xml: <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/NCT06004115</url>
    </required_header>
    <id_info>
      <org_study_id>2022-009</org_study_id>
      <secondary_id>R01MH132565</secondary_id>
      <nct_id>NCT06004115</nct_id>
    </id_info>
    <brief_title>Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression</brief_title>
    <official_title>Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Laureate Institute for Brain Research, Inc.</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Institute of Mental Health (NIMH)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
      <collaborator>
        <agency>California Institute of Technology</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Laureate Institute for Brain Research, Inc.</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>
      <is_us_export>Yes</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This mechanistic study uses an anti anxiety drug and brain imaging to study the threat&#xD;
        processing system and associated brain circuits in people with depression, anxiety disorders&#xD;
        and comorbid depression and anxiety disorders. In a double blind, placebo controlled&#xD;
        crossover design, up to 65 individuals will be recruited who will have a diagnosis of major&#xD;
        depressive disorder (MDD) and at least one anxiety disorder (AD) (AD-MDD group), up to 65&#xD;
        participants will have a diagnosis of MDD and no diagnosis of an AD and up to 65 participants&#xD;
        will have no diagnosis of MDD and a diagnosis of at least one AD will be enrolled to&#xD;
        participate in an two session study to obtain 150 completers (50 per group). All participants&#xD;
        will receive a single dose of Lorazepam and placebo (order randomized) taken orally. After&#xD;
        the ~2.5 hr screening session, participants will complete two identical ~5 hr experimental&#xD;
        sessions, each of which include a 30 min eyeblink startle session and a 1 hr functional&#xD;
        magnetic resonance imaging (MRI) brain scan session. The total time involved in the study is&#xD;
        approximately 10.5 hours.&#xD;
  &#xD;
        The main questions the study seeks to answer are:&#xD;
  &#xD;
          -  are people with comorbid depression and anxiety different than those with depression&#xD;
             alone in terms of their eyeblink startle response to threat?&#xD;
  &#xD;
          -  are people with comorbid depression and anxiety different than those with depression&#xD;
             alone in terms of their brain activation in response to threat?&#xD;
  &#xD;
          -  are people with comorbid depression and anxiety different than those with depression&#xD;
             alone in terms of their responses to anxiety drugs?&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This mechanistic study of major depressive disorder (MDD), anxiety disorders (AD) and&#xD;
        comorbid anxiety and depression (AD-MDD) aims to break down threat sensitivity into acute&#xD;
        threat (AT) and potential threat (PT). A well validated startle task (Neutral, Predictable,&#xD;
        Unpredictable or NPU-threat task) and a cutting-edge computational functional magnetic&#xD;
        resonance imaging (fMRI) probe of predator escape decisions (Flight Initiation Distance or&#xD;
        FID task) will be used to determine whether AD-MDD show increased PT or AT and how the&#xD;
        behavioral dynamics of escape decisions are most impaired in AD-MDD. Based on prior studies,&#xD;
        we hypothesize that AD is associated with exaggerated PT, whereas MDD is associated with&#xD;
        blunted reward/salience responding. Thus, AD-MDD may differ from AD through blunted&#xD;
        AT/salience (periaqueductal grey/insula circuitry and Fear-Potentiated Startle [FPS]) and may&#xD;
        differ from MDD through increased PT (hippocampal - ventromedial prefrontal cortex (vmPFC) -&#xD;
        amygdala dependent circuitry and Anxiety-Potentiated Startle [APS]). To causally probe this&#xD;
        circuitry, we will manipulate gamma-aminobutyric acid (GABA) to demonstrate different&#xD;
        responses in PT between these three groups, providing further evidence for PT as a targetable&#xD;
        process. This mechanistic R01 uses a benzodiazepine within an experimental medicine approach&#xD;
        to causally modulate the threat processing system and associated circuits in AD-MDD (N=50),&#xD;
        MDD (N=50), and AD (N=50). After the ~2.5 hr screening session, participants will complete&#xD;
        two identical ~5 hr experimental sessions, each of which include a 30 min electromyography&#xD;
