Antidepressant Effects of Nitrous Oxide
Primary Purpose
Major Depressive Disorder, Treatment Resistant Depression
Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Nitrous oxide gas for inhalation
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Major Depressive Disorder focused on measuring Depression, Antidepressant, Nitrous Oxide
Eligibility Criteria
Inclusion Criteria:
- Adult (≥18 years, both sexes)
- DSM-5 criteria for MDD without psychosis, as determined using a structured clinical interview [Mini International Neuropsychiatric Interview], MDD, defined by a pre-treatment score >16 on the HDRS-21 scale and meeting DSM-5 for MDD
Exclusion Criteria:
- A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
- Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
- Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
- Active or recent (<12 months) substance use disorder; 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).
Sites / Locations
- University of Chicago MedicineRecruiting
- The Alfred HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Treatment; Nitrous Oxide 50% or 25%, group
Control; Oxygen-air mixture, group
Arm Description
Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned.
Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture.
Outcomes
Primary Outcome Measures
Change in HDRS-21 score
Monitor changes in Hamilton Depression Rating Scale-21 (HDRS-21) scores to determine whether a series of four, 60-minute sessions of inhaled nitrous oxide vs placebo (once-per-week) has significant antidepressant activity.
The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.
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
Treatment response
Treatment response (≥50% reduction on HDRS-21) to nitrous oxide vs placebo will be measured.
Changes in 'Profile of Mood States' scores
Monitoring daily mood changes using the Profile of Mood States (POMS) a validated 'self-report' psychological diagnostic containing 65 emotions or 'mood states' to determine the pattern of treatment response
Patients rank their current mood states using a scale of 'not-at-all', 'a-little', 'moderately', 'quite-a-lot', 'extremely'. Responses are scored to calculated the Total Mood Disturbance (TMD):
TMD = (tension + depression + anger + fatigue + confusion) - Vigor
Sustainability of treatment response
Determine sustained response and remission following study treatments (nitrous vs placebo) using Hamilton Depression Rating Scale-21 (HDRS-21) score.
The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.
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
Treatment dose response comparison
Compare dose response of 25% vs 50% nitrous oxide to establish whether the concentration is related to outcome.
Determined with treatment-by-dose (group) interaction term in a logistic regression model to assess for statistical significance.
Treatment cycle compliance
Evaluate compliance to complete 4-cycle inhalation treatments of nitrous oxide vs placebo.
Determined by ability, inability, or refusal to receive all 4-treatments of randomized inhalation sessions (nitrous oxide vs placebo).
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'depression' scores
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'depression'.
Generated scores include severity and liklihood percentile:
- depression = (%) normal, mild, moderate, severe
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'anxiety' scores
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'anxiety'.
Generated scores include severity and liklihood percentile:
- anxiety = (%) normal, mild, moderate, severe
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'suicide' scores
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide'.
Generated scores include severity and liklihood percentile:
- suicide = (%) low, intermediate, high
Suicidal ideation tracking
Suicidal ideation will be be tracked using the Sheehan Suicidality Tracking Scale (S-STS), a validated self-report diagnostic tool designed to assess and monitor suicidality.
The standard S-STS consists of 14 core questions related to suicidality phenomena and is designed for use in clinical research studies and in clinical settings.
Scores are summed based on individual responses 'not-at-all = 0', 'a little = 1', 'moderately = 2', 'very = 3', 'extremely = 4', to generate a summated score (total score), individual factor scores for suicidal ideation, suicidal intent, suicidal planning, suicidal behavior, and non-suicidal self-injury.
All results are monitored in real time by a trained psychiatry (MD) rater.
Visual Analog Scale (VAS)
The VAS is a unidimensional measure of pain intensity and use in the field of psychology to measure 'well-being'.
Patients mark on a line the point that they feel represents their perception of their current state, with the score determined by measuring in millimetres from the left hand end of the line to the point that the patient marks.
The range of score from 0-100 mm and represent: no pain (0-4 mm), mild pain(5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm).
Treatment remission
Treatment remission (HDRS-21 ≤7 points) to nitrous oxide vs. placebo will be measured.
