<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/NCT02255175</url>
  </required_header>
  <id_info>
    <org_study_id>13-3572</org_study_id>
    <secondary_id>K12HD001441-15</secondary_id>
    <secondary_id>K23MH105569-01A1</secondary_id>
    <nct_id>NCT02255175</nct_id>
  </id_info>
  <brief_title>Perimenopausal Effects of Estradiol on Reward Responsiveness</brief_title>
  <acronym>PEERS</acronym>
  <official_title>Effects of Estradiol on Neural Reward System and Depression in the Perimenopause</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Mental Health (NIMH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Using neuroimaging, the investigator will study the effects of estrogen on mood and brain&#xD;
      function in perimenopausal women either with or without depression.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Despite decades of research, affective disorders are prevalent and associated with&#xD;
      significant morbidity and mortality. Unraveling the pathophysiology of affective disorders&#xD;
      has been uniquely challenging because depressive syndromes are heterogeneous and have diverse&#xD;
      etiologies. Thus, past studies aimed at identifying neural and genetic biomarkers that would&#xD;
      improve the prediction of susceptibility, course of illness, and treatment response have&#xD;
      yielded inconsistent results. The investigator proposes to address this problem by studying&#xD;
      perimenopausal major depressive disorder (MDD), a depression subtype with a specific&#xD;
      endocrine trigger (i.e., ovarian hormone withdrawal). Evidence supporting ovarian hormone&#xD;
      withdrawal as a trigger for affective dysfunction in perimenopausal MDD includes the&#xD;
      following: perimenopausal women show a temporal association between ovarian hormone&#xD;
      withdrawal and the onset of mood symptoms; treatment with estrogen reduces mood symptoms; and&#xD;
      blinded estradiol withdrawal re-precipitates depression in women with a history of&#xD;
      perimenopausal MDD (manuscript in preparation). Focusing on perimenopausal MDD, a more&#xD;
      homogeneous subtype with a specific endocrine trigger, will increase the likelihood of&#xD;
      identifying meaningful neurobiological markers.One of the most powerful tools for&#xD;
      understanding the neural mediators of MDD is brain imaging. Prior research suggests that the&#xD;
      frontostriatal reward system is regulated by estradiol and implicated in MDD. However, neural&#xD;
      mechanisms of perimenopausal MDD have never been studied. We will assess the neural reward&#xD;
      system in perimenopausal women with and without MDD using functional magnetic resonance&#xD;
      imaging (fMRI) at baseline and following estradiol treatment. The central hypothesis is that&#xD;
      the neural reward system is hypoactive in perimenopausal MDD, and the antidepressant effects&#xD;
      of a three-week transdermal estradiol intervention will be mediated by increased activity in&#xD;
      the neural reward system, assessed using fMRI. The investigator will test the hypothesis by&#xD;
      executing the following aims:&#xD;
&#xD;
      Aim 1: To measure the frontostriatal response to reward in perimenopausal MDD and test the&#xD;
      effects of estradiol on neural activation in perimenopausal women. The investigator will use&#xD;
      fMRI at baseline and following estradiol treatment in women with and without MDD to probe&#xD;
      frontostriatal reward circuitry.&#xD;
&#xD;
      Aim 2: To quantify motivated behavior at baseline and following estradiol administration in&#xD;
      perimenopausal women with and without MDD. Motivated behavior will be operationally defined&#xD;
      as the response latency to reward versus non-reward during the fMRI reward task.&#xD;
&#xD;
      Aim 3: To measure the psychological correlates of the frontostriatal response to reward in&#xD;
      women with perimenopausal MDD at baseline and following estradiol administration. Depressive&#xD;
      symptoms will be assessed at baseline and following estradiol administration.&#xD;
&#xD;
      The results will provide critical information about the neuroendocrine pathophysiology of&#xD;
      perimenopausal depression and may subsequently contribute to the development of novel&#xD;
      pharmacologic interventions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 1, 2015</start_date>
  <completion_date type="Actual">October 17, 2018</completion_date>
  <primary_completion_date type="Actual">October 17, 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Caudate Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</measure>
    <time_frame>Pre-treatment (visit 3)</time_frame>
    <description>Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</measure>
    <time_frame>Pre-treatment (visit 3)</time_frame>
    <description>Nucleus Accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Putamen Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</measure>
    <time_frame>Pre-treatment (visit 3)</time_frame>
    <description>Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Caudate Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</measure>
    <time_frame>Post-treatment (visit 6)</time_frame>
    <description>Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</measure>
