주요우울증과 세로토닌수송단백질 유전자의 다형성

임신원,손성은,김도관,김이영 大韓神經精神醫學會 2000 신경정신의학 Vol.39 No.1

연구목적 : 세로토닌 수송단백질(serotonin transporter, 5-hydroxytryptamine transporter, 5-HTT)은 세로토닌계에서 이루어지는 신경전달을 시냅스전 신경세포로 재흡수함으로써 종결시키는 데 중요한 역할을 하고, 삼환계 항우울제나 선택적인 세로토닌 재흡수 차단제의 주요 항우울제의 작용 개시 부위로 알려져 왔다. 본 연구에서는 5-HTT 유전자와 주요 우울증 간의 관련성을 알아보고 이 유전자의 유전자형 특성이 항우울제에 대한 반응정도와 관련이 있는지 알아보고자 하였다. 방 법 : 142명의 우울증 환자들(주요 우울증과 기분 저하증 환자)과 성별, 나이와 대응시킨 252명의 정상 성인들로 모두 한국인을 대상으로 하였다. 약물에 대한 반응 정도를 평가하기 위하여 5-HTT에 작용하는 항우울제를 투여하기 전 우울증상의 정도와 투여 후 6주 이상이 지난 후의 우울증상의 정도를 17 항목의 Hamilton Depression Rating Scale(HDRS)를 이용하여 측정하였다. 5-HTT 유전자 다형성은 genomic DNA의 2번째 intron과 조절부위(promoter region)를 PCR 증폭함으로 분석하였고, sequencing하여 염기서열의 copy 수를 확인하였다. 결 과 : Allele의 빈도는 정상 성인군과 환자군 간에서 차이점을 발견할 수 없었다(STin 2.12, 90.5% vs, 89.9% ; 14-copy 5-HTTLPR, 74.8% vs. 75.2%). 항우울제에 대해 반응을 보이는 군이 반응을 보이지 않는 군보다 intron2 부위의 12 copy allele과 promoter 부위의 14 copy allele과 통계적으로 유의한 관련성을 보였다.(각각 p<0.0001, p=0.0028, by Fisher exact test). 결 론 : 이러한 결과는 5-HTT 유전자 다형성이 주요 우울증에 대한 취약성과의 관련성보다는, 항우울제에 대한 반응성이 5-HTT 유전자 변화와 관련이 있음을 나타낸다. Objectives : Serotonin transporter(5-hydroxytrytamine transporter, 5-HTT) plays a critical role in the termination of serotonergic neurotransmission into the presynaptic neuron and represents an initial site of uptake inhibiting antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. We investigated the possible association between the 5-HTT gene and major depression, and examined whether there are genotypic characteristics in 5-HTT gene that result in treatment nonresponsiveness to uptake inhibiting antidepressants. Methods : 5-HTT gene polymorphisms are analyzed with the primers flanking the second intron and regulatory region from genomic DNA. We genotyped 142 patients with major depression and dysthymia, and 252 age and sex matched normal subjects. All individuals were Korean. Results : We found no significant differences in the allele frequency(2nd intron, p=0.941 ; promoter, p=0.122) between patients and controls. However, in association studies between antidepressant responsiveness in depressive patients and allele frequencies of 5-HTT gene polymorphism in intron2 and promoter regions, there was shown significant differences in both (p<0.0001, p=0.0028, respectively by Fisher exact test). Conclusions : These results suggest that there is no major effect of 5-HTT gene polymorphisms on the susceptibility to major depressions, while antidepressant nonresponding is related with genotypic alteration in 5-HTT gene.

