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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2016 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier:
NCT00025935
First received: October 31, 2001
Last updated: November 23, 2016
Last verified: November 2016

October 31, 2001
November 23, 2016
October 2001
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Complete list of historical versions of study NCT00025935 on ClinicalTrials.gov Archive Site
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Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder
Characterization and Pathophysiology of Severe Mood and Behavioral Dysregulation in Children and Youth
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

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. In 2013 the Diagnostic and Statistical Manual (DSM) added Disruptive Mood Dysregulation Disorder, (DMDD) that is very similar to SMD in that it shares features of severe irritability. 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 or DMDD as defined in the DSM. Data suggest that there is a strong likelihood for those DMDD/SMD in youth to develop Major Depression. Thus, youth with Major Depressive Disorder (MDD) (with and without prior DMDD) are an important comparison group. We are examining the developmental trajectory, phenomenology, behavioral correlates, and underlying neural mechanisms of chronic irritability and MDD in youth. Our overall goal is to gain a clearer understanding of the course and neurophysiology these disorders to inform treatment and improve the outcome for children with SMD/DMDD and MDD. 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), MDD) and to typically developing youth.
  3. to examine genetic and familial correlates of SMD, DMDD and MDD

Study population

There are 4 separate populations being studied in this protocol:

  1. Children and adolescents between the ages of 7-17 years old who meet criteria for SMD or DMDD
  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.
  4. Children and adolescents between the ages of 12-17 years old who meet criteria for

major depressive disorder (MDD)

Design

For children and adolescents with SMD or 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 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 or DMDD and/or MDD, BD (BD, see protocol 00-M-0198) (Leibenluft et al., 2003), and healthy volunteers.

Children with SMD or DMDD and/or MDD 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 or DMDD and these conditions.

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

Observational
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  • Mood Disorder
  • Bipolar Disorder
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
950
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  • CHILDREN WITH SEVERE MOOD AND BEHAVIORAL DYSREGULATION (SMD) OR DMDD

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.
  5. 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.
  6. The onset of symptoms must be prior to age 12 years.
  7. 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.

    CHILDREN WITH SMD OR DMDD ENTERING TREATMENT. IN ADDITION TO CRITERIA ABOVE:

    • Has no exclusionary criteria for MRI scanning
    • the child is failing his/her treatment as defined as:

      • The child s current CGAS score less than or equal to 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).

    EXCLUSION CRITERIA FOR THOSE WITH SMD OR DMDD:

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

    HEALTHY VOLUNTEER CONTROLS (Children):

    HEALTHY VOLUNTEER INCLUSION CRITERIA:

    Control subjects will be group matched to the patients.

    Have an identified primary care physician.

    Speaks English

    HEALTHY VOLUNTEER EXCLUSION CRITERIA:

    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.

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

    HEALTHY VOLUNTEER (ADULTS)

    INCLUSION CRITERIA:

    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

    EXCLUSION CRITERIA:

    IQ< 70

    Pregnant

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

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

    CHILDREN WITH MAJOR DEPRESSIVE DISORDER (MDD):

    Inclusion criteria (all must be met):

    Ages 12-17 at the time of recruitment; will be followed in the longitudinal component of the study until age 25.

    DSM-5 Major Depressive Disorder

    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.

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

    CHILDREN WITH MDD ENTERING TREATMENT. IN ADDITION TO THE CRITERIA ABOVE, THE CHILD:

    Has no exclusionary criteria for MRI scanning

    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).

    EXCLUSION CRITERIA FOR THOSE WITH MDD:

    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

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

Both
7 Years to 25 Years   (Child, Adult)
Yes
Contact: Ellen Leibenluft, M.D. (301) 496-9435 leibs@mail.nih.gov
United States
 
NCT00025935
020021, 02-M-0021
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National Institute of Mental Health (NIMH)
National Institute of Mental Health (NIMH)
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Principal Investigator: Ellen Leibenluft, M.D. National Institute of Mental Health (NIMH)
National Institutes of Health Clinical Center (CC)
November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP