A distinct pattern of EEG and ECG changes associated with inhalational nitrous oxide’s rapid antidepressant effects

Abstract

Two recent randomized, placebo-controlled, double-blind trials have provided exciting new evidence for the rapid antidepressant effects of inhalational nitrous oxide [1, 2]. Intriguingly, nitrous oxide has been shown to faithfully mimic, in experimental rodents, key characteristics of drugs that block N-methyl-d-aspartate (NMDA) glutamate receptors such as, most notably, ketamine [3], the first nextgeneration antidepressant [4]. Crucially, synaptic responses in hippocampal slices harvested from adult rats confirmed critical similarities between nitrous oxide and ketamine, most notably NMDA-dependent synaptic enhancement, activation of tropomyosin receptor kinase B (TrkB) receptors, and activation of mechanistic target of rapamycin (mTOR) signaling, while also noting some differences between the two molecules [5]. In human patients, ketamine increases heart rate and blood pressure via sympathetic pathways [6]. Moreover, brain effects of ketamine and, in particular, the antidepressant response to intravenous ketamine have been linked with decreases in electroencephalographic (EEG) alpha activity [7]. However, the basis of nitrous oxide’s antidepressant action in humans remains to be delineated. Here, in a case series of three patients, we reproduce the rapid antidepressant effects of nitrous oxide in patients with difficult-to-treat depression and investigate the physiological and EEG responses to nitrous oxide to allow a comparison with ketamine’s well-established effects. Methods