기분 장애 환자에서 나타나는 불특정 CAG 삼핵산 반복서열의 확장

손성은,임신원,이소영,황혜진,진동규,박정의,김도관,김이영 대한신경정신의학회 2000 신경정신의학 Vol.39 No.2

연구목적: 기분장애는 그 원인과 발생기전은 아직 밝혀져 있지 않고 있지만, 과거부터 유전적 요인이 질병의 발생과 중요한 연관성을 가지고 있다고 알려져 있다. 특히 양극성 정동장애는 가족력이 있는 경우에 발병될 가능성이 높고, 같은 가족 내에서 발생했을 때 세대가 내려감에 따라서 발병시기가 점차 빨라지며 증세가 심해지는 경향이 있어서 그 유전적 배경에 대해 많은 의문이 있어 왔다. 연구자들은 다양한 증상의 기분장애 환자들의 DNA에서 불특정 CAG 삼핵산 반복(trinucleotide repeat. TNR) 정도를 분석함으로써 TNR 확장이 기분장애의 유전과 관련되는지 살펴보았다. 방법: 환자 군은 DSM-Ⅲ-R 진단기준에 의거하여 양극성 정동장애(N=55), 주요우울장애(N=67) 환자들을 선발하였다. 정상인(N=89)은 정신과적 병력이 없고 다면성 인성검사상 정상의 profile을 나타내는 병원 종사자, 학생 및 건강의학센타 방문자들 중 선발하였다. TNR의 확장은 genomic DNA를 순수분리한 후, (CTG)₁□의 oligonucleotide를 □-□□P-ATP로 방사선 표지하여 반복서열 확장 탐지법(repeat expansion detection)으로 측정하였다. 집단간의 비교를 위해 Mann-Whitney U 검증을 실시하였다. 결과: DNA에서 관찰되는 불특정 CAG 삼핵산 반복 길이의 평균은 양극성 정동장애에서 169.8bp(S.D=58.6), 주요우울장애에서 167.5bp(S.D=63.9)로서 대조군 178.7bp(S.D=56.5)과 비교하였을 때 유의미한 차이는 관찰되지 않았다. 각각의 환자군을 가족력이 있는 군과 없는 환자군으로 나누어 대조군과 비교하였을 때도 유의미한 차이는 관찰되지 않았다. 결론: 불특정 CAG 삼핵산 반복서열 확장이 양극성 정동장애 환자와 주요우울장애 환자들의 유전 양식에 영향을 미친다는 가설을 뒷받침하지 않는다. Objectives: The genetic facotrs have been suggested for the etiology of mood disorders but the mode of inheritance is complex. Increased severity and an earlier onset of the bipolar and major depressive disorder over generations within families(Anticipation) were reported. In order to test the hypothesis that trinucleotide repeat expansions underlie the genetic basis of Bipolar and major depressive disorders, we have analyzed the extent of CAG reapeats in genomic DNA from mood disorder patients. Methods: 55 bipolar disorder, 67 major depressive disorder patients were recruited accord-ing to the DSM-Ⅲ-R criteria. 89 normal controls were recruited from the medical personnel, students and the visitors to the health services center who had no history of psychiatric illness and show normal profile of MMPI. The genomic DNA of patients and controls was analyzed by use of the (CTG)□ oligonucleotide and the repeat expansion detection(RED) method. The Mann-Whitney U test was used to compare the distribution of the number of CAG repeats among the groups. Results: when the bipolar disorder, major depressive disorder patients were compared with the control group, no significant differences were observed. Conclusions: Our results do not support the hypothesis that expanding CAG repeats are causing the observed genetic anticipation in bipolar disorders and major depressive disorders.

