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1 KISEP Original Articles 생물정신의학 Vol. 10, No. 2, November 2003 지연성운동장애와 5-HT 2A 수용체유전자 T103C 다형성과의관계 한상우 1) 신정원 2) 최태윤 2) 우성일 1) 정한용 4) 정희연 3) 한선호 1) Association between Tardive Dyskinesia and T103C Polymorphisms of 5-HT 2A Receptor Gene Sang Woo Hahn, M.D., 1) Jeong Won Shin, M.D., 2) Tae Youn Choi, M.D., 2) Sung Il Woo, M.D., 1) Han Yong Jung, M.D., 4) Hee Yeoun Jung, M.D., 3) Sun Ho Han, M.D. 1) bjective O Method Result Conclusion KEY WORDS ABSTRACT Department of Psychiatry, College of Medicine, Soonchunhyang University Hospital, Seoul, Korea Department of Laboratory Medicine, College of Medicine, Soonchunhyang University Hospital, Seoul, Korea Department of Psychiatry, College of Medicine, Soonchunhyang University Hospital, Cheonan, Korea Department of Psychiatry, College of Medicine, Soonchunhyang University Hospital, Bucheon, Korea 교신저자

2 서론

3 1. 연구대상 방 - 2. 연구방법 1) Genomic DNA 추출 법 Table 1. Nucleotide sequences of primer set Polymorphism 102T/C ) 중합효소연쇄반응 (Polymerase chain reaction: PCR) - 3) 제한효소절편다형성분석 (Restriction fragment length polymorphism:rflp) Msp Primer sequences F : 5 -GAG AAC AGC ATG TAC ACC AGC 3 R : 5 -CAT GAC AAG GAA ACC CAG CAG 3

4 4) T102C 유전자형판별 3. 자료분석및통계처리 결 1. T102C 다형성의발현율및빈도 Table 3. Genotype and allele frequencies of T102C allele in the schizophrenic patients with TD and without TD n 과 Genotype distribution Allele frequency T-T% T-C% C-C% T% C% TD No TD , df1, p0.18, , df1, p0.15, TDTardive dyskinesia 2. 지연성운동장애증상위치에따른 T102C 다형성의발현율 Kb M M kb Fig 1. Agarose gel analysis of restriction fragment length polymorphism pattern for T102CFragment sizes of 506bp correspond to 102T/T, whereas 506bp, 282bp and 224bp are diagnostic bands for 102 T/C, whereas 282bp and 224bp are diagnostic bands for 102T/T. Lane M, 123bp DNA ladder size markerlanes 1, 2 and 3 are 102T/T genotype lanes 4, 5 and 6 are 102T/C genotype. Table 4. Genotype distribution of T102C in three AIMS categories of patients with TD Genotype distribution T-T% T-C% C-C% Orofacial Distal Trunk , df1, p0.013, TDTardive dyskinesia, AIMSAbnormal involuntary movement scale Table 2. Demographic characteristic of 119 schizophrenic subjects for 5-HT2A polymorphisms TDN=59 No TDN=60 t 2 df p value Ageyrs SexM/F 33/26 36/ Duration of medicationyrs Duration of illness(yrs

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6 결론 중심단어 : 참고문헌 1. Faurbye A, Rasch PJ, Petersen PB. Neurological symptoms in pharmacotherapy in psychosis. Acta Psychiar Scand 1964;40: Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia. Arch Gen Psychiatry 1982;39: Jeste DV, Caligiuri. Tardive dyskinesia. Schizophr Bull 1993;19: Kaplan HI, Sadock BJ. Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry.8th ed. Williams and Willkins, Baltimore, Maryland; Yassa R, Jeste DV. Gender differences in tardive dyskinesia: A critical review of the literature. Schizophr Bull 1992;18: Miller CH, Simioni I, Oberbauer H, Schwitzer J, Barnas C, Kulhanek F, Boissel KE, Tardive dyskinesia prevalence rates during a ten-year follow-up. J Nerv Ment Dis 1995;183: Sweet RA, Mulsant BH, Gupta B, Rifai AH, Pasternak RE, McEachran A, Zubenko GS. Duration of neuroleptic treatment and prev-alence of tardive dyskinesia in late life. Arch Gen Psychiatry 1995;52: Kane JM, Woerner M, Borenstein M, Wegner J, Lieberman J. Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 1986;22:

7 9. William M, Glazer. Extrapyramidal side effects, tardive dyskinesia and the concept of atypicality. J Clin Psychiatry 2000;61 Suppl 3: Rubovits R, Klawans HL Jr. Implications of amphetamine-induced stereotyped behavior as a model for tardive dyskinesia. Arch Gen Psychiatry 1972;27: Jeste DV, Wyatt RJ. Understanding and treating tardive dyskinesia. Cuilford Press. New York; O Callaghan E, Larkin C, Kinsella A, Waddington JL. Obstetric complications the putative familial sporadic distinction and tardive dyskinesia in schizophrenia. Br J Psychiatry 1990;157: Rosengarten H, Schweitzer JW, Friedhoff AJ. A mechanism underlying neuroleptic induced oral dyskinesia in rats. Pol J Pharmacol 1993;45: Rosengarten H, Schweitzer JW, Friedhoff AJ. A subpopulation of dopamine D receptors mediate repetitive jaw movements in rats. Pharmacol Biochem Behav 1993;45: Swartz JR, Burgoyne K. Tardive dyskinesia and ethnicity: review of the literature. Ann Clin Psychiatry 1997; 9: Tollefsom GD, Beasley CM, Tamura RN, Tran PV, Potvin JH. Blind, controlled long term study of the comparative incidence of treatment emergent tardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 1997;154: Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21 Suppl 2: Casey DE. Effects of clozapine therapy in schizophrenic individuals at risk for tardive dykinesia. J Clin Psychiatry 1998;59 Suppl 3: Kusumi I, Takahashi Y, Suzuki K, KAmeda K, Kyama T. Differential effects of subchronic treatment with atypical antipsychotic dugs on dopamine D2 and serotonin 5-HT2A receptors in the rat brain. J Neural Transm 2000;107: Rosengarten H, Schiweitzer JW, Friedhoff AJ. The effect of novel antipsychotics in rat oral dyskinesia. Prog Neuropsychopharmacolgy Biol 1999;23: Barwick VS, Jones DH, Richter JT, Hicks PB, Young KA. Subthalamic nucleus microinjections of 5-HT2 receptor antagonist supress stereotype in rats, Neuroreport 2000;11: Glazer WM. Expected incidence of tardive dykinesia associated with aypical antipsychotics. J clin Psychiatry 2000;61 Suppl: Kapur S, Zipursky RB, Remingtom G. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998; 155: Farde L, Nordstrom AL, Wiesel FA, et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine; relation to extrapyramidal side effects. Arch Gen Psychiatry 1992;49: Kapur S, Remingtom G, Zipursky RB, et al. The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study. Life Sci 1995;57: Marazziti D, Rossai A, Palegn L. 3Hketanserin binding in human brain postmortem. Neurochem Res 1997;22: Schimidt CJ, Sorensen SM, Kehen JH, Carr AA, Palfeyman MG. The role of 5-HT2A receptors in antipsychotic activity. Life Sci 1995;56: Warren JT, Peacock ML, Rodriguez LC, Fink JK. Mspl polymorphism in the human serotonin receptor gene: detection by DGGE and RFLP analysis. Hum Mol Genet 1993;2: Ozaki N, Rosenthal NE, Pesonen U. Two naturally occuring amino acid substitution of the 5-HT2A receptor similar prevalence in patients with seasonal affective disorder and controls. Biol psychiatry 1996;40: Collier DA, Arranz MJ, Li T, Mupita D, Brown N, Treasure J. Association between 5-HT2A gene promoter polymorphism and anorexia nervosa. Lancet 1997; 350: Erdmann J, Shimron-Abarbanell D, Rietschel M, et al. Systemic screening for mutations in the human serotonin-2a5-ht2a receptor gene: identification of two naturally occuring receptor variants and association analysis in schizophrenia. Hum Genet 1996;97: Ohara K, Ino A, Ishgaki T, Tani K, Tsukamoto T, Nakamura Y. Analysis of the 5 -flanking promoter region of the 5-HT2A receptor gene in schizophrenia. Neuropsychopharmacolgy 1997;17: Zhu QS, Chen K, Shih JC. Characterization of the human 5-HT2 A receptor gene promoter. J Neurosci 1996; 15: Du YL, Wilcox ED, Jeffrey JJ. Regulation of rat 5- hydroxytryptamine type2 receptor gene activity: Identification of cis elements that mediate basal and 5- hydroxytryptamine-dependent gene activation. Mol Pharmacology 1995;47: Jeste DV, Wyatt RJ. Understanding and treating tardive dyskinesia. Guilford Press, New York; Yassa R, Ananth J. Familial tardive dyskinesia. Am J Psychiatry 1981;138: Weinhold P, Wegner JT, Kane JM. Familial occurrence of tardive dyskinesia. J Clin Psychiatry 1981;42: Hsiel CL, Bowcock AM, Farrer LA, Hebert JM, Huang KM, Cavallisforza LL, et al. The serotonin receptor subtype 2 locus HTR2 is on chromosome 13 near genes for esterase D and retinoblastoma and on mouse chromosome 14. Somat cell genet 1990;16: Willams J, McGuffin P, Nothen M, Owen MJ. Metaanalysis of association between 5-HT2a receptor T102C polymorphism and schizophrenia EMASS Collaborative

