NIMETOX-informed Precision Nomothetic Models of Major Depressive Disorder: Group, Phenome, and Individual Signatures

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.