An umbrella review of inflammatory biomarkers and their relationship to treatment response in MDD

Abstract

Major depressive disorder (MDD) is often resistant to standard antidepressant therapy. Inflammation has been implicated in MDD pathophysiology and inflammatory biomarkers have been proposed as predictors of treatment response. This umbrella review synthesises meta-analytic evidence on associations between inflammatory biomarkers and treatment response in MDD. The review followed PRISMA guidelines and was pre-registered on PROSPERO (CRD420251162554). PubMed, Embase, PsycINFO and the Cochrane Database of Systematic Reviews were searched using terms related to depression, treatment response, inflammation and biomarkers. Eligible studies were meta-analyses reporting associations between inflammatory markers and treatment outcomes in MDD. Data were extracted on sample size, effect sizes, heterogeneity, publication bias and conclusions. Methodological quality was assessed using the JBI Critical Appraisal Checklist, and primary study overlap was quantified using the Corrected Covered Area method. Eight meta-analyses met inclusion criteria, covering antidepressant medication and electroconvulsive therapy (ECT). Primary study overlap was 'very high' as measured by the CCA. For antidepressants, lower baseline C-reactive protein (CRP) and interleukin-8 (IL-8), and reductions in tumour necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) during treatment, were associated with better response in some meta-analyses; however, findings were inconsistent and effect sizes generally small. For ECT, a single meta-analysis reported only nominally significant associations between higher baseline CRP and interleukin-6 (IL-6), and lower kynurenine and tryptophan, and greater symptom improvement; none survived false discovery rate correction. Overall, the small effect sizes and inconsistency of findings do not yet support the clinical use of inflammatory biomarkers to guide treatment decisions.