Peripheral Metabolic–Redox Signaling as a Core Mechanism of Major Depressive Disorder: Evidence From Deep Metabolomic Phenotyping

Major depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile. To identify metabolic abnormalities that differentiate inpatients with severe MDD from healthy controls through high-resolution, untargeted metabolomics. Serum samples from 125 MDD inpatients and 40 healthy controls were analyzed utilizing liquid chromatography and mass spectrometry. A meticulously regulated multistage machine learning pipeline with leakage-prevention protocols was employed to analyze differences between MDD and controls and to predict phenome scores. Feature selection showed that 16 metabolites and 6 functional modules reliably distinguished MDD. The functional profile of the metabolites indicates a convergence of lipotoxicity, phospholipid remodeling, disruptions in fatty acid metabolism, mitochondrial redox imbalance, and plasmalogen and antioxidant depletion. This MDD metabotype was not affected by metabolic syndrome. A substantial portion of the variance in overall depression severity (72.5%), physiosomatic symptoms (55.8%) and suicidal ideation (23.6%) was accounted for by increased lipitoxicity, phospholipid remodeling, and fatty acid storage/signaling. The recurrence of illness (27.7%) was associated with a self-reinforcing lipid-redox-inflammatory module that maintains cellular stress. The MDD metabotype represents a cohesive metabolic network that is associated with the NIMETOX pathogenesis of MDD. Metabolomics provides a comprehensive foundation for subtyping and precision psychiatry. Lipoxygenase-15, plasmalogen, lipotoxicity, phospholipase A2, and lipid-redox intersections are important drug targets to treat MDD.