<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/NCT03779477</url>
  </required_header>
  <id_info>
    <org_study_id>453594</org_study_id>
    <nct_id>NCT03779477</nct_id>
  </id_info>
  <brief_title>Effect of Coping With Stress Program to Depression, Anxiety, Brain Functions in Adolescent at High-Risk for Depression</brief_title>
  <official_title>Effect of &quot;Coping With Stress Program&quot; to Depression and Anxiety Symptoms and Brain Functions in Adolescent at High-Risk for Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dokuz Eylul University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Dokuz Eylul University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Depression is one of the leading diseases that cause disability, disease burden and threaten&#xD;
      public health all over the world. In addition to the economic burdens brought on by&#xD;
      depression, it also leads to many individual problems such as deterioration in education,&#xD;
      increased psychiatric illnesses in the future, self-harm and suicide. For these reasons, it&#xD;
      is important to prevent depression or delay the onset of depression. One of the depression&#xD;
      prevention programs, &quot;Coping with Stress Program&quot;, is a psychoeducational group program based&#xD;
      on cognitive-behavioral therapy and researches shows that the program reduces the rate of&#xD;
      diagnosing depression and depressive symptoms in adolescents. Although it is an important&#xD;
      mental health problem, studies on adolescent depression are limited in Turkey and existing&#xD;
      studies are descriptive and there are no randomized controlled trials. It is believed that&#xD;
      this research will encourage studies to prevent depression in Turkey.&#xD;
&#xD;
      The primary aim of this research is to determine the effect of coping with stress program on&#xD;
      adolescents' depression and anxiety symptoms, which is applied to adolescents with high risk&#xD;
      for depression. The second aim is to examine the changes in brain functions of adolescents&#xD;
      participating in the coping with stress program. In the first step, high school students will&#xD;
      be screened for depression and adolescents with high levels of depression will be identified.&#xD;
      In the second step, randomized controlled experimental design will be used. At the first&#xD;
      stage of the study, adolescents with high levels of depression and volunteering to&#xD;
      participate in the study will be randomly assigned to the experimental and control groups.&#xD;
      After pre-test measurements (determination of depression and anxiety level, functional&#xD;
      magnetic resonance imaging (fMRI)), the Coping with Stress Program will be applied to the&#xD;
      adolescents in the experimental group. Post-test measures (determination of depression and&#xD;
      anxiety level, fMRI) will be performed. The amygdala stimulation test will be used for the&#xD;
      fMRI experiment and the data obtained from the fMRI before and after the program will be&#xD;
      investigated using the general linear model with Statistical Parametric Mapping (SPM).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Type: The study was designed as a randomized controlled trial. Site and Date of the&#xD;
      Study: The study will be conducted between October 2018 and January 2020 with the first-year&#xD;
      high school students who are registered in the high schools under the governance of Izmir&#xD;
      Balcova District National Education Directorate.&#xD;
&#xD;
      Participants: The calculation of the sampling size was based on the Brain Functions outcome.&#xD;
      It was recommended that at least 20 subjects should be included in each group for brain&#xD;
      imaging studies. Taking into consideration the parametric characteristics of the data, which&#xD;
      will be obtained with the scale, the investigators planned to include a total of 60 subjects&#xD;
      (30 subjects in each group) in the study. The investigators also planned that 6-10 subjects&#xD;
      should be adolescents in each group in experimental group. Experimental group will be&#xD;
      evaluated with the help of the Coping with Stress Program.&#xD;
&#xD;
      The sampling process of the study: During the initial phase of the study, adolescents, who&#xD;
      will score 19 or more in the Children's Depression Scale, will be determined. The&#xD;
      adolescents, who will fulfill the inclusion criteria, will be evaluated by the investigator&#xD;
      with the help of the Hamilton Depression Scale. Adolescents, who will have a score equal to&#xD;
      or more than 29 will be referred by the investigator to the Outpatient Department of the&#xD;
      Children/Adolescent Mental Health at Dokuz Eylül University.&#xD;
&#xD;
