한국형 정신분열병 약물치료 알고리듬의 임상 적용 가능성 (I): 치료효과 측면에서의 분석

배승오,안용민,권준수,박원명,강대엽,기백석,김승현,김창윤,신영철,심주철,양병환,윤보현,윤진상,조성남,한상익,이홍식,김용식 대한정신약물학회 2006 대한정신약물학회지 Vol.17 No.1

Objectives: The Korean College of Neuro psychopharmacology and the Korean Academy of Schizophrenia developed the Korean algorithm project for schizophrenia to aid clinical decisions. The purpose of this study was to assess the feasibility of Korean Medication Algorithm for Schizophrenia patients in clinical settings in Korea. Methods: A total of 108 schizophrenia and schizophreniform disorder patients were enrolled at 19 centers and treated according to the algorithm. PANSS(Positive and Negative Symptom Scale) and CGI(Clinical Global Impression) were used to evaluate symptom severity. Also UKU(UKU side effect rating scale) and LUNSERS(Liverpool University neuroleptic side effect rating scale), DAI-10(Drug Attitude Inventory–10), PPS(Patient Preference Scale), SWN (self-rating scale to measure subjective well-being under neuroleptic treatment) and WHOQOL were used to evaluate tolerability and satisfaction of patient respectively. Results: Overall ratings including symptom severity, compliance of medication, side effect of medication, quality of life were favorable. The treatment response(PANSS improvement ≥20%) rate was 63%, 75% at the first Clinical decision point(CDP) and 4 month respectively. Conclusion: Symptom improvement, tolerability and quality of life were all favorable. These results suggest that this algorithm can be useful in clinical practices. 목 적:주요 정신과 질환의 약물치료에 대한 한국형 알고리듬의 개발사업으로 대한정신약물학회와 대한정신분열병학회에 의해 정신분열병에 대한 한국형 약물 치료 알고리듬이 개발되었다. 본 연구는 개발된 한국형 알고리듬을 실제 임상에 적용하여 그 효과 및 안정성 그리고 환자의 만족도에 대해 살펴보고자 하였다.방 법:19개 병원에서 정신분열병 및 정신분열형장애로 진단된 환자 108명을 대상으로 21명의 연구자들에 의해 한국형 알고리듬에 따라 치료를 시작하였다. 알고리듬에 따라 항정신병약물의 선택, 용량 조절, 단계이동, 부작용 및 동반증상에 대한 치료를 하였으며 이에 따른 증상호전을 위해 PANSS(Positive and Negative Sym-ptom Scale, 이하 PANSS)및 CGI(Clinical Global Im -presion)를, 내약성 평가를 위해 UKU(UKU side efect rating scale, 이하 UKU) 및 LUNSERS(Liver-pol University neuroleptic side effect rating scale, 이하 LUNSERS)를, 환자의 만족도 및 삶의 질에 대한 평가를 위해 DAI-10(Drug Atitude Inventory-10, 이하 DAI-10), PPS(Patient Preference Scale, 이하 PPS), Naber의 SWN(self-rating scale to measure subjective wel-being under neuroleptic treatment, 이하 SWN), 한국형 WHO-삶의 질 평가 척도를 사용하였다. 결 과:정신분열병 및 정신분열형장애 환자를 대상으로 한국형 알고리듬을 적용한 결과 치료효과 및 약물순응도, 부작용 척도 및 삶의 질 척도 모두에서 유의한 효과가 있었다. 또한 PANSS의 호전도를 기준으로 했을 때 약물투여 후 첫 번째 임상적 판단시점에서의 반응률은 63% (N=45)이었으며 4개월 종료시점에서는 75%(N=54)배승오 등 33 에 달하였다.

