Sustained Mood Improvement With Laughing Gas Exposure: A Randomized Controlled Pilot Trial (SMILE)

The purpose of the study is to investigate a short-term treatment option for major depressive disorders by administering nitrous oxide gas. At this time, the main purpose is to complete a feasibility study with 40 participants suffering from treatment-resistant depression. Participants will be randomized to (1) Study group: Nitrous oxide (inhaled) + solution of saline (injected) and the (2) Control group: Oxygen (inhaled) + Midazolam (injected) as an Active Placebo.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder; Treatment Resistant Depression
• Intervention / Treatment: Drug: Nitrous Oxide 99 %; Drug: Oxygen + Midazolam

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18 to 65 years of age
2. Meeting Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for Major Depressive Disorder (MDD)
3. Current major depressive episode as confirmed by the Mini International Neuropsychiatric Interview (MINI) for DSM-5
4. Experiencing moderate to severe depressive episode, as defined by the Hamilton Depression Rating Scale (HAMD)>17
5. Failure of two trials of antidepressant therapy of adequate dose and duration, during the current depressive episode
6. For women of childbearing potential, use of highly effective or double-barrier methods of contraception. Abstinence is acceptable if it is the preferred and usual lifestyle of the female participant
7. Capacity to provide informed consent.

Exclusion criteria

1. Acute suicidality defined as score ≥3 on HAMD item 3
2. Major Depressive Episode in people with Bipolar Disorder
3. Current substance abuse or dependence and/or history of alcohol abuse or dependence within the past year
4. Dementia
5. Current or lifetime history of schizophrenia or schizoaffective disorder
6. Current history of dissociative disorders
7. Known history of hypersensitivity or allergy to Nitrous Oxide, Midazolam or any ingredients in the study formulations
8. Contraindication to receiving nitrous oxide
9. Chronic cobalamin or folate deficiency
10. Contraindication to receiving the placebo midazolam
11. Use of centrally acting medicinal products, such as opioid agonists, morphine derivatives, benzodiazepines and/or other central nervous system depressants such as barbiturates and alcohol
12. Pregnancy or breastfeeding in female participants
13. Electroconvulsive therapy within the current depressive episode
14. Receiving ketamine treatment within the current depressive episode
15. Unwilling to maintain current antidepressant regimen.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nitrous Oxide + saline solution	Drug: Nitrous Oxide 99 %; Nitrous oxide will be administered at an inspiratory concentration of 50% with concurrent intravenous saline (100ml) for one hour.
Active Comparator: Oxygen + Midazolam	Drug: Oxygen + Midazolam; Oxygen will be administered at 50% with intravenous midazolam (0.02mg/kg in 100ml) for one hour

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Recruitment rate	2 Years
Withdrawal rate		2 Years
Adherence rate	Feasibility	2 Years
Frequency of adverse events	Safety and tolerability	2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montgomery-Åsberg Depression Rating Scale (MADRAS) Score 0-60 (Higher scores represent higher depression). Measure changes in symptoms of depression	Frequencies on numbers of 1.- Remissions (defined as MADRS score < 10), 2.- Responses (defined as ≥ 50% reduction in MADRS score from baseline) 3.- No Responses	6 weeks
Toronto Side Effects Scale (TSES) - 32 items (each item has a score 1-25; higher score means higher intensity). Measure adverse side effects from antidepressant treatment	Frequencies of safety and tolerability	6 weeks

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: Unity Health Toronto

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2021
• Primary Completion (Actual): February 27, 2024
• Study Completion (Actual): February 27, 2024

Study Registration Dates

• First Submitted: April 26, 2021
• First Submitted That Met QC Criteria: July 9, 2021
• First Posted (Actual): July 12, 2021

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Nitrous Oxide; Feasibility trial
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anesthetics, Inhalation; Midazolam; Nitrous Oxide
• Other Study ID Numbers: 21-096

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No individual participant data has been planned to be shared with other researchers at this point since this is a feasibility study with only 40 participants

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No