Toxic rise of clozapine plasma concentrations in relation to inflammation

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.

Introduction

[8-Chloro-11-(4-methyl-1-piperazinyl)5H-dibenzodiazepine known as Clozapine is an atypical neuroleptic drug. Clozapine has led to substantial improvement in the treatment of schizophrenic patients (Meltzer, 1999), especially for those who are refractory to classic neuroleptic drugs or suffer too much from their extra pyramidal side effects Kane et al., 1988, Meltzer, 1997, Safferman et al., 1991. New data indicate that it reduces suicidality in schizophrenic patients at high risk of suicide (Melzer et al., 2002). It is likely that the use of clozapine will increase further. Clozapine is also known for its characteristic toxic effects, like acute agranulocytosis and leucopoenia Krupp and Barnes, 1992, Miller, 2000.

Knowledge about the pharmacokinetics of clozapine is still incomplete. There is a large between-subject variability in the pharmacokinetic parameters of clozapine and its metabolites (Guitton et al., 1998). Clozapine is metabolized in the liver by the P450 system mainly into four metabolites: desmethylclozapine (norclozapine) and clozapine N-oxide, hydroxylated metabolites and a protein-reactive metabolite (Eiermann et al., 1997). Conversion to norclozapine is the major metabolic route. CYP1A2 and CYP3A4 are involved in the demethylation of clozapine and CYP3A4 in the N-oxidation of clozapine (Eiermann et al., 1997). Clozapine is protein-bound for about 95%; its metabolites N-desmethylclozapine and clozapine N-oxide for about 90 and 75%, respectively (Schaber et al., 1998). The metabolism of clozapine is also influenced by smoking, xantines (caffeine, theobromine and theofylline) and other drugs which are metabolized by CYP1A2 Byerly and DeVane, 1996, Carrillo et al., 1998.

There is a wide intra- and inter-individual variability of plasma levels in patients on stable clozapine dose Guitton et al., 1999, Kurz et al., 1998. Clozapine plasma levels are correlated with clinical, adverse and toxic effects, though there is considerable intra- and inter-individual variability in the response at any given drug concentration Olesen, 1998, Perry, 2000. Although the correlation between the dose of clozapine and its clinical effect is not high, the recommended threshold plasma level of 300–420 μg/l of clozapine is associated with an increased probability of a good clinical response. However, the results may vary with the study design Perry, 2000, Killian et al., 1999. The incidence of side effects is two times higher at concentrations above 350 μg/l compared to lower concentrations (Spina et al., 2000). High clozapine levels are associated with a higher risk for liver enzyme elevation (Hummer et al., 1997), a decrease in heart rate variability (Rechlin et al., 1998), EEG alterations (Haring et al., 1994) and seizures (Cooper, 1996). Toxic effects of clozapine may be expected at plasma levels of 1000 ng/ml and higher.

The cases described here consist of four patients with a mean age of 43 years, two males and two females. Three were inpatients and one was in outpatient treatment. The DSM-IV diagnosis of three patients was chronic schizophrenia. One patient was diagnosed with a psychosis NOS and a main diagnosis of borderline personality disorder. The mean (±S.D.) duration of treatment with clozapine was 39 months, mean dose 400 (±130) mg/day and mean plasma level 525 (±50) μg/l.

The course of the first case led to an adaptation of the clozapine protocol. Clozapine and norclozapine, ESR and blood leucocyte count and differentials were measured for every client treated with clozapine having a 2–3-day period of temperature rise and/or suspected having an infection, inflammation or intoxication. Blood samples were taken 12 h after the last dose. The plasma concentrations of clozapine and norclozapine were determined by reversed high-performance liquid chromatography with UV-detection at 296 nm. In case of intoxication the medication was stopped abruptly without substitution and gradually restarted when clozapine plasma levels returned to normal.