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系統識別號 U0026-3007202002124000
論文名稱(中文) 失智症老人跌倒及骨折風險評估—探討抗精神病藥物與膽鹼酶抑制劑之交互作用
論文名稱(英文) Risk of falls and fractures in elderly patients with dementia—assessment of the interaction between antipsychotics and cholinesterase inhibitors
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 108
學期 2
出版年 109
研究生(中文) 王馨敏
研究生(英文) Hsin-Min Wang
學號 S66084026
學位類別 碩士
語文別 英文
論文頁數 94頁
口試委員 指導教授-賴嘉鎮
召集委員-楊淑瑜
口試委員-張維紘
口試委員-文鏡彰
口試委員-韓雅斐
中文關鍵字 膽鹼酶抑制劑  抗精神病藥物  跌倒  骨折  交互作用 
英文關鍵字 cholinesterase inhibitors  antipsychotics  falls  fractures  interaction 
學科別分類
中文摘要 研究背景
隨著高齡人口比例上升,老化議題對家庭及社會造成的負擔日趨增加。例如跌倒不
僅是造成台灣老年人死亡常見的事故傷害,亦可能導致病患骨折而住院。跌倒的危
險因子包含與病人本身情況相關的內在因素,像是年紀增加、肌肉無力、步態不
穩、視力減退、姿勢性低血壓,及一些慢性病,例如失智症。還有一些是可改變的
外在因素,例如危險的環境以及影響精神行為的藥物。大部分失智症老人伴隨有行
為及精神方面的異常,因此需要使用抗精神病藥物,但2017 年FDA 發布的警告和
2019 年的Beers criteria 皆顯示此類藥物會增加跌倒及骨折的風險。膽鹼酶抑制劑也
是失智症常見的治療藥物,會造成病患心跳變慢而昏厥,可能間接增加跌倒及骨折
的風險。然而,目前的文獻上未能對此做出定論。此外,過去研究顯示上述兩種藥
物並用會產生交互作用,增加錐體外症候群副作用的發生。如此一來,跌倒和骨折
的風險可能也會受到影響,但尚無文獻對此進行評估。
研究目的
本研究旨在評估膽鹼酶抑制劑及抗精神病藥物之間的交互作用是否會增加失智症老
人跌倒及骨折的風險,並分別探討兩種藥單用及並用相對於沒有用藥的發生率比。
研究方法
本研究採取個案自我對照法(self-controlled case series),資料來源為2003 至2017 年
台灣衛生福利部衛生福利資料科學中心加值資料,包含全民健保處方及治療明細檔_
門急診、全民健保處方及治療明細檔_西醫住院、全民健保處方及治療明細檔_藥
局、全民健保處方及治療醫令明細檔_門急診、全民健保處方及治療醫令明細檔_住
院、全民健保處方及治療醫令明細檔_藥局、全民健保承保檔,以及死因統計檔。研
究對象為 65 歲(含)以上新使用抗精神病藥物與膽鹼酶抑制劑的患者,且在研究期間
曾並用上述兩者藥物,並發生過至少一次跌倒或骨折。為了確保納入的患者皆患有
失智症合併精神行為症狀,我們排除過去病史需要使用到抗精神病藥物,包含思覺
失調症、雙極性疾患,以及憂鬱症的病患。我們使用條件式泊松回歸(Conditional
Poisson regression)計算病患在使用膽鹼酶抑制劑、抗精神病藥物,以及並用上述兩
種藥,各時間段相對於沒有用藥時的跌倒及骨折發生率,並評估這兩類藥物是否具
有交互作用會對跌倒及骨折造成影響。由於時間可能會對結果造成影響,我們也將
觀察期間以年為單位進行校正。
結果
本研究收錄10,750 位病患,以女性居多(64.4%),平均年齡為74.9 歲,發生第一次
跌倒或骨折的平均年齡則為80.2 歲。大多數事件為骨折(94.8%),只有少部分患者是
跌倒(2.8%)或是兩者皆發生(2.4%)。發生事件時,13.9%患者正在使用膽鹼酶抑制
劑,主要是donepezil (58.1%),因為它被核准用於輕度至重度阿茲海默症;其次是
rivastigmine (32.3%),因為它是唯一被核准用於帕金森式失智症的膽鹼酶抑制劑。
8.7%有服用抗精神病藥物,主要是quetiapine (76.6%),因為它的副作用相對較小;
其次是risperidone (24.2%),因為它是唯一被核准用於失智症病人具嚴重攻擊性的抗
精神病藥物。8.4%並用這兩種藥物,而其他的人都是沒有使用上述藥物的。本研究
結果並沒有發現膽鹼酶抑制劑及抗精神病藥物之間有會增加跌倒及骨折風險的交互
作用。然而,不論是單用或並用膽鹼酶抑制劑及抗精神病藥物,跌倒及骨折的發生
率都比沒有用藥時來得高。其中,增加幅度以並用時最大(發生率比值:1.53,95%
