Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder

Objective:

Irritability is a common and impairing clinical presentation in youth (Collishaw et al 2010,
Leibenluft 2011, Peterson et al 1996). Despite its significant public health impact, the
clinical course and pathophysiology of irritability remains poorly understood. Chronic and
severe irritability is the primary symptom of the new DSM-5 diagnosis, disruptive mood
dysregulation disorder (DMDD) (APA 2013), is an associated symptom of other pediatric
disorders including Attention-Deficit/Hyperactivity Disorder (ADHD) (Ambrosini et al 2013,
Burke et al 2014, Jensen et al 2007, Shaw et al 2014, Stoddard et al 2014), and can be a
clinical precursor to Major Depressive Disorder (MDD) and anxiety disorders. In addition,
irritability is a trait distributed continuously in youth (Stringaris & Taylor 2015), thereby
fitting well within the National Institute of Mental Health (NIMH) Research Domain Criteria
(RDoC) initiative (Insel et al 2010).

Clinically impairing irritability in children and adolescents began to gain more attention as
interest grew in the diagnosis of pediatric bipolar disorder (Baroni et al 2009, Biederman et
al 1998, Carlson 1998, Leibenluft et al 2003, Nottelman 2001). Beginning in the 1990s, child
psychiatry researchers suggested that while pediatric bipolar disorder can present with
distinct episodes of mania or hypomania as in adults, the more typical pediatric presentation
was chronic, severe irritability and hyperarousal symptoms. However, data collected under
this protocol comprise a series of longitudinal (Deveney et al 2015, Stringaris et al 2010),
family (Brotman et al 2007), behavioral (Dickstein et al 2007, Rich et al 2008b), and
pathophysiological (Adleman et al 2012, Adleman et al 2011, Brotman et al 2010, Rich et al
2007, Thomas et al 2014, Thomas et al 2012, Thomas et al 2013, Tseng et al 2016) studies that
differentiated classically defined episodic pediatric bipolar disorder from chronic
irritability without distinct manic or hypomanic episodes [see (Leibenluft 2011) for review].
These findings are consistent with reports from other groups and meta-analyses (Althoff et al
2014; Copeland et al 2014; Fristad et al 2016; Vidal-Ribas et al 2016).

Among the several strands of research designed to differentiate pediatric bipolar disorder
from chronic irritability, longitudinal studies provide the strongest evidence that these two
phenotypes are distinct. Children with chronic irritability are at elevated risk for later
depression, but not manic episodes (Althoff et al 2014, Brotman et al 2006, Leibenluft et al
2006, Stringaris et al 2010, Stringaris et al 2009, Vidal-Ribas et al 2016). Thus, youth with
MDD (with and without prior DMDD) are an important comparison group to explore, and we are
examining the developmental trajectory, phenomenology, behavioral correlates, and underlying
neural mechanisms of chronic irritability and MDD in youth. Further, because irritability and
ADHD symptoms are highly comorbid in youth (e.g.,Brotman et al., 2006; Costello et al., 2003;
Shaw et al., 2014), participants with ADHD are an important comparison group in our work on
irritability.

