Nitrous Oxide for the Treatment of Major Depressive Disorder

• ClinicalTrials.gov Identifier: NCT03869736
• Recruitment Status: Recruiting
• First Posted: March 11, 2019
• Last Update Posted: April 22, 2020
• Sponsor: Bayside Health
• Information provided by (Responsible Party): Bayside Health

Study Description

Brief Summary:

The investigators are conducting a randomized controlled trial to evaluate the antidepressant effects of nitrous oxide in people with Major Depressive Disorder (MDD). MDD is a global medical condition that causes significant health and economic burden. Recent studies have shown that a single dose of ketamine, an NMDA-antagonist, has fast and long lasting anti-depressant effect. Nitrous oxide, another NMDA-antagonist, is widely used for anesthesia and analgesia, safer to administer and has fewer side effects than ketamine.

A randomized controlled crossover feasibility study showed significant reduction in depressive symptoms at 2 and 24 hours after a single 1-hour treatment session of inhaled nitrous oxide compared with placebo. Nitrous oxide is inexpensive and can be safely administered by any trained clinician. If found to be efficacious, it could be used to provide rapid anti-depressant effect whilst the benefit of traditional anti-depressants has its delayed effect. Another potential application could be in acutely suicidal patients.

This investigated-initiated phase 2b trial will enable confirmation and extension of the findings from the feasibility study, and identify the optimal dose and regimen in a broader population of those with MDD. Participants will be randomized to receive a weekly 1-hour inhalational sessions of either nitrous oxide or placebo (oxygen-air mixture) for 4 weeks, and the nitrous group will be further randomly assigned to a dose of 50% nitrous oxide or 25% nitrous oxide. Depression severity will be assessed by a blinded observer pre-treatment and at weekly intervals during and for 4 weeks after treatment using the Hamilton Depression Rating Scale.

Condition or disease	Intervention/treatment	Phase
Depression; Major Depressive Disorder	Drug: Nitrous Oxide; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
• Actual Study Start Date: January 22, 2019
• Estimated Primary Completion Date: December 10, 2020
• Estimated Study Completion Date: December 10, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nitrous Oxide 50% or 25%; Nitrous oxide at an inhaled concentration of 50% or 25%	Drug: Nitrous Oxide; 1-hour sessions of inhaled nitrous oxide at concentrations of 25% or 50% (randomly assigned) to be administered weekly for 4 weeks.
Sham Comparator: Placebo; Oxygen-air mixture	Drug: Placebo; 1-hour sessions of inhaled oxygen-air mixture (inspired oxygen concentration ~23-30%) to be administered weekly for 4 weeks.

Outcome Measures

Primary Outcome Measures :

1. Change in HDRS-21 score [ Time Frame: over 4 weeks from baseline ]

   21-point Hamilton Depression Rating Scale

   Interview-based questionnaire used to measure the severity of depression. Consists of 21 items with a score calculated from the first 17 answers. Higher scores are associated with more severe depression:

   0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52

Secondary Outcome Measures :

1. Treatment response and remission [ Time Frame: at 24 hours ]
   Treatment response (≥50% reduction on HDRS-21) and remission (HDRS-21 ≤7 points), nitrous oxide vs. placebo
2. Pattern of treatment response [ Time Frame: Up to 1 week after treatment ]

   Assessed using daily Profile of Mood States scale. The POMS measures six different dimensions of mood swings over a period of time. score range with lower scores indicative of people with more stable mood profiles The Profile of Mood States (POMS) questionnaire is a validated psychological test containing 65 emotions/ mood states. Participants are asked to rank their current mood states using the scale 'not at all', 'a little', 'moderately', 'quite a lot' or 'extremely'. Total Mood Disturbance (TMD) score and an analysis of tension, depression, anger, vigour, fatigue and confusion is performed based on the participants mood states. Total Mood Disturbance (TMD) can be calculated by adding the scores for Tension, Depression, Anger, Fatigue and Confusion and then subtracting the score for Vigour.

