Metabolomic Profiling of Extracellular Vesicles Reveals Distinct Metabolic Dysregulation and Treatment-Specific Signatures in Depression.
Nikola Balic, Gordana Nedic Erjavec, Marcela Konjevod, Jorge Saiz, Tina Curkovic, Lucija Tudor, Dubravka Svob Strac, Alja Videtic Paska, Julija Smon, Magda Tusek-znidaric, Marina Sagud, Bjanka Vuksan Cusa, Tea Fabijanic, Zrinka Pesut, Biljana Kosanovic Rajacic, Zoran Bradas, Nela Pivac, Matea Nikolac Perkovic
Biomolecules April 2, 2026 Peer reviewed DOI: 10.3390/biom16040533 via PubMed
Summary
Major depressive disorder (MDD) shows significant metabolic changes, especially in treatment-resistant depression (TRD) patients. This study analyzed plasma extracellular vesicle metabolomes in healthy controls (50), responsive MDD patients (60), and TRD patients (65). After 8 weeks of treatment with duloxetine, bright-light therapy, or esketamine, all treatments improved clinical outcomes and partially normalized metabolic profiles. Notably, TRD exhibited distinct alterations in lipid, amino acid, and energy metabolism pathways.
Study at a glance
| Design | longitudinal study |
|---|---|
| Sample size | 205 |
| Population | healthy controls, responsive MDD patients, and patients with treatment-resistant depression |
| Key finding | The most pronounced metabolic alterations were observed in treatment-resistant depression patients, particularly affecting lipid, amino acid, and energy metabolism pathways. |
Abstract
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.