Classification and determination of cerebral bioavailability of fluoxetine: pharmacokinetic, pharmaco-EEG, and psychometric analyses

Abstract

In a double-blind placebo-controlled cross-over study, the pharmacokinetic, encephalotropic, and psychotropic properties of fluoxetine were investigated in 8 normal volunteers. Subjects received in randomized order, at 2-week intervals, single oral doses of placebo and 30, 60, and 75 mg of fluoxetine. Data were obtained at baseline and 2, 4, 6, 8, and 10 hours after drug administration. There was a dose-dependent rise in plasma levels up to the 4th to 6th hour, followed by a slow decline, consistent with the reported long half-life. Digital computer period EEG analysis showed only mild encephalotropic effects of fluoxetine compared with placebo. The EEG changes, especially in the vigilance-controlled recordings, were similar to those seen after antidepressants of the desipramine type; changes in resting EEGs after the highest dose resembled those seen after imipramine-like drugs. Maximal CNS efficacy occurred between the 8th and 10th hours postdrug. The hysteresis between peak blood levels and maximal pharmacodynamic effects suggests formation of an active metabolite. Psychometric investigations showed behavioral changes after fluoxetine that are known to occur after the administration of antidepressants to normal subjects. The drug was well tolerated.