<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/NCT03752853</url>
  </required_header>
  <id_info>
    <org_study_id>Stress_DEP</org_study_id>
    <nct_id>NCT03752853</nct_id>
  </id_info>
  <brief_title>Stress Systems and Psychotherapy in Depression</brief_title>
  <acronym>Bio-COPE</acronym>
  <official_title>Biological Correlates of an Internet-based Psychological Intervention for Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Freie Universität Berlin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Freie Universität Berlin</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis as well as maladaptive&#xD;
      activation of the autonomic nervous system (ANS) are discussed as relevant factors in the&#xD;
      development of a major depressive episode and as a correlate of its clinical manifestation.&#xD;
      Preliminary evidence suggests that the hypercortisolaemic pattern in a subgroup of depressed&#xD;
      patients may predict non-responses to psychotherapeutic treatment. At the same time, it is&#xD;
      conceivable that disorder-related alterations in HPA axis and ANS regulation change in&#xD;
      response to effective treatment, such as cognitive behavioural therapy (CBT), and that those&#xD;
      changes could parallel changes in depressive symptoms. Identifying such associations may shed&#xD;
      light on biological and psychological mechanisms of action underlying successful treatment.&#xD;
&#xD;
      However, so far, no studies have investigated depressed patients with regard to dysregulation&#xD;
      in both stress systems, HPA axis and ANS, before psychotherapeutic treatment, nor have&#xD;
      changes in functioning of both systems been inspected in response to treatment. Moreover, a&#xD;
      detailed investigation of depressive symptom trajectories over the course of treatment and&#xD;
      its associations with changes in HPA axis and ANS regulation is lacking. It can be speculated&#xD;
      that specific techniques of the treatment, e.g., typical CBT elements, such as behavioural&#xD;
      activation or cognitive restructuring, might particularly be associated with changes in HPA&#xD;
      axis and ANS regulation.&#xD;
&#xD;
      The main aims of this project are to investigate:&#xD;
&#xD;
        1. whether diurnal salivary cortisol and alpha-amylase as well as hair cortisol&#xD;
           concentrations change from pre- to post-intervention in treatment responders compared to&#xD;
           non-responders;&#xD;
&#xD;
        2. whether diurnal salivary cortisol and alpha-amylase concentrations change from pre- to&#xD;
           mid-intervention and from mid- to post-intervention in treatment responders compared to&#xD;
           non-responders;&#xD;
&#xD;
        3. whether changes in diurnal salivary cortisol, alpha-amylase and hair cortisol&#xD;
           concentrations are significantly correlated with changes in depressive symptoms;&#xD;
&#xD;
        4. whether concentrations of diurnal salivary cortisol and alpha-amylase as well as hair&#xD;
           cortisol at pre-treatment predict future treatment response (i.e., on a psychological&#xD;
           level).&#xD;
&#xD;
           On an exploratory level, it will be investigated:&#xD;
&#xD;
        5. which elements of a CBT intervention for depression (behavioural activation vs.&#xD;
           cognitive restructuring) are associated with changes in diurnal salivary cortisol and&#xD;
           alpha-amylase concentrations.&#xD;
&#xD;
      It is hypothesised:&#xD;
&#xD;
        1. that pre- to post-intervention decreases in diurnal salivary cortisol and alpha-amylase&#xD;
           as well as hair cortisol concentrations will be more pronounced in responders compared&#xD;
           to non-responders.&#xD;
&#xD;
        2. that pre- to mid-intervention and mid- to post-intervention decreases in diurnal&#xD;
           salivary cortisol and alpha-amylase will be more pronounced in responders compared to&#xD;
           non-responders.&#xD;
&#xD;
        3. that changes in depressive symptoms will significantly correlate with changes in diurnal&#xD;
           cortisol and diurnal alpha-amylase as well as hair cortisol concentrations.&#xD;
&#xD;
        4. that pre-intervention diurnal salivary cortisol and alpha-amylase as well as hair&#xD;
           cortisol concentrations will be higher in future non-responders, compared to responders.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recruitment:&#xD;
&#xD;
      Patients will be recruited from an ongoing project providing an internet-based cognitive&#xD;
      behavioral intervention for patients suffering from mild to moderate depression.&#xD;
&#xD;
      Protocol:&#xD;
&#xD;
      In this study, a total of N=42 patients fulfilling criteria for a current major depressive&#xD;
      episode will undergo a 6-week internet-based cognitive behavioural intervention which&#xD;
      consists of seven consecutive modules. Diurnal (salivary) and hair cortisol as well as&#xD;
      diurnal (salivary) alpha-amylase will be assessed immediately before and after treatment, and&#xD;
      at mid-treatment (i.e., after four of seven modules). Saliva samples (six samples per day)&#xD;
      will be collected over two consecutive days. One hair sample will be obtained at pre- and&#xD;
      post-intervention assessments respectively.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 20, 2018</start_date>
  <completion_date type="Actual">August 6, 2020</completion_date>
  <primary_completion_date type="Actual">August 6, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in salivary cortisol concentration</measure>
    <time_frame>pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)</time_frame>
    <description>Changes in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of salivary cortisol concentration (nmol/l), measured on two consecutive days, at mid-intervention and post-intervention in responders compared to non-responders to the psychological intervention (assessed by Patient Health Questionnaire (PHQ-9))</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences in salivary cortisol concentration</measure>
    <time_frame>pre-intervention</time_frame>
    <description>Differences in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of cortisol concentration (nmol/l), measured on two consecutive days, at pre-intervention in responders compared to non-responders to the psychological intervention (assessed by PHQ-9)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in salivary alpha-amylase concentration</measure>
    <time_frame>pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)</time_frame>
    <description>Changes in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of salivary alpha-amylase concentration (U/ml), measured on two consecutive days, at mid-intervention and post-intervention in responders compared to non-responders to the psychological intervention (assessed by Patient Health Questionnaire (PHQ-9))</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences in salivary alpha-amylase concentration</measure>