The current translational model of irritability emphasizes the role of abnormal threat and
reward processing, but also underlines the relevance of environmental factors in the
emergence and maintenance of irritability. More precisely, it is assumed that irritable
children experience environments, where rewards and punishments are inconsistently delivered
leading to unintentional reinforcement of disruptive behavior through the parents. Reasons
for this inconsistent parent behavior could be manifold spanning instrumental learning
deficits and exaggerated responses to threat and frustrative non-reward in the parents
themselves as well as lack of knowledge regarding learning principles (Soenens et al., 2006;
Sanders et al., 1999) and increased levels of stress (Kiff et al., 2011). These factors might
contribute to instrumental-learning deficits in the children increasing frequency and
intensity of temper outbursts. Heightened levels of chronic irritability, another symptom of
DMDD, might be more associated with features of the parent-child interaction. There is a rich
literature within the framework of attachment theory (Ainsworth et al. 2015, Bolwby, 2008)
showing that behavior of children with anxious-resistant insecure attachment is characterized
by a general angry tone and is also associated with increased amygdala responses to negative
social scenes (Vrticka et al., 2012). In addition, it was also shown that highly irritable
infants are less sociable in terms of being less responsive and more fearful towards others
and displaying an angry emotional tone in general as toddlers when they had been insecurely
attached and more sociable when they had been securely attached (Stupica et al, 2011). Adding
another layer of complexity, it is also conceivable that inconsistent parent behavior
diminishes parent s perceived trust-worthiness. This could be of relevance as recent studies
showed that persons are less willing to delay rewards an action bound to increase levels of
frustration if their interaction partner is perceived as little reliable (Michaelson, 2013,
Front Psychol; Michaelson & Munakata, 2016 Dev Science). We aim to gain a clearer
understanding of the potential environmental and biological factors contributing to
irritability in youth. Therefore, we are studying the clinical, behavioral,
neuropsychological, neurophysiological and neuroanatomical features of the parents that
contribute to the symptomatology in the children and adolescents. We are extending this
assessment to another form of clinical information on the parents using self-report ratings
of their own emotions and irritability. This information is critical in understanding
associations between child and parent irritability.

The overall goal is to gain a clearer understanding of the environmental factors contributing
to irritability in order to inform treatment and improve the outcome for children. In order
to advance this aim, we plan to investigate parents of youth with DMDD enrolled in this study
and subthreshold DMDD enrolled in this study in order to determine clinical, behavioral,
neuropsychological, neurophysiological and neuroanatomical features of the parents that
contribute to the symptomatology in the children and adolescents. Further, we plan to examine
parent-child interaction and its influence on irritability observed in the youth.

Study population:

There are 6 separate populations being studied in this protocol:

1. Children and adolescents between the ages of 7-17 years old who meet criteria for DMDD
or subthreshold DMDD.

2. Parents of children and adolescents, who meet criteria for DMDD or subthreshold DMDD and
are enrolled in 02-M-0021, and are 25 59 years old will be studied.

3. Healthy volunteer children and adolescents between the ages of 7-17 years old.

4. Healthy volunteer adults between the ages of 18-25 years old.

5. Children and adolescents between the ages of 12-17 years old who meet criteria for major
depressive disorder (MDD).

6. Children and adolescents between ages of 8-17 years who meet criteria for
attention-deficit/hyperactivity disorder (ADHD) who do not have a mood disorder.

Design:

For children and adolescents with full or subthreshold DMDD and/or MDD, this study is an
outpatient characterization and longitudinal follow-along design. Once determined to be
eligible, individuals come for an initial assessment, and then return at varying intervals
until age 25 for clinical interviews, behavioral tasks, and structural and functional MRI.

For healthy volunteer children, adults and parents of healthy volunteer children, this study
is an outpatient cross-sectional study that includes clinical interviews, behavioral tasks,
and structural and functional MRI.

For all individuals, genetic material from saliva or blood is obtained under protocol
01-M-0254.

Outcome measures:

There are two primary outcome measures. First, this study will examine associations between
irritability and clinical, behavioral, genetic, neuroanatomical, and neurophysiological
variables in individuals with full or subthreshold DMDD and/or MDD, ADHD, BD (see protocol
00-M-0198) (Leibenluft et al 2003), anxiety (see protocol 00-M-0192), and healthy volunteers
(see protocol 00-M-0198). Second, this study will examine between-group differences in
clinical, behavioral, genetic, neuroanatomical, and neurophysiological variables in
individuals with full or subthreshold DMDD and/or MDD, ADHD, BD (see protocol 00-M-0198)
(Leibenluft et al 2003), anxiety (see protocol 00-M-0192), and healthy volunteers (see
protocol 00-M-0198).

- 1. Inclusion criteria for children with DMDD, subthreshold DMDD:

1.1.1 Ages 7-17 at the time of recruitment; will be followed in the longitudinal component
of the study until age 25.

1.1.2 Abnormal mood (specifically, anger, sadness, and/or irritability), present at least
half of the day most days (or at least half the day at least one day per week for
subthreshold), and of sufficient severity to be noticeable by people in the child s
environment (e.g. parents, teachers, peers).

