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Characterization and Treatment of Adolescent Depression

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ClinicalTrials.gov Identifier: NCT03388606
Recruitment Status : Recruiting
First Posted : January 3, 2018
Last Update Posted : September 18, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Tracking Information
First Submitted Date December 30, 2017
First Posted Date January 3, 2018
Last Update Posted Date September 18, 2020
Actual Study Start Date December 28, 2017
Estimated Primary Completion Date July 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: September 12, 2020)
Mood and Feelings Questionnaire [ Time Frame: Ongoing ]
changes in MFQ scores over time
Original Primary Outcome Measures
 (submitted: December 30, 2017)
Moody and Feelings Questionnaire [ Time Frame: 2 weeks ]
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Characterization and Treatment of Adolescent Depression
Official Title Characterization and Treatment of Adolescent Depression
Brief Summary

Background:

Almost 20% of Americans have depression. It is a leading cause of disability because it is chronic and it starts early. The highest incidence is among adolescents and young adults. But researchers don t know much about why some people become depressed whilst others don t. One possibility is that the way people process rewarding stimuli could be related to their risk for depression.

Objective:

To characterize and treat depression in youth by focusing on reward processing.

Eligibility:

People ages 11 17 with major depressive disorder or subthreshold depression

Healthy volunteers ages 11 17

Design:

Participants will be screened with interviews and questionnaires. They will have memory, thinking, and concentration tests. They may have a urine pregnancy test or have photos or videos taken.

At the initial visit, participants will:

Perform tasks and be interviewed

Have functional magnetic resonance imaging (MRI) scans. For this, participants will lie in a metal cylinder in a magnetic field. They will do study tasks while looking at a screen in the scanner.

Look at pictures of stimuli that signal win (rewards) or loss and get money for making certain choices.

Have brain and eye activity monitored

Do tasks in a virtual reality environment

Wear an activity monitor

Choose to have blood taken for research studies

Perform tasks while in magneto-encephalography a machine that uses sensitive magnetic sensors to measure the brain s electric activity

Participants will get phone prompts at home to ask about their mood.

Participants will have several follow-up visits the first year, then 1-2 each year until they are 25. They will repeat some tasks above.

Some participants with depression can elect to receive outpatient treatment at NIH and can receive inpatient treatment at NIH, if they wish. None of the treatments are experimental, that is, all treatments are standard and have an evidence base. Patients will have more visits before and after they have treatment. They will do some of the tests above plus drug testing. Participants who are in treatment and their parents will talk with a Senior Attending physician, a nurse, social worker, or psychologist. Those in outpatient treatment will have practice work between visits. Those who are inpatients will have practice work during their inpatient treatment and adjustments to medication can be made.

Detailed Description

Objective:

Depression has a prevalence of 19% in the US population (Kessler & Bromet, 2013) and close to 350 million people suffer from the disorder worldwide (WHO, 2012). The chronic course of depression and its early onset-a maximal incidence in adolescence and young adulthood (Beesdo et al., 2009)-contribute to it being a leading cause of disability worldwide (WHO, 2014). Yet, compared to many other medical conditions, we know little about the mechanisms underlying depression. In recent years, reward processing has been proposed to underlie several key behavioral and neural aberrations observed in depression (Treadway & Zald, 2011;Whitton, Treadway, & Pizzagalli, 2015). This has led to the promise that targeting reward processing may lead to much needed breakthroughs in the field. In this protocol we seek to characterize and treat depression in youth by integrating methodological and conceptual approaches that specifically focus on reward processing. Patients and their families can elect to participate in standard outpatient or inpatient clinical care in this protocol. Our objective is to answer four key questions:

