Molindone: 약물학적 특성과 임상적 적용 : Molindone: A Review of Pharmacological Properties and Clinical Use

곽경필,정성훈 대한생물치료정신의학회 1999 생물치료정신의학 Vol.5 No.1

새로운 비전형적 항정신병약물은 전형적 약물에 비해 효능과 부작용 측면에서 많은 이점을 가지고 있으나, 비전형적 약물 역시 체중증가라는 부작용을 보인다. 체중증가는 치료의 순응도 뿐만 아니라 신체적 건강 그 자체에도 중요한 의미를 가진다. 항정신병약물 중 molindone만이 체중변화가 거의 없고 일부 환자에서는 체중감소가 보고된 바 있다. 그래서 본 논문에서는 molindone의 약동학적, 약력학적 특성, 치료적 효능 및 부작용에 대해 검토해 보았다. Molindone은 다른 항정신병약물과 여러 면에서 많은 유사성을 가지지만, 구조적 차이와 D1, D2, M, H1, α 수용체의 친화력에서 차이를 보인다. 약동학적 면에서도 매우 짧은 반감기, 낮은 지용성 등이 다른 항정신병약물과 차이를 가지고 있다. 정신분열병에 있어 molindone의 치료적 효능은 다른 항정신병약물과 차이가 없다. 약동학적, 약력학적 특성으로 노인, 내과적 질환이 병합된 환자, 임신부에게 안정성과 적은 부작용을 고려할 때 molindone이 선택될 수 있다고 제안되고 있다. 중추신경계와 기타 부작용 역시 전형적 항정신병약물과 유사한 경향을 가지나, 체중변화와 경련 유발에는 기타 항정신병약물에 비해 우수하다고 할 수 있겠다. 1980년대 말까지 molindone은 독특한 약동학적 특성으로 비전형적이라 분류되기도 하였지만, 현재의 비전형적 약물 즉 세로토닌-도파민 길항제가 소개되면서 molindone에 대한 임상연구는 거의 찾아보기 힘들다. 그러나 비전형적 항정신병약물이 과거처럼 전형적인 항정신병약물에 반응을 보이지 않거나 부작용이 심각한 환자에게만 사용되는 것이 아니라, 모든 정신병적 증상의 일차 치료제로 선택되는 현 시점에서 과도한 체중증가가 문제가 되는 환자들 중 일부는 molindone으로 교체하여 증상호전의 유지 및 체중감소를 동시에 얻을 수 있는 군이 있을 가능성이 높다. 다만 국내 및 국외에서 최근 molindone의 임상연구가 부족한 편이기 때문에 molindone으로 교체가능한 환자군에 대한 지침을 얻을 수 없어 임상의의 경험에 의존할 수밖에 없다는 문제점이 있다. 그래서 향후 항정신병약물에 의한 체중증가 부작용에 대한 잘 계획된 연구들이 필요할 것으로 생각된다. Although the side effect profiles of the new atypical antipsychotics are more advantageous than those of the conventional neuroleptics, the atypical antipsychotics have also been associated with weight gain. Weight gain is common and troublesome side effect and may have a significant effect on compliance as well as physical health. Several reports suggest that molindone is less harmful in this respect and alleviates the obesity of some patients. So, the authors review literatures concerning the pharmacodynamics, pharmacokinetics, therapeutic effects, and side effects of molindone.Molindone, an indole derivative dopamine antagonist, is structurally distinct from other classes of neuroleptics. Molindone exhibits many similarities to other neuroleptics, including dopamine receptor blockade, antipsychotic efficacy, and extrapyramidal side effects. Despite these similarities, molindone also has different properties. Molindone has very little affinity to bind centrally to either the D1 or D2 receptor site and has the lowest affinity for cholinergic, noradrenergic and histaminic receptors. Molindone also inhibits the enzyme monoamine oxidase in vitro and in vivo. Molindone is unlike any other neuroleptic agent with respect to its pharmacokinetic parameters. Tmax of molindone is very short and is less lipophilic than other neuroleptics. Although the elimination half-life of molindone is approximately 2 hours, the clinical duration of action of molindone is at least 24 hours.Molindone appears to be comparable in efficacy to conventional antipsychotics in schizophrenia and to be both effective and well-tolerated in geriatric and medically ill patients. Molindone does not appear to have the same propensity to induce side effects as other neuroleptic agents. But, clinically, molindone has a tendency to cause weight loss than conventional antipsychotic agents. The mechanism producing this weight loss is uncertain. A wide range of studies is still needed before we can fully appreciate the usefulness of molindone.

