<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/NCT04400266</url>
  </required_header>
  <id_info>
    <org_study_id>2019P003783</org_study_id>
    <nct_id>NCT04400266</nct_id>
  </id_info>
  <brief_title>Buspirone and Melatonin for Depression Following Traumatic Brain Injury</brief_title>
  <official_title>Buspirone and Melatonin for Depression Following Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Traumatic brain injuries (TBIs) are common. Post-TBI depression is associated with anxiety,&#xD;
      aggression, fatigue, distractibility, anger, irritability, and rumination. The current&#xD;
      research group conducted a pilot clinical trial, which investigated the novel treatment&#xD;
      combination of buspirone and melatonin (B+MEL) in outpatients with clinical depression.&#xD;
      Compared to placebo, B+MEL was associated with a significant improvement in depressive&#xD;
      symptoms. Depression following TBI may be different from clinical depression. The B+MEL&#xD;
      combination has never been studied in patients with post-TBI depression. The B+MEL has shown&#xD;
      promise in ameliorating cognitive difficulties in people with depression. Because cognitive&#xD;
      problems are typical in people with post-TBI depression, we plan to measure the effect of the&#xD;
      B+MEL combination on cognitive ability in post-TBI depression. Additionally, we are&#xD;
      interested in measuring functional magnetic resonance imaging changes before and after&#xD;
      treatment with B+MEL in order to gain insight into the brain mechanisms of our hypothesized&#xD;
      clinical symptom changes.&#xD;
&#xD;
      The goals of the proposed pilot research project are to assess changes in symptoms in&#xD;
      patients with post-TBI depression following Buspirone + Melatonin combination (B+MEL), and&#xD;
      the corresponding brain mechanisms underlying these hypothesized changes by measuring: 1)&#xD;
      depressive symptoms; 2) cognitive symptoms; 3) functional magnetic resonance imaging.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and significance:&#xD;
&#xD;
      Buspirone and Melatonin Combination for the Treatment of Post-TBI Depression Traumatic brain&#xD;
      injuries (TBIs) are common (1.7 million cases each year in the US), and major depressive&#xD;
      disorder (MDD) occurs in up to 33% of TBI patients. Post- TBI depression is associated with&#xD;
      anxiety, aggression, fatigue, distractibility, anger, irritability, and rumination. The&#xD;
      current research group conducted a pilot clinical trial, which investigated the novel&#xD;
      treatment combination of buspirone (15 mg/day) and melatonin (3mg), in a small outpatient&#xD;
      cohort with MDD. Compared to the placebo group, the B+MEL group demonstrated significant&#xD;
      improvements in depressive symptoms, at buspirone doses significantly below the recommended&#xD;
      therapeutic range for anxiety and recommended dose (40-60 mg) for MDD. Compared to placebo,&#xD;
      B+MEL was associated with a significant antidepressant response on the Clinical Global&#xD;
      Impressions- Severity (CGI-S, p=0.046) and -Improvement (CGI-I, p=0.04) scales, and on the&#xD;
      Inventory of Depressive Symptomatology (IDS, p=0.034). B+MEL was also superior to the pooled&#xD;
      buspirone and placebo populations (CGI-S, p=0.009; CGI-I, p=0.021; IDS, p=0.031). This&#xD;
      treatment combination has never been studied in patients with post-TBI depression. Depression&#xD;
      following TBI may be phenomenologically and neurobiologically distinct from MDD, and the&#xD;
      neuroanatomical and biopsychological mechanisms underlying B+MEL response in post-TBI&#xD;
      depression are currently unknown. The goal of the proposed pilot research project is to&#xD;
      generate pilot data that would serve as a base for an R01 application for a study that will&#xD;
      fill this critical gap.&#xD;
&#xD;
      Buspirone and Melatonin Combination and Its Effect on Cognition The current research group&#xD;
      compared the effects of B+MEL, buspirone, and placebo on the self-rated Cognitive and&#xD;
      Physical Functioning Questionnaire (CPFQ). The CPFQ cognitive dimension score favored the&#xD;
      B+MEL combination treatment, compared to the pooled buspirone and placebo groups (p = 0.050).&#xD;
      In another randomized, double-blind, SPCD clinical study by the current research group,&#xD;
      treatment with NSI-189 - a compound shown to stimulate neurogenesis in in vitro and in vivo,&#xD;
      was associated with improvement in cognition, objectively measured by the dimensions of&#xD;
      memory (p=0.002) and attention (p=0.048), compared to placebo in MDD patients. The etiology&#xD;
      of cognitive impairment in post-TBI depression is complex, and the cognitive changes in&#xD;
      response to this novel treatment combination has not been investigated. A possible mechanism&#xD;
      of B+MEL action could be the promotion of neurogenesis. Although studying neurogenesis is&#xD;
      beyond the scope of the current research, we speculate that a treatment stimulating&#xD;
