Neuroinflammatory Mechanisms in Treatment-Resistant Depression: A Systematic Review

Abstract

Treatment-resistant depression TRD defined as the failure to achieve an adequate response after at least two antidepressant trials of sufficient dose and duration affects nearly one-third of patients with major depressive disorder MDD and emerging evidence implicates dysregulated neuroinflammatory processes in its pathophysiology, potentially explaining the limited efficacy of conventional monoamine-based therapies. This systematic review synthesizes current evidence on neuroinflammatory mechanisms in TRD, focusing on peripheral inflammatory biomarkers, central microglial activation, blood-brain barrier dysfunction, and the therapeutic implications of targeting inflammation. A comprehensive search of PubMed MEDLINE, PsycINFO, Embase the Cochrane Library and Web of Science identified studies published between January 2005 and December 2025 reporting inflammatory biomarkers, neuroimaging findings, or anti-inflammatory interventions in adults with TRD or MDD with inflammatory subgroup analyses, and study quality assessed using the Newcastle Ottawa Scale, the Cochrane Risk of Bias 2 tool, and the GRADE framework. A total of 23 studies met the inclusion criteria, including observational studies, randomized controlled trials, neuroimaging studies, translational studies, and theoretical reviews, with consistent findings showing elevated levels of interleukin 6 (IL-6), C-reactive protein CRP and tumor necrosis factor alpha (TNF-alpha) in TRD and MDD patients compared to healthy controls. At the same time, TSPO PET neuroimaging demonstrated increased microglial activation in the prefrontal cortex, anterior cingulate cortex, and insula, and evidence suggested that blood-brain barrier disruption facilitates peripheral cytokine entry into the central nervous system. Anti-inflammatory agents, including infliximab, celecoxib, and ketamine, showed greater efficacy in patients with elevated baseline inflammatory markers. Overall, neuroinflammation represents a mechanistically coherent and clinically actionable subtype of TRD, and inflammatory biomarkers, particularly IL-6 and CRP, hold promise for patient stratification and personalized treatment approaches. Future research should prioritize biomarker-stratified prospective trials of targeted immunotherapy in well-defined TRD populations.