BLOOD FLOW CHANGES AND ANTIPSYCHOTIC DRUG ACTION

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DESCRIPTION (adapted from applicant's abstract): Antipsychotic drugs reduce psychosis, induce motor effects, and have miscellaneous other actions. The brain substrates of these effects, beyond actions on receptor populations are poorly understood. The investigator proposes to determine the dynamic time course of the effects of antipsychotics on regional cerebral blood flow (rCBF) using PET and 15OH2 in drug-free schizophrenia patients as a direct pharmacodynamic assessment of drug action in the human brain. rCBF measurements would span the pharmacokinetic time course. The investigator proposes to characterize the dynamic time course of rCBF alterations following the acute and six days of administration of two different antipsychotic drugs, the traditional antipsychotic haloperidol and the newer antipsychotic olanzapine. The ability of the changes in rCBF following acute and subacute antipsychotic administration to predict subsequent treatment response would also be evaluated. Based on their preliminary findings, the investigators hypothesize that acute and subacute drug-induced rCBF changes in selected regions will predict treatment response for positive symptoms (anterior cingulate and medial frontal cortex), for negative symptoms (middle frontal cortex and inferior parietal cortex), and motor side effects (basal ganglia). The proposed subacute drug administration regimen would approximate a pharmacokinetic steady state for both antipsychotics. An additional aim of the proposal is to compare the rCBF changes induced by haloperidol versus olanzapine during the scanning sessions obtained with acute and subacute (steady state) antipsychotic administration. The investigator proposes that the pattern of activation in the basal ganglia will best discriminate the two antipsychotic agents. These studies will hopefully provide rCBF correlates of antipsychotic activity. This information will allow the development of hypotheses related to drug mechanism of action, as well as potential surrogate markers of drug action.