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

Introduction

Guimara and colleagues frame their study within limitations of monoaminergic antidepressants and growing evidence implicating glutamatergic dysfunction in major depressive disorder (MDD). Previous preclinical and clinical work has shown that antagonism of the N-methyl-D-aspartate receptor (NMDAR), notably by ketamine, can produce rapid antidepressant effects. Nitrous oxide (N2O) is another NMDAR antagonist with additional actions on opioid receptors, GABAergic sites, and serotonergic systems; a 2015 proof-of-concept crossover trial reported short-term antidepressant benefit after a single 50% N2O inhalation in treatment-resistant depression. Safety concerns with N2O include effects on vitamin B12 and homocysteine metabolism, but at therapeutic concentrations it is commonly considered safe for outpatient use. This pilot trial was designed to test whether repeated adjunctive N2O inhalation would reduce depressive symptoms in patients with MDD who remained symptomatic despite at least 4 weeks of antidepressant treatment. The investigators hypothesised that 50% N2O administered twice weekly for 4 weeks, added to ongoing antidepressant therapy, would produce greater reductions in clinician-rated depressive symptoms than placebo (100% oxygen). The study therefore examined both acute (within-session) and cumulative antidepressant effects over a 1-month course of semiweekly N2O sessions.