Higher Neutrophil-to-Lymphocyte Ratio Is Associated With Better Response to Esketamine in Treatment-Resistant Depression

BACKGROUND: Growing evidence links inflammation with major depressive disorder (MDD) and treatment resistance. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a simple peripheral marker of systemic inflammation and immune balance and it may capture clinically meaningful heterogeneity in inflammatory burden, potentially contributing to variability in antidepressant response and vulnerability to treatment resistance. This study exploratively investigated whether baseline NLR values are associated with clinical response in patients with treatment-resistant depression (TRD) treated with intranasal esketamine in routine clinical practice. METHODS: This retrospective observational study included patients with TRD treated with adjunctive intranasal esketamine at the Mood Disorder Unit of San Raffaele Hospital (Milan, Italy). Baseline NLR was calculated from complete blood count samples collected 1 to 7 days before treatment initiation. Clinical outcome was assessed after 7 months using the Clinical Global Impression-Improvement scale (CGI-I). Patients were classified as responders (CGI-I ≤2) or non-responders (CGI-I ≥3). An analysis of covariance (ANCOVA) was conducted to examine differences in baseline NLR while adjusting for age. RESULTS: The final sample included 16 patients (8 responders and 8 non-responders). Responders showed higher baseline NLR values compared with non-responders (1.81±0.81 vs. 1.23±0.29). After controlling for age, baseline NLR differed significantly between the 2 outcome groups (P=0.003). CONCLUSIONS: Higher baseline NLR was associated with sustained clinical improvement after 6 months of esketamine treatment in patients with TRD. Although preliminary and limited by the small sample size and retrospective design, these findings suggest that a patient's inflammatory status at baseline may affect their treatment response. Larger prospective studies are needed to clarify the role of inflammatory markers as predictors of response to esketamine.