Nitrous oxide for treatment-resistant major depression: A proof-of-concept trial

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, Charles R. Conway

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114 Scopus citations


BACKGROUND: N-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. METHODS: In 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. RESULTS: Mean duration of nitrous oxide treatment was 55.6 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, 24.8 points, 95% confidence interval [CI], 21.8 to 27.8 points, p =.002; at 24 hours, 25.5 points, 95% CI, 22.5 to 28.5 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. CONCLUSIONS: This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.

Original languageEnglish
Pages (from-to)10-18
Number of pages9
JournalBiological Psychiatry
Issue number1
StatePublished - 2015


  • Major depression
  • Nitrous oxide
  • Treatment-resistant depression


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