Last updated on May 2020

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

Brief description of study

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.

Detailed Study Description


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.

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).

Clinical Study Identifier: NCT00025935

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