- 學位論文
臺灣精神分裂症病患使用thioridazine之潛在嚴重藥物交互作用研究： 全民健康保險研究資料庫分析
Potential Drug Interactions with Thioridazine in Patients with Schizophrenia in Taiwan： An analysis of National Health Insurance Research Database
摘要
藥物交互作用（Drug-Drug Interaction，DDI）可能導致藥物不良反應的發生，甚至死亡。文獻指出有些抗精神病藥物會延長QT 間隔，可能造成torsade de pointes，甚至猝死；其中又以thioridazine之危險性較高，而藥物交互作用在很多因藥物引發QT間隔延長而致死的病例中扮演著重要角色。2000年7月起，世界各國衛生單位先後發佈thioridazine藥物安全警訊，將會抑制CYP 2D6活性或可能延長QT 間隔的藥物列為併用禁忌，以提醒重視thioridazine可能的心臟毒性。 本研究使用全民健康保險研究資料庫中「精神疾病住院病患歸人檔（Psychiatric Inpatient Medical Claim Dataset，簡稱PIMC）」，目的在分析台灣精神分裂症病患使用thioridazine之相關潛在嚴重藥物交互作用發生情形，並探討病患特質與處方型態，以及各醫療機構潛在嚴重藥物交互作用處方分布情形。 利用MICROMEDEX®與Drug Interaction Facts建立與thioridazine有潛在嚴重藥物交互作用的藥物檔，依此藥物檔來比對住院診斷為精神分裂症（ICD-9：295），且曾於住院或門診處方thioridazine的病患，其1997年至2001年的處方。將住院期間有開立thioridazine和與其具潛在嚴重藥物交互作用的藥品之住院記錄，列為住院病患有DDI之案例。門診處方則係利用比對藥品之用藥期間，有任何一日重疊者視為併用，依此篩選出同一處方和不同處方間有thioridazine相關DDI之處方。 研究結果發現，住院和門診使用thioridazine之精神分裂症病患，暴露在與thioridazine相關之潛在嚴重藥物交互作用發生情形，無論是依處方數或人數分析，在1997年至2001年各年度DDI組合發生率較高的藥品是haloperidol（>15.9%）、propranolol（>15.9%）、chlorpromazine（>3.5%）、lithium（>8.6%）、risperidone（除1997年外，>4.6%）和trifluoperazine（>2.9%）。 1997年至2001年門診使用thioridazine的病患，有55.4％∼59.7％的人曾暴露在同一處方DDI；65.2％∼68.9％的人曾暴露在不同處方間DDI；整體而言有75.0％∼77.4％的人曾暴露在thioridazine相關的DDI。同一期間，門診thioridazine的處方中，49.2％∼55.2％的處方有同一處方DDI；51.8％∼55.3％的處方有不同處方間DDI；59.2％∼65.0％的處方有thioridazine相關DDI。 病患之性別與是否發生DDI並無相關性；曾暴露在DDI的病患之平均每年門診就醫次數（25.3∼29.9次）比未曾暴露在DDI的病患（17.2∼20.3次）多（p<0.0001），顯示出就醫次數愈多的病患，愈容易暴露於thioridazine相關潛在藥物交互作用的風險中。有DDI之thioridazine處方的平均藥品品項數（5.3∼5.5項）比無DDI之處方的品項數（3.8∼4.1項）多（p<0.0001），且發現隨著開方藥品品項數愈多，DDI發生率愈高。有DDI之處方的thioridazine平均每日劑量（124.8∼143.2毫克）較無DDI之處方（150.3∼183.6毫克）低（p<0.0001）。且在有DDI的處方中，有併用其他與thioridazine有DDI之抗精神病藥物組之thioridazine平均每日劑量（120.5∼134.3毫克），較沒有併用組（143.7∼178.1毫克）顯著地低（p<0.0001）。推測在抗精神病藥物的多重用藥情況下，醫師會有降低個別抗精神病藥物劑量的傾向，或可能thioridazine是作為輔助性藥物而非主要治療藥物，以致有併用抗精神病藥物組之thioridazine平均每日劑量較低的結果。 各特約類別醫事機構於1998年至2001年皆以「醫學中心」及「基層院所」之DDI發生率較高；權屬別分析發現「私立」醫事機構的DDI發生率大於「公立」，且其中「私立診所」的DDI發生率逐年上升；型態別分析卻發現只有「一般診所醫務室」的DDI發生率大幅上升，其他型態別包括「專科診所」的DDI發生率則是有下降之趨勢。顯然「私立診所」之DDI發生率逐年上升的現象，其實是反應「一般診所醫務室」之DDI發生率的增加。另一方面，除了1999年外之各年度，皆顯示型態別是否為「精神科醫院」與是否同一處方有thioridazine相關DDI有高度相關性。推測可能與第二代抗精神病藥物問市後，減少第一代抗精神病藥物的使用有關。分析各地區DDI發生率則以「中區」和「南區」較高。 研究也發現，精神分裂症病患之thioridazine處方主要仍由精神科所開方（92.6％∼93.9％）。Type B-DDI處方對之處方來源分析顯示，其他精神科相關用藥的處方與thioridazine處方有併用的情形，主要來自相同醫事機構之開方，且有極高比例處方對之兩藥品處方皆來自精神科。 由本研究結果顯示，1997年至2001年thioridazine處方之相關潛在嚴重交互作用發生率很高，其中以與精神科相關用藥的併用較普遍。雖然thioridazine的處方量及使用人數已逐年降低，但相較於國際上各國衛生單位自2000年7月起紛紛發佈thioridazine藥物安全警訊，我國中央衛生主管機關對藥物安全的管理仍應有努力空間。
並列摘要