      The adolescents, who will fulfill the inclusion criteria, will be informed about the study's&#xD;
      objective and methodology during a face-to-face conversation and their families will be&#xD;
      informed by phone. The consent form will be handed to the adolescents in order that&#xD;
      participants forward it to the parents for signing if they approve the participation of their&#xD;
      children in the study. The adolescents, who will accept to participate, will be numbered&#xD;
      starting from 1 and they will be randomized in the experimental and control groups with the&#xD;
      help of a simple table of randomized numbers (experimental group: 30 subjects; control group:&#xD;
      30 subjects).&#xD;
&#xD;
      In the school, the subjects will undergo pre-test evaluation with Children Depression Scale,&#xD;
      The Center for Epidemiological Studies Depression Scale, and Beck's Anxiety Scale after the&#xD;
      obtainment of their verbal and written consent. Then 20 adolescents from the experimental&#xD;
      group and 20 healthy adolescents will undergo fMRI examination. The individual&#xD;
      characteristics of the groups (age, gender, socio-economic status, history of depression in&#xD;
      parents) will be compared regarding the significant differences.&#xD;
&#xD;
      Instruments At this phase of the study, the investigators plan to use the following forms,&#xD;
      scales, and examinations: Information Questionnaire, Children Depression Scale, The Center&#xD;
      for Epidemiological Studies Depression Scale, Beck's Anxiety Scale, Hamilton Depression&#xD;
      Rating Scale, 3 Tesla Magnetic Resonance Imaging Device and Functional Magnetic Resonance&#xD;
      Imaging (fMRI).&#xD;
&#xD;
      Magnetic Resonance Imaging (MRI) Technique The MRI examinations will be conducted with 3.0&#xD;
      Tesla magnet (Siemens, Erlangen, Germany) using a 12-channel head coil. First, the&#xD;
      investigators will obtain structural images with the axial turbo spin echo (TSE) T2-weighted,&#xD;
      coronary 3D-SPACE FLAIR (Dark fluid) and 3D-MPRAGE sequences. The obtained images will be&#xD;
      immediately examined by the radiologist and interpreted for the presence of a brain&#xD;
      anomaly/pathology considered among the inclusion criteria. Subjects without any&#xD;
      radio-pathological finding will also be referred to the fMRI examination. The blood oxygen&#xD;
      level-dependent (BOLD) technique, which is previously designed in concordance with the task&#xD;
      design will be used for the fMRI.&#xD;
&#xD;
      fMRI Task Meta-analyses which are focused on the evaluation of the structural and functional&#xD;
      MRI studies of the depression patients, demonstrated anomalies in the amygdala, hippocampus,&#xD;
      and subcortical regions. Therefore, the investigators decided to use an fMRI task, which will&#xD;
      stimulate these structures. The amygdala stimulation test developed by Hariri, Bookheimer &amp;&#xD;
      Mazziotta is widely used in the studies and it was demonstrated that it could strongly and&#xD;
      consistently stimulate amygdala.&#xD;
&#xD;
      This test will be performed in a single session and the subjects will be asked to fulfill two&#xD;
      different tasks. The first task consists of 3 blocks of cognitive face processing task and&#xD;
      the second task consists of 4 blocks of sensorimotor control task. Facial expressions of&#xD;
      anger, fear, surprise, and neutral faces from the FACES stimulus set will be used for this&#xD;
      purpose (with equal numbers of male and female faces). Face-matching blocks will exhibit&#xD;
      three faces, with one on the top and two at the bottom. The expressions will consist of&#xD;
      anger, fear, surprise, and neutral outlook. The participant will be asked to match the face&#xD;
      on the top with one of the faces at the bottom, which he/she will consider having the same&#xD;
      expression. For each face expression (e.g. fear) there will be 6 trials which are equalized&#xD;
      for the gender distribution. Each test will last 6 seconds. There will be an interval of 3&#xD;
      seconds between each test (inter-stimulus interval). Each block lasts 54 seconds. In the&#xD;
      sensorimotor control blocks, the participant will have 3 geometric shapes (circle,&#xD;
      horizontal, and vertical ellipses), one on the top and two at the bottom and will be asked to&#xD;
      match the shape on the top with one at the bottom, which he/she will consider as same. Each&#xD;
      control block contains 6 different shapes matching and each test lasts 6 seconds. There will&#xD;
      be a 3-second inter-stimulus interval between each test. Each block lasts 54 seconds. The&#xD;
      blocks will start after a short instruction (&quot;match the shapes&quot; or &quot;match the faces&quot;). The&#xD;