1.1.3 Compared to his/her peers, the child exhibits markedly increased reactivity to
negative emotional stimuli that is manifest verbally or behaviorally. For example, the
child responds to frustration with extended temper tantrums (inappropriate for age and/or
precipitating event), verbal rages, and/or aggression toward people or property. Such
events occur, on average, at least three times a week. For subthreshold DMDD such tantrums
occur on average at least once per month.

1.1.4 The symptoms in # 1.1.2, and 1.1.3 above are currently present and have been present
for at least 12 months without any symptom-free periods exceeding three months.

1.1.5 The onset of symptoms must be prior to age 10 years.

1.1.6 For DMDD the symptoms are severe in at least in one setting (e.g. violent outbursts,
assaultiveness at home, school, or with peers) and at least mild (distractibility,
intrusiveness) in a second setting. For subthreshold DMDD, there must be evidence of
impairment causing distress to the child or to those around him/her in at least one
setting.

1.2. Children with DMDD entering treatment. Those eligible for treatment must meet all
criteria for DMDD; subthreshold DMDD is not eligible for treatment. In addition to criteria
in VI.B.1.1 (above),

1.2.1 Has no exclusionary criteria for MRI scanning

1.2.2. The child is failing his/her treatment as defined as:

1.2.2.1 The child s current CGAS score less than or equal to 60.

1.2.2.2 The child s psychiatrist/treater agrees that the child s response to his/her
current treatment makes it clinically appropriate to change the child s current treatment.

1.2.2. 3 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>2).

2. Parents of children and adolescents with DMDD or subthreshold DMDD enrolled in 02-M-0021

2.1.1. Are capable of performing behavioral tasks and/or scanning.

2.1.2. Speaks English

3. Healthy Volunteer (Control) Children

3.1.1. Control subjects will be group matched to the patients.

3.1.2. Have an identified primary care physician.

3.1.3. Speaks English

4. Healthy Volunteer Adults

4.1.1 Control subjects will be group matched to the patients.

4.1.2. They will have normal physical and neurological examinations by history or checklist

4.1.3. Have an identified primary care physician.

4.1.4 Speaks English

5. Children with Major Depressive Disorder (MDD) Inclusion criteria (all must be met):

5.1.1 Ages 11-17 at the time of recruitment; will be followed in the longitudinal component
of the study until age 25.

5.1.2. DSM-5 Major Depressive Disorder

5.1.2.1 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.

5.1.2.1.1 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.)

5.1.2.1.2 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.

5.1.2.1.3. 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.

5.1.2.1.4. Insomnia (inability to get to sleep or difficulty staying asleep) or hypersomnia
(sleeping too much) nearly every day

5.1.2.1.5. 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

5.1.2.1.6. 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).

5.1.2.1.7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day
(e.g., ruminating over minor past failings).

5.1.2.1.8. Diminished ability to think or concentrate, or indecisiveness, nearly every day
(e.g. appears easily distracted, complains of memory difficulties).

5.1.2.1.9. 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

5.1.2.1.10 Symptoms cause clinically significant distress or impairment in social,
occupational/academic, or other important areas of functioning.

5.1.2.1.11. The episode is not attributable to the physiological effects of a substance or
to another medical condition.

5.1.3. Youth with MDD who are continuing in research as adults must also be receiving
psychiatric care for their MDD, if it is ongoing

5.2. Children with MDD entering treatment. In addition to criteria in VI.B.4.1. (above),
the child

5.2.1. has no exclusionary criteria for MRI scanning

5.2.2 is failing his/her treatment as defined as:

5.2.2.1. The child s current CGAS score <60.

5.2.2.2. The child s psychiatrist/treater agrees that the child s response to his/her
4.2.2.3. current treatment makes it clinically appropriate to change the child s current
treatment.

5.2.2.4. 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>2).

