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1 online ML Comm 생물정신의학 Vol. 14, No. 4, November 2007 원저 주요우울증환자에서세로토닌 6(5-HT6) 수용체 C267T 다형성과 Citalopram 치료반응에대한연구 * 한상우 1) 임세원 2) 오강섭 2) 강이헌 3) 이민수 3) No Association between the 5-HT6 Receptor C267T Polymorphism and Response to Citalopram Treatment in Patient with Major Depressive Disorder * Sang-Woo Hahn, M.D., 1) Se-Won Lim, M.D., 2) Kang-Seob Oh, M.D., 2) Rhee-Hun Kang, M.D., 3) Min-Soo Lee, M.D. 3) ABSTRACT T he serotonin 6(5-HT6) receptor gene is a candidate gene for influencing the clinical response to treatment with antidepressants. The purpose of this study was to determine the relationship between the C267T polymorphism in the 5-HT6 receptor gene and the treatment response to citalopram in a Korean population with major depressive disorder(mdd). Methods:Citalopram was administered for 8 weeks to the 90 patients who completed study. 21-item Hamilton depression rating scale(hamd-21) was used as a outcome measure. Results:We found that the genotype, allele, and allele-carrier distributions did not differ significantly between MDD patients and normal controls. A main effect of an interaction of genotype with time on the decrease in the HAMD-21 score during the 8 weeks study period was not found. ANOVA revealed no significant effects of the C825T polymorphism on the decrease in the HAMD-21 score at each time period. Conclusions:These results suggest that the C267T polymorphism in the 5-HT6 receptor gene is not associated with the treatment response to citalopram. KEY WORDS:Major depressive disorder 5-HT6 receptor C267T polymorphism Citalopram. * 본연구는 2007 년도보건의료기술연구개발사업의지원에의해이루어진것임 (03-PJ10-PG13-GD ). 본연구는보건복지부보건의료기술진흥사업의지원에의해이루어진것임 ( 과제번호 :A050047). 1) 순천향대학교의과대학순천향대학병원정신과학교실 Department of Psychiatry, Soonchunhyang University of College of Medicine, Seoul, Korea 2) 성균관대학교의과대학강북삼성병원정신과학교실 Department of Psychiatry, Sungkunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea 3) 고려대학교의과대학신경정신과학교실 Department of Psychiatry, Korea University College of Medicine, Seoul, Korea 교신저자 : 이민수, 서울성북구안암동 5 가 전화 ) (02) , 전송 ) (02) , ) leeminso@korea.ac.kr

