Treatment of Psychosis and Agitation in Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 77
- 试验地点
- 4
- 主要终点
- Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score
研究概览
简要总结
Clinically, many patients with AD show no response or minimal response to antipsychotics for symptoms of agitation/aggression or psychosis, or they have intolerable side effects on these medications. Antipsychotics have a wide range of side effects, including the risk of increased mortality (60-70% higher rate of death on antipsychotic compared to placebo) that led to an FDA black box warning for patients with dementia; a more recent review and meta-analysis showed a 54% increased risk of mortality. In addition, some patients show only partial response to antipsychotics and symptoms persist. For these reasons, the investigators need to study alternative treatment strategies. Currently, there is no FDA-approved medication for the treatment of psychosis or agitation in AD.
The investigators innovative project will examine 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, doubleblind, placebo-controlled, 