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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2016 by National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ) Identifier:
First received: October 31, 2001
Last updated: May 24, 2016
Last verified: May 2016
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.

Condition Phase
Mood Disorder
Bipolar Disorder
Phase 4

Study Type: Observational
Official Title: Characterization and Pathophysiology of Severe Mood and Behavioral Dysregulation in Children and Youth

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 850
Study Start Date: October 2001
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Detailed Description:


The past decade has seen a dramatic increase in focus on pediatric bipolar disorder (BD), as the number of children receiving the diagnosis has escalated (Blader and Carlson, 2007; Leibenluft, 2008; Moreno et al., 2007). Discussion has centered on the diagnostic boundaries of bipolar disorder, and whether nonepisodic severe irritability is a developmental presentation of mania. Beginning in 2002, our work defined a specific phenotype [severe mood dysregulation (SMD)] including youth with chronic angry mood with behavioral outbursts and hyperarousal symptoms (Leibenluft, 2011; Leibenluft et al., 2003). The purpose of this work has been to examine similarities and differences between youth with BD and SMD, and address the nosological question of whether the diagnosis of BD should be separated from a chronic angry mood with behavioral outbursts and hyperarousal symptoms similar to those present in children and adolescents with attention deficit hyperactivity disorder (ADHD). Before this work began, there was substantial debate (Baroni et al., 2009; Biederman et al., 1998; Carlson, 1998; Leibenluft et al., 2003; Nottelman, 2001), with little evidence to support either position.

Over the last decade, there has been substantial progress suggesting these might be best viewed a separate conditions, but important questions remain. Future work needs to address the relationship between classic presentations of BD (as in protocol 00-M-0198) and SMD, as defined in this protocol. We are examining the developmental trajectory, phenomenology, behavioral correlates, and underlying neural mechanisms of chronic irritability in youth. Our overall goal is to gain a clearer understanding of the course and neurophysiology the disorder to inform treatment and improve the outcome for children with SMD. In order to advance this aim this protocol has 3 objectives:

  1. to use longitudinal techniques to characterize the clinical and physiological manifestations of SMD
  2. to identify and follow longitudinally behavioral, neuropsychological, neurophysiological, and neuroanatomical correlates of SMD, and compare them to pediatric disorders that bear some similarities (BD, and attention deficit hyperactivity disorder (ADHD)) and to typically developing youth.
  3. to examine genetic and familial correlates of SMD

Study population

There are 3 separate populations being studied in this protocol:

  1. Children and adolescents between the ages of 7-17 years old who meet criteria for SMD
  2. Healthy volunteer children and adolescents between the ages of 7-17 years old
  3. Healthy volunteer adults between the ages of 18-25 years old.


For children and adolescents with SMD, 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 1-2-year 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

This study will examine between-group differences in clinical, behavioral, genetic, neuroanatomical, and neurophysiological variables in individuals with SMD, BD (BD, see protocol 00-M-0198) (Leibenluft et al., 2003), and healthy volunteers.

Children with SMD may also be compared on these features to those with other disorders (e.g. anxiety, depression) who are studied under Dr. Daniel Pine s protocol 01-M-0192 in order to elucidate differences between SMD and these conditions.

Longitudinal clinical, behavioral, and neuroanatomical data will also be obtained.


Ages Eligible for Study:   7 Years to 25 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes

INCLUSION CRITERIA (all must be met):

  1. Ages 7-17 at the time of recruitment; will be followed in the longitudinal component of the study until age 25.
  2. Abnormal mood (specifically, anger, sadness, and/or irritability), present at least half of the day most days, and of sufficient severity to be noticeable by people in the child s environment (e.g. parents, teachers, peers).
  3. Hyperarousal, as defined by at least three of the following symptoms: insomnia, agitation, distractibility, racing thoughts or flight of ideas, pressured speech, intrusiveness
  4. 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.

    • The symptoms in # 2, 3, and 4 above are currently present and have been present for at least 12 months without any symptom-free periods exceeding two months.
    • The onset of symptoms must be prior to age 12 years.
    • The symptoms are severe in at least in one setting (e.g. violent outbursts, assaultiveness at home, school, or with peers). In addition, there are at least mild symptoms (distractibility, intrusiveness) in a second setting.


    In addition to criteria above, the child is failing his/her treatment as defined as:

    • The child s current CGAS score < 60.
    • 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.
    • 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).


    The individual exhibits any of these cardinal bipolar symptoms:

    • Elevated or expansive mood
    • Grandiosity or inflated self-esteem
    • Decreased need for sleep
    • Increase in goal-directed activity (this can result in the excessive involvement in pleasurable activities that have a high potential for painful consequences)
    • Has BD symptoms in distinct periods lasting more than 1 day.

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

    IQ< 70

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

    Currently pregnant or lactating

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

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



    Control subjects will be group matched to the patients.

    Have an identified primary care physician.

    Speaks English


    I.Q. < 70;

    Any serious medical condition or condition that interferes with fMRI scanning

    Pregnant or lactating;

    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.

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

    History of sexual abuse.

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



    Control subjects will be group matched to the patients.

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

    Have an identified primary care physician.

    Speaks English


    IQ< 70


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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00025935

Contact: Ellen Leibenluft, M.D. (301) 496-9435

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Principal Investigator: Ellen Leibenluft, M.D. National Institute of Mental Health (NIMH)
  More Information

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: National Institute of Mental Health (NIMH) Identifier: NCT00025935     History of Changes
Other Study ID Numbers: 020021  02-M-0021 
Study First Received: October 31, 2001
Last Updated: May 24, 2016
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Mood Disorders
Bipolar Disorder
Emotional Dysregulation
Conduct Disorder
Children and Adolescents
Affective Neuroscience
Behavioral Dysregulation
Mood Disorder
Healthy Volunteer
Normal Control

Additional relevant MeSH terms:
Bipolar Disorder
Mood Disorders
Pathologic Processes
Bipolar and Related Disorders
Mental Disorders processed this record on July 21, 2016