1、1,失智症合併精神及行為症狀(BPSD)的治療,歐陽文貞1,2,3,41.署立嘉南療養院高年精神科主任,兼臨床研究中心主任2.陽明大學公衛所流行病學碩士及博士3.中華醫事大學部定助理教授, 澳洲格里夫茲大學海外副教授4.台灣老年精神醫學會常務理事, 台灣失智症協會及臨床失智症學會理事, 熱蘭遮失智協會常務監事,2,Jianan Mental Hospital D.O.H Taiwan,行政院衛生署嘉南療養院,3,Geographical Location of Jianan Mental Hospital, D.O.H.,4,Outline,前言: 老人的社會 , 失智症是甚麼? What i
2、s BPSD?對BPSD的了解- ABCD. BPSD的產生原因- Bio-psycho-social .BPSD的處理_ DCBA結論與討論,5,percentage of the elderly & population growth in Taiwan,6,Prevalence: Taiwan(TW) & U.S ECA study Weissmen & Hwu. (%),7,7,介紹失智症,失智症是腦部疾病造成的症候群，病程通常為慢性或進行性，其症狀可能同時出現多種高級大腦皮質功能的障礙，以認知障礙為主。,8,阿茲海默症 : 發病率及發生率,60歲之後出現症狀, 65-85歲間每五年即
3、加倍預估全球現有2500萬人罹病中一般在診斷後7-10年死亡在已開發國家中佔死亡率的第四位,Ritchie K and Kildea D, 1995 9,65 69 7074 7579 8084 8589 9094 9599 Age,9,失智症的認知症狀,近期記憶力不好（amnesia）、失語症（aphasia）、認識能力不好（agnosia）、操作能力不好（apraxia，包括吃飯、如廁、穿衣、沐浴盥洗、及運動功能）、定向感、抽象思考、規劃、計算、學習、理解、判斷能力等。,10,11,11,失智症的症狀,失智症病患意識狀態（consciousness）大部分是清醒的，除非因身體疾病而同時合併
4、譫妄。 在疾病的某種程度時或其中一部分病人會同時合併情緒控制、社會行為問題、動機或驅力調節功能退化（食慾、睡眠習慣、性慾）、憂鬱、妄想或幻覺等症狀。,12,十大警訊 : 別以為這是正常老化現象,記憶力衰退, 忘東忘西對時間, 地點, 人物感到混淆無法作一些日常生活工作個性, 行為逐漸改變溝通困難判斷力減退心情時好時壞常把東西放錯位置穿著不乾淨,不合時宜的衣服做事失去主動性,13,13,失智症的症狀,失智症病患意識狀態（consciousness）大部分是清醒的，除非因身體疾病而同時合併譫妄。 在疾病的某種程度時或其中一部分病人會同時合併情緒控制、社會行為問題、動機或驅力調節功能退化（食慾、睡眠
5、習慣、性慾）、憂鬱、妄想或幻覺等症狀。,14,失智症的行為精神症狀-BPSD,Affect 憂鬱(達重鬱症否),焦慮,躁症 ,易怒Behavior自言自語,反覆衝動或持續行為,遊走, 不適切行為,坐立不安,傷人或自傷, Cognition 被偷妄想,錯認妄想,忌妒妄想,被害 妄想,宗教妄想(?),反覆固著的想法(不尋常 內容的想法或妄想),虛談現象,答非所問, 聽幻覺,視幻覺,觸幻覺,嗅幻覺, include 4A (so BPSD are not non-cognitive s/s. Ouyang )Drive 不想動或低動機,失眠或嗜睡,暴食,厭食 或胃口差(食慾高或低),體重減輕,性慾過
6、高 或不適切的性行為,15,失智症的行為精神症狀-BPSD,Affect 憂鬱(達重鬱症否),焦慮,躁症 ,易怒,16,失智症的行為精神症狀-BPSD,Behavior自言自語,反覆衝動或持續行為,遊走,不適切行為,坐立不安,傷人或自傷,17,失智症的行為精神症狀-BPSD,Cognition 被偷妄想,錯認妄想,忌妒妄想,被害妄想,宗教妄想少見(?),反覆固著的想法(不尋常內容的想法或妄想),虛談現象,答非所問,視幻覺,聽幻覺,觸幻覺,嗅幻覺,18,失智症的行為精神症狀-BPSD,Drive 不想動或低動機,失眠或嗜睡,暴食,厭食或胃口差(食慾低),體重減輕,性慾過高或不適切的性行為,19,
7、19,失智症的精神行為症狀-BPSD,Bassiny2000 - 342 AD in OPD: delusion22%, hallucination 3%, both 9% Int J Geriatr Psychiatry黃正平1995住院VaD有妄想50%(n=24), AD61% (n=54),AD妄想亞型42.6%,譫妄亞型14.8%,憂鬱亞型3.7%,無併發症38.9%(台灣精醫),所有失智症-想59%,幻覺25.6%,精神症狀71.8%.Prevalence of psychotic symptoms in dementia 10-75%(Wragg1989 Am J Psychia
8、try, Ballard1995 Int J Geriatr Psychiatry, Devanand1997,Drevet & Rubin1991, Skoog 1993 Int J Geriatr Psychiatry)BPSD常造成照顧者負擔及病患送機構照顧(就醫 in Taiwan) Steel 1990 Am J Psychiatry, Magni 1996Int J Geriatr Psychiatry, Stern 1997 JAMA,20,20,失智症合併精神行為問題-1,失智症合併行為問題常造成照顧者負擔及病患送機構照顧在台灣第一次失智症就醫往往導因於持續行為問題出現或家屬負
9、荷重其實有許多早期失智症完全沒有行為困擾,或只有相當輕微的行為問題,21,21,失智症合併的精神行為問題-2,某些行為的量減少不想動,不想說話,某些行為的量增加持續說話及計劃行為的質改變穿同一件衣服,大小便無法在適當處所,炒菜變鹹不尋常行為出現對家人發脾氣,尤其是媳婦回家時,反覆找東西或藏東西,晚上鄰居說拍窗戶吵鬧,收集許多東西,“吃肥皂” ,胡言亂語-問東答西,反覆提到同一件事,意識不清,大腦 萎縮 Brain atrophy,Katzman, 1986; Cummings and Khachaturian, 1996,阿茲海默症的病理:老化斑 &神經纖維糾結,神經細胞外:老化斑Senile
10、 plaques,神經細胞內:神經纖維糾結Neurofibrillary Tangles (NFTs),BPSD-精神藥物使用的適當性,23,23,了解精神行為背後的原因-1,1.腦部病變-因腦功能退化(結構及傳導物質) 與適應暴食,不適切性行為,大小便失禁, 2.心理上需求-個性改變或某部分個性變得明顯或失控,因認知功能退化無法表達或適應孤獨,不安心(反覆打電話),認知功能退化引起的判斷失誤,因為妄想或幻覺而引發的不尋常行為被偷妄想,忌妒妄想,視幻覺,觸幻覺3.社會-病前與照顧者的相處, 照顧者的情緒,24,24,了解精神行為背後的原因-2,4.身體疾病造成疼痛或身體不舒服坐立不安(肛門周圍
11、化膿), 身體疾病造成意識不清脫水,血糖高,營養差,泌尿道發炎,甲狀腺疾病5.失智病患的憂鬱或輕躁-病前就有或因疾病適應後才有或是失智症的腦部病變造成的6.藥物副作用錐體外副作用,流口水7.不明的原因,如衝動控制反覆吐口水,尖叫,呻吟,唱哭調,25,26,BPSD 在失智症的重要性,單純/認知障礙(4A)不能充分解釋失智症患者功能傷殘或生活品質缺損。對於失智症患者家屬或照顧者而言，BPSD是最重要的特點，因它常產生或加劇他們照顧負擔。BPSD在其護理之家安置的選擇和精神病藥物治療開立上，常常是重要決定因素。患者和照顧者的生活品質也負面地受到BPSD的影響。McKeith I., Cumming
12、s J. Behavioural changes and psychological symptoms in dementia disorders. Lancet Neurol 2005; 4: 73542.,27,失智症帶給家人的負擔,1.由於兒女已開始離家或各自成家心理負擔重（罪惡感、焦慮、無望無力感重）且需往一定的努力才得已連接社會網絡系統（子女過少或分散各地）2.照顧者體力上的負荷（大小便、協助行動或就醫）3.需要長期照顧時的人力成本（失智症本身份或合併身體疾病時）,28,失智症帶給家人的負擔,4.破壞、遊蕩、干擾、暴力或自殺造成社區困擾5.法律問題（立遺囑）或造成法律案件（是否禁制產
13、宣告）6.獨居或被忽略的病患無法連接社會資源系統（社會介入困難且無制度、理想且可連接上的醫療資源極少）7.長期照顧衍生經濟負擔,29,29,照顧者需要照顧,體力心理壓力社區網絡經濟負擔66%的照顧者是配偶60%的照顧者有精神症狀30%左右的照顧者符合憂鬱症,甚至有自殺想法,需要治療放鬆及替手-心境與轉念 支持的親友適當的藥物治療憂鬱,焦慮,失眠照顧者協會及支持團體,30,30,失智症併精神行為問題的處置,尋求專業的醫療評估腦及身體疾病適當治療身體疾病學習照顧失智症的技巧與知識活到老,學到老接受適當的藥物治療改善認知功能,穩定情緒或緩和行為或精神症狀的藥物,尋求資源協助照顧者身心負擔情緒支持團體
14、,日托或老人日間留院,長期照顧,31,吉野櫻-阿里山2004.03,32,BPSD治療的整體方向 D C B A,雖然因為失智症的種類不同， 臨床症狀也因人而異，但是在藥物治療或處置的整體方向上都是1.優先治療 D身體問題或譫妄、2.其次優先治療C認知功能、3.再其次才處理B行為及情緒問題、4.最後才是處理A日常生活功能。,33,BPSD的鑑別診斷,譫妄(delirium,acute confusional state,metabolic encephalopathy, toxic encephalopathy)-非併發於癡呆症F05.0,譫妄-併發於癡呆症F05.1(beclouding d
15、ementia)身體狀況OK? 2個病還是1個病, D/D Agitated depression, / pain, dysuria, dyspnea, abdomenal discomfort, constipation, pruritus並存其他器質性原因造成精神病如CVA,藥物,巴金森氏病合併精神症狀?精神分裂病或躁症至中老年期合併失智症(F2x,F3x)不同失智症的BPSD症候群都一樣嗎? AD/VaD/FTD/DLB,34,D,身體問題或譫妄Disease or delirium,找出緊急及必需處理的身體問題或病因,35,Delirium鑑別診斷-身體疾病,D(drug)-Antic
