Metabolomic Profiling of Extracellular Vesicles Reveals Distinct Metabolic Dysregulation and Treatment-Specific Signatures in Depression

Major depressive disorder (MDD) is associated with complex metabolic alterations. In this study, we applied a multiplatform metabolomics approach (GC-MS and LC-MS) to characterize the plasma extracellular vesicle (EV) metabolome in healthy controls (N = 50), responsive MDD patients (N = 60), and patients with treatment-resistant depression (TRD; N = 65). Longitudinal analyses were performed following 8-week treatment with duloxetine (N = 30), bright-light therapy (BLT; N = 30), or esketamine (N = 35). A total of 230 metabolites were identified, with the most pronounced metabolic alterations observed in TRD patients, particularly in lipid, amino acid, and energy metabolism pathways. Elevated lysophospholipids and fatty acids in TRD suggested dysregulated lipid metabolism and inflammatory processes. All treatments resulted in clinical improvement, accompanied by partial normalization of metabolic profiles. Duloxetine treatment was associated with modulation of amino acid and glycerophospholipid metabolism, including increases in tryptophan-related metabolites and normalization of specific lipid species. BLT primarily reduced lysophospholipids and mannose levels, while esketamine modulated metabolites related to lipid turnover, short-chain fatty acids, carbohydrate metabolism, and neuroendocrine function, including increased thyrotropin-releasing hormone levels. These findings support the concept that TRD represents a biologically distinct and more metabolically dysregulated subtype of depression and highlight EV-based metabolomics as a promising approach for elucidating disease and treatment mechanisms.