Characterization and Treatment of Adolescent Depression
Characterization and Treatment of Adolescent Depression
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.
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
-  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.