Depression remains a global public health challenge, prompting interest in translational targets which allow for more effective and rapidly acting interventions. Nitrous oxide (N2O), an N-methyl-d-aspartate receptor antagonist, has demonstrated potential as a rapid-acting antidepressant. This study synthesised existing data on the efficacy and safety of N2O in depressive disorders.
We systematically reviewed clinical trials, exploratory studies, and protocol papers evaluating N2O for the treatment of depression, including major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression, following PRISMA guidelines. Meta-analysis was completed where possible. Primary outcomes were change in depressive symptoms and adverse events (AEs). Pooled mean differences (MD) and relative risk ratios were calculated using random- or fixed-effects models. Evidence mapping described trial characteristics across completed and ongoing studies.