정신분열병 환자의 KCNN3 유전자에서 나타나는 삼핵산 반복서열

김도관,임신원,고효정,서민영,손성은,이소영,황혜진,진동규,김병로 大韓神經精神醫學會 2001 신경정신의학 Vol.40 No.5

연구목적 : 연구자들은 NMDA 수용체의 channel protein 합성에 관여하는 KCNN3 유전자에서 나타나는 삼핵산 반복서열(triple nucleotide repeat, TNR) 확장이 과연 정신분열병의 발병에 기여하는지를 최근 개발된 TNR copy 수를 정량화 함으로써 알아보고자 하였다. 방 법 : 연구대상은 정신과 외래 및 입원 환자 중 정신분열병 환자 245명과 건강 의학센타를 방문한 정상 성인 116명을 각각 선발하였다. 정신분열병 환자들이 정상인에 비하여 불특정 CAG 삼핵산 반복 서열 확장에 차이가 나는지 repeat expansion detection(RED) 방법을 확인한 다음, 그것이 KCNN3이나 CTG18.1 유전자의 CAG 반복서열 증가에 의한 영향인지 분석하였다. 그리고 untranslated region에서 TNR 증가를 불특정하게 일으킬 수 있는 ERDA1의 CAG 삼핵산 반복서열의 영향을 검증함으로써 KCNN3나 CTG18.1 유전자가 정신분열병의 발병에 기여하는 바를 평가하였다. 결 과 : 정신분열병 환자는 정상인에 비하여 KCNN3 유전자 부위에서 TNR 확장이 현저한 longer allele이 빈번하게 관찰되었다. 즉, KCNN3 유전자 부위에서 CAG 삼핵산 반복이 19번 이상 확장되는 염색체가 신분열병 환자군에서는 73.3% 발견되는 데 비해서 정상인군에서는 65.1% 발견되어 유의한 차이가 있었다(p=0.029, Fisher's exact test). 이러한 차이는 가족력이 있는 정신분열병 환자군(79.7%)에서 가족력이 없는 환자군(70.8%)보다 더욱 현저하게 관찰되었다(p=0.003, Fisher's exact test). 음성형과 양성형 정신분열병 환자군 간에서의 차이는 관찰되지 않았다. CTG18.1 유전자 부위의 TNR 확장이나 불특정 부위 염색체 전체에서의 TNR 확장은 환자군과 정상 대조군 간에 차이가 없었다. 환자군과 대조군 모두에서 불특정 TNR 확장은 ERDA1의 전사와 유의하게 관련성이 있었다(각각 r=0.45, p<0.001 ; r=0.44, p<0.001). 하지만 KCNN3 유전자 부위에서 TNR 확장은 ERDA1 score와 유의한 관련성을 보이지 않았다. 결 론 : 이상의 결과는 KCNN3 유전자가 한국인 정신분열병의, 특히 가족력이 있는 정신분열병의, 발병에 관여할 수 있음을 시사한다. 또한 ERDA1 전사는 불특정 TNR 확장의 원인으로 작용한다는 가설을 뒷받침한다. Objects : We investigated a possible association between the polymophic trinucleotide repeat(TNR) expansion in neuronal potassium channel gene KCNN3 and schizophrenia. Methods : CAG/CTG repeat distribution in KCNN3, CTG8.1 and ERDA1 was examined and the copy number of ligation product in repeat expansion detection(RED) was measured in Korean patients with schizophrenia(n=245) and ethnically matched healthy controls(n=116). Results : Longer alleles in the KCNN3 gene were over-represented in patients. The frequency of alleles with CAG repeats longer than 19 copy in the KCNN3 gene was higher in the patients with schizophrenia as compared to controls(73.3% vs 65.1% ; p=0.029, Fisher's exact test). And this difference was more prominent in schizophrenic patients with familial background(p=0.03, Fisher's exact test). We found no difference in the frequency of longer alleles between negative and positive subtypes of schizophrenia. Ligation product size in RED and alleles with CAG repeat number in the CTG18.1 gene was not increased in the patients. The copy number of ligation product in RED was highly correlated with CAG/CTG copies if ERDA1 in the patient group(r=0.45, p<0.001) as well as in the control group(r=0.44, p=<0.001). However, CAG repeat length in the KCNN3 gene was not correlated with ERDA1 score. Conclusions : Our results support the hypothesis that the longer allele of KCNN3 may be considered as a candidate gene for schizophrenia, especially in the case with familial background. And the RED assay results was affected by the CAG copy number of ERDA1.

