Park Minkyung, Niciu Mark J, Zarate Carlos A
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD U.S.A., 20892.
Curr Behav Neurosci Rep. 2015 Dec;2(4):198-208. doi: 10.1007/s40473-015-0050-5. Epub 2015 Oct 9.
All currently approved antidepressant medications for major depressive disorder (MDD) and bipolar disorder act primarily on the monoaminergic system and have varying affinities for serotonergic, norepinephrine-ergic, and/or dopaminergic receptors. Unfortunately, these drugs are only effective in approximately two-thirds of patients. Glutamate is the major excitatory neurotransmitter in the central nervous system, and the glutamatergic system has been implicated in the pathophysiology of MDD. Here, we review the putative involvement of the glutamate receptor subtypes-N-methyl-D-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and the group I, II, and III metabotropic glutamate receptors (mGluRs)-in the development of novel and more effective treatments for MDD as well as preclinical and clinical trials of drugs targeting these receptors. The rapid and robust antidepressant effects of ketamine-an NMDA receptor antagonist-have been consistently replicated in multiple trials. Other glutamatergic drugs have been investigated with varying success. Here, we highlight some of the most interesting results, including: 1) repeated oral, intramuscular, and sublingual ketamine appears to be less robustly effective than intravenous ketamine, but also causes fewer significant adverse effects; 2) the glycine partial agonist GLYX-13 appears to be effective both as monotherapy and adjunctive treatment in the treatment of MDD. An oral analogue, NRX-1074, is currently under investigation; and 3) mGluR modulators targeting mGluR5 have demonstrated convincing preclinical results.
目前所有获批用于治疗重度抑郁症（MDD）和双相情感障碍的抗抑郁药物主要作用于单胺能系统，对5-羟色胺能、去甲肾上腺素能和/或多巴胺能受体具有不同的亲和力。不幸的是，这些药物仅对约三分之二的患者有效。谷氨酸是中枢神经系统中的主要兴奋性神经递质，谷氨酸能系统已被认为与MDD的病理生理学有关。在此，我们综述了谷氨酸受体亚型——N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）、海人酸，以及第I、II和III组代谢型谷氨酸受体（mGluRs）——在开发新型、更有效的MDD治疗方法以及针对这些受体的药物的临床前和临床试验中的假定作用。氯胺酮（一种NMDA受体拮抗剂）的快速而强大的抗抑郁作用已在多项试验中得到一致验证。其他谷氨酸能药物也已进行了不同程度的研究。在此，我们重点介绍一些最有趣的结果，包括：1）重复口服、肌肉注射和舌下含服氯胺酮的效果似乎不如静脉注射氯胺酮显著，但产生的严重不良反应也较少；2）甘氨酸部分激动剂GLYX-13作为单一疗法和辅助疗法治疗MDD似乎均有效。一种口服类似物NRX-1074目前正在研究中；3）靶向mGluR5的mGluR调节剂已在临床前研究中取得了令人信服的结果。
