Comparative placebo-controlled pharmacodynamic studies with zotepine and clozapine utilizing pharmaco-EEG and psychometry.

In a double-blind, placebo-controlled study the encephalotropic and psychotropic properties of zotepine - a new tricyclic dibenzothiepine with antidopaminergic, adrenolytic and antiserotoninergic properties - were investigated utilizing quantitative EEG, psychometric and psychophysiological tests as well as clinical observations. Fifteen normal volunteers received randomized (latin square design) and at weekly intervals single oral doses of placebo, 25 mg, 50 mg and 100 mg zotepine as well as 50 mg clozapine as reference compound. Plasma samplings for blood levels, EEG recordings, and evaluation of blood pressure, pulse rate and side-effects were carried out at the hours 0, 1, 2, 4, 6 and 8, while psychometric data were recorded at the same time except the first hour. Computer-assisted spectral analysis of the EEG demonstrated after all three doses significant changes as compared with placebo characterized by an augmentation of delta and theta activity, decreased of alpha and beta activity, slowing of the centroid of the total activity and alpha activity, and decrease of the dominant frequency and its absolute and relative power. Such changes are typical for low-potency basic neuroleptics of the sedative type such as chlorpromazine. Clozapine also augmented slow activities, decreased alpha activity, the dominant frequency and the alpha centroid, but induced in contrast to zotepine a concomitant increase of fast beta activity, acceleration of the beta centroid and no slowing of the dominant frequency, while the total power was significantly attenuated. These findings confirm earlier reports about the pharmaco-EEG profile of clozapine, which has a resemblance to profiles of anticholinergic antidepressants of the amitriptyline type. Psychometric tests demonstrated after the higher doses of zotepine and clozapine a deterioration of noopsychic and thymospsychic functions which was more pronounced after the reference compound than after zotepine. The lowest dose of zotepine, 25 mg, even produced an improvement in numerical memory and complex reaction. CFF, skin conductance, pupillary diameter and pupillary response measurements decreased after both compounds. Dose-efficacy calculations showed 100 mg zotepine and clozapine to be the most CNS-effective compounds, followed by 50 mg and 25 mg zotepine, while placebo induced the least changes. Time-efficacy calculations showed neurophysiological and behavioral peak effects after zotepine at the 4th and 6th hour, as compared with the 2nd and 4th hour after clozapine. Pulse rate increased with both compounds; blood pressure decreased after clozapine but remained unchanged after zotepine.(ABSTRACT TRUNCATED AT 400 WORDS)