Forum:Use of antipsychotic medications in dementia Treating the behavioral and psychological symptoms of senile dementia with antipsychotic drugs

Shifu XIAO

· Forum ·

Forum:Use of antipsychotic medications in dementia Treating the behavioral and psychological symptoms of senile dementia with antipsychotic drugs

Shifu XIAO

Most elderly patients with dementia have behavioral and psychological symptoms that co-occur with the characteristic cognitive impairment and social dysfunction; these symptoms are often referred to by the acronym BPSD (Behavioral and Psychological Symptoms of Dementia). In fact, the very first case of Alzheimer’s Disease reported (by Alzheimer in 1906)had hallucinations, delusions and aggressive behavior in addition to cognitive impairment[1]. In fronto-temporal dementia and Lewy Body Dementia the behavioral and psychological symptoms are quite prominent and often become the primary focus of clinical treatment[2,3].Cross-sectional studies report BPSD in 50%-90% of all patients with dementia; 30%-50% have hallucinations,30%-80% have delusions, 30%-40% have depression,and 30%-70% have other abnormal behaviors[4-6]. And long-term follow-up studies find that almost all patients with dementia manifest BPSD at some point during the course of their illness[6]. BPSD can exacerbate the cognitive and social dysfunction of dementia leading to a decreased quality of life for both the patient and the caregiver, more frequent hospitalization or chronic institutionalization, and, thus, a higher burden of illness.

There is an ongoing controversy about the role of antipsychotic medications in the management of BPSD[7,8]. Previous studies had found that antipsychotic medications were effective in the management of BPSD but over the last decade several studies have reported increased rates of severe adverse events and death among patients with dementia who are treated with antipsychotic medications[9,10]. A meta-analysis of 17 studies[9]found a 1.5-1.7-fold increase in mortality in patients with dementia who were treated with atypical antipsychotic medications versus those treated with placebo;a total of 4.2% died in the atypical antipsychotic group versus 2.6% in the placebo group, primarily from cardiovascular events and respiratory infections.Responding to these new findings, in 2005 the Food and Drug Administration in the United States required the addition of a black-box warning to the instructions for the use of atypical antipsychotic medications.

Typical antipsychotic drugs are also associated with increased mortality in patients with BPSD: a retrospective study[11]of 22,890 cases over 65 years of age using typical antipsychotic medications found a 1.37-fold increase in mortality. The authors of this study estimated that replacing typical with atypical medications would increase mortality by 7%. The large CATIE-AD study of Alzheimer’s Disease patients supported by the National Institute of Mental Health in the United States[12]concluded that the treatment benefit of using antipsychotic medications in patients with dementia is offset by the adverse effects and that there were no significant differences in efficacy or tolerability between the different types of antipsychotic medications.

Currently, the management of BPSD is NOT one of the approved indications for antipsychotic medications.However, in routine clinical care antipsychotic medications are often used for conditions not listed in the indications. For example, widely-used treatment guidelines for dementia in the United States[9], the European Union[10]and China[13]recommend the judicious use of atypical antipsychotic medications if the symptoms are severe or endanger the safety of the patient or others. In this situation the recommended starting doses are usually 1/3 to 1/2 of the standard adult dosage, the final target dose should be as low as possible, and the patient’s response and side-effects need to be carefully monitored. The risk-benefit ratios for continuing low maintenance doses of antipsychotic medication versus gradually stopping the medication after the behavioral and psychological symptoms have been controlled are, as yet, unclear, so clinicians must rely on their clinical judgment about whether and when to stop the medication.

Given the very real danger of serious complications or death, more long-term follow-up studies of the management of the BPSD are urgently needed to give clinicians guidance about how best to serve their patients with dementia who have associated behavioral or psychological symptoms.

1. Maurer K, Maurer U. Alzheimer:The life of a physician and career of a disease. New York: Columbia University Press, 2003.

2. Neary D, Snowden J. Fronto-temporal dementia:nosology,neuropsychology, and neuropathology. Brain Cogn, 1996,31(2):176-187.

3. Mckeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, FeldmmH et al. Diagnosis and management of dementia with Lewy bodies:third report of the DLB consortium. Neurology, 2005,65(12):1863-1872.

4. Seitz D, Purandare N, Conn D. Prevalence of psychiatric disorders among older adults in long-term care homes:a systematic review. Int Psychogeriatr, 2010, 22(7):1025-1039.

5. Ballard C, Gray A, Ayre G. Psychotic symptoms, aggression and restlessness in dementia. Rev Neurol, 1999, 155 Suppl 4:S44-52.

6. Shah A,Dalvi M,Thompson T. Behavioural and psychological signs and symptoms of dementia across cultures:current status and the future. Int J Geriatr Psychiatry, 2005, 20(12):1187-1195.

7. Finkel SI. Behavioral and psychological symptoms of dementia:a current focus for clinician, researchers, and caregiver. J Clin Psychiatry, 2001, 62 (suppl21):3-6.

8. Finkel SI, Burns A, Cohen GD. Over review of behavioral and psychological symptoms of dementia. Int Psychogeriatr, 2000,12(suppl1):13-18.

