Efficacy and safety of nitrous oxide for patients with treatment-resistant depression, a randomized controlled trial

•A single inhalation of 50% nitrous oxide has an antidepressant effect for treatment-resistant depression.•The antidepressant effect of 50% nitrous oxide lasts for no more than one week.•Nitrous oxide is safe for patients with treatment-resistant depression. Nitrous oxide (N2O), an N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect for treatment-resistant depression (TRD) preliminarily in the United States. This study aimed to test the efficacy and safety of N2O for TRD patients in China. In this double-blinded, placebo-controlled trial, 44 patients with TRD were randomized to receive a one-hour inhalation of a mixture of either 50% N2O/50% oxygen (N2O group) or 50% air/50% oxygen (placebo group). The primary outcome was the change on the 17-item Hamilton Depression Rating Scale (HDRS-17) over a course of two weeks. Using modified intention-to-treat analysis, the between group difference was found in the HDRS-17 score at two hours and 24 h after inhalation treatment, while no significant difference was found in week one and week two. Patients receiving N2O reported a significantly higher number of adverse events. All the adverse events lasted for no more than 24 h. No serious adverse events were reported. A single inhalation of 50% N2O effectively alleviates depression in patients with TRD in China. The efficacy lasts for no more than one week. N2O is safe for patients with TRD.