흰쥐 대뇌에서 몇 가지 기분조절제에 의해 유도되는 공통 유전자 검색 및 발굴 유전자에 대한 연합연구

배승오,김재민,안용민,이규영,노재우,윤진상,김용식 대한정신약물학회 2007 대한정신약물학회지 Vol.18 No.4

Objective: This study sought to identify candidate genes related to the clinical effects of several mood stabilizers through gene expression profiles using microarrays and real time RT-PCR. Method: Rats were treated with lithium carbonate, valproate, or clozapine for 10 days. Total RNA was extracted from the rat brains and used for microarray analysis. Of 54 genes showing more than 1.5-fold changes induced by all three mood stabilizers, seven genes were selected, and drug-induced changes in gene expression were confirmed by real time RT-PCR. In addition, genotype distribution of the GRIK2 gene was compared between 181 patients with bipolar disorder and 350 normal controls. Results: Of the seven candidate genes, GRIK2 and PRKAR were confirmed as being down-regulated by lithium and valproate. However, none of the genes was affected by all three drugs. The allele and genotype distribution in two SNPs of GRIK2 did not differ between the patient and control groups. Conclusions: Although this study demonstrated overall negative results, the present findings will be usedin future studies for establishing various mechanisms of mood stabilizers. 본 연구는 몇 가지 기분조절제의 임상효과와 관련된 후보 유전자를 검색하고 실제 발굴된 유전자와 양극성 장애의 연관성을 확인하고자 시행되었다. 리튬, 발프론산, 클로자핀 처치군으로 나누어 각 군 당 7마리의 흰쥐 복강에 10일 간 약물 투여 후 전두엽으로부터 RNA를 추출하였다. 추출된 RNA는 micro-array를 통해 유전자들의 발현 정도의 변화가 측정되었는데, 세가지 기분조절제 모두에서 1.5배 이상의 변화를 보인 유전자는 총 54개로 이 중 7개를 선택해 RT-PCR을 시행하였다. 이 후 GRIK2 유전자의 유전형 분포를 181명의 양극성 장애 환자와 350명의 정상 대조군간 비교하였다. 7개의 후보 유전자 중 GRIK2와 PRKAR은 발프론산과 리튬 처치군에서 공통적으로 발현이 감소하였지만 세 배승오 등 219가지 기분조절제 모두에서 발현의 증감을 보이는 유전자는 없었다. GRIK2 유전자에서 두 가지 단일 염기 다형성의 유전형 분포를 비교하였으나 환자군과 대조군 간의 유의한 차이는 관찰되지 않았다. 본 연구에서 세 가지 기분조절제에 의해 유도되는 공통 유전자는 확증할 수 없었지만 향후 기분 조절제의 다양한 기전을 밝히는데 유용하게 활용될 것이다.

고등학생을 대상으로 한 양극성 장애의 선별검사

배승오,윤보현,박원명,김문두,김희철,서정석,석정호,우영섭,이정구,최명수,김태운,홍정완 대한신경정신의학회 2009 신경정신의학 Vol.48 No.6

Objectives This study aimed to assess the prevalence of bipolar spectrum disorders among Korean high school students (individuals in late adolescence) using the Korean version of the Mood Disorder Questionnaire (K-MDQ). Methods Two thousand male and female participants were proportionately selected from among high school students nationwide. From November 2007 through February 2008, we conducted an epidemiological survey of, and administered the K-MDQ to, these participants, assessed their psychometric properties, and compared characteristics between K-MDQ-positive and K-MDQ-negative participants. Results The K-MDQ’s internal consistency (Cronbach’s alpha) was 0.74. The item-total score correlations ranged from 0.35 to 0.57, and all were statistically significant (p<.001). Factor analysis with varimax rotation revealed 3 factors that explained 42.6% of total variance. We found the cutoff endorsement of the K-MDQ score (7 or more in criteria 1) in 1207 students (60.4%) and found 104 (5.2%) subjects were K-MDQ-positive, meeting all 3 K-MDQ criteria. The mean K-MDQ total score was 7.2±2.9 and total scores of K-MDQ-positives and K-MDQ-negatives were 9.9±1.7 and 7.0±2.9, respectively. K-MDQ-positives and K-MDQ-negatives showed no differences in the sociodemographic variables we assessed. Endorsement of items in total subject ranged from 15.7% to 77.7%. All items except item 8 (more energy) differed significantly in endorsement between K-MDQ-positives and K-MDQ-negatives. Items accounting for over 30% of the endorsement differences between K-MDQ-positives and K-MDQ-negatives were“feel so good,” “so irritable,” and“excessive, foolish, risky behavior.” Conclusion The K-MDQ was a relatively valid screening tool for Korean high school students. Per the result of the K-MDQ survey, suspected lifetime prevalence of bipolar spectrum disorders for those in late adolescence (high school students) seems to be 5.2%, suggesting that systemic screening for bipolar spectrum disorder should be required for this age group.

