Robert R. Althoff - US grants

DESCRIPTION (provided by applicant): This application describes a 5 year mentored training program to develop a research career in Child and Adolescent Psychiatry focused on improving phenotypic approaches to defining pediatric bipolar disorder. The principal investigator has completed M.D., Ph.D. and residency training in child and adolescent psychiatry. He will now gain expertise in taxonomic approaches, multi-informant assessment, family and twin designs, and latent variable models. As primary sponsor, Dr. James Hudziak will mentor the Pi's scientific development. Dr. Hudziak is an expert in taxonomic approaches using family study and twin study behavioral genetic designs in concert with latent variable measures to developmental psychopathology. The training program will enlist the co-sponsorship of Dr. Dorret Boomsma, Professor at the Vrije University of Amsterdam and internationally known expert on twin studies and Dr. Thomas Achenbach, Professor at the University, of Vermont. In addition, three internationally-renowned scientists, Drs. Frank Verhulst, Ellen Leibenluft and Michael Neale will provide scientific consultation. Research will focus on diagnostic approaches to children often diagnosed as having pediatric bipolar disorder and related severe dysregulation in affect, behavior and cognition. The training and research will emphasize the use of categorical DSM-based approaches and compare them to quantitative CBCL- based approaches. The proposed studies will combine and contrast DSM and quantitative measures in order to advance the understanding of highly troubled youth. New to this application are proposed research projects allowing for testing of the relations between DSM and quantitative measures, the familiality of DSM and quantitative definitions, the overlap between the approaches, and the construct validity of CBCL-based phenotyping in longitudinal, genetically informative designs. The long term goal of this research is to develop more refined phenotypic approaches for children with severe problems in dysregulation who may or may not meet narrowly defined DSM criteria for pediatric bipolar disorder. If realized, these approaches can then be used in genetic, neuroimaging, and treatment studies aimed at reducing the burden of suffering that children and families with these disorders endure. PUBLIC HEALTH RELEVANCE: By characterizing children with profound problems with attention, mood swings, and aggression I hope to identify modifiable genetic and environmental factors to reduce depression, personality disorders and substance use in adolescence and adulthood. I hope to add perspective on children who are called "bipolar" but who likely have a disorder different from adult bipolar disorder and may need different treatments.

PROJECT SUMMARY (See instructions): This proposal describes a 3 year program to investigate the relations between childhood dysregulation and adult substance abuse, psychopathology, and metabolic syndrome. In this COBRE Project the junior principal investigator, an M.D., Ph.D. with training in child and adolescent psychiatry will work with primary mentor James Hudziak, MD, senior mentors Hugh Garavan, MD and Phil Ades, MD to investigate the metabolic, epigenetic, executive function/decision-making, and psychophysiological mechanisms of a child behavioral syndrome termed dysregulation. The study proposes that dysregulation is a common prodrome for a variety of negative adult outcomes (substance abuse, persistent psychopathology, and the cluster of non-psychiatric disorders referred to as Metabolic Syndrome (MS) - diabetes, dyslipedemia, hypertension, and obesity. We propose a model consisting of environmental impact (e.g., low socioeconomic status, chronic adversity) on a genetic predisposition (e.g., family history of self-regulatory problems) affecting the systems involved in self-regulation. The dysregulatory effects in turn affect gluocorticoid and autonomic nervous system (e.g., heart rate variability) responses. We will test this model through the use of a family study approach. In order to do this work, we propose adding measurement of metabolic, epigenetic, executive function/decision-making, and psychophysiological data to parents of children in an ongoing family study of children with dysregulation (NIMH K08MH082116). Through the course of the 3 year study, we will determine the rates of substance use disorders, psychopathology, and metabolic syndrome in the families of children with dysregulation. We will determine the rates of delay discounting (a measure of impulsivity) and the levels of heart rate variability (a measure of autonomic stability) in these children and their families. Using two complementary methods, we will determine the epigenetic profiles in dysregulated children and their family members in two gene promoters known to be associated withs stress reactivity (NR3C1 and FKBP5).