Background: Drug-drug interactions (DDIs) may contribute to the occurance of adverse drug reactions, and unfortunately may cause death. It is one of the major concerns in clinical practice. It has been well-documented that some antipsychotics may cause QT interval prolongation or torsade de pointes leading to sudden death. The potential cardiotoxicity of thioridazine, in which drug interactions may play an important role, has caught lots of attention than other antipsychotics. The bulletins of the health regulatory agencies in many countries have continuously provided warnings with thioridazine to alert the potential cardiotoxicity of thioridazine since July, 2000. Drugs that may inhibit CYP 2D6 or prolong QT interval are considered as contraindications to combined use with thioridazine. Objective : The objective of this study is to evaluate potential significant DDIs with thioridazine in patients with schizophrenia from 1997 to 2001 in Taiwan using National Health Insurance Research Database – Psychiatric Inpatient Medical Claim Dataset (PIMC). Method:Criteria for DDIs regarding thioridazine was established based on the information from the MICROMEDEX® software program and Drug Interaction Facts. Patients with schizophrenia, who were prescribed thioridazine in the ambulatory settings from 1997 to 2001 based on the PIMC, were enrolled in this study. Concomitant administration is defined when the dates of prescriptions of drug interaction pairs were overlapped. Results: Our results showed that interactive drugs that most frequently combined with thioridazine (incidence >3.5%) were haloperidol, propranolol, chlorpromazine, lithium, risperidone and trifluoperazine., Of patients who were prescribed thioridazine from 1997 to 2001, 55.4% to 59.7% were exposed to potential risk of thioridazine related DDIs in the same prescription sheet, 65.2% to 68.9% were exposed to potential risk of thioridazine related DDIs from different prescription sheets. Overall, 75.0% to 77.4% were exposed to potential DDIs with thioridazine. According to thioridazine prescriptions, the rates of potential thioridazine-related DDIs in the same prescription sheet were 49.2% to 55.2%; and were 51.8% to 55.3% from different prescription sheets. Overall, the rates of potential DDIs with thioridazine were 59.3% to 65.0% per prescription. We found that polypharmacy is one of the factors that contribute to the high incidence of thioridazine related DDIs. The average daily dose of thioridazine (124.8∼143.2 mg) of the prescriptions with thioridazine related DDIs were lower than that of those without thioridazine related DDIs (150.3∼183.6 mg) (p<0.0001). Moreover, the average daily dose of thioridazine in combination with potential interactive antipsychotics (120.5∼134.3 mg) were lower than that of thioridazine without such combination (143.7∼178.1 mg) (p<0.0001). The dosage difference is most likely because physicians may prescribe thioridazine with low dose under antipsychotics polypharmacy or the thioridazine was used to as an adjunct treatment to other antipsychotics.