Rosa Ilenia, Padula Lorenzo Pio, Semeraro Francesco, Marrangone Carlotta, Inserra Antonio, De Risio Luisa, Boffa Marta, Zoratto Francesca, Borgi Marta, Guidotti Roberto, Lorenzo Giorgio Di, D'Addario Claudio, Pettorruso Mauro, Martinotti Giovanni
Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti-Pescara, Italy.
Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti-Pescara, Italy; Behavioral Neuroscience Laboratory, Postgraduate Program in Health Sciences, University of South Santa Catarina (UNISUL), Tubarão, Brazil.
Psychiatry Res. 2025 Aug 16;352:116697. doi: 10.1016/j.psychres.2025.116697.
Depression is a prevalent and heterogeneous disorder with significant personal and social consequences. The rise of treatment-resistant depression (TRD) challenges traditional approaches and underscores the need for a broader neurobiological perspective. When monoaminergic modulation proves insufficient, clinical guidelines increasingly turn to non-monoaminergic interventions such as neuromodulation techniques and glutamatergic agents, which operate through distinct mechanisms. Despite their heterogeneity, these treatments may act on shared final pathways that differ from those of conventional antidepressants. Among these pathways, the endocannabinoid system (ECS) has emerged as a critical mood regulator and a potential mediator of antidepressant effects. This narrative review draws from preclinical and clinical literature to explore the role of the ECS in depression and its involvement in various non-monoaminergic treatments effective in TRD. Evidence suggests that physical interventions like repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), as well as glutamatergic and serotonergic agents such as ketamine, esketamine, and psychedelics, influence ECS components. rTMS and ECT elevate levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors and other ECS targets, contributing to their rapid effects. Psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions, while LSD affects the broader endocannabinoidome in the prefrontal cortex and hippocampus. These findings suggest that ECS modulation may constitute a unifying mechanism through which diverse, non-monoaminergic interventions exert antidepressant effects in TRD, positioning the ECS as a promising target of novel treatment strategies for individuals who do not respond to conventional treatments.
抑郁症是一种普遍且异质性的疾病，会造成重大的个人和社会后果。难治性抑郁症（TRD）的增多对传统治疗方法构成挑战，并凸显了从更广泛的神经生物学角度进行研究的必要性。当单胺能调节被证明不足时，临床指南越来越多地转向非单胺能干预措施，如神经调节技术和谷氨酸能药物，它们通过不同的机制发挥作用。尽管这些治疗方法具有异质性，但它们可能作用于与传统抗抑郁药不同的共同最终通路。在这些通路中，内源性大麻素系统（ECS）已成为关键的情绪调节因子和抗抑郁作用的潜在介导者。这篇叙述性综述借鉴临床前和临床文献，探讨ECS在抑郁症中的作用及其在TRD中有效的各种非单胺能治疗中的参与情况。证据表明，重复经颅磁刺激（rTMS）和电休克疗法（ECT）等物理干预措施，以及氯胺酮、艾氯胺酮和迷幻剂等谷氨酸能和血清素能药物，会影响ECS的组成部分。rTMS和ECT会提高内源性大麻素花生四烯酸乙醇胺（AEA）和2-花生四烯酸甘油酯（2-AG）的水平，这与临床改善相关。氯胺酮和艾氯胺酮调节CB1受体和其他ECS靶点，促成它们的快速起效。裸盖菇素可恢复2-AG并增强与情绪相关脑区的CB1表达，而麦角酸二乙胺（LSD）会影响前额叶皮质和海马体中更广泛的内源性大麻素组。这些发现表明，ECS调节可能构成一种统一机制，通过该机制，多种非单胺能干预措施在TRD中发挥抗抑郁作用，使ECS成为对传统治疗无反应的个体新型治疗策略的一个有前景的靶点。