급성기 조증에서 Topiramate 병용 투여

윤보현,배승오,윤진상,이경윤,최영 대한정신약물학회 2002 대한정신약물학회지 Vol.13 No.4

Objectives: The rapid therapeutic action of mood stabilizers is critical to the initial management of acute mania, because it enables to minimize the psychological sequelae of the patients commonly occurred in post manic episodes and to increase the compliance to the medications. The aim of this study was to evaluate the efficacy and safety of topiramate as the combination regimen in the treatment of acute mania. Methods: Twenty manic patients were selected through various screening tests. Ten patients were randomly assigned to valproate alone and the other ten patients to the combination of topiramate and valproate. Antipsychotics were not allowed and benzodiazepines were available as needed. Young Mania Rating Scale (YMRS) and Clinical Global Impression severity of illness scores (CGI-S) were used to evaluated the improvement of manic symptoms at pre-drug baseline and at 1st, 2nd, 4th and 8th week of post-drug. UKU side effect rating scales were done for assessment of drug-induced side effects. Additionally, body weights were checked at weekly basis to monitor the weight change. Repeated measures ANOVA was done to compare the effects between two groups. Results: YMRS of topiramate combination groups were significantly decreased at 1st, 2nd weeks. There were no marked differences in side effects. There was significant weight decrease in topiramate combination group whereas the increase of weight in valproate alone group. Conclusion: The results suggest that the combination of topiramte may be used effectively and safely in treatment of acute mania and can be the good choice in manic patients with weight problem. 목적: 본 연구는 급성기 조증에서 topiramate의 병용투여로 인한 항조증 효과의 신속성과 안전성을 평가하기 위해 시도되었다. 연구방법: 10명의 topiramate 병용투여군과 valproate 단독투여군을 대상으로 인구통계학적 특성, 임상력을 평가하였으며, Young Mania Ration Scale (YMRS), Clinical Global Impression severity of illness scores (CGI-S), 17 문항의 Hamilton Rating Scale for Depression (HAM-D), UKU side effect rating scale (UKU)을 이용하여 약물 투여 전과 약물 투여 후 1, 2, 4, 8주에서 양군간에 비교하였고, topiramate의 체중감소 효과를 확인하기 위해서 매주 체중을 측정하였다. 약물의 효과를 비교하기 위해 repeated measures ANOVA로 통계분석하였다. 결과: Topiramate 병용투여군은 valproate 단독투여군에 비해 YMRS의 감소가 유의하였는데, 특히 약물 투여 후 1, 2주에서 약물 투여 전에 비해 유의하였다. UKU에서 양군간에 현저한 부작용의 차이는 관찰되지 않았다. 또한 체중의 비교에서 topiramate 병용투여군은 체중감소 효과가 두드러진 반면에 valproate 단독투여군에서는 체중증가를 보였다. 결론: 이상의 결과로서 급성기 조증에서 topiramate 병용투여가 유의한 부작용이 없으면서 신속한 효과를 위해 안전하게 사용할 수 있는 치료적인 한 방편일 수 있음을 시사한다. 특히 체중 증가로 인해 문제가 되는 경우에는 더욱 긍정적으로 고려될 수 있을 것이다.

