Nitrous Oxide for the Treatment of Major Depressive Disorder

NCT03869736 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: 438/19
• Study Type: interventional
• Target: 81
• Locations: 2 countries
• Sites: 2

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.

Conditions

Depression; Major Depressive Disorder

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Change in HDRS-21 score

  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

  over 4 weeks from baseline

Secondary Outcomes (8)

• Treatment response and remission

  at 24 hours

• Pattern of treatment response

  Up to 1 week after treatment

• Sustainability of treatment response - change in HDRS-21 scores

  over 7 weeks

• Sustainability of treatment response - response and remission rates

  over 7 weeks

• Treatment compliance rate

  over 4 weeks

Other Outcomes (1)

• Adverse events

  over 7 weeks

Study Arms (2)

Nitrous Oxide 50% or 25%

EXPERIMENTAL

Nitrous oxide at an inhaled concentration of 50% or 25%

Drug: Nitrous Oxide

Placebo

SHAM COMPARATOR

Oxygen-air mixture

Drug: Placebo

Interventions

Nitrous Oxide DRUG

1-hour sessions of inhaled nitrous oxide at concentrations of 25% or 50% (randomly assigned) to be administered weekly for 4 weeks.

Nitrous Oxide 50% or 25%

Placebo DRUG

1-hour sessions of inhaled oxygen-air mixture (inspired oxygen concentration \~23-30%) to be administered weekly for 4 weeks.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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
• Active or recent (\<12 months) substance abuse or dependence; excluding nicotine
• Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
• Ongoing treatment with ECT
• Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
• Pregnancy or breastfeeding
• 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).

Sponsors & Collaborators

• Bayside Health: lead

Study Sites (2)

University of Chicago Medicine

Chicago, Illinois, 60637, United States

Location

Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

MeSH Terms

Conditions

Depression; Depressive Disorder, Major; Mood Disorders; Mental Disorders

Interventions

Nitrous Oxide

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Depressive Disorder

Intervention Hierarchy (Ancestors)

Nitrogen Oxides; Gases; Inorganic Chemicals; Nitrogen Compounds; Oxides; Oxygen Compounds

Study Officials

• Paul Myles, MD

  The Alfred

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2018
• First Posted: March 11, 2019
• Study Start: January 22, 2019
• Primary Completion: June 10, 2023
• Study Completion: December 10, 2023
• Last Updated: December 16, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); AU (1)