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)

论坛: 抗精神病药在痴呆中的应用抗精神病药治疗老年期痴呆精神行为症状的争议

肖世富

上海交通大学医学院附属精神卫生中心老年科, 上海交通大学阿尔茨海默病诊治中心 200030。电子信箱: 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

老年期痴呆的临床表现除认知缺损和社会生活功能减退外, 几乎所有病人在病程中都表现有精神行为症状, 一般称为痴呆的精神行为症状(behavioral and psychological symptoms of dementia,BPSD)。早在1906年, Alzheimer报道的首例阿尔茨海默病(Alzheimer's disease, AD)病人就曾描述, 病人除了认知损害外,还表现有明显的幻觉、妄想、吵闹、攻击等精神症状[1]。额颞叶痴呆和Lewy体痴呆的精神行为症状更为突出,有时成为主要临床症状[2,3]。横断面研究报道的BPSD总发生率多为50%～90%, 其中幻觉30%～50%, 妄想30%～80%, 抑郁30%～40%, 行为异常30%～70%[4-6]。长期随访研究表明, 几乎所有痴呆病人在其病程中都会出现精神行为症状[6]。BPSD加重病人的认知和社会生活功能障碍, 给病人、家属或照料者带来许多心理痛苦, 影响他们的生活质量。BPSD是痴呆患者早期住院或需要机构护理的主要原因,增加医疗和护理负担。

近年来,对抗精神病药(包括传统和新型药物)治疗老年期痴呆的精神行为症状存在许多争议[7,8]。早在本世纪初, 一些相关的研究就显示, 非典型抗精神病药治疗痴呆的精神行为症状的严重不良事件和死亡率高于安慰剂[9,10]。此后的一些荟萃分析显示,抗精神病药治疗组痴呆病人的死亡人数比安慰剂组增高约1.5～1.7倍[9]。对17项非典型抗精神病药老年期痴呆的精神行为症状研究分析显示, 药物治疗组的死亡率为4.5%, 安慰剂组为2.6%, 主要原因是心脑血管事件和肺部感染等严重不良事件。2005年美国FDA要求在非典型抗精神病药的说明书上以黑框警示。

doi (包括论坛栏目中所有的内容): 10.3969/j.issn.1002-0829.2011.06.009

典型抗精神病药同样与死亡率增高有关, 1项22 890例65岁以上老年人使用典型抗精神病药的回顾研究显示, 与非典型抗精神病药比较, 死亡的相对危险度为1.37, 显著高于非典型抗精神病药[11]。作者的结论是如果用典型抗精神病药替代非典型抗精神病药治疗, 死亡率会增加7%。先前的研究显示抗精神病药治疗老年期痴呆的精神行为症状有效, 但美国国立精神卫生研究所发起的、针对阿尔茨海默病的研究(CATIE-AD)显示, 患者精神行为症状的治疗获益可能被不良反应抵消, 不同非典型抗精神病药之间的疗效和耐受性无显著性差异[12]。目前所有抗精神病药物的适应证中均不包括BPSD, 但在临床实际工作中时常会非适应证使用。尽管争议很大, 美国[9]、欧盟[10]和中国[13]的痴呆诊治指南还是有条件地推荐非典型抗精神病药治疗痴呆的精神病性症状。对轻度的精神行为首先是非药物治疗症状和促认知药治疗。对前述治疗无效又影响病人和他人安全的严重症状, 或者严重症状的应急治疗, 临床医师在权衡利弊的情况下可谨慎使用非典型抗精神病。一般以成人推荐起始剂量的1/3～1/2起始, 在加强观察和谨慎评估的前提下缓慢加量, 目标剂量不宜过高, 在症状控制后应及时减量维持或停药。在治疗过程中要反复评价疗效和安全性, 适当调整药物剂量。这些一般原则很难回答诸如药物治疗应维持多长时间; 何时能完全停药; 小剂量的药物维持, 患者是否仍能获益等问题。这使得在临床实际工作中, 医师往往在疗效与风险的困境中左右为难, 仅凭个人经验来选择和调整药物。

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