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

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.