Interaction between clozapine and oxcarbazepine: a case report.

Abstract

Combinations of psychoactive treatments are frequently used to treat impulsivity, aggressiveness, or anxiety in patients with resistant schizophrenia. Antipsychotics, as recommended by the French authorities [Haute Autorite de Sante, 2007], can be co-prescribed with antiepileptic agents in order to reduce impulsivity, to stabilize mood or to treat epilepsy. The prevalence of psychotic disorders in epileptic patients is significantly higher compared with the general population [Clancy et al. 2014]. Clozapine (CLZ; 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine) is an atypical antipsychotic indicated for resistant schizophrenia or in cases of intolerance to the other antipsychotic agents. CLZ has a complex pharmacological profile because of its binding properties. It presents an antagonist action on serotoninergic and dopaminergic systems (5HT2A and D4) and, to a lesser extent, an antagonist activity on histaminergic (H1), cholinergic-like muscarinic (M3 and M1) and adrenergic (α1) systems [Stahl, 2015]. CLZ is recommended as third-line treatment because of the side effects in 25.2% of patients [Mustafa et al. 2015]. The coadministration of treatments may induce the modulation of the pharmacokinetics of CLZ via the enzyme inhibition or induction of cytochrome P450 (CYP450). CLZ is metabolized mainly in N-desmethylclozapine (NCLZ or norclozapine) and CLZ N-oxide by the isoenzymes of CYP450: CYP1A2, CYP3A4 and to a lesser extent by CYP2D6, CYP2C19 and CYP2C9 [Kennedy et al. 2013; Rouleau et al. 2008]. As documented, NCLZ is known to present anticholinergic and hypersalivation effects [de Leon et al. 2012]. Uridine 5′-diphospho-glucuronosyltransferase (UGT) catalyses glucuronidation reactions of NCLZ facilitating its elimination [Rouleau et al. 2008]. A correlation between plasma concentrations of CLZ, NCLZ and the occurrence of side effects have been previously reported [Llorca and Pere, 2004]. This led to an evaluation of the factors of variability in plasma concentration of CLZ and its active metabolites. Plasma levels are also indicative of the quality of compliance. The relative rate of CLZ/NCLZ is also useful to estimate the quality of the observance with CLZ [Couchman et al. 2010]. Oxcarbazepine (OXC; 10, 11-dihydro-10-oxo-5H-dibenzo[b, f]azepine-5-carboxamide) is developed from structural rearrangements of carbamazepine (CBZ) [Schmidt and Elger, 2004] in order to minimize the involvement of isoenzymes of CYP450 in OXC metabolism. This is a choice anti-epileptic treatment, anti-impulsive and mood stabilizer as with CBZ [Stahl, 2015]. OXC is indicated in the treatment of partial seizures with or without secondary generalization. After absorption, an important proportion of OXC undergoes rapid reduction in a pharmacologically active metabolite, monohydroxy derivative (MHD; 10, 11-dihydro-10-hydroxy-5H-dibenzo[f,b]azepine-5-carboxamide or licarbazepine) while a minority of MHD is oxidized in pharmacologically inactive dihydroxy derivative (DHD; carbamazepine-10,11-dihydro-10,11-dihydroxy) [Flesch, 2004]. In comparison with CBZ which is significantly inductive of CYP3A4 (about 46% higher than that of OXC), OXC is known to present a less pronounced dose-dependent effect [Andreasen et al. 2007]. The induction effect is more effective at high doses (900–1200 mg/day). In fact, OXC weakly induced CYP3A4 and UGT in vitro [Patsalos, 2013a,2013b], as documented by a decrease in plasma concentrations of oral contraceptives, felodipine, imatinib and lamotrigine. To our knowledge, there is no report of a putative interaction between CLZ and OXC. In this paper, we report the case of important variations of CLZ and NCLZ concentrations after OXC introduction. This raises the hypothesis of an interaction between CLZ and OXC in a schizophrenic patient for whom we performed a therapeutic drug monitoring of plasma concentration of CLZ and NCLZ, before, during and after treatment of OXC.