European Neuropsychopharmacology 13 (2003) 381–385 www.elsevier.com / locate / euroneuro Toxic rise of clozapine plasma concentrations in relation to inflammation a,b c,d d Marie-Jeanne Haack M.D. , M.L.F.J. Bak M.D. , Rob Beurskens M.D. , Michael Maes M.D., e, f d,g * Ph.D. , L.M.L Stolk Ph.D., Philippe A.E.G. Delespaul M.A., Ph.D. a Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, The Netherlands b Department of Psychiatric Rehabilitation, Psychiatric Hospital Vijverdal, Maastricht, The Netherlands c Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands d Psychiatric Hospital Vijverdal, Maastricht, The Netherlands e Department of Psychiatry and Neuropsychology, University Hospital of Maastricht, Maastricht, The Netherlands f Hospital pharmacist, clinical pharmacologist, Department of Clinical Pharmacy and Toxicology, University Hospital of Maastricht, Maastricht, The Netherlands g Assistant professor in Ecological Psychiatry, Brain and behavior Institute, Maastricht University, Maastricht, The Netherlands Received 10 December 2001; received in revised form 27 February 2003; accepted 27 February 2003 Abstract Recently a small number of patients were observed in two psychiatric hospitals in the Netherlands with clozapine intoxications that complicate or mimic infections. These patients were on chronic medication and normally had stable clozapine blood plasma levels. This article presents four of these cases. Medline was searched for reports of similar cases. A hypothesis was formulated and tested by literature study. Immune modulatory and toxic effects of clozapine protein reactive metabolites or haptens, may play a role in the development of inflammation. Clozapine has a direct influence on different cytokines resembling an inflammatory reaction. Infection or inflammation could induce bioactivation of clozapine into its nitrenium ion that can exert a toxic reaction that induces apoptosis and gives rise to elevated cytokine levels. Clozapine can function as a hapten and induce an IgG, IgM or IgE mediated hypersensitivity reaction. The cytokines released during infection or inflammation downregulate the clozapine metabolism in the P450 system through CYP 1A2. Clozapine plasma levels should be monitored closely if an inflammatory or infectious process is suspected.  2003 Elsevier B.V./ECNP. All rights reserved. Keywords: Clozapine; P450 metabolism; Infection; Inflammation; Cytokines; Toxic 1. Introduction 2002). It is likely that the use of clozapine will increase further. Clozapine is also known for its characteristic toxic [8 - Chloro - 11 - (4-methyl-1-piperazinyl)5H - dibenzodia- effects, like acute agranulocytosis and leucopoenia (Krupp zepine] known as Clozapine is an atypical neuroleptic and Barnes, 1992; Miller, 2000). drug. Clozapine has led to substantial improvement in the Knowledge about the pharmacokinetics of clozapine is treatment of schizophrenic patients (Meltzer, 1999), espe- still incomplete. There is a large between-subject vari- cially for those who are refractory to classic neuroleptic ability in the pharmacokinetic parameters of clozapine and drugs or suffer too much from their extra pyramidal side its metabolites (Guitton et al., 1998). Clozapine is metabo- effects (Kane et al., 1988; Meltzer, 1997; Safferman et al., lized in the liver by the P450 system mainly into four 1991). New data indicate that it reduces suicidality in metabolites: desmethylclozapine (norclozapine) and schizophrenic patients at high risk of suicide (Melzer et al., clozapine N-oxide, hydroxylated metabolites and a protein- reactive metabolite (Eiermann et al., 1997). Conversion to norclozapine is the major metabolic route. CYP1A2 and *Corresponding author. Tel.: 131-43-387-1025; fax: 131-43-387- CYP3A4 are involved in the demethylation of clozapine 1026. E-mail address: crc-mh@skynet.be (M. Maes). and CYP3A4 in the N-oxidation of clozapine (Eiermann et 0924-977X / 03 / $ – see front matter  2003 Elsevier B.V./ECNP. All rights reserved. doi:10.1016 / S0924-977X(03)00042-7