Bipolar disorder (BD) commonly begins during childhood or adolescence, and those with early onset typically have greater severity of illness and suicidality. Early identification of this disorder is paramount for implementing psychosocial and pharmacologic interventions that might prevent the full disorder. Due to the nonspecificity of early symptoms of BD, such as hyperactivity or depression, biologic markers that signify highest-risk for BD would aid in early identification as well as contribute to the understanding of BD pathogenesis. Children with BD have abnormalities in amygdalar volume and prefrontal-limbic circuits, but it is unclear if these abnormalities are present before the development of BD. Furthermore, polymorphisms of the serotonin transporter (5-HTT) and brain-derived neurotrophic growth factor (BDNF) genes may adversely affect these circuits and be risk factors for BD. In order to study the trait-status of these neurobiological abnormalities and their relationship to genetic polymorphisms, it is necessary to study a high-risk group of children before the development of BD, such as children of parents with BD (""""""""bipolar offspring""""""""). We propose to study 100 offspring from families having one or more parents with BD, comprised of 50 sibling pairs discordant for putative prodromal BD (""""""""Prodromal Siblings""""""""), and 30 singleton healthy controls. Prodromal Siblings will be children with depression and/or ADHD + moderate mood symptoms. All subjects will be carefully assessed by semi-structured interviews, clinician rated scales, and questionnaires relevant to family function and life stressors. Blood will be obtained from parents and siblings for genotyping polymorphism status of the 5-HTT and BNDF genes. Subjects will be scanned on a high-field (3T) magnet, obtaining amygdalar morphometric and functional MRI data in response to two separate affective probes designed to elicit activation of prefrontal-amygdalar circuits. Finally, subjects will be reassessed by interview 3 years after initial evaluation to assess for development of BD. By studying genetic and brain characteristics of high-risk discordant siblings before the development of full BD, we will be able to determine non-environmental risk factors for BD that are not caused by later events, such as substance abuse or recurrent mood episodes. We will also be able to determine possible gene-effects on brain structure and function in this cohort and create a repository for genetic and neuroimaging data that can be used for future longitudinal studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH077047-04
Application #
7760112
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Avenevoli, Shelli A
Project Start
2007-02-08
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$581,406
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Park, Min-Hyeon; Chang, Kiki D; Hallmayer, Joachim et al. (2015) Preliminary study of anxiety symptoms, family dysfunction, and the brain-derived neurotrophic factor (BDNF) Val66Met genotype in offspring of parents with bipolar disorder. J Psychiatr Res 61:81-8
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Singh, Manpreet K; Spielman, Daniel; Libby, Allison et al. (2011) Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder. Bipolar Disord 13:189-97

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