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研究生:秦禮萱
研究生(外文):CHIN, LI-HSUAN
論文名稱:使用網絡統合分析法評估第二、三代抗癲癇藥品於局部癲癇輔助治療之自殺風險
論文名稱(外文):Using Network Meta-analysis to Evaluate the Suicide Risk of the Second- and Third-Generation Antiepileptics for Adjunctive Therapy of Focal Epilepsy
指導教授:陳崇鈺陳崇鈺引用關係
指導教授(外文):CHEN, CHUNG-YU
口試委員:黃耀斌柯志鴻賴嘉鎮
口試委員(外文):HUANG, YAW-BINKO, CHIH-HUNGLAI, CHIA-CHENG
口試日期:2021-07-14
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:藥學系碩士在職專班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2021
畢業學年度:109
語文別:中文
論文頁數:179
中文關鍵詞:局部癲癇輔助藥物自殺風險網絡統合分析
外文關鍵詞:Focal epilepsyAdjunctive medicationSuicide riskNetwork meta-analysis
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研究背景:
抗癲癇藥物的使用長期被認為與自殺事件有關,但礙於多樣的風險因子與研究方法,即使將研究族群聚焦於癲癇甚至特定高自殺風險癲癇患者亦未有長期一致的結論。本研究嘗試限縮探討範圍,以台灣可取得之第二、三代抗癲癇藥品為限,評估局部癲癇患者使用不同輔助藥品之自殺相關不良事件的風險,並依結果推論選用不同輔助藥品是否會影響相關結果。

研究方法:
本研究藉由PubMed、Embase、MEDLINE、Cochrane Central Register of Controlled Trials和ClinicalTrials.gov等資料庫,搜尋2021年2月28日前發表之隨機對照試驗研究。英文發表之局部癲癇患者試驗將被納入,摻有新生兒或嬰兒等族群、僅比較同成分之不同劑型或頻次、非平行設計之試驗皆被排除在外。接著以Risk of Bias 2.0版工具評讀文獻後再萃取數據進行網絡統合分析。本研究共有五項結局:「任何自殺相關不良事件」、「自殺意念或傾向」、「自殺行為」、「自殺相關不良事件導致停止、減少試驗用藥或退出試驗」以及「自殺相關嚴重不良事件」。效應量為勝算比並取95%為可信區間(credible interval, CrI)。

研究結果:
本研究共收納53篇有數據之文獻,受試者共13612人。分析結果顯示所有比較結果皆沒有顯著差異。與安慰劑相比,對於「任何自殺相關不良事件」,勝算比範圍從0.19 (95%CrI: 0.00-8.56; lamotrigine)至2.63 (0.00-∞; levetiracetam)、對於「自殺意念或傾向」從0.68 (0.14-3.07; topiramate)至1.61 (0.04-∞; vigabatrin)、對於「自殺行為」從0.16 (0.00-301.20; levetiracatam) 至2.50 (0.19-100.00; vigabatrin)、對於「自殺相關不良事件導致停止、減少試驗用藥或退出試驗」從0.20 (0.00-286.70; gabapentin) 至1.74 (0.24-25.00; vigabatrin)、對於「自殺相關嚴重不良事件」從0.23 (0.01-2.72; gabapentin) 至1.75 (0.24-25.00; vigabatrin) 。
即使是針對摻有精神疾患族群或抗藥性癲癇之族群,亦未於各組比較中偵測到顯著差異。不同自殺相關事件定義可能會導致不同藥品間的相對風險排序錯置,且「任何自殺相關事件」之分析結果會偏向「自殺意念或傾向」而非傾向「自殺行為」。

結論與建議:
癲癇患者之自殺風險高於常人,而病況控制不良與多重用藥皆為其自殺之風險因子。在必須使用輔助用藥的前提下,若能避開高自殺特性者則有助於維護患者用藥安全。但根據本研究結果,不論使用何種自殺相關事件定義,所探討之抗癲癇藥物在短期使用的情況下並未有明顯差別。考量到自殺事件的罕見特性,以及未妥善控制病情之其他併發症風險,建議依照時下主流做法,以選用不同治療機轉、多重適應症且臨床療效反應佳者為優先考量,並搭配定期追蹤情緒以及精神狀態。

Background:
The usage of antiepileptic drugs has been thought to be related to suicides for a long time. However, due to the diversity of risk factors and research methods, there is still no long-term consistent conclusion even if the research population focuses on patients with epilepsy or more high risk ones. The study aimed to limit the medications to the second- and third-generation antiepileptic drugs available in Taiwan, and evaluate the risk of suicide-related adverse events of different adjunctive drugs in patients with uncontrolled focal epilepsy. And I would infer whether the results will be affected by different medications.