2 서론 세로토닌신경전달물질은 (5-hydroxytryptamine ; 5-HT) 인간의감각, 운동, 정동, 인지기능의조절에폭넓게관여하는것으로알려져있다. 1) 이를근거로최근의우울증의치료약물은세로토닌성신경전달을증가시키는것이주된흐름이며 2) 이것이또한기분장애에서단가아민가설의근거가되고있다. 3) 세로토닌수용체는 14가지아형이알려져있고이들은 5-HT1A-F, 5-HT2A-C, 5-HT3, 5-HT4, 5- HT5, 5-HT6 와 5-HT7 수용체이며이것은일곱개의세부아형 (subcalss) 으로나누어진다. 2)4) 그러나각각의세로토닌수용체아형기능이 depression 의원인과치료와의연관성에대한근거는아직부족한상태이다. 5) 따라서각각의세로토닌수용체세부아형과우울증에대한연관성을규명하기위한연구들이필요하고그중요성이증가되고있다. 7가지수용체세부아형중 5- HT6 수용체가우울증과의연관성을시사하는여러가지근거들이제시되어왔다. 첫째로 5-HT6 수용체는중추신경계에만분포하고있으며특히 striatum, nucleus accumbens, olfactory tubercle 에높은밀도로분포하고있고 amygdala, hypothalamus, thalamus, hippocampus 와 cerebral cortex 에중등도의밀도로분포하는것이밝혀짐으로서 6-10) 우울증의해부학적부위인변연계와밀접한연관성이알려지게되었다. 두번째로항우울제의작용기전과관련된근거로서우울증환자에서낮아져있는 GABA 활성도가 selective serotonin receptor inhibitors(ssris) 장기투여에의해정상화된다는연구와 11) WAY 과 WAY 과같은 5-HT6 agonist 가 GABA 활성도를증가시킨다는연구, 12)13) 그리고 5-HT6 agonists 에의해나타나는초기효과와 SSRIs 장기투여에의한효과와의연관성이제기됨으로서 14) 항우울제작용기전과 5-HT6 수용체의연관성에대한추가적인연구의필요성증가되었다. 이후에도기분장애와항우울제작용에서 5-HT6 수용체가중요한역할을할가능성이높다는연구들로인 해 15-18) 5-HT6 수용체는우울증연구의중요한후보 유전자로서의가치가매우높다고하겠다. 그러나지금까지시행된연구중주요우울장애에서 5-HT6 수용체와항우울제치료반응의연관성에대한연구는거의없 는상태이며결과또한일관성이부족한상태이다. Wu 등 20) 과 Yu 등 21) 이주요우울증환자에서항우울제반응과 5-HT6 수용체 C267T 다형성과의상관관계연구에서연관성을발견하지못하였으며 Vogt 등 22) 은양극성장애우울증환자에서항우울제반응과 5- HT6 수용체 C267T 다형성과의상관관계를찾지못하였다. 단지 Lee 등 23) 의연구만 CT 유전자형이항우울제치료반응과의미있는상관관계를보였다고하였다. 이는그동안축적되어온 5-HT6 수용체와기분장애와의연관성을시사하는여러가지근거와항우울제치료반응에서 5-HT6 수용체의중요한역할을제시하는다양한연구가있음에도불구하고이를확인하는연구가부족하며결과도일관되지못한상태이므로저자는주요우울장애환자에서대표적 SSRI 항우울제인 citalopram 을사용하여 5-HT6 수용체 C267T 다형성과항우울제치료효과와의상관관계를알아보고자한다. 방법 1. 연구대상고려대학교안암병원정신과에입원혹은외래진료를받았던환자들중, 두명의정신과전문의에의한면담과임상적관찰, 의무기록조사와보호자들에의한정보등에의하여 DSM-IV 에따른주요우울장애로진단된환자들을대상으로하였다. 대조군은건강검진을위해병원을방문한신체건강한사람으로서정신과전문의에의한면담에서정신과질환이없는사람을대상으로무작위선정하였다. 약물남용, 약물중독, 주요정신과질환의개인력이나가족력이있는환자는대상에서제외하였다. 우울증의심각도는 Hamilton Depression Rating(HA- MD-21) scale 24) 과 CGI-S(Clinical Global Impression of Severity) scale로 baseline과 1, 2, 4, 8주에각각측정하였으며 baseline HAM-D 점수가 18점이상의환자만을대상으로선정하였다. 반응군 (Rp) 에대한정의는 HAM-D 점수가 baseline 에비해최소 50% 이상감소한경우로, 관해군 (Rm) 에대한정의는 4주혹은 8주치료후 HAM-D 점수가 7점이하인경우로정하였다. 연구이전 citalopram 의대사에영향을미칠수있는약물을복용하던환자들에게는 2주간의 wash out 기간을가졌으며 citalopram 의하루처방용량은 10~40mg 이었다. 모든대상환자들은본연구의목적과과정에대한설명

3 을들은후서면동의를하였다. 이연구는고려대학교안암병원임상연구심사위원회 (IRB) 심의를통과하였다. 정맥혈채취는고려대학교안암병원임상연구윤리위원회에서승인한 protocol 에따라환자의동의서를받고시행하였다. 2. 연구방법 DNA 는 proteinase K를이용하여전혈에서채취하였다. 시발체 (forward;f:5'-tgc TGA TCG CGC TCATCT GCA CTC A-3' and reverse;5'-ctg CAG CGT CTC CGA GGC CTG ACT G-3') 를합성하여표적 DNA를 PCR 로증폭하였다. 시료는 thermocycler(perkin-elmer, Boston, MA, USA) 를사용하여중합효소연쇄반응을시행하였다. 94 에서 5분을수행한후 94 에서 30초 58 에서 30초 72 에서 30초간 35주기를시행한후마지막으로반응후신장을위하여 72 에서 5분수행후 4 에서보관하였다. 중합효소연쇄반응을통해증폭된생성물의다형성을분석하기위해제한효소인 NlaIII(New England Biolabs) 를사용하여 37 에서 2시간처리후제한효소처리생성물을 2% agarose gels 을이용하여분리하였다. 