<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/NCT03786614</url>
  </required_header>
  <id_info>
    <org_study_id>18.1351</org_study_id>
    <nct_id>NCT03786614</nct_id>
  </id_info>
  <brief_title>Antidepressant Discontinuation in Treatment Resistant Depression</brief_title>
  <official_title>Antidepressant Discontinuation in Treatment Resistant Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Louisville</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Louisville</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare the effects on depressive symptoms of subjects who&#xD;
      discontinue serotonergic antidepressants (a certain type of antidepressant, such as Prozac,&#xD;
      that works on serotonin receptors in the brain) with the effects on depressive symptoms of&#xD;
      subjects who continue to take serotonergic antidepressants. During this study, subjects will&#xD;
      also be presented with the opportunity to undergo genetic testing for the serotonin gene&#xD;
      transporter which has a short or long form. This is being done because it has been&#xD;
      demonstrated that genetic testing improves outcome while treating treatment-resistant&#xD;
      depression.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 20, 2019</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>The person performing the data collection (rater) will be blind to the randomization of the patient for the entire duration of the study</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Comparing the difference of response as measured by the Montgomery-Åsberg Depression Rating Scale [MADRS] between both arms.</measure>
    <time_frame>From baseline and every visit [every 4 weeks] to the end of the study. [6 months]</time_frame>
    <description>The MADRS is a psychiatric scale to assess the depressive symptoms from the patient's prospective. The final score ranges from 0 to 60 with 0 indicating no depression and higher scores indicating greater depression. The final scores will be evaluated with a non-paired, two-tailed t-test.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparing the difference of response as measured by the Montgomery-Åsberg Depression Rating Scale [MADRS] between subjects with low expressing alleles and high expressing alleles of the serotonin gene transporter.</measure>
    <time_frame>End of study [6 months].</time_frame>
    <description>Genetic testing for the serotonin transporter gene will be done for every patient in the study. All subjects with homozygous and heterozygous low expression alleles will be combined as one group, and all high expression subjects will be the other group. One-way ANOVAs will be conducted for each genotype group, with genotype group as the independent variable (IV) and MADRS scores as the dependent variables (DV).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluating changes in levels of anxiety as measured by the Hamilton Anxiety Rating Scale [HAM-A] between both arms.</measure>
    <time_frame>From baseline and every visit [every 4 weeks] to the end of the study. [6 months]</time_frame>
    <description>The HAM-A will be collected to assess changes in anxiety levels from the patient's prospective. It ranges from 0 to 56 with greater scores indicating more anxiety. The final scores will be evaluated with a non-paired, two-tailed t-test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluating the difference of response as measured by the Columbia Suicide Severity Rating Scale [C-SSRS] between both arms.</measure>
    <time_frame>From baseline and every visit [every 4 weeks] to the end of the study. [6 months]</time_frame>
    <description>The C-SSRS is a psychiatric scale to assess suicidality. It ranges from 0 to 5 with 0 indicating no suicidal ideas and higher scores indicating greater suicidal ideas. The final scores will be evaluated with a non-paired, two-tailed t-test.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Treatment Resistant Depression</condition>
  <arm_group>
    <arm_group_label>Discontinuation arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This group will be discontinued from serotonergic antidepressants and shifting them to other categories of antidepressants, i.e., medications that work through dopamine or nor-epinephrine, or by reducing the serotonin signal rather than increasing synaptic serotonin, as might be accomplished with low dose, sub-anti-psychotic doses of some second-generation anti-psychotics.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Continuation arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This group will continue taking serotonergic antidepressants which is the standard care of treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Discontinuation of serotonergic antidepressants</intervention_name>
    <description>Discontinuation of serotonergic antidepressants and possibly shift to other antidepressant categories that were proven to be effective in treating depression such as pramipexole, bupropion, quetiapine, lurasidone, brexpipazole. Additionally, subjects will have access to other treatment measures of treating treatment resistant depression.</description>
    <arm_group_label>Discontinuation arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Continuation of serotonergic medications</intervention_name>
    <description>Continuation of serotonergic medications which is the standard care of treatment. Additionally, subjects will have access to other treatment measures of treating treatment resistant depression.</description>
