Pharmacokinetics of Fenfluramine and Neuroleptics in the Treatment of Refractory Schizophrenia

Abstract

This study was designed to investigate whether the addition of fenfluramine to neuroleptic therapy could produce an improvement in chionic schizophrenics who were limited responders to neuroleptics. Initially, each of 9 inpatients received at least 6 weeks' treatment with placebo fenfluramine for baseline data collection. Thereafter, active fenfluramine therapy commenced at 60 mg/day with increments of 20 mg/day implemented every 2 weeks until a maximum daily dose of 120mg of fenfluramine was attained. This dosage level was maintained until fenfluramine was withdrawn by stepwise decrements, so that the duration of fenfluramine treatment did not exceed 12 weeks. The patients then continued to receive placebo fenfluramine for a minimum of 4 weeks for further evaluation and data collection. Throughout the study each patient was maintained on a constant dose of a neuroleptic drug.The stepwise addition offenfluramine revealed significant correlations between dose and plasma concentrations for both isomers offenfluramine and its pharmacologically active metabolite, norfenfluramine. Dose proportionality with the plasma concentrations of the isomers of parent and metabolite was also maintained during dose tapering. The plasma concentrations of the I-isomers of both fenfluramine and norfenfluramine were significantly higher than those of the corresponding d-isomers. Moreover, the I: d optical isomer ratios were constant at 1.9 for fenfluramine and 1.4 for norfenfluramine. Thus, it would appear that the enantioselective aspects of fenfluramine and its metabolite norfenfluramine were not affected by changes in the dose offenfluramine. The presence of fenfluramine had no consistent effects on the steady-state plasma concentrations of either the neuroleptic drugs or metabolites.