This application requests five years of support for the Clinical Research Center (MHCRC) for the Study of Suicidal Behavior. There are approximately 30,000 suicides per year in the United States and ten times that number of suicide attempts. To respond to this major health problem, we must improve on the current predictors of suicide risk which have high sensitivity but inadequate specificity. The MHCRC employs a multi-disciplinary approach to develop a predictive model for suicidal behavior because potential risk factors are demographic, social, developmental, psychiatric, genetic and biologic. Cross-sectional identification of risk factors, and subsequent prospective testing, require the MHCRC to recruit patient populations where the frequency and severity of suicidal behavior are sufficient to test putative risk factors. Identifying such predictors will facilitate inception of treatment studies, which are almost non-existent at present. During the current 5 years of funding, MHCRC investigators have found evidence for a stress-diathesis model where lifetime impulsivity is a major correlate of past and future suicide attempts in a sample of over 340 patients with major depression, schizophrenia or borderline personality disorder. In parallel, the MHCRC has studied clinical and biological correlates of suicide in suicide victims. Identified altered serotonin function in ventral prefrontal cortex of suicide victims, and in serious suicide attempters in vivo, using PET, may underly increased impulsivity and suicide risk. There has been growth in related R01- supported research, development and testing of research instrumentation, training of investigators, and research publications. Goals for the next 5 years include: 1) add newly developed neuropsychological measures of impulsivity and serotonin related gene markers to the integrated series of multidisciplinary core measures to evaluate hypothesized risk factors for suicidal behavior; 2) apply uniform measures to different adult patient populations, including affective disorders, personality disorders and schizophrenia and across the life cycle (prepubertal, adolescents and the elderly) to establish which risk factors are disease specific and age- dependent: 3) add systematic biological testing to our schizophrenia study; 4) conduct a prospective follow-up study of the major depression, borderline personality disorder and schizophrenia patients, and depressed adolescents, to validate promising predictors suggested by cross-section findings; 5) initiate a study of familial transmission of suicidality, aggression/impulsivity and psychopathology from our adult probands with major depression to their offspring; 6) create a Brain Imaging Core to support existing studies and develop PET ligands for 5-HT/1A, 5-HT/2A and the serotonin transporter binding sites to conduct receptor studies in patients in vivo, analogous to our postmortem studies; 7) conduct pilot treatment studies in high risk adolescents and adults; and 8) expand biochemical and quantitative morphometric studies of brainstem nuclei and ventral prefrontal cortex in postmortem brain to determine loci and molecular basis of primary and secondary pathology in suicide victims.
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