      total duration of the fMRI task is 399 seconds. Responses and the response time will be&#xD;
      recorded.&#xD;
&#xD;
      Data Collection Implementation 9th grader high school students will be screened during the&#xD;
      2018-2019 school year and the Coping with Stress Program will be implemented in the&#xD;
      experimental group, which will consist of 30 students. The demographic data of each student&#xD;
      in the experimental and control groups will be collected with a data collection questionnaire&#xD;
      before the start of the study (pre-test measurements).&#xD;
&#xD;
      After the pre-test measurements, 20 volunteers from the control group will be scheduled for&#xD;
      the fMRI examination. The adolescents and their family will be instructed about the measures,&#xD;
      which are to be considered at the examination day and the adolescents will be informed that&#xD;
      he/she should not fasten before the examination. On the examination day, the adolescents will&#xD;
      be interviewed in the room of the Standardization of Computational Anatomy Techniques fıor&#xD;
      Cognitive and Behavioral Sciences (SoCAT) research group in the Ege University, Department of&#xD;
      Mental Health, and Psychiatry. During the interview, the adolescents will receive&#xD;
      instructions about the fMRI task. During this instruction, which will last approx. 15&#xD;
      minutes, a facial expression set, a shorter version of the set used during the fMRI&#xD;
      examination, will be implemented. The adolescents, who have completed the instruction, will&#xD;
      be referred to the 3 Tesla MRI unit of the Radiology Department in Ege University and will&#xD;
      undergo MRI examination. The fMRI examination will be performed between 10:00-14:00 in&#xD;
      weekends, as the unit is overloaded in weekdays. The adolescents will be asked not to move in&#xD;
      the MRI device and will be informed that the fMRI process will start just after the&#xD;
      structural imaging is completed. The structural imaging will last approx. 5 minutes and will&#xD;
      be followed by the fMRI. During the whole process, the investigator Burcu Özkul and the&#xD;
      radiology technician will be present in the MRI unit. Healthy adolescents will also undergo&#xD;
      fMRI.&#xD;
&#xD;
      The subjects in the experimental group will undergo the Coping with Stress Program. There&#xD;
      will be no intervention in the control group; only pre-test, final test and monitoring&#xD;
      measurements will be performed. After the completion of the program implemented in the&#xD;
      experimental group (final test), all measurements will be repeated in the 3rd, 6th and 12th&#xD;
      months in both experimental and control groups. fMRI imaging will be repeated for the&#xD;
      subjects in the experimental group in the 2nd month.&#xD;
&#xD;
      Data Analysis The data obtained during the study will be analyzed with the Statistical&#xD;
      Package for the Social Sciences (SPSS) v.22 software package. Demographic data will be&#xD;
      expressed with descriptive statistics, such as percentage, mean, and standard deviation. The&#xD;
      distribution of the continuous data will be analyzed with the Kolmogorov-Smirnov Test and the&#xD;
      homogeneity of the groups will be evaluated with Chi-square test. Regarding the repeated&#xD;
      comparative measurements performed before the start of the program, they will be evaluated&#xD;
      after the instruction, in the 3rd, 6th and 12th months with the variance analysis.&#xD;
&#xD;
      fMRI Analysis: The images in DICOM format will be uploaded in the SPM 12 software and the&#xD;
      standard pre-processing will be carried out. This process constitutes of a re-alignment&#xD;
      process (aligning of the images in the time sequence in a 3D format), the normalization to&#xD;
      the standard space (MNI) and finally the smoothing process. A general linear model (GLM) will&#xD;
      be used for the statistical analysis. Therefore, the common and different neural circuits&#xD;
      between the groups will be determined. The p-value of 0.05 will be considered as&#xD;
      statistically significant for the intergroup comparisons (after the correction according to&#xD;
      the multiple comparisons with the family-wise error correction). The minimum cluster&#xD;
      threshold will be limited to 5 voxels.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 5, 2018</start_date>
  <completion_date type="Actual">February 15, 2020</completion_date>
  <primary_completion_date type="Actual">February 3, 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>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>20 of participants' change from baseline brain functions at 2 months assessed by functional Magnetic Resonans Imaging</measure>
