DepressionPhase 2NCT03869736
Nitrous Oxide for the Treatment of Major Depressive Disorder
A Phase 2 study testing Nitrous Oxide in people with Depression and Major Depressive Disorder, run by Bayside Health at 2 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Depression, Major Depressive Disorder
- What is being tested?
- Nitrous Oxide
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 81 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 22 Jan 2019to 10 Dec 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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).
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United States1 site
University of Chicago Medicine
Chicago, Illinois, 60637
About this study
Official title: Evaluation of the Antidepressant Effects of Nitrous Oxide in People With 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.
- Conditions
- Depression, Major Depressive Disorder
- Being tested
- Nitrous Oxide, Placebo
- Keywords
- Depression, Depressive Disorder, Major, Mood Disorders, Mental Disorders, Nitrous Oxide, Anesthetics, Inhalational, Anesthetics, Anesthetics, General, Physiologic Effects of Drugs, Analgesics, Non-Narcotic, Analgesics
- Medical subject headings
- Depression, Depressive Disorder, Major, Mood Disorders, Mental Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitrous OxideDrug
1-hour sessions of inhaled nitrous oxide at concentrations of 25% or 50% (randomly assigned) to be administered weekly for 4 weeks.
PlaceboDrug
1-hour sessions of inhaled oxygen-air mixture (inspired oxygen concentration ~23-30%) to be administered weekly for 4 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Nitrous Oxide 50% or 25% | Experimental | Nitrous oxide at an inhaled concentration of 50% or 25% Receives: Drug: Nitrous Oxide |
| Placebo | Sham comparator | Oxygen-air mixture Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: over 4 weeks from baseline
Secondary outcomes (8)
Treatment response and remission
Treatment response (≥50% reduction on HDRS-21) and remission (HDRS-21 ≤7 points), nitrous oxide vs. placebo
Measured: at 24 hours
Pattern of treatment response
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
Measured: Up to 1 week after treatment
Sustainability of treatment response - change in HDRS-21 scores
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
Measured: over 7 weeks
Sustainability of treatment response - response and remission rates
Response and remission rates (%), nitrous oxide vs placebo
Measured: over 7 weeks
Treatment compliance rate
Refusal or inability to attend further treatments, nitrous oxide vs placebo
Measured: over 4 weeks
Dose effect of nitrous oxide using treatment-by-dose interaction term in a logistic regression model
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.
Measured: over 7 weeks
Computerized Adaptive Test-Depression Inventory (CAT-DI)
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.
Measured: over 7 weeks
Computerized Adaptive Test-Suicide Scale (CAT-SS)
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.
Measured: over 7 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Mar 2019
- Study start22 Jan 2019
- Primary completion10 Jun 2023
- Study completion10 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bayside Health
- Sponsor type
- Other government
- Responsible party
- Sponsor
- Investigators
- Paul Myles, MD, Principal investigator, The Alfred
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03869736
- Sponsor's protocol ID
- 438/19
- Status last verified
- Dec 2024
- First submitted
- 16 Dec 2018
- Last updated
- 16 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
- ClinicalTrials.gov ID
- NCT03869736
- Acronym / sponsor ID
- 438/19
- Conditions
- Depression, Major Depressive Disorder
- Keywords
- Depression, Depressive Disorder, Major, Mood Disorders, Mental Disorders, Nitrous Oxide, Anesthetics, Inhalational, Anesthetics, Anesthetics, General
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 81 participants (actual)
- Lead sponsor
- Bayside HealthOther government
- Study start
- 22 Jan 2019 (actual)
- Primary completion
- 10 Jun 2023 (actual)
- Study completion
- 10 Dec 2023 (actual)
- First posted
- 11 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitrous Oxide 50% or 25% | Experimental | Drug: Nitrous OxideNitrous oxide at an inhaled concentration of 50% or 25% |
| Placebo | Sham comparator | Drug: PlaceboOxygen-air mixture |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitrous Oxide1-hour sessions of inhaled nitrous oxide at concentrations of 25% or 50% (randomly assigned) to be administered weekly for 4 weeks. | Drug | Nitrous Oxide 50% or 25% |
| Placebo1-hour sessions of inhaled oxygen-air mixture (inspired oxygen concentration ~23-30%) to be administered weekly for 4 weeks. | Drug | Placebo |
Primary outcome
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
8 secondary outcomes
Treatment response and remission
Time frame: at 24 hours
Pattern of treatment response
Time frame: Up to 1 week after treatment
Sustainability of treatment response - change in HDRS-21 scores
Time frame: over 7 weeks
Sustainability of treatment response - response and remission rates
Time frame: over 7 weeks
Treatment compliance rate
Time frame: over 4 weeks
Dose effect of nitrous oxide using treatment-by-dose interaction term in a logistic regression model
Time frame: over 7 weeks
Computerized Adaptive Test-Depression Inventory (CAT-DI)
Time frame: over 7 weeks
Computerized Adaptive Test-Suicide Scale (CAT-SS)
Time frame: over 7 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Dec 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul Myles, MD principal investigator
The Alfred
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitrous Oxide in people with Depression and Major Depressive Disorder, run by Bayside Health at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in HDRS-21 score (time frame: over 4 weeks from baseline). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Dec 2024.