This project studies the psychobiology of schizophrenia and attempts to develop improved strategies for its treatment. An important goal is the understanding of the mechanism of action of neuroleptic drugs. We have observed that neuroleptic-induced time-dependent decrease in levels of plasma homovanillic acid (HVA), a major dopamine metabolite, correlates with antipsychotic drug response, suggesting that slow to develop changes in dopamine turnover may underlie the antipsychotic action of neuroleptics. This clinically relevant dopamine marker is further studied using a strategy in which peripherally derived HVA is reduced by the administration of debrisoquin, a MAO inhibitor which does not enter the CNS. In a double-blind, treatment trial, we have observed significant reduction in psychosis in some patients when alprazolam is added to neuroleptic treatment; the use of benzodiazepines to augment neuroleptic response is under investigation in outpatient trails. These data contrast with the negative results found when the calcium channel blocker, verapamil, was administered to neuroleptic-free schizophrenic patients. In a recently completed study using magnetic resonance imaging (MRI) performed in collaboration with the Clinical Brain Disorders Branch, NIMH, compelling evidence was gained which supports enlargement of lateral and 3rd ventricular volumes in schizophrenic patients. A follow-up study of previous inpatients from our program has recently been completed and holds promise for delineating biological correlates of outcome in schizophrenia. A controlled study of expressed emotion in families of schizophrenic patients is in progress. The proposed course involves the further development of an outpatient research program which includes controlled pharmacologic treatment studies and the evaluation of family schizophrenia pedigrees for collaboration with the Clinical Neuroscience Molecular Biology Laboratory. Collaboration with the NIMH positron emission tomography (PET) program focusing on the mechanism of action of typical and atypical neuroleptics using glucose utilization studies and the development of new PET ligands will be pursued.