Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression

Abstract

Background Nitrous oxide has shown potentially as an efficacious intervention for treatment-resistant depression, yet there remains insufficient evidence pertaining to repeated administration of nitrous oxide over time and active placebo-controlled studies with optimal blinding. Thus, we aim to examine the feasibility and preliminary efficacy of a six-week follow up study examining the effects of a 4 week course of weekly administered nitrous oxide as compared to the active placebo, midazolam. Methods In this randomized, active placebo-controlled, pilot trial, 40 participants with treatment-resistant depression will receive either inhaled nitrous oxide (1 hour at 50% concentration) plus intravenous saline (100mL) or inhaled oxygen (1 hour at 50% concentration) plus intravenous midazolam (0.02 mg/kg in 100mL, up to 2mg) once per week, for 4 consecutive weeks. Participants will be followed up for 6 weeks starting from the first treatment visit. Primary feasibility outcomes include recruitment rate, withdrawal rate, adherence, missing data, and adverse events. The primary exploratory clinical outcome is change in Montgomery-Åsberg Depression Rating Scale (MADRS) score at day 42 of the study. Other exploratory clinical outcomes include remission (defined as MADRS score <10), response (defined as ≥ 50% reduction in MADRS score), and adverse side effects. Discussion This pilot study will provide valuable information regarding the feasibility and preliminary efficacy of repeated nitrous oxide administration over time for treatment-resistant depression. If feasible, this study will inform the design of a future definitive trial of nitrous oxide as an efficacious and fast-acting treatment for treatment-resistant depression. Trial registration ClinicalTrials.gov NCT04957368. Registered on July 12, 2021.