Peripheral Inflammatory Biomarkers as Predictors of Antidepressant Treatment Response in Major Depressive Disorder: An Updated Systematic Review and Meta-Analysis.

Abstract

Rationale Peripheral inflammatory biomarkers are potential predictors of antidepressant response in major depressive disorder (MDD). Objective This study updated a 2022 meta-analysis by extending the literature through January 2026 to clarify these biomarker-response associations. Methods PubMed was searched from February 2021 to January 2026. Eligible studies evaluated baseline peripheral biomarkers in adults with MDD before starting ⩾4 weeks of pharmacotherapy, comparing responders vs. non-responders. Standardized mean differences (SMD; Hedges' g) were pooled using random-effects models. Subgroup analyses and meta-regressions examined antidepressant class and publication period. Results Twenty-four studies (16 from the prior review, 8 new) were quantitatively analyzed. In primary pooled analyses, no baseline biomarkers (including CRP and IL-8) significantly differentiated responders from non-responders. However, exploratory analyses revealed a nominal interaction by publication period for IL-2 (p = 0.0112). In recent studies (2021-2026), baseline IL-2 was nominally lower in responders than non-responders (SMD = -0.81; 95% CI -1.59 to -0.03; p = 0.04). Similarly, in recent studies restricted to Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin-norepinephrine reuptake inhibitors (SNRIs), baseline IL-6 was nominally lower among responders (SMD = -0.37; 95% CI -0.69 to -0.05; p = 0.02). Leave-one-out analyses confirmed overall robustness, though IL-6 showed moderate sensitivity. Conclusion While individual baseline biomarkers have limited utility as standalone predictors when pooling all historical data, lower baseline IL-2 and IL-6 emerge as promising signals for predicting treatment response in contemporary studies (2021-2026) and specific antidepressant classes (SSRIs/SNRIs).