The efficacy and tolerability of inhaled nitrous oxide in major depressive disorder: a systematic review and meta-analysis.

Nitrous oxide (N2O) has been initially confirmed by clinical trials to benefit to patients with major depressive disorder (MDD). However, there needs to be a meta-analysis to compare the efficacy and tolerability of N2O in MDD. PubMed, EMBASE, and Cochrane Library were searched for relevant studies up to Jan 1st, 2023. The meta-analysis mainly compared the outcome of the change in depression severity scores, response, remission, and adverse events in patients with MDD receiving 50% N2O and placebo. Four studies with 133 patients were eventually identified. We found that the N2O group and control group showed an overall significant difference in the change in depression severity score for patients at 2 h, 24 h, and 2 weeks or more (2 h, SMD = - 0.64, 95% CI - 0.01 to - 0.28, p < 0.0001) (24 h, SMD = - 0.65, 95% CI - 1.01 to - 0.29, p < 0.0001) (2 weeks, SMD = - 0.76, 95% CI - 1.16 to - 0.36, p < 0.0001). For the response and remission rate, the long-term effect of N2O was also statistically significant (for the response, RR = 2.33, 95% CI 1.23 to 4.44, p = 0.01) (for the remission, RR = 4.68, 95% CI 1.49 to 14.68, p = 0.008). For safety outcomes, patients treated with N2O had higher odds of nausea or vomiting (RR = 10.15, 95% CI 1.96 to 52.59, p = 0.009). Our study suggested that N2O has a rapid and long-lasting antidepressant effect in patients with MDD. However, the efficacy of lower or titrated concentration of N2O should be further investigated.