      neurogenesis may contribute to cognitive improvements in post-TBI depression. Hence, we will&#xD;
      investigate the effect of B+MEL on cognitive measures of verbal memory, executive&#xD;
      functioning, and speed of information processing, in post-TBI depression pre and&#xD;
      post-treatment.&#xD;
&#xD;
      Resting State Functional Connectivity in Depression and in TBI MDD is characterized by&#xD;
      altered resting state functional connectivity (rsFC) between distinct neural networks. A&#xD;
      recent study compared rsFC in TBI with co-morbid depressive symptoms, relative to TBI without&#xD;
      depressive symptoms. The results demonstrated increased rsFC between the amygdala and parts&#xD;
      of the DAN, salience, somatomotor, and visual networks. Meta-analyses investigating&#xD;
      fMRI-based rsFC in MDD demonstrated decreased rsFC within the frontoparietal control network&#xD;
      (FPCN), and increased rsFC within the default network (DN). Increased rsFC between the FPCN&#xD;
      and DN, and decreased rsFC between the FPCN and dorsal attentional network (DAN) may reflect&#xD;
      increased attentional bias toward ruminative thoughts. Decreased rsFC between the affective&#xD;
      network (AN) and medial prefrontal cortex may reflect impaired emotional regulation and&#xD;
      arousal. Altered rsFC between the ventral attentional network (VAN) and posterior regions may&#xD;
      reflect impaired salience detection in MDD. Changes in rsFC have been detected in response to&#xD;
      different treatments, such as medication and cognitive behavioral therapy, for depression.&#xD;
      Altered rsFC in post-TBI depression is associated with cognitive impairments. A neuroimaging&#xD;
      study measuring rsFC in post-TBI depression has not been performed in the context of the&#xD;
      novel B+MEL combination treatment. The proposed research is novel with respect to design,&#xD;
      technology, and its multi-level integration probing psychological and neurobiological&#xD;
      constructs assumed to be critically implicated depression following TBI. Furthermore, it may&#xD;
      provide valuable insight regarding rsFC biomarkers implicated in the effective treatment of&#xD;
      post-TBI depression.&#xD;
&#xD;
      Specific Aims Specific Aim 1: Assess the changes in depressive symptoms following Buspirone +&#xD;
      Melatonin combination (B+MEL) in post-TBI depression.&#xD;
&#xD;
      Hypothesis 1: The B+MEL treatment combination will be associated with improvements in&#xD;
      depressive symptoms (changes in HAM-D scores pre- to post-treatment).&#xD;
&#xD;
      Specific Aim 2: Assess the changes in cognitive symptoms following Buspirone + Melatonin&#xD;
      combination (B+MEL) in post-TBI depression.&#xD;
&#xD;
      Hypothesis 2: The B+MEL treatment combination will be associated with improvements in&#xD;
      measures of verbal memory, executive functioning, and speed of information processing pre- to&#xD;
      post-treatment.&#xD;
&#xD;
      Specific Aim 3 (exploratory aim): To assess neuroimaging changes in fMRI resting state&#xD;
      functional connectivity in outpatients with post-TBI depression treated with the B+MEL&#xD;
      combination.&#xD;
&#xD;
      Hypothesis 3: The B+MEL treatment combination will show pre- to post-treatment resting state&#xD;
      functional connectivity increases within the frontoparietal control network (implicated in&#xD;
      cognitive control of attention), decreases within the default network (implicated in&#xD;
      internally oriented and self-referential thought), and decreases between the frontoparietal&#xD;
      control network and the default network.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 1, 2020</start_date>
  <completion_date type="Anticipated">July 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This is a single-arm, open-label study of the Buspirone and Melatonin combination administered over 6 weeks.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Depression</measure>
    <time_frame>6 weeks</time_frame>
    <description>Hamilton Depression Rating Scale - 21 item</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cognition</measure>
    <time_frame>6 weeks</time_frame>
    <description>NIH-Toolbox Cognition Battery Fluid Cognition Composite Score</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Functional neuroimaging</measure>
    <time_frame>6 weeks</time_frame>
    <description>fMRI resting state functional connectivity</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Depression</condition>
  <condition>Brain Injuries, Traumatic</condition>
  <arm_group>
    <arm_group_label>Buspirone and Melatonin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Buspirone 15mg and Melatonin 3mg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>B+MEL</intervention_name>
    <description>Buspirone and Melatonin</description>
    <arm_group_label>Buspirone and Melatonin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients with mild or moderate TBI will be included. To be included, a subject must meet&#xD;
