Treatment of psychosis and agitation in Alzheimers disease

阿尔茨海默病精神病和躁动的治疗

• 批准号: 8670190
• 负责人: DAVANGERE P DEVANAND
• 金额: $ 57.93万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670190
• 关键词: 7q11.2; Address; Adverse effects; Aggressive behavior; Agitation; Alzheimer' s Disease; Antipsychotic Agents; Behavior; Behavioral Symptoms; Biological Markers; Bipolar Disorder; Blood; Boxing; Brain-Derived Neurotrophic Factor; Caregivers; Case Series; Case Study; Clinical; Clinical Trials; Clinical assessments; Cognition; Data; Death Rate; Delusions; Dementia; Distress; Dose; Double-Blind Method; Equipment and supply inventories; FDA approved; Genes; Goals; Hallucinations; Haloperidol; Healthcare; Healthcare Systems; Institutionalization; Introns; Lead; Literature; Lithium; Maintenance; Measures; Meta-Analysis; Patient Selection; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Placebo Control; Placebos; Plasma; Prevalence; Psychotic Disorders; Publishing; Randomized; Relapse; Reporting; Risk; Risperidone; Role; Serum; Sum; Symptoms; Therapeutic; Time; United States; Variant; aging population; alternative treatment; base; discontinuation trial; double-blind placebo controlled trial; improved; indexing; innovation; mortality; neuropsychiatry; older patient; partial response; public health relevance; response; treatment response; treatment strategy; week trial

DESCRIPTION (provided by applicant): Symptoms of agitation/aggression and psychosis commonly occur in patients with Alzheimer's disease (AD), are distressing to patients and caregivers, often lead to institutionalization, are associated with increased mortality and financil burden to the healthcare system, and are very difficult to treat. Among the psychotropic medications, antipsychotics show superiority to placebo in randomized, double-blind, placebo-controlled trials in dementia, albeit with small to medium effect sizes. Antipsychotic side effects including the increased risk of mortality that led to an FDA black box warning, suggest that other treatments need to be evaluated. Our initial open treatment pilot data demonstrated that patients with AD who showed no response or partial response to antipsychotics improved on lithium, supporting the systematic study of lithium treatment for agitation/aggression with or without psychosis in AD. Low doses of lithium (150-600 mg daily) with low blood levels (0.2-0.6 mmol/l) are tolerated well in elderly patients with dementia. Our innovative project will examine, for the first time, the efficacy and side effects of low dose lithium treatment of agitation/aggression with or without psychosis in 80 patients with AD in a randomized, double-blind, placebo-controlled, 12-week trial. The results will determine the potential for a large-scal clinical trial to establish the utility of lithium in these patients. The primary hypothesis is tha the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) will decrease significantly more on lithium than placebo. The secondary hypothesis is that the proportion of responders on lithium will be significantly greater than the proportion of responders on placebo. The exploratory hypothesis is that the psychosis score, measured by the sum of the NPI domains for delusions and hallucinations, will decrease significantly more on lithium than placebo. We will also evaluate tolerability by assessing emergent somatic side effects over the course of the trial on lithium compared to placebo. We will evaluate plasma brain-derived neurotrophic factor (BDNF) at baseline and 12 weeks, a SNP on intron 1 of the ACCN1 gene, and the 7q11.2 gene locus, and examine whether these indices can predict lithium response with the goal of improving patient selection for clinical trials and eventually personalized treatment. Change over time in BDNF levels will be examined as a biomarker correlate of lithium treatment. Our study will provide initial data on three potential roles for low-dose lithiu treatment if it is found to be effective and safe (these roles are not mutually exclusive) in clinial practice: (1) first-line treatment; (2) adjunct treatment to antipsychotics in partial responders; 3) second-line agent after antipsychotic non-response or intolerability. If positive effects in the piot trial are confirmed in a large-scale trial there is considerable potential to markedly alter clinicl practice to benefit these patients in the United States and around the world.

描述（由申请人提供）：躁动/攻击和精神病症状通常发生在阿尔茨海默病（AD）患者身上，给患者和护理人员带来痛苦，经常导致住院，与死亡率增加和医疗保健系统的经济负担有关，并且很难治疗。在精神药物中，抗精神病药物在痴呆的随机、双盲、安慰剂对照试验中表现出优于安慰剂的效果，尽管效果大小为小到中等。抗精神病药物的副作用包括死亡风险的增加，这导致了FDA的黑框警告，这表明需要评估其他治疗方法。我们最初的开放治疗试点数据表明，对抗精神病药物无反应或部分反应的AD患者服用锂后病情有所改善，这支持了锂治疗伴有或不伴有精神病的AD患者躁动/攻击的系统研究。低血药浓度（0.2-0.6 mmol/l）的低剂量锂（150- 600mg /天）在老年痴呆患者中耐受性良好。我们的创新项目将首次在一项随机、双盲、安慰剂对照的12周试验中，对80名AD患者进行低剂量锂治疗伴有或不伴有精神病的躁动/攻击的疗效和副作用进行研究。结果将决定大规模临床试验的潜力，以确定锂在这些患者中的效用。主要假设是神经精神量表（NPI）的躁动/攻击领域分数在服用锂后比服用安慰剂后显著降低。第二个假设是，锂的应答者比例将显著大于安慰剂的应答者比例。探索性假设是，精神病评分（由妄想和幻觉的NPI域的总和衡量）在服用锂的情况下比服用安慰剂的情况下下降得明显更多。我们还将通过评估锂与安慰剂在试验过程中出现的躯体副作用来评估耐受性。我们将在基线和12周时评估血浆脑源性神经营养因子（BDNF）、ACCN1基因内含子1上的SNP和7q11.2基因位点，并检查这些指标是否可以预测锂反应，以改善临床试验患者的选择，最终实现个性化治疗。BDNF水平随时间的变化将作为锂治疗相关的生物标志物进行检查。如果在临床实践中发现低剂量锂治疗是有效和安全的（这些作用不是相互排斥的），我们的研究将提供三种潜在作用的初步数据：(1)一线治疗；(2)部分缓解者辅助抗精神病药物治疗；3)抗精神病药无反应或不耐受后使用二线药物。如果试点试验的积极效果在大规模试验中得到证实，那么将有相当大的潜力显著改变临床实践，使美国和世界各地的这些患者受益。