한국판 Hamilton 우울증 평가 척도의 신뢰도, 타당도 연구

이중서,배승오,안용민,박두병,노경선,신현균,우행원,이홍식,한상익,김용식 大韓神經精神醫學會 2005 신경정신의학 Vol.44 No.4

Objectives : The reliability and validity of the Korean version of Hamilton Depression Rating Scale (K-HDRS) were examined in Korean patients depressive symptoms. Methods : 33 inpatients and 70 outpatients diagnosed as major depressive disorder or depressive episode of bipolar I disorder according to the DSM-IV criteria were assessed with K-HDRS, Clinical Global Impression score (CGI), Beck Depression Inventory (BDI) and Montgomery-Aberg Depression Rating Scale (MADRS). Results : Internal consistency (Cronhach's alpha coefficeint=0.76) and interrater reliability (r=0.94, p<0.001) were Statistically significant. Principal axis factoring analysis revealed 4 factors that accounted for 50.4% of the total variance. The Correlations of K-HDRS with CGI, BDI and MADRS were 0.84, 0.54, 0.58 respectively. Conclusion : These results showed that the K-HDRS could be a reliable and valid tool for the assessment of depressive Korean patients. The K-HDRS will be a useful tool for assessing depressive symptoms in Korea.

제2형 양극성 장애의 다양하고 복잡한 임상양상과 경과

윤보현,배승오 대한우울조울병학회 2009 우울조울병 Vol.7 No.2

The aim of this review is to understand the complex clinical features and courses of bipolar II disorder. This article is based on the review of articles related to the clinical features and courses of bipolar II disorder. The papers included in this review were selected on the basis of the quality of findings related to the review topic. Bipolar II disorder is not a less severe variant of bipolar I disorder. Bipolar II disorder, compared with bipolar I disorder, has a substantially mo- re chronic course, significantly more suicidal risks, more comorbidities, and shorter inter-episode well-functioning pe- riods. Understanding of comorbidities and mixed depression, more common in bipolar II disorder compared with other mood disorders, is essential to identify complex clinical feature and course of Bipolar II disorder.

입원중인 정신분열병 환자에서 비전형 및 전형 항정신병약물에 대한 주관적인 반응

윤보현,시영화,배승오,이은숙,이형영 대한생물치료정신의학회 2002 생물치료정신의학 Vol.8 No.2

입원중인 정신분열병 환자를 대상으로 항정신분열약물에 대한 주관적 반응과 약물에 대한 태도가 비전형 및 전형 항정신병약물에 따라 다르게 나타나는지를 알아보고자 하였다. 비전형 항정신병약물을 복용중인 31명과 전형 항정신병약물을 복용중인 42명의 정신분열병 환자를 대상으로 하였으며, 이들은 모두 급성기를 지나 안정기에 있는 환자들이었다. 이들을 대상으로 인구통계학적 자료, 임상력 및 임상상태를 비교하였으며, 항정신병약물에 대한 주관적 반응 및 약물에 대한 태도를 평가하기 위해 10문항의 자가 평가 설문지인 Drug Attitude Inventory(DAI-10)를 시행하여 양군 간에 비교하였다. 전형 항정신병약물군은 비전형 항정신병약물군에 비해 입원 치료 중에 더 많은 항콜린성 약물을 복용하고 있었으며, 추체외로계 증후군과 약물의 진정효과로 인한 불편감을 호소하였다. DAI-10에서 비전형 항정신병약물군은 전형 항정신병약물군에 비해 항정신병약물에 대한 주관적 부정적 느낌이 적었으며, 최종 점수에서 훨씬 긍정적인 약물에 대한 주관적 반응과 태도를 보였다. 본 연구의 결과로서 전형 항정신병약물은 약물로 인한 부작용의 효과로 인해 부정적 반응에 영향을 주었으며, 반면에 비전형 항정신병약물은 긍정적인 약물에 대한 반응과 태도에 영향을 주었음을 확인하였다. Objectives : Drug Attitude Inventory(DAI) was used to compare the subjective response to antipsychotics between schizophrenic inpatients receiving atypical and typical antipsychotic medications. Method : Seventy three patients meeting selection criteria and receiving atypical(N=31) and typical antipsychotics(N=42) were examined. All of them were in the stabilized stage of their illnesses. Subjective response to neurolepics was evaluated using 10-items of Drug Attitude Inventory(DAI-10). Demographic and clinical data were also analyzed between two groups. Results : Patients receiving typical antipsychotics had adjuvant medications such as anticholinergics and more complained of the neuroleptic-induced side effects. They showed more dysphoric responses to the subjective responses to neuroleptics. Patients taking atypical antipsychotics showed significantly non-dysphoric responses on the items asking the negative aspects of medications and more subjective positive responses on the final scores. Conclusion : These results suggest that atypical antipsychotics influenced on the subjective positive responses to neuroleptics and neuroleptic-induced side effect affected the subjective negative feelings and attitude to antipsychotics.

