This project will study the pharmacokinetic characteristics of haloperidol in schizophrenic patients after acute administration and the relatioships between drug dose, drug levels in plasma and CSF, and clinical response during fixed-dose subchronic treatment periods. Approximately 40 patients will be studied over three years; they will manifest a variety of symptoms of schizophrenia and comprise a range of subcategories of the syndrome (e.g. paranoid, disorganized, deficit state, undifferentiated). Several hypothesis have already been raised to account for the poor drug-level/clinical-response correlation obtained by others: neuroleptic-resistant psychosis, reflecting pharmacologic heterogeneity among schizophrenics; response correlations studied in conditions of neuroleptic drug excess; and individual differences in drug compartmentatlization. Participants in this study will be inpatients hospitalized for reasons of their psychotic condition who have a diagnosis of schizophrenia or schizoaffective psychosis; patients will include those with acute and chronic illness, with differences in neuroleptic history (type and duratio), and a spectrum of major symptomatic manifestations. Each patient will receive a complete diagnostic workup with baseline ratings to be repeated during the treatment phases. After a four week neuroleptic-free period, a 24 hour plasma drug level curve will be generated following a fixed 20 mg oral dose of haloperidol. Subsequently, three, fixed-dose treatment phases of one month's duration each will be carried out; treatments will be placebo, low dose (0.1 mg/kg.day), and moderate dose (0.3 mg/kg/day) in random order. Plasma drug level, CSF drug level, and clinical ratings of psychosis and side effects will be done during the last 1.5 weeks of each treatment period. The data will be analyzed to see whether characteristics of the acute metabolism of haloperidol predict drug-induced psychosis changes. Furthermore, the data will explore any significant relationships between drug plasma level, CSF drug levels, and clinical response: in diagnostic and symptomatic sub-groups, between other drug compartment measures, or with lower neuroleptic dosage. These data may lead to improved pharmacotherapeutic management of schizophrenic psychosis.
