The clinical neuroscience of schizophrenia is an integrated research program addressing pharmacotherapeutic and pathophysiological mechanisms in schizophrenia. The delineation of the therapeutic profiles of the prototype atypical antipsychotic, clozapine, in comparison to traditional and other new atypical antipsychotics (e.g., risperidone) has been a central clinical focus. Comparative D2 receptor occupancies and regional metabolic effects of these drugs have been studied using in vivo brain imaging techniques. Increasing emphasis is now placed on examining allelic variation in candidate genes for schizophrenia and psychopharmacological drug response. Recent findings have suggested phenotype differences in schizophrenia in association with allelic variation in the 5HT transporter gene and in the Apolipoprotein (APOE) E gene (see Z01 MH 02735-02 ETB). Ketamine, a noncompetitive antagonist of the NMDA-type glutamate receptor is currently being used to probe glutameteric function. We have observed focal ketamine-induced psychotic symptoms which are correlated with metabolic activation of the prefrontal cortex in normals but not in patients with schizophrenia. A novel research technique for estimating synaptic dopamine concentrations through amphetamine-induced displacement of 11-C-raclopride imaged by PET. We have found significantly increased amphetamine-induced raclopride displacement in drug free schizophrenic patients in comparison with controls, findings which provide the most direct support available for the dopamine hypothesis of psychosis. We are currently investigating the effects of ketamine on dopamine displacement in normal controls and in patients with schizophrenia.