  1. What is the concordance of measures of reward processing in depression over time? Measurement is fundamental to answering substantive questions in science. Our review of the literature identified gaps in the reliability of reward measurement, the concordance between measures, and a dearth of studies that employ repeated-measure designs. We propose to tackle this using a multi-method approach in a longitudinal design.
  2. Are reward processing aberrations in depression similar to those in other common problems of childhood, such as anxiety and irritability? Specificity-in this case establishing which reward aberrations are unique to a certain phenotype as opposed to a generic finding related to psychopathology-is important for both nosology (disease classification) and for designing rational treatments for psychiatric problems. Below, we describe how we propose to answer this question by characterizing reward processing in those with depression and comparing it to processing in those with other common psychiatric problems in youth, such as anxiety and irritability.
  3. How does reward processing interact with systems subserving sense of agency? As described above, decision-making is an intricate part of reward processing. It is assumed that higher-order cognitive processes, such as the sense of ownership of one s actions-referred to as sense of agency-influence reward processing. Establishing the role of such higher-order processes in depression could lead to developing treatments that boost cognition and restore reward processing in depression. Below, we propose to answer this question by testing whether inter-individual differences in sense of agency explain variation in depression via reward processing (a mediation model).
  4. How is reward processing affected by changes in metabolic, inflammatory, and neuroendocrinological markers? There is mounting evidence for differences in metabolic, inflammatory, and neuroendocrine markers when comparing those with and without MDD; however, the relationship of such differences to reward processing-the focus of this protocol-remain poorly examined. We wish to explore the direction of effect between inflammatory responses and metabolic changes with depression and reward processes. We wish to do this informed by knowledge of an individual s genetic background. The aim is to establish trajectories of stability/change in metabolic and inflammatory markers and relate them to mood changes and reward changes over time. We also wish to align our protocol with Dr Zarate s Protocol 17-M-0060, Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder that focuses on depression in adults. Collecting these data on adolescents will allow us to identify differences and overlaps between adolescents (from this protocol) and the adults in Dr. Zarate s protocol 17-M-0060.
  5. How is reward processing affected by environmentally-generated stress?

    Studies from our own group demonstrate that stress in early life has an impact on how rewards and punishers are processed in the brain several years later (Vidal-Ribas et al 2019, Biol Psychiatry CNNI). Similarly, there is good evidence for the acute effects of stress on reward processing, as indicated in our recent metanalysis (Harreweijn et al 2020). And, of course, there is ample evidence for the role on how stressful events worsen symptoms of depression (Hettema et al 2006 Psychol Med; Kendler et al, Arch Gen Psych 2003; Kendler et al, AmJPsych 1999; Surtees et al, 1986). The emergence of the COVID-19 pandemic presents an unprecedented challenge for the world s physical health, but is also expected to have a profound impact on people s psychological wellbeing. The COVID-19 pandemic is a huge medical challenge to be sure, and, by virtue of being a naturally occurring stress, presents an opportunity for us, using longitudinal methods, to learn more about how humans respond to such environmental influences. Moreover, it offers an opportunity for us to understand more about human behaviour and potentially use such knowledge to inform future interventions. The aim, using remote on-line methods, is to learn about how such environmental stress is experienced by healthy volunteer teens and those with depression, the relationship between stress and self-rated measures of depression, and the association of measures of stress and depression on reward processing.

    Study population:

    We will study four populations: (1) Healthy volunteer children and adults (HVs; n=600); (2) Participants with Major Depressive Disorder (MDD; n=500); (3) Participants with subthreshold depression (s-MDD; n=200); (4) parents (biological or legal guardians) of children with MDD, s-MDD, or HVs who are enrolled in this protocol (N=800 total as 400/200/200 respectively). Study participants will be aged 11-1; years at the time of screening and initial enrollment in Characterization; this is a longitudinal study and participants who turn 18 may continue in it until they are 25.

    Design:

    This is a Characterization study hat includes longitudinal observation of three adolescent cohorts. HV, s-MDD and MDD subjects will take part in a longitudinal,observational study that involves clinical assessment, computer tasks, blood for inflammatory and neuroendocrinological markers, fMRI and MEG scanning and continue to return until they reach 25 years of age. A sample of young adult HVs (18-30 years old) will also be enrolled as a comparison cohort.

    Adolescent patients who still suffer from MDD will be offered outpatient clinical care in the form ofopen-label Cognitive Behavioral Therapy (CBT; up to 26 weeks). During and following outpatient clinical care, participants with MDD will continue in Characterization. Upon completion of clinical care patients will return to care in the community.

    MDD patients who are clinically unstable and are eligible for standard clinical treatment as inpatients or day-patients may enter treatment at NIH. They may do this after starting in Characterization or at their initial enrollment.

