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Michael Maes1,2,3,4,5,6,7, Abbas F Almulla1,2,8, Drozdstoj Stoyanov4,5,6

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Major depressive disorder (MDD) recurrence is linked to neuro-immune-metabolic-oxidative stress (NIMETOX) pathways. Targeting these pathways with NIMETOX-guided interventions offers a future for recurrent MDD therapeutics.

Keywords:
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Area of Science:

  • Neuroscience
  • Immunology
  • Metabolic disorders
  • Oxidative stress

Background:

  • Major Depressive Disorder (MDD) is increasingly understood as a complex NIMETOX disorder.
  • Approximately 50% of MDD patients experience episode recurrence, often with increased severity and functional impairment.
  • The Recurrence of Illness (ROI) index quantifies recurrence, aiding in understanding disease trajectory.

Purpose of the Study:

  • To review the calculation of the ROI index based on lifetime depressive episodes, suicidal attempts, and ideation.
  • To examine associations between ROI and specific neuroimmune, metabolic, and oxidative stress pathways.
  • To investigate potential interventions targeting ROI-associated NIMETOX pathways.

Main Methods:

  • Literature review focusing on the ROI index calculation and its biological correlates.
  • Analysis of associations between ROI and neuroimmune markers (M1 macrophages, Th1/Th17 cells).
  • Examination of links between ROI and metabolic (cholesterol transport) and oxidative stress (lipid peroxidation) pathways.

Main Results:

  • ROI is associated with heightened M1 macrophage activity and Th1/Th17 polarization.
  • ROI correlates with impaired reverse cholesterol transport and reduced antioxidant defenses.
  • Abnormalities in gut microbiota, neurotrophic factors, and brain structure/function are linked to ROI.

Conclusions:

  • Future recurrent MDD therapeutics should multi-target ROI-associated NIMETOX pathways.
  • NIMETOX-guided interventions aim to reduce immune sensitization, metabolic dysfunction, and oxidative toxicity.
  • Integrative therapies are crucial to alter the course of recurrent depression and restore neuroplasticity.