Project Summary

Cynthia R. Pfeffer, M.D. (Distinguished Investigator 2005) of New York Presbyterian Hospital/Cornell University, aims to identify whether a length polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and severe stress of parental death interact to affect vulnerability to psychiatric morbidity and hypothalamic-pituitary-adrenal (HPA) axis function, measured as salivary cortisol levels, among a unique sample of children, age 6-15 years, who suffered sudden, unexpected parental death resulting from the terrorist attacks on September 11,2001 (N=45) or suicide (N=45) and who are compared to an age, gender, race/ethnicity, social status matched community sample of nonbereaved children (n=90). She believes NARSAD funding is essential for personnel to obtain genetic samples, conduct genetic analysis, and statistically evaluate data. It is hypothesized that the interaction between severe stress of bereavement (versus no bereavement) and a length polymorphism (presence of the short allele versus presence of the homozygous long allele) in the 5-HTTLPR will be associated with more severe anxiety and depressive symptoms, higher salivary baseline cortisol levels and lack of negative feedback to dexamethasone challenge in children. The results will have important implications for developing indicated prevention strategies and new treatments for children's mood/anxiety symptoms and long-term effects on reducing risk factors for mortality, such as youth suicide. Sudden, unexpected parental death is among the most severe stresses that increase vulnerability for anxiety/depression in children and adults. Animal and human studies suggest early stresses produce dysregulation of the HPA axis, evident as increased baseline cortisol levels and increased reactivity to stressors that is modulated by environmental stress and genetic factors. Her study is based on previous findings that two common alleles, the short (s) and long (1) alleles, of the 5-HTTLPR have been differentially associated with anxiety/depression in maltreated children, adults enduring stress, human neuroimaging, and animal studies. Given sample size and structure limitations, her main strategy is to test hypotheses for a specific polymorphism for which there exist prior data, evidence supporting a functional role in anxiety/depression, and a relatively high allele frequency (heterozygote state of s allele was 51% of an epidemiological child sample with no genotype differences regarding gender). Ultimately, this study may aid in recognizing which children are at greatest risk, thus indicating the need for intervention. Treatment could cover a wide range from medications to supportive or behavioral therapy.

Program Area: MULTIPLE FOCUS AREAS\Anxiety/Unipolar Depression

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