한국형 양극성 장애 약물치료 알고리듬 2006(V):유지치료

윤보현,박원명,배승오,정상근,김원,신영철,조현상,권준수,서정석,하규섭,민경준,이은,전덕인 대한정신약물학회 2006 대한정신약물학회지 Vol.17 No.6

Objective: Since the previous publication of Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP) in 2002, there has been a substantial need for the revision of treatment algorithm due to rapid progress in the management for bipolar disorder. We focused on the maintenance treatment of bipolar I and bipolar II disorders of KMAP-BP revised in 2006. Method: The questionnaire to survey the expert opinion of medication for bipolar disorder was completed by the review committee consisting of 70 experienced psychiatrists. It was composed of 37 questions, and each question includes various sub-items. We classified the expert opinion to 3 categories (the first-line treatment, the second-line, the third-line) by X2 test. A part of this revision regarding maintenance treatment had 6 items; 2 on bipolar I and 4 on bipolar II disorder. Results: There was no ‘treatment of choice’ in maintenance treatment. In case of bipolar I mania without history of depression, mood stabilizer (MS) monotherapy was 1st-line treatment. In maintenance management for bipolar II disorder, two treatment options were recommended. Treatment with MS alone or combinations of MS and atypical antipsychotics were preferred in recently recovered patients from hypomania. Atypical antipsychotics were more favored in the maintenance treatment for bipolar I and II disorders than previous KMAP-BP. Conclusions: There is no ‘treatment of choice’ in maintenance strategies for bipolar disorder. Atypical antipsychotics are more preferred than the previous KMAP-BP. Also there is an increasing interest on the maintenance use of lamotrigine in bipolar depression.

한국형 양극성 장애 약물치료 알고리듬 2006(VI):다른 치료 지침들과의 비교

윤보현,박원명,배승오,민경준,신영철,조현상,정상근,하규섭,권준수,서정석,이은,전덕인,김원 대한정신약물학회 2008 대한정신약물학회지 Vol.19 No.1