Full Information
NCT ID
NCT05357040
First Posted
November 9, 2021
Last Updated
December 21, 2022
Sponsor
University of Chicago
Collaborators
The Alfred
1. Study Identification
Unique Protocol Identification Number
NCT05357040
Brief Title
Antidepressant Effects of Nitrous Oxide
Official Title
Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 30, 2021 (Actual)
Primary Completion Date
February 1, 2024 (Anticipated)
Study Completion Date
April 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Chicago
Collaborators
The Alfred
4. Oversight
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.
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
To evaluate the acute and sustained antidepressant effects of nitrous oxide in people with major depressive disorder; and further evaluate these effects by identifying the optimal dose and regimen to guide current practice, and to plan a future large pragmatic trial.
Detailed Description
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 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 session 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% or 25% nitrous oxide. Depression severity and outcomes related to treatment responses will be continuously assessed by a 'blinded-to-randomization' psychiatry (MD) rater at weekly intervals during study patient participation, using validated psychiatric diagnostics (Hamilton Depression Rating Scale-21 [HDRS-21 or HAM-D]; Profile of Mood States [POMS]; Computerized Adaptive Test-Mental Health [CAT-MH]; Sheehan-STS [S-STS]; Visual Analog Scale [VAS]).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder, Treatment Resistant Depression
Keywords
Depression, Antidepressant, Nitrous Oxide
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Parallel-group, controlled trial; randomized participants (1:1) to nitrous oxide (Nitrous group) or oxygen-air mixture (FiO2 ≈0.3, Control group). The Nitrous group will be further randomly assigned to either 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75).
Masking
ParticipantOutcomes Assessor
Masking Description
Patient and assessor blinded to study group assigned.
Allocation
Randomized
Enrollment
172 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment; Nitrous Oxide 50% or 25%, group
Arm Type
Active Comparator
Arm Description
Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned.
Arm Title
Control; Oxygen-air mixture, group
Arm Type
Placebo Comparator
Arm Description
Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture.
Intervention Type
Drug
Intervention Name(s)
Nitrous oxide gas for inhalation
Other Intervention Name(s)
N2O, Laughing gas, Nitrous Oxide, Nitrous
Intervention Description
60-minute sessions of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) or 25% nitrous oxide in oxygen (FiO2 0.75), administered weekly for 4-weeks.
Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
60-minute sessions of inhaled oxygen-air mixture (FiO2 ≈0.3) to be administered weekly for 4-weeks.
Administration will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.
Primary Outcome Measure Information:
Title
Change in HDRS-21 score
Description
Monitor changes in Hamilton Depression Rating Scale-21 (HDRS-21) scores to determine whether a series of four, 60-minute sessions of inhaled nitrous oxide vs placebo (once-per-week) has significant antidepressant activity.
The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.
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
Time Frame
Over 4-weeks from baseline
Secondary Outcome Measure Information:
Title
Treatment response
Description
Treatment response (≥50% reduction on HDRS-21) to nitrous oxide vs placebo will be measured.
Time Frame
At 24-hours (following treatment-1)
Title
Changes in 'Profile of Mood States' scores
Description
Monitoring daily mood changes using the Profile of Mood States (POMS) a validated 'self-report' psychological diagnostic containing 65 emotions or 'mood states' to determine the pattern of treatment response
Patients rank their current mood states using a scale of 'not-at-all', 'a-little', 'moderately', 'quite-a-lot', 'extremely'. Responses are scored to calculated the Total Mood Disturbance (TMD):
TMD = (tension + depression + anger + fatigue + confusion) - Vigor
Time Frame
Up to 1-week (following treatment-1)
Title
Sustainability of treatment response
Description
Determine sustained response and remission following study treatments (nitrous vs placebo) using Hamilton Depression Rating Scale-21 (HDRS-21) score.
The HDRS-21 is an interview-based psychiatric diagnostic used to evaluate depression severity. Scores are calculated by using the first 17 responses of this 21 item questionnaire.
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
Time Frame
Over 7-weeks (length of study participation).
Title
Treatment dose response comparison
Description
Compare dose response of 25% vs 50% nitrous oxide to establish whether the concentration is related to outcome.
Determined with treatment-by-dose (group) interaction term in a logistic regression model to assess for statistical significance.