        (EMG) session and a 1 hr functional magnetic resonance imaging (fMRI) session. The total time&#xD;
        involved in the study is approximately 10.5 hours. In a double-blind placebo crossover&#xD;
        design, participants will receive a single 1mg dose of Lorazepam/Placebo and complete threat&#xD;
        tasks that delineate PT/AT during startle EMG (NPU task; unpredictable vs predictable shock)&#xD;
        and fMRI (FID task; slow vs fast threat).&#xD;
  &#xD;
        Specific aims of this project are:&#xD;
  &#xD;
        Aim 1: Determine EMG signatures of dysregulated threat processing in AD-MDD.&#xD;
  &#xD;
        Hypothesis 1 A (H1A): AD-MDD/AD will exhibit higher PT sensitivity (greater APS) than MDD&#xD;
        (NPU APS: AD-MDD &gt; MDD; AD &gt; MDD).&#xD;
  &#xD;
        Hypothesis 1 B (H1B): AD-MDD/MDD will exhibit lower AT sensitivity (smaller FPS) than AD (NPU&#xD;
        FPS: AD-MDD &lt; AD; MDD &lt; AD).&#xD;
  &#xD;
        Aim 2: Determine neural computational signatures of dysregulated threat processing in AD-MDD.&#xD;
  &#xD;
        Hypothesis 2 A (H2A): AD-MDD and AD will show higher hippocampal-vmPFC-amygdala responses to&#xD;
        FID slow threat (PT) than MDD (FID slow: AD-MDD &gt; MDD; AD &gt; MDD).&#xD;
  &#xD;
        Hypothesis 2 B (H2B): AD-MDD and MDD will show lower periaqueductal grey/insula responses to&#xD;
        FID fast threat (AT) than AD. (FID fast: AD-MDD &lt; AD; MDD &lt; AD).&#xD;
  &#xD;
        Hypothesis 2 C (H2C): Utility functions for the FID task will show both blunted reward and&#xD;
        exaggerated threat valuation in AD-MDD, leading to less optimal choices than both MDD and AD.&#xD;
  &#xD;
        Aim 3: Determine the relevance of comorbidity to GABAergic manipulation of threat circuitry.&#xD;
  &#xD;
        Hypothesis 3 A (H3A): In the NPU task Lorazepam will decrease APS (PT) but not FPS (AT) in AD&#xD;
        and AD-MDD but not MDD.&#xD;
  &#xD;
        Hypothesis 3 B (H3B): In the FID task Lorazepam will decrease neural response to slow (PT)&#xD;
        but not fast (AT) threat and decrease the computational threat valuation parameter in AD and&#xD;
        AD-MDD but not MDD.&#xD;
  &#xD;
        Significance: These aims seek to mechanistically define and pharmacologically probe process&#xD;
        dysfunction and associated targetable circuitry unique to AD-MDD and provide evidence that&#xD;
        AD-MDD and MDD should be separated in future clinical trials. This will also inform&#xD;
        intervention strategies with circuit-based targets (e.g. for neuromodulation treatments) for&#xD;
        AD-MDD, which is a large but under-served treatment resistant group.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 2023</start_date>
    <completion_date type="Anticipated">March 31, 2028</completion_date>
    <primary_completion_date type="Anticipated">March 31, 2028</primary_completion_date>
    <phase>Phase 4</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>
      <intervention_model_description>double blind crossover design</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
      <masking_description>placebo preparation by the pharmacy</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Eyeblink startle magnitude under threat in AD-MDD compared to MDD.</measure>
      <time_frame>1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2)</time_frame>
      <description>Difference in magnitude of eyeblink startle response under threat of predictable and unpredictable shock conditions compared to neutral condition in the Neutral, Predictable, Unpredictable (NPU) Threat Task measured with electromyography. Comparing the AD-MDD group to the MDD group.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Magnitude of blood oxygenated level dependent (BOLD) response to threat in AD-MDD compared to MDD.</measure>
      <time_frame>1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2)</time_frame>
      <description>Magnitude of hippocampal-vmPFC-amygdala and periaqueductal grey/insula blood oxygenated level dependent (BOLD) responses to fast and slow threat compared to a no threat condition in the Flight Initiation Distance (FID) Task, measured with functional magnetic resonance imaging (fMRI). Comparing the AD-MDD group to the MDD group.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The effect of Lorazepam on eyeblink startle magnitude and BOLD response to threat in AD-MDD compared to MDD</measure>
      <time_frame>1-2 hours after single session drug administration, after both Lorazepam and sessions have been completed, an average of 5 weeks after enrollment</time_frame>
