This application is for a five-year project that uses a high-risk design to study the familial transmission of early-onset suicidal behavior. The probands consist of 200 adolescents depressed suicide attempters and non-attempters who will be well characterized in studies at NYS Psychiatric Institute. We will recruit some of this group from a cohort of 100 individuals previously studied for serotonergic function by us under R01 MH47113 at which time they were adolescents with major depression and half were suicide attempters. For each proband, the biological parents and full siblings (age 10 and older) of adolescent/young adult attempters and non-attempters will also be studied. Probands and their biological first-degree relatives will be characterized as to Axis I and II disorder, suicide attempt history, tendency to impulsive aggression and family environment. Parents and siblings will be genotyped with polymorphic markers for tryptophan hydroxylase and other candidate genes per Projects 2 and 4. After initial assessment, the probands and their siblings 24 years old or less will be followed at one and years after intake to observe the development of aggression, psychopathology, and suicidal behavior. The project will test the following hypotheses: (1) first- degree relatives of adolescent attempters will have higher rates of suicide attempts than the offspring of non-attempters; (2) impulsive aggression will be greater in relative of attempters, and will predict development of suicide attempts in siblings, especially in those siblings who also develop Axis I disorders; (3) the familial transmission of suicide attempts will not be explained by the familial transmission of mood disorders alone; (4) familial transmission of suicide attempts will persist after controlling for the expected greater exposure to familial adversity in the offspring of attempters; and (5) polymorphism of the of the tryptophan hydroxylase gene and other genes related to central serotonergic function will be associated with impulsive aggression and suicide attempts among proband and their first-degree relatives. We will also acquire pilot data on the relationship of baseline serotonergic and clinical indices to long-term outcome in the 100 previously studied cases.
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