    <time_frame>Data will be collected before the program starts (pretest) and two months after the end of the program</time_frame>
    <description>Functional magnetic resonance imaging measures brain activity by detecting changes associated with blood flow. The amygdala stimulation test will be used for the functional magnetic resonance imaging experiment and the data obtained from the fMRI analysis with Statistical Parametric Mapping (SPM). Functional Magnetic resonance imaging of the participants will be performed with Siemens 3 Tesla MRI device.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline depressive symptoms at 3, 6 and 12 months assessed by Children Depression Inventory</measure>
    <time_frame>Data will be collected before the program starts (pretest), three months,six months and one-year after the end of the program</time_frame>
    <description>Data will be collected by the Children Depression Inventory. 0-54 points can be taken from the Children Depression Inventory. The higher the score indicates the greater the severity of depression.The cutpoint of the scale is 19 points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline depressive symptoms at 3, 6 and 12 months assessed by Center of Epidemiological Studies Depression Scale</measure>
    <time_frame>Data will be collected before the program starts (pretest), three months,six months and one-year after the end of the program</time_frame>
    <description>Data will be collected by the Center of Epidemiological Studies Depression Scale. 0 to 60 points can be obtained from the Center for Epidemiological Studies Depression Scale and the higher the score indicates the more depressive symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline anxiety symptoms at 3, 6 and 12 months assessed by Beck Anxiety Inventory</measure>
    <time_frame>Data will be collected before the program starts (pretest), three months,six months and one-year after the end of the program</time_frame>
    <description>Data will be collected by the Beck Anxiety Inventory. The total score ranges from 0 to 63. As the total scores of the scale increase, the level of anxiety of the person increases.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">57</enrollment>
  <condition>Depression</condition>
  <arm_group>
    <arm_group_label>Coping with Stress Course</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The Coping with Stress Program that consists of 8 sessions will be implemented to the experimental group. 8-10 adolescents will be included in this program. The session frequency will be one session per week. After the completion of 8 sessions, two 90-minute sessions will be carried out each month in the following two months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>There will be no intervention in the control group. If the program will be effective, this group will also undergo the Coping with Stress Program after the termination of the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Coping with Stress Course</intervention_name>
    <description>The Coping with Stress Program is a group program, which is developed by Clarke and Lewinson (1995) for the prevention of depression in high-risk adolescents. It is based on cognitive-behavioral therapy principles and contains psychoeducation and cognitive-behavioral therapy interventions. There are handbooks available for the group leader of the program and the participating adolescents. In the handbook developed for the group leader, there is detailed information about the objective of each session and the implemented interventions. The adolescents will find lists organized for the fulfillment of the tasks in the handbook prepared for them. The handbooks of the program were translated in Turkish and experts were consulted for their validity.</description>
    <arm_group_label>Coping with Stress Course</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Being first-grader high school student&#xD;
&#xD;
          -  Being volunteer for participation in the study&#xD;
&#xD;
          -  Obtaining the consent of parents' adolescent&#xD;
&#xD;
          -  Being literate&#xD;
&#xD;
          -  Fluent speaking and understanding of Turkish language&#xD;
&#xD;
          -  Scores equal to or higher than 19 in the Children Depression Scale&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previously diagnosed with depression&#xD;
&#xD;
          -  Previously diagnosed with a psychiatric disease&#xD;
&#xD;
          -  Presence of a diagnosis of bipolar I or schizophrenia in parents&#xD;
&#xD;
          -  Usage of psychotropic agents&#xD;
&#xD;
          -  Previous participation in a cognitive-behavioral therapy (more than 8 sessions)&#xD;
&#xD;
          -  Previous head trauma (with a conscious loss more than 3 minutes)&#xD;
&#xD;
          -  Any reason preventing the participant to enter the MRI device (pacemaker, prosthesis,&#xD;
             claustrophobia, etc.).&#xD;
