Journal of Neuroscience
November 2, 2016
Charles F. Zorumski, Yukitoshi Izumi, Steven Mennerick
252 citations
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.
Molecular psychiatry
June 1, 2026
Charles F Zorumski, Joseph Cichon, Yukitoshi Izumi et al.
5 citations
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.
medRxiv : the preprint server for health sciences
August 17, 2024
Charles R Conway, Ben Julian A Palanca, Thomas Zeffiro et al.
preprint
Nitrous oxide (N2O) reduces functional connectivity in mood-related brain networks in people with treatment-resistant major depression (TRD) but increases connectivity in healthy controls. In a crossover trial, 14 TRD patients and 16 healthy controls received one-hour inhalations of 50% N2O or placebo. Resting-state fMRI scans before, 2 hours, and 24 hours after inhalation showed that N2O progressively decreased connectivity in TRD patients across five brain networks (salience, default mode, reward, cingulo-opercular, and the dorsal nexus), while increasing connectivity in controls. The findings suggest N2O's antidepressant effects involve specific alterations in depressed brains.
Frontiers in psychiatry
January 1, 2015
Charles F Zorumski, Peter Nagele, Steven Mennerick et al.
Treatment-resistant major depression (TRMD) affects 15-30% of people with major depressive disorder. N-methyl-d-aspartate receptors (NMDARs) have become targets for treating depression, with most research focusing on ketamine, though its psychotomimetic and other side effects may limit its use. A recent pilot clinical trial tested nitrous oxide, an NMDAR antagonist that works through a different mechanism than ketamine, in patients with severe TRMD. This paper reviews TRMD as a subtype of MDD, the development of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant.
Joseph Cichon, Thomas Joseph, Xinguo Lu et al.
A single dose of inhaled nitrous oxide (N2O) rapidly activates layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress, rescuing a stress-associated hypoactivity state. This activation persists after exposure and is necessary for N2O's antidepressant-like effects. Although N2O is believed to act primarily through NMDA-receptor antagonism, L5 neurons activate even when NMDA-receptor function is blocked. Instead, N2O-induced inhibition of calcium-sensitive potassium (SK2) channels drives specific L5 activity and the ensuing antidepressant-like effects. These results indicate that N2O's fast antidepressant action relies on novel molecular actions in distinct cortical cell types.