9. American Psychiatric Association:practice guideline for the treatment of patients with Alzheimer’s disease and other dementia. Am J Psychiatry, 2007, 164(12 Suppl):5-56.

10. Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia:EFNS guideline. Eur J Neurol, 2007, 14:e1-e26.

11. Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H,Solomon DH, et al. Risk of death in elderly users of conventional vs atypical antipsychotic medications. N Engl J Med, 2005,353(22):2335-2341.

12. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med, 2006, 355(15):1525-1538.

13. Jia JP. Chinese guideline for the diagnosis and treatment of patients with Alzheimer’s disease and other dementia.Beijing:People’s Health Publishing Company, 2010. (in Chinese)

論壇: 抗精神病藥在癡呆中的應用抗精神病藥治療老年期癡呆精神行為癥狀的爭議

肖世富

上海交通大學醫學院附屬精神衛生中心老年科, 上海交通大學阿爾茨海默病診治中心 200030。電子信箱: xiaoshifu@msn.com

doi(combining all the papers in the Forum Section): 10.3969/j.issn.1002-0829.2011.06.009

Alzheimer’s Disease and Related Disorders Center, Shanghai Mental Health Center, Shanghai Jiao Tong University school of Medicine, Shanghai 200030, China. E-mail: xiaoshifu@msn.com

老年期癡呆的臨床表現除認知缺損和社會生活功能減退外, 幾乎所有病人在病程中都表現有精神行為癥狀, 一般稱為癡呆的精神行為癥狀(behavioral and psychological symptoms of dementia,BPSD)。早在1906年, Alzheimer報道的首例阿爾茨海默病(Alzheimer's disease, AD)病人就曾描述, 病人除了認知損害外,還表現有明顯的幻覺、妄想、吵鬧、攻擊等精神癥狀[1]。額顳葉癡呆和Lewy體癡呆的精神行為癥狀更為突出,有時成為主要臨床癥狀[2,3]。橫斷面研究報道的BPSD總發生率多為50%～90%, 其中幻覺30%～50%, 妄想30%～80%, 抑郁30%～40%, 行為異常30%～70%[4-6]。長期隨訪研究表明, 幾乎所有癡呆病人在其病程中都會出現精神行為癥狀[6]。BPSD加重病人的認知和社會生活功能障礙, 給病人、家屬或照料者帶來許多心理痛苦, 影響他們的生活質量。BPSD是癡呆患者早期住院或需要機構護理的主要原因,增加醫療和護理負擔。

近年來,對抗精神病藥(包括傳統和新型藥物)治療老年期癡呆的精神行為癥狀存在許多爭議[7,8]。早在本世紀初, 一些相關的研究就顯示, 非典型抗精神病藥治療癡呆的精神行為癥狀的嚴重不良事件和死亡率高于安慰劑[9,10]。此后的一些薈萃分析顯示,抗精神病藥治療組癡呆病人的死亡人數比安慰劑組增高約1.5～1.7倍[9]。對17項非典型抗精神病藥老年期癡呆的精神行為癥狀研究分析顯示, 藥物治療組的死亡率為4.5%, 安慰劑組為2.6%, 主要原因是心腦血管事件和肺部感染等嚴重不良事件。2005年美國FDA要求在非典型抗精神病藥的說明書上以黑框警示。

doi (包括論壇欄目中所有的內容): 10.3969/j.issn.1002-0829.2011.06.009

典型抗精神病藥同樣與死亡率增高有關, 1項22 890例65歲以上老年人使用典型抗精神病藥的回顧研究顯示, 與非典型抗精神病藥比較, 死亡的相對危險度為1.37, 顯著高于非典型抗精神病藥[11]。作者的結論是如果用典型抗精神病藥替代非典型抗精神病藥治療, 死亡率會增加7%。先前的研究顯示抗精神病藥治療老年期癡呆的精神行為癥狀有效, 但美國國立精神衛生研究所發起的、針對阿爾茨海默病的研究(CATIE-AD)顯示, 患者精神行為癥狀的治療獲益可能被不良反應抵消, 不同非典型抗精神病藥之間的療效和耐受性無顯著性差異[12]。目前所有抗精神病藥物的適應證中均不包括BPSD, 但在臨床實際工作中時常會非適應證使用。盡管爭議很大, 美國[9]、歐盟[10]和中國[13]的癡呆診治指南還是有條件地推薦非典型抗精神病藥治療癡呆的精神病性癥狀。對輕度的精神行為首先是非藥物治療癥狀和促認知藥治療。對前述治療無效又影響病人和他人安全的嚴重癥狀, 或者嚴重癥狀的應急治療, 臨床醫師在權衡利弊的情況下可謹慎使用非典型抗精神病。一般以成人推薦起始劑量的1/3～1/2起始, 在加強觀察和謹慎評估的前提下緩慢加量, 目標劑量不宜過高, 在癥狀控制后應及時減量維持或停藥。在治療過程中要反復評價療效和安全性, 適當調整藥物劑量。這些一般原則很難回答諸如藥物治療應維持多長時間; 何時能完全停藥; 小劑量的藥物維持, 患者是否仍能獲益等問題。這使得在臨床實際工作中, 醫師往往在療效與風險的困境中左右為難, 僅憑個人經驗來選擇和調整藥物。

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