&#xD;
          -  Scores equal to or higher than 29 in the Hamilton Depression Rating Scale.&#xD;
&#xD;
          -  Plow&#xD;
&#xD;
          -  Presence of a chronic physical disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>14 Years</minimum_age>
    <maximum_age>15 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Dokuz Eylul University</name>
      <address>
        <city>İzmir</city>
        <state>Balçova</state>
        <zip>35340</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Turkey</country>
  </location_countries>
  <reference>
    <citation>Mumford JA. A power calculation guide for fMRI studies. Soc Cogn Affect Neurosci. 2012 Aug;7(6):738-42. doi: 10.1093/scan/nss059. Epub 2012 May 28.</citation>
    <PMID>22641837</PMID>
  </reference>
  <reference>
    <citation>Simmons JP, Nelson LD, Simonsohn U. False-positive psychology: undisclosed flexibility in data collection and analysis allows presenting anything as significant. Psychol Sci. 2011 Nov;22(11):1359-66. doi: 10.1177/0956797611417632. Epub 2011 Oct 17.</citation>
    <PMID>22006061</PMID>
  </reference>
  <reference>
    <citation>Foland-Ross LC, Hardin MG, Gotlib IH. Neurobiological markers of familial risk for depression. Curr Top Behav Neurosci. 2013;14:181-206. doi: 10.1007/7854_2012_213.</citation>
    <PMID>22573472</PMID>
  </reference>
  <reference>
    <citation>Murray EA, Wise SP, Drevets WC. Localization of dysfunction in major depressive disorder: prefrontal cortex and amygdala. Biol Psychiatry. 2011 Jun 15;69(12):e43-54. doi: 10.1016/j.biopsych.2010.09.041. Epub 2010 Dec 15.</citation>
    <PMID>21111403</PMID>
  </reference>
  <reference>
    <citation>Schmaal L, Veltman DJ, van Erp TG, Samann PG, Frodl T, Jahanshad N, Loehrer E, Tiemeier H, Hofman A, Niessen WJ, Vernooij MW, Ikram MA, Wittfeld K, Grabe HJ, Block A, Hegenscheid K, Volzke H, Hoehn D, Czisch M, Lagopoulos J, Hatton SN, Hickie IB, Goya-Maldonado R, Kramer B, Gruber O, Couvy-Duchesne B, Renteria ME, Strike LT, Mills NT, de Zubicaray GI, McMahon KL, Medland SE, Martin NG, Gillespie NA, Wright MJ, Hall GB, MacQueen GM, Frey EM, Carballedo A, van Velzen LS, van Tol MJ, van der Wee NJ, Veer IM, Walter H, Schnell K, Schramm E, Normann C, Schoepf D, Konrad C, Zurowski B, Nickson T, McIntosh AM, Papmeyer M, Whalley HC, Sussmann JE, Godlewska BR, Cowen PJ, Fischer FH, Rose M, Penninx BW, Thompson PM, Hibar DP. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. Mol Psychiatry. 2016 Jun;21(6):806-12. doi: 10.1038/mp.2015.69. Epub 2015 Jun 30.</citation>
    <PMID>26122586</PMID>
  </reference>
  <reference>
    <citation>Hariri AR, Bookheimer SY, Mazziotta JC. Modulating emotional responses: effects of a neocortical network on the limbic system. Neuroreport. 2000 Jan 17;11(1):43-8. doi: 10.1097/00001756-200001170-00009.</citation>
    <PMID>10683827</PMID>
  </reference>
  <reference>
    <citation>Baranger DAA, Margolis S, Hariri AR, Bogdan R. An earlier time of scan is associated with greater threat-related amygdala reactivity. Soc Cogn Affect Neurosci. 2017 Aug 1;12(8):1272-1283. doi: 10.1093/scan/nsx057.</citation>
    <PMID>28379578</PMID>
  </reference>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>February 2, 2021</last_update_submitted>
  <last_update_submitted_qc>February 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dokuz Eylul University</investigator_affiliation>
    <investigator_full_name>Burcu Özkul</investigator_full_name>
    <investigator_title>Research Assistant</investigator_title>
  </responsible_party>
  <keyword>Depression</keyword>
  <keyword>High-Risk</keyword>
  <keyword>Adolescent</keyword>
  <keyword>fMRI</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>
  <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/NCT03779477
org study id: 453594
nct id: NCT03779477
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Depression is one of the leading diseases that cause disability, disease burden and threaten
      public health all over the world. In addition to the economic burdens brought on by
      depression, it also leads to many individual problems such as deterioration in education,
      increased psychiatric illnesses in the future, self-harm and suicide. For these reasons, it
      is important to prevent depression or delay the onset of depression. One of the depression
      prevention programs, "Coping with Stress Program", is a psychoeducational group program based
      on cognitive-behavioral therapy and researches shows that the program reduces the rate of
      diagnosing depression and depressive symptoms in adolescents. Although it is an important
      mental health problem, studies on adolescent depression are limited in Turkey and existing
      studies are descriptive and there are no randomized controlled trials. It is believed that
      this research will encourage studies to prevent depression in Turkey.

