<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02994433</url>
  </required_header>
  <id_info>
    <org_study_id>201606120</org_study_id>
    <nct_id>NCT02994433</nct_id>
  </id_info>
  <brief_title>NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits</brief_title>
  <official_title>NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Most clinical major depression responds to standard treatments (medication and&#xD;
      psychotherapy); however, a significant subset of depressed patients (15-20%) do not respond&#xD;
      to these treatments and are referred to as treatment-resistant major depression (TRMD). New&#xD;
      treatments for TRMD are needed, and one promising line of research are drugs known as&#xD;
      N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. In a recent pilot study, our&#xD;
      group demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD. This&#xD;
      application proposes to take the next important step in understanding how nitrous oxide&#xD;
      exerts its effects in the human brain by using state-of-the-art brain neuroimaging&#xD;
      (functional connectivity magnetic resonance imaging) in a group of non-depressed, healthy&#xD;
      volunteers and comparing the results to a group of TRMD patients.&#xD;
&#xD;
      This study involves exposing 20 non-depressed healthy participants and 20 TRMD participants&#xD;
      to nitrous oxide and a placebo gas, to compare their brain images before and after each of&#xD;
      the inhalation sessions. Sessions will be separated by at least one month to prevent&#xD;
      treatment effects from carrying over into the following session. All willing and eligible&#xD;
      subjects will undergo up to six functional connectivity MRI scans, and two inhalation&#xD;
      sessions. Functional imaging in the brain will allow us to trace the interconnections between&#xD;
      various parts of the brain, including those involved with emotion and depression.&#xD;
&#xD;
      Other procedures will involve screening materials to ensure safety of the participants before&#xD;
      beginning the study (i.e. no MRI scan contraindications) and that subjects meet eligibility&#xD;
      criteria to being in the targeted age range, depression/non-depressed state, neurological&#xD;
      disorder history, and no medication exclusions.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    remaining visits and enrollment terminated due to the pandemic&#xD;
  </why_stopped>
  <start_date type="Actual">January 27, 2017</start_date>
  <completion_date type="Actual">February 28, 2020</completion_date>
  <primary_completion_date type="Actual">February 28, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Comparison of functional connectivity between default mode network of treatment-resistant depressed and non-depressed participants</measure>
    <time_frame>2 hours after inhalation</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of functional connectivity between affective network of treatment-resistant depressed and non-depressed participants</measure>
    <time_frame>2 hours after inhalation</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of functional connectivity between cognitive control network of treatment-resistant depressed and non-depressed participants</measure>
    <time_frame>2 hours after inhalation</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of functional connectivity between dorsal nexus of treatment-resistant depressed and non-depressed participants</measure>
    <time_frame>2 hours after inhalation</time_frame>
    <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.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">49</enrollment>
  <condition>Depressive Disorder, Major</condition>
  <condition>Depressive Disorder, Treatment-Resistant</condition>
  <arm_group>
    <arm_group_label>Nitrous Oxide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One hour inhalation of nitrous oxide</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Gas</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>One hour inhalation of placebo gas</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitrous Oxide</intervention_name>
    <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.</description>
    <arm_group_label>Nitrous Oxide</arm_group_label>
    <other_name>laughing gas</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo gas</intervention_name>
    <description>Placebo gas given at 50% nitrogen [inert]/50% oxygen.</description>
    <arm_group_label>Placebo Gas</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>MRI</intervention_name>
    <description>MRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI.</description>
    <arm_group_label>Nitrous Oxide</arm_group_label>
    <arm_group_label>Placebo Gas</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults 18-65 years of age&#xD;
&#xD;
          -  Right-handed&#xD;
&#xD;
          -  Controls: Not meet The Fourth Edition of the Diagnostic and Statistical Manual of&#xD;
             Mental Disorders (DSM-IV) criteria for major depressive disorder (MDD) by scoring ≤7&#xD;
             on the Hamilton Depression Rating Scale (HDRS), 17-item; Treatment-Resistant Major&#xD;
             Depression (TRMD) patients: Must meet a ≥17 score on the HDRS.&#xD;
