Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg 10 CRC, Unit 7 Southeast, Room 7-5342, Bethesda, MD, 20892, USA.
CNS Drugs. 2021 May;35(5):527-543. doi: 10.1007/s40263-021-00816-x. Epub 2021 Apr 26.
The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.
标准抗抑郁药对于许多患有心境障碍的患者（如重度抑郁症和双相抑郁症）的疗效有限，这凸显出开发新型疗法的迫切需要。临床和临床前研究都表明，谷氨酸能系统功能障碍与心境障碍的病理生理学有关。特别是，在患有心境障碍的个体中，亚麻醉剂量的谷氨酸调节剂外消旋（R，S）-氯胺酮可迅速减轻抑郁症状。这些结果促使人们研究其他用于治疗抑郁症的谷氨酸能调节剂，无论是单独使用还是联合使用。已经在多项概念验证研究中测试了几种谷氨酸受体调节剂用于心境障碍。本文简要概述了谷氨酸系统及其与快速抗抑郁反应的相关性，并讨论了现有的谷氨酸受体调节剂的临床证据，包括：（1）广泛的谷氨酸调节剂[（R，S）-氯胺酮、艾氯胺酮、（R）-氯胺酮、（2R，6R）-羟基去甲氯胺酮[HNK]、右美沙芬、Nuedexta[右美沙芬和奎尼丁的混合物]、右美托咪定[AVP-786]、Axsome[AXS-05]、右美沙芬[REL-1017]、一氧化二氮、AZD6765、CLE100、AGN-241751]；（2）甘氨酸位点调节剂[D-环丝氨酸（DCS）、NRX-101、拉帕替林（GLYX-13）、阿皮莫斯特林（NRX-1074）、肌氨酸、4-氯犬尿氨酸（4-Cl-KYN/AV-101）]；（3）亚基（NR2B）特异性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂[伊利普罗迪（EVT-101）、特拉佐普罗迪（CP-101、606）、利森美达唑（MK-0657/CERC-301）]；（4）代谢型谷氨酸受体（mGluR）调节剂[巴西米拉（basimglurant）、AZD2066、RG1578、TS-161]；（5）哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）激活剂[NV-5138]。这些药物中有许多仍处于初步开发阶段。此外，迄今为止，与（R，S）-氯胺酮和艾氯胺酮相比，大多数药物的效果相对温和，尽管有些药物具有更有利的特征。在这些新型药物中，最有前途的，也是证据最多的，似乎是那些针对离子型谷氨酸受体的药物。
