KISEP Original Article 15 3 2004 정신분열병환자에서 Clozapine 에의한체중증가와 Serotonin 5-HT 2C 수용체유전자 -759C/T 다형성과의연관성 신동훈 1 김철민 2 김학중 2 정영인 1 부산대학교의과대학정신과학교실, 1 생화학교실 2 ABSTRACT Association between Clozapine-Induced Weight Gain and Serotonin 5-HT 2C Receptor Gene Polymorphism in Patients with Schizophrenia Dong Hun Shin, MD, 1 Cheol Min Kim, MD, PhD, 2 Hak Jung Kim, BS 2 and Young In Chung, MD, PhD 1 1 Department of Psychiatry, 2 Biochemistry, College of Medicine, Pusan National University, Busan, Korea Objective:Weight gain is one of the troublesome adverse reaction to clozapine treatment. This problem can lead to poor adherence to treatment. Clozapine-induced weight gain may be associated with genetic predisposition. Recent studies have shown that a polymorphism of the promoter region of the serotonin 5-HT 2C receptor gene is associated with antipsychotic-induced weight gain. This study is to investigate the association of clozapine-induced weight gain with -759C/T polymorphism of serotonin 5-HT 2C receptor promoter gene in schizophrenic patients. Methods:Fifty three patients with schizophrenia were included in this study. The subjects were divided into two groups according to body weight change between the start and 10 weeks of clozapine. The cutoff level of weight change is 5% increase of initial body weight. Genotypes of -759C/T polymorphism were identified from AciI-digested fragments of two-primer products amplified by polymerase chain reaction corresponding to -885 to -634 of the serotonin 5-HT 2C receptor gene promoter region on chromosome X. Results:There were no differences of baseline variables between patient groups with and without weight gain. 4 of 32 male patients and 6 of 21 female patients had -759T allele, respectively. The authors found that patients with -759T allele had tendency to show less weight gain than those without this allele. Conclusion:These findings suggest that clozapine-induced weight gain may be associated with genetic predisposition in schizophrenic patients. (Korean J Psychopharmacol 2004;15(3):312-318) KEY WORDS:Clozapine Weight gain 5-HT 2C receptor Polymorphism. 서 론 교신저자 312
- - - 1. 연구대상 대상및방법 313
2. 연구방법 1) Genomic DNA 추출 2) Serotonin 5-HT 2C 수용체유전자의중합효소연쇄반응 - 3) Serotonin 5-HT 2C 수용체유전자다형성확인 Aci Aci 5 C^ C G C 3 3 G G C^ G 5 3. 통계처리 결 과 314 Korean J Psychopharmacol 2004;15(3):312-318
M U C T M U C/C C/T 300 bp 200 bp 100 bp A Male 250 bp 160 bp 126 bp 300 bp 200 bp 100 bp B Female 250 bp 160 bp 126 bp Figure 1. Restriction patterns of Aci digestion from male A and female B DNA. RFLP patterns from male DNA showed 126 bp band for C allele or 160 bp band for T allele. RFLP patterns from female DNA showed 126 bp band for C/C homozygote or 126 bp and 160 bp bands for C/T heterozygote. Mmolecular weight marker, Uuncut PCR product 252 bp. A B C Figure 2. Electropherograms of polymorphism sequences in 5-HT 2C receptor promoter region. Ashows the wild type of 'C' found in male or C/C found in female. Bshows the mutant type of C to 'T' transition found in male. C shows the heterozygote genotype of C and 'T' found in female. Table 1. Association of baseline variables with weight gain Variables Weight gain 5% 5% Sex M/F* 8/7 24/14 Age yrs 032.306.2 033.809.9 Doses mg 279.497.3 306.665.2 2 2.283, df1, p0.131, t0.542, df51, p 0.590, t1.185, df51, p0.242 315
Table 2. Association of genotype with weight gain Genotype 고 Weight gain 5% 5% C or C/C 15 28 T or C/T 00 10 Fisher s exact testp0.046 Table 3. Difference by sex of the association between genotype and weight gain Male* Genotype 찰 Weight gain 5% 5% 759C 8 20 759T 0 04 Female 759C/C 7 08 759C/T 0 06 Fisher s exact test, p0.550, p0.061 - - 316 Korean J Psychopharmacol 2004;15(3):312-318
