Characterization and Treatment of Adolescent Depression

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 have been proposed to underlie
several key behavioral and neural aberrations observed in depression (Michael T 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. 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.

Study population:

We will study four populations: (1) Healthy volunteers (HVs; n=300); (2) Participants with
Major Depressive Disorder (MDD; n=300); (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 11-17 years.

Design:

This is a Characterization study. HV, s-MDD and MDD subjects will be 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 age 25 years. Adolescent patients who still suffer from MDD will be offered
open-label Cognitive Behavioral

Therapy (CBT; up to 26 weeks). During and following completion of CBT, participants with MDD
will continue in Characterization.

Upon completion of CBT 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 and may enter treatment at NIH after having started in Characterization or at
the time of 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

- 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 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 (i.e. CGI-I greater than 2)

- 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.

- Healthy volunteer youths (Group 3)

- Youth 11 to 17 years of age at time of enrollment in Characterization

- Subjects must be competent to assent; parents must be able comprehend and provide
permission for their child (consent).

- Youth 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.

- Subjects willing to undergo an evaluation which may include a psychiatric
interview, review of medical history (including Tanner staging for minors),
pregnancy testing.

- Speaks English

- Has an identified primary care clinician

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.

- Currently pregnant or lactating by self and parent report and urine pregnancy test

- 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.

- Parent or sibling with a history of any disorder with psychosis.

- NIMH IRP Employees/staff and immediate family members will be excluded from the study
per NIMH policy.

-Healthy volunteer youth 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.

- Currently pregnant or lactating by self and parent report and urine pregnancy test

- 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.

- Parent or sibling with a history of any disorder with psychosis.

- NIMH IRP Employees/staff and immediate family members will be excluded from the study
per NIMH policy.