      <description>Comparing the effects of Lorazepam to placebo (within subject) and AD-MDD to MDD (between subject) on the magnitude of eyeblink startle response under threat of predictable and unpredictable shock conditions compared to neutral condition in the NPU Threat Task measured with EMG.&#xD;
  Comparing the effects of Lorazepam to placebo (within subject) and AD-MDD to MDD (between subject) on the magnitude of hippocampal-vmPFC-amygdala and periaqueductal grey/insula blood oxygenated level dependent (BOLD) responses to fast and slow threat compared to a no threat condition in the Flight Initiation Distance Task, measured with fMRI.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">165</enrollment>
    <condition>Depression, Anxiety</condition>
    <condition>Fear</condition>
    <condition>Depression</condition>
    <condition>Anxiety and Fear</condition>
    <condition>Anxiety Disorders</condition>
    <condition>Anxious Depression</condition>
    <arm_group>
      <arm_group_label>Lorazepam</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants will receive a single 1mg dose of Lorazepam, to be taken orally under registered nurse (RN) supervision</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Participants will receive a single dose of placebo, to be taken orally under RN supervision</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Lorazepam</intervention_name>
      <description>1mg of Lorazepam will be prepared by pharmacy (Barnes, Tulsa) in capsule form</description>
      <arm_group_label>Lorazepam</arm_group_label>
      <other_name>Lorazepam Intensol</other_name>
      <other_name>Ativan</other_name>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>placebo will be prepared by pharmacy (Barnes, Tulsa) in capsule form</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          All subjects:&#xD;
  &#xD;
            -  Female or male sex assigned at birth;&#xD;
  &#xD;
            -  Normal or corrected to normal vision/hearing, as protocol elements may not be valid&#xD;
               otherwise;&#xD;
  &#xD;
            -  Fluent English speaker, capable of providing written informed consent&#xD;
  &#xD;
          MDD and AD-MDD subjects:&#xD;
  &#xD;
            -  Current major depressive episode assessed by clinician administered MINI;&#xD;
  &#xD;
            -  Minimum score of 60 on the Patient Recorded Outcomes Measurement Information System&#xD;
               (PROMIS) Depression scale&#xD;
  &#xD;
          AD and AD-MDD subjects:&#xD;
  &#xD;
            -  Current anxiety disorder (generalized anxiety disorder, panic disorder, agoraphobia&#xD;
               and social phobia) assessed by clinician administered MINI;&#xD;
  &#xD;
            -  Minimum score of 60 on PROMIS Anxiety Scale&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          All subjects:&#xD;
  &#xD;
            -  Has uncontrolled, clinically significant neurologic (including seizure disorders):&#xD;
               cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic,&#xD;
               immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which&#xD;
               may impact the ability of the subject to participate or potentially confound the study&#xD;
               results;&#xD;
  &#xD;
            -  Reported body mass index (BMI) &gt; 40;&#xD;
  &#xD;
            -  History of moderate or severe traumatic brain injury (TBI), as assessed by a TBI&#xD;
               questionnaire;&#xD;
  &#xD;
            -  History of eating disorder or obsessive-compulsive disorder, schizophrenia,&#xD;
               schizo-affective disorder, bipolar disorder or any sign of psychosis;&#xD;
  &#xD;
            -  Current post-traumatic stress disorder (PTSD) diagnosis (although history of trauma is&#xD;
               allowed);&#xD;
  &#xD;
            -  Current use of medications with major effects on brain function or the fMRI&#xD;
               hemodynamic response (e.g., methylphenidate, acetazolamide, excessive caffeine intake&#xD;
               &gt; 1000 mg/day) following an initial list compiled by the Laureate Institute for Brain&#xD;
               Research (LIBR) but also assessed on a case-by-case basis. Individuals who are&#xD;
               currently on medication [antidepressants such as selective serotonin reuptake&#xD;
               inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin and norepinephrine&#xD;
               reuptake inhibitors (SNRIs), and Bupropion] and who have not undergone dose or&#xD;
               medication changes over the past 6 weeks will be allowed to participate;&#xD;
  &#xD;
            -  Current benzodiazepine use;&#xD;
  &#xD;