Methods:
I searched PubMed, Embase, MEDLINE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for randomized controlled trials from database inception to Feb 28, 2021. Trials with uncontrolled focal epilepsy population published in English would be included. And those with neonates or infants, comparisons about different dosage forms or frequencies for the same ingredient, or non-parallel designs were all excluded. Then data were extracted for network meta-analysis after critical appraisal with the Risk of Bias 2.0 tool. There were five outcomes in this study: any suicide-related adverse event, suicidal ideation or tendency, suicidal behavior, suicide-related events leading to discontinuation/tapering or drop-out, and serious suicide-related adverse events. Effect size measures were odds ratio with 95% credible intervals (CrIs).

Results:
There were 53 articles with data included for 13612 participants. No significant difference was found in any comparison. Odds ratio compared with placebo for any suicide-related adverse event varied from 0.19 (95% CrI: 0.00-8.56; lamotrigine) to 263(0.00-∞;levetiracetam), for suicidal ideation or tendency from 0.68 (0.14-3.07; topiramate) to 1.61 (0.04-∞; vigabatrin), for suicidal behavior from 0.16 (0.00-301.20; levetiracatam) to 2.50 (0.19-100.00; vigabatrin), for suicide-related events leading to discontinuation/tapering or drop-out from 0.20 (0.00-286.70; gabapentin) to 1.74 (0.24-25.00; vigabatrin), for serious suicide-related adverse events from 0.23 (0.01-2.72; gabapentin) to 1.75 (0.24-25.00; vigabatrin).
There was still no significant difference found in any comparison even if the population focuses on patients with mental disorders or drug-resistant epilepsy. Using different definitions of suicide-related events may change the relative rankings of drugs. The results of any suicide-related adverse event will tends to the rankings of suicidal ideation or tendency rather than suicidal behavior.

Conclusion:
The risk of suicide in patients with epilepsy is higher than general population. Uncontrolled status and multi-drug therapy are both risk factors for suicide. On the premise of adding on medications, patients may be protected by avoiding medications with suicidal properties. According to the results of this study, no matter what definition of suicide-related events is used, there is no significant difference among the antiepileptic drugs under short-term use. Considering the rarity of suicides and the risk of other complications, it is recommended to follow the current practices and select drugs with different mechanisms, multiple indications and good clinical response, combined with regular follow-up of mood and mental state.

目錄
中文摘要 I
Abstract III
致謝 VI
目錄 VII
表目錄 XI
圖目錄XII
第一章、 緒論1
第一節、 研究背景與動機1
第二章、 文獻回顧2
第一節、 癲癇2
第一項、 定義與流行病學2
第二項、 治療原則3
第三項、 降低的生活品質與精神相關併發症5
第二節、 抗癲癇藥物7
第一項、 隨機對照試驗研究之特點7
第二項、 作用機轉與概述7
第三項、 個別簡介8
第三節、 自殺15
第一項、 相關術語以及流行病學15
第二項、 風險因子16
第三項、 自殺之評估17
第四節、 癲癇、抗癲癇藥物與自殺事件19
第一項、 癲癇與自殺19
第二項、 抗癲癇藥物之角色 19
第三項、 可能機轉24
第四項、 現況25
第三章、 研究目的及目標27
第四章、 研究方法27
第一節、 研究流程與研究材料27
第一項、 文獻搜尋27
第二項、 關鍵字28
第三項、 納入條件28
第四項、 排除標準29
第五項、 結果定義29
第六項、 文獻選擇與資料蒐集31
第七項、 評讀標準31
第八項、 統計分析32
第五章、 結果34
第一節、 資料萃取流程34
第二節、 文獻基本描述36
第三節、 傳統統合分析47
第一項、 任何自殺相關不良事件之評估47
1. 主要結果 47
2. 異質性 47
3. 發表偏差 48
第四節、 網絡統合分析49
第一項、 主要結果49
1. 任何自殺相關不良事件之評估49
 初步分析 49
 次分類分析結果53

第二項、 次要結果57
1. 自殺意念或傾向之評估57
 初步分析 57
 次分類分析結果60
2. 自殺行為之評估64
 初步分析 64
 次分類分析結果68
3. 自殺相關不良事件導致須停止、減少試驗用藥或退出試驗之評估 72
 初步分析 72
 次分類分析結果77
4. 自殺相關嚴重不良事件之評估82
 初步分析 82
 次分類分析結果86
第六章、 討論91
第一節、 指標事件發生率與意義92
第二節、 使用不同抗癲癇輔助藥品對於各指標事件之影響93
第三節、 各次分類對於指標事件之影響96
第一項、 排除精神疾患史或未排除之族群96
第二項、 具有抗藥性或未排除無抗藥性之族群97
第三項、 追蹤時間至少126日或不滿126日之文獻98
第四項、 文獻高偏差風險與非高偏差風險99
第五項、 年齡未滿或超過18歲99
第六項、 併用藥物數量100
第四節、 研究優點與局限性101
第一項、 優點與特色101
第二項、 偏差風險102
第三項、 基礎用藥的可能影響102
第四項、 校正法對於原始數據的影響102
第五節、 未來研究方向103
第七章、 結論104
參考文獻 105
附件123

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