Clinical trial NCT05357040: Antidepressant Effects of Nitrous Oxide
Official title: Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Major Depressive Disorder
Treatment Resistant Depression
Keywords: Depression
Antidepressant
Nitrous Oxide
Lead sponsor: University of Chicago
Sponsor class: OTHER
Collaborators: name: The Alfred
First posted: 2022-05-02
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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).
Primary purpose: TREATMENT

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 \[VAS\]).

Eligibility criteria: Inclusion Criteria:

1. Adult (≥18 years, both sexes)
2. 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:

1. A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder.
2. Current obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses
3. Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination
4. Active or recent (\<12 months) substance use disorder; excluding nicotine
5. Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
6. Ongoing treatment with ECT
7. Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
8. Pregnancy or breastfeeding
9. 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).

Primary outcomes:
measure: Change in HDRS-21 score
timeFrame: Over 4-weeks from baseline
Secondary outcomes:
measure: Treatment response
timeFrame: At 24-hours (following treatment-1)
measure: Changes in 'Profile of Mood States' scores
timeFrame: Up to 1-week (following treatment-1)
measure: Sustainability of treatment response
timeFrame: Over 7-weeks (length of study participation).
measure: Treatment dose response comparison
timeFrame: Over 7-weeks (length of study participation)
measure: Treatment cycle compliance
timeFrame: Over 4-weeks (weekly treatment sessions)
measure: Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'depression' scores
timeFrame: Over 7-weeks (length of study participation) from Baseline
measure: Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'anxiety' scores
timeFrame: Over 7-weeks (length of study participation) from Baseline
measure: Changes in Computerize Adaptive Testing - Mental Health (CAT-MH) 'suicide' scores
timeFrame: Over 7-weeks (length of study participation) from Baseline
measure: Suicidal ideation tracking
timeFrame: Over 7-weeks (length of study participation) from Baseline
measure: Visual Analog Scale (VAS)
timeFrame: At Baseline (Prior to treatment-1)
measure: Treatment remission
timeFrame: At 24-hours (following treatment-1)
Other outcomes:
measure: Adverse Events
timeFrame: Over 7-weeks (length of study participation).
Locations:
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
Study officials:
affiliation: University of Chicago, Department of Anesthesia and Critical Care
name: Peter Nagele, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: The Alfred Hospital, Department of Anesthesiology and Perioperative Medicine
name: Paul Myles, MD
role: PRINCIPAL_INVESTIGATOR
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