16、holinergic (anti-parkisonic ,TCA) ,BZD abuse/ dependence (intoxication or withdrawal ), lithium or caffeine intoxication ,CV藥物E (electrolyte)- Hyponatremia ,hyperkalemia(dehydration)M (metabolism)- hypoxia (COPD, sleep apnea,heart failure, arythymia,unstable MI), hepatoencephalopathyE (endocrine )-
17、Hyperthyroidism ,hypo-/hyper-glycemia(DM), hyper-or hypo-parathyroidism or pituitarism, steroid-Cushing syndrome,N (neurolocal disease or nutrition ) - CVA, SDH, TIA, vertigo, seizure, Parkisons disease, Vit B1 or B12 deficiencyT (tumor)- Paraneoplastic(limbic encephalitis), metastasis, SIADHI (infe
18、ction)-Sepsis (UTI, pneumonia)A (alcohol)-Alcohol withdrawal syndrome(reverse tolerance),36,C,認知維持及膽鹼代謝酶抑制劑Cognitive maintenance & ChEI,早期維持基本認知功能及學習基礎,37,Pathology of BPSD & use of ChEI,BPSD in AD related to loss of cholinergic neurons and a resultant decline in Ach in Brain region such as limbic s
19、ystem .Donepezil for BPSD,mild to moderate AD, placebo - control study :24 wks,非機構有效,機構無效Rivastigmine: 有效.BPSD,mild to moderate-severe AD and DLB, placebo-control study,且機構化個案減少其他精神治療藥物的量.Galanthamine: 有效.placebo-control study,delay onset of BPSD in AD and improve BPSD in VaD.Robert p2002 Curr Med R
20、es opin;18(3):156-71.,38,Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. using MEDLINE, the Cochrane Database of Systematic Reviews, English-language articles published 1966-2004,JUL,Five trials of antidepressants were included; results showed no efficac
21、y for treating neuropsychiatric symptoms other than depression,with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTsinvestigating valproate showed no efficacy. Two small RCTs of carbamazepine had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors gener
22、ally showed small, although statistically significant, efficacy. Two RCTs of memantine also had conflicting results for treatment of neuropsychiatricsymptoms. Sink KM, Holden KF, Yaffe K. JAMA. 2005 Feb 2;293(5):596-608.,AChE = acetylcholinesterase 乙醯膽素 ; BuChE = 丁醯 butyrylcholinesterase; ChAT = cho
23、line acetyltransferase; CoA = coenzyme A.,Choline+Acetate,Pre-synaptic neurone突觸 前,Synaptic cleft,Post-synaptic neurone 突觸 後,Cholinergic receptor 膽鹼激素 接受體,Choline,Acetyl CoA 乙醯膽鹼輔媒A +Choline,BuChE,ChAT 膽鹼激素 轉化媒,阿茲海默症病患：大腦中BuChE被活化釋放出來，也參與了ACh的調控,AChE,Dual Inhibition,ACh,BuChE,ACh,NEW !,Adem, Acta Ne