3. 통계분석통계분석을위해 SPSS version 10.0 을사용하였다. 주요우울장애환자군의유전자형및대립유전자의빈도를비교하기위하여 chi-square test 를이용하였다. 변량분석 (ANOVA) 와 student t-test 를사용하여유전자형과대립유전자의분포에따른 HAM-D 점수를분석하였다. 통계적유의수준은양측검증, p<0.05 이하로정의하였다. 결과 연구대상이된주요우울증환자는 134 명정상대조군은 167명이었다. 환자군과대조군간의성별에유의한차이는없었다 (p=0.4113). 그러나나이과교육수준에서는유의한차이를보였다 ( 표 1). ITT(Intent-to-treat) 군에대한분석에서유전자형분포는주요우울장애환자군과대조군모두에서 Hardy- Weinberg equilibrium 범위에있었다. 주요우울장애환자군에서 C/C군은 43명 (47.8%), T/C군은 38명 (42.2%), T/T 군은 9명 (10.0%) 였으며정상대조군은 C/C 군은 77 명 (52.4%), T/C 군은 58 명 (39.5%), T/T 군은 12 명 (8.1 %) 로두군간의유전자형분포는통계적으로유의한차이는없었다 ( 표 2, p=0.759). ITT 군에대한분석에서주요우울증환자군에서치료반응군과비반응군간의유전자형 (p=0.9128) 과대립유 Table 1. Baseline characteristics Variable Group MDD Normal p-vlaue Male sex 39(29.1%) 56(33.5%) <0.4113* Age 53.1± ±9.0 < Education(yr) Middle school graduate 55(45.8%) 45(27.1%) <0.0034* High school graduate 32(26.7%) 52(31.3%) More than high school 33(27.5%) 69(41.6%) *:chi-squared test, :two-sample t-test Table 2. Distribution of genotype and allele frequencies of HTR6T267C polymorphism among MDD and normal patients Group Genotype Alleles C/C T/C T/T C T MDD(n=90) a * 43(47.8%) 38(42.2%) 9(10.0%) 124(68.9%) 56(31.1%) Normal(n=147) 77(52.4%) 58(39.5%) 12(8.1%) 212(72.1%) 82(27.9%) a:intent-to-treat group. LOCF(last-observation-carried-forward) analysis is performed for missing data in HAMD scores. *:Hardy-Weinberg equilibrium test for MDD group:χ 2 =0.0194, d.f.=2, p=0.9903, :Comparison of genotype frequencies between MDD and normal group:χ 2 =0.5516, d.f.=2, p=0.7590, :Comparison of allele frequencies between MDD and normal group:χ 2 =0.5609, d.f.=1, p=0.4539, :Hardy-Weinberg equilibrium test for normal group:χ 2 =0.0492, d.f.=2, p=

4 Table 3. Distribution of genotype and allele frequencies of HTR6T267C polymorphism among responsive and non-responsive patients ITT group a Genotype* Allele C/C T/C T/T C T Responsive(n=63) 31(49.2%) 26(41.3%) 6(09.5%) 88(69.8%) 38(30.2%) Non-responsive(n=27) 12(44.4%) 12(44.4%) 3(11.2%) 36(66.7%) 18(33.3%) a:intent-to-treat group. LOCF(last-observation-carried-forward) analysis is performed for missing data in HAMD scores. *:Comparison of genotype frequencies between responsive and non-responsive group:χ 2 =0.1824, d.f.=2, p=0.9128, :Comparison of allele frequencies between responsive and non-responsive group:χ 2 = , d.f.