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GABA and glutamate systems as therapeutic targets in depression and mood disorders.γ-氨基丁酸（GABA）和谷氨酸系统作为抑郁症和情绪障碍的治疗靶点。
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A hypothesis of monoamine (5-HT) - Glutamate/GABA long neural circuit: Aiming for fast-onset antidepressant discovery.单胺（5-HT）-谷氨酸/GABA 长神经回路假说：旨在快速发现抗抑郁药物。
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Glutamatergic Modulators in Depression.谷氨酸能调节剂在抑郁症中的作用。
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Positive AMPA and Kainate Receptor Modulators and Their Therapeutic Potential in CNS Diseases: A Comprehensive Review.阳性AMPA和海人酸受体调节剂及其在中枢神经系统疾病中的治疗潜力：综述
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1
Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3.依他佐辛鼻喷剂联合口服抗抑郁药治疗老年难治性抑郁症的疗效和安全性-TRANSFORM-3。
Am J Geriatr Psychiatry. 2020 Feb;28(2):121-141. doi: 10.1016/j.jagp.2019.10.008. Epub 2019 Oct 17.
2
Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism.阿片受体拮抗作用对氯胺酮抗抑郁作用的衰减。
Am J Psychiatry. 2018 Dec 1;175(12):1205-1215. doi: 10.1176/appi.ajp.2018.18020138. Epub 2018 Aug 29.
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Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study.鼻腔内使用艾司氯胺酮治疗有自杀风险的抑郁症和自杀意念患者快速减轻症状的疗效和安全性：一项双盲、随机、安慰剂对照研究的结果。
Am J Psychiatry. 2018 Jul 1;175(7):620-630. doi: 10.1176/appi.ajp.2018.17060720. Epub 2018 Apr 16.
4
Convergent Mechanisms Underlying Rapid Antidepressant Action.快速抗抑郁作用的潜在汇聚机制。
CNS Drugs. 2018 Mar;32(3):197-227. doi: 10.1007/s40263-018-0492-x.
5
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial.鼻腔内依他佐辛辅助口服抗抑郁药治疗难治性抑郁症的疗效和安全性：一项随机临床试验。
JAMA Psychiatry. 2018 Feb 1;75(2):139-148. doi: 10.1001/jamapsychiatry.2017.3739.
6
Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of l-4-chlorokynurenine in healthy volunteers.随机、双盲、安慰剂对照、剂量递增研究：L-4-氯犬尿氨酸在健康志愿者中的安全性、药代动力学及抗痛觉过敏活性研究
Scand J Pain. 2017 Oct;17:243-251. doi: 10.1016/j.sjpain.2017.05.004. Epub 2017 Jun 15.
7
The Ketamine Metabolite 2R,6R-Hydroxynorketamine Blocks NMDA Receptors and Impacts Downstream Signaling Linked to Antidepressant Effects.氯胺酮代谢物2R,6R-羟基去甲氯胺酮阻断NMDA受体并影响与抗抑郁作用相关的下游信号传导。
Neuropsychopharmacology. 2018 Jan;43(1):221-222. doi: 10.1038/npp.2017.210.
8
A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders.氯胺酮用于治疗精神疾病的临床非标签使用情况调查。
Am J Psychiatry. 2017 Jul 1;174(7):695-696. doi: 10.1176/appi.ajp.2017.17020239.
9
Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.产后抑郁的 Brexanolone（SAGE-547 注射液）：一项随机对照试验。
Lancet. 2017 Jul 29;390(10093):480-489. doi: 10.1016/S0140-6736(17)31264-3. Epub 2017 Jun 12.
10
A Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Design Trial of Adjunctive Riluzole for Treatment-Resistant Major Depressive Disorder.一项伴有利鲁唑治疗抵抗性重性抑郁障碍的随机、双盲、安慰剂对照、序贯平行对照设计的临床试验。
Neuropsychopharmacology. 2017 Dec;42(13):2567-2574. doi: 10.1038/npp.2017.106. Epub 2017 May 29.

新一代抗抑郁药：基于谷氨酸/GABA 神经递质系统的新型快速作用治疗情绪障碍药物研发管线的最新进展。

A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems.

机构信息

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Connecticut Mental Health Center, New Haven, CT, USA.

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Connecticut Mental Health Center, New Haven, CT, USA.

出版信息

Drug Discov Today. 2019 Feb;24(2):606-615. doi: 10.1016/j.drudis.2018.11.007. Epub 2018 Nov 14.

DOI:10.1016/j.drudis.2018.11.007
PMID:30447328
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6397075/
Abstract

Mood disorders represent the largest cause of disability worldwide. The monoaminergic deficiency hypothesis, which has dominated the conceptual framework for researching the pathophysiology of mood disorders and the development of novel treatment strategies, cannot fully explain the underlying neurobiology of mood disorders. Mounting evidence collected over the past two decades suggests the amino acid neurotransmitter systems (glutamate and GABA) serve central roles in the pathophysiology of mood disorders. Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217.

摘要

心境障碍是全球范围内导致残疾的最大原因。单胺能不足假说主导了心境障碍病理生理学和新治疗策略研究的概念框架，但不能完全解释心境障碍的潜在神经生物学。过去二十年收集的越来越多的证据表明，氨基酸神经递质系统（谷氨酸和 GABA）在心境障碍的病理生理学中起核心作用。在这里，我们回顾了作用于这些系统的化合物的开发进展及其假定的作用机制。我们包括靶向谷氨酸的药物，如消旋酮、依他佐辛、lanicemine（AZD6765）、traxoprodil（CP-101,606）、EVT-101、rislenemdaz（CERC-301/MK-0657）、AVP-786、AXS-05、rapastinel（前身为 GLYX-13）、apimostinel（NRX-1074/AGN-241660）、AV-101、NRX-101、basimglurant（RO4917523）、decoglurant（RG-1578/RO4995819）、tulrampator（CX-1632/S-47445）和利鲁唑；以及靶向 GABA 的药物，如 brexanolone（SAGE-547）、 ganaxolone 和 SAGE-217。