Functional outcomes with esketamine in treatment-resistant depression: A 6-month multicenter real-world study

Background. Esketamine has demonstrated efficacy in treatment-resistant depression (TRD), but medium-term real-world functional outcomes remain understudied. This study described 6-month depressive symptom and functional trajectories during routine esketamine treatment, focusing on functional outcomes and remission correlates. Methods. In this prospective multicenter study, 60 patients with TRD initiating intranasal esketamine augmentation were assessed at baseline, Month 1, Month 3, and Month 6 using the Montgomery-Åsberg Depression Rating Scale (MADRS) and Sheehan Disability Scale (SDS). Mixed-effects models, Turnbull interval-censored time-to-remission analysis, logistic regression, and ROC analyses were performed. Results. MADRS and SDS improved significantly at all follow-up timepoints (p < 0.001). At Month 6, symptomatic response and remission rates were 78.3% and 46.7%, while functional response and remission rates were 78.3% and 33.3%. Turnbull estimates showed cumulative functional remission rates of 5.0%, 15.0%, and 33.3% at Months 1, 3, and 6, respectively. MADRS-SDS correlations decreased over time, supporting partial symptomatic-functional dissociation. Higher baseline SDS (OR = 0.73, 95% CI 0.59–0.89) and more previous antidepressant trials (ADTs; OR = 0.53, 95% CI 0.35–0.82) were associated with lower odds of Month 6 functional remission; bootstrap internal validation supported coefficient stability. ROC-derived thresholds were considered sample-dependent and not clinically validated. Cumulative esketamine dosage was associated with functional response, but not remission. Conclusions. Depressive symptoms and functioning improved progressively over 6 months during esketamine treatment in routine clinical care. Functional remission followed a slower trajectory than symptomatic remission and had partly distinct correlates, supporting functional monitoring as a distinct TRD outcome.