, 2025
- Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. International Journal of Molecular Sciences December 5, 2024
- Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry July 2, 2025
and 6 more in the library