NIMETOX-informed Precision Nomothetic Models of Major Depressive Disorder: Group, Phenome, and Individual Signatures
Journal:
medRxiv
Published Date:
Jan 24, 2026
Abstract
Background: Major depressive disorder (MDD) is a neuro-immune-metabolic-oxidative (NIMETOX) disorder. Nevertheless, the effects of alterations in immune responsiveness, oxidative stress, antioxidant defenses, gut-derived short-chain fatty acids (SCFAs), metabolic hormones and adipokines on metabolomic modules and the MDD phenome have remained elusive. Methods: Serum samples from 125 MDD inpatients and 40 healthy controls were analyzed using high-resolution metabolomics assays (liquid chromatography, mass spectrometry) in conjunction with assays of 68 additional NIMETOX markers. A machine learning pipeline was implemented to delineate the associations between MDD, clinical phenome features, metabolomic modules, and 68 NIMETOX biomarkers. Results: The metabolomics and NIMETOX biomarkers distinguished MDD from controls with a cross-validated accuracy of >95%. Core biomarkers of MDD encompass (in order of decreasing importance) diacylglycerol lipotoxicity, phospholipid remodeling, fatty acid signaling, mitochondrial-redox dysfunction, diminished antioxidant defenses (including decreased paraoxonase 1 activity, Apolipoprotein A1, reverse cholesterol transport, ether lipids), inflammatory response, increased epidermal growth factor, disbalances in gut-derived SCFAs, increased oxidized high-density lipoprotein cholesterol, and changes in metabolic hormones. A large part of the variance in overall severity of illness (76.3%), physiosomatic symptoms (61.9%), current suicidal ideation (40.6%), and recurrence of illness (28.8%) was explained by those pathways. Lipotoxicity, phospholipid remodeling, fatty acid storage, and clinical phenome features converge onto a singular latent construct-the metabolic phenome of MDD. The various NIMETOX pathways mediate the impact of adverse childhood experiences on metabolomics and MDD. Conclusions: MDD is a NIMETOX disorder in which metabolomic signals represent a final common pathway underlying symptom severity, recurrence of illness, and suicidality.
