The proposed study is designed to identify biobehavioral """"""""markers"""""""" or """"""""indicators"""""""" of a genetic vulnerability to schizophrenia that, in weighted combination, will serve to predict future illness in the unaffected relatives of schizophrenic individuals. The project is divided into two research components. Phase I, for which funds are being requested, will serve to recruit the full sample, collect all of the biobehavioral data and complete baseline clinical assessments. Phase II is the clinical follow-up component, and will serve to establish clinical outcome and validate the data collected in Phase I. In Phase I, 100 adolescents with AXIS I schizophrenia spectrum disorders, 125 of their at-risk siblings, 100 normal controls matched to the patient probands and 125 siblings of the normal control probands will participate. Candidate markers will include measures of attention, smooth pursuit eye-movements, frontal lobe (executive) functions and temporal lobe (verbal memory) processing- all of which have been implicated in the pathophysiology of schizophrenia. The innovative aspect of this design is that, by selecting young patients as probands, a new at-risk population can be studied. The sibling risk rate for schizophrenia spectrum disorders is similar to that of the offspring of a schizophrenic parent. Nevertheless, at-risk siblings are virtually an untapped research population, since siblings of adult schizophrenic patients (more typically studied) are too old to constitute a viable high-risk sample. Moreover, the probands are themselves a group of considerable interest. Young patients in the early stages of psychosis, even though considered likely to have a severe form of schizophrenia, have rarely ben studied. In Phase I, a weighted composite of biobehavioral deficits will be derived (the Diathesis Index) that will differentiate the siblings of schizophrenic probands from the siblings of normal controls. It is assumed that this index reflects a biological vulnerability for schizophrenia. In Phase II, based on clinical outcome, a comparable composite of biobehavioral indicators (the Predictor Index) will be calculated to differentiate between the high-risk siblings who do and do not become ill. The Predictor Index will enable individuals with a true vulnerability for expressing schizophrenia to be identified, many years prior to onset of the illness. Comparisons between the Phase I Diathesis Index and the Phase II Predictor Index will indicate the extent to which deficits identifying individuals as being vulnerable relative to normal controls overlap with the deficits that lead to the actual expression os schizophrenia. In the long run, the Predictor Index is expected to provide a means of carrying out cost- effective population screening a currently unavailablE first step toward establishing effective intervention programs.
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