Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder
Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder
This study seeks to learn more about the symptoms of severe mood dysregulation in children
 and adolescents ages 7-17. Children and adolescents with severe mood dysregulation (SMD)
 display chronic anger, sadness, or irritability, as well as hyperarousal (such as insomnia,
 distractibility, hyperactivity) and extreme responses to frustration (such as frequent,
 severe temper tantrums). Researchers will describe the moods and behaviors of children with
 these symptoms and use specialized testing and brain imaging to learn about the brain changes
 associated with this 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).

 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. As part of
 this overall goal, we plan to collect information on numerous environmental factors. First,
 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. Second, we plan to
 investigate the role of environmental stressors, such as the COVID-19 pandemic, on youth s
 irritability symptoms.

 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).
-  INCLUSION CRITERIA:

 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.

 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-IV or 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

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

 6.1.1. Age 8-17

 6.1.2. Currently meets DSM-IV or DSM-5 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 primary care physician.

 6.1.5. Speaks English

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

 1.3.7. 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.

 5.3<TAB>Exclusion criteria for those with MDD:

 5.3.1<TAB>The individual exhibits any of these cardinal bipolar symptoms:

 5.3.1.1<TAB>Elevated or expansive mood

 5.3.1.2<TAB>Grandiosity or inflated self-esteem

 5.3.1.3<TAB>Decreased need for sleep

 5.3.1.4<TAB>Increase 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.<TAB>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.<TAB>Currently pregnant or lactating

 5.3.6.<TAB>Meets criteria for alcohol or substance abuse with the last three months

 5.3.7.<TAB>NIMH IRP Employees/staff and immediate family members will be excluded from the
 study per NIMH policy.

 6.2.<TAB>Exclusion criteria for those with ADHD:

 6.2.1. IQ<70

 6.2.2.<TAB>Pregnancy (excludes for scanning only)

 6.2.3.<TAB>Ongoing medical illness or neurological disorder other than ADHD

 6.2.4.<TAB>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