Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Impact of the Allergy Clarification for Cefazolin Evidence-based Prescribing Tool on Receipt of Preferred Perioperative Prophylaxis: An Interrupted Time Series Study.

Implementation of a perioperative allergy and antibiotic assessment tool in patients with reported beta-lactam allergy resulted in a pronounced and sustained increase in perioperative cefazolin use. This intervention could result in improved efficiencies surrounding perioperative antibiotic administration and possible reductions in surgical site infection rates.

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

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.