FLUPHENAZINE BLOOD LEVELS, EFFICACY & PHARMACOKINETICS

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A four-year renewal is proposed of a study of fluphenazine (FPZ) blood levels, efficacy and side effects during acute oral and chronic depot therapy. This study was funded for two years to permit initiation of data collection, but further data concerning the FPZ radioimmunoassay were requested prior to funding to completion. Further data are now available supporting the validity of the assay, as well as early data supporting a relationship between FPZ plasma levels and improvement in neuroleptic-responsive patients. It is proposed to complete the study with an enlarged primary sample, an additional sample of acute patients with schizophrenia and stimulant abuse, and additional procedures to assess changes in plasma homovanillic acid (pHVA) and brain anatomic abnormalities (by MRI) as predictors of response. (1) FPZ plasma levels will be measured during four weeks of acute oral treatment of 75 patients with RDC schizophrenic and schizoaffective (mainly schizophrenic subtype) disorders. The large N will increase statistical power and permit separate analysis of patients meeting a criterion of improvement. (2) A sample of 36 patients with chronic syndromal schizophrenia complicated by chronic stimulant (alone or polysubstance) abuse will be studied acutely in an identical design. (3) In cooperating patients, pHVA and prolactin response to an initial FPZ dose and to 4 weeks of treatment will be studied. Individual differences in dopamine (DA) release and in reduction of DA release during neuroleptic treatment (as indexed by pHVA) may be important factors in the therapeutic action of neuroleptics, and may interact with drug levels. Absence of brain anatomic abnormalities (MRI) may also define a group with stronger correlations among improvement, FPZ level and pHVA measures suggesting DA-ergic mechanisms. (4) FPZ plasma levels will be measured in 16 patients during up to 1 year of fixed dose FPZ decanoate therapy and (in selected patients) 4 months of drug withdrawal, to assess accumulation and disappearance characteristics of the drug and the relationship between levels during oral and depot treatment.