      The primary aim of this research is to determine the effect of coping with stress program on
      adolescents' depression and anxiety symptoms, which is applied to adolescents with high risk
      for depression. The second aim is to examine the changes in brain functions of adolescents
      participating in the coping with stress program. In the first step, high school students will
      be screened for depression and adolescents with high levels of depression will be identified.
      In the second step, randomized controlled experimental design will be used. At the first
      stage of the study, adolescents with high levels of depression and volunteering to
      participate in the study will be randomly assigned to the experimental and control groups.
      After pre-test measurements (determination of depression and anxiety level, functional
      magnetic resonance imaging (fMRI)), the Coping with Stress Program will be applied to the
      adolescents in the experimental group. Post-test measures (determination of depression and
      anxiety level, fMRI) will be performed. The amygdala stimulation test will be used for the
      fMRI experiment and the data obtained from the fMRI before and after the program will be
      investigated using the general linear model with Statistical Parametric Mapping (SPM).
Study Type: The study was designed as a randomized controlled trial. Site and Date of the
      Study: The study will be conducted between October 2018 and January 2020 with the first-year
      high school students who are registered in the high schools under the governance of Izmir
      Balcova District National Education Directorate.

      Participants: The calculation of the sampling size was based on the Brain Functions outcome.
      It was recommended that at least 20 subjects should be included in each group for brain
      imaging studies. Taking into consideration the parametric characteristics of the data, which
      will be obtained with the scale, the investigators planned to include a total of 60 subjects
      (30 subjects in each group) in the study. The investigators also planned that 6-10 subjects
      should be adolescents in each group in experimental group. Experimental group will be
      evaluated with the help of the Coping with Stress Program.

      The sampling process of the study: During the initial phase of the study, adolescents, who
      will score 19 or more in the Children's Depression Scale, will be determined. The
      adolescents, who will fulfill the inclusion criteria, will be evaluated by the investigator
      with the help of the Hamilton Depression Scale. Adolescents, who will have a score equal to
      or more than 29 will be referred by the investigator to the Outpatient Department of the
      Children/Adolescent Mental Health at Dokuz Eylül University.

      The adolescents, who will fulfill the inclusion criteria, will be informed about the study's
      objective and methodology during a face-to-face conversation and their families will be
      informed by phone. The consent form will be handed to the adolescents in order that
      participants forward it to the parents for signing if they approve the participation of their
      children in the study. The adolescents, who will accept to participate, will be numbered
      starting from 1 and they will be randomized in the experimental and control groups with the
      help of a simple table of randomized numbers (experimental group: 30 subjects; control group:
      30 subjects).

      In the school, the subjects will undergo pre-test evaluation with Children Depression Scale,
      The Center for Epidemiological Studies Depression Scale, and Beck's Anxiety Scale after the
      obtainment of their verbal and written consent. Then 20 adolescents from the experimental
      group and 20 healthy adolescents will undergo fMRI examination. The individual
      characteristics of the groups (age, gender, socio-economic status, history of depression in
      parents) will be compared regarding the significant differences.

      Instruments At this phase of the study, the investigators plan to use the following forms,
      scales, and examinations: Information Questionnaire, Children Depression Scale, The Center
      for Epidemiological Studies Depression Scale, Beck's Anxiety Scale, Hamilton Depression
      Rating Scale, 3 Tesla Magnetic Resonance Imaging Device and Functional Magnetic Resonance
      Imaging (fMRI).

      Magnetic Resonance Imaging (MRI) Technique The MRI examinations will be conducted with 3.0
      Tesla magnet (Siemens, Erlangen, Germany) using a 12-channel head coil. First, the
      investigators will obtain structural images with the axial turbo spin echo (TSE) T2-weighted,
      coronary 3D-SPACE FLAIR (Dark fluid) and 3D-MPRAGE sequences. The obtained images will be
      immediately examined by the radiologist and interpreted for the presence of a brain
      anomaly/pathology considered among the inclusion criteria. Subjects without any
      radio-pathological finding will also be referred to the fMRI examination. The blood oxygen
      level-dependent (BOLD) technique, which is previously designed in concordance with the task
      design will be used for the fMRI.