24、urol Scand, 1992, 139:69,40,摘自Rachelle S. Doody(2003), J Clin Psychiatry 64:11-17,41,Figure 1 Cognitive function in AD patients receiving donepezil 5 or 10 mg/day or placebo . Values are mean ( standard error of the mean SEM) change from baseline. Reassessment 6 weeks after withdrawal of donepezil r
25、eveals that the benefits of drug treatment were lost upon withdrawal. (From Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimers disease. Neurology. 1998;50:136-45.).摘自Reichman WE.(2003). Ann Gen Hosp Psychia
26、try 2(1):1,26,長期服藥的益處-越早服藥,改善 ADAS-Cog越多,Proj. placebo,Dose optimisation with Exelon,0 10 20 30 40 50,612 mg/day Exelon,14 mg/day Exelon,Placebo,Cognition,Study week,Messina et al., 2000,202468,43,Galantamine,2001通過,競爭性抑制AChE及allosteric調節nicotinic受體 (Figure 4) 14,37.節前尼古丁受體可調節釋放AChEI, glutamate, ser
27、otonin, norepinephrine ,因此Galantamine增加突觸間Ach的量. 短效Bid,劑量一天16-24mg/dl有效,副作用GI為主,但是沒有失眠,肝腎有問題需減至16mg/d或是不能用此藥.Wilkinson DG, ,Int J Clin Pract 2002;56:509-514 Galantamine provides broad benefits in patients with advanced moderate Alzheimers disease (MMSE or = 12) for up to six months. ),44,摘自Rachelle
28、S. Doody(2003), J Clin Psychiatry 64:11-17,45,46,Figure 5. Cognitive function in AD patients receiving galantamine 24 mg/day for 12 months or placebo for 6 months followed by galantamine 24 mg/day for 6 months . Although patients who took galantamine 24 mg/day for 12 months were able to maintain cog
29、nitive function at baseline levels, patients who were on placebo for the first 6 months and then switched to galantamine could not achieve this level of functioning, indicating that early treatment provides the greatest benefit. (From Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: a 6-
30、month randomized, placebo-controlled trial with a 6-month extension. Neurology. 2000;54:2261-8.)摘自Reichman WE.(2003). Ann Gen Hosp Psychiatry 2(1):1,47,48,49,新藥- Memantine,Memantine (Merz & Co., Frankfurt/Main, Germany) is a noncompetitive, N-methyl D-aspartate (NMDA) receptor antagonist approved in
31、 Germany for more than 10 years for the treatment of dementia. The proposed mechanism by which memantine exerts its effects on dementia is thought to be related to its neuroprotective characteristics 73,74. Clinical safety and efficacy have been investigated both in clinical trials and postmarketing