8 Group, European Multicenter Association Study of Schizophrenialetter Lancet 1997;349: Spurlock G, Heils A, Holmans P, Williams J, D'Souza UM, Cardno A, et al. A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identifications of new polymorphism in the promoter. Mol psychiatry 1998;3: Tay AH, Lim LC, Lee WL, Wong KE, Wong LY, Tsoi WF. Association between allele 1 of T102C polymorphism, 5-hydroxytryptamine 2a receptor gene and schizophrenia in Chinese males in Singapore. Hum Hered 1997;47: Hawi Z, Myakishev MV, Strub RE. No association or linkage between the 5-HT2A/T102C polymorphism and schizophrenia in Irish families. Am J Med Genet 1997; 74: Kouzmenku AP, Scadffi A, Pereira AM, Hayes WL, Copolov DL, Dean B. No correlation between A-1483 G polymorphism in 5-HT2A receptor gene promoter and the density of frontal cortical 5- HT2A receptors in schizophrenia. Hum Hered 1999;49: Ohara K, Nagai M, Tani K, Tsukamoto T. Schizophreina and the serotonin-2a receptor promoter polymorphism. Psychiatry Res 1999;85: Shinkai T, Ohmori O, Kojima H, Terao T, Suzuki T, Abe K. Negative association between T102C polymorphism of the 5-HT2A receptor genes and schizophrenia in japan. Hum Hered 1998;48: Arranz MJ, Munro J, Sham P. Meta -analysis of studies on genetic variations in 5-HT2A receptor and clozapine response. Schizophrenia patients. Schizophr Res 1998; 32: Malhotra AK, Goldmann D, Ozaki N, Breira, Buchann R, ickar D. Lack of association between polymorphism in the 5-HT2A receptors and the antipsychotic response to clozapine. Am J Psy Res 1996;153: Segman RH, Heresco-Levy U, Jinkel B, Goltser T, et al. Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 2001;6: Basile VS, Ozdemir V, Masellis M, Meltzer HY, Lieberman JA, Potkin SG, et al. Lack of association between serotonin-2a receptor genehtr2a polymorphisms and tardive dyskinesia in schizophrenia. Mol Psychiatry 2001;6: 지익성, 이시경, 왕성근, 이영호, 신석철. 한국인정신분열병환자에서 5-HT2A 수용체유전자의 102T/C 와 452His/Tyr 다형성에대하여. 신경정신의학 1999;38: Muscettola G, Giuseppe B, Pampallona S. Casiello M, Bonli P. Extrapyramidal syndromes in neuroleptictreated patients: prevalence risk factors and association with tardive dyskinesa. J Clin Psychopharmacol 1999; 19: Paulsen JS, Caligiuri MP, Palmer B, Macadmas LA, Jeste DV. Risk factors for orofacial and limbtruncal tardive dyskinesia in older patients: a prospective longitudinal study. Berl1996;123: Gureje O. Topographic subtypes of TD in schizophreinic patients aged less than 60 years: relationship to demographic clinical treatment and neuropsychological variables. J Neurol Neurosurg Psychiatry 1988; 51: Glazer WM, Morgenstern H, Niedzweiki D, Hughes J. Heterogenity of tardive dyskinesia. A multivariate analysis. Br J Psychiatry 1988;152:

연구대상 대상및방법 313

연구대상 대상및방법 313 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