        the criteria below:&#xD;
&#xD;
          1. Non-penetrating mild or moderate traumatic brain injury that occurred 3 or more months&#xD;
             prior to study entry (to minimize natural recovery from TBI)&#xD;
&#xD;
          2. Age: 18-64 years&#xD;
&#xD;
          3. Meeting any one of the following severity criteria, as documented in the patient's&#xD;
             medical records:&#xD;
&#xD;
               1. Glasgow Coma Scale (GCS) score of 9-15 within 4 hours after injury&#xD;
&#xD;
               2. Loss of consciousness (LOC) &gt;1 minute and &lt;=24 hours&#xD;
&#xD;
               3. Post-traumatic amnesia (PTA) &lt; 7 days&#xD;
&#xD;
          4. English-speaking&#xD;
&#xD;
          5. Current DSM-5 diagnosis of Major Depressive Episode by medical record diagnosis&#xD;
&#xD;
          6. HAM-D-21 score of 18 or higher&#xD;
&#xD;
          7. Patients who are considered to be appropriate by their clinician and who are willing&#xD;
             to be started on Buspirone and Melatonin for clinical purposes.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of neurological disorder (e.g., stroke, epilepsy, multiple sclerosis, HIV,&#xD;
             neurodegenerative disorders) or any acute or unstable medical condition that is likely&#xD;
             to interfere with the assessments or with participation in treatment, as determined by&#xD;
             history by the patient or review of their medical records.&#xD;
&#xD;
          2. Evidence from the history of TBI severity greater than moderate, i.e., GCS of 8 or&#xD;
             less, LOC &gt; 24 hours, or PTA &gt; 7 days.&#xD;
&#xD;
          3. Inability to attend regular appointments&#xD;
&#xD;
          4. Imminent risk of suicide, as determined by the assessing clinician; HAM-D, Question 3,&#xD;
             answers &gt; 1; SDQ, Question 11, answers &gt; 3; spontaneous expressions of suicidal&#xD;
             ideation will result in emergency evaluation by a licensed clinician member of study&#xD;
             staff for appropriate assessment and triage.&#xD;
&#xD;
          5. Lifetime history of schizophrenia or other primary psychotic disorders, as determined&#xD;
             by history by the patient or review of their medical records.&#xD;
&#xD;
          6. History of bipolar disorder, as determined by history by the patient or review of&#xD;
             their medical records.&#xD;
&#xD;
          7. Alcohol or substance dependence in the past 3 months, as determined by history by the&#xD;
             patient or review of their medical records.&#xD;
&#xD;
          8. Pregnancy or breast-feeding&#xD;
&#xD;
          9. Concomitant use of buspirone, any psychostimulant, or modafinil/armodafinil&#xD;
&#xD;
         10. Patients currently on an antidepressant or who have been on antidepressant in the past&#xD;
             4 weeks&#xD;
&#xD;
         11. Patients with prior intolerances to buspirone or melatonin.&#xD;
&#xD;
         12. Conditions that would preclude a subject from participating in the MRI procedures&#xD;
             (e.g., metal implants, aneurysm clips, shrapnel/retained particles, pacemakers,&#xD;
             claustrophobia).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Kaloyan Tanev</last_name>
    <phone>6177267511</phone>
    <email>ktanev@partners.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02144</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 19, 2020</study_first_submitted>
  <study_first_submitted_qc>May 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 22, 2020</study_first_posted>
  <last_update_submitted>May 19, 2020</last_update_submitted>
  <last_update_submitted_qc>May 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Kaloyan Tanev, MD</investigator_full_name>
    <investigator_title>Associate psychiatrist</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04400266
org study id: 2019P003783
nct id: NCT04400266
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Traumatic brain injuries (TBIs) are common. Post-TBI depression is associated with anxiety,
      aggression, fatigue, distractibility, anger, irritability, and rumination. The current
      research group conducted a pilot clinical trial, which investigated the novel treatment
      combination of buspirone and melatonin (B+MEL) in outpatients with clinical depression.
      Compared to placebo, B+MEL was associated with a significant improvement in depressive
      symptoms. Depression following TBI may be different from clinical depression. The B+MEL
      combination has never been studied in patients with post-TBI depression. The B+MEL has shown
      promise in ameliorating cognitive difficulties in people with depression. Because cognitive
      problems are typical in people with post-TBI depression, we plan to measure the effect of the
      B+MEL combination on cognitive ability in post-TBI depression. Additionally, we are
      interested in measuring functional magnetic resonance imaging changes before and after
      treatment with B+MEL in order to gain insight into the brain mechanisms of our hypothesized
      clinical symptom changes.

