Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype

SummaryA 40-yr.-old woman with paranoid schizophrenia developed asymptomatic pancreatitis without eosinophilia one month after receiving clozapine, slowly increased to 300 mg/day. She had elevated serum levels of clozapine and hyperglycemia, but not hyperlipidemia. She improved after discontinuation and recovered in about ten days. After a subsequent rechallenge with 100 mg clozapine, she redeveloped pancreatitis associated with clozapine serum level elevation. Clozapine was definitively discontinued, and this was followed by resolution of pancreatic symptoms. Pharmacogenomic analysis of her CYP 1A2 isoenzyme showed her to possess the *1F/1F genotype and the 3A4*1A/1A wildtype allelic variant. Pharmacogenomic data may not match those of therapeutic drug monitoring. We would have expected high clozapine levels to result from particular CYP 1A2 or 3A4 alleles that confer the status of poor metabolizer, but this was not so.

BackgroundPancreatitis during treatment with classical neuroleptics is rarely reported; its relationship to a specific antipsychotic has not been established1A. The risk for hospitalization for acute pancreatitis was higher in patients receiving low-potency phenothiazines in a Danish population, even adjusting for presence of diabetes, gallstones, alcohol-related disease, or use of antidepressants, statins, or nonsteroidal anti-inflammatory drugs2A, but these figures were not correcting for market share. After the introduction of second-generation antipsychotics, the frequency of reports of pancreatitis in the course of antipsychotic treatment rose steeply3A. The reason for this is not clear, as the newer antipsychotics are chemically heterogeneous, but so were also the classical antipsychotics.

Pancreatitis is suspected to result from drug-induced hyperlipidaemia4A.Clozapine and other newer antipsychotics have been linked hyperlipidemia and hyperglycemia5A, but a dose- or plasma level-related elevation of these measures isstill not established.

Rating scales. Psychopathology. We used the 24-item, expanded Brief Psychiatric Rating Scale (BPRS)6A (range, 24-168) to rate psychosis.

Attribution of side effect and classification. We rated the likelihood that the side effect was due to clozapine on the Naranjo ADR Probability Scale7A and obtained a score of 9, which is compatible with high probability. Following Cerulli’s et al.4A subdivision into definite, probable, and possible association, we found the event to be definitively associated with the use of clozapine.

Antibiotic treatment. We added intravenous ciprofloxacin, 400 mg/day for 14 days, according to current guidelines for acute pancreatitis with acute phase reaction8A. This drug could interfere with residual clozapine levels, elevating them9A,10A,11A.

Wash-out.Wash-out is indicated when using drugs like risperidone, because this drug may elevate plasma clozapine levels9A.

Pharmacogenomics.Genomic DNA was isolated from peripheral blood using the X-tractor Gene system (Corbett Life Science, Australia). Allelic variants of CYP1A2 and CYP3A4 were genotyped by pyrosequencing technology. In particular the CYP 1A2 -163C>A (*1F allele variant) and the CYP3A4 -392A>G (*1B allele variant) polymorphisms were characterized. Briefly, region covering the SNPs of interest was amplified by real-time PCR using specific primers set, obtained by PSQ Assay Design software (BiotageAB and Biosystems, Uppsala, Sweden). The amplicon was then sequenced by the Pyrosequencer PyroMark ID system (BiotageAB and Biosystems, Uppsala, Sweden). Genetic analysis showed the patient to be homozygous for the CYP1A2*1F/*1F and for the CYP3A4*1A/*1A (“wild type”) allelic variants. The CYP1A2*1F polymorphism yields an isoenzyme that is inducible by nicotine and drugs like omeprazole, but otherwise accounts for normal metabolism of about 80% of plasma clozapine12A.

Pharmacogenomic analysis showed the patient to be a normal clozapine metabolizer. In fact, her CYP1A2*1F/*1F genotype does not interfere with clozapine clearance13A, while the CYP3A4*1A/*1A genotype is the wild-type14A.The use of nicotine would have decreased, rather than increased her clozapine serum levels, as smoke has a CYP1A2 inducing effect that lowers clozapine levels15A.Furthermore, omeprazole is also an inducer of CYP1A2, but not in nonsmokers16A. Moreover, the CYP1A2*1F/*1F genotype is related with lower, rather than higher blood levels of olanzapine17A, a drug structurally related to clozapine. Hence, there were no identifiable genetic reasons for which clozapine plasma levels could be so high with both full and reduced doses of clozapine in the absence of other concomitant factors.

Nitrenium toxicity. Clozapine, like olanzapine, under certain conditions may form a transient nitrenium+intermediate metabolite, which may cause toxicity18A.Clozapine may bind activated neutrophils irreversibly and give rise to an unstable nitrenium19Athat in turn induces increased apoptosis20A and activation of cytokines and immunoglobulins, which further interfere with CYP1A2 function21A, hence raising toxic clozapine serum levels6. This mechanism, which has been advanced to explain clozapine agranulocytosis, may fit better to pancreatitis, as it is shared by olanzapine, which is far less associated with agranulocytosis than clozapine itself. Moreover, fluperlapine, which does not share this mechanism, yet was stopped from marketing due to the induction of agranulocytosis22Ahas not been associated with nitrenium formation.

Comparison to other clinical reportsTherapeutic drug monitoring is not suggested as routine procedure for clozapine6. Among all reports on clozapine-associated pancreatitis, only Schmitz-Hübsch’s et al.8 reported blood clozapine values, which were in the therapeutic range, as were levels at rechallenge in our case. In our case, we recorded higher levels than the therapeutic window would allow at first assay; we presume that these had to do with the first occurrence of pancreatitis, and that the second episode occurred at therapeutic serum levels due to sensitization.

Our case compares with other cases reported in literature and differs from many of them in several aspects (Table A). Differently from Frankenburg and Kando23A, Chengappa et al.24A and Garlipp et al.25A, we did not observe eosinophilia, but this abnormality is by no means the rule with clozapine-associated pancreatitis. Our patient was asymptomatic, like the cases reported by Bergemann et al.26A and Garlipp et al.25A;her pancreatic derangement was discovered during routine pancreatic enzyme examination. The presence of cholelithiasis is intriguing; Chengappa et al.24Aalso reported cholelithiasis, and the patient underwent cholecystectomy. Subsequent rechallenge was followed suit by reappearance of pancreatitis, adding credit to our hypersensitivity hypothesis. Huang’s et al.27Areport of pancreatitis with clozapine several years after cholecystectomy lends support to the concept that a lithiasic tendency in a patient could foretell subsequent pancreatitis with clozapine.On the other hand, Schmitz-Hübsch et al.8 reported the case of a patient who developed recurrent pancreatitis with clozapine and was found with gallstones. After cholecystectomy, there was no evidence of pancreatitis afterclozapine rechallenge and at subsequent follow-up, while psychosis had improved. At any rate, the relationship between gallstones and susceptibility to clozapine-associated pancreatitis is currently unclear.

One of the criteria to establish the strength of the association with a given side effect is the disappearance of the effect upon discontinuation and its reappearance after rechallenge. Comprising our report, seven cases were rechallenged with clozapine and in four of them and in our case pancreatitis reoccurred23A,24A,26A,27A, while in two it did not8,28A.

SupplementalReferences

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