DEBRISOQUIN AS AN AGENT FOR STUDY OF PSYCHOTIC STATES

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Schizophrenic/psychotic patients and controls will be studied in a cross sectional and longitudinal design to evaluate whether noradrenergic activity is increased in these patients. The metabolites of norepinephrine specifically to be studied are VMA, normetanephrine and MHPG. We will also look at levels of norepinephrine and metabolites in CSF. The functioning of the dopamine system will be assessed by measuring HVA and DOPAC in urine, plasma and CSF. The general hypotheses are that noradrenergic systems are hyperactive in schizophrenic subjects and that schizophrenia/psychosis is characterized by an increased level of norepinephrine and/or its metabolites in all body fluids and that there is also an increased level of plasma HVA without an increase in total DA synthesis (urine HVA). Neurotransmitter metabolites will be studied with patients on and off debrisoquin (DBQ) and during treatment with either neuroleptics (haloperidol) or the alpha2 agonist clonidine. We will use DBQ as it has monoamine oxidase inhibiting activity but does not penetrate brain. By reducing the peripheral contribution of metabolites of DA and NE present in urine and plasma its use results in the metabolites of dopamine and perhaps norepinephrine in plasma and urine better reflecting the activity and concentrations of amine metabolites in the central nervous system than without the drug. This use of DBQ has proven quite valuable in our prior studies. The long-term goal of this work is to understand the role of the NE system in schizophrenia/psychosis and to apply this knowledge to the design of improved treatments. This proposed work with DBQ is a continuation and extension of our program of research that may yield clinically useful information regarding present and future diagnostic and treatment efforts with schizophrenic patients.