Transdiagnostic metabolic architecture across major depressive disorder and schizophrenia: a NIMETOX systems-biology approach

Background: Major depressive disorder (MDD) is conceptualised within a neuroimmune metabolic oxidative (NIMETOX) framework. From a systems-biology perspective, related metabolic oxidative disturbances may extend across diagnostic boundaries, including schizophrenia (SCZ), but their relationships with childhood adversity and dimensional psychopathology remain unclear. Objectives: To characterize shared and divergent serum metabolic signatures across MDD and SCZ and their associations with childhood adversity, resilience, and dimensional clinical phenotypes. Methods: We studied 89 participants (26 HC, 34 MDD, 29 SCZ). Untargeted serum metabolomics yielded 1,419 metabolites, of which 38 selected markers were integrated into 11 metabolic modules. Group comparisons, nested cross-validated OPLS-DA, and multiple regression analyses were performed. Results: Compared with HC, MDD and SCZ exhibited reduced mitochondrial lipid bioenergetics and metabolic resilience and increased sphingolipid stress signalling, oxidative lipid damage, and renin angiotensin aldosterone system stress. PUFA membrane remodelling increased progressively from HC to SCZ to MDD, whereas antioxidants were selectively reduced in MDD. An integrated OPLS-DA discriminated HC from MDD+SCZ (cross-validated AUC=0.946). Across dimensional models, mitochondrial lipid bioenergetics, PUFA remodelling, sphingolipid stress, oxidative lipid damage, and metabolic resilience explained substantial variance in mood, positive and negative psychotic symptoms, resilience, and suicidal behaviors. A terpenoid exposure biotransformation module was strongly associated with psychosis and suicidal behaviors. Conclusion: MDD and SCZ share an interconnected NIMETOX metabolic architecture while clinical dimensions show partly distinct psychosocial metabolic configurations. These findings support a transdiagnostic NIMETOX systems biology model linking NIMETOX dysfunction with dimensional psychopathology and provide a framework for future stratification and biomarker validation.