Transdiagnostic metabolic architecture across major depressive disorder and schizophrenia: a NIMETOX systems-biology approach
- 11. International NIMETOX Center, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic
Abstract
BackgroundMajor 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.
ObjectivesTo characterize shared and divergent serum metabolic signatures across MDD and SCZ and their associations with childhood adversity, resilience, and dimensional clinical phenotypes.
MethodsWe 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.
ResultsCompared 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.
ConclusionMDD 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.
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BibTeX
@misc{luo2026transdiagnostic,
title = {{Transdiagnostic metabolic architecture across major depressive disorder and schizophrenia: a NIMETOX systems-biology approach}},
author = {Y. Luo and H. Wu and C. Yang and T. Chen and A. F. Almulla and Y. Zhang and M. Maes},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.26364141},
url = {https://www.medrxiv.org/content/10.64898/2026.09.28.26364141v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Transdiagnostic metabolic architecture across major depressive disorder and schizophrenia: a NIMETOX systems-biology approach
AU - Y. Luo
AU - H. Wu
AU - C. Yang
AU - T. Chen
AU - A. F. Almulla
AU - Y. Zhang
AU - M. Maes
PY - 2026
DA - 2026/09/28
PB - medRxiv
DO - 10.64898/2026.09.28.26364141
UR - https://www.medrxiv.org/content/10.64898/2026.09.28.26364141v1
AB - BackgroundMajor 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. ObjectivesTo characterize shared and divergent serum metabolic signatures across MDD and SCZ and their associations with childhood adversity, resilience, and dimensional clinical phenotypes. MethodsWe 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. ResultsCompared 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. ConclusionMDD 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.
ER -