Fast-acting approaches for treatment-resistant depression: real-world comparative effectiveness of Intranasal Esketamine versus accelerated rTMS

Background: Treatment-Resistant Depression (TRD) often persists despite adequate pharmacotherapy. Intranasal Esketamine and accelerated repetitive Transcranial Magnetic Stimulation (aTMS) are rapid-acting options, but head-to-head comparisons remain limited. Methods: We conducted a retrospective study on TRD patients receiving either aTMS (n = 18) or Intranasal Esketamine (n = 22). Depression severity (Montgomery-Asberg Depression Rating Scale, MADRS) was assessed at baseline and 1, 3, and 6 months. Primary outcomes were response (≥50% MADRS reduction) and remission (MADRS <10). Longitudinal change was modelled with linear mixed-effects; moderators included clinical and demographics features. Results: At 1 month, aTMS showed higher response (72.2% vs 20%; p < 0.001) and remission (66.6% vs 10%; p = 0.0031) than Esketamine. Between-group differences were not significant at 3 months or 6 months. Mixed-effects models showed greater MADRS reduction with aTMS at 1 (p < 0.001) and 3 months (p = 0.007), but not at 6 months (p = 0.057). Psychiatric comorbidities were associated with greater improvement at 3 and 6 months within the Esketamine subgroup, with no analogous association in the aTMS subgroup. Conclusions: aTMS showed a stronger early antidepressant effect, but its advantage over esketamine progressively diminished and was no longer evident at six months. Prospective, well-powered comparative trials are required to validate these findings.