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.
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 (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.
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 (Brotman et al., 2017). 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. 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.
There are 5 separate populations being studied in this protocol:
Children and adolescents between the ages of 7-17 years old who meet criteria for DMDD or
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).
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
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, 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, BD (see protocol 00-M-0198)
(Leibenluft et al 2003), anxiety (see protocol 00-M-0192), and healthy volunteers (see
- 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
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:
220.127.116.11 The child s current CGAS score less than or equal to 60.
18.104.22.168 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
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
22.214.171.124 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.
126.96.36.199.1 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.)
188.8.131.52.2 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
184.108.40.206.3. 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
220.127.116.11.4. Insomnia (inability to get to sleep or difficulty staying asleep) or hypersomnia
(sleeping too much) nearly every day
18.104.22.168.5. 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
22.214.171.124.6. 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).
126.96.36.199.7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day
(e.g., ruminating over minor past failings).
188.8.131.52.8. Diminished ability to think or concentrate, or indecisiveness, nearly every day
(e.g. appears easily distracted, complains of memory difficulties).
184.108.40.206.9. 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
220.127.116.11.10 Symptoms cause clinically significant distress or impairment in social,
occupational/academic, or other important areas of functioning.
18.104.22.168.11. 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),
5.2.1. has no exclusionary criteria for MRI scanning
5.2.2 is failing his/her treatment as defined as:
22.214.171.124. The child s current CGAS score <60.
126.96.36.199. The child s psychiatrist/treater agrees that the child s response to his/her
188.8.131.52. current treatment makes it clinically appropriate to change the child s current
184.108.40.206. 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
c. Exclusion criteria
1.3 Exclusion criteria for those with DMDD:
1.3.1 The individual exhibits any of these cardinal bipolar symptoms:
220.127.116.11 Elevated or expansive mood
18.104.22.168 Grandiosity or inflated self-esteem
22.214.171.124 Decreased need for sleep
126.96.36.199 Increase in goal-directed activity (this can result in the excessive involvement in
pleasurable activities that have a high potential for painful consequences)
188.8.131.52. 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
3.2.5. History of sexual abuse.
3.2.6. Parent or sibling with Bipolar Disorder, recurrent MDD, or any disorder with
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