Antidepressant Effects of Nitrous Oxide

The University of Chicago

Status and phase: Enrolling; Phase 2

Conditions: Major Depressive Disorder; Treatment Resistant Depression

Treatments: Drug: Nitrous oxide gas for inhalation; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT05357040

IRB18-1856

Details and patient eligibility

About

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.

Full 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]).

Enrollment: 172 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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172 participants in 2 patient groups, including a placebo group

Treatment; Nitrous Oxide 50% or 25%, group

Active Comparator group

Description:

Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned.

Treatment:

Drug: Nitrous oxide gas for inhalation

Control; Oxygen-air mixture, group

Placebo Comparator group

Description:

Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture.

Treatment:

Drug: Placebo