Plasma Concentrations of Risperidone and 9-Hydroxyrisperidone: Effect of Comedication With Carbamazepine or Valproate

Abstract

To evaluate the pharmacokinetic interaction between risperidone and the mood-stabilizing agents carbamazepine and valproic acid, steady state plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone) were compared in patients treated with risperidone alone (controls, n = 23) and in patients comedicated with carbamazepine (n = 11) or sodium valproate (n = 10). The three groups were matched for sex, age, body weight, and antipsychotic 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 carbamazepine, although the difference reached statistical significance only for the metabolite (p < 0.001). The sum of the concentrations of risperidone and 9-OH-risperidone in patients receiving carbamazepine (median 44 nmol/L) was 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-risperidone concentrations were significantly lower when the patients received combination therapy than when they received risperidone alone. In three patients assessed with and without valproate, no major changes in the levels of risperidone and its metabolite were observed. These findings demonstrate that carbamazepine markedly decreases the plasma concentrations of risperidone and its active 9-OH-metabolite, probably by inducing CYP3A4-mediated metabolism. This interaction is likely to be clinically significant. Conversely, valproic acid does not cause any major change in plasma antipsychotic levels.

Metabolic Effects of Sodium Valproate on Atypical Antipsychotics in Japanese Psychotic Patients

“…Concurrent use of valproic acid significantly decreases the serum concentration of olanzapine to an extent comparable to smoking [24], and valproate did not alter the concentration of risperidone or 9-OH-risperidone [25]. The changes in the metabolic outcomes associated with olanzapine or paliperidone plus VPA found in our study are likely to reflect a pharmacodynamic interaction between these atypical antipsychotics and VPA.…”

Priapism associated with risperidone: a case report, literature review and review of the South London and Maudsley hospital patients’ database

“…However, other studies suggest that valproate does not affect risperidone levels. A study by Spina and colleagues compared 10 patients taking sodium valproate and risperidone with 23 patients taking risperidone alone and found no significant difference in the levels of risperidone and its metabolite, 9-hydroxyrisperidone [Baxter, 2012;Spina et al 2000]. Yoshimura and colleagues looked at 12 patients with schizophrenia given valproic acid 400-800 mg daily and risperidone 2-6 mg daily and came to the same conclusion [Baxter, 2012;Yoshimura et al 2007].…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Of this class, risperidone is the most well studied with respect to CYP2D6 which, together with other P450s, e.g., CYP3A (Odou et al, 2000;Yasui-Furukori et al, 2001), produces a metabolite with comparable activity, 9-hydroxyrisperidone (Mannens et al, 1993;van Beijsterveldt et al, 1994). 9-Hydroxyrisperidone is further metabolized by N-dealkylation, possibly by CYP3A (Spina et al, 2000). The ratio of risperidone to 9-hydroxyrisperidone concentrations is Ͻ1 in EMs, and Ͼ1 in PMs, but the sum of active moieties is similar (Mannens et al, 1993;Nyberg et al, 1995a;Olesen et al, 1998;Scordo et al, 1999;Roh et al, 2001b;Bondolfi et al, 2002).…”