클로자핀 반응의 임상적 예측인자 : 치료 저항성 정신분열증 환자군 중 반응군과 비반응군간의 차이 Comparison between Clozapine Responders and Non-Responders in Treatment-Refractory Schizophrenic Patients

곽경필,이양현,강병조 대한생물치료정신의학회 1998 생물치료정신의학 Vol.4 No.1

요 약치료 저항성 정신분열증 환자의 클로자핀반응의 임상적 예측인자를 알아보고자 70명의 환자를 대상으로 개방 연구를 실시하였다. 기존의 항정신병 약물을 중지하고 7일간의 배설기간을 가진 후 기초평가를 실시하였고 최종 12주까지 임상적 평가를 실시하였다.최종평가시 PANSS 전체점수가 기초평가에 비해 20%이상 호전되었을 때를 반응군이라 하였을 때 78.5%가 반 응군에 속하였다. 치료 전 평가한 PANSS 세부항목상 환각행동, 흥분, 적개심, 빈약한 신뢰감, 비협조성, 판단과 병식의 결여, 충동조절장애 등의 소항목들이 반응-비반응군간에 유의한 차이가 있었다. 그리하여 이런 항목들이 있는 환자들이 클로자핀에 의하여 좋은 예후를 가져온다고 볼 수 있다.비록 본 연구가 대조군이 없는 개방연구라는 점을 감안해 볼 때 본 연구의 결과에 대한 추후 보완된 이중맹검 대조군 연구가 필요할 것으로 생각된다. In order to find the clinical predictors of clozapine response in patients with refractory schizophrenia, the clinical responses of 70 schizophrenic inpatients with treatment-refractory illness were examined in open trial. After all previous antipsychotic medications had been withdrawn for 1 week, the patients were treated with clozapine according to a standardized titration and dosage schedule. Patients who tolerated and responded to treatment were maintained on a regimen(100-600mg/day) of clozapine for up to 12 weeks. The psycho- pathologic severity and functioning status of the patients were assessed by PANSS, CGI, GAF at baseline and weeks 4, 12 of treatment. Clinical improvement as defined by a 20% or more reduction in total PANSS score at end point, was shown by 77.1% of the patients. The predictors of response to clozapine were associated with hallucinatory behavior, excitement, hostility, poor rapport, uncooperativeness, lack of judgement and insight, poor impulse control subscale of PANSS. These findings have important implications for the use of clozapine and our understanding of the pathophysiology of treatment-resistant schizophrenia.

림프구에 대한 clozapine의 생체내 유전독성

임정호,곽경필,김문두,강병조 대한생물치료정신의학회 1997 생물치료정신의학 Vol.3 No.1

최근 난치성 정신분열증 환자에서 가장 효과적인 약으로 알려진 clozapine은 골수에 작용하여 심각한 부작용인 무과립 구증을 일으킬 수 있다. 무과립구증의 원인 및 기전에 대한 연구는 매우 많으나 현재까지 확실한 결론이 나지 않은 상태이다. 저자들은 clozapine의 이러한 골수 독성에 근거하여 clozapine이 인체내에서 염색체에 어떤 변화를 주는지 아닌지를 알아보기 위해 clozapine 단독치료를 시행한 환자에게서 치료전과 치료중에 얻어진 말초혈액 림프구를 배양하여 염색체에 어떤 변화가 생기는지를 조사하였으나, clozapine에 의한 염색체의 자발적인 변이는 관찰되지 않았다. Objective : Many drugs and environmental chemicals can induce aneuploidy or chromosome instability in vivo or in vitro. Modification of the fidelity of cellular division may occur via a variety of mechanisms and chemical interactions. The clozapine is new antipsychotic drug with superior effect than classic antipsychotics. But, it may produce agranulocytosis and seizure in some patients. Agranulocytosis is a serious side effect of this drug but the cause and mechanism of this side effect is not clearly explained. Some study suggested that oxidative stress can induce chromosome aberration and the other study suggested that clozapine produce free radical and it can induce oxidative stress on some kind of cells. Therefore we decided to investigate whether clozapine and its metabolites can induce genotoxic effect in vivo. Method : The patients were chronic schizophrenic patients without a treatment at least one year. Diagnosis was made by DSM-IV criteria and agreed by both of two psychiatrists. Blood sampling was done before the treatment and during the treatment with considerable time interval. We used peripheral blood lymphocyte culture method and we counted the numerical aberrations, sister chromatid exchanges. Results : Chromosome aberration was not detected in all samples. Conclusion : Clozapine did not induce spontaneous chromosome aberration to human lymphocytes in vivo.

