Major depression & NMDA receptor A growing body of evidence has pointed to the ionotropic glutamate N-methyl-d-aspartate (NMDA) receptor as an important player in the etiology of psychopathologies, including anxiety and major depression [4,5]. In fact, drugs that block NMDA receptor signaling have shown antidepressant properties in both preclinical and clinical studies [6]. In this way, chemical compounds acting on NMDA receptors could be interesting as pharmacological targets for the treatment of mood disorders. Several preclinical studies have demonstrated that NMDA antagonists, such as MK-801, AP7, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, neramexane and others, display anxiolyticand antidepressant-like effects in rodents subjected to distinct animal models of anxiety and depression [7–12]. Of those NMDA receptor antagonists preclinically tested, ketamine displayed an outstanding profile of antidepressant-like action, which will be discussed further in the text.