            -  Moderate to severe current substance use disorder, defined as 5 or more symptoms of&#xD;
               the criteria for Substance Use Disorder according to the Diagnostic and Statistical&#xD;
               Manual of Mental Disorders (DSM 5);&#xD;
  &#xD;
            -  Drug or alcohol intoxication [based on positive urine toxicology (UTOX) or&#xD;
               breathalyzer test at screen] or reported alcohol/drug withdrawal;&#xD;
  &#xD;
            -  Has a risk of suicide according to the Investigator's clinical judgement or per&#xD;
               Columbia-Suicide Severity Rating Scale (C-SSRS), the subject scores &quot;yes&quot; on items 4&#xD;
               or 5 in the Suicidal Ideation section with referent to a 30-day period prior to&#xD;
               Screening/Baseline or the subject has had one or more suicidal attempts with reference&#xD;
               to a 2-year period prior to Screening;&#xD;
  &#xD;
            -  MRI contraindications;&#xD;
  &#xD;
            -  Is pregnant or lactating or intending to become pregnant before, during, or within 12&#xD;
               weeks after participating in this study; or intending to donate ova during this&#xD;
               time-period;&#xD;
  &#xD;
            -  Any subject judged by the Investigator to be inappropriate for the study.&#xD;
  &#xD;
          MDD subjects:&#xD;
  &#xD;
            -  Current (assessed by MINI) or past (self-reported) anxiety disorder;&#xD;
  &#xD;
            -  Score of &gt; 60 on PROMIS Anxiety Scale&#xD;
  &#xD;
          AD subjects:&#xD;
  &#xD;
            -  Current (assessed by MINI) or past (self-reported) major depressive episode;&#xD;
  &#xD;
            -  Score of &gt; 55 on PROMIS Depression scale&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>65 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Maria Ironside, DPhil</last_name>
      <role>Principal Investigator</role>
      <affiliation>Laureate Institute for Brain Research</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Maria Ironside, DPhil</last_name>
      <phone>16174175065</phone>
      <email>mironside@laureateinstitute.org</email>
    </overall_contact>
    <location>
      <facility>
        <name>Laureate Institute for Brain Research</name>
        <address>
          <city>Tulsa</city>
          <state>Oklahoma</state>
          <zip>74136</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 7, 2023</study_first_submitted>
    <study_first_submitted_qc>August 16, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 22, 2023</study_first_posted>
    <last_update_submitted>August 16, 2023</last_update_submitted>
    <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 22, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>depression</keyword>
    <keyword>anxiety</keyword>
    <keyword>fMRI</keyword>
    <keyword>threat sensitivity</keyword>
    <keyword>flight initiation distance</keyword>
    <keyword>startle reflex</keyword>
    <keyword>benzodiazepine</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Hypersensitivity</mesh_term>
      <mesh_term>Depression</mesh_term>
      <mesh_term>Depressive Disorder</mesh_term>
      <mesh_term>Anxiety Disorders</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lorazepam</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06004115
  org study id: 2022-009
  secondary id: R01MH132565
  nct id: NCT06004115
  lead sponsor: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: Yes
  This mechanistic study uses an anti anxiety drug and brain imaging to study the threat
        processing system and associated brain circuits in people with depression, anxiety disorders
        and comorbid depression and anxiety disorders. In a double blind, placebo controlled
        crossover design, up to 65 individuals will be recruited who will have a diagnosis of major
        depressive disorder (MDD) and at least one anxiety disorder (AD) (AD-MDD group), up to 65
        participants will have a diagnosis of MDD and no diagnosis of an AD and up to 65 participants
        will have no diagnosis of MDD and a diagnosis of at least one AD will be enrolled to
        participate in an two session study to obtain 150 completers (50 per group). All participants
        will receive a single dose of Lorazepam and placebo (order randomized) taken orally. After
        the ~2.5 hr screening session, participants will complete two identical ~5 hr experimental
        sessions, each of which include a 30 min eyeblink startle session and a 1 hr functional
        magnetic resonance imaging (MRI) brain scan session. The total time involved in the study is
        approximately 10.5 hours.
  
