Treatment-resistant depression (TRD) remains a challenge despite the growing number of interventions. Peripheral interleukin-6 (IL-6) levels have repeatedly been associated with both the presence and response to different treatments in TRD. There is currently no information available on the effects of bright light therapy (BLT) on serum IL-6 levels. This study assessed the effects of BLT on serum IL-6 levels in TRD patients. Serum IL-6 was determined at two points in TRD patients—at baseline and after 4 weeks of BLT—and at a single point in the healthy controls. Depression severity was measured by the Hamilton Rating Scale for Depression (HAMD)-17 and the Montgomery–Åsberg Depression Rating Scale (MADRS). The study included 104 females, 54 diagnosed with TRD (median age 52.5) and 50 healthy controls (median age 44.5). At baseline, patients had higher IL-6 levels than the controls. BLT treatment reduced HAMD-17 and MADRS scores. Serum IL-6 levels were not significantly affected by the 4 weeks of BLT. However, when patients were divided according to treatment response, IL-6 levels were increased in responders to BLT. The neuroinflammatory mechanism may be involved in the etiopathogenesis and the treatment of TRD, while changes in serum IL-6 levels may be potential indicators of response to treatment.

Brain-derived neurotrophic factor (BDNF) is implicated in the etiology and treatment response in major depressive disorder (MDD). However, peripheral BDNF concentrations have not been compared across different MDD stages. Bright light therapy (BLT) offers some potential in treatment-resistant depression (TRD), but its effects on BDNF levels are unknown. This study included a cross-sectional analysis of plasma BDNF concentration in females with TRD, unmedicated MDD patients, and healthy controls (HC), and measurements of longitudinal BLT effects on plasma BDNF levels in TRD patients. The present study included 55 drug-naïve, first-episode patients, 25 drug-free recurrent-episode MDD patients, 71 HC participants, and 54 TRD patients. Patients were rated by Hamilton Depression Rating Scale (HAMD)-17 and the Montgomery–Åsberg Depression Rating Scale (MADRS). Patients with TRD received BLT during 4 weeks. The total HAMD-17 and MADRS scores decreased following BLT. All patient groups had lower plasma BDNF than HC, but BDNF levels did not differ between first- and recurrent-episode BDNF patients and TRD patients before or after BLT. However, responders and remitters to BLT had higher post-treatment plasma BDNF concentrations than patients who did not achieve response or remission. The changes in plasma BDNF levels may be candidates for biomarkers of treatment response to BLT in TRD patients.

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.