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NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits

Primary Purpose

Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Nitrous Oxide
Placebo gas
MRI
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Depressive Disorder, Major

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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).

Sites / Locations

  • Washington University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Nitrous Oxide

Placebo Gas

Arm Description

One hour inhalation of nitrous oxide

One hour inhalation of placebo gas

Outcomes

Primary Outcome Measures

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.
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.
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.
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.

Secondary Outcome Measures

Full Information

First Posted
December 2, 2016
Last Updated
July 29, 2021
Sponsor
Washington University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT02994433
Brief Title
NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits
Official Title
NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Terminated
Why Stopped
remaining visits and enrollment terminated due to the pandemic
Study Start Date
January 27, 2017 (Actual)
Primary Completion Date
February 28, 2020 (Actual)
Study Completion Date
February 28, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 20 non-depressed healthy participants and 20 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
49 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nitrous Oxide
Arm Type
Experimental
Arm Description
One hour inhalation of nitrous oxide
Arm Title
Placebo Gas
Arm Type
Placebo Comparator
Arm Description
One hour inhalation of placebo gas
Intervention Type
Drug
Intervention Name(s)
Nitrous Oxide
Other Intervention Name(s)
laughing gas
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo gas
Intervention Description
Placebo gas given at 50% nitrogen [inert]/50% oxygen.
Intervention Type
Device
Intervention Name(s)
MRI
Intervention Description
MRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI.
Primary Outcome Measure Information:
Title
Comparison of functional connectivity between default mode network of treatment-resistant depressed and non-depressed participants
Description
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.
Time Frame
2 hours after inhalation
Title
Comparison of functional connectivity between affective network of treatment-resistant depressed and non-depressed participants
Description
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.
Time Frame
2 hours after inhalation
Title
Comparison of functional connectivity between cognitive control network of treatment-resistant depressed and non-depressed participants
Description
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.
Time Frame
2 hours after inhalation
Title
Comparison of functional connectivity between dorsal nexus of treatment-resistant depressed and non-depressed participants
Description
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.
Time Frame
2 hours after inhalation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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: 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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Charles R Conway, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

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NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits

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