The Role of Inflammatory Markers as Predictors of Response to Antidepressants in Major Depressive Disorder: A...

Major depressive disorder (MDD) is a leading cause of global disability, with fewer than half of patients achieving remission following first-line antidepressant treatment. Inflammatory processes have been implicated in MDD, but the extent to which baseline inflammatory markers predict treatment outcomes remains uncertain, particularly given potential confounding and bidirectional relationships. We conducted a systematic review and meta-analysis following the PRISMA 2020 statement, searching PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and PsycINFO from January 1995 to December 2025. Eligible studies included adults with MDD who had at least one baseline inflammatory biomarker measured prior to antidepressant treatment and reported response or remission outcomes. Random-effects meta-analysis (DerSimonian-Laird) was used to estimate pooled ORs for nonresponse in individuals with elevated versus normal inflammatory markers. Risk of bias was assessed using Cochrane Risk of Bias 2.0 (RoB 2) and Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tools. Seventeen studies (n = 1,535 participants) were included. Elevated baseline inflammatory markers were associated with increased odds of antidepressant nonresponse (pooled OR = 2.11; 95% CI: 1.84-2.43; p < 0.001; I² = 15%). Subgroup analyses suggested that CRP, particularly at thresholds around ≥3 mg/L, showed the most consistent association (OR = 2.47; 95% CI: 1.96-3.11). However, definitions of "elevated" inflammation varied substantially across studies, and important confounders (e.g., obesity, smoking, and metabolic conditions) were not consistently adjusted for. The evidence base included both randomized and observational studies, and no prospective biomarker-guided treatment trials were identified. Elevated baseline inflammatory markers are associated with a higher likelihood of antidepressant nonresponse in MDD, but this relationship is correlational and may reflect confounding or reverse causality. Current evidence does not support routine clinical use of inflammatory markers for treatment selection. These findings are hypothesis-generating and highlight the need for prospective, biomarker-guided studies to determine whether inflammation can meaningfully inform antidepressant treatment strategies.