Patients with treatment-resistant unipolar major depressive disorder who qualified for the RECOVER trial—the largest randomized sham-controlled study of vagus nerve stimulation for a psychiatric condition—had severe disability, a median of 11.0 prior failed antidepressant treatments, and high rates of suicidality (77% with suicidal ideation, 40% with previous suicide attempts). Seventy-one percent had received at least one prior interventional psychiatric treatment (electroconvulsive therapy, transcranial magnetic stimulation, or esketamine). Compared to those without such history, recipients of interventional treatments were younger, more severely depressed, had greater suicidal ideation, earlier onset of depression, and more failed medication trials.
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.