Introduction: Current antidepressant therapies exhibit low therapeutic efficiency and delayed onset of antidepressant action. Thus, the search for better acting agents is a continuous process. One of the primary targets for the development of new antidepressant drugs is the glutamate N-methyl-D-aspartate (NMDA) receptor. Areas covered: The present review aims to summarize and provide an update on published preclinical data evaluating the antidepressant efficacy of various NMDA antagonists and their mechanisms of action. The review also provides an update on the clinical efficacy of ketamine and esketamine as well as other NMDA receptor antagonists based on published results from clinical studies. Expert opinion: The recent approval of esketamine by the FDA for the treatment of major depressive disorder (MDD) culminates the almost 30 years of research focused on the NMDA receptor as a target for the development of antidepressants. This action gives hope to patients who do not respond to currently available pharmacotherapy. While knowledge of the mechanism of action of ketamine/esketamine will pave the way for the creation of a new class of antidepressants, recent results have shown that several issues regarding the use of these compounds or other NMDA receptor antagonists must be clarified.
Keywords: NMDA receptor; antagonist; antidepressant; depression; ketamine.