难治性抑郁症(treatment-resistant depression, TRD)是一种严重的精神心理疾病,对患者的生命健康造成了巨大威胁。近年来,TRD已经成为国内外学者关注的重点。目前对于TRD 的定义尚存在争议。在临床治疗方面,主要采用优化药物剂量和疗程、药物转换、药物联合以及增效疗法等策略。此外,基于不同病理改变的各种TRD动物模型被成功构建并应用于TRD机制研究中,揭示了该病的多种可能发病机制,包括过度的炎症反应、下丘脑-垂体-肾上腺轴亢进、谷氨酸能系统紊乱、色氨酸代谢异常等。这些为TRD的新药研发提供了许多新思路,而且目前有些在研新药已经取得了重大突破。本综述就以上问题进行了详细的阐述,旨在为未来的TRD 研究和新药研发提供参考和依据。

Treatment-resistant depression (TRD) is a severe mental illness that poses a significant threat to the health and well-being of patients. In recent years, TRD has garnered increased attention from scholars both domestically and internationally. Currently, there is ongoing debate regarding the definition of TRD. Clinical treatment strategies for TRD primarily include optimizing drug dosage and duration, switching medications, combining drugs, and employing synergistic therapies. Additionally, various animal models of TRD, based on different pathological changes, have been successfully established and utilized in research to reveal the potential pathogenesis of TRD, such as excessive inflammatory responses, hyperactivity of the hypothalamic-pituitary-adrenal axis, dysregulation of the glutamatergic system, and disturbances in tryptophan metabolism. These findings have generated new insights for the development of novel medications for TRD, with some candidates currently in the pipeline having achieved significant breakthroughs. This review comprehensively discusses these issues, aiming to provide a reference for future research and drug development in TRD.