Preliminary evidence that serum interleukin-6 is a candidate biomarker of response to esketamine in treatment-resistant depression

BACKGROUND: Interleukin-6 (IL-6) has been implicated as a potential predictor of ketamine response in treatment-resistant depression (TRD). Esketamine, the S-enantiomer of ketamine, produces rapid antidepressant effects and offers improved safety and intranasal administration. OBJECTIVE: To examine whether baseline IL-6 predicts treatment response to esketamine in individuals with TRD. METHODS: Fourteen adults with TRD received intranasal esketamine twice weekly for 4 weeks, followed by a tapering phase, in a 24-week open-label Phase 2 trial. Depression severity and functional disability were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and World Health Organization Disability Assessment Schedule at baseline, week 8, and week 24. Serum IL-6 levels were measured at the same time points. Linear mixed-effects models were used to evaluate the predictive value of IL-6. RESULTS: MADRS scores improved significantly over time. Higher IL-6 levels were associated with more rapid symptom reduction, whereas lower IL-6 predicted greater symptom severity and higher disability. IL-6 levels did not change significantly over the course of treatment. CONCLUSIONS: Baseline IL-6 may predict response to esketamine in TRD, highlighting the potential role of inflammation in treatment resistance and supporting biomarker-guided personalized interventions.