한국에서 11년간 Clozapine 투여에 의한 무과립구증과 호중구감소증 = Clozapine-induced Agranulocytosis and Neutropenia for 11 Years in South Korea

국문 초록 (Abstract)

목적 :
Clozapine은 치료저항성 정신분열병환자의 치료에 많이 사용되고 있지만 생명을 위협하는 혈액학적 부작용 때문에 사용에 많은 제한이 따른다. 본 연구자들은 한국에서 장기간의 clozapine 투여에 의한 무과립구증과 호중구감소증의 전체 발생률과 투여 기간에 따른 발생률의 변화를 알아보고자 한다.
방법 :
1993년 2우러부터 2004년까지 11년간 Clozaril Patient Monitoring System(CPMS)에 등록된 7367명 중 분석 기준에 합당한 6,782명의 자료를 분석하였다.
결과 :
조사 대상 6,782명 중 54명에서 무과립구증, 697명에서 호중구감소증이 발생하였다. 따라서 11년간 무과립구증의 일반발생률은 0.8%였고, 호중구감소증의 일반발생률은 1028%였다. 무과립구증이 발생한 환자들 중 53.7%가 18주 이내에 발생하였고, 위험률은 2,3개월째 각각 0.0014, 0.0025로 가장 높았다. 또한 최종 누적발생률은 1.64%였다. 호중구감소증이 발생한 환자들 중 52.4%가 18주 이내 나타났고 위험률은 3개월 이내에 가장 높았다. 무과립구증의 발생에 있어서 성별이나 연령에 따른 유의한 차이는 관찰되지 않았다.
결론 :
Clozapine에 의한 혈액학적 부작용은 18주 이내에 많이 나타나고, 무과립구증의 발생률은 외국과 유사한 수준을 보였다. 수 년 이상 장기간의 clozapine 투여 후에도 무과립구증이 발생하였기 때문에 지속적인 혈액학적 감시가 필요할 것으로 판단된다. 향후, 혈액검사의 빈도를 줄일 수 있을 지에 대한 연구가 필요하며, “일시적인 무과립구증(transient agranulocytosis)”이 존재할 가능성도 고려되어야 할 것으로 사료된다.

다국어 초록 (Multilingual Abstract)

Objectives : Clozapine is effective in treating patients with treatment-resistant schizophrenia. Because of producing a potentially fatal agranulocytosis, the use of clozapine is restricted to patients who are resistant to, or intolerant of, conventional antipsychotic medication. This study documents the incidence of agranulocytosis and neutropenia, and pattern of variation in incidence of these side effects in a long-term clozapine treatment.
Methods : An analysis was made of the hematological, demographic, and other characteristics data from Clozaril Patient Monitoring System(CPMS) data on 6782 patients on clozapine over about 11 years in South Korea.
Results : During the study period, agranulocytosis developed in 54 patients with 29(53.7%) cases within 18 weeks. The cumulative incidence of agranulocytosis was 1.64% at 6 to 11 years and the crude incidence was 0.8%, with the hazard rates peaking at the 3rd month(0.0025) and 2nd month(0.0014). Neutropenia occurred in 697 patients, and 365(52.4%) cases developed within 18 weeks. The cumulative incidence of this blood abnormality was 19.8% at 8 to 11 years, the crude incidence was 10.3%, and the hazard rates peaked at the 2nd month(0.0188).
Conclusions : These results showed that the incidence of agranulocytosis in South Korea is similar to that in the rest of the world. Because of agranulocytosis that occurred after several years of clozapine use, long-term monitoring of patients' white blood cell counts is necessary. In the future, studies of reducing the frequency of hematologic monitoring are needed, and the concept of "transient agranulocytosis'' should be taken into consideration.

목차 (Table of Contents)

• 영어 초록
• 서론
• 대상 및 방법
• 결과
• 고찰
• 요약
• 감사의 글
• 참고문헌

참고문헌 (Reference)

1 "Yan W. Clozapine in China A review and preview of US/PRC collaboration. Psychopharmacology 1989"

2 "The textbook of clinical psychiatry." American Psychiatric Publishing, Inc. 1096-1098, 2003.

3 "Reducing clozapine-related morbidity and mortality : 5 years of experience with the Clozaril Registry." 59 : 3 -7, 1998

4 "Novartis Pharmaceuticals Product Information : Clozaril (Clozapine). In Physicians’ Desk Reference." Anonymous Medical Economics Company 2008-2012, 2000

5 "Neutropenia and agranulocytosis in patient receiving clozapine in the UK and Ireland." 169 : 483-488, 1996

6 "Meltzer H. Clozapine for the treatment-resistant schizophrenic A double-blind comparison with chloropromazine. Arch Gen Psychiatry 1988" 789-96,

7 "Konings SA. 51Cr release assay of clozapine-induced cytotoxicity Evidence for immunogenic mechanism. J Clin Psychiatry 1994" 143-8,

8 "Incidence and risk factors in the United States. N Engl J Med 1993" 162-7,

9 "Goldstein DS. The effect of clozapine on plasma norepinephrine Relationship to clinical effecacy. Neuropsychopharmacology. 1994" 1-7,

10 "Fleischhacker WW. Transient neutropenia induced by clozapine. Psychopharmacol Bull 1992" 287-90,

11 "Effects of the Clozapine National Registry System on incidence of death related to agranulocytosis." 47 : 52-56, 1996

12 "DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry 1990" caso (caso): 945-8,

13 "Clozapine에 의한 무과립구증과 호중구감소증." 10 : 166-172, 1999

14 "Clozapine treatment in Australia a review of haematological monitoring." 168 : 495-497, 1998

15 "Blood dyscrasias in clozapine-treated patients in Italy." 85 : 233-237, 2000

16 "A review of the situation. Psychopharmacology 1989"

17 "A clozapine metabolite that suppresses hematopoiesis. Br J Haematol 1994" 555-61,