    Outcome measures:

    For Objective 1

    Primary Outcomes

    fMRI: Monetary incentive delay task

    Magnetoencephalography: Monetary incentive delay task

    Automated Affect encoding: variables obtained through machine learning analysis

    For Objective 2

    Primary outcomes:

    fMRI: Monetary Incentive Delay Task

    Questionnaires: MFQ, ARI, SCARED

    For Objective 3

    Primary outcomes:

    Questionnaires: PCSC, SCSC, MFQ

    Imaging (fMRI): Activity in prefrontal cortex and striatum in response to controllable setback cues in the Persistence after Setbacks task

    For Objective 4

    Primary outcomes:

    Inflammatory and metabolic markers in blood

    fMRI: Monetary Incentive Delay Task

    Questionnaires: MFQ, ARI, SCARED

    For Objective 5

    Pirmary outcomes:

    Questionnaires: MFQ, ARI-self, SCARED, COVID-19 Questionnaire,

    Behavioral task: SMT

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population A clinical population of depressed adolescents age 11-17 (inclusive)@@@
Condition Depression
Intervention Not Provided
Study Groups/Cohorts
  • Adolescents with Major Depression
    Adolescents with a current or past history of meeting full critieria for major depressive disorder
  • Adolescents with sub-threshold Major Depression
    Adolescents with no past or current history of major depression who meet criteria at initialenrollment of sub-threshold major depression as defined in the protocol
  • Health volunteer adolescents
    Adolescents with no history of significant psychiatric or medical disorders (as defined in the protocol) currently or in the past.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: August 12, 2020)
4100
Original Estimated Enrollment
 (submitted: December 30, 2017)
3000
Estimated Study Completion Date July 1, 2025
Estimated Primary Completion Date July 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria
  • INCLUSION CRITERIA:
  • Youths who meet DSM 5 criteria for Major Depressive Disorder (Group 1)

Inclusion criteria for Youth with MDD (all must be met):

  • Ages 11-17 at the time of enrollment in Characterization;
  • Current diagnosis of DSM-5 Major Depressive Disorder (within the last six months from assessment) which are:

    • Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

      • Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feeling sad, blue, "down in the dumps,"or empty) or observation made by others (e.g., appears tearful or about to cry). (In children and adolescents, this may present as an irritable or cranky, rather than sad, mood.)
      • Markedly diminished interest or pleasure in all, or almost all, activities every day, such as no interest in hobbies, sports, or other things the person used to enjoy doing.
      • Significant weight loss when not dieting or weight gain (e.g., a change of more than 5 percent of body weight in a month), or decrease or increase in appetite nearly every day.
      • Insomnia (inability to get to sleep or difficulty staying asleep) or hypersomnia (sleeping too much) nearly every day
      • Psychomotor agitation (e.g., restlessness, inability to sit still, pacing, pulling at clothes or clothes) or retardation (e.g., slowed speech, movements, quiet talking) nearly every day
      • Fatigue, tiredness, or loss of energy nearly every day (e.g., even the smallest tasks, like dressing or washing, seem difficult to do and take longer than usual).
      • Feelings of worthlessness or excessive or inappropriate guilt nearly every day (e.g., ruminating over minor past failings).
      • Diminished ability to think or concentrate, or indecisiveness, nearly every day (e.g. appears easily distracted, complains of memory difficulties).
      • Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideas without a specific plan, or a suicide attempt or a specific plan for committing suicide
    • Symptoms cause clinically significant distress or impairment in social, occupational/academic, or other important areas of functioning.
    • The episode is not attributable to the physiological effects of a substance or to another medical condition.
  • Added criteria for Children with MDD entering inpatient treatment. In addition to criteria above, the youth:

    • Is failing his/her treatment as defined as a current CGAS score less than or equal to 60
    • If the child has a psychiatrist, the child s psychiatrist or treater agrees that the child s response to his/her current treatment makes it clinically appropriate to change the child s current treatment
    • On the basis of record review and interviews with child and parent, the research team agrees that the child s response to his/her current treatment is no more than minimal
  • Added criteria for Children with MDD entering outpatient treatment. In addition to criteria in above, the youth:

    ---Meets criteria for on-going MDD

  • Youths who meet modified DSM criteria for Subthreshold Depression (Group 2)

    • Inclusion criteria for subthreshold depressive disorder are:

      • Ages 11-17 at the time of enrollment in Characterization;
      • An episode of depressed mood or loss of interest or pleasure lasting at least 1 week plus
      • At least two of the seven other DSM-5-associated symptoms for major depression
      • Occurring in the last six months.

