Psychiatric disorders have traditionally been conceptualized as conditions primarily affecting the brain. However, mounting evidence challenges this view, revealing complex interactions between systemic energy metabolism, immune function, and brain physiology. This chapter examines the critical role of metabolic abnormalities in psychiatric disorders, advocating for a “whole-body” framework of investigation. Recent research demonstrates that individuals with severe psychiatric disorders experience significantly reduced life expectancy, largely due to metabolic and cardiovascular conditions that are not fully attributable to medication side effects. Evidence from genetic as well as peripheral and central nervous system studies reveals multifaceted metabolic dysregulation across psychiatric disorders, including altered glucose metabolism, mitochondrial function, and oxidative stress. Notably, specific metabolic signatures may correspond to distinct clinical phenotypes that cut across traditional diagnostic boundaries, suggesting the need for a transdiagnostic approach to both research and treatment strategies. The relationship between metabolic dysfunction and psychiatric symptoms is bidirectional and complex. Although metabolic abnormalities may not directly cause psychiatric disorders, they likely represent significant risk factors that interact with genetic, physiological, environmental, and socioeconomic conditions. Understanding these interactions is crucial for developing more effective, personalized therapeutic strategies. Future investigations focused on identifying biology-based symptom constructs may be better able to guide individualized treatment approaches than traditional diagnostic categories.