Antidepressant Effects of Nitrous Oxide

Study Overview
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Brief Summary
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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
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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]).

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

Conditions
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Major Depressive Disorder, Treatment Resistant Depression

Intervention / Treatment
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* Drug: Nitrous oxide gas for inhalation
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment; Nitrous Oxide 50% or 25%, group<br>Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned. | Drug: Nitrous oxide gas for inhalation<br>* 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.<br>* Other names: Nitrous;|
| Placebo Comparator: Control; Oxygen-air mixture, group<br>Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Over 4-weeks from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment response | Treatment response (≥50% reduction on HDRS-21) to nitrous oxide vs placebo will be measured. | At 24-hours (following treatment-1) | 
| 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 | Up to 1-week (following treatment-1) | 
| 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 | Over 7-weeks (length of study participation). | 
| 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. | Over 7-weeks (length of study participation) | 
| 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). | Over 4-weeks (weekly treatment sessions) | 
| 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 | Over 7-weeks (length of study participation) from Baseline | 
| 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 | Over 7-weeks (length of study participation) from Baseline | 
| 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 | Over 7-weeks (length of study participation) from Baseline | 
| 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. | Over 7-weeks (length of study participation) from Baseline | 
| 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). | At Baseline (Prior to treatment-1) | 
| Treatment remission | Treatment remission (HDRS-21 ≤7 points) to nitrous oxide vs. placebo will be measured. | At 24-hours (following treatment-1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Antidepressant, Nitrous Oxide