信賴區間:1.40-1.66),再來是單用抗精神病藥物(發生率比值:1.45,95%信賴區
間:1.33-1.58),最後是單用膽鹼酶抑制劑(發生率比值:1.23,95%信賴區間:1.15-
1.32)。此外,使用第一代抗精神病藥物(發生率比值:3.55,95%信賴區間:2.92-
4.31)時的發生率也較第二代抗精神病藥物(發生率比值:1.28,95%信賴區間:1.17-
1.40)來的高。



結論
由本研究結果可知用藥時相比於沒有用藥時有更高的機率會發生跌倒或骨折。然
而,我們也發現在第一次用藥前發生跌倒或骨折的機率甚至高過有用藥的時段(發生
率比值:4.95,95%信賴區間:4.57-5.36)。這可能是因為病患當下病情特別嚴重(例
如:躁動或是神智不清),才導致跌倒或骨折風險竄高。用藥後可能反而降低了風
險,只是還未能降到與平時完全相同。因此,我們的建議是穩定情況下應避免或小
心用藥,但若醫師評估後認為有需要,則仍應使用藥物。



關鍵詞
膽鹼酶抑制劑、抗精神病藥物、跌倒、骨折、交互作用
英文摘要 Since both antipsychotics (APs) and cholinesterase inhibitors (ChEIs) have the potential to enhance the risk of falls and fractures (FFs), plus they cause severe extrapyramidal symptoms when used concomitantly, we hypothesized that there is an interaction between the study drugs leading to increased FFs. We conducted a self-controlled case series and calculated the incidence rate ratio (IRR) using conditional Poisson regression during monotherapy and combination therapy of the study drugs compared with the unexposed periods. Eligible participants included elderly people who newly used both APs and ChEIs as well as newly experienced FF during 2006-2017. We ruled out those with underlying diseases that require APs, such as schizophrenia, bipolar disorder and depression before the first prescription of ChEI to assure that APs were used for dementia. After adjusting by year, we found no interaction on FFs. Additionally, patients had the highest occurrence of FFs under combination therapy (IRR: 1.53, 95%CI: 1.40-1.66), followed by monotherapy of APs (IRR: 1.45, 95%CI: 1.33-1.58) and ChEIs (IRR: 1.23, 95%CI: 1.15-1.32). To be specific, the risk was higher when using first-generation antipsychotics (IRR: 3.55, 95%CI: 2.92, 4.31) than second-generation ones (IRR: 1.28, 95%CI: 1.17-1.40). Nonetheless, the risk was even higher within 2 weeks before the first prescription of each drugs (IRR: 4.95, 95%CI: 4.57-5.36), indicating that patients might be under extremely severe conditions at that time. Therefore, the drugs might actually decrease the risk of FFs, even if it had not returned to the baseline.

