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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