    <time_frame>Post-treatment (visit 6)</time_frame>
    <description>Nucleus accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Putamen Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</measure>
    <time_frame>Post-treatment (visit 6)</time_frame>
    <description>Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response Latency to Reward During the MID fMRI Task at Pre-treatment</measure>
    <time_frame>Pre-treatment (visit 3)</time_frame>
    <description>Time (ms) between stimulus and response will be measured during the Monetary Incentive Delay (MID) task during the win trials. During MID the task, participants need to select the correct response during &quot;win&quot; and &quot;lose&quot; conditions by pressing a button on a button box in the MRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Latency to Reward During the MID fMRI Task Following Estradiol Treatment</measure>
    <time_frame>Post-treatment (visit 6)</time_frame>
    <description>Time (ms) between stimulus and response will be measured during reward trials of the Monetary Incentive Delay (MID) task. During MID the task, participants need to select the correct response during &quot;win&quot; and &quot;lose&quot; conditions by pressing a button on a button box in the MRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Inventory of Depression and Anxiety Symptoms (IDAS) Dysphoria Scores</measure>
    <time_frame>Assessed at pre- and post-treatment (visits 3 and 6)</time_frame>
    <description>The Dysphoria Scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be used to assess the change in depressive symptom severity. The IDAS Dysphoria Scale consists of 10 items and uses a 5-point Likert-type scale, ranging from 1 to 5 with 1 indicating &quot;not at all&quot; and 5 indicating &quot;extremely&quot;. As such, the range of possible scores is 10 to 50. The Dysphoria scale includes items assessing feelings of depression, inadequacy, psychomotor agitation, guilt, discouragement, anhedonia, poor concentration, difficulty with decision-making, psychomotor retardation, and worry. Higher scores indicate worse depression symptoms.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">64</enrollment>
  <condition>Perimenopausal Depression</condition>
  <arm_group>
    <arm_group_label>Perimenopausal women, depressed</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Perimenopausal women, non-depressed</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Estradiol</intervention_name>
    <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks</description>
    <arm_group_label>Perimenopausal women, depressed</arm_group_label>
    <arm_group_label>Perimenopausal women, non-depressed</arm_group_label>
    <other_name>Transdermal estradiol</other_name>
    <other_name>Climara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Progesterone</intervention_name>
    <description>Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
    <arm_group_label>Perimenopausal women, depressed</arm_group_label>
    <arm_group_label>Perimenopausal women, non-depressed</arm_group_label>
    <other_name>Prometrium</other_name>
    <other_name>Micronized progesterone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Perimenopause Status: We will employ the Stages of Reproductive Aging Workshop (STRAW)&#xD;
             criteria70 to confirm perimenopausal status. The stages are primarily based on the&#xD;
             characteristics of the menstrual cycle and secondarily on follicle stimulating hormone&#xD;
             (FSH) levels. The anchor for the staging system is the final menstrual period (FMP).&#xD;
             We will enroll women who have ≥ 2 skipped cycles and an interval of amenorrhea ≥ 60&#xD;
             days, consistent with the late menopause transition (stage -1), and who demonstrate an&#xD;
             FSH level &gt; 25 IU/mL. Because extremes of body weight (BMI &lt; 18 or &gt; 30 kg/m2) or a&#xD;
             history of chronic menstrual cycle irregularity can contribute to inaccurate&#xD;
             reproductive staging, these will serve as additional exclusion criteria;&#xD;
&#xD;
          2. MDD Group Eligibility Criterion: current diagnosis of MDD with an onset associated&#xD;
             with menstrual cycle irregularity, and no history of psychiatric illness during the 2&#xD;
             years before the onset of the current depressive episode as determined by the&#xD;
             Structured Clinical Interview for DSM-IV-TR (Diagnostic and Statistical Manual-4-Text&#xD;
             Revision) for Axis I Disorders (SCID);&#xD;
&#xD;
          3. Control Group Eligibility Criterion: absence of any past or present psychiatric&#xD;
             disorder as assessed by the SCID.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients will not be permitted to enter this protocol if they have any of the following:&#xD;
&#xD;
          1. current medication use (i.e., psychotropics, anti-hypertensives, statins, hormonal&#xD;
             preparations, or frequent use of anti-inflammatory agents (&gt; 10 times/month)). Women&#xD;
             will be allowed to enroll who take medications without known mood effects (e.g. stable&#xD;
             thyroid hormone replacement and occasional (&lt; 5 times/month) use of Ambien)*;&#xD;
&#xD;
          2. pregnant, breastfeeding or trying to conceive;&#xD;