주요우울증에서 단가아민 전달체 유전자 다형성과 Mirtazapine 치료 반응의 연관성에 대한 연구

최홍,임신원,김수연,김혜란,정재원,김도관 대한정신약물학회 2008 대한정신약물학회지 Vol.19 No.5

Objective:Genetic differences may contribute to the inter-individual differences in treatment response to antidepressants among patients suffering from major depression. This study investigated a possible association of various monoamine transporter genetic polymorphisms with treatment response to mirtazapine in major depressive patients in elderly. Methods:In this study, three genetic polymorphisms were selected:serotonin transporter 5- HTTLPR, serotonin transporter 5-HTT intron 2 VNTR, and norepinephrine transporter NET (G1287A). The patients with major depression diagnosed by DSM-IV were recruited to a 6 week naturalistic mirtazapine treatment study in Samsung Medical Center. Treatment response to mirtazapine was defined as ≥50% decrease in HAMD- 17 scores at 6 weeks, and the genotypes in the patients were determined using the polymerase chain reaction. Results:Our results showed that ss allele carriers were included more in responder group (ss allele in responder vs. non responder group;69.4% vs. 40.0%). In addition, l-allele (sl/ll) carriers were included less in responder group (sl/ll allele in responder vs. non responder group;30.6% vs. 60.0%). Multiple logistic regression analyses showed the 5-HTTLPR polymorphism as an predictor of the mirtazapine response (5HTTLPR ss allele carrier vs. l-allele (sl/ll) carrier;odds ratio:3.81;95% confidence interval [CI], 1.32-11.0;p=0.013). However, 5-HTT intron 2 VNTR l/s (p=0.33 by multiple logistic regression;[OR], 0.53;95% [CI], 0.15-1.88), and NET (G1287A) G/A (p=0.68 by multiple logistic regression;[OR], 1.25;95% [CI], 0.44-3.53) showed no statistical significant influences on response rate. Conclusion:In conclusion, 5HTTLPR polymorphism may predict treatment response to mirtazapine in major depressive patients in elderly. 우울증 환자의 치료 반응이 개개인 마다 차이가 나지 만, 이를 미리 예측할 수 있는 방법은 아직 확립되지 못 하였다. 이러한 치료 반응을 예측하기 위해서 많은 연구 가 진행되고 있으며, 특히 유전자 다형성과 치료 반응의 연관성에 대한 연구가 활발히 진행되고 있다. 본 연구에 서는 한국인 우울증 환자를 대상으로 단가아민 전달체 관련 유전자 다형성과 mirtazapine 치료 반응의 연관성 을 연구하였다. 단가아민 전달체 유전자 다형성 중에서 세로토닌 전달 체 5-HTTLPR, 5-HTT intron 2 VNTR, 노르에피네 프린 전달체 NET(G1287A) 등을 선택하였고, 6주 간 의 mirtazapine 약물치료가 종료된 66명의 주요 우울 증 환자들을 대상으로 HAMD-17의 총점수가 치료 전 에 비해 50% 이하로 떨어지는 환자를 치료 반응군으로, 그렇지 않은 경우에 비반응군으로 분류한 다음, 단가아 민 전달체 유전자 다형성들이 치료 반응에 어떤 영향을 미치고 있는지 연구하였다. 그 결과 5HTTLPR ss allele 보유자는 치료 반응군 에 유의하게 많이 분포하고 있으며(69.4% vs. 40.0%), 5HTTLPR l-allele(sl/ll) 보유자 경우에는 치료 반응군 에서 유의하게 적게 분포하고 있음이(30.6% vs. 60.0%) 확인되었다(p=0.013 by multiple logistic regression; odds ratio [OR], 3.81;95% confidence interval [CI], 1.32-11.0). 그렇지만, 동일한 환자군에서 5HTT intron2 VNTR, NET(G1287A) 유전자 다형성은 mirtazapine 치료 반응에 유의한 영향을 주지 못하는 것이 확인되었다. 이러한 결과는 단가아민 전달체 중에서 세로토닌 전 달체의 5-HTTLPR ss allele을 가진 우울증 환자군의 경우에, l-allele (sl/ll)을 가진 환자군 보다 mirtazapine 치료에 잘 반응한다는 것으로 해석할 수 있다.