32、 surveillance studies 75-77.2003,50,副作用Memantine is generally well tolerated, with the most common adverse events being vertigo, restlessness, hyperexcitation, and fatigue 76. It may become a neuroprotective treatment for dementias in the near future, and it may also be combined with AChEIs for symp
33、tomatic relief of AD 78.,51,摘自Reichman WE.(2003). Ann Gen Hosp Psychiatry 2(1):1,Galantamine50%由肝排除50%經腎Exelon由腎,Aricept由肝排除,52,Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. using MEDLINE, the Cochrane Database of Systematic Reviews, English-language a
34、rticles published 1966-2004,JUL,Five trials of antidepressants were included; results showed no efficacy for treating neuropsychiatric symptoms other than depression,with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTsinvestigating valproate showed no efficacy. Two small RCTs of
35、 carbamazepine had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors generally showed small, although statistically significant, efficacy. Two RCTs of memantine also had conflicting results for treatment of neuropsychiatricsymptoms. Sink KM, Holden KF, Yaffe K. JAMA. 200
36、5 Feb 2;293(5):596-608.,53,一葉蘭,54,B,行為問題儘快藉由藥物改善Burden or Behavior problems should be controlled by drugs rapidly,避免照顧者崩潰及善用藥物副作用,55,BPSD用藥前的考量-1,(不同診斷間)認知改變嚴重度和BPSD症狀相關不強 (weakly correlated)，這暗示BPSD與認知改變代表著不同的潛在病生理機制。在AD認知症狀和海馬迴與記憶、語言及視覺空間有關的後腦區有關(hippocampus and posterior association cortex 【memor
37、y, language, visuospatial disturbances】)，而在AD，BPSD與認知改變和額顳葉相關有限。故中重度較多。BPSD對家屬及社區影響多大(推積如山 )。日常生活活動的損傷和BPSD症狀的出現是強烈相關日常生活活動包括了複雜的計劃(planning)，這部份需靠額葉皮質及皮質下結構主導執行功能，BPSD合併ADL者和此區域有關。 McKeith I., Cummings J. Lancet Neurol 2005; 4: 73542.,56,BPSD用藥前的考量-2,BPSD受神經生物學、環境及先前的心理人格傾向交互作用而影響。 BPSD的治療包括非藥物(尤其是
38、輕中度)和藥物介入。非藥物學處置包括行為療法、系統性的改變照護環境、運動及音樂。另外，教育及訓練照顧者照護技巧，幫助其適當地反應病患出現的行為變化和減少病患症狀逐步惡化。家庭照顧者常受心理壓力所影響，所以也要適當的處理照顧者可能出現的憂鬱、焦慮及物質使用，來儘可能減少照顧者病痛機會和改進照顧者與患者間的關係。 McKeith I., Cummings J. Lancet Neurol 2005; 4: 73542.,57,精神藥物使用前的基本考量,副作用(side effect or adverse effect)與治療作用安全性與藥效(safety and efficacy)需要用藥嗎?起始
39、劑量,有效劑量與維持劑量使用頻次/半衰期,服藥規律性(compliance/adherence)使用足夠劑量到有治療效果所需的時間 立刻有效?,4-6週, 8-12週,/多久該減藥或停藥?診斷腦神經科,精神科診斷,其他身體診斷, 老人或整體身體老化的情形藥物的交互作用與代謝,58,使用抗精神病藥物,診斷與indication(適應症) 建立治療性關係Target symptoms(目標症狀)Initial dose (starting dose,起始劑量)Target dose(預定的有效劑量)Maintenance dose(長期維持劑量)Days to mid-target dose (調