&#xD;
          3. FMP more than 12 months prior to enrollment;&#xD;
&#xD;
          4. history of undiagnosed vaginal bleeding;&#xD;
&#xD;
          5. undiagnosed enlargement of the ovaries;&#xD;
&#xD;
          6. polycystic ovary syndrome;&#xD;
&#xD;
          7. history of breast or ovarian cancer;&#xD;
&#xD;
          8. first degree relative with ovarian cancer;&#xD;
&#xD;
          9. first degree relative with premenopausal onset or bilateral breast cancer;&#xD;
&#xD;
         10. 2+ first degree relatives with breast cancer (regardless of onset);&#xD;
&#xD;
         11. 3+ relatives with postmenopausal breast cancer;&#xD;
&#xD;
         12. abnormal finding in a provider breast exam and/or mammogram;&#xD;
&#xD;
         13. known carrier of BRCA1 or 2 mutation;&#xD;
&#xD;
         14. endometriosis;&#xD;
&#xD;
         15. blood clots in the legs or lungs;&#xD;
&#xD;
         16. porphyria;&#xD;
&#xD;
         17. diabetes mellitus;&#xD;
&#xD;
         18. malignant melanoma;&#xD;
&#xD;
         19. Hodgkin's disease;&#xD;
&#xD;
         20. recurrent migraine headaches that are preceded by aura;&#xD;
&#xD;
         21. gallbladder or pancreatic disease**;&#xD;
&#xD;
         22. heart or kidney disease**;&#xD;
&#xD;
         23. liver disease;&#xD;
&#xD;
         24. cerebrovascular disease (stroke);&#xD;
&#xD;
         25. first degree relative with history of heart attack or stroke;&#xD;
&#xD;
         26. current cigarette smoking;&#xD;
&#xD;
         27. current suicidal ideation or psychosis;&#xD;
&#xD;
         28. past suicide attempts or psychotic episodes requiring hospitalization;&#xD;
&#xD;
         29. chronic depression (i.e., episode(s) lasting 3+ years);&#xD;
&#xD;
         30. recurrent depression (i.e., more than 1 prior episode, not including episodes with&#xD;
             postpartum onset)&#xD;
&#xD;
         31. depressive episode(s) within 2 years of enrollment;&#xD;
&#xD;
         32. self-reported claustrophobia&#xD;
&#xD;
         33. peanut allergy&#xD;
&#xD;
               -  all reported prescription medications will be reviewed and cleared by a study&#xD;
                  physician prior to a participant's enrollment; **participants will be given the&#xD;
                  opportunity to describe these conditions in the online screening survey. Reported&#xD;
                  conditions that are acute in nature and/or benign will be reviewed by a study&#xD;
                  physician and exclusions will be decided case-by-case. All chronic conditions&#xD;
                  will be exclusionary.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>44 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Crystal Schiller, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina at Chapel Hill Psychiatry Department</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of North Carolina</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27514</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>September 29, 2014</study_first_submitted>
  <study_first_submitted_qc>September 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2014</study_first_posted>
  <results_first_submitted>September 25, 2019</results_first_submitted>
  <results_first_submitted_qc>October 21, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">November 12, 2019</results_first_posted>
  <last_update_submitted>October 21, 2019</last_update_submitted>
  <last_update_submitted_qc>October 21, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 12, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Reproductive Affective Disorder</keyword>
  <keyword>Depression</keyword>
  <keyword>Perimenopause</keyword>
  <keyword>Estrogen</keyword>
  <keyword>Estradiol treatment</keyword>
  <keyword>Mood Disorders</keyword>
  <keyword>Estrogen Replacement Therapy</keyword>
  <keyword>Sex Steroids</keyword>
  <keyword>Depressive disorder</keyword>
  <keyword>Mental Disorders</keyword>
  <keyword>Estradiol</keyword>
  <keyword>Hormones</keyword>
  <keyword>Physiological effects of drugs</keyword>
  <keyword>Reproductive Control Agents</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Estradiol 17 beta-cypionate</mesh_term>
    <mesh_term>Estradiol 3-benzoate</mesh_term>
    <mesh_term>Estradiol</mesh_term>
    <mesh_term>Polyestradiol phosphate</mesh_term>
    <mesh_term>Progesterone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 12, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/75/NCT02255175/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The recruitment process included, social media advertising using Facebook, Instagram, and Craigslist; mass emailing using university wide emails and a database of select University of North Carolina (UNC) healthcare patients (Carolina data warehouse); and flyer advertisements placed in university buildings and local businesses.</recruitment_details>
      <pre_assignment_details>Enrolled participants were excluded prior to the start of study intervention due to: exclusionary psychiatric history (i.e. substance abuse, past hypomania, persistent depression), exclusionary gynecological history (i.e. fibroids, abnormal pap), exclusionary medical history (i.e. abnormal lab values), exclusionary medication, and imaging concerns.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Perimenopausal Women, Depressed</title>