Clozapine이 인체내에서 인간조직적합성항원에 미치는 영향

강병조,김문두,곽경필 경북대학교 의학연구소 2000 경북대학교병원의학연구소논문집 Vol.4 No.1

The histocompatibillty antigen (human leukocyte antigen : HLA) has been used for organ transplantation, discrimination of one's real children and transfusion, etc. The objective of this study was to find out how dozapine affects HLA class I and II type in the humanbody when therapeutic doses are applied. The subject consists of 3 persons for lass I and class II They were administered for about 3 months with clozapine 157-250mg/day (mean dally dose 200mg). Analysis of HLA lass I type was the microcytotoxicity test of Terasaki and class II type was PCR method of Erhich. The results were as followings: Two of 3 were changed in HLA-A, B, C type. All three were not chanced in HLA-DR type. In conclusion, the short-term application, about 3 months, of therapeutic dose of clozapine is not considered to bring about changes in DNA level.

우리나라 치매관리 현황과 치매국가책임제

곽경필(Kyung Phil Kwak) 한국보건의료연구원 2018 근거와 가치 Vol.4 No.1

재가치매환자를 위한 수요자 맞춤형 인지 프로그램 운영 경험에 관한 질적 연구

곽경필(Kyung-Phil Kwak),박수현(Su-Hyun Park),하아경(A-kyung Ha) 한국인지운동치료협회 2021 한국신경인지재활치료학회지 Vol.13 No.1

목적: 본 연구는 재가치매환자를 위한 맞춤형 개별 인지프로그램(customized cognitive program)의 운영 경험을 분석하여 수요자 중심(client-centered) 지역사회 치매관리사업의안착을 위해 필요한 현실적이고 구체적인 지원 방안을 모색하고자 실시되었다. 방법: 2 020년 10월, 맞춤형 개별화 인지 프로그램 운영자17명을 5~6명의 소집단으로 나누어 집단심층면담(Focus Group Interview)을 실시하였으며 전통적인 내용분석(conventional content analysis)을 이용하여 자료를 분석하였다. 결과: 분석결과, 8개의 범주(categories), 22가지 하위범주(subcategories)가 도출되었다. 연구 참여자들은 운영 경험을통해 새롭게 시도된 프로그램 운영을 통해 자기다움을 찾아가는 치매환자를 발견할 수 있었으며 운영자로써 자신의책임감과 자신감을 회복을 도출하였다. 또한 경험부족으로인한 시행착오와 운영 부담의 현실적인 어려움을 표현하였다. 마지막으로 프로그램의 활성화를 방안으로 인적지원과운영체계 개선, 환경지원이 도출하였다. 결론: 치매가 있어도 자신이 살던 곳에 지속적으로 거주하기 위해서는 치매환자에 대한 지원 뿐 아니라 서비스 지속성을 위한 전문 인력 양성과 효율적인 운영 환경 조성의 다각적노력이 필요하다. This study was conducted to analyze the experience of operators in implementing a tailored cognitive program devised for community-dwelling individuals with dementia. This study also aims to identify realistic and specific support plans necessary to establish client-centered community dementia management projects. In October 2020, 17 individualized cognitive program operators were divided into small groups of 5 to 6 members, and focus group interviews were conducted. The resulting data were analyzed using conventional content analysis. From the analysis, three areas, eight categories, and 22 subcategories of operational experience and activation plans were derived. Based on their operational experiences, the participants were able to identify patients who had recovered their self-esteem through the newly attempted program. In addition, the operators recovered their sense of responsibility and confidence. However, challenges faced by the operators were trial and error due to a lack of experience and practical difficulties in implementing the cognitive program Lastly, human support, improvement of the operating system, and environmental support were necessary to improve the program. For individuals with dementia to continue living comfortably in their residences, efforts such as professional manpower training and creating an efficient operating environment for the operators are required to ensure continuity of the operators services.

