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P.3.c.058 Clozapine-induced agranulocytosis in monozygotic twins and association with multidrug resistance gene MDR1 polymorphisms
P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical) and medical history and treatment. Patients for whom a switch in antipsychotic treatment had been deemed necessary in the previous twelve weeks were identified and these constituted the Switch population. Patients from the ‘Switch population’ as well as percentage of switch per country are described and presented here. Summary of results: The Screening population was composed of 23 441 patients. 40.9% of patients were from Poland, 14.4% from Slovakia, 11.0% from India and 10.7% from Algeria. Of these patients, 22 126 patients were included in the primary analysis population, and 5128 patients reported a treatment switch in the previous twelve weeks patients. Overall, the percentage of patients switching treatment in the previous twelve weeks was 23.2%. However, this composite figure masked significant variation between different countries participating in the study (p < 0.0001; c2 test). The switch rate was higher in countries which included a higher percentage of inpatients. Switch rates ranged from 11.9% in India to 68.1% in Ukraine, which have 10% and 85% of inpatients respectively. Switch rates were highest in patients who had received a diagnosis of paranoid schizophrenia (70.4%). The global incidence of switching also varied according to gender and age. Switching was more frequent in women (24.2% vs 22.5% in men, p = 0.002; c2 test) and patients who switched were younger (mean age: 39.2±12.6 years) than patients who did not (41.2±13.1 years, p < 0.0001 Mann-Whitney U-test); the highest rate of switching was observed in the 22−29 yr age group, the rate declining with age thereafter. Conclusions: In this study, switching between antipsychotic drug treatment regimens was frequent, with on average one in five of patients consulting having switched therapy in the previous twelve weeks. Switch rates varied significantly between countries, were highest in inpatients, women and younger patients. P.3.c.058 Clozapine-induced agranulocytosis in monozygotic twins and association with multidrug resistance gene MDR1 polymorphisms A.E. Anil Yagcioglu1 ° , B. Cetin Ilhan1 , M.T. Goktas2 , M.O. Babaoglu2 , E. Uz3 , M.K. Yazici1 . 1 Hacettepe University Faculty of Medicine, Department of Psychiatry, Ankara, Turkey; 2 Hacettepe University Faculty of Medicine, Department of Pharmacology, Ankara, Turkey; 3 Hacettepe University Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey Despite its proven superior efficacy in treatment resistant schizophrenia, clozapine’s use has been limited by the serious side effect of agranulocytosis. This adverse event has been suggested to be immune mediated or due to toxic or apoptotic effects mediated by clozapine or its metabolites which are determined by genetic factors [1]. Clozapine’s oxidation to a toxic nitrenium ion has been implicated in the pathogenesis of agranulocytosis. In addition, clozapine and possibly its metabolites interact with the multidrug resistance transporter (MDR1) gene product, P-glycoprotein, which is highly expressed in leukocytes. Among various polymorphisms C3435T and G2677T have been shown to alter the function of this transporter [2]. However, there are no investigations regarding the role of these MDR1 polymorphisms in clozapine-induced agranulocytosis. We present a case report of clozapine-induced agranulocytosis in monozygotic twins with schizophrenia as evidence for a genetic basis of this adverse event. Further, we have also genotyped these patients regarding MDR1 polymorphisms.
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Thirty-four year old twin brothers have been followed at the outpatient clinic of Hacettepe University Faculty of Medicine, Department of Psychiatry with a diagnosis of paranoid schizophrenia. Twin I developed clozapine-induced agranulocytosis at the age of 26, on the 5th week of treatment, receiving 200 mg/day of clozapine. His routine leukocyte count was found to be 1900/mm3 (260/mm3 neutrophils) and clozapine was discontinued. No fever or other complications were observed. Twin II developed clozapine-induced agranulocytosis at the age of 33, on the 6th month of treatment, receiving 500 mg/day of clozapine. His leukocyte count was found to be 1500/mm3 (183/mm3 neutrophils) and was admitted to the inpatient psychiatry clinic, developing a fever of 38.6 ºC on the 4th day of agranulocytosis. He was isolated and treated with antibiotics, an antiviral and granulocyte-stimulating growth factor analog (G-CSF). G-CSF was discontinued in 6 days. Both patients had showed their best treatment response on clozapine. After the onset of clozapine-induced agranulocytosis in the second twin, venous blood sample was collected from both patients for DNA extraction. Genotyping results of Affymetrix GeneChip Mapping 250 K SNP Chip revealed a genotype consensus of 96.2% confirming the monozygotic status. In addition, the twin patients were genotyped for MDR1 C3435T and G2677T genetic variants and found to be heterozygotes, i.e. CT and GT, respectively for both C3435T and G2677T polymorphisms. To our knowledge, this is the second report of clozapineinduced agranulocytosis in monozygotic twins. Contrary to the first report [3], our report suggests that the timing of agranulocytosis in monozygotic twins can vary. If a monozygotic twin sibling has a history of clozapine-induced agranulocytosis, the other sibling should not be started on clozapine before zygosity is determined. Our genotyping results also suggest that the existence of both C3435T and G2677T MDR1 polymorphisms might have led to an additive functional loss in P-glycoprotein action, resulting in toxic metabolite accumulation in leukocytes and thus agranulocytosis. Further investigations are necessary to clarify the role of MDR1 allelic variants on development of clozapineinduced agranulocytosis. References [1] Mosyagin, I., Dettling, M., Roots, I., et al., 2004 Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol 24, 613–617. [2] Pauli-Magnus, C., Kroetz, D.L., 2004 Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharm Res 21, 904–913. [3] Horacek, J., Libiger, J., Hoschl, C. et al., 2001 Clozapine-induced concordant agranulocytosis in monozygotic twins. Int J Psychiatry Clin Pract 5, 71−73.
