• Peter Nagele, Andreas Duma, Michael Kopec, Marie Anne Gebara, Alireza Parsoei, Marie Walker, Alvin Janski, Vassilis N Panagopoulos, Pilar Cristancho, J Philip Miller, Charles F Zorumski, and Charles R Conway.
• Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Electronic address: nagelep@wustl.edu.
• Biol. Psychiatry. 2015 Jul 1; 78 (1): 10-18.

BackgroundN-methyl-D-aspartate receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD.MethodsIn this blinded, placebo-controlled crossover trial, 20 patients with TRD were randomly assigned to 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). The primary endpoint was the change on the 21-item Hamilton Depression Rating Scale (HDRS-21) 24 hours after treatment.ResultsMean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) min at a median inspiratory concentration of 44% (interquartile range, 37%-45%). In two patients, nitrous oxide treatment was briefly interrupted, and the treatment was discontinued in three patients. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared with placebo (mean HDRS-21 difference at 2 hours, -4.8 points, 95% confidence interval [CI], -1.8 to -7.8 points, p = .002; at 24 hours, -5.5 points, 95% CI, -2.5 to -8.5 points, p < .001; comparison between nitrous oxide and placebo, p < .001). Four patients (20%) had treatment response (reduction ≥50% on HDRS-21) and three patients (15%) had a full remission (HDRS-21 ≤ 7 points) after nitrous oxide compared with one patient (5%) and none after placebo (odds ratio for response, 4.0, 95% CI, .45-35.79; OR for remission, 3.0, 95% CI, .31-28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity.ConclusionsThis proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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