Immuno-Metabolic Depression: From Immune–Metabolic Dysregulation to Biomarker-Guided Precision Psychiatry

Immuno-metabolic depression (IMD) describes the clustering of atypical energy-related symptoms, low-grade inflammation, and metabolic dysregulation within major depressive disorder. This structured narrative review evaluates its biological basis and potential utility for patient stratification and treatment selection. PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library were searched through July 2026 without a lower publication-date restriction. Clinical, genetic, multi-omics, and neuroimaging evidence links energy-related symptom profiles with inflammatory and metabolic abnormalities. Human observations and preclinical experiments implicate interacting immune, metabolic, endocrine, kynurenine, dopaminergic, and gut–brain pathways, although an IMD-specific causal sequence remains uncertain. C-reactive protein, symptom profiles, and metabolic indices may support research stratification; their ability to predict differential treatment benefit requires validation. Anti-inflammatory and dopaminergic studies report preliminary mechanistic or symptom-related findings in selected samples, while exercise has shown favorable effects on immunometabolic indices. The reviewed semaglutide trial did not demonstrate benefit for the primary executive-function outcome or depressive symptoms, despite favorable secondary findings for global cognition and weight. IMD therefore remains a research framework with potential clinical relevance. Standardized definitions, longitudinal studies, and adequately powered randomized trials are needed to establish whether biomarker-guided treatment selection improves depressive, functional, and cardiometabolic outcomes beyond standard care.