Glutamatergic Modulators for Major Depression from Theory to Clinical Use.

IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY
CNS drugs Pub Date : 2024-11-01 Epub Date: 2024-08-16 DOI:10.1007/s40263-024-01114-y
Roger S McIntyre, Rakesh Jain
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引用次数: 0

Abstract

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.

Abstract Image

治疗重度抑郁症的谷氨酸能调节剂从理论到临床应用。
重度抑郁症(MDD)是一种以情绪低落和情感淡漠为特征的慢性、负担沉重的高发疾病。由于已获批准的单胺抗抑郁剂治疗在临床获益前会有长达数周的延迟,且缓解率低,因此重度抑郁症的负担尤为沉重。在过去的二十年中,出现了一个有希望改善抑郁症治疗效果的靶点:谷氨酸能信号传导。这篇叙述性综述高度概括了谷氨酸信号在突触生成和神经可塑性中的作用,以及谷氨酸失调对抑郁症的影响。基于谷氨酸与抑郁症有关的临床前证据,以及氯胺酮治疗在概念验证试验中对抑郁症的迅速改善,一系列以 N-甲基-D-天冬氨酸(NMDA)为靶点的疗法已被研究。虽然在已登记的 2 期或 3 期临床试验中对一系列疗法进行了研究,但其中大多数药物的研发工作已经停止。多种谷氨酸靶向抗抑郁药物正在积极研发中,其中两种已获得批准。美国食品和药物管理局(FDA)于2019年批准鼻腔给药艾司卡胺(Spravato®)用于治疗成人耐药性抑郁症,并于2020年批准其用于治疗伴有急性自杀意念或行为的成人多发性抑郁症。右美沙芬-安非他酮口服复方制剂(AXS-05,Auvelity® 缓释片)于 2022 年获得 FDA 批准,用于治疗成人 MDD。这些批准加强了谷氨酸在抑郁症中的重要性,是当代精神病学中令人兴奋的突破,为作为一线治疗或对单胺类抗抑郁药反应不佳或有不可接受的副作用的患者提供了新的治疗途径。
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来源期刊
CNS drugs
CNS drugs 医学-精神病学
CiteScore
12.00
自引率
3.30%
发文量
82
审稿时长
6-12 weeks
期刊介绍: CNS Drugs promotes rational pharmacotherapy within the disciplines of clinical psychiatry and neurology. The Journal includes: - Overviews of contentious or emerging issues. - Comprehensive narrative reviews that provide an authoritative source of information on pharmacological approaches to managing neurological and psychiatric illnesses. - Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. - Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in neurology and psychiatry. - Original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in CNS Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.
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