          <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
        </group>
        <group group_id="P2">
          <title>Perimenopausal Women, Non-depressed</title>
          <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="33"/>
                <participants group_id="P2" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Perimenopausal Women, Depressed</title>
          <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
        </group>
        <group group_id="B2">
          <title>Perimenopausal Women, Non-depressed</title>
          <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="33"/>
            <count group_id="B2" value="31"/>
            <count group_id="B3" value="64"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <title>Age</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50.13" lower_limit="44" upper_limit="55"/>
                    <measurement group_id="B2" value="50.76" lower_limit="44" upper_limit="55"/>
                    <measurement group_id="B3" value="50.44" lower_limit="44" upper_limit="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="64"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race/Ethnicity</title>
              <category_list>
                <category>
                  <title>White or Caucasion</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="53"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Multi-Racial</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Cuban or Carribean</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Caudate Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</title>
        <description>Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
        <time_frame>Pre-treatment (visit 3)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Caudate Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</title>
          <description>Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
          <units>percent signal change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".027" spread=".105"/>
                    <measurement group_id="O2" value=".043" spread=".074"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.620</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=.501, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</title>
        <description>Nucleus Accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
        <time_frame>Pre-treatment (visit 3)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</title>
          <description>Nucleus Accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
          <units>percent signal change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".045" spread=".117"/>
                    <measurement group_id="O2" value=".052" spread=".108"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.855</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=.185, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Putamen Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</title>
        <description>Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
        <time_frame>Pre-treatment (visit 3)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Putamen Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment</title>
          <description>Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.</description>
          <units>percent signal change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".015" spread=".103"/>
                    <measurement group_id="O2" value=".004" spread=".093"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.758</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=-.310, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Caudate Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</title>
        <description>Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
        <time_frame>Post-treatment (visit 6)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Caudate Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</title>
          <description>Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
          <units>percent signal change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".005" spread=".079"/>
                    <measurement group_id="O2" value=".026" spread=".103"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.518</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=.653, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</title>
        <description>Nucleus accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
        <time_frame>Post-treatment (visit 6)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</title>
          <description>Nucleus accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
          <units>percent signal change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".040" spread=".110"/>
                    <measurement group_id="O2" value=".059" spread=".118"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.645</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=.465, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Putamen Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</title>
        <description>Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
        <time_frame>Post-treatment (visit 6)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Putamen Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.</title>
