Inflammatory and Immune Biomarkers in Mood Disorders: From Mechanistic Pathways to Clinical Translation
Mario Pinzi, Andrea Fagiolini, Despoina Koukouna, Giacomo Gualtieri, Maria Beatrice Rescalli, Caterina Pierini, Simone Pardossi, Benjamin Patrizio, Alessandro Cuomo
Abstract
Over the past two decades, immune-inflammatory dysregulation has emerged as a central paradigm in the biology of mood disorders. Patients with major depression (MDD) and bipolar disorder (BD) frequently display low-grade systemic inflammation. Elevated C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) identify clinically relevant subgroups of patients characterized by greater severity, cognitive impairment, and poor treatment response. Changes in the gut microbiota and disruptions of the blood-brain barrier (BBB) act as important gateways through which systemic immune activity can influence the brain. At the intracellular level, pattern-recognition receptors activate convergent hubs including NF-κB, JAK/STAT, and MAPK cascades, while the NLRP3 inflammasome integrates mitochondrial dysfunction and oxidative stress with IL-1β release and pyroptosis. These pathways converge on glial dysregulation, impaired BDNF/TrkB signaling, and kynurenine pathway (KP) alterations, fostering excitotoxicity and synaptic deficits. Translational studies demonstrate that elevated CRP and IL-6 predict poor antidepressant outcomes. Anti-inflammatory agents such as infliximab and celecoxib show efficacy in specific subgroups of patients. Emerging multi-omics approaches identify immuno-metabolic biotypes, supporting the rationale for biomarker-guided stratification. These findings define an 'inflammatory biotype' of mood disorders and highlight the need for biomarkers and precision-based trials to guide treatment.