On central effects of serotonin re-uptake inhibitors: quantitative EEG and psychometric studies with sertraline and zimelidine.

In a double-blind placebo-controlled cross-over study the encephalotropic and psychotropic properties of sertraline--a new potent and highly selective inhibitor of synaptosomal serotonin uptake--were studied along with blood levels of the parent drug and main metabolite in ten normal healthy volunteers. They received randomized at weekly intervals oral single doses of placebo, 100, 200 and 400 mg setraline and 100 mg zimelidine as reference drug. Blood sampling, EEG recordings, psychometric tests and evaluation of pulse, blood pressure and side-effects were carried out at the hours 0, 2, 4, 6, and 8. Blood level investigations demonstrated that sertraline is slowly absorbed with dose-dependent blood concentrations peaking in the 4th to 6th hour and remaining high thereafter, while the main metabolite, CP-53261 exhibited an even slower rise in plasma concentration up to the 8th hour. Computer-assisted spectral analysis of the EEG demonstrated slight effects of 100 mg zimelidine and 100 mg sertraline on human brain function, but moderate to marked effects after 200 and 400 mg sertraline as compared with placebo. Changes after 100 mg sertraline and the reference compound resembled the pharmaco-EEG profiles of antidepressants of the desipramine type and were indicative of some vigilance-improving properties while higher doses of sertraline induced alterations reminiscent of those after antidepressants of the imipramine type, thereby reflecting vigilance changes of the dissociative type. This neurophysiological conclusion was supported by the psychometric and psychophysiological data showing partly after 100 mg sertraline and zimelidine an improvement in psychometric performance, while 200 and 400 mg sertraline induced a deterioration of noopsyche and thymopsyche of the normal volunteers. Psychophysiological variables exhibited a dose-dependent change in CNS activation and a widening of the pupillary size. Time-efficacy calculations based on pharmacodynamic changes demonstrated maximal encephalotropic effects after 100 mg zimelidine in the 2nd to 4th hour, and after setraline in the 4th to the 6th hour, which is in agreement with the blood level data. Pulse, systolic and diastolic blood pressure showed no clinically relevant findings. Side-effects were non-existent to minimal after 100 mg zimelidine and sertraline, but marked after 200 and 400 mg sertraline characterized by nausea, vomiting, diarrhea, giddiness, restlessness, tremor and trismus.