Empirical evidence for the neurocognitive effect of nitrous oxide as an adjunctive therapy in patients with treatment resistant depression: A randomized controlled study.

Nitrous oxide (NO) has demonstrated an antidepressant effect for treatment-resistant depression (TRD), but no studies investigated the effects of NO on different cognition domains. This study aimed to test whether NO would display pro-cognitive effects. We conducted a double-blinded, placebo-controlled, randomized controlled trial, 44 patients with TRD were randomized to NO group (one-hour inhalation of 50% NO/50% oxygen) or placebo group (50% air/50% oxygen). Thirty-four patients completed cognitive tests at the pre-treatment phase, 1-week, and 2 weeks post-treatment including subjective cognitive function, processing speed, attention, and executive function. Although the antidepressant effect of NO was not significant at 1 week, patients still showed better performance of executive function at 1 week after receiving NO compared with the placebo. Moreover, this significant improvement still existed at 1 week after controlling for the change in depressive symptoms over-time. Additionally, no significant difference was observed in subjective cognitive function, processing speed, and attention between these two groups across the 2-week follow-up period. As the first study investigating the treatment effects of NO on improving cognitive function in TRD patients, the current study indicated that NO has a potential pro-cognitive effect on executive function and this effect might be independent from improvements in depressive symptoms.