&#xD;
          -  Controls: Must not have any history of depression as determined by reported history&#xD;
             and medical record review; TRMD: Documented (chart review) failure to respond to ≥3-4&#xD;
             adequate dose/duration antidepressant treatments; ≥1 in the current depressive&#xD;
             episode.&#xD;
&#xD;
          -  Good command of the English language&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Meets criteria for any DSM-IV Axis I diagnosis as documented in medical records and as&#xD;
             determined by structured clinical interview (except MDD for the TRMD group)&#xD;
&#xD;
          -  Known primary neurological disorders or medical disorders including dementia, stroke,&#xD;
             encephalopathy Parkinson's Disease, brain tumors, multiple sclerosis, seizure&#xD;
             disorder, severe cardiac or pulmonary disease&#xD;
&#xD;
          -  Any central nervous system active medication as determined by study investigator&#xD;
&#xD;
          -  Any known disease affecting drug metabolism and excretion (e.g. renal or liver&#xD;
             disease) as determined by study investigator&#xD;
&#xD;
          -  Left-handedness&#xD;
&#xD;
          -  Not eligible for MRI scans (e.g. history of claustrophobia/implanted metal as per MRI&#xD;
             Screening Tool)&#xD;
&#xD;
          -  Current use of psychotropic medications, antidepressants, or prescription or&#xD;
             non-prescription drugs/herbals intended to treat depression or anxiety (control group&#xD;
             only)&#xD;
&#xD;
          -  Any recent (within past 12 months) history of substance dependence or abuse,&#xD;
             determined by reported history or urine drug screen&#xD;
&#xD;
          -  Ability to become pregnant and not using effective contraception&#xD;
&#xD;
          -  Contraindication against the use of nitrous oxide:&#xD;
&#xD;
               1. Pneumothorax&#xD;
&#xD;
               2. Bowel obstruction&#xD;
&#xD;
               3. Middle ear occlusion&#xD;
&#xD;
               4. Elevated intracranial pressure&#xD;
&#xD;
               5. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12&#xD;
&#xD;
               6. Pregnant patients&#xD;
&#xD;
               7. Breastfeeding women&#xD;
&#xD;
          -  Inability to provide informed consent&#xD;
&#xD;
          -  Any other factor that in the investigators' judgment may affect patient safety or&#xD;
             compliance (e.g. distance greater than 100 miles from clinic).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Charles R Conway, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>December 2, 2016</study_first_submitted>
  <study_first_submitted_qc>December 12, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 15, 2016</study_first_posted>
  <last_update_submitted>July 29, 2021</last_update_submitted>
  <last_update_submitted_qc>July 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
    <mesh_term>Depressive Disorder, Treatment-Resistant</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitrous Oxide</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02994433
org study id: 201606120
nct id: NCT02994433
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Comparison of functional connectivity between default mode network of treatment-resistant depressed and non-depressed participants
time frame: 2 hours after inhalation
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.
measure: Comparison of functional connectivity between affective network of treatment-resistant depressed and non-depressed participants
time frame: 2 hours after inhalation
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.
measure: Comparison of functional connectivity between cognitive control network of treatment-resistant depressed and non-depressed participants
time frame: 2 hours after inhalation
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.
measure: Comparison of functional connectivity between dorsal nexus of treatment-resistant depressed and non-depressed participants
time frame: 2 hours after inhalation
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.
arm group label: Nitrous Oxide
arm group type: Experimental
description: One hour inhalation of nitrous oxide
arm group label: Placebo Gas
arm group type: Placebo Comparator
description: One hour inhalation of placebo gas
intervention type: Drug
intervention name: Nitrous Oxide
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.
arm group label: Nitrous Oxide
other name: laughing gas
intervention type: Drug
intervention name: Placebo gas
description: Placebo gas given at 50% nitrogen [inert]/50% oxygen.
arm group label: Placebo Gas
intervention type: Device
intervention name: MRI
description: MRIs done on all participants, this is a tool we are using to measure outcomes. No treatment is from an MRI.
arm group label: Nitrous Oxide
arm group label: Placebo Gas
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Charles R Conway, MD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
responsible party type: Sponsor
mesh term: Depressive Disorder
mesh term: Depression
mesh term: Depressive Disorder, Major
mesh term: Depressive Disorder, Treatment-Resistant
mesh term: Nitrous Oxide