- - - 중심단어 참고문헌 1) Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: A comprehensive research synthesis. Am J Psychiatry 1999;156:1686-1696. 2) Ryan MC, Thakore JH. Physical consequences of schizophrenia and its treatment: The metabolic syndrome. Life Sci 2001;71: 239-257. 3) Zimmermann U, kraus T, Himmerich H, Schuld A, Pollmächer T. Epidemiology, implications and mechanisms underlying druginduced weight gain in psychiatric patients. J Psychiatr Res 2003; 37:193-220. 4) Baptista T, Kin NM, Beaulieu S. Treatment of the metabolic disturbances caused by antipsychotic drugs: Focus on potential drug interactions. Clin Pharmacokinet 2004;43:1-15. 5) Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics: Literature review and clinical implications. Drugs 2004;64:701-723. 6) Perkins DO. Adherence to antipsychotic medications. J Clin Psychiatry 1999;60(suppl 21):25-30. 7) Henderson DC, Cagliero E, Gray C, Nasrallah RA, Harden DL, Schoenfeld DA, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry 2000;157:975-981. 8) Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, D- owns M. Clozapine-induced weight gain: Prevalence and clinical relevance. Am J Psychiatry 1992;149:68-72. 9) Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics 2001;11:265-268. 10) Wade J, Milner J, Krondle M. Evidence for a physiological regulation of food selection and nutrient intake in twins. Am J Clin Nutr 1981;34:143-147. 11) Comuzzie AG, Allison DB. The search for human obesity genes. Science 1998;280:1374-1378. 12) Casey DE, Zorn SH. The Pharmacology of weight gain with antipsychotics. J Clin Psychiatry 2001;62(suppl 7):4-10. 13) Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, et al. Eating disorder and epilepsy in mice lacking 5-HT sub 2C serotonin receptors. Nature 1995;374:542-546. 14) Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu DH, et al. Identification, expression, and pharmacology of a Cys 23 -Ser 23 substitutiom in the human 5-HT 2C receptor gene (HTR2C). Genomics 1995;27:274-279. 15) Sodhi MS, Arranz MJ, Curtis D, Ball DM, Sham P, Roberts GW, et al. Association between clozapine response and allelic variation in the 5-HT 2C receptor gene. Neuroreport 1995;7:169-172. 16) Lentes KU, Hinney A, Ziegler A, Rosenkranz K, Wurmser H, Barth N, et al. Evaluation of a Cys23Ser mutation within the human 5-HT 2C receptor gene: No evidence for an association of the mutant allele with obesity or underweight in children, adolescents and young adults. Life Sci 1997;61:9-16. 17) Yuen X, Yamada K, Lshiyama-Shigemoto S, Koyama W, Nonaka K. Identification of polymorphic loci in the promoter region of the serotonin 5-HT 2C receptor gene and their association with obesity and type II diabetes. Diabetologia 2000;43:373-376. 18) Segman RH, Heresci-Levy U, Finkel B, Inbar R, Neeman T, Schlafman M, et al. Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: Additive contribution of 5-HT2C Ser and DRD3 Gly alleles to susceptibility. Psychopharmacology 2000;152:408-413. 19) Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with 5-HT 2C receptor gene polymorphism. Lancet 2002;359:2086-2087. 20) Reynolds GP, Zhang ZJ, Zhang XB. Polymorphism of the promoter region of the serotonin 5-HT 2C receptor gene and clozapine-induced weight gain. Am J Psychiatry 2003;60:677-679. 21) Pooley EC, Fairburn CG, Cooper Z, Sodhi MS, Cowen PJ, Harrison PJ. A 5-HT 2C receptor promoter polymorphism (HTR2C- 759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes. Am J Med Gen 2004;126B:124-127. 22) Milatovich A, Hsieh CL, Bonaminio G, Tecott L, Julius D, Francke U. Serotonin receptor 1c gene assigned to X chromosome in 317
human (band q24) and mouse (bands D-F4). Hum Mol Genet 1992;1:681-684. 23) Davis J, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60: 553-564. 24) Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, et al. Clozapine treatment for suicidality in schizophrenia: International suicide prevention trial (InterSePT). Arch Gen Psychiatry 2003;60:82-91. 25) Meltzer HY, Baldessarini RJ. Reducing the risk for suicide in schizophrenia and affective disorders. J Clin Psychiatry 2003;64: 1122-1129. 318 Korean J Psychopharmacol 2004;15(3):312-318