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.

标准抗抑郁药的功效对于许多患有重度抑郁症 (MDD) 和双相抑郁症等情绪障碍的患者来说是有限的，这凸显了开发新疗法的迫切需要。临床和临床前研究都表明谷氨酸能系统功能障碍与情绪障碍的病理生理学有关。特别是，在亚麻醉剂量的谷氨酸能调节剂消旋体 ( R,S)-氯胺酮用于情绪障碍患者。这些结果促使人们对抑郁症的其他谷氨酸能调节剂进行调查，无论是作为单一疗法还是辅助疗法。几种谷氨酸受体调节剂已在情绪障碍的概念验证研究中进行了测试。这份手稿简要概述了谷氨酸系统及其与快速抗抑郁反应的相关性，并讨论了谷氨酸受体调节剂的现有临床证据，包括 (1) 广泛的谷氨酸能调节剂 (( R, S )-氯胺酮、艾氯胺酮、( R )-氯胺酮，(2 R ,6 R)-羟基去甲氯胺酮 [HNK]、右美沙芬、Nuedexta [右美沙芬和奎尼丁的组合]、右美沙芬 [AVP-786]、轴体 [AXS-05]、右美沙酮 [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、rapastinel [GLYX-13]、apimostinel [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 (eliprodil [EVT-101]、traxoprodil [CP-101,606]、rislenemdaz [MK-0657/CERC-301])；(4) 代谢型谷氨酸受体 (mGluR) 调节剂 (basimglurant, AZD2066, RG1578, TS-161)；(5) 雷帕霉素复合物 1 (mTORC1) 激活剂 (NV-5138) 的哺乳动物靶标。其中许多代理仍处于开发的初步阶段。此外，迄今为止，与 ( R,S )-氯胺酮和艾氯胺酮相比，大多数都表现出相对温和的效果，尽管有些表现出更有利的特性。在这些新的药物中，最有希望的，并且存在最多证据的药物似乎是那些靶向离子型谷氨酸受体的药物。