    <arm_group_label>Continuation arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must be a man or woman 18 to 70 years of age, inclusive.&#xD;
&#xD;
          -  Subject must meet criteria for a major depressive disorder as confirmed by the Mini&#xD;
             International Neuropsychiatric Interview [MINI].&#xD;
&#xD;
          -  Subjects must have a current Treatment-Resistant Depression as defined below.&#xD;
&#xD;
          -  Subjects must have been taking serotonergic antidepressants (serotonin reuptake&#xD;
             inhibitor or monoamine oxidase inhibitor) for at least 2 years but not more than 4&#xD;
             years, and have failed 2 previous medication trial for the current episode. Current&#xD;
             Montgomery-Åsberg Depression Rating Scale [MADRS] score must be equal to or more than&#xD;
             25.&#xD;
&#xD;
          -  Subject must be medically stable.&#xD;
&#xD;
          -  Female subjects must have a negative urine pregnancy test at screening, and agree to&#xD;
             avoid pregnancy during the study.&#xD;
&#xD;
          -  Each subject must sign an informed consent form indicating that he/she understands the&#xD;
             purpose of the study and the procedures required and are willing to participate in the&#xD;
             study.&#xD;
&#xD;
          -  Subject must be able to participate in symptom measurement.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject has a current Diagnostic and Statistical Manual of Mental Disorders-5 [DSM-5]&#xD;
             diagnosis of bipolar disorder or has a positive screening for bipolar disorder by Mini&#xD;
             International Neuropsychiatric Interview [MINI] or Mood Disorder Questionnaire [MDQ].&#xD;
&#xD;
          -  Subject has a current DSM-5 diagnosis of schizophrenia, schizoaffective disorder,&#xD;
             autistic disorder, or intellectual disability.&#xD;
&#xD;
          -  Subject has a substance use disorder (except for nicotine or cannabis) within 3 months&#xD;
             prior to screening or has a positive drug screen test for any recreational drugs at&#xD;
             the time of screening with the exception of Cannabis.&#xD;
&#xD;
          -  Subject has evidence of any clinically significant, unstable medical problems that may&#xD;
             create a safety risk for a subject, interfere with study participation, or make&#xD;
             results difficult to interpret.&#xD;
&#xD;
          -  Subject is at imminent risk of suicide according to the investigator's clinical&#xD;
             judgment and/or a Columbia-Suicide Severity Rating Scale (C-SSRS) 3 or more at any&#xD;
             time in the study.&#xD;
&#xD;
          -  Subject is a woman who is pregnant, breast-feeding or planning to become pregnant&#xD;
             while enrolled in the study.&#xD;
&#xD;
          -  Subject has any condition (according to the investigator) for which participation will&#xD;
             not be the best interest for the subject or it can prevent, limit or confound the&#xD;
             protocol-specified assessments.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rifaat S. El-Mallakh, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Louisville, Department of Psychiatry and Behavioral Sciences</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lucas Miozza</last_name>
    <phone>502-588-0678</phone>
    <email>lgmioz01@louisville.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Louisville, Department of Psychiatry and Behavioral Sciences</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lucas Miozza</last_name>
      <phone>502-588-0678</phone>
      <email>lgmioz01@louisville.edu</email>
    </contact>
    <investigator>
      <last_name>Rif S. El-Mallakh, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ziad A. Ali, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>December 23, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 26, 2018</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 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Louisville</investigator_affiliation>
    <investigator_full_name>Rifaat S. El-Mallakh</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>treatment resistant depression</keyword>
  <keyword>serotonergic antidepressants</keyword>
  <keyword>short form of serotonin transporter</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</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>Antidepressive Agents</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/NCT03786614
org study id: 18.1351
nct id: NCT03786614
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to compare the effects on depressive symptoms of subjects who
      discontinue serotonergic antidepressants (a certain type of antidepressant, such as Prozac,
      that works on serotonin receptors in the brain) with the effects on depressive symptoms of
      subjects who continue to take serotonergic antidepressants. During this study, subjects will
      also be presented with the opportunity to undergo genetic testing for the serotonin gene
      transporter which has a short or long form. This is being done because it has been
      demonstrated that genetic testing improves outcome while treating treatment-resistant
      depression.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: The person performing the data collection (rater) will be blind to the randomization of the patient for the entire duration of the study
measure: Comparing the difference of response as measured by the Montgomery-Åsberg Depression Rating Scale [MADRS] between both arms.