        The main questions the study seeks to answer are:
  
          -  are people with comorbid depression and anxiety different than those with depression
             alone in terms of their eyeblink startle response to threat?
  
          -  are people with comorbid depression and anxiety different than those with depression
             alone in terms of their brain activation in response to threat?
  
          -  are people with comorbid depression and anxiety different than those with depression
             alone in terms of their responses to anxiety drugs?
  This mechanistic study of major depressive disorder (MDD), anxiety disorders (AD) and
        comorbid anxiety and depression (AD-MDD) aims to break down threat sensitivity into acute
        threat (AT) and potential threat (PT). A well validated startle task (Neutral, Predictable,
        Unpredictable or NPU-threat task) and a cutting-edge computational functional magnetic
        resonance imaging (fMRI) probe of predator escape decisions (Flight Initiation Distance or
        FID task) will be used to determine whether AD-MDD show increased PT or AT and how the
        behavioral dynamics of escape decisions are most impaired in AD-MDD. Based on prior studies,
        we hypothesize that AD is associated with exaggerated PT, whereas MDD is associated with
        blunted reward/salience responding. Thus, AD-MDD may differ from AD through blunted
        AT/salience (periaqueductal grey/insula circuitry and Fear-Potentiated Startle [FPS]) and may
        differ from MDD through increased PT (hippocampal - ventromedial prefrontal cortex (vmPFC) -
        amygdala dependent circuitry and Anxiety-Potentiated Startle [APS]). To causally probe this
        circuitry, we will manipulate gamma-aminobutyric acid (GABA) to demonstrate different
        responses in PT between these three groups, providing further evidence for PT as a targetable
        process. This mechanistic R01 uses a benzodiazepine within an experimental medicine approach
        to causally modulate the threat processing system and associated circuits in AD-MDD (N=50),
        MDD (N=50), and AD (N=50). After the ~2.5 hr screening session, participants will complete
        two identical ~5 hr experimental sessions, each of which include a 30 min electromyography
        (EMG) session and a 1 hr functional magnetic resonance imaging (fMRI) session. The total time
        involved in the study is approximately 10.5 hours. In a double-blind placebo crossover
        design, participants will receive a single 1mg dose of Lorazepam/Placebo and complete threat
        tasks that delineate PT/AT during startle EMG (NPU task; unpredictable vs predictable shock)
        and fMRI (FID task; slow vs fast threat).
  
        Specific aims of this project are:
  
        Aim 1: Determine EMG signatures of dysregulated threat processing in AD-MDD.
  
        Hypothesis 1 A (H1A): AD-MDD/AD will exhibit higher PT sensitivity (greater APS) than MDD
        (NPU APS: AD-MDD > MDD; AD > MDD).
  
        Hypothesis 1 B (H1B): AD-MDD/MDD will exhibit lower AT sensitivity (smaller FPS) than AD (NPU
        FPS: AD-MDD < AD; MDD < AD).
  
        Aim 2: Determine neural computational signatures of dysregulated threat processing in AD-MDD.
  
        Hypothesis 2 A (H2A): AD-MDD and AD will show higher hippocampal-vmPFC-amygdala responses to
        FID slow threat (PT) than MDD (FID slow: AD-MDD > MDD; AD > MDD).
  
        Hypothesis 2 B (H2B): AD-MDD and MDD will show lower periaqueductal grey/insula responses to
        FID fast threat (AT) than AD. (FID fast: AD-MDD < AD; MDD < AD).
  
        Hypothesis 2 C (H2C): Utility functions for the FID task will show both blunted reward and
        exaggerated threat valuation in AD-MDD, leading to less optimal choices than both MDD and AD.
  