식이유도 비만 마우스에서 칸나비디올(Cannabidiol) 오일의 체중 감량 효과에 대한 검증연구

한새샘,임신원,이수진,김도관 대한신경정신의학회 2022 신경정신의학 Vol.61 No.4

Objectives This study aimed at investigating the pharmacological and physiological effects of cannabidiol (CBD) oil on weight loss in diet-induced obese (DIO) mice. Methods A DIO mice model was constructed with 33 C57BL/6 male mice, aged six weeks, who had been fed a high-fat diet for 13 weeks. Subsequently, 20 mg/kg (n=11) or 60 mg/kg (n=11) of CBD oil or sesame seed oil (n=11) per day was given along with a high-fat diet for four weeks. The body weight of each subject was measured weekly, and venous blood was drawn for biochemistry and enzyme-linked immunoassay before and after the four-week trial period. An oral glucose tolerance test was performed to assess glucose metabolism. At the end of the CBD oil treatment, dual-energy X-ray absorptiometry was used to calculate body fat composition, and the mesenteric adipose tissue was measured as representative of the fat mass of each subject. For statistical analysis, we used the Kruskal-Wallis test, Turkey’s test using ranks and generalized estimating equations. Results After administration of CBD oil (60 mg/kg) for four weeks, the DIO mice showed significant weight loss, compared to the sham control mice (p=0.027). Mice fed with 60 mg/kg of CBD oil also had a significant reduction in fat percentage (p=0.009) and mesenteric fat weight loss (p=0.024), compared to the sham control mice, even with higher food intake (p=0.029). Moreover, mice fed with 60 mg/kg of CBD oil showed a significant improvement in glucose tolerance (p=0.003) and lower plasma leptin levels (p=0.006). Conclusion This study shows that orally administered CBD oil induces weight loss in DIO mice. It has been postulated that CBD oil attenuates an over-activated endocannabinoid system, thereby increasing energy expenditure, and improving glucose metabolism and leptin resistance.

Serum Cytokine Levels in Major Depressive Disorder and Its Role in Antidepressant Response

명우재,임신원,우혜인,박진홍,심상홍,Soo-Youn Lee,김도관 대한신경정신의학회 2016 PSYCHIATRY INVESTIGATION Vol.13 No.6

ObjectiveaaCytokines have been reported to have key roles in major depressive disorder (MDD). However, much less is known about cytokines in MDD and antidepressant treatment due to the diversity of cytokines and the heterogeneity of depression. We investigated the levels of cytokines in patients with MDD compared with healthy subjects and their associations with antidepressant response. MethodsaaWe investigated the changes of several cytokines (eotaxin, sCD40L, IL-8, MCP-1alpha, TNF-alpha, INF-gamma and MIP-1alpha) by Luminex assay in 66 patients with MDD and 22 healthy controls. The antidepressant response was assessed by 17-item Hamilton Rating Scale for Depression. ResultsaaWe found the levels of sCD40L (p=0.001), IL-8 (p=0.004) and MCP-1 (p=0.03) of healthy controls were significantly higher than those of depressive patients. However, the level of eotaxin and TNF-alpha were not associated with MDD. In addition, we found the level of MCP-1 was significantly changed after antidepressant treatment (p=0.01). ConclusionaaThese findings suggest the roles of cytokines in MDD are complex, and could vary according to the individual characteristics of each patient. Further studies regarding the relationship between cytokines and MDD will be required.

식이유도 비만 마우스에서 대마 추출물의 체중 감량 효과에 대한 예비 연구

장유진,임신원,우숙영,김수연,김도관 대한신경정신의학회 2020 신경정신의학 Vol.59 No.3

Objectives This study aimed to investigate the pharmacological effect of cannabis extract on weight loss in diet-induced obese mice. Methods A total of 12 C57BL/6 male mice (Orient Bio), aged 6 weeks, were fed a high-fat diet for 13 weeks to construct a diet-induced obesity model. During the following 5 weeks, diet-induced obese mice were daily administered cannabis extract or sesame seed oil orally along with the high-fat diet. The body weight of each subject was measured weekly. Venous blood was drawn for biochemistry, enzyme-linked immunoassay, and oral glucose tolerance test before and after treatment. Body fat was measured by dual-energy X-ray absorptiometry, and the mesenteric adipose tissue was also measured after sacrifice. We used exact Wilcoxon’s two-sample analyses and generalized estimating equations to test the differences between the cannabis-treated group and control. Results There was significant weight loss (p=0.009) observed in the cannabis-treated mice compared to the control group after 5 weeks of treatment. High-fat diet-induced glucose intolerance in the cannabis-treated group was significantly ameliorated (p=0.032), whereas there were no profound differences between the two groups in terms of other physiological markers, including corticosterone level. Conclusion This study shows that orally administered cannabis extract had a pharmacological effect of weight loss in diet-induced obese mice. This weight loss might be attributed to an increase in energy expenditure and regulation of glucose homeostasis.