          <description>Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to &quot;win&quot; trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more &quot;active&quot; or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.</description>
          <units>percent signal change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-.030" spread=".068"/>
                    <measurement group_id="O2" value=".032" spread=".073"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.015</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=2.56, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response Latency to Reward During the MID fMRI Task at Pre-treatment</title>
        <description>Time (ms) between stimulus and response will be measured during the Monetary Incentive Delay (MID) task during the win trials. During MID the task, participants need to select the correct response during &quot;win&quot; and &quot;lose&quot; conditions by pressing a button on a button box in the MRI.</description>
        <time_frame>Pre-treatment (visit 3)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Response Latency to Reward During the MID fMRI Task at Pre-treatment</title>
          <description>Time (ms) between stimulus and response will be measured during the Monetary Incentive Delay (MID) task during the win trials. During MID the task, participants need to select the correct response during &quot;win&quot; and &quot;lose&quot; conditions by pressing a button on a button box in the MRI.</description>
          <units>Milliseconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="204.17" spread="25.11"/>
                    <measurement group_id="O2" value="209.63" spread="20.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.486</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=.705, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response Latency to Reward During the MID fMRI Task Following Estradiol Treatment</title>
        <description>Time (ms) between stimulus and response will be measured during reward trials of the Monetary Incentive Delay (MID) task. During MID the task, participants need to select the correct response during &quot;win&quot; and &quot;lose&quot; conditions by pressing a button on a button box in the MRI.</description>
        <time_frame>Post-treatment (visit 6)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Response Latency to Reward During the MID fMRI Task Following Estradiol Treatment</title>
          <description>Time (ms) between stimulus and response will be measured during reward trials of the Monetary Incentive Delay (MID) task. During MID the task, participants need to select the correct response during &quot;win&quot; and &quot;lose&quot; conditions by pressing a button on a button box in the MRI.</description>
          <units>Milliseconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="190.68" spread="34.98"/>
                    <measurement group_id="O2" value="193.43" spread="39.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.831</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>t=.216, df=33</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Inventory of Depression and Anxiety Symptoms (IDAS) Dysphoria Scores</title>
        <description>The Dysphoria Scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be used to assess the change in depressive symptom severity. The IDAS Dysphoria Scale consists of 10 items and uses a 5-point Likert-type scale, ranging from 1 to 5 with 1 indicating &quot;not at all&quot; and 5 indicating &quot;extremely&quot;. As such, the range of possible scores is 10 to 50. The Dysphoria scale includes items assessing feelings of depression, inadequacy, psychomotor agitation, guilt, discouragement, anhedonia, poor concentration, difficulty with decision-making, psychomotor retardation, and worry. Higher scores indicate worse depression symptoms.</description>
        <time_frame>Assessed at pre- and post-treatment (visits 3 and 6)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Perimenopausal Women, Depressed, Baseline</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O2">
            <title>Perimenopausal Women, Non-depressed, Baseline</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O3">
            <title>Perimenopausal Women, Depressed, Following Estradiol Treatment</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
          <group group_id="O4">
            <title>Perimenopausal Women, Non-depressed, Following Estradiol</title>
            <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Inventory of Depression and Anxiety Symptoms (IDAS) Dysphoria Scores</title>
          <description>The Dysphoria Scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be used to assess the change in depressive symptom severity. The IDAS Dysphoria Scale consists of 10 items and uses a 5-point Likert-type scale, ranging from 1 to 5 with 1 indicating &quot;not at all&quot; and 5 indicating &quot;extremely&quot;. As such, the range of possible scores is 10 to 50. The Dysphoria scale includes items assessing feelings of depression, inadequacy, psychomotor agitation, guilt, discouragement, anhedonia, poor concentration, difficulty with decision-making, psychomotor retardation, and worry. Higher scores indicate worse depression symptoms.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="19"/>
