EEG PROFILE OF LITOXETINE AFTER SINGLE AND REPEATED ADMINISTRATION IN HEALTHY-VOLUNTEERS

1 Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2 This double-blind, cross-over, placebo-controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4-T4, F3-T3, T4-02 and T3-01) was done up to 12 h post-dose. 3 In single or multiple doses, litoxetine induced EEG changes characterised by a dose-related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4 EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml(-l). With repeated administrations, the pharmacodynamic steady-state was achieved as the increase in beta 2 energies was the same before and 12 h post-dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml(-l) with the 10 mg dosage and from 8 to 18 ng ml(-l) with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5 C-max and AUC showed proportionality between the administered dosages of 10 and 25 mg. Mean t(max) ranged from 3 to 4 h and mean elimination half-life from 7 to 9 h independently of the dosage. Pharmacokinetic steady-state was achieved on day 4. Litoxetine did not accumulate with a twice daily regimen. 6 In conclusion, the EEG profile of litoxetine resembles those previously described with non-sedative antidepressants. Such EEG changes generally occur at therapeutic dosages.