말초 T 림프구 내의 CREB 유전자 발현과 항우울제에 대한 반응성

신지영,임신원,정성호,김혜란,김도관 대한정신약물학회 2004 대한정신약물학회지 Vol.15 No.4

Objectives: The molecules related with the intracellular signal transduction system are one of the main targets for the mode of mechanisms of antidepressant treatment in depressive patients. In vivo and in vitro studies have provided the evidence that the transcription factor, CREB (c-AMP response element binding protein) is the key mediator of the therapeutic response to antidepressants. We investigated the relationship between the treatment response to fluoxetine for 6 weeks and the change of CREB immunoreactivity in peripheral T lymphocyte. Methods: CREB-expression and phosphorylation were quantified via western blot, and binding activity between transcription factor and CRE-oligonucleotide via electrophoretic mobility shift assay (EMSA) in nuclear extracts from 14 normal controls and 31 depressed patients at 0 and 6th week during fluoxetine treatment (20mg/day). Responder was defined as the 50% of reduction or 7 of HAM-D score. We compared the changes of CREB during 6 weeks of fluoxetine treatment between drug responders and non-responders using SPSS11.0. Results: After six weeks of treatment with fluoxetine, the drug responders showed a significant increase in CREB (p=0.024 by t-test) and p-CREB (p=0.045 by Mann-Whitney U test) compared with the non-responders. The change of CREB immunoreactivity was positively correlated with the change of p-CREB (r=0.770 p=0.000 by Spearman's rho), and the change of p-CREB was also positively correlated with CRE-DNA binding (r=0.753, p=0.000 by Spearman's rho). Conclusion: These results suggest that CREB response in peripheral lymphocyte may reflect and mediate the response to antidepressant treatment in depressed patients.

Association between the BDNF Val66Met Polymorphism and Chronicity of Depression

이유진,임신원,김수연,정재원,김진우,명우재,송지혜,김선우,Bernard J Carroll,김도관 대한신경정신의학회 2013 PSYCHIATRY INVESTIGATION Vol.10 No.1

Objective Both clinical and biological factors influence the course of depressive disorders. This study tested for associations between the brain-derived neurotrophic factor (BDNF) gene at the Val66Met locus and the course of major depressive disorder (MDD). Methods Three hundred ten Korean subjects (209 patients, 101 controls) were genotyped for rs6265 at nucleotide 196 (G/A), which produces an amino acid substitution at codon 66 (Val66Met) of the gene for BDNF. Course of illness was evaluated both by chronicity of current episode (episode duration >24 months) and by the lifetime history of recurrences. Results Patients with the Met/Met BDNF genotype had a significantly higher rate of chronic depression than all others. There was a significant dose effect of the Met allele on chronicity. Compared with the Val/Val genotype, the relative risk of chronicity was 1.67 for the Val/Met genotype, and 2.58 for the Met/Met genotype. Lifetime history of recurrent episodes was not related to BDNF genotypes but was significantly associated with younger age of onset and with a history of depression in first degree relatives. Conclusion BDNF genotyping may be informative for anticipating chronicity in major depression.

Serotonin Transporter Gene Polymorphisms and Chronic Illness of Depression

명우재,임신원,김진우,이유진,송지혜,장기원,김도관 대한의학회 2010 Journal of Korean medical science Vol.25 No.12

Clinical course of depression is variable. The serotonin transporter gene is one of the most studied genes for depression. We examined the association of serotonin transporter gene polymorphisms with chronicity and recurrent tendency of depression in Korean subjects. This cross-sectional study involved 252 patients with major depression. Patients were genotyped for s/l polymorphisms in 5-HTT promoter region (5-HTTLPR), s/l variation in second intron of the 5-HTT gene (5-HTT VNTR intron2). Chronicity was associated with 5-HTTLPR. Patients with l/l had higher rate of chronicity than the other patients (l/l vs s/l or s/s; odds ratio, 4.45; 95% confidence interval, 1.59-12.46; P=0.005; logistic regression analysis). Recurrent tendency was not associated with 5-HTTLPR. Chronicity and recurrent tendency were not associated with 5-HTT VNTR intron2. These results suggest that chronic depression is associated with 5-HTTLPR.