                <count group_id="O3" value="16"/>
                <count group_id="O4" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.56" spread="1.47"/>
                    <measurement group_id="O2" value="13.79" spread="1.35"/>
                    <measurement group_id="O3" value="15.25" spread="1.13"/>
                    <measurement group_id="O4" value="11.84" spread="1.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.0002</p_value>
            <method>Repeated measures ANOVA</method>
            <method_desc>F(1,33)=17.91</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data was tracked over a participants time in the protocol (1 month), all unresolved adverse events were tracked by the investigator until the events were resolved, the subject was lost to follow-up, or the adverse event was otherwise explained.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Perimenopausal Women, Depressed</title>
          <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
        </group>
        <group group_id="E2">
          <title>Perimenopausal Women, Non-depressed</title>
          <description>Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.&#xD;
Estradiol: Participants will receive transdermal estradiol (100μg/day) for 3 weeks&#xD;
Progesterone: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <description>Water retention or bloating</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Hot Flashes</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Waking during the night</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Lower Back Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headaches</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Breast Tenderness</sub_title>
                <description>Breast fullness or tenderness.</description>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Cramps</sub_title>
                <description>menstrual type cramps, abdominal pain and tenderness, sensitive groin</description>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Menstrual Bleeding</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Itchiness at patch site</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Acne</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Crystal Edler Schiller, PhD</name_or_title>
      <organization>UNC School of Medicine</organization>
      <phone>919-966-4810</phone>
      <email>crystal_schiller@med.unc.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02255175
org study id: 13-3572
secondary id: K12HD001441-15
secondary id: K23MH105569-01A1
nct id: NCT02255175
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Using neuroimaging, the investigator will study the effects of estrogen on mood and brain
      function in perimenopausal women either with or without depression.
Despite decades of research, affective disorders are prevalent and associated with
      significant morbidity and mortality. Unraveling the pathophysiology of affective disorders
      has been uniquely challenging because depressive syndromes are heterogeneous and have diverse
      etiologies. Thus, past studies aimed at identifying neural and genetic biomarkers that would
      improve the prediction of susceptibility, course of illness, and treatment response have
      yielded inconsistent results. The investigator proposes to address this problem by studying
      perimenopausal major depressive disorder (MDD), a depression subtype with a specific
      endocrine trigger (i.e., ovarian hormone withdrawal). Evidence supporting ovarian hormone
      withdrawal as a trigger for affective dysfunction in perimenopausal MDD includes the
      following: perimenopausal women show a temporal association between ovarian hormone
      withdrawal and the onset of mood symptoms; treatment with estrogen reduces mood symptoms; and
      blinded estradiol withdrawal re-precipitates depression in women with a history of
      perimenopausal MDD (manuscript in preparation). Focusing on perimenopausal MDD, a more
      homogeneous subtype with a specific endocrine trigger, will increase the likelihood of
      identifying meaningful neurobiological markers.One of the most powerful tools for
      understanding the neural mediators of MDD is brain imaging. Prior research suggests that the
      frontostriatal reward system is regulated by estradiol and implicated in MDD. However, neural
      mechanisms of perimenopausal MDD have never been studied. We will assess the neural reward
      system in perimenopausal women with and without MDD using functional magnetic resonance
      imaging (fMRI) at baseline and following estradiol treatment. The central hypothesis is that
      the neural reward system is hypoactive in perimenopausal MDD, and the antidepressant effects
      of a three-week transdermal estradiol intervention will be mediated by increased activity in
      the neural reward system, assessed using fMRI. The investigator will test the hypothesis by
      executing the following aims:

      Aim 1: To measure the frontostriatal response to reward in perimenopausal MDD and test the
      effects of estradiol on neural activation in perimenopausal women. The investigator will use
      fMRI at baseline and following estradiol treatment in women with and without MDD to probe
      frontostriatal reward circuitry.