    <time_frame>pre-intervention</time_frame>
    <description>Differences in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of salivary alpha-amylase concentration (U/ml), measured on two consecutive days, at pre-intervention in responders compared to non-responders to the psychological intervention (assessed by PHQ-9)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in hair cortisol concentration</measure>
    <time_frame>pre-intervention, post-intervention (after an average of six weeks)</time_frame>
    <description>Changes in hair cortisol concentrations (nmol/l) at post-intervention in responders compared to non-responders to the psychological intervention (assessed by Patient Health Questionnaire (PHQ-9))</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences in hair cortisol concentration</measure>
    <time_frame>pre-intervention</time_frame>
    <description>Differences in hair cortisol concentrations (nmol/l) at pre-intervention in responders compared to non-responders to the psychological intervention (assessed by PHQ-9)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Sleep quality (self-report)</measure>
    <time_frame>pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)</time_frame>
    <description>Changes in Pittsburgh Sleep Quality Index (PSQI); scale ranges from 0 to 21</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chronic stress (self-report)</measure>
    <time_frame>pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)</time_frame>
    <description>Changes in Trier Inventory for the assessment of chronic stress - TICS (Trier Inventar zum chronischen Stress), scale ranges from 0 to 48</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive biases (self-report)</measure>
    <time_frame>pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)</time_frame>
    <description>Changes in Cognitive Styles Assessment (COSTA-21); scale ranges from 0 to 5 per item</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">42</enrollment>
  <condition>Major Depressive Episode</condition>
  <arm_group>
    <arm_group_label>iCBT for depression - behavioral activation first (BAF)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>internet-based intervention for mild to moderate depression: patients receive behavioral activation first, followed by cognitive restructuring</description>
  </arm_group>
  <arm_group>
    <arm_group_label>iCBT for depression - cognitive restructuring first (CRF)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>internet-based intervention for mild to moderate depression: patients receive cognitive restructuring first, followed by behavioral activation</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>internet-based intervention for mild to moderate depression</intervention_name>
    <description>The six-weeks, therapist-guided, internet-based intervention for depression includes expressive writing tasks and further consists of key elements of cognitive behavioral therapy (CBT) for depression. In seven consecutive modules, patients receive psychoeducation and instructions for weekly tasks, and an individualized feedback letter of their therapist after each module. The intervention is effective in reducing depressive symptoms (Zagorscak et al., 2018). In the current study, patients will be randomly assigned to two different conditions with varying orders of modules: 1. patients will receive two modules (module 3 and 4) of behavioral activation, followed by two modules (modules 5 and 6) of cognitive restructuring; 2. patients will receive two modules (module 3 and 4) of cognitive restructuring, followed by two modules (modules 5 and 6) of behavioral activation. All other modules (1, 2 and 7) will be identical across conditions.</description>
    <arm_group_label>iCBT for depression - behavioral activation first (BAF)</arm_group_label>
    <arm_group_label>iCBT for depression - cognitive restructuring first (CRF)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Current major depressive episode (F32.0, F32.1, F33.0, F33.1)&#xD;
&#xD;
          -  Agreement to participate in the study&#xD;
&#xD;
          -  At least 18 years of age&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of schizophrenia, schizotypal and delusional disorders (F20-F29)&#xD;
&#xD;
          -  Acute suicidal patients&#xD;
&#xD;
          -  Acute manic episode&#xD;
&#xD;
          -  Substance related abuse or addiction&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Chronic somatic diseases&#xD;
&#xD;
          -  Severe somatic diseases (e.g., endocrinological, neurological, autoimmune diseases)&#xD;
&#xD;
          -  Glucocorticoid medication intake during the last six months&#xD;
&#xD;
          -  Concurrent psychotherapeutic treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Freie Universitaet Berlin</name>
      <address>
        <city>Berlin</city>
        <zip>14195</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <reference>
    <citation>Zagorscak P, Heinrich M, Sommer D, Wagner B, Knaevelsrud C. Benefits of Individualized Feedback in Internet-Based Interventions for Depression: A Randomized Controlled Trial. Psychother Psychosom. 2018;87(1):32-45. doi: 10.1159/000481515. Epub 2018 Jan 6.</citation>
    <PMID>29306945</PMID>
  </reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>November 13, 2018</study_first_submitted>
  <study_first_submitted_qc>November 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 26, 2018</study_first_posted>
  <last_update_submitted>October 22, 2020</last_update_submitted>
  <last_update_submitted_qc>October 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 23, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Freie Universität Berlin</investigator_affiliation>
    <investigator_full_name>Dr. Sarah Schumacher</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>major depressive episode</keyword>
  <keyword>cortisol</keyword>
  <keyword>alpha-amylase</keyword>
  <keyword>psychotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03752853
org study id: Stress_DEP
nct id: NCT03752853
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis as well as maladaptive
      activation of the autonomic nervous system (ANS) are discussed as relevant factors in the
      development of a major depressive episode and as a correlate of its clinical manifestation.
      Preliminary evidence suggests that the hypercortisolaemic pattern in a subgroup of depressed
      patients may predict non-responses to psychotherapeutic treatment. At the same time, it is
      conceivable that disorder-related alterations in HPA axis and ANS regulation change in
      response to effective treatment, such as cognitive behavioural therapy (CBT), and that those
      changes could parallel changes in depressive symptoms. Identifying such associations may shed
      light on biological and psychological mechanisms of action underlying successful treatment.