40、藥時間間隔)Days to effect(等待藥效開始的時間)Days to maintenance dose(減至維持劑量的時間)Full dose,Full term (考慮有效的最大劑量及時間,59,“癡呆症合併精神症狀“的藥物治療 Medline,2004.03.31找尋Medline上1989-2003,找尋字眼dementia and (antipsychotics的英文)Ziprasidone 及amisulpride 0篇Clozapine 沒有,但在回顧中文章有提到.Zotepine 1篇Open label 2004Quetiapine 1篇Open label 2002O
41、lanzapine及rsiperidone至少都各有7篇,60,Clozapine,1999回顧,for elderly use with no neurological comorbidity,Medline 1966-1997,n=133,似乎有效tolerate,34位有副作用,16位因此停藥,mean dose =134mg/day, 7位leukopenia(5%) Compr Psychiatry1999;40:320-5其他回顧clozapine1970s使用,1974停用,1990復用,可用在老人合併Parkisonism 及dementia個案Iqbal 2003 Ann C
42、lin Psychiatry15(1):33-48,61,Zotepine,2004 open label ,8 wks,失智 with BPSD, 12AD, 12 other, MMSE, NPI, 12.5-150mg, 36% case improved, tolerated-sedation, no EPS,no 記憶力退化,未增加家屬負擔(Rainer CNS drug2004;18:49-55.),62,Olanzapine,詳述2篇RCT雙盲,placebo-control研究Denyn 2004, n=652,10 wks, dosage: 1,2.5, 5.0, 7.5mg
43、四組,NPI/NH,只有7.5mg組與placebo組有療效差異,CGI只有2.5mg組與placebo組有差異,療效不夠大,且placebo組也進步不少,體重增加?Street 2000,n=206,6 wks, dosage:5,10,15mg三組,NPI/NH,只有5及10mg組與placebo組有療效差異,嗜睡即步態不穩為常見副作用,63,Quetiapine,2002 open label trial,OPD, 12wks, 10位AD with aggression or psychosis, ADAS-cog, NPI,dose 50-150mg有效且記憶不退化(Scharre
44、Alzeimer Dis Assoc Disord2002Apr-Jun;16(2):128-30.)2000 For sexaully inappropriate behavior in dementia(J Am Geriatr Soc2000;48:707)2003 2 case report for aricept-refractory VH2003 1 case for DLB (Takahshi), Bid use , fast dissociation hypothesis, dose?,64,Comparison of quetiapine study in the elder
45、ly between McManus and Hwangs study,_ McManus et al Hwang et al_ Cases numbers 151 100Method open trial (12 weeks) open trial (4 weeks)Mean age 76.8 75.3Inpatient, % 9 100Average dose 100 mg/day (13-400) 276 mg/day (50-800)Effective (BPRS) 52% of cases 84.6% of cases Drop-out rate, % 23.8 9Body weig
46、ht mean gain :0.8 kg mean gain : 1.5kgSide effects Somnolence (32%) Somnolence (30%) Dizziness (14%) Dizziness (27%) hypotension (12%) Hypotension (9%) Constipation (7%) Constipation (13%) EPS(6%) EPS (7%) Diarrhea (5%) Diarrhea (5%) Dry mouth (3%) Dry mouth (6%) Weakness of legs (28%) pitting edema (9%) _ McManus DQ et al : J Clin Psychiatry 1999;60:292-298 (黃正平主任提供),
