Systemic Inflammation and Depression: Clinical Implications and Emerging Therapies

A systematic review and meta-analysis in the American Journal of Psychiatry found that targeted anti-inflammatory therapy reduced overall depressive symptom severity and anhedonia in patients with elevated systemic inflammation.

Standard antidepressant response has long varied among patients with elevated inflammatory markers. Pooled data now shift emphasis toward immunologic contributors rather than purely monoaminergic explanations. Trials that enrolled biomarker-positive subgroups tested endpoints of overall depressive symptom severity and anhedonia and found measurable improvements, supporting selective assessment of systemic inflammation as part of individualized treatment planning for some patients.

Elevated C-reactive protein and raised proinflammatory cytokines (for example, interleukin-6 and tumor necrosis factor–related markers) were the biomarkers most commonly linked to treatment benefit. Many trials used CRP thresholds or relative elevations to define the inflamed subgroup; reported cut points varied (some used CRP >3 mg/L, others used lower cutoffs or percentile-based definitions), and aggregate heterogeneity limits a single universal threshold. Using CRP and cytokine patterns as part of a composite assessment—rather than relying on a single absolute cutoff—can help refine candidate selection for inflammation-targeted approaches.

Cytokine-targeting agents and several repurposed anti-inflammatory or immunomodulatory drugs comprised the intervention classes studied, and primary endpoints that improved across trials were overall depressive symptom severity and measures of anhedonia; effect sizes were concentrated in biomarker-selected subgroups.