INCLUSION FOR HEALTHY VOLUNTEERS:

Adolescent Healthy Volunteers (Group 3a)

  • Youth 11 to 17 years of age at time of enrollment in Characterization
  • The adolescent must be competent to assent; parents must be able comprehend and provide permission for their child (consent).
  • Participants will be willing to participate in NIMH IRB approved research protocols. Minors will be asked to sign assent forms and their parents will sign the consent form.
  • Participants will be willing to undergo an evaluation which may include a psychiatric interview, review of medical history (including Tanner staging for minors), and pregnancy testing.
  • Speaks English
  • Have an identified primary care clinician

Adult Healthy Volunteers (Group 3b)

  • Adults 18 to 30 years of age at time of enrollment in Characterization
  • Subjects must be competent to consent.
  • Participants will be willing to participate in NIMH IRB approved research protocols.
  • Participants will be willing to undergo an evaluation, which may include a psychiatric interview, review of medical history, and pregnancy testing (for females).
  • Speaks English.
  • Has an identified primary care clinician.

INCLUSION CRITERIA FOR PARENTS OF ENROLLED YOUTH (Group 4):

  • Are the biological parent or legal guardian of an enrolled adolescent (who is a healthy volunteer, has s-MDD, or has MDD) participant
  • Those of all ages are eligible if they are a parent of a currently enrolled participant

EXCLUSION CRITERIA: (All patients)

-Exclusion Criteria for MDD patients (Group 1)

  • Meets criteria for schizophrenia, schizophreniform disorder, schizoaffective illness, bipolar disorder, more than mild Autism Spectrum Disorder, Anorexia Nervosa or other severe Eating Disorder.
  • Intellectual disability (clinically identified or IQ less than 70)
  • For subjects with major depression or sub-threshold major depressive episode: Symptoms of depression are due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition by self and parent report.
  • Currently pregnant or lactating by self and parent report and urine pregnancy test.
  • Meets DSM-5 criteria for alcohol or substance use disorder (excluding tobacco and nicotine use) within the last three months. This is determined solely by clinical interview of child and parent (e.g. KSADS).
  • Current active suicidal ideation (i.e., presence of intent for engaging in suicidal behaviors).

Youths with passive suicidal ideation and/or past active suicidal ideation are still eligible.

  • Participants with repeated self-harm occurring in the context of inter-personal conflict.
  • NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy.

    -Exclusion criteria for youths meeting modified DSM criteria for Subthreshold Depression (Group 2):

  • Intellectual disability (clinically identified or IQ less than 70).
  • Any serious medical condition (such as epilepsy, heart disease requiring medication) by self and parent report.
  • Past or current diagnosis of a manic or hypomanic episode, major depression), schizophrenia, schizophreniform disorder, schizoaffective illness, Tourette Disorder, or Autism Spectrum Disorder, Anorexia Nervosa or other severe Eating Disorder.
  • Meets DSM-5 criteria for alcohol or substance abuse within the last three months by self and parent report.
  • NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy.

    -Healthy volunteer youths and/adults exclusion criteria:

  • Intellectual disability (clinically identified or IQ less than 70).
  • Any serious medical condition (such as epilepsy, heart disease requiring medication) by self and parent report.
  • Past or current diagnosis of any mood disorder (manic or hypomanic episode, major depression), anxiety disorder (except specific phobia), Obsessive Compulsive Disorder (OCD), Post-Traumatic Stress Disorders (PTSD), Conduct Disorder, schizophrenia, schizophreniform disorder, schizoaffective illness, Tourette Disorder, or Autism Spectrum Disorder.
  • Meets criteria for subthreshold depression (as defined above)
  • Meets DSM-5 criteria for alcohol or substance abuse within the last three months by self and parent report; for adults, past history of substance dependency or substance abuse within the last three months by self-report.
  • NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy.

Parents of enrolled participants exclusion criteria:

  • Parents who are unable to understand or read English well enough to complete the study interview and tests.
  • Parents who are a current NIMH employee, or staff member, or a family member of an NIMH employee. NIMH IRP Employees/staff and immediate family members will be excluded from the study per NIMH policy.
Sex/Gender
Sexes Eligible for Study: All
Ages 11 Years to 25 Years   (Child, Adult)
Accepts Healthy Volunteers Yes
Contacts
Contact: Argyris Stringaris, M.D. (301) 443-8019 argyris.stringaris@nih.gov
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03388606
Other Study ID Numbers 180037
18-M-0037
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
Study Sponsor National Institute of Mental Health (NIMH)
Collaborators Not Provided
Investigators
Principal Investigator: Argyris Stringaris, M.D. National Institute of Mental Health (NIMH)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 16, 2020