CLINICAL PERSPECTIVES OF SOME NEUROLEPTICS THROUGH DEVELOPMENT AND APPLICATION OF THEIR ASSAYS

Attempts to investigate relationships between plasma levels of neurole ptics and therapeutic outcome in schizophrenic patients have been hamp ered due to such factors as the chemical nature of these drugs, their metabolism, and the very heterogeneous nature of the disease states. T wo clinical studies are described that investigate the relationship be tween plasma levels of fluphenazine (FLU) and its metabolites and ther apeutic outcome in schizophrenic patients. In the first of these studi es the levels of FLU and fluphenazine sulfoxide (FLUSO) in schizophren ics receiving either 5 or 25 mg of fluphenazine decanoate (FLUD) intra muscularly every 2 weeks were monitored. Patients given 25 mg of FLUD required 3 months to reach plasma level steady state. The results sugg est that such patients, when being switched from the oral to the depot formulation of FLU, should continue to receive oral supplementation d uring the 1st 3 months after conversion. The relationship between log- transformed plasma levels at 26 and 38 weeks with subsequent psychotic exacerbation was investigated with the use of logistic regression and survival analysis. Both demonstrated significant relationships betwee n FLU plasma levels and a risk of psychotic exacerbation at 26 and 38 weeks. The possibility of any correlations between neurological side e ffects and plasma concentrations were also investigated, with statisti cally significant correlations between FLU levels and akinesia found a t 2 and 26 weeks. In the second of these studies the levels of FLU, FL USO, 7-hydroxyfluphenazine (7-OHFLU), and fluphenazine N4'-oxide (FLUN O) in schizophrenics receiving 5, 10, or 20 mg of oral fluphenazine di hydrochloride daily for 4 weeks were monitored. The relationships betw een log-transformed plasma levels, disabling side effects, and global improvement were examined by logistic regression for the 4-week period . The study showed a significant correlation between increases in both plasma levels and disabling side effects such that at a plasma level of 2.7 ng/ml, approximately 90% of acutely ill patients experienced di sabling side effects. Conversely, the study also showed that at a plas ma level of 0.67 ng/ml, 48% of patients experienced improvement withou t the development of disabling side effects. When relationships betwee n metabolite levels, disabling side effects, and global improvement we re examined by logistic regression, a stronger correlation between dis abling side effects and FLUNO levels than between side effects and FLU levels was found. No correlations between disabling side effects and plasma levels of FLUSO or 7-OHFLU were observed. These studies illustr ate the usefulness of measuring plasma levels of neuroleptic drugs.