      The goals of the proposed pilot research project are to assess changes in symptoms in
      patients with post-TBI depression following Buspirone + Melatonin combination (B+MEL), and
      the corresponding brain mechanisms underlying these hypothesized changes by measuring: 1)
      depressive symptoms; 2) cognitive symptoms; 3) functional magnetic resonance imaging.
Background and significance:

      Buspirone and Melatonin Combination for the Treatment of Post-TBI Depression Traumatic brain
      injuries (TBIs) are common (1.7 million cases each year in the US), and major depressive
      disorder (MDD) occurs in up to 33% of TBI patients. Post- TBI depression is associated with
      anxiety, aggression, fatigue, distractibility, anger, irritability, and rumination. The
      current research group conducted a pilot clinical trial, which investigated the novel
      treatment combination of buspirone (15 mg/day) and melatonin (3mg), in a small outpatient
      cohort with MDD. Compared to the placebo group, the B+MEL group demonstrated significant
      improvements in depressive symptoms, at buspirone doses significantly below the recommended
      therapeutic range for anxiety and recommended dose (40-60 mg) for MDD. Compared to placebo,
      B+MEL was associated with a significant antidepressant response on the Clinical Global
      Impressions- Severity (CGI-S, p=0.046) and -Improvement (CGI-I, p=0.04) scales, and on the
      Inventory of Depressive Symptomatology (IDS, p=0.034). B+MEL was also superior to the pooled
      buspirone and placebo populations (CGI-S, p=0.009; CGI-I, p=0.021; IDS, p=0.031). This
      treatment combination has never been studied in patients with post-TBI depression. Depression
      following TBI may be phenomenologically and neurobiologically distinct from MDD, and the
      neuroanatomical and biopsychological mechanisms underlying B+MEL response in post-TBI
      depression are currently unknown. The goal of the proposed pilot research project is to
      generate pilot data that would serve as a base for an R01 application for a study that will
      fill this critical gap.

