Comparison of rTMS and esketamine for treatment-resistant depression: A target trial emulation

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.