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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

Contemporary Clinical Trials Communications September 1, 2020 DOI: 10.1016/j.conctc.2020.100600 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized controlled trial Double-blind Peer reviewed
Sample size 40
Population Adults with treatment-resistant bipolar depression (BD-I or BD-II) currently experiencing a major depressive episode
Interventions Nitrous oxide Midazolam
Duration Single administration
Topics Depression
Keywords Bipolar depression Cerebral blood flow Nitrous oxide Novel therapeutics
Key findings The study is a proof-of-concept trial; no results are reported, but the authors hypothesize that N2O will improve mood and increase frontal cerebral blood flow in bipolar depression.

Abstract

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.

Comparable studies

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Study Year Design Participants
A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Subjects with DSM-IV major depression (treatment resistant) 2006 Randomized, placebo-controlled, double-blind crossover study n = 18
Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. Recovered recurrently depressed patients 2000 Randomized controlled trial n = 145
Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety 2016 Randomized controlled trial n = 51
Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression 2016 Double-blind, placebo-controlled, crossover trial n = 29
Mindfulness-Based Cognitive Therapy for Depression: Replication and Exploration of Differential Relapse Prevention Effects. Recovered recurrently depressed patients 2004 Randomized controlled trial n = 73

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