Nitrous oxide as a putative novel dual-mechanism treatment for bipolar depression: Proof-of-concept study design and...

Depressive symptoms predominate in the course of bipolar disorder (BD) and there is an urgent need to evaluate novel application of repurposed compounds that act on pre-specified treatment targets. Several lines of reasoning suggest that nitrous oxide (N₂O) is an ideal medication to study as a potential treatment and as a strategy to identify the underlying pathophysiology of bipolar depression. N₂O is a potent cerebral vasodilator and there is compelling evidence of reduced frontal cerebral blood flow (CBF; i.e. hypoperfusion) in depression. Therefore, N₂O may increase CBF and thereby improve symptoms of depression. The goal of this randomized, double-blind trial is to study the effect of a single administration of N₂O versus the active comparator midazolam on mood and CBF in adults with treatment-resistant bipolar depression.

Participants with BD-I/-II currently experiencing a major depressive episode will be randomized to one of two conditions (n = 20/group): 1) inhaled N₂O plus intravenous saline, or 2) inhaled room air plus intravenous midazolam. Montgomery-Asberg Depression Rating Scale scores will serve as the primary endpoint. CBF will be measured via arterial spin labelling magnetic resonance imaging.

N₂O is a potential novel treatment for bipolar depression, as it causes cerebral vasodilation. This proof-of-concept study will provide valuable information regarding the acute impact of N₂O on mood and on CBF. If N₂O proves to be efficacious in future larger-scale trials, its ubiquity, safety, low cost, and ease of use suggest that it has great potential to become a game-changing acute treatment for bipolar depression.