      However, so far, no studies have investigated depressed patients with regard to dysregulation
      in both stress systems, HPA axis and ANS, before psychotherapeutic treatment, nor have
      changes in functioning of both systems been inspected in response to treatment. Moreover, a
      detailed investigation of depressive symptom trajectories over the course of treatment and
      its associations with changes in HPA axis and ANS regulation is lacking. It can be speculated
      that specific techniques of the treatment, e.g., typical CBT elements, such as behavioural
      activation or cognitive restructuring, might particularly be associated with changes in HPA
      axis and ANS regulation.

      The main aims of this project are to investigate:

        1. whether diurnal salivary cortisol and alpha-amylase as well as hair cortisol
           concentrations change from pre- to post-intervention in treatment responders compared to
           non-responders;

        2. whether diurnal salivary cortisol and alpha-amylase concentrations change from pre- to
           mid-intervention and from mid- to post-intervention in treatment responders compared to
           non-responders;

        3. whether changes in diurnal salivary cortisol, alpha-amylase and hair cortisol
           concentrations are significantly correlated with changes in depressive symptoms;

        4. whether concentrations of diurnal salivary cortisol and alpha-amylase as well as hair
           cortisol at pre-treatment predict future treatment response (i.e., on a psychological
           level).

           On an exploratory level, it will be investigated:

        5. which elements of a CBT intervention for depression (behavioural activation vs.
           cognitive restructuring) are associated with changes in diurnal salivary cortisol and
           alpha-amylase concentrations.

      It is hypothesised:

        1. that pre- to post-intervention decreases in diurnal salivary cortisol and alpha-amylase
           as well as hair cortisol concentrations will be more pronounced in responders compared
           to non-responders.

        2. that pre- to mid-intervention and mid- to post-intervention decreases in diurnal
           salivary cortisol and alpha-amylase will be more pronounced in responders compared to
           non-responders.

        3. that changes in depressive symptoms will significantly correlate with changes in diurnal
           cortisol and diurnal alpha-amylase as well as hair cortisol concentrations.

        4. that pre-intervention diurnal salivary cortisol and alpha-amylase as well as hair
           cortisol concentrations will be higher in future non-responders, compared to responders.
Recruitment:

      Patients will be recruited from an ongoing project providing an internet-based cognitive
      behavioral intervention for patients suffering from mild to moderate depression.