Time Frame
Over 7-weeks (length of study participation)
Title
Treatment cycle compliance
Description
Evaluate compliance to complete 4-cycle inhalation treatments of nitrous oxide vs placebo.
Determined by ability, inability, or refusal to receive all 4-treatments of randomized inhalation sessions (nitrous oxide vs placebo).
Time Frame
Over 4-weeks (weekly treatment sessions)
Title
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'depression' scores
Description
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'depression'.
Generated scores include severity and liklihood percentile:
- depression = (%) normal, mild, moderate, severe
Time Frame
Over 7-weeks (length of study participation) from Baseline
Title
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'anxiety' scores
Description
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'anxiety'.
Generated scores include severity and liklihood percentile:
- anxiety = (%) normal, mild, moderate, severe
Time Frame
Over 7-weeks (length of study participation) from Baseline
Title
Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'suicide' scores
Description
This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'suicide'.
Generated scores include severity and liklihood percentile:
- suicide = (%) low, intermediate, high
Time Frame
Over 7-weeks (length of study participation) from Baseline
Title
Suicidal ideation tracking
Description
Suicidal ideation will be be tracked using the Sheehan Suicidality Tracking Scale (S-STS), a validated self-report diagnostic tool designed to assess and monitor suicidality.
The standard S-STS consists of 14 core questions related to suicidality phenomena and is designed for use in clinical research studies and in clinical settings.
Scores are summed based on individual responses 'not-at-all = 0', 'a little = 1', 'moderately = 2', 'very = 3', 'extremely = 4', to generate a summated score (total score), individual factor scores for suicidal ideation, suicidal intent, suicidal planning, suicidal behavior, and non-suicidal self-injury.
All results are monitored in real time by a trained psychiatry (MD) rater.
Time Frame
Over 7-weeks (length of study participation) from Baseline
Title
Visual Analog Scale (VAS)
Description
The VAS is a unidimensional measure of pain intensity and use in the field of psychology to measure 'well-being'.
Patients mark on a line the point that they feel represents their perception of their current state, with the score determined by measuring in millimetres from the left hand end of the line to the point that the patient marks.
The range of score from 0-100 mm and represent: no pain (0-4 mm), mild pain(5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm).
Time Frame
At Baseline (Prior to treatment-1)
Title
Treatment remission
Description
Treatment remission (HDRS-21 ≤7 points) to nitrous oxide vs. placebo will be measured.
Time Frame
At 24-hours (following treatment-1)
Other Pre-specified Outcome Measures:
Title
Adverse Events
Description
Psychiatric AEs, such as new suicidal ideation and psychotic symptoms; AEs such as nausea and vomiting; or any other AEs determined probably, possibly, or unrelated to the study intervention.
Study patient safety is monitored by the investigators (MD) with experience in critical care anesthesia, and psychiatry, as well as an experienced clinical research team responsible for monitoring and reporting events.
Time Frame
Over 7-weeks (length of study participation).
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Adult (≥18 years, both sexes)
DSM-5 criteria for MDD without psychosis, as determined using a structured clinical interview [Mini International Neuropsychiatric Interview], MDD, defined by a pre-treatment score >16 on the HDRS-21 scale and meeting DSM-5 for MDD
Exclusion Criteria:
A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
Active or recent (<12 months) substance use disorder; 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).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Clinical Trials Manager
Phone
773-834-5778
Email
fbrown@dacc.uchicago.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Nagele, MD, MSc
Organizational Affiliation
University of Chicago, Department of Anesthesia and Critical Care
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Paul Myles, MD
Organizational Affiliation
The Alfred Hospital, Department of Anesthesiology and Perioperative Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Chicago Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Manager
Phone
773-834-5778
Email
fbrown@dacc.uchicago.edu
First Name & Middle Initial & Last Name & Degree
Peter Nagele, MD, MSc
First Name & Middle Initial & Last Name & Degree
Royce Lee, MD
Facility Name
The Alfred Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Research Manager
Phone
03 90762651
Email
S.Wallace@alfred.org.au
First Name & Middle Initial & Last Name & Degree
Paul Myles, MD
12. IPD Sharing Statement
Plan to Share IPD
No
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Antidepressant Effects of Nitrous Oxide
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