Fluoxetine augmentation in citalopram non-responders: pharmacokinetic and clinical consequences

In an open trial II in-patients with a major depressive episode (ICD-IO), extensive metabolizers of mephenytoin (CYP2C19) and dextromethorphan (CYP2D6) and who were non-responders to a 3-wk pretreatment with 40 mg/d citalopram (Cit), were eo-medicated for 7 wk (days 0-49) with fluoxetine (Fluox) (10 mg/d). Plasma concentrations of S-Cit and R-Cit significantly increased from day 0 (means+/-S.D.: 28+/-9 and 47+/-11 mu g/l, respectively) to day 49 (58 +/- 12 and 72 +/- 21 mu g/l, respectively) (p < 0.01 for each comparison), and the S-Cit/R-Cit ratio increased from 0.61+/-0.16 to 0.82 +/- 0.12 (p < 0.01). Therefore, Fluox increases the pharmacologically more active S-Cit (in comparison with R-Cit) with some stereoselectivity, most probably by inhibition of CYP2D6 and CYP3A4. Eight of the II patients showed clinical improvement (reduction > 50% of the MADRS score) and the combined treatment was generally well tolerated.