Immunometabolic dysregulation in depression predates illness onset and associates with lower brain gray matter volume

Depression often co-occurs with physical health conditions, including heart disease, diabetes and obesity. 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 structural brain changes linked to the disorder remain poorly understood. Using brain imaging and metabolomics data from the UK Biobank, we comprehensively evaluated cross-sectional and longitudinal immunometabolic profiles in depression, including inflammatory markers, lipoprotein lipids, fatty acids, amino acids, glycolysis metabolites and various low-molecular-weight metabolites. 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 with small-to-modest effect sizes (|Cohens d| = 0.01-0.16), and predates illness onset (mean prodromal period: 7 years). We mapped network-level systemic changes in metabolites, implicating the core role of glycolysis in depression-related metabolic dysregulation. We also showed that peripheral immunometabolic dysfunction, particularly elevated inflammation, is associated with lower brain gray matter volume in depression. We concluded that altered lipids and inflammatory markers predate the onset of depression, remain altered throughout the illness course and associate with lower gray matter volume. By comprehensively profiling immunometabolic dysfunction in depression and related brain changes, our work highlights the importance of monitoring and managing chronic low-grade inflammation and altered lipid and glucose metabolism in the disorder.