NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits

April 24, 2026 updated by: Washington University School of Medicine

Most clinical major depression responds to standard treatments (medication and psychotherapy); however, a significant subset of depressed patients (15-20%) do not respond to these treatments and are referred to as treatment-resistant major depression (TRMD). New treatments for TRMD are needed, and one promising line of research are drugs known as N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. In a recent pilot study, our group demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD. This application proposes to take the next important step in understanding how nitrous oxide exerts its effects in the human brain by using state-of-the-art brain neuroimaging (functional connectivity magnetic resonance imaging) in a group of non-depressed, healthy volunteers and comparing the results to a group of TRMD patients.

This study involves exposing approximately 25 non-depressed healthy participants and 25 TRMD participants to nitrous oxide and a placebo gas, to compare their brain images before and after each of the inhalation sessions. Sessions will be separated by at least one month to prevent treatment effects from carrying over into the following session. All willing and eligible subjects will undergo up to six functional connectivity MRI scans, and two inhalation sessions. Functional imaging in the brain will allow us to trace the interconnections between various parts of the brain, including those involved with emotion and depression.

Other procedures will involve screening materials to ensure safety of the participants before beginning the study (i.e. no MRI scan contraindications) and that subjects meet eligibility criteria to being in the targeted age range, depression/non-depressed state, neurological disorder history, and no medication exclusions.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Missouri
      • St Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University School of Medicine
        • Contact:
        • Principal Investigator:
          • Charles R Conway, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Adults 18-65 years of age
  • Right-handed
  • Controls: Not meet The Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder (MDD) by scoring ≤7 on the Hamilton Depression Rating Scale (HDRS), 17-item; Treatment-Resistant Major Depression (TRMD) patients: Must meet a ≥17 score on the HDRS.
  • Controls: Must not have any history of depression as determined by reported history and medical record review; TRMD: Documented (chart review) failure to respond to ≥3-4 adequate dose/duration antidepressant treatments; ≥1 in the current depressive episode.
  • Good command of the English language

Exclusion Criteria:

  • Meets criteria for any DSM-IV Axis I diagnosis as documented in medical records and as determined by structured clinical interview (except MDD for the TRMD group)
  • Known primary neurological disorders or medical disorders including dementia, stroke, encephalopathy Parkinson's Disease, brain tumors, multiple sclerosis, seizure disorder, severe cardiac or pulmonary disease
  • Any central nervous system active medication as determined by study investigator
  • Any known disease affecting drug metabolism and excretion (e.g. renal or liver disease) as determined by study investigator
  • Left-handedness
  • Not eligible for MRI scans (e.g. history of claustrophobia/implanted metal as per MRI Screening Tool)
  • Current use of psychotropic medications, antidepressants, or prescription or non-prescription drugs/herbals intended to treat depression or anxiety (control group only)
  • Any recent (within past 12 months) history of substance dependence or abuse, determined by reported history or urine drug screen
  • Ability to become pregnant and not using effective contraception

  • Contraindication against the use of nitrous oxide:

    1. Pneumothorax
    2. Bowel obstruction
    3. Middle ear occlusion
    4. Elevated intracranial pressure
    5. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
    6. Pregnant patients
    7. Breastfeeding women
  • Inability to provide informed consent
  • Any other factor that in the investigators' judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from clinic).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Nitrous Oxide
One hour inhalation of nitrous oxide
Drug: Nitrous Oxide
Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at 50% nitrous oxide/50% oxygen in this study.
Other Names:
  • laughing gas
Device: MRI
MRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI.
Placebo Comparator: Placebo Gas
One hour inhalation of placebo gas
Drug: Placebo gas
Placebo gas given at 50% nitrogen [inert]/50% oxygen.
Device: MRI
MRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison of functional connectivity between default mode network of treatment-resistant depressed and non-depressed participants
Time Frame: 2 hours after inhalation
Functional connectivity is measured between groups after inhaling nitrous oxide/placebo using an individual seed-voxel z map and pared t-test group analysis to identify effects on inter-regional connectivity.
2 hours after inhalation
Comparison of functional connectivity between affective network of treatment-resistant depressed and non-depressed participants
Time Frame: 2 hours after inhalation
Functional connectivity is measured between groups after inhaling nitrous oxide/placebo using an individual seed-voxel z map and pared t-test group analysis to identify effects on inter-regional connectivity.
2 hours after inhalation
Comparison of functional connectivity between cognitive control network of treatment-resistant depressed and non-depressed participants
Time Frame: 2 hours after inhalation
Functional connectivity is measured between groups after inhaling nitrous oxide/placebo using an individual seed-voxel z map and pared t-test group analysis to identify effects on inter-regional connectivity.
2 hours after inhalation
Comparison of functional connectivity between dorsal nexus of treatment-resistant depressed and non-depressed participants
Time Frame: 2 hours after inhalation
Functional connectivity is measured between groups after inhaling nitrous oxide/placebo using an individual seed-voxel z map and pared t-test group analysis to identify effects on inter-regional connectivity.
2 hours after inhalation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Washington University School of Medicine

Investigators

  • Principal Investigator: Charles R Conway, MD, Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 27, 2017

Primary Completion (Estimated)

April 30, 2027

Study Completion (Estimated)

April 30, 2027

Study Registration Dates

First Submitted

December 2, 2016

First Submitted That Met QC Criteria

December 12, 2016

First Posted (Estimated)

December 15, 2016

Study Record Updates

Last Update Posted (Actual)

April 29, 2026

Last Update Submitted That Met QC Criteria

April 24, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201606120

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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