D3.409 - Immunological Mechanisms in Treatment-Resistant Depression

Treatment-resistant depression (TRD) has been increasingly associated with immune dysregulation extending beyond the classical monoaminergic model. This study aimed to synthesize current evidence on immunological mechanisms underlying TRD and evaluate the concept of an inflammatory TRD phenotype.

A PRISMA-guided systematic review of studies published between 2016 and 2026 was conducted. Clinical and mechanistic studies evaluating inflammatory biomarkers, transcriptomic signatures, and immunomodulatory treatment effects in TRD were included. Seventy-eight studies met the inclusion criteria.

Patients with TRD consistently exhibited elevated inflammatory markers, including C-reactive protein, interleukin-6, tumor necrosis factor-α, and soluble TNF receptors. Transcriptomic analyses revealed enrichment of type I interferon signatures and activation of innate immune pathways. The inflammatory phenotype was associated with activation of monocytes, plasmacytoid dendritic cells, and natural killer cells. Elevated neurofilament light chain levels suggested concurrent neuroaxonal injury. Interventional findings were heterogeneous. In several studies, elevated baseline inflammation was linked to differential treatment response. Rapid antidepressant effects of ketamine often occurred without parallel early reductions in inflammatory markers.

Current evidence supports the concept of an inflammatory TRD phenotype characterized by cytokine and interferon pathway activation. Peripheral immune profiling may enable biologically informed patient stratification, although larger prospective studies integrating immunological and clinical outcomes are required.