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NCT Number: NCT03869736

Nitrous Oxide for the Treatment of Major Depressive Disorder

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.

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Key information

Conditions

Depression Behavior Behavioral Symptoms Depressive Disorder Depressive Disorder, Major Major Depressive Disorder Mental Disorders Mood Disorders

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Alfred Hospital, Melbourne, Victoria, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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).

Treatment and study plan

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.

Placebo

Drug

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

Primary outcomes

  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 outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Bayside Health

Other Gov

Registry information

Official study title

Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder

Important dates

Study start
2019
Primary completion
2023
Study completion
2023
First posted
Mar 11, 2019
Registry last updated
Dec 16, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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