On acute and chronic CNS effects of antidepressants in normals: neurophysiological, behavioral and pharmacokinetic studies with pirlindol.

: In a double-blind placebo-controlled cross-over study the pharmacokinetic and pharmacodynamic properties of acutely and chronically administered prilindol--a new antidepressant possessing both catecholamine-uptake and MAO-inhibitory properties--were investigated in ten normal healthy volunteers. Each subject had a treatment period of two weeks with 3 X 75 mg pirlindol daily and another period of two weeks with placebo. A treatment-free inverval of one week was introduced in between. For comparison purposes a single dosis of 300 mg pirlindol was given as well. Blood level determination, quantitative EEG recordings, psychometric analyses and evaluation of pulse, blood pressure and side effects were carried out at hrs 0, 1, 2, 4, 6, 8 after the administration of one single dosis of 75 mg and 300 mg pirlindol, after one week's and two week's chronic administration of 3 X 75 mg pirlindol, as well as after one additional superimposed dosage of 75 mg and 225 mg on days 8 and 15 of chronic treatment, respectively. Pharmacokinetic analyses by HPLC method with fluorescence detection demonstrated a dose-dependent rapid rise in plasma concentrations peaking in the 1st hr and declining rapidly thereafter (t1/2 TERM = 3 hrs). Computer-assisted spectral analysis of the EEG demonstrated after single doses of 75 mg pirlindol only slight and after 300 mg marked changes in brain activity characterized after the latter by an increase of slow, a decrease of alpha and an increase of beta activity (imipramine-type profile). After one week treatment with 3 X 75 pirlindol, and more so after a superimposed dosage of 75 mg, a significant decrease of delta and increase of alpha activity and slow beta activity occurred (desipramine-type profile). Surprisingly, after two weeks of pirlindol treatment CNS changes were again less marked, suggesting adaptive phenomena. Psychometric analysis demonstrated significant changes after both acute and chronic pirlindol with the latter somewhat superior to the former, as on day 15 a significant improvement of concentration, cognitive function and complex reaction was noted along with a decrease in critical flicker frequency, increase of the total score of the affectivity polarity profile and increase of skin conductance. Time-efficacy calculations demonstrated the pharmacodynamic peak effect in the 4th-6th hr. The time lag between kinetic and dynamic data is discussed. Evaluation of blood pressure, pulse rate and side effects demonstrated good tolerability of pirlindol.