      Aim 2: To quantify motivated behavior at baseline and following estradiol administration in
      perimenopausal women with and without MDD. Motivated behavior will be operationally defined
      as the response latency to reward versus non-reward during the fMRI reward task.

      Aim 3: To measure the psychological correlates of the frontostriatal response to reward in
      women with perimenopausal MDD at baseline and following estradiol administration. Depressive
      symptoms will be assessed at baseline and following estradiol administration.

      The results will provide critical information about the neuroendocrine pathophysiology of
      perimenopausal depression and may subsequently contribute to the development of novel
      pharmacologic interventions.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Caudate Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment
time frame: Pre-treatment (visit 3)
description: Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.
measure: Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment
time frame: Pre-treatment (visit 3)
description: Nucleus Accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.
measure: Putamen Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment
time frame: Pre-treatment (visit 3)
description: Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.
measure: Caudate Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.
time frame: Post-treatment (visit 6)
description: Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.
measure: Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.
time frame: Post-treatment (visit 6)
description: Nucleus accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.
measure: Putamen Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment.
time frame: Post-treatment (visit 6)
description: Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.
measure: Response Latency to Reward During the MID fMRI Task at Pre-treatment
time frame: Pre-treatment (visit 3)
description: Time (ms) between stimulus and response will be measured during the Monetary Incentive Delay (MID) task during the win trials. During MID the task, participants need to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI.
measure: Response Latency to Reward During the MID fMRI Task Following Estradiol Treatment
time frame: Post-treatment (visit 6)
description: Time (ms) between stimulus and response will be measured during reward trials of the Monetary Incentive Delay (MID) task. During MID the task, participants need to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI.
measure: Change in Inventory of Depression and Anxiety Symptoms (IDAS) Dysphoria Scores
time frame: Assessed at pre- and post-treatment (visits 3 and 6)
description: The Dysphoria Scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be used to assess the change in depressive symptom severity. The IDAS Dysphoria Scale consists of 10 items and uses a 5-point Likert-type scale, ranging from 1 to 5 with 1 indicating "not at all" and 5 indicating "extremely". As such, the range of possible scores is 10 to 50. The Dysphoria scale includes items assessing feelings of depression, inadequacy, psychomotor agitation, guilt, discouragement, anhedonia, poor concentration, difficulty with decision-making, psychomotor retardation, and worry. Higher scores indicate worse depression symptoms.
arm group label: Perimenopausal women, depressed
arm group type: Experimental
description: Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
arm group label: Perimenopausal women, non-depressed
arm group type: Active Comparator
description: Participants will receive transdermal estradiol (100μg/day) for 3 weeks. Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
intervention type: Drug
intervention name: Estradiol
description: Participants will receive transdermal estradiol (100μg/day) for 3 weeks
arm group label: Perimenopausal women, depressed
arm group label: Perimenopausal women, non-depressed
other name: Transdermal estradiol
other name: Climara
intervention type: Drug
intervention name: Progesterone
description: Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
arm group label: Perimenopausal women, depressed
arm group label: Perimenopausal women, non-depressed
other name: Prometrium
other name: Micronized progesterone
criteria: 
gender: Female
minimum age: 44 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Crystal Schiller, PhD
role: Principal Investigator
affiliation: University of North Carolina at Chapel Hill Psychiatry Department
facility: 
country: United States
responsible party type: Sponsor
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Estradiol 17 beta-cypionate
mesh term: Estradiol 3-benzoate
mesh term: Estradiol
mesh term: Polyestradiol phosphate
mesh term: Progesterone
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 