6. Children with Attention-Deficit/Hyperactivity Disorder (ADHD)

6.1.1. Age 8-17

6.1.2. Currently meets DSM-IV criteria for ADHD

6.1.3. Subjects with other primary psychiatric disorders including anxiety disorders,
dysthymic disorder, past major depression, oppositional defiant disorder, tic disorders,
and the learning, communication, and elimination disorders may be accepted

6.1.4. Have an identified

c. Exclusion criteria

1.3 Exclusion criteria for those with DMDD:

1.3.1 The individual exhibits any of these cardinal bipolar symptoms:

1.3.1.1 Elevated or expansive mood

1.3.1.2 Grandiosity or inflated self-esteem

1.3.1.3 Decreased need for sleep

1.3.1.4 Increase in goal-directed activity (this can result in the excessive involvement in
pleasurable activities that have a high potential for painful consequences)

1.3.1.5. Has BD symptoms in distinct periods lasting more than 1 day.

1.3.2. Meets criteria for schizophrenia, schizophreniform disorder, schizoaffective
illness, PDD, or PTSD.

1.3.3. IQ< 70

1.3.4. The symptoms are due to the direct physiological effects of a drug of abuse, or to a
general medical or neurological condition.

1.3.5. Currently pregnant or lactating

1.3.6. Subjects who are ineligible for MRI scanning (e.g. braces, implanted metal devices)
will be excluded from treatment.

1.3.7. Meets criteria for alcohol or substance abuse with the last three months

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

2. Exclusion of parents of children and adolescents with DMDD or subthreshold DMDD

2.1Are an NIMH IRP Employees/staff

2.2Have an I.Q. < 70

2.3 Have any serious medical condition or condition that interferes with participation

3.2 Healthy Volunteer Exclusion criteria:

3.2.1. I.Q. < 70;

3.2.2. Any serious medical condition or condition that interferes with fMRI scanning

pregnant or lactating;

3.2.3. Past or current diagnosis of any anxiety disorder (panic disorder, GAD, Separation
Anxiety Disorder, Social Phobia), mood disorder (manic or hypomanic episode, major
depression), OCD, PTSD, Conduct Disorder, psychosis, current suicidal ideation, Tourette
Disorder, Autism Spectrum Disorder or ADHD.

3.2.4. Substance abuse within two months prior to study participation or present substance
abuse

3.2.5. History of sexual abuse.

3.2.6. Parent or sibling with Bipolar Disorder, recurrent MDD, or any disorder with
psychosis.

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

4.2 Healthy Volunteer Adult Exclusion criteria:

4.2.1. IQ< 70

4.2.2. Pregnant

4.2.3. Any past or current history of Bipolar Disorder (any manic or hypomanic episode),
recurrent MDD, or any disorder with psychosis

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

5.3Exclusion criteria for those with MDD:

5.3.1The individual exhibits any of these cardinal bipolar symptoms:

5.3.1.1Elevated or expansive mood

5.3.1.2Grandiosity or inflated self-esteem

5.3.1.3Decreased need for sleep

5.3.1.4Increase in goal-directed activity (this can result in the excessive
involvement in pleasurable activities that have a high potential for painful consequences)

5.3.1.5. Has BD symptoms in distinct periods lasting more than 1 day.

5.3.2. Meets criteria for schizophrenia, schizophreniform disorder, schizoaffective
illness, PDD, or PTSD.

5.3.3. IQ< 70

5.3.4.The symptoms are due to the direct physiological effects of a drug of abuse, or
to a general medical or neurological condition.

5.3.5.Currently pregnant or lactating

5.3.6.Subjects who are ineligible for MRI scanning (e.g. braces, implanted metal
devices) will be excluded from treatment.

5.3.7.Meets criteria for alcohol or substance abuse with the last three months

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

6.2.Exclusion criteria for those with ADHD:

6.2.1. IQ<70

6.2.2.Pregnancy (excludes for scanning only)

6.2.3.Ongoing medical illness or neurological disorder other than ADHD

6.2.4.Any condition that would interfere with the participants ability to perform

research tasks

6.2.5. Current Major Depression

6.2.6. Any past or present manic or hypomanic episode

For all groups:

NIMH employees are excluded