Currently available antidepressants can take weeks to months to exert their therapeutic effects; during this latent period, patients are at an increased risk of suicide. Moreover, treatment-resistance is common in depression. Interest was therefore raised by preclinical and clinical studies demonstrating that the NMDAR (N-methyl-D-aspartate receptor)-antagonist ketamine produced rapid and marked antidepressant effects. However, the current use of intravenous, subanesthetic doses of ketamine in depression remains off-label, limited to a medical setting, and is burdened by other significant challenges.

Results from Phase II trials with selective NR2B NMDAR antagonists have largely been viewed as disappointing. However, failures to produce ketamine-like antidepressant effects may result from inadequate dosing.

In 2013, the Food and Drug Administration (FDA, USA) granted Breakthrough Therapy Designation (BTD) for intranasal esketamine (the S-enantiomer of ketamine) to treat major depressive disorder with imminent risk for suicide. A study comparing both ketamine enantiomers would be desirable because in several rodent models of depression, R-ketamine exhibited both a higher potency and longer-lasting antidepressant-like activity compared to the S-enantiomer (esketamine), although the latter has a four-fold higher affinity for NMDAR.

Esketamine and the glycineB-like functional partial agonist rapastinel are now being assessed in Phase III studies, with primary completion dates within the next two-three years. These results will be crucial for both development of these compounds and the exploration of other glutamatergic targets for the treatment of depression and other neuropsychiatric disorders.

目前可用的抗抑郁药可能需要数周至数月才能发挥出治疗作用；在此潜伏期中，患者自杀的风险增加。而且，在抑郁症中常见的是抗治疗性。因此，临床前和临床研究引起了人们的兴趣，这些研究表明NMDAR（N-甲基-D-天冬氨酸受体）-拮抗剂氯胺酮可产生快速而显着的抗抑郁作用。然而，目前在抑郁症中静脉内使用亚麻醉剂量的氯胺酮仍然是标签外的，仅限于医学领域，并受到其他重大挑战的负担。

使用选择性NR2B NMDAR拮抗剂进行的II期试验的结果在很大程度上被认为令人失望。但是，剂量不足可能会导致无法产生类似于氯胺酮的抗抑郁作用。

2013年，美国食品药品监督管理局（FDA）授予鼻内七氯胺酮（氯胺酮的S-对映异构体）突破疗法称号（BTD），以治疗即将自杀的重度抑郁症。比较这两种氯胺酮对映体的研究将是可取的，因为在几种啮齿动物抑郁模型中，R-氯胺酮与S-对映体（乙草胺）相比具有更高的效力和更长的抗抑郁剂样活性，尽管后者具有4个-对NMDAR具有更高的亲和力。

乙草胺和类似甘氨酸B的功能性部分激动剂雷帕替尼目前正在III期研究中进行评估，主要的完成日期是在接下来的两年内。这些结果对于开发这些化合物以及探索其他用于治疗抑郁症和其他神经精神疾病的谷氨酸能靶标都是至关重要的。