University of Toronto, Toronto, ON, Canada.
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
CNS Drugs. 2024 Nov;38(11):869-890. doi: 10.1007/s40263-024-01114-y. Epub 2024 Aug 16.
Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2 decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.
重度抑郁症（MDD）是一种慢性、负担沉重、普遍存在的疾病，其特征是情绪低落和快感缺失。由于经批准的单胺类抗抑郁药在临床获益前需要数周的延迟，且缓解率低，因此 MDD 的负担尤其沉重。在过去的 20 年中，一个改善抑郁症治疗患者预后的有前途的目标出现了：谷氨酸能信号。本综述提供了一个关于谷氨酸在突触发生和神经可塑性中的信号传递的高级概述，以及谷氨酸失调在抑郁症中的意义。基于这一临床前证据表明谷氨酸与抑郁症有关，以及氯胺酮治疗在概念验证试验中迅速改善抑郁症，一系列靶向 NMDA 的治疗方法已被研究。虽然已经在注册的 2 期或 3 期临床试验中研究了一系列治疗方法，但这些药物的开发大多已被停止。多种谷氨酸靶向抗抑郁药正在积极开发中，其中两种已获得批准。鼻腔给予氯胺酮（Spravato）于 2019 年获得美国食品和药物管理局（FDA）批准，用于治疗治疗抵抗性抑郁症的成年人，2020 年用于伴有急性自杀意念或行为的 MDD 成年人。口服右美沙芬-安非他酮（AXS-05，Auvelity 缓释片）于 2022 年获得 FDA 批准，用于治疗成年人 MDD。这些批准增强了谷氨酸在抑郁症中的重要性，并代表了当代精神病学的一个令人兴奋的突破，为患者提供了新的治疗途径，作为一线治疗或对单胺类抗抑郁药反应不佳或不可接受的副作用。