        Aim 3: Determine the relevance of comorbidity to GABAergic manipulation of threat circuitry.
  
        Hypothesis 3 A (H3A): In the NPU task Lorazepam will decrease APS (PT) but not FPS (AT) in AD
        and AD-MDD but not MDD.
  
        Hypothesis 3 B (H3B): In the FID task Lorazepam will decrease neural response to slow (PT)
        but not fast (AT) threat and decrease the computational threat valuation parameter in AD and
        AD-MDD but not MDD.
  
        Significance: These aims seek to mechanistically define and pharmacologically probe process
        dysfunction and associated targetable circuitry unique to AD-MDD and provide evidence that
        AD-MDD and MDD should be separated in future clinical trials. This will also inform
        intervention strategies with circuit-based targets (e.g. for neuromodulation treatments) for
        AD-MDD, which is a large but under-served treatment resistant group.
  allocation: Randomized
  intervention model: Crossover Assignment
  intervention model description: double blind crossover design
  primary purpose: Basic Science
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  masking description: placebo preparation by the pharmacy
  measure: Eyeblink startle magnitude under threat in AD-MDD compared to MDD.
  time frame: 1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2)
  description: Difference in magnitude of eyeblink startle response under threat of predictable and unpredictable shock conditions compared to neutral condition in the Neutral, Predictable, Unpredictable (NPU) Threat Task measured with electromyography. Comparing the AD-MDD group to the MDD group.
  measure: Magnitude of blood oxygenated level dependent (BOLD) response to threat in AD-MDD compared to MDD.
  time frame: 1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2)
  description: Magnitude of hippocampal-vmPFC-amygdala and periaqueductal grey/insula blood oxygenated level dependent (BOLD) responses to fast and slow threat compared to a no threat condition in the Flight Initiation Distance (FID) Task, measured with functional magnetic resonance imaging (fMRI). Comparing the AD-MDD group to the MDD group.
  measure: The effect of Lorazepam on eyeblink startle magnitude and BOLD response to threat in AD-MDD compared to MDD
  time frame: 1-2 hours after single session drug administration, after both Lorazepam and sessions have been completed, an average of 5 weeks after enrollment
  description: Comparing the effects of Lorazepam to placebo (within subject) and AD-MDD to MDD (between subject) on the magnitude of eyeblink startle response under threat of predictable and unpredictable shock conditions compared to neutral condition in the NPU Threat Task measured with EMG.
  Comparing the effects of Lorazepam to placebo (within subject) and AD-MDD to MDD (between subject) on the magnitude of hippocampal-vmPFC-amygdala and periaqueductal grey/insula blood oxygenated level dependent (BOLD) responses to fast and slow threat compared to a no threat condition in the Flight Initiation Distance Task, measured with fMRI.
  arm group label: Lorazepam
  arm group type: Experimental
  description: Participants will receive a single 1mg dose of Lorazepam, to be taken orally under registered nurse (RN) supervision
  arm group label: Placebo
  arm group type: Placebo Comparator
  description: Participants will receive a single dose of placebo, to be taken orally under RN supervision
  intervention type: Drug
  intervention name: Lorazepam
  description: 1mg of Lorazepam will be prepared by pharmacy (Barnes, Tulsa) in capsule form
  arm group label: Lorazepam
  other name: Lorazepam Intensol
  other name: Ativan
  intervention type: Other
  intervention name: Placebo
  description: placebo will be prepared by pharmacy (Barnes, Tulsa) in capsule form
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 65 Years
  healthy volunteers: No
  last name: Maria Ironside, DPhil
  role: Principal Investigator
  affiliation: Laureate Institute for Brain Research
  last name: Maria Ironside, DPhil
  phone: 16174175065
  email: mironside@laureateinstitute.org
  facility: 
  country: United States
  responsible party type: Sponsor
  mesh term: Hypersensitivity
  mesh term: Depression
  mesh term: Depressive Disorder
  mesh term: Anxiety Disorders
  mesh term: Lorazepam
  sharing ipd: No