      fMRI Task Meta-analyses which are focused on the evaluation of the structural and functional
      MRI studies of the depression patients, demonstrated anomalies in the amygdala, hippocampus,
      and subcortical regions. Therefore, the investigators decided to use an fMRI task, which will
      stimulate these structures. The amygdala stimulation test developed by Hariri, Bookheimer &
      Mazziotta is widely used in the studies and it was demonstrated that it could strongly and
      consistently stimulate amygdala.

      This test will be performed in a single session and the subjects will be asked to fulfill two
      different tasks. The first task consists of 3 blocks of cognitive face processing task and
      the second task consists of 4 blocks of sensorimotor control task. Facial expressions of
      anger, fear, surprise, and neutral faces from the FACES stimulus set will be used for this
      purpose (with equal numbers of male and female faces). Face-matching blocks will exhibit
      three faces, with one on the top and two at the bottom. The expressions will consist of
      anger, fear, surprise, and neutral outlook. The participant will be asked to match the face
      on the top with one of the faces at the bottom, which he/she will consider having the same
      expression. For each face expression (e.g. fear) there will be 6 trials which are equalized
      for the gender distribution. Each test will last 6 seconds. There will be an interval of 3
      seconds between each test (inter-stimulus interval). Each block lasts 54 seconds. In the
      sensorimotor control blocks, the participant will have 3 geometric shapes (circle,
      horizontal, and vertical ellipses), one on the top and two at the bottom and will be asked to
      match the shape on the top with one at the bottom, which he/she will consider as same. Each
      control block contains 6 different shapes matching and each test lasts 6 seconds. There will
      be a 3-second inter-stimulus interval between each test. Each block lasts 54 seconds. The
      blocks will start after a short instruction ("match the shapes" or "match the faces"). The
      total duration of the fMRI task is 399 seconds. Responses and the response time will be
      recorded.

      Data Collection Implementation 9th grader high school students will be screened during the
      2018-2019 school year and the Coping with Stress Program will be implemented in the
      experimental group, which will consist of 30 students. The demographic data of each student
      in the experimental and control groups will be collected with a data collection questionnaire
      before the start of the study (pre-test measurements).

      After the pre-test measurements, 20 volunteers from the control group will be scheduled for
      the fMRI examination. The adolescents and their family will be instructed about the measures,
      which are to be considered at the examination day and the adolescents will be informed that
      he/she should not fasten before the examination. On the examination day, the adolescents will
      be interviewed in the room of the Standardization of Computational Anatomy Techniques fıor
      Cognitive and Behavioral Sciences (SoCAT) research group in the Ege University, Department of
      Mental Health, and Psychiatry. During the interview, the adolescents will receive
      instructions about the fMRI task. During this instruction, which will last approx. 15
      minutes, a facial expression set, a shorter version of the set used during the fMRI
      examination, will be implemented. The adolescents, who have completed the instruction, will
      be referred to the 3 Tesla MRI unit of the Radiology Department in Ege University and will
      undergo MRI examination. The fMRI examination will be performed between 10:00-14:00 in
      weekends, as the unit is overloaded in weekdays. The adolescents will be asked not to move in
      the MRI device and will be informed that the fMRI process will start just after the
      structural imaging is completed. The structural imaging will last approx. 5 minutes and will
      be followed by the fMRI. During the whole process, the investigator Burcu Özkul and the
      radiology technician will be present in the MRI unit. Healthy adolescents will also undergo
      fMRI.

      The subjects in the experimental group will undergo the Coping with Stress Program. There
      will be no intervention in the control group; only pre-test, final test and monitoring
      measurements will be performed. After the completion of the program implemented in the
      experimental group (final test), all measurements will be repeated in the 3rd, 6th and 12th
      months in both experimental and control groups. fMRI imaging will be repeated for the
      subjects in the experimental group in the 2nd month.

