Abstract
Depression often co-occurs with chronic physical illnesses. While dysregulation of the immunometabolic system is posited to underpin several of these comorbidities, the course of immunometabolic dysregulation in depression and its impact on brain structure remain poorly understood. Here we comprehensively evaluated longitudinal immunometabolic profiles in depression using neuroimaging and metabolomics data from the UK Biobank. We found that depression is characterized by a relatively persistent pattern over time of elevated systemic inflammation, upregulated very-low-density lipoprotein and lipids and downregulated high-density lipoprotein (|Cohen’s d| = 0.01-0.16) and that it predates illness onset. We mapped network-level systemic changes in metabolites, implicating the core role of glycolysis. We also showed that peripheral immunometabolic dysfunction, particularly elevated inflammation, is associated with lower brain gray matter volume in depression. By comprehensively profiling immunometabolic dysfunction in depression and related brain changes, our work highlights the importance of managing chronic low-grade inflammation and altered lipid and glucose metabolism in this disorder.