Objective: The Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP) was developed in 2002 and revised in 2006. The aim of this study was to compare the KMAP-BP 2006 with other recently published treatment guidelines for bipolar disorder. Methods: We conducted a systematic review of the six most recently published guidelines and treatment algorithms for bipolar disorder to compare the similarities and differencesbetween these guidelines and the KMAP-BP 2006. Results: Most treatment guidelines had similarities in their treatment options. The guidelinesgenerally advocated atypical antipsychotics as first-line treatment in the manic phase and lamotrigine in the depressive phase. While lithium and divalproex were commonly used as mood stabilizers in the manic phase,divalproex was recommended in mixed or dysphoric mania. Mood stabilizers or atypical antipsychotics were selected as first-line treatment in maintenanceSome guidelines were more concerned about special clinical situations such as pregnancy, obesity, and metabolic syndrome, and elderly patients, which were not described in the KMAP-BP 2006. Conclusion: Our findings suggest that the medication strategies for bipolar disorder are based on data from recent studies and clinical experiences. Useful information and a rationale for making sequential treatment decisions can be provided by critically reviewing the treatment guidelines. The treatment algorithms and guidelines are not substitutesfor clinical judgment, but can serve as critical references to complement individual clinical assessments. KMAP-BP 2006과 기존의 치료 지침들을 요약하면, 급성 조증의 초기 치료에서 대부분의 지침들은 기분조절제 또는 비정형 항정신병약물의 단독치료를 선호하지만 일부 지침들에서는 기분조절제와 비정형 항정신병약물의 병합치료도 선호되었다. 특히 비정형 항정신병약물의 선호도가 예전에 비해 증가되었으며, 기분조절제의 경우 divalproex와 lithium이 여전히 선호되는 반면에 carbamazepine의 선호도는 감소하였다. 양극성 우울증의 경우 중등도의 우울증에서는 기분조절제 단독치료를 선호하였으며 중증 및 정신병적 우울증의 경우에는 기분조절제와 항우울제 병합 또는 기분조절제와 비정형 항정신병약물의 병합치료를 선호하였다. 이때 기분조절제로는 lithium, divalproex, lamotrigine을 선호하였고 항우울제는 bupropion과 SSRI제재들을 선호하였다. 유지치료의 경우 먼저 양극성 장애 I형의 경우 각각의 지침들마다 정확하게 일치하지는 않았지만 기분조절제 또는 비정형 항정신병약물의 단독치료를 선호하는 경향이었고 거의 모든 지침들에서 lamotrigine을 1차 선택약물로 채택하였다. 급속 순환에 있어서는 각 지침들 간에 명확한 컨센서스가 이루어지지는 않았다. 하지만 대부분 지침들에서 급속 순환에 대해 자세하게 기술하지 않고 있는 점은 주목할 만하다. 선호하는 기분조절제로는 lithium, divalproex, lamotrigine 등이며, 일부 지침들에서만 carbamazepine이 1차 치료약물로 포함되었다. KMAP-BP 2006은 전반적으로 다른 치료 지침들과 일치하는 경우가 대부분이었다. 특히 lamotrigine과 비정형 항정신병약물에 대한 선호도 증가, 그리고 carbamazepine, 삼환계 항우울제, 전형 항정신병약물 등에 대한 선호도의 감소 등은 대체적으로 일치하는 부분이었다. 하지만 공존질환 및 부작용, 소아 청소년 및 노인, 임산부와 같은 특수한 상황에 대한 언급이 없어 앞으로 이와 관련된 내용이 추가 될 경우, 실제 임상상황에서 보다 나은 선택을 하는데 도움을 줄 수 있을 것이다.

한국인에서 NOTCH4 유전자 내 두 개의 단일염기다형성과 정신분열병의 연합연구

주은정,정성훈,김미재,구영진,배승오,안용민,이규영,김용식 大韓神經精神醫學會 2005 신경정신의학 Vol.44 No.6

Objectives : Previous studies on N0TCH4 gene and schizophrenia have not produced consistent results, and more studies with various ethnicities and populations were warranted. This study was performed with Korean population to find the role of the N0TCH4 gene in the development of schizophrenia. Methods : 235 schizophrenics and 236 normal controls participated in the study. Two SNPs (-1725 A/G and -25 T/C) on the N0TCH4 gene were investigated. Genotyping was done by Taqman assay, and statistical analysis was done by contingency chi-square test for the allele and genotype frequencies and PowerMarker V3.0 for the haplotype. Results : The two SNPs did not deviate from Hardy-Weinberg equilibrium in neither schizophrenics or normal controls. Two groups were not different in terms of allele and genotype distribution for both SNPs. Two SNPs were found to be in linkage disequilibrium. Haplotype analysis could not find an association between schizophrenia and these two SNPs. There was no association between the age at onset and the genotypes for both SNPs. Conclusion : We could not find any significant association between schizophrenia and the N0TCH4 gene in this Korean population. Although there are limitations in this study, this result supports the conclusion that the N0TCH4 gene is less likely to play a major role on the development of schizophrenia in the Asian population.