time frame: From baseline and every visit [every 4 weeks] to the end of the study. [6 months]
description: The MADRS is a psychiatric scale to assess the depressive symptoms from the patient's prospective. The final score ranges from 0 to 60 with 0 indicating no depression and higher scores indicating greater depression. The final scores will be evaluated with a non-paired, two-tailed t-test.
measure: Comparing the difference of response as measured by the Montgomery-Åsberg Depression Rating Scale [MADRS] between subjects with low expressing alleles and high expressing alleles of the serotonin gene transporter.
time frame: End of study [6 months].
description: Genetic testing for the serotonin transporter gene will be done for every patient in the study. All subjects with homozygous and heterozygous low expression alleles will be combined as one group, and all high expression subjects will be the other group. One-way ANOVAs will be conducted for each genotype group, with genotype group as the independent variable (IV) and MADRS scores as the dependent variables (DV).
measure: Evaluating changes in levels of anxiety as measured by the Hamilton Anxiety Rating Scale [HAM-A] between both arms.
time frame: From baseline and every visit [every 4 weeks] to the end of the study. [6 months]
description: The HAM-A will be collected to assess changes in anxiety levels from the patient's prospective. It ranges from 0 to 56 with greater scores indicating more anxiety. The final scores will be evaluated with a non-paired, two-tailed t-test.
measure: Evaluating the difference of response as measured by the Columbia Suicide Severity Rating Scale [C-SSRS] between both arms.
time frame: From baseline and every visit [every 4 weeks] to the end of the study. [6 months]
description: The C-SSRS is a psychiatric scale to assess suicidality. It ranges from 0 to 5 with 0 indicating no suicidal ideas and higher scores indicating greater suicidal ideas. The final scores will be evaluated with a non-paired, two-tailed t-test.
arm group label: Discontinuation arm
arm group type: Active Comparator
description: This group will be discontinued from serotonergic antidepressants and shifting them to other categories of antidepressants, i.e., medications that work through dopamine or nor-epinephrine, or by reducing the serotonin signal rather than increasing synaptic serotonin, as might be accomplished with low dose, sub-anti-psychotic doses of some second-generation anti-psychotics.
arm group label: Continuation arm
arm group type: Active Comparator
description: This group will continue taking serotonergic antidepressants which is the standard care of treatment.
intervention type: Other
intervention name: Discontinuation of serotonergic antidepressants
description: Discontinuation of serotonergic antidepressants and possibly shift to other antidepressant categories that were proven to be effective in treating depression such as pramipexole, bupropion, quetiapine, lurasidone, brexpipazole. Additionally, subjects will have access to other treatment measures of treating treatment resistant depression.
arm group label: Discontinuation arm
intervention type: Other
intervention name: Continuation of serotonergic medications
description: Continuation of serotonergic medications which is the standard care of treatment. Additionally, subjects will have access to other treatment measures of treating treatment resistant depression.
arm group label: Continuation arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Rifaat S. El-Mallakh, MD
role: Principal Investigator
affiliation: University of Louisville, Department of Psychiatry and Behavioral Sciences
last name: Lucas Miozza
phone: 502-588-0678
email: lgmioz01@louisville.edu
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Louisville
investigator full name: Rifaat S. El-Mallakh
investigator title: Professor
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Treatment-Resistant
mesh term: Antidepressive Agents