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

Mikaela K Dimick, Danielle Omrin, Bradley J MacIntosh, Rachel H B Mitchell, Daniel Riegert, Anthony Levitt, Ayal Schaffer, Susan Belo, John Iazzetta, Garfield Detzler, Mabel Choi, Stephen Choi, Beverley A Orser, Benjamin I Goldstein, Mikaela K Dimick, Danielle Omrin, Bradley J MacIntosh, Rachel H B Mitchell, Daniel Riegert, Anthony Levitt, Ayal Schaffer, Susan Belo, John Iazzetta, Garfield Detzler, Mabel Choi, Stephen Choi, Beverley A Orser, Benjamin I Goldstein

Abstract

Introduction: 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.

Methods: 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.

Conclusions: 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.

Keywords: Bipolar depression; Cerebral blood flow; Nitrous oxide; Novel therapeutics.

© 2020 Published by Elsevier Inc.

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Source: PubMed

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