Introduction: With regards to depression, the role of N-methyl-D-aspartate receptor (NMDA) was pursued many years ago, mainly in the form of preclinical studies. Since then, there have been several clinical data in the literature indicating the efficacy of NMDA receptor antagonists of either stand-alone or as an adjunct therapy in depression and depression-related diseases.
Areas covered: The present review focuses on clinical data of well-known and recently discovered NMDA receptor antagonists/modulators and their mechanisms of action.
Expert opinion: Several NMDA receptor modulators have been tested in both human and animal studies to examine their potential antidepressant activity. Most of the compounds that exhibited beneficial properties in the animal tests and models of depression either have never been tested or did not show efficacy in humans. For some of them, such as ketamine, where a consistently reproducible antidepressant effect was found, clinical use is limited by a variety of adverse effects. However, ketamine has become a standard tool for identifying the biological factors associated with rapid antidepressant action and, as such, is a novel target for the development of new therapeutics.