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

Abstract

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.

EEG profile of litoxetine after single and repeated administration in healthy volunteers.

“…In the 50 to 300 mg dose range, it exhibited a typical desipramine profile with a marked increase in alpha activity and, even with the highest dose, an increase in beta energies [16,17]. These activating properties were confirmed by improvements in attention and concentration evidenced by psychometric tests [16].…”

Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker

“…This was surprising, considering the mydriatic effects demonstrated in a study of citalopram [12] and studies of other SSRIs [12,20,21]. The mydriatic effect of SSRIs has previously been explained by an increased sympathetic outflow of noradrenaline [12,21,22], but this may not be the case.…”

“…This was surprising, considering the mydriatic effects demonstrated in a study of citalopram [12] and studies of other SSRIs [12,20,21]. The mydriatic effect of SSRIs has previously been explained by an increased sympathetic outflow of noradrenaline [12,21,22], but this may not be the case. Several SSRIs, including escitalopram and citalopram, have actually been demonstrated to decrease the firing activity of the noradrenergic neurons [23,24].…”

Early Changes in Prefrontal Activity Characterize Clinical Responders to Antidepressants

“…Prior work with "pharmaco-EEG" techniques has shown that the administration of antidepressant compounds yields reproducible changes in EEG activity in healthy control subjects within a few hours of dosing (Saletu et al 1982(Saletu et al , 1983(Saletu et al , 1986(Saletu et al , 1987(Saletu et al , 1987 Grunberger 1985, 1988;Sannita et al 1983;Sannita 1990; …”

“…Prior work with "pharmaco-EEG" techniques has shown that the administration of antidepressant compounds yields reproducible changes in EEG activity in healthy control subjects within a few hours of dosing (Saletu et al 1982(Saletu et al , 1983(Saletu et al , 1986(Saletu et al , 1987(Saletu et al , 1987Grunberger 1985, 1988;Sannita et al 1983;Sannita 1990;Itil et al 1984;Herrmann et al 1991;Luthringer et al 1996). The relationship of these immediate EEG changes in control subjects to eventual clinical response in a depressed population is unclear.…”