This revised two-site R-10 application, based at Western Psychiatric Institute and Clinic (WPIC, the site of this proposal) and at New York State Psychiatric Institute (NYPSI), requests five years of support for a high risk design to study the familial transmission of early-on site suicidal behavior. The probands are adult depressed suicide attempters and depressed non-attempters well characterized in previous interrelated studies in Pittsburgh and New York. In Pittsburgh, approximately 161 offspring of 36 attempters and 25 non-attempters, and in New York, 338 offspring of 90 attempters and 68 non-attempters will be studied. Because clinical and demographic characteristics of the probands in Pittsburgh and New York are similar, it is likely that the data can be pooled across sites. Probands, biological offspring over the age of 10, and the other biological parent will be characterized as to Axis I and II disorder, suicide attempt history, aggression, impulsivity, and family environment. Probands will be genotyped with polymorphic markers for tryptophan hydroxylase and other candidate genes related to central serotonergic metabolism. After the initial assessment, offspring will be followed up at one and two years after intake to observe the development of aggression, impulsivity, psychopathology, and suicidal behavior. It is predicted that the confluence of aggression and impulsivity, """"""""impulsive aggression,"""""""" the tendency to impulsively respond to provocation of frustration with anger or overt aggression, is central to the familial transmission of suicidal behavior. The project will test the following hypotheses: (1) offspring of attempters will have higher rates of suicide attempts than the offspring of non-attempters; (2) aggression, impulsivity, and the dimension of impulsive aggression will be greater in offspring of attempters, and will predict development of suicide attempts, especially in those who also develop mood disorders; (3) the familial transmission of suicide attempts will not be explained by the familial transmission of mood disorder alone; (4) there will be evidence of familial transmission of suicide attempt even after controlling for the expected greater exposure to family adversity in the offspring of attempters; and (5) polymorphisms of the tryptophan hydroxylase gene and other genes related to central serotonergic function will be associated with impulsive aggression and suicide attempts among probands.
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