=1, p= Table 4. Distribution of genotype and allele frequencies of HTR6T267C polymorphism among patients with remission and without remission ITT a group Genotype Allele C/C T/C T/T C T Remission*(n=36) 19(52.8%) 12(33.3%) 5(13.9%) 50(69.4%) 22(30.6%) No remission(n=54) 24(44.4%) 26(48.2%) 4(07.4%) 74(68.5%) 34(31.5%) a:intent-to-treat group. LOCF(last-observation-carried-forward) analysis is performed for missing data in HAMD scores. *:Remission group is defined by patients whose HAMD score at week 8 is less than 7, :Comparison of genotypes between patients with remission and without remission χ 2 =2.3442, d.f.=2, p=0.3097, :Comparison of alleles between patients with remission and without remission χ 2 =0.0173, d.f.=1, p= Table 5. Comparison of changes of HAMD scores across study period among genotypes(itt group analysis, n=91) Genotype HAMD score Baseline Week 1 Week 2 Week 4 Week 8 p-value* p-value C/C 25.0± ± ± ± ±8.5 C/T 23.6± ± ± ± ±5.5 C/T 23.9± ± ± ± ±6.2 < Overall, 24.3± ± ± ± ±7.1 p-value *:Repeated measures ANOVA p-value for testing overall mean HAMD score changes across time period, : ANOVA test at each of time period, :Testing overall mean HAMD score changes comparing to that of baseline:week 1 vs. baseline(p<0.0001);week 2 vs. baseline(p<0.0001);week 4 vs. baseline(p<0.0001);week 8 vs. baseline(p<0.0001), :Testing cubic trend of overall mean HAMD score changes:p=0.0121, :Repeated measures ANOVA p-value for testing mean HAMD score changes by genotypes across time period 전자의분포 (p=0.6733) 는유의한차이는없었다 ( 표 3). ITT 군에대한분석에서 8주치료후관해군과비관해군간의유전자형 (p=0.3097) 과대립유전자의분포 (p= ) 는유의한차이는없었다 ( 표 4). 주요우울장애환자군의모든유전자형에서 baseline 보다 1, 2, 4, 8주모두 HAMD 점수상통계적으로유의하게우울증상이개선되었다 ( 표 5, p=0.0001). 토론 1993 년에 5-HT6 수용체의발견과함께염기서열이밝혀진이후다른 5-HT 수용체와구별되는약물역학적 특성이알려지게되었다 ) Gerard 등 28) 은 5-HT6 수용체는 5-HT 신경원의외부에위치해있어서자가수용체가아니라는것을발견하였고, Ward 등 29) 은 5- HT6 수용체 mrna 가 5-HT 신경세포체보다 5-HT 신경말단에더많이발현되는것으로보아 5-HT6 수용체는주로시냅스후연접부위에위치한다고밝혔다. 이후 5-HT6 수용체 agonist 의발견은주요우울증과 5- HT6 수용체기능과의연관성에관심을가지게되는길을열어주었다 ) 5-HT6 수용체 agonist 가항우울제기능을나타낼가능성에대한근거로 SSRI 와같은항우울제들이 BDNF 유전자발현을증가시키는것과유사하게 5-HT 수용체아형중에 5-HT6 수용체가 BDNF

5 변화를조절하는데관여하고있어 5-HT6 수용체와항우울제반응과의연관성에대한근거로제시하였다. 30) 5- HT6 agonist 인 LY586713이투여직후와투여초기 (4 day) 모두에서 hippocampus BDNF mrna 발현을증가시켰으며이효과는 5-HT6 antagonist 에의해차단되는것을밝혀내었다. 31) 5-HT6 수용체와항우울제반응과의연관성에대한또다른근거로 5-HT6 수용체가대뇌피질과변연계영역에주로위치하는특성을가지고있으며, 6-10) 여러항우울제들이 5-HT6 수용체에강력한친화력을보이고주요우울증에서 5-HT6 수용체의잠재적인기능을강하게시사하는여러연구들에 32-35) 기초하여시행한본연구는기대와달리주요우울증환자와대조군비교에서 5-HT6 gene C267T 유전형과대립유전자분포에서의미있는차이를보이지않았다. 