[Relation between blood levels and average quantitative EEG and psychometrically assessed pharmacodynamic changes...

In a double-blind, placebo-controlled study, the relationships between blood levels and pharmacodynamics of zotepine were investigated in 15 healthy subjects. They received randomized at weekly intervals single oral doses of 25, 50 and 100 mg zotepine and 50 mg clozapin as reference substance. Blood sampling for zotepine and prolactin plasma levels, quantitative EEG analyses, psychometry and tolerability measures were carried out at the hours 0, 1, 2, 4, 6 and 8. There was a dose-dependent increase in zotepine plasma levels with a tmax between 2-4 hours post-drug and cmax: 6.9, 14.8 and 19.6 ng/ml for the 3 doses, respectively and a slow decline thereafter. Prolactin levels also rose dose dependently, peaking in the 4th hour. Regression and correlation analyses demonstrated: the higher the zotepine plasma levels, the more delta/theta, the less alpha activity and the slower the centroid in the spectral analysed EEG and the more decrease in reaction time performance, numerical memory and CFF in psychometry. Neurophysiological changes started at 8 ng/ml, psychometric ones at 9 ng/ml. Our pharmacodynamic findings suggested zotepine to be a sedative broad-band neuroleptic, which was also reflected in the side effects.