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.
Nitrous oxide (N2O), an inhalational anesthetic used for over 150 years, shows rapid and durable antidepressant effects in patients with major depressive disorder and treatment-resistant depression, according to recent clinical trials. Like ketamine, N2O inhibits N-methyl-D-aspartate receptors (NMDARs) but through distinct mechanisms. Cellular and neuronal circuit studies are early but suggest N2O shares some downstream mechanisms with ketamine while also having unique effects on neurophysiology and signaling. Human neuroimaging studies have begun identifying acute and persisting effects of N2O on brain circuits relevant to antidepressant responses. This review highlights current clinical and preclinical research, major unanswered questions, future directions, and potential barriers to clinical use.