Depressive Disorder, MajorPhase 1NCT02994433
NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits
A Phase 1 study testing Nitrous Oxide and MRI in people with Depressive Disorder, Major and Depressive Disorder, Treatment-Resistant, run by Washington University School of Medicine at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant
- What is being tested?
- Nitrous Oxide and MRI
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Jan 2017to 30 Apr 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 19Show fewer
- 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:
- Pneumothorax
- Bowel obstruction
- Middle ear occlusion
- Elevated intracranial pressure
- Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
- Pregnant patients
- 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).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Washington University School of Medicine
St Louis, Missouri, 63110
Britt Gott, MS, 314-362-2463, gottb@wustl.edu
Charles R Conway, MD
About this study
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.
- Being tested
- Nitrous Oxide, Placebo gas, MRI
- Medical subject headings
- Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitrous OxideDrug
Also called laughing gas
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.
Placebo gasDrug
Placebo gas given at 50% nitrogen [inert]/50% oxygen.
MRIDevice
MRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI.
| Study group | Role | What they receive |
|---|---|---|
| Nitrous Oxide | Experimental | One hour inhalation of nitrous oxide Receives: Drug: Nitrous Oxide; Device: MRI |
| Placebo Gas | Placebo comparator | One hour inhalation of placebo gas Receives: Drug: Placebo gas; Device: MRI |
What is being measured
The primary outcome is the main question the study is designed to answer.
Comparison of functional connectivity between default mode network of treatment-resistant depressed and non-depressed participants
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.
Measured: 2 hours after inhalation
Comparison of functional connectivity between affective network of treatment-resistant depressed and non-depressed participants
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.
Measured: 2 hours after inhalation
Comparison of functional connectivity between cognitive control network of treatment-resistant depressed and non-depressed participants
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.
Measured: 2 hours after inhalation
Comparison of functional connectivity between dorsal nexus of treatment-resistant depressed and non-depressed participants
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.
Measured: 2 hours after inhalation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2016 (estimated)
- Study start27 Jan 2017
- Primary completion30 Apr 2027 (estimated)
- Study completion30 Apr 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Depressive Disorder, MajorStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Charles R Conway, MD, Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02994433
- Sponsor's protocol ID
- 201606120
- Status last verified
- Apr 2026
- First submitted
- 2 Dec 2016
- Last updated
- 29 Apr 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Conway CR, Palanca BJA, Zeffiro T, Gott BM, Brown F, de Leon V, Barnes L, Nguyen T, Xiong W, Lessov-Schlaggar CN, Espejo G, Mennerick S, Zorumski CF, Nagele P. Nitrous Oxide Alters Functional Connectivity in Medial Limbic Structures in Treatment-Resistant Major Depression. medRxiv [Preprint]. 2024 Aug 17:2024.08.12.24311729. doi: 10.1101/2024.08.12.24311729.
PubMed 39185528de Leon VC, Kumar A, Nagele P, Palanca BJ, Gott B, Janski A, Zorumski CF, Conway CR. Nitrous Oxide Reduced Suicidal Ideation in Treatment-Resistant Major Depression in Exploratory Analysis. J Clin Psychiatry. 2023 Aug 16;84(5):22br14725. doi: 10.4088/JCP.22br14725. No abstract available.
PubMed 37585253
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits
- ClinicalTrials.gov ID
- NCT02994433
- Acronym / sponsor ID
- 201606120
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Study start
- 27 Jan 2017 (actual)
- Primary completion
- 30 Apr 2027 (estimated)
- Study completion
- 30 Apr 2027 (estimated)
- First posted
- 15 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitrous Oxide | Experimental | Drug: Nitrous Oxide, Device: MRIOne hour inhalation of nitrous oxide |
| Placebo Gas | Placebo comparator | Drug: Placebo gas, Device: MRIOne hour inhalation of placebo gas |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (19 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitrous OxideAlso: laughing gasNitrous 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. | Drug | Nitrous Oxide |
| Placebo gasPlacebo gas given at 50% nitrogen [inert]/50% oxygen. | Drug | Placebo Gas |
| MRIMRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI. | Device | Nitrous Oxide, Placebo Gas |
Primary outcome
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.
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.
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.
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.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2026.
- Derived from this study: PubMed 39185528Conway CR, Palanca BJA, Zeffiro T, Gott BM, Brown F, de Leon V, Barnes L, Nguyen T, Xiong W, Lessov-Schlaggar CN, Espejo G, Mennerick S, Zorumski CF, Nagele P. Nitrous Oxide Alters Functional Connectivity in Medial Limbic Structures in Treatment-Resistant Major Depression. medRxiv [Preprint]. 2024 Aug 17:2024.08.12.24311729. doi: 10.1101/2024.08.12.24311729.
- Derived from this study: PubMed 37585253de Leon VC, Kumar A, Nagele P, Palanca BJ, Gott B, Janski A, Zorumski CF, Conway CR. Nitrous Oxide Reduced Suicidal Ideation in Treatment-Resistant Major Depression in Exploratory Analysis. J Clin Psychiatry. 2023 Aug 16;84(5):22br14725. doi: 10.4088/JCP.22br14725. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Charles R Conway, MD principal investigator
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Nitrous Oxide and MRI in people with Depressive Disorder, Major and Depressive Disorder, Treatment-Resistant, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Britt Gott, MS (314-362-2463, gottb@wustl.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Comparison of functional connectivity between default mode network of treatment-resistant depressed and non-depressed participants (time frame: 2 hours after inhalation). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02994433, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Apr 2026.