Key words: cholinesterase inhibitors, antipsychotics, falls, fractures, interaction
論文目次 摘要 ................................................................................................................................... I
Abstract ......................................................................................................................... III
致謝 ................................................................................................................................ VI
CONTENT OF TABLES .............................................................................................. XI
CONTENT OF FIGURES ........................................................................................... XII
EPISODE Ⅰ RISK OF FALLS AND FRACTURES IN ELDERLY PATIENTS
WITH DEMENTIA—ASSESSMENT OF THE INTERACTION BETWEEN
ANTIPSYCHOTICS AND CHOLINESTERASE INHIBITORS ..................................1
1. BACKGROUND ......................................................................................................1
2. LITERATURE REVIEW ........................................................................................3
2.1 Dementia ....................................................................................................3
2.1.1 Manifestations of dementia .................................................................3
2.1.2 Antidementia medications ...................................................................4
2.1.3 Other medications for dementia ...........................................................5
2.2 Association between ChEIs and FFs ...........................................................6
2.2.1 Association between ChEIs and falls ...................................................6
2.2.2 Association between ChEIs and fractures .......................................... 10
2.3 Association between APs and FFs ............................................................. 12
2.3.1 Association between APs and falls .................................................... 13
2.3.2 Association between APs and fractures.............................................. 15
2.4 Drug-drug interaction ................................................................................ 16
2.4.1 Interaction between APs and ChEIs ................................................... 16
3. RESEARCH GAPS AND HYPOTHESIS ............................................................. 17
3.1 Research gaps ........................................................................................... 17
3.2 Hypothesis ................................................................................................ 17
4. OBJECTIVE AND AIMS....................................................................................... 19
4.1 Objective and aims.................................................................................... 19
4.2 Clinical relevance ..................................................................................... 19
5. METHOD ............................................................................................................... 20
5.1 Study design ............................................................................................. 20
5.2 Data sources ............................................................................................. 21
5.3 Study population ....................................................................................... 22
5.4 Intervention and comparison ..................................................................... 23
5.5 Outcome ................................................................................................... 27
5.5.1 Baseline variables and definitions...................................................... 27
5.5.2 Outcome variables and definitions ..................................................... 30
5.5.3 Incidence rate ratio of falls and fractures ........................................... 31
5.5.4 Drug utilization pattern ..................................................................... 31
5.5.5 Distribution ....................................................................................... 31
5.6 Statistical Analysis .................................................................................... 32
6. RESULT .................................................................................................................. 33
6.1 Study cohort ............................................................................................. 33
6.2 Cohort characteristics ................................................................................ 34
6.2.1 Baseline characteristics ..................................................................... 34
6.2.2 Outcome characteristics .................................................................... 37
6.2.3 Duration from the closest prescription to the first FF ......................... 40
6.2.4 PDD/DDD ratio of the closest prescription to the first FF .................. 42
6.3 Incidence rate ratio.................................................................................... 43
6.4 Drug utilization pattern ............................................................................. 47
6.5 Distribution ............................................................................................... 48
6.5.1 Distribution of patient-year ............................................................... 48
6.5.2 Distribution of event ......................................................................... 51
6.5.3 Distribution of incidence rate ............................................................ 53
7. DISCUSSION ......................................................................................................... 56
7.1 Interpretation of patient characteristics ...................................................... 56
7.2 Interpretation of the association between ChEIs, APs and FFs ................... 58
7.3 Interpretation of the distribution ................................................................ 64
7.4 Strength and limitation .............................................................................. 65
7.4.1 Strength............................................................................................. 65
7.4.2 Limitation ......................................................................................... 66
7.4.3 Future works ..................................................................................... 67
8. CONCLUSION....................................................................................................... 68
EPISODE II CLINICAL SERVICE.............................................................................. 69
第一章 背景與目的 ........................................................................................................ 69
第二章 執行計畫 ........................................................................................................... 70
第一節 專案藥師 .......................................................................................... 70
壹、 服務對象 .......................................................................................... 70
貳、 服務內容與執行方式 ....................................................................... 70
參、 服務成果 .......................................................................................... 70
肆、 討論 .................................................................................................. 72
第二節 衛教單張 .......................................................................................... 77
壹、 服務對象 .......................................................................................... 77
貳、 服務內容與執行方式 ....................................................................... 77
參、 服務成果 .......................................................................................... 79
肆、 討論 .................................................................................................. 87
第三章 心得與期許 ........................................................................................................ 88
9. REFERENCE ......................................................................................................... 89
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