Rapid antidepressant potential of nitrous oxide: current state and major questions.

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.

Study at a glance

Abstract

The success of ketamine, a dissociative anesthetic and non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, as a rapidly acting antidepressant has ignited efforts to identify other novel depression treatments. In recent years, several clinical trials indicated that nitrous oxide (N2O), an inhalational dissociative anesthetic in clinical use for over 150 years, also has rapid and durable antidepressant effects in patients with major depressive disorder (MDD) and treatment resistant major depression (TRMD). N2O is a non-competitive NMDAR inhibitor but acts on NMDARs by mechanisms distinct from ketamine. Cellular and neuronal circuit studies of N2O-induced psychotropic and antidepressant effects are in their infancy and suggest that N2O shares at least some downstream mechanisms with ketamine, while also having unique effects on neurophysiology and signaling. Human neuroimaging and brain network connectivity studies of N2O have begun to identify acute and persisting effects of the drug on brain circuits likely relevant for antidepressant responses. In this review, we highlight the current state of clinical and preclinical research into the effects of N2O and emphasize major unanswered questions, some of which are currently being explored. We emphasize future directions and potential barriers to clinical use of N2O for treatment of patients with psychiatric illnesses.