Pediatric Emotion And Resilience Lab (PEARL)

Antidepressants are commonly prescribed medications used by American youth today to treat a variety of childhood onset psychiatric disorders. However, serious psychiatric adverse events may also emerge from antidepressant use including irritability, agitation, elevated mood, and other adverse events associated with increased dysfunctional emotional arousal. For some youth, these adverse events lead to the development of lifelong psychopathologies such as bipolar disorder.  Importantly, the mechanisms through which antidepressants increase risk for developing these adverse events are largely unknown. Moreover, there is a pressing clinical need to better identify which youth taking antidepressants will develop adverse outcomes.

Youth who are highly likely to develop adverse responses to antidepressants are those who are already vulnerable to developing dysfunctional emotional arousal. Compelling data from family studies have shown that youth with a family history of bipolar disorder have high rates of major mood and other disorders of emotional arousal, and demonstrate early disruptions of neurobiological systems critical for the regulation of emotional arousal, most notably in the amygdala and ventrolateral prefrontal cortex (VLPFC) neural circuit. Antidepressants are commonly used to treat dysfunctional emotional arousal in high-risk youth; however, they may also increase and accelerate the onset of mood disorders in some of these youth.

Research has implicated involvement of the Arousal construct of the NIMH Research Domain Criteria (RDoC) Arousal and Regulatory Systems, which describes fundamental aspects of emotional dysfunction when youth experience an adverse antidepressant-related psychiatric event. This proposal aims to use an RDoC framework in a randomized trial to investigate the etiological mechanisms and risk factors associated with antidepressant-related dysfunctional emotional arousal in high-risk youth. To accomplish these aims, 150 (75/site) high-risk youth, i.e. having at least one first-degree relative with bipolar I disorder, who have moderate to severe depression or anxiety symptoms, will be randomized to receive double-blind treatment either with psychotherapy plus escitalopram or psychotherapy plus placebo.  Prior to randomization, we will collect baseline magnetic resonance imaging (MRI), behavioral, and physiological measures of arousal. After randomization, youth will undergo a second MRI scan at 4 weeks, and then will be clinically assessed for up to 16 weeks to evaluate for changes in arousal. We aim to determine whether antidepressant-related changes in arousal are mediated by changes in amygdala-VLPFC circuitry, and to identify neurobiological risk factors for developing dysfunctional arousal. This knowledge will be vitally important to mental health professionals who have limited empirical evidence on which to base their treatment of youth most vulnerable for emotion dysregulation.  It also has potential to inform the pathophysiology of disorders associated with dysfunctional emotional arousal and the development of novel targets for treating this complex problem.

Details

Randomized controlled trial in youth ages 12-17 who have a first degree relative with bipolar disorder and seek treatment for depression or anxiety (contact: Lexi Staver at thepearlab@stanford.edu).

Depression and obesity are reaching epidemic proportions in American youth today, and when they co-occur, they may have compounding deleterious effects, including the development of impaired insulin sensitivity toward insulin resistance (a precursor to diabetes in which cells fail to respond to the normal actions of the hormone insulin). Traditionally, depression and impaired insulin sensitivity have been compartmentalized as separate emotional and physical health syndromes.  However, recent evidence suggests interactions and common neurobehavioral pathways between these syndromes that can lead to worsening depressive symptoms. To date, no study has investigated the underlying mechanisms or risk factors for developing worsening of depressive symptoms in youth with depression and impaired insulin sensitivity.

There is a pressing clinical need to better identify which youth with depression and impaired insulin sensitivity are most likely to develop worsening depressive symptoms, as current pharmacological and dietary/lifestyle strategies to overcome the burgeoning threat of lifelong depression and obesity are of limited efficacy, have adverse side effects, and in most cases are not curative. Compelling recent data have shown that depressed youth, independent of changes in weight, have early disruptions of neurobiological systems critical for the response and regulation of reward, most notably in the nucleus accumbens, anterior cingulate cortex, insula, and amygdala neural reward circuit. This Research has implicated involvement of the Approach Motivation construct of the NIMH Research Domain Criteria (RDoC) Positive Valence Systems, which describes fundamental aspects of reward dysfunction when youth with depression engage in unhealthy lifestyle behaviors (e.g. overeating) that place them at high risk for progressively worsening depressive symptoms.