   • TMD = (Tension + Depression + Anger + Fatigue + Confusion) - Vigour

3. Sustainability of treatment response - change in HDRS-21 scores [ Time Frame: over 7 weeks ]

   Change in the HDRS-21 score, nitrous oxide vs placebo

   HDRS-21 is an interview-based questionnaire used to measure the severity of depression. Consists of 21 items with a score calculated from the first 17 answers. Higher scores are associated with more severe depression:

   0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52

4. Sustainability of treatment response - response and remission rates [ Time Frame: over 7 weeks ]
   Response and remission rates (%), nitrous oxide vs placebo
5. Treatment compliance rate [ Time Frame: over 4 weeks ]
   Refusal or inability to attend further treatments, nitrous oxide vs placebo
6. Dose effect of nitrous oxide using treatment-by-dose interaction term in a logistic regression model [ Time Frame: over 7 weeks ]
   Dose effect of nitrous oxide at 25% and 50% using a treatment-by-dose (group) interaction term in a logistic regression model to assess for statistical significance.
7. Computerized Adaptive Test-Depression Inventory (CAT-DI) [ Time Frame: over 7 weeks ]
   Adaptive testing questionnaire that assesses severity, likelihood and percentile of depression based on an average of 12 items administered from a question bank of 400 items. Questions are adapted to the participants answers and targeted to their level of impairment. Results generate include: severity of depression (normal, mild, moderate, severe), likelihood of depression (out of probability of 1), percentile of severity.
8. Computerized Adaptive Test-Suicide Scale (CAT-SS) [ Time Frame: over 7 weeks ]
   Adaptive testing questionnaire that assesses risk and severity of suicide based on items administered from a question bank. Questions are adapted to the participants answers and targeted to their level of impairment. Results generate include: risk of suicide (low, intermediate, high) and a percentile of risk.

Other Outcome Measures:

1. Adverse events [ Time Frame: over 7 weeks ]
   Psychiatric AEs, such as new suicidal ideation and psychotic symptoms Other AEs, such as cardiorespiratory AEs or nausea and vomiting

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult (≥18 years, both sexes), with DSM-IV-TR criteria for MDD without psychosis, as determined using a structured clinical interview [Mini International Neuropsychiatric Interview]
2. MDD, as defined by a pretreatment score >18 on the HDRS-21 scale

Exclusion Criteria:

1. A history of bipolar disorder, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses; active suicidal intention, as determined by clinical interview
2. Active or recent (<12 months) substance abuse or dependence; excluding nicotine
3. Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
4. Ongoing treatment with ECT
5. Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
6. Pregnancy or breastfeeding
7. Any contraindications to the use of nitrous oxide (e.g., pneumothorax, middle ear occlusion, elevated intracranial pressure, chronic cobalamin or folate deficiency unless treated with folic acid or vitamin B12).

Contacts and Locations

Contacts

Contact: Carolyn Deng, MBChB; +61399030760; c.deng@alfred.org.au

Contact: Sophie Wallace, MPH; +61 3 90762651; s.wallace@alfred.org.au

Locations

United States, Illinois

University of Chicago Medicine; Not yet recruiting

Chicago, Illinois, United States, 60637

Contact: Peter Nagele, MD, MSc pnagele@dacc.uchicago.edu

Australia, Victoria

Alfred Hospital; Recruiting

Melbourne, Victoria, Australia, 3004

Contact: Paul Myles, MD, DSc +61390763176 p.myles@alfred.org.au

Contact: Sophie Wallace, MPH +61 3 90762651 s.wallace@alfred.org.au

Sponsors and Collaborators

Bayside Health

Investigators

• Principal Investigator: Paul Myles, MD; The Alfred

More Information

• Responsible Party: Bayside Health
• ClinicalTrials.gov Identifier: NCT03869736
• Other Study ID Numbers: 438/19
• First Posted: March 11, 2019
• Last Update Posted: April 22, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Bayside Health:

Depression; Depressive Disorder, Major; Mood Disorders; Mental Disorders; Nitrous Oxide; Anesthetics, Inhalational; Anesthetics; Anesthetics, General; Physiologic Effects of Drugs; Analgesics, Non-Narcotic; Analgesics

Additional relevant MeSH terms:

Disease; Depression; Depressive Disorder; Depressive Disorder, Major; Pathologic Processes; Behavioral Symptoms; Mood Disorders; Mental Disorders; Nitrous Oxide; Anesthetics, Inhalation; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents