Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder
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|ClinicalTrials.gov Identifier: NCT00025935|
Recruitment Status : Recruiting
First Posted : November 1, 2001
Last Update Posted : March 29, 2018
|First Submitted Date||October 31, 2001|
|First Posted Date||November 1, 2001|
|Last Update Posted Date||March 29, 2018|
|Study Start Date||October 29, 2001|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures||Not Provided|
|Original Primary Outcome Measures||Not Provided|
|Change History||Complete list of historical versions of study NCT00025935 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures||Not Provided|
|Original Secondary Outcome Measures||Not Provided|
|Current Other Outcome Measures||Not Provided|
|Original Other Outcome Measures||Not Provided|
|Brief Title||Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder|
|Official Title||Characterization and Pathophysiology of Severe Mood and Behavioral Dysregulation in Children and Youth|
|Brief Summary||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 subthreshold DMDD.
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 01-M-0254.
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 protocol 00-M-0198).
|Study Design||Not Provided|
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Not Provided|
|Study Population||Not Provided|
|Study Groups/Cohorts||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Study Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
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:
126.96.36.199 The child s current CGAS score less than or equal to 60.
188.8.131.52 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
184.108.40.206 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.
220.127.116.11.1 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.)
18.104.22.168.2 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.
22.214.171.124.3. 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.
126.96.36.199.4. Insomnia (inability to get to sleep or difficulty staying asleep) or hypersomnia (sleeping too much) nearly every day
188.8.131.52.5. 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
184.108.40.206.6. 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).
220.127.116.11.7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day (e.g., ruminating over minor past failings).
18.104.22.168.8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (e.g. appears easily distracted, complains of memory difficulties).
22.214.171.124.9. 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
126.96.36.199.10 Symptoms cause clinically significant distress or impairment in social, occupational/academic, or other important areas of functioning.
188.8.131.52.11. 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:
184.108.40.206. The child s current CGAS score <60.
220.127.116.11. The child s psychiatrist/treater agrees that the child s response to his/her 18.104.22.168. current treatment makes it clinically appropriate to change the child s current treatment.
22.214.171.124. 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).
c. Exclusion criteria
1.3 Exclusion criteria for those with DMDD:
1.3.1 The individual exhibits any of these cardinal bipolar symptoms:
126.96.36.199 Elevated or expansive mood
188.8.131.52 Grandiosity or inflated self-esteem
184.108.40.206 Decreased need for sleep
220.127.116.11 Increase in goal-directed activity (this can result in the excessive involvement in pleasurable activities that have a high potential for painful consequences)
18.104.22.168. 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
|Ages||7 Years to 25 Years (Child, Adult)|
|Accepts Healthy Volunteers||Yes|
|Listed Location Countries||United States|
|Removed Location Countries|
|Other Study ID Numbers||020021
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )|
|Study Sponsor||National Institute of Mental Health (NIMH)|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||January 11, 2018|