Early clinical pharmacological studies with sercloremine—a novel antidepressant—utilizing pharmacokinetic, pharmaco‐EEG, and psychometric analyses

Pharmacokinetic and pharmacodynamic properties of sercloremine (CGP 4718A), a novel, selective monoamine oxidase A and serotonin uptake inhibitor, were investigated in healthy volunteers in a double‐blind, placebo‐controlled, crossover study. The effect of single, oral doses of the drug (50, 100, 200 mg) were, in addition, compared to the effect of 75 mg amitriptyline, which was use as a reference compound. Pharmaco‐EEG recordings and plasma level determinations as well as psychometric testings were performed intermittently from O hr up to 8 or 48 hr (pharmacokinetics), respectively. In addition, blood pressure, heart rate, and side effects were recorded. Pharmacokinetic analyses by means of gasliquid chromatography showed a rapid rise in plasma levels of sercloremine with peak concentrations 2 hr after administration. There was a rapid decline thereafter: the distribution and elimination half‐lives were estimated to be 4–5 and 14 hr, respectively. Plasma concentrations as well as the area under the curve (AUC) showed clear‐cut dose dependency. Computer‐assisted spectral analyses of the EEG findings provided evidence of central effects of sercloremine, which were slight but characteristically reminiscent of effect provided by activating antidepressants (“desipramine‐type”). Thus, sercloremine produced an increase in total power, alpha activity, and increase of relative and absolute power of dominant frequency, in particular 6 hr after administration. Entirely opposite and remarkably prominent changes were, by contrast, produced by amitriptyline. They were characterized by decrease of relative and absolute power of the dominant frequency and increase of delta and theta activity as well as of superimposed fast activity. Moreover, the centroid of the total activity was slowed down. These changes were previously described as typical for antiderpressants with sedative qualities. Psychometric testing largely confirmed the pharmaco‐EEG findings. They indicated vigilance‐improving properties of sercloremine which at all three tested doses significantly ameliorated the performance of the volunteers and increased the concentration, attention, cognitive, and mnestic functions. Also, at a dose of 100 mg, there was an improvement of wakefulness, mood, and extroversion as indicated by semantic differential polarity profile records. A vigilance‐increasing effect of the drug was also suggested by parallel widening of the pupillary diameter. Consistent deterioration of all subjective and objective varibales tested was observed after administration of amitriptyline. Dose‐efficacy calculations indicated that amitriptyline is the most effective centrally active compound, always clearly distinguished from placebo. By contrast, sercloremine was not at all times and in all measures significantly different from placebo. Time‐efficacy calculations showed that the peak effect of amitriptyline was situated between 4 and 6 hr after administration, whereas sercloremine exerted maximal pharmacodynamic activity 6–8 hr after dosing. This time lag between the peak plasma concentrations and maximum pharmacodynamic action, described as a “hysteresis loop,” is discussed. Altogether, the results of this study suggest vigilance‐increasing properties of sercloremine. The compound was also well tolerated; no cardiovascular or note worthy subjective side effects were recorded.