Targeting Neuroinflammation in Difficult-to-Treat Depression: From Anti-Inflammatory Agents to Multi-Target Immunopsychiatric Interventions

Difficult-to-treat depression (DTD) with inflammatory features (e.g., hs-CRP ≥3 mg/L and/or elevated IL-6) may represent a clinically and biologically distinct presentation characterized by chronicity, functional impairment, prominent cognitive-motivational symptoms, and suboptimal response to conventional treatments. Classical anti-inflammatory strategies (e.g., COX-2 inhibitors or cytokine-targeting biologics) have shown signals of efficacy in selected biomarker-enriched subgroups; however, overall evidence remains heterogeneous, with modest effect sizes and substantial limitations for real-world implementation. This Commentary advances a complementary perspective, proposing that in many patients “inflamed DTD” reflects not only increased pro-inflammatory drive but also impaired physiological resolution mechanisms across immune, autonomic, circadian, and metabolic systems. Within this “resolution failure” framework, we discuss emerging therapeutic targets and multimodal strategies and their integration into endotype-guided immunopsychiatric care. We further address limitations of the current evidence base, outline biomarker-enriched trial designs with patient-centred outcomes (functioning, quality of life, cognition), and highlight real-world barriers, including access to biomarkers, reimbursement, and equity of care. Overall, this perspective argues for moving beyond single-pathway anti-inflammatory approaches towards pragmatic, mechanistically informed interventions for inflamed DTD.