This proposal aims to use an RDoC framework in the first prospective study to investigate the mechanisms and risk factors for worsening depressive symptoms that are associated with dysfunctional Approach Motivation in youth with depression and impaired insulin sensitivity. To accomplish these aims, 120 overweight girls and boys (ages 9-15 years) seeking treatment for moderate to severe depressive symptoms, will be assessed at baseline, 6 months, and 24 months with cognitive and behavioral markers of Approach Motivation, serum markers of insulin sensitivity, and clinical markers of depression. Youth will be scanned with multimodal MRI at baseline and at 6 months. We aim to determine whether worsening depressive symptoms in youth with depression and impaired insulin sensitivity is mediated by changes in neural reward circuitry, and to identify clinical, demographic, and familial risk factors for developing worsening depression in these youth. This knowledge will be vitally important to mental health and primary care professionals who have limited empirical evidence on which to base their practice.  It also has potential to inform the pathophysiology of other disorders associated with dysfunctional approach motivation and to catalyze the development of novel treatment targets.

Details

9-17 year old youth struggling with healthy eating habits and sad moods who are able to receive clinical and laboratory assessments, a brain MRI, and be observed at three time points over a 2 year period (contact Elizabeth Weisman eweisman@stanford.edu).

Sex differences in psychiatric disorders are common and occur early in development. The etiologic pathways that lead to sex differences in psychiatric disorders stem from complex interactions among clinical, cognitive, genetic, and neural factors that vary as a function of developmental stage. Past studies have been insufficiently powered in the size of their samples and the number of measures assessed to model these risk factors systematically within or between girls and boys, within or across multiple psychiatric disorders, or across developmental stages. Because of these limitations, we do not have a comprehensive understanding of the neurobiology of sex differences in childhood-onset psychiatric disorders, which has hindered timely diagnosis and treatment.

Given that current pharmacological and psychotherapeutic strategies to address the burgeoning threat of lifelong psychiatric disorders are of limited efficacy, have adverse side-effects, and in most cases are not curative, there is a pressing clinical need to identify early risk factors for the development of psychiatric disorders. Compelling recent data in children have implicated anomalies throughout development in neural circuitry that is critical for cognitive processing, most notably in prefrontal, limbic, and striatal neural circuits, that may be transdiagnostic and conditioned on sex. Moreover, advances in genetic pathways associated with key cognitive regulatory functions have been translated into increased characterization of the neurocircuitry that subserves psychiatric disorders.

This proposal aims to leverage the large multimodal dataset of the Philadelphia Neurodevelopmental Cohort (PNC) to address the pressing questions of which core risk factors predict specific psychiatric disorders conditioned on sex (i.e., within girls and within boys), which factors explain sexual dimorphism in childhood-onset psychiatric disorders, and when sex differences in psychiatric disorders emerge. To accomplish these aims, we will use state-of-the-art high-dimensional modeling methods to develop a parsimonious risk model that integrates clinical, cognitive, genetic, and neural factors in the PNC database to predict sex differences in childhood-onset psychiatric disorders. We will model clinical, cognitive, and genetic data from a large cohort of almost 10,000 boys and girls who are between the ages of 8-21 years, and neuroimaging data in a subset of ~1,500 youth. The PNC database includes measures of normal and abnormal functioning across a wide age range to enable comparisons of outcomes in psychiatric disorders across age and in developmental subgroups. Understanding how clinical, cognitive, genetic, and neural factors interact in the development of sex differences in psychiatric disorders will provide more precise neurobiologically-informed treatment targets.

The conceptual overview for this study is based on 4 key challenges:

(a) family history is the strongest risk factor for developing mood disorders in childhood, including major depressive (MDD) or bipolar (BD) disorder, but the mechanisms underlying this risk are unknown

(b) mood disorders in childhood are complicated by diagnostic confusion, which can lead to improper or delayed treatments

(c) multivariate analyses have been underutilized for differentiating etiological risks of BD from MDD or for predicting outcome, and

(d) not all youth of parents with BD or MDD develop symptoms suggesting that some are resilient to developing mood disorders. 

However, the neurobiological basis of resilience from mood disorders is unknown. This project aims to provide innovative solutions to these challenges by charting the evolution of mood symptoms in youth at risk starting from health in order to understand ideal times and methods for intervention. To accomplish these aims, we are conducting an integrative study of 150 families comprised of fathers, mothers, and gender balanced healthy youth, ages 8-15 years: 50 healthy offspring will be of parents with BD, 50 healthy offspring will be of parents with MDD, and 50 healthy controls will have no family history of psychopathology. After screening for eligibility, youth will complete interviews and questionnaires confirming absence of any symptoms of psychopathology and neurocognitive assessments at baseline; they will also do home collection of diurnal cortisol over 2 days, and then return to the lab for an MRI scan. Youth will return for an 18-month clinical follow-up.

Details

8-15 year old healthy offspring of: 1) parents with Bipolar I or Bipolar II disorder, 2) parents with Major Depressive Disorder, or 3) parents without any psychiatric conditions.  All youth will receive a clinical assessment, neuroimaging, cortisol, and genetics (contact: PEARL at thepearlab@stanford.edu).