Ketamine: NMDA Receptors and Beyond

Ketamine, a dissociative anesthetic, has drawn attention for both its psychosis-like effects and its rapid antidepressant action. While ketamine clearly inhibits NMDARs and may preferentially affect interneurons, recent research questions whether NMDAR blockade is essential for its mood-elevating effects. This viewpoint reviews evidence that NMDARs are important triggers for some psychiatric effects, but the antidepressant trigger might be unrelated to NMDARs. The evolving understanding of ketamine's mechanisms holds promise for disentangling and treating the biology of depression and psychosis.

Study at a glance

Abstract

Human studies examining the effects of the dissociative anesthetic ketamine as a model for psychosis and as a rapidly acting antidepressant have spurred great interest in understanding ketamine's actions at molecular, cellular, and network levels. Although ketamine has unequivocal uncompetitive inhibitory effects on N-methyl-d-aspartate receptors (NMDARs) and may preferentially alter the function of NMDARs on interneurons, recent work has questioned whether block of NMDARs is critical for its mood enhancing actions. In this viewpoint, we examine the evolving literature on ketamine supporting NMDARs as important triggers for certain psychiatric effects and the possibility that the antidepressant trigger is unrelated to NMDARs. The rapidly evolving story of ketamine offers great hope for untangling and treating the biology of both depressive and psychotic illnesses.