Carmellini Pietro, Cuomo Alessandro, Rescalli Maria Beatrice, Fagiolini Andrea
Department of Molecular and Developmental Medicine, Division of Psychiatry, School of Medicine, University of Siena, 53100 Siena, Italy.
Life (Basel). 2025 Sep 10;15(9):1422. doi: 10.3390/life15091422.
Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are among the leading causes of disability worldwide and are frequently associated with treatment resistance, functional impairment, and high comorbidity with metabolic dysfunction. Increasing evidence implicates insulin resistance (IR) as a key pathophysiological factor linking metabolic and psychiatric illness. IR is associated with chronic low-grade inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, impaired neuroplasticity, mitochondrial dysfunction, and altered reward processing mechanisms that may contribute to core depressive features such as anhedonia, cognitive slowing, and emotional dysregulation. These processes are further exacerbated by the metabolic side effects of many psychotropic medications, creating a self-perpetuating cycle that worsens both psychiatric and physical health outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for type 2 diabetes and obesity, have emerged as promising candidates to address this metabolic-psychiatric interface. Beyond improving glycemic control and promoting weight loss, GLP-1 RAs exert central actions relevant to mood disorders, including modulation of dopaminergic reward pathways, enhancement of hippocampal neurogenesis, attenuation of neuroinflammation, and regulation of appetite and energy balance. Preclinical studies demonstrate that GLP-1 RAs reduce microglial activation, promote hippocampal neurogenesis, and normalize stress-induced behavioral changes. Early clinical trials in patients with metabolic disorders suggest improvements in depressive symptoms, quality of life, and cognitive function, with some effects independent of weight loss or glycemic outcomes. Observational evidence also indicates reduced antidepressant use and psychological distress in diabetic and obese populations receiving GLP-1 RAs. While these findings are promising, large randomized controlled trials in primary psychiatric populations are lacking. Key challenges include clarifying dose-response relationships, disentangling central from peripheral effects, and addressing safety and adherence concerns in individuals with comorbid psychiatric conditions. Future research should focus on biomarker-informed stratification, comparative trials with standard treatments, and integration of GLP-1 RAs into multimodal care frameworks. Overall, GLP-1 RAs represent a biologically plausible and clinically relevant approach to bridging metabolic and psychiatric care, with the potential to improve outcomes in patients with mood disorders who carry a high metabolic burden.
情绪障碍，包括重度抑郁症（MDD）和双相情感障碍（BD），是全球致残的主要原因之一，并且经常与治疗抵抗、功能损害以及与代谢功能障碍的高共病率相关。越来越多的证据表明胰岛素抵抗（IR）是连接代谢和精神疾病的关键病理生理因素。IR与慢性低度炎症、下丘脑 - 垂体 - 肾上腺（HPA）轴失调、神经可塑性受损、线粒体功能障碍以及改变的奖赏处理机制有关，这些机制可能导致诸如快感缺失、认知迟缓及情绪调节障碍等核心抑郁特征。许多精神药物的代谢副作用进一步加剧了这些过程，形成了一个自我延续的循环，使精神和身体健康状况都恶化。胰高血糖素样肽 -1受体激动剂（GLP -1 RAs）最初是为2型糖尿病和肥胖症开发的，已成为解决这种代谢 - 精神界面问题的有前景的候选药物。除了改善血糖控制和促进体重减轻外，GLP -1 RAs还发挥与情绪障碍相关的中枢作用，包括调节多巴胺能奖赏通路、增强海马神经发生、减轻神经炎症以及调节食欲和能量平衡。临床前研究表明，GLP -1 RAs可减少小胶质细胞激活，促进海马神经发生，并使应激诱导的行为变化正常化。对患有代谢紊乱的患者进行的早期临床试验表明，抑郁症状、生活质量和认知功能有所改善，其中一些效果独立于体重减轻或血糖结果。观察性证据还表明，接受GLP -1 RAs的糖尿病和肥胖人群中抗抑郁药的使用和心理困扰减少。虽然这些发现很有前景，但缺乏针对原发性精神疾病人群的大型随机对照试验。关键挑战包括明确剂量 - 反应关系、区分中枢和外周效应，以及解决合并精神疾病个体的安全性和依从性问题。未来的研究应集中在生物标志物指导的分层、与标准治疗的比较试验，以及将GLP -1 RAs纳入多模式护理框架。总体而言，GLP -1 RAs代表了一种生物学上合理且临床相关的方法，用于连接代谢和精神护理，有可能改善代谢负担高的情绪障碍患者的结局。