      Buspirone and Melatonin Combination and Its Effect on Cognition The current research group
      compared the effects of B+MEL, buspirone, and placebo on the self-rated Cognitive and
      Physical Functioning Questionnaire (CPFQ). The CPFQ cognitive dimension score favored the
      B+MEL combination treatment, compared to the pooled buspirone and placebo groups (p = 0.050).
      In another randomized, double-blind, SPCD clinical study by the current research group,
      treatment with NSI-189 - a compound shown to stimulate neurogenesis in in vitro and in vivo,
      was associated with improvement in cognition, objectively measured by the dimensions of
      memory (p=0.002) and attention (p=0.048), compared to placebo in MDD patients. The etiology
      of cognitive impairment in post-TBI depression is complex, and the cognitive changes in
      response to this novel treatment combination has not been investigated. A possible mechanism
      of B+MEL action could be the promotion of neurogenesis. Although studying neurogenesis is
      beyond the scope of the current research, we speculate that a treatment stimulating
      neurogenesis may contribute to cognitive improvements in post-TBI depression. Hence, we will
      investigate the effect of B+MEL on cognitive measures of verbal memory, executive
      functioning, and speed of information processing, in post-TBI depression pre and
      post-treatment.

      Resting State Functional Connectivity in Depression and in TBI MDD is characterized by
      altered resting state functional connectivity (rsFC) between distinct neural networks. A
      recent study compared rsFC in TBI with co-morbid depressive symptoms, relative to TBI without
      depressive symptoms. The results demonstrated increased rsFC between the amygdala and parts
      of the DAN, salience, somatomotor, and visual networks. Meta-analyses investigating
      fMRI-based rsFC in MDD demonstrated decreased rsFC within the frontoparietal control network
      (FPCN), and increased rsFC within the default network (DN). Increased rsFC between the FPCN
      and DN, and decreased rsFC between the FPCN and dorsal attentional network (DAN) may reflect
      increased attentional bias toward ruminative thoughts. Decreased rsFC between the affective
      network (AN) and medial prefrontal cortex may reflect impaired emotional regulation and
      arousal. Altered rsFC between the ventral attentional network (VAN) and posterior regions may
      reflect impaired salience detection in MDD. Changes in rsFC have been detected in response to
      different treatments, such as medication and cognitive behavioral therapy, for depression.
      Altered rsFC in post-TBI depression is associated with cognitive impairments. A neuroimaging
      study measuring rsFC in post-TBI depression has not been performed in the context of the
      novel B+MEL combination treatment. The proposed research is novel with respect to design,
      technology, and its multi-level integration probing psychological and neurobiological
      constructs assumed to be critically implicated depression following TBI. Furthermore, it may
      provide valuable insight regarding rsFC biomarkers implicated in the effective treatment of
      post-TBI depression.

      Specific Aims Specific Aim 1: Assess the changes in depressive symptoms following Buspirone +
      Melatonin combination (B+MEL) in post-TBI depression.

      Hypothesis 1: The B+MEL treatment combination will be associated with improvements in
      depressive symptoms (changes in HAM-D scores pre- to post-treatment).

      Specific Aim 2: Assess the changes in cognitive symptoms following Buspirone + Melatonin
      combination (B+MEL) in post-TBI depression.

      Hypothesis 2: The B+MEL treatment combination will be associated with improvements in
      measures of verbal memory, executive functioning, and speed of information processing pre- to
      post-treatment.

      Specific Aim 3 (exploratory aim): To assess neuroimaging changes in fMRI resting state
      functional connectivity in outpatients with post-TBI depression treated with the B+MEL
      combination.

      Hypothesis 3: The B+MEL treatment combination will show pre- to post-treatment resting state
      functional connectivity increases within the frontoparietal control network (implicated in
      cognitive control of attention), decreases within the default network (implicated in
      internally oriented and self-referential thought), and decreases between the frontoparietal
      control network and the default network.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a single-arm, open-label study of the Buspirone and Melatonin combination administered over 6 weeks.
primary purpose: Treatment
masking: None (Open Label)
measure: Depression
time frame: 6 weeks
description: Hamilton Depression Rating Scale - 21 item
measure: Cognition
time frame: 6 weeks
description: NIH-Toolbox Cognition Battery Fluid Cognition Composite Score
measure: Functional neuroimaging
time frame: 6 weeks
description: fMRI resting state functional connectivity
arm group label: Buspirone and Melatonin
arm group type: Experimental
description: Buspirone 15mg and Melatonin 3mg
intervention type: Drug
intervention name: B+MEL
description: Buspirone and Melatonin
arm group label: Buspirone and Melatonin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: No
last name: Kaloyan Tanev
phone: 6177267511
email: ktanev@partners.org
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Kaloyan Tanev, MD
investigator title: Associate psychiatrist
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Wounds and Injuries
mesh term: Depression
mesh term: Depressive Disorder
sharing ipd: No