Comparing transcranial magnetic stimulation and esketamine treatment response trajectories in resistant depression

Objective Repetitive transcranial magnetic stimulation (rTMS) and intranasal esketamine are FDA-approved for treatment-resistant depression (TRD), yet comparative real-world data on response trajectories and predictors of outcomes remain limited. Methods A retrospective analysis was performed using electronic medical records from UC San Diego Health. Adults with TRD treated with rTMS ( n = 279) or intranasal esketamine ( n = 93) between 2017 and 2025 were included. The primary outcome was clinical response (≥50% PHQ-9 reduction). Time-to-response was assessed using inverse probability treatment weighted (IPTW) Cox models; Kaplan-Meier curves and log-rank tests provided descriptive comparisons. Covariates included age, trauma history, anxiety comorbidity, benzodiazepine use, tobacco use history, BMI, and baseline symptom severity. Secondary outcomes included remission (PHQ-9 < 5) and suicidal ideation (SI). Results Esketamine demonstrated earlier response over 90 days (RMST difference = −11.94 days) and faster time-to-response in the IPTW Cox model (HR = 1.62, p = 0.005); KM estimates showed median response at 36 vs. 49 days ( p = 0.0096) with convergence by ~90 days. Cumulative response and remission rates were numerically higher for esketamine (68.8% / 45.2%) than rTMS (59.4% / 40.1%), supporting a speed-of-response difference rather than superior overall efficacy. SI improved more rapidly with esketamine (median 9 vs. 26 days; p = 0.001). In the rTMS cohort, comorbid anxiety (HR = 0.69, p = 0.039) and benzodiazepine use (HR = 0.73, p = 0.046) predicted slower response, while former tobacco use predicted faster response (HR = 1.31, p = 0.006). No significant predictors emerged for esketamine. Conclusions Esketamine was associated with earlier observed antidepressant and anti-suicidal improvement than rTMS. Baseline factors, including benzodiazepine use, may help inform expectations regarding rTMS response trajectory.