Targeting the Organ‐Brain Axis: The Modulatory Role of Peripheral Organs in Depression

Major Depressive Disorder (MDD) is a highly prevalent mental illness whose pathophysiology remains incompletely understood. Although MDD has traditionally been conceptualized primarily as a disorder of central nervous system dysfunction, accumulating evidence supports a broader brain-body framework, particularly in biologically defined subgroups characterized by inflammatory, metabolic, endocrine, autonomic, or microbiome-related abnormalities. This review summarizes how selected peripheral organs, including the gut, liver, heart, spleen, skeletal muscle, adipose tissue, bone marrow, and endocrine glands, may communicate with the brain through neural, metabolic, immune, endocrine, and microbial pathways. Emerging preclinical and clinical evidence suggests that these peripheral signals may participate in neuroinflammation and physiological alterations associated with depressive phenotypes. However, their causal status in humans remains incompletely established, and peripheral alterations may represent contributors to, correlates of, or consequences of central pathological states. We further discuss how multi-organ communication networks may converge on shared central pathways and provide a conceptual framework for understanding selected MDD phenotypes. Finally, we evaluate therapeutic strategies targeting systemic inflammation, metabolic homeostasis, and endocrine regulation, while emphasizing current translational limitations.