      Data Analysis The data obtained during the study will be analyzed with the Statistical
      Package for the Social Sciences (SPSS) v.22 software package. Demographic data will be
      expressed with descriptive statistics, such as percentage, mean, and standard deviation. The
      distribution of the continuous data will be analyzed with the Kolmogorov-Smirnov Test and the
      homogeneity of the groups will be evaluated with Chi-square test. Regarding the repeated
      comparative measurements performed before the start of the program, they will be evaluated
      after the instruction, in the 3rd, 6th and 12th months with the variance analysis.

      fMRI Analysis: The images in DICOM format will be uploaded in the SPM 12 software and the
      standard pre-processing will be carried out. This process constitutes of a re-alignment
      process (aligning of the images in the time sequence in a 3D format), the normalization to
      the standard space (MNI) and finally the smoothing process. A general linear model (GLM) will
      be used for the statistical analysis. Therefore, the common and different neural circuits
      between the groups will be determined. The p-value of 0.05 will be considered as
      statistically significant for the intergroup comparisons (after the correction according to
      the multiple comparisons with the family-wise error correction). The minimum cluster
      threshold will be limited to 5 voxels.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
measure: 20 of participants' change from baseline brain functions at 2 months assessed by functional Magnetic Resonans Imaging
time frame: Data will be collected before the program starts (pretest) and two months after the end of the program
description: Functional magnetic resonance imaging measures brain activity by detecting changes associated with blood flow. The amygdala stimulation test will be used for the functional magnetic resonance imaging experiment and the data obtained from the fMRI analysis with Statistical Parametric Mapping (SPM). Functional Magnetic resonance imaging of the participants will be performed with Siemens 3 Tesla MRI device.
measure: Change from baseline depressive symptoms at 3, 6 and 12 months assessed by Children Depression Inventory
time frame: Data will be collected before the program starts (pretest), three months,six months and one-year after the end of the program
description: Data will be collected by the Children Depression Inventory. 0-54 points can be taken from the Children Depression Inventory. The higher the score indicates the greater the severity of depression.The cutpoint of the scale is 19 points.
measure: Change from baseline depressive symptoms at 3, 6 and 12 months assessed by Center of Epidemiological Studies Depression Scale
time frame: Data will be collected before the program starts (pretest), three months,six months and one-year after the end of the program
description: Data will be collected by the Center of Epidemiological Studies Depression Scale. 0 to 60 points can be obtained from the Center for Epidemiological Studies Depression Scale and the higher the score indicates the more depressive symptoms.
measure: Change from baseline anxiety symptoms at 3, 6 and 12 months assessed by Beck Anxiety Inventory
time frame: Data will be collected before the program starts (pretest), three months,six months and one-year after the end of the program
description: Data will be collected by the Beck Anxiety Inventory. The total score ranges from 0 to 63. As the total scores of the scale increase, the level of anxiety of the person increases.
arm group label: Coping with Stress Course
arm group type: Experimental
description: The Coping with Stress Program that consists of 8 sessions will be implemented to the experimental group. 8-10 adolescents will be included in this program. The session frequency will be one session per week. After the completion of 8 sessions, two 90-minute sessions will be carried out each month in the following two months.
arm group label: Control
arm group type: No Intervention
description: There will be no intervention in the control group. If the program will be effective, this group will also undergo the Coping with Stress Program after the termination of the study.
intervention type: Behavioral
intervention name: Coping with Stress Course
description: The Coping with Stress Program is a group program, which is developed by Clarke and Lewinson (1995) for the prevention of depression in high-risk adolescents. It is based on cognitive-behavioral therapy principles and contains psychoeducation and cognitive-behavioral therapy interventions. There are handbooks available for the group leader of the program and the participating adolescents. In the handbook developed for the group leader, there is detailed information about the objective of each session and the implemented interventions. The adolescents will find lists organized for the fulfillment of the tasks in the handbook prepared for them. The handbooks of the program were translated in Turkish and experts were consulted for their validity.
arm group label: Coping with Stress Course
criteria: 
gender: All
minimum age: 14 Years
maximum age: 15 Years
healthy volunteers: No
facility: 
country: Turkey
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PMID: 28379578
responsible party type: Principal Investigator
investigator affiliation: Dokuz Eylul University
investigator full name: Burcu Özkul
investigator title: Research Assistant
mesh term: Depression
mesh term: Depressive Disorder
sharing ipd: Undecided