Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial

Objective: Major depressive disorder (MDD) is related to glutamatergic dysfunction. Antagonists of glutamatergic N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have antidepressant properties. Nitrous oxide (N2O) is also a NMDAR antagonist. Thus, this study aimed to evaluate the effects of augmenting antidepressant treatment with N2O. Methods: This double blind, placebo-controlled randomized parallel pilot trial was conducted from June 2016 to June 2018 at the Hospital das Clinicas, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo. Twenty-three subjects with MDD (aged 18 to 65, on antidepressants, with a score > 17 on the 17-item-Hamilton Depression Rating Scale [HAM-D-17]) received 50% N2O (n=12; 37.17 +/- 13.59 years) or placebo (100% oxygen) (n=11; 37.18 +/- 12.77 years) for 60 minutes twice a week for 4 weeks. The primary outcome was changes in HAM-D-17 from baseline to week 4. Results: Depressive symptoms improved significantly in the N2O group (N2O: from 22.58 +/- 3.83 to 5.92 +/- 4.08; placebo: from 22.44 +/- 3.54 to 12.89 +/- 5.39, p < 0.005). A total of 91.7% and 75% of the N2O group subjects achieved response (>= 50% reduction in HAM-D-17 score) and remission (HAM-D-17 < 7), respectively. The predominant adverse effects of N2O treatment were nausea, vomiting, and headache. Conclusion: N2O treatment led to a statistically significant reduction in HAM-D-17 scores compared to placebo.