      Protocol:

      In this study, a total of N=42 patients fulfilling criteria for a current major depressive
      episode will undergo a 6-week internet-based cognitive behavioural intervention which
      consists of seven consecutive modules. Diurnal (salivary) and hair cortisol as well as
      diurnal (salivary) alpha-amylase will be assessed immediately before and after treatment, and
      at mid-treatment (i.e., after four of seven modules). Saliva samples (six samples per day)
      will be collected over two consecutive days. One hair sample will be obtained at pre- and
      post-intervention assessments respectively.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Changes in salivary cortisol concentration
time frame: pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)
description: Changes in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of salivary cortisol concentration (nmol/l), measured on two consecutive days, at mid-intervention and post-intervention in responders compared to non-responders to the psychological intervention (assessed by Patient Health Questionnaire (PHQ-9))
measure: Differences in salivary cortisol concentration
time frame: pre-intervention
description: Differences in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of cortisol concentration (nmol/l), measured on two consecutive days, at pre-intervention in responders compared to non-responders to the psychological intervention (assessed by PHQ-9)
measure: Changes in salivary alpha-amylase concentration
time frame: pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)
description: Changes in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of salivary alpha-amylase concentration (U/ml), measured on two consecutive days, at mid-intervention and post-intervention in responders compared to non-responders to the psychological intervention (assessed by Patient Health Questionnaire (PHQ-9))
measure: Differences in salivary alpha-amylase concentration
time frame: pre-intervention
description: Differences in diurnal profiles (six time points: awakening, +30 min., 11am, 2 pm, 6pm, 9pm) of salivary alpha-amylase concentration (U/ml), measured on two consecutive days, at pre-intervention in responders compared to non-responders to the psychological intervention (assessed by PHQ-9)
measure: Changes in hair cortisol concentration
time frame: pre-intervention, post-intervention (after an average of six weeks)
description: Changes in hair cortisol concentrations (nmol/l) at post-intervention in responders compared to non-responders to the psychological intervention (assessed by Patient Health Questionnaire (PHQ-9))
measure: Differences in hair cortisol concentration
time frame: pre-intervention
description: Differences in hair cortisol concentrations (nmol/l) at pre-intervention in responders compared to non-responders to the psychological intervention (assessed by PHQ-9)
measure: Sleep quality (self-report)
time frame: pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)
description: Changes in Pittsburgh Sleep Quality Index (PSQI); scale ranges from 0 to 21
measure: Chronic stress (self-report)
time frame: pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)
description: Changes in Trier Inventory for the assessment of chronic stress - TICS (Trier Inventar zum chronischen Stress), scale ranges from 0 to 48
measure: Cognitive biases (self-report)
time frame: pre-intervention, mid-intervention (after an average of three weeks), post-intervention (after an average of six weeks)
description: Changes in Cognitive Styles Assessment (COSTA-21); scale ranges from 0 to 5 per item
arm group label: iCBT for depression - behavioral activation first (BAF)
arm group type: Experimental
description: internet-based intervention for mild to moderate depression: patients receive behavioral activation first, followed by cognitive restructuring
arm group label: iCBT for depression - cognitive restructuring first (CRF)
arm group type: Experimental
description: internet-based intervention for mild to moderate depression: patients receive cognitive restructuring first, followed by behavioral activation
intervention type: Behavioral
intervention name: internet-based intervention for mild to moderate depression
description: The six-weeks, therapist-guided, internet-based intervention for depression includes expressive writing tasks and further consists of key elements of cognitive behavioral therapy (CBT) for depression. In seven consecutive modules, patients receive psychoeducation and instructions for weekly tasks, and an individualized feedback letter of their therapist after each module. The intervention is effective in reducing depressive symptoms (Zagorscak et al., 2018). In the current study, patients will be randomly assigned to two different conditions with varying orders of modules: 1. patients will receive two modules (module 3 and 4) of behavioral activation, followed by two modules (modules 5 and 6) of cognitive restructuring; 2. patients will receive two modules (module 3 and 4) of cognitive restructuring, followed by two modules (modules 5 and 6) of behavioral activation. All other modules (1, 2 and 7) will be identical across conditions.
arm group label: iCBT for depression - behavioral activation first (BAF)
arm group label: iCBT for depression - cognitive restructuring first (CRF)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
facility: 
country: Germany
citation: Zagorscak P, Heinrich M, Sommer D, Wagner B, Knaevelsrud C. Benefits of Individualized Feedback in Internet-Based Interventions for Depression: A Randomized Controlled Trial. Psychother Psychosom. 2018;87(1):32-45. doi: 10.1159/000481515. Epub 2018 Jan 6.
PMID: 29306945
responsible party type: Principal Investigator
investigator affiliation: Freie Universität Berlin
investigator full name: Dr. Sarah Schumacher
investigator title: Principal Investigator
mesh term: Depression
sharing ipd: Undecided