Neuroinflammation in Major Depressive Disorder: Mechanisms, Biomarkers, and Therapeutic Implications

Abstract

Background: Major depressive disorder (MDD) is heterogeneous, and low-grade systemic inflammation may contribute to illness in a clinically relevant subgroup. Methods: This narrative review examined human studies published between January 2010 and June 2026, prioritizing systematic reviews, meta-analyses, cohort studies, central biomarker research, and randomized trials. Results: Approximately one-quarter of patients with depression have CRP levels above 3 mg/L, supporting an inflammatory phenotype rather than a universal inflammatory model. Immune signals may affect brain function through blood–brain barrier, neural, neurovascular, and metabolic pathways, influencing neurotransmission, stress regulation, oxidative balance, and neuroplasticity. CRP is the most accessible clinical marker, but no biomarker reliably identifies inflammatory depression. Anti-inflammatory treatments show inconsistent benefits, with the strongest signals observed in biomarker-selected patients. Conclusion: Inflammation contributes to MDD in some patients, but single-marker diagnosis and routine anti-inflammatory treatment are not currently justified. Biomarker-stratified trials are needed to develop precision therapies.