NCT02994433

Brief 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). 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.

Trial Health

77
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
60

participants targeted

Target at P75+ for phase_1

Timeline
12mo left

Started Jan 2017

Longer than P75 for phase_1

Geographic Reach
1 country

1 active site

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress90%
Jan 2017Apr 2027

First Submitted

Initial submission to the registry

December 2, 2016

Completed
13 days until next milestone

First Posted

Study publicly available on registry

December 15, 2016

Completed
1 month until next milestone

Study Start

First participant enrolled

January 27, 2017

Completed
10.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 30, 2027

Expected
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

April 30, 2027

Last Updated

April 29, 2026

Status Verified

April 1, 2026

Enrollment Period

10.3 years

First QC Date

December 2, 2016

Last Update Submit

April 24, 2026

Conditions

Depressive Disorder, MajorDepressive Disorder, Treatment-Resistant

Outcome Measures

Primary Outcomes (4)

  • 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.

    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.

    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.

    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.

    2 hours after inhalation

Study Arms (2)

Nitrous Oxide

EXPERIMENTAL

One hour inhalation of nitrous oxide

Drug: Nitrous OxideDevice: MRI

Placebo Gas

PLACEBO COMPARATOR

One hour inhalation of placebo gas

Drug: Placebo gasDevice: MRI

Interventions

Nitrous OxideDRUG

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.

Also known as: laughing gas
Nitrous Oxide
Placebo gasDRUG

Placebo gas given at 50% nitrogen \[inert\]/50% oxygen.

Placebo Gas
MRIDEVICE

MRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI.

Nitrous OxidePlacebo Gas

Eligibility Criteria

Age18 Years - 65 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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:
  • Pneumothorax
  • Bowel obstruction
  • Middle ear occlusion
  • Elevated intracranial pressure
  • Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
  • +4 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Related Publications (2)

  • 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.

    PMID: 39185528DERIVED

  • de 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.

    PMID: 37585253DERIVED

MeSH Terms

Conditions

Depressive Disorder, MajorDepressive Disorder, Treatment-Resistant

Interventions

Nitrous Oxide

Condition Hierarchy (Ancestors)

Depressive DisorderMood DisordersMental Disorders

Intervention Hierarchy (Ancestors)

Nitrogen OxidesGasesInorganic ChemicalsNitrogen CompoundsOxidesOxygen Compounds

Study Officials

  • Charles R Conway, MD

    Washington University School of Medicine

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Britt Gott, MS

CONTACT

314-362-2463gottb@wustl.edu

Anvita Vishwanath, BS

CONTACT

314-273-1921a.vishwanath@wustl.edu

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
CROSSOVER
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

December 2, 2016

First Posted

December 15, 2016

Study Start

January 27, 2017

Primary Completion (Estimated)

April 30, 2027

Study Completion (Estimated)

April 30, 2027

Last Updated

April 29, 2026

Record last verified: 2026-04

Locations

US(1)