Skip to content

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

Karim S Ladha, Jiwon Lee, Gabriella Mattina, Janneth Pazmino-Canizares, Duminda N Wijeysundera, Fatemeh Gholamali Nezhad, Kaylyssa Philip, Vanessa K Tassone, Fathima Adamsahib, Venkat Bhat

PLoS One 2024 DOI: 10.1371/journal.pone.0297330 (opens in new tab)

Read Full Text
Relevant Not relevant

Study at a glance

AI-extracted from the abstract
Characteristics Randomized active placebo-controlled pilot trial Pilot study Peer reviewed
Sample size 40
Population Participants with treatment-resistant depression
Interventions Nitrous oxide Midazolam
Dose Nitrous oxide: 1 hour at 50% concentration; Midazolam: 0.02 mg/kg in 100mL, up to 2mg
Duration 4-week intervention, 6-week follow-up
Measures Montgomery-Åsberg Depression Rating Scale (MADRS)
Topics Depression
Registration NCT04957368
Key findings The study will assess feasibility and preliminary efficacy of repeated nitrous oxide for treatment-resistant depression.

Abstract

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. 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. 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. ClinicalTrials.gov NCT04957368. Registered on July 12, 2021.

Comparable studies

Other randomized controlled trials on depression, most cited first.

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

Citations in the library

Cited by 6

and 1 more in the library

Cites 12

and 7 more in the library

Related reading

Explore topics

Depression