Nitrous oxide for the treatment of psychiatric disorders: A systematic review of the clinical trial landscape

Abstract

Objective: To systematically review published research studies and ongoing clinical trials investigating nitrous oxide (N 2 O) in psychiatric disorders, providing an up-to-date snapshot of the clinical research landscape.Methods: A comprehensive literature search was conducted for studies published until June 2021 using the OVID databases (MEDLINE, Embase, APA PsycInfo) and the clinical trial registries (ClinicalTrials.gov, ICTRP). Results:In total, five relevant published articles were identified, among which four investigated N 2 O for depression. One single-dose randomized controlled trial (RCT) for treatment-resistant depression (TRD), one triple crossover RCT comparing 50% vs. 25% N 2 O for TRD, and one repeated-dose RCT for major depressive disorder (MDD) suggest that N 2 O has preliminary feasibility with rapidacting effects on symptoms of depression. From the public registries, 10 relevant ongoing clinical trials were identified. They aim to explore the use of N 2 O for MDD, post-traumatic stress disorder, bipolar disorder, obsessive-compulsive disorder, and suicidal ideation. To date, the typical treatment protocol parameters were a single session of 50% N 2 O delivered for 60 min, although the concentration of 25% is also being explored. Projected enrolment numbers for ongoing trials (M = 55.0) were much higher than sample sizes for published studies (M = 13.0), suggesting that there potentially will be more large-scale RCTs published in the next few years. Conclusion:Preliminary studies support the feasibility of administering N 2 O for depression; however, appropriate blinding is a critical challenge. Larger-scale RCTs with repeated doses of N 2 O and follow-up times beyond 1 month are needed to confirm the feasibility, therapeutic efficacy, and sustainability of response.

Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide Inhalation

“…However, this study did include up to 30 minutes of BOLD resting-state scanning time for each scan session, which is considerably longer than in most trials. In addition, the lack of an active placebo must be acknowledged ( 48 ). Furthermore, extrapolating our findings from healthy control participants without depression to patients with depression is not unprecedented ( 20 ) but should be done cautiously because drug effects on the two populations may be disparate ( 49 ).…”

Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care

“…The use of psychoactive comparators is an ongoing research priority in studies designed to determine optimal concentrations and regimens for treatment of depressive disorders. 95,96 In this trial, a cohort of adults with bipolar disorder type I or II and contemporaneous treatment-refractory depression were treated with nitrous oxide or midazolam (0.5 mg and 1.5 mg intravenously). 97 In addition, these patients underwent concurrent magnetic resonance imaging studies during drug administration to examine cerebral perfusion as a predictor and indicator of a treatment response.…”

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“…Notwithstanding positive results from a triple crossover RCT comparing different concentrations in MDD suggest feasibility. Several trials with N 2 O are currently enrolling for depression (MDD and bipolar), suicidal ideation, post-traumatic stress disorder, and others [129].…”