This ADAMHA RSDA-Level II will enable the candidate to continue his investigation of the psychobiology of schizophrenia. The core project involves the ascertainment and prospective study of first episode treatment naive schizophrenics utilizing serial assessments of symptomatology, treatment response and side effects, neuromorphologic measures [magnetic resonance imaging (MR)] and neuroendocrine measures (growth hormone response to dopamine agonists) as well as a provocative pharmacologic challenge test (behavioral response to methylphenidate) and tests of eye movement dysfunction. In the past five years (RSDA-Level I) the candidate has successfully initiated this investigation and obtained NIMH grant support for its implementation. Preliminary results have demonstrated the prevalence of specific pathobiologic markers in the first episode treatment naive schizophrenics including abnormal brain morphology, psychotogenic response to methylphenidate and impaired smooth pursuit eye movements, and the relationship of these markers to each other and clinical outcome. In addition, the candidate will continue to pursue related studies of mechanisms of pharmacologic response involving the use of dopamine agonists as pharmacologic probes and clozapine and the atypical antipsychotic drug. The specific aim of this work is to utilize pathobiologic markers and pharmacologic response as indices of heterogeneity which will lead to the delineation of pathophysiologic mechanisms of schizophrenia and valid subtypes of the illness. The RSDA will also enable the candidate to continue his professional development by extending his expertise in brain imaging through the acquisition of additional skills in MR for morphometric studies and to begin to learn the techniques of functional brain imaging with MR spectroscopy and single photon emission tomography (SPECT). The candidate intends to combine these strategies with his expertise in psychopharmacology by utilizing pharmacodynamically selective compounds in the context of functional neuroimaging activation paradigms. To achieve this the candidate will continue his collaboration with members of the Department of Radiology, Dr. Bernhard Bogerts (University of Dusseldorf) and establish consultative relationships with specific investigators in the field working in his area of interest.