우울증에서 Brain - Derived Neurotrophic Factor의 역할

곽경필(Kyung-Phil Kwak),이상희(Sang Hee Lee) 대한생물치료정신의학회 2005 생물치료정신의학 Vol.11 No.2

Brain-derived neurotrophic factor(BDNF) is involved in the development, survival, maintenance and plasticity of neurons in the nervous systems. Recent pre-clinical studies suggest that the expression of BDNF is up-regulated by antidepressant treatments and the expression of BDNF might be a downstream target of antidepressant treatments. In addition, BDNF exerts antidepressant activity in animal models of depression. BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved In the pathogenesis of the depression. In human studies, serum levels of BDNF in drug-naive patients with major depressive disorder are significantly decreased as compared with normal controls, and that BDNF might be a Important agent for therapeutic recovery from major depressive disorder. These findings suggest that BDNF plays a critical role in the pathophysiology of depression and in the mechanism of action of antidepressant agents.

노인 우울증과 혈관질환과의 공통 위험인자

곽경필 동국대학교 의학연구소 2009 東國醫學 Vol.15 No.2

고혈압, 심혈관계질환, 뇌혈관질환과 같은 혈관 질환에서 우울증 병발하는 경우가 많으며, 우울증 환자에서 혈관성 질환을 가지는 경우가 많다. 우울증과 혈관성 질환은 다양한 환경인자를 공유한다. 이들 공통 혈관 위험인자로는 혈소판 과활성 기능, 혈관 내피의 기능이상, 사이토카인의 기능, 오메가 3 지방산의 기능, 유전학적 요인 등이 보고 되었다. 우울증과 혈관 질환의 단일 기전은 현재까지 알려진 바 없으나, 노인 우울중 환자의 치료에 있어 공존하는 혈관 질환에 대한 관심과 혈관 위험 인자의 지속적인 관리가 우울증의 치료와 예방에 필요하다. Depression may occur as a result of vascular disease. Support for vascular disease as an underlying etiology of depression includes the high rate of depression in patients with vascular disease. This paper examines possible mechanisms that may explain the bidirectional relationship between vascular disease and depression. Several vascular risk factors were considering including that were platelet activation, endothelial dysfunction, hypothalamic pituitary axis activation, cytokines, omega 3 fatty acids, homcysteine, autonomic dysfunction and genetics. The relationship between vascular disease and depression cannot soley be explained by current established risk factors or the effects of treatment for depression. Important areas for future study includes evaluation of the treatment of vascular risk factors on the course of depression, assessment of the relationship between vascular factor, depression and dementia.

