Dyndał Kinga, Pańczyszyn-Trzewik Patrycja, Sowa-Kućma Magdalena
Student's Science Club of Physiology "NEURON", Faculty of Medicine, Collegium Medicum, University of Rzeszów, Kopisto 2a, 35-315 Rzeszów, Poland.
Department of Human Physiology, Faculty of Medicine, Collegium Medicum, University of Rzeszów, Al. Tadeusza Rejtana 16C, 35-959 Rzeszów, Poland.
Int J Mol Sci. 2025 Sep 8;26(17):8755. doi: 10.3390/ijms26178755.
Depressive disorder is the most prevalent mental illness, and increasing evidence suggests its potential bidirectional relationship with metabolic disorders. Given the limited efficacy of conventional antidepressants (including Selective Serotonin Reuptake Inhibitors; SSRIs) and the growing prevalence of treatment-resistant depression, there is a significant need to identify alternative molecular pathways underlying the pathophysiology of depressive disorder, which may represent novel therapeutic targets for other agents. Emerging evidence indicates that metabolic dysfunction and depressive disorder share a common pathophysiological molecular mechanism and increase each other's risk. Targeting peripheral metabolic pathways and their interactions with the central nervous system may alleviate depressive symptoms. Glucagon-Like Peptide-1 agonists (GLP-1 RAs) and Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors, widely used in the treatment of type 2 diabetes and obesity, exhibit neurotrophic and anti-inflammatory effects, ameliorate oxidative stress, and enhance mitochondrial function, collectively contributing to the antidepressant-like effects observed in preclinical studies. Peroxisome Proliferator-Activated Receptor (PPAR) α agonists primarily regulate lipid and glucose metabolism, which may potentially improve neuronal plasticity and mood regulation. Moreover, agents such as Angiotensin Receptor Blockers (ARBs) and Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), used in hypertension treatment, exert central anti-inflammatory and neuroprotective effects via the modulation of the renin-angiotensin-aldosterone system (RAAS), implicated in affective disorders. Nevertheless, long-term, head-to-head trials are required to establish their efficacy, safety, and therapeutic positioning within current treatment paradigms. The aim of this review is to summarize current evidence on metabolic modulators as potential antidepressant strategies, focusing on their molecular mechanisms, preclinical and clinical findings, and prospects for integration into future therapies for depression.
抑郁症是最常见的精神疾病，越来越多的证据表明它与代谢紊乱之间可能存在双向关系。鉴于传统抗抑郁药（包括选择性5-羟色胺再摄取抑制剂；SSRIs）疗效有限以及难治性抑郁症患病率不断上升，迫切需要确定抑郁症病理生理学背后的替代分子途径，这可能代表其他药物的新治疗靶点。新出现的证据表明，代谢功能障碍和抑郁症共享一种共同的病理生理分子机制，并且会增加彼此的风险。针对外周代谢途径及其与中枢神经系统的相互作用可能会减轻抑郁症状。胰高血糖素样肽-1激动剂（GLP-1 RAs）和钠-葡萄糖协同转运蛋白-2（SGLT2）抑制剂广泛用于治疗2型糖尿病和肥胖症，具有神经营养和抗炎作用，可改善氧化应激并增强线粒体功能，共同促成了临床前研究中观察到的类抗抑郁作用。过氧化物酶体增殖物激活受体（PPAR）α激动剂主要调节脂质和葡萄糖代谢，这可能潜在地改善神经元可塑性和情绪调节。此外，用于治疗高血压的血管紧张素受体阻滞剂（ARBs）和血管紧张素受体-脑啡肽酶抑制剂（ARNIs）等药物通过调节肾素-血管紧张素-醛固酮系统（RAAS）发挥中枢抗炎和神经保护作用，而该系统与情感障碍有关。然而，需要进行长期的、直接比较的试验来确定它们在当前治疗模式中的疗效、安全性和治疗定位。本综述的目的是总结关于代谢调节剂作为潜在抗抑郁策略的当前证据，重点关注其分子机制、临床前和临床研究结果以及整合到未来抑郁症治疗中的前景。