P.3.c.059 Oxidative stress status in schizophrenic patients treated with typical versus atypical antipsychotics M. Padurariu1 ° , I. Dobrin1 , C. Stefanescu1 , A. Ciobica2 , R.P. Dobrin1 . 1 Socola Hospital-Gr.T. Popa University of Medicine and Pharmacy, Dept. of Psychiatry, Iasi, Romania; 2 Al. I. Cuza University, Dept. of Biology, Iasi, Romania Introduction: Schizophrenia is a common psychiatric disorder, marked by gross distortion from reality; disturbances in thinking, feeling, and behavior. However, the chemical nature of the schizophrenic brain is still not completely understood.
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Thirty-four year old twin brothers have been followed at the outpatient clinic of Hacettepe University Faculty of Medicine, Department of Psychiatry with a diagnosis of paranoid schizophrenia. Twin I developed clozapine-induced agranulocytosis at the age of 26, on the 5th week of treatment, receiving 200 mg/day of clozapine. His routine leukocyte count was found to be 1900/mm3 (260/mm3 neutrophils) and clozapine was discontinued. No fever or other complications were observed. Twin II developed clozapine-induced agranulocytosis at the age of 33, on the 6th month of treatment, receiving 500 mg/day of clozapine. His leukocyte count was found to be 1500/mm3 (183/mm3 neutrophils) and was admitted to the inpatient psychiatry clinic, developing a fever of 38.6 ºC on the 4th day of agranulocytosis. He was isolated and treated with antibiotics, an antiviral and granulocyte-stimulating growth factor analog (G-CSF). G-CSF was discontinued in 6 days. Both patients had showed their best treatment response on clozapine. After the onset of clozapine-induced agranulocytosis in the second twin, venous blood sample was collected from both patients for DNA extraction. Genotyping results of Affymetrix GeneChip Mapping 250 K SNP Chip revealed a genotype consensus of 96.2% confirming the monozygotic status. In addition, the twin patients were genotyped for MDR1 C3435T and G2677T genetic variants and found to be heterozygotes, i.e. CT and GT, respectively for both C3435T and G2677T polymorphisms. To our knowledge, this is the second report of clozapineinduced agranulocytosis in monozygotic twins. Contrary to the first report [3], our report suggests that the timing of agranulocytosis in monozygotic twins can vary. If a monozygotic twin sibling has a history of clozapine-induced agranulocytosis, the other sibling should not be started on clozapine before zygosity is determined. Our genotyping results also suggest that the existence of both C3435T and G2677T MDR1 polymorphisms might have led to an additive functional loss in P-glycoprotein action, resulting in toxic metabolite accumulation in leukocytes and thus agranulocytosis. Further investigations are necessary to clarify the role of MDR1 allelic variants on development of clozapineinduced agranulocytosis. References [1] Mosyagin, I., Dettling, M., Roots, I., et al., 2004 Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol 24, 613–617. [2] Pauli-Magnus, C., Kroetz, D.L., 2004 Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharm Res 21, 904–913. [3] Horacek, J., Libiger, J., Hoschl, C. et al., 2001 Clozapine-induced concordant agranulocytosis in monozygotic twins. Int J Psychiatry Clin Pract 5, 71−73.
P.3.c.059 Oxidative stress status in schizophrenic patients treated with typical versus atypical antipsychotics M. Padurariu1 ° , I. Dobrin1 , C. Stefanescu1 , A. Ciobica2 , R.P. Dobrin1 . 1 Socola Hospital-Gr.T. Popa University of Medicine and Pharmacy, Dept. of Psychiatry, Iasi, Romania; 2 Al. I. Cuza University, Dept. of Biology, Iasi, Romania Introduction: Schizophrenia is a common psychiatric disorder, marked by gross distortion from reality; disturbances in thinking, feeling, and behavior. However, the chemical nature of the schizophrenic brain is still not completely understood.