Integrated Metabolomics Identifies Mitochondrial Dysfunction, Oxidative Membrane Remodeling, and Reduced Lipophilic Antioxidant Defenses in First-Episode Simple Dysmood Disorder

Background: Metabolomic abnormalities in major depression have largely been investigated at the level of individual metabolites. We hypothesized that coordinated metabolic pathways, rather than isolated biomarkers, characterize first-episode simple dysmood disorder (FE-SDMD). Methods: Untargeted LC-MS metabolomics was performed in plasma from 44 FE-SDMD patients and 44 healthy controls. Differential metabolites were identified using Wilcoxon tests with false discovery rate correction and integrated with complementary machine-learning approaches. Curated metabolites were grouped into biologically informed functional modules, validated using principal component analysis, and examined in relation to clinical phenome dimensions, adverse childhood experiences (ACEs), and negative life events (NLEs). Results: Of 450 detected metabolites, 298 remained significant after FDR correction and 240 additionally met fold-change criteria. Complementary feature-selection methods yielded a consensus panel of 20 biologically relevant metabolites that discriminated FE-SDMD from controls across multivariate and machine-learning analyses. Six functional modules revealed increased oxidative membrane remodeling, gut-liver dysfunction, mitochondrial bioenergetic dysfunction, reduced lipophilic antioxidant defenses and glucocorticoid metabolism, and altered dietary phytochemical metabolism. ACEs, particularly emotional neglect, and NLEs were associated with greater abnormalities across all modules. Gut-liver and mitochondrial dysfunction, oxidative stress, NLEs, and/or ACEs explained substantial variance in overall depression severity (66%), physiosomatic symptoms (41%), and suicidal ideation (43%). Conclusions: Functional metabolic modules provide a biologically interpretable systems-biology framework linking metabolomic abnormalities, psychosocial adversity, and clinical phenotypes, supporting the neuroimmune-metabolic-oxidative (NIMETOX) model of depression.