Current therapeutic options for major depressive disorder (MDD) and bipolar disorder (BD) are associated with a lag of onset that can prolong distress and impairment for patients, and their antidepressant efficacy is often limited. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, and in the development of novel therapeutics for this disorder. The rapid and robust antidepressant effects of the N-methyl-d-aspartate (NMDA) antagonist ketamine were first observed in 2000. Since then, other NMDA receptor antagonists have been studied in MDD. Most have demonstrated relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics. This article reviews the clinical evidence supporting the use of novel glutamate receptor modulators with direct affinity for cognate receptors: (1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); (2) subunit (GluN2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); (3) NMDA receptor glycine-site partial agonists (GLYX-13); and (4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). We also briefly discuss several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy that have yet to be studied clinically; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists and mGluR2/3 negative allosteric modulators. The review also discusses other promising, non-glutamatergic targets for potential rapid antidepressant effects, including the cholinergic system (scopolamine), the opioid system (ALKS-5461), corticotropin releasing factor (CRF) receptor antagonists (CP-316,311), and others.

中文翻译：

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快速抗抑郁作用的新目标。


目前针对重度抑郁症（MDD）和双相情感障碍（BD）的治疗选择与发病滞后有关，这可能会延长患者的痛苦和损害，而且其抗抑郁功效往往有限。目前批准的所有治疗重度抑郁症的抗抑郁药物主要通过单胺能机制发挥作用。谷氨酸是中枢神经系统中主要的兴奋性神经递质，谷氨酸及其同源受体与 MDD 的病理生理学以及该疾病的新疗法的开发有关。 N-甲基-D-天冬氨酸 (NMDA) 拮抗剂氯胺酮快速而强大的抗抑郁作用于 2000 年首次被观察到。此后，其他 NMDA 受体拮抗剂在 MDD 中得到了研究。与氯胺酮相比，大多数药物表现出相对温和的抗抑郁作用，但有些药物表现出更有利的特性。本文回顾了支持使用与同源受体具有直接亲和力的新型谷氨酸受体调节剂的临床证据：（1）非竞争性 NMDA 受体拮抗剂（氯胺酮、美金刚、右美沙芬、AZD6765）； (2)亚基(GluN2B)特异性NMDA受体拮抗剂(CP-101，606/traxoprodil，MK-0657)； (3) NMDA受体甘氨酸位点部分激动剂(GLYX-13)； (4) 代谢型谷氨酸受体 (mGluR) 调节剂（AZD2066、RO4917523/basimglurant）。我们还简要讨论了其他几个具有临床前抗抑郁药功效但尚未进行临床研究的理论谷氨酸受体靶点；这些包括 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 激动剂和 mGluR2/3 负变构调节剂。 该综述还讨论了其他有希望的、具有潜在快速抗抑郁作用的非谷氨酸靶点，包括胆碱能系统（东莨菪碱）、阿片类药物系统（ALKS-5461）、促肾上腺皮质激素释放因子（CRF）受体拮抗剂（CP-316,311）等。