Advancements in the molecular understanding of major depressive disorder uncovering novel targets with therapeutic promise: focus on recurrence of illness

作者：Michaël Maes, Abbas F. Almulla, Drozdstoy Stoyanov, Yingqian Zhang · 发表于：Expert Opinion on Therapeutic Targets · 年份：2025 · DOI：10.1080/14728222.2025.2608029 · 被引用次数：5 · 研究领域：Tryptophan and brain disorders、Treatment of Major Depression、Pharmacological Receptor Mechanisms and Effects

INTRODUCTION: Major depressive disorder (MDD) is a neuro-immune-metabolic-oxidative stress (NIMETOX) disorder. A significant proportion (50%) of individuals with MDD experience recurrence of episodes and suicidal behaviors. Recurrent MDD is characterized by greater severity of depression and increased functional impairments. Recently, the recurrence of illness (ROI) index was introduced as a quantitative metric for assessing this recurrence. AREA COVERED: This paper reviews how ROI should be calculated based on the number of lifetime depressive episodes, suicidal attempts, and ideation. This paper examines the associations between ROI and neuroimmune pathways (e.g. increased M1 macrophage activity, T helper (Th)1/Th17 polarization), metabolic pathways (e.g. reduced reverse cholesterol transport), and oxidative pathways (e.g. diminished lipid-associated antioxidant defenses, increased lipid peroxidation), as well as gut dysbiosis and abnormalities in neurotrophic factors, brain structure, and function. This study investigates potential interventions that could be employed to normalize each of the ROI-associated NIMETOX pathways. EXPERT OPINION: The future of recurrent MDD therapeutics resides in multi-targeting the ROI-associated pathways with NIMETOX-guided interventions aimed at attenuating immune sensitization, rectifying metabolic dysfunction, reducing oxidative toxicity, and concurrently restoring neuroplasticity. The development of such integrative therapies is an urgent...