또한 citalopram 치료에반응군과무반응군의비교와관해군과비관해군의비교에서도의미있는차이를발견할수없었다. 이런결과는이전의소수연구에서도보여준부정적결과와일치하고있어서, 20-22) 주요우울증에서항우울제반응과 5-HT6 gene C267T 유전자형의기능이상관관계가없는것으로생각된다. 그러나이러한결과를일반화하기위해서는몇가지이번연구가가지는한계점에대한검토가필요하다고생각된다. 첫째, 단지 90명의주요우울장애환자가 8주간의 citalopram 치료를완료하였다. 작은표본크기로인해보통의경우신뢰구간이확장되고검증력이낮아지는문제점때문에우리의결과를일반화하는데한계점이있다. 향후연구는충분한분석력을확보하는대상군이필요하겠다. 둘째, 투여된 citalopram 의혈장농도를측정하여비반응군과비관해군에서개개인의차이를고려하지않은점이다. 그러나 Arias 등 36) 의연구에서는 citalopram 의혈장농도와치료반응사이에연관성이없었다고보고하였으므로혈장농도가연구결과에영향을미치지않았을가능성이높지만개인간의다양한차이가존재할가능성을배제할수는없으므로직접확인하지못한점은한계점으로남는다. 셋째, 주요우울증환자군에초발환자와재발환자군이구분되지않고섞여있다는점이다. 재발횟수에따라투여약물에대한환자의순응도및치료반응에영향을미쳤을가능성이있다. 따라서향후연구에서는초발환자군만을대상으로하는것이주요우울증환자의유전자형에따른치료반응의편차를줄이는방법이될것이다. 향후충분한숫자의대상군에서약물농도, 입원경력, 발병연령, 재발횟수등의변인을고려한연구를통해 5-HT6 유전자와의관련성을확인해보는과정이필요하다. 중심단어 :MDD 5HT6 C267T Citalopram. 참고문헌 1. Williams RB. Neurobiology, cellular and molecular biology, and psychosomatic medicine. Psychosom Med 1994; 56: Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999;38: Iversen L. The monoamine hypothesis of depression. In: Biology of depression(licinio J, Wong ML, eds); p Weinheim, Germany: Wiley-VCH. 4. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ. International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 1994;46: Heninger GR, Delgado PL, Charney DS. The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 1996;29: Boess FG, Riemer C, Bös M, Bentley J, Bourson A, Sleight AJ. The 5-hydroxytryptamine6 receptor-selective radioligand [3H]Ro labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum. Molecular Pharmacology 1998;54: Gerard C, el Mestikawy S, Lebrand C, Adrien J, Ruat M, Traiffort E. Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mrna in the central nervous system of control or 5, 7-dihydroxytryptamine-treated rats. Synapse 1996;23: Gerard C, Martres MP, Lefevre K, Miquel MC, Verge D, Lanfumey L. Immuno-localization of serotonin 5- HT6 receptor-like material in the rat central nervous system. Brain Research 1997;23: Ward RP, Hamblin MW, Lachowicz JE, Hoffman BJ, Sibley DR, Dorsa DM. Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry. Neuroscience 1995;64: Yoshioka M, Matsumoto M, Togashi H, Mori K, Saito H. Central distribution and function of 5-HT6 receptor subtype in the rat brain. Life Sciences 1998;62: Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 2002;159: Schechter LE, Smith DL, Zhang G, Li P, Lin Q, Lu

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar