DOPAMINE FUNCTIONAL SUBTYPES OF SCHIZOPHRENIA

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Our objective is to define those psychotic symptoms associated with central dopamine (DA) receptor supersensitivity. One hundred fourteen inpatients meeting RDC for schizophrenia, or a schizoaffective disorder, mainly schizophrenia will be studied. Experiment 1 will identify schizophrenic patients (N=66) demonstrating a central DA receptor supersensitivity employing the centrally mediated growth hormone response following administration of the DA agonist, apomorphine. Patients will be divided into three GH groups; subsensitive, average or supersensitive response in reference to a sex and age matched normal control group. The prevalence of individual psychotic symptoms (SADS, SANS, NHSI) in the three patient groups will be determined. Pilot data suggest that thought disorder is associated with central DA receptor supersensitivity. Additional pilot data concomitantly measuring central DA receptor activity (GH response) and central DA release (CSF HVA) in the same schizophrenic patient indicates an inverse relationship between DA release and DA receptor activity. These clinical data support a release mediated down regulation of DA receptors previously reported in preclinical studies, but to our knowledge never reported in man. The present proposal will extend these data. It is hypothesized that the inverse relationship between these two biologic variables will be reflected in the clinical variables (SADS, SANS, NHSI). If a particular psychotic symptom cluster is associated with DA receptor supersensitivity, then this symptom cluster should respond most rapidly and completely to medication whose mechanism of action is to block DA receptors (neuroleptics). In Experiment 2, schizophrenic patients (N=48) will receive a double-blind trial of: 1) cis-thiothixene (Navane), 2) trans-thiothixene - a clinically inactive stereoisomer which shows a similar biochemical profile as the active stereoisomer but does not bind to DA receptors and 3) placebo. The time course of symptom remission (SADS-C, SANS and NHSI) will be determined. The specific aim of this study is to identify that cluster of psychotic symptoms that responds most rapidly and completely to cis-thiothixene. Experiments 1 and 2 should identify the same cluster of DA associated psychotic symptoms even though the methods differ greatly.