Plasma concentrations of risperidone and 9-hydroxyrisperidone: Effect of comedication with carbamazepine or valproate

To evaluate the pharmacokinetic interaction between risperidone and the moo d-stabilizing agents carbamazepine and valproic acid, steady state plasma c oncentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone) we re compared in patients treated with risperidone alone (controls, n = 23) a nd in patients comedicated matched for sex, age, body weight, and antipsych otic dosage. Plasma concentrations of risperidone and 9-OH-risperidone did not differ between valproate-comedicated patients and controls. By contrast , the concentrations of both compounds were lower in patients taking carbam azepine, although the difference reached statistical significance only for the metabolite (p < 0.001). The sum of the concentrations of risperidone an d 8-OH-risperidone in patients receiving carbamazepine (median 44 nmol/L) w as also significantly lower than in patients receiving valproate (168 nmol/ L) and in controls (150 nmol/L), In five patients assessed with and without carbamazepine comedication, dose-normalized plasma risperidone and 9-OH-ri speridone concentrations were significantly lower when the patients receive d combination therapy than when they received risperidone alone. In three p atients assessed witt and without valproate, no major changes in the levels of risperidone and its metabolite were observed. These findings demonstrat e that carbamazepine markedly decreases the plasma concentrations of risper idone and its active 9-OH-metabolite, probably by inducing CYP3A4-mediated metabolism. This interaction is likely to be clinically significant. Conver sely, valproic acid does not cause any major change in plasma antipsychotic levels.