자살 위험요인의 평가와 예측

곽경필,송창진,사공정규,이광헌 東國大學校醫學硏究所 2004 東國醫學 Vol.11 No.1

자살은 정신과 영역에서 주된 관심의 대상이 되어 왔으며, 자살사고, 자살시도, 자살성공 둥은 응급정신의학의 가장 핵심적인 문제 중 하나이다. 자살의 위험성을 평가함에 있어, 가장 높은 위험성을 가진 대상으로 평가되나 교정 할 수 없는 자살 위험요인이 있고, 자살 위험의 가능성을 가지나 효과적인 치료로 수정 가능한 자살 위험요인들로 크게 분류할 수 있으며 이 구분은 임상적으로 매우 유용하다. 교정 불가능한 자살 위험요인에는 이전 자살 시도, 가장 최근에 자살 시도된 시기에 가졌던 자살기도, 성별, 인종, 연령, 결혼 상태, 경제적 상황, 성적 편향성 등이 포함된다. 적절한 조치에 의해 교정 가능한 자살 위험요인에는 불안, 무망감, 연속적인 치료, 정신과적 장애의 동반, 사회적 고립, 의학적 질환 등이 있다. 그리고 보다 객관적인 자살 위험 요인을 평가하고 예측하기 위해 현재 여러 가지 심리검사와 평가 척도가 이용되고 있다. 상기의 요인에 대한 조사와 평가는 자살시도나 자살사고를 가진 환자에 대한치료를 계획하고 자살예방 프로그램을 개발하는데 도움이 된다. Suicidal ideation, suicide attempts, and the specter of completed suicide form one of the core problems in emergency psychiatry. In the assessment of an individual at risk for suicide, it is important to distinguish between the factors that help to identify very high-risk individuals but that are not modifiable and the risk factors not only that place an individual at high risk but that may be modified by effective treatment. "Fixed" risk factors include previous suicide attempts, suicidal intent at the time of the most recent attempt, sex, ethnicity, age, marital status, economic situation, and sexual orientation. Potentially "modifiable" risk factors include anxiety, hopelessness and life situation, access to means, continuity of care, psychiatric illness, social isolation, medical illness. There are many of psychometric scales included Beck Depression Inventory, Beck Hopelessness Scale, Scale for Suicidal Ideation, Scale for Escape from the Self and so on. These risk factors and psychometric scales operate as the foundation for treatment planning in those with suicidal ideation or who have made suicidal attempts.

Ten Years of Korea-U.S. FTA: focusing on agri-food trade

Kim Kyung-Phil(김경필),Lee Hyun-Keun(이현근),Kwak Hye-Sun(곽혜선),Myeong Su-Hwan(명수환),Ku Hye-Min(구혜민),Park Seo-Yun(박서윤) 한국농촌경제연구원 2022 한국농촌경제연구원 농정포커스 Vol.- No.207

10 years have passed since the Korea-U.S. FTA came into force on March 15, 2012. Tariffs on 97.9% of agricultural products have since been abolished. • Seoul and Washington had eight negotiations with two additional rounds of talks before the treaty finally went into effect in March 2012. Through their talks, the two sides agreed to open 97.9% of agricultural items (based on the Harmonized System). The bilateral trade volume in agricultural products has increased since the effectuation of the Korea-U.S. FTA. Korea’s trade deficit has widened during the period, while FTA application for goods exported to the U.S. has been relatively low. • The agricultural and livestock products imported from America reached $10.32 billion in the 10<SUP>th</SUP> year (2021) of the treaty, up 73.8% from the average before the treaty went into effect. The average import volume between the 6<SUP>th</SUP> and 10<SUP>th</SUP> year of the treaty amounted to $9.07 billion, up 52.7% before the enforcement. • Korea’s agricultural and livestock exports to the U.S. posted $1.26 billion, 214% up from the average before the treaty. The average export between the 6<SUP>th</SUP> and 10<SUP>th</SUP> year reached $980 million, up 43.6% during the same period. • Korea’s trade deficit rose to $809 million in the 6<SUP>th</SUP>-10<SUP>th</SUP> year, up 46.1% from the average before the treaty. • The average import unit prices for American beef, pork, grape, and kidney beans in the 6<SUP>th</SUP>-10<SUP>th</SUP> year were up from the figures before the treaty. However, the imported volumes and their shares to the total expanded during the same period. • The fill rates of U.S. items subject to tariff rate quotas (TRQs) were around 50% due to changes in import sources and decreased demand for American products. ASG measures were triggered for five items. • FTA application for items imported from the U.S. amounted to 71.6% on average in the 10<SUP>th</SUP> year of the treaty. However, the application for items exported to the U.S. slightly rose from 42.9% in 2012 to 49.5% in 2021, with the livestock category at 70.7%, the highest of all. The Korean government has signed free trade agreements with various nations. While doing so, it should also pursue self-sufficiency by expanding the domestic output of high-quality agricultural and livestock products. At the same time, it must focus on education to increase FTA application to Korean products exported to America. • Korea should use digitalized, smart farming to expand high-quality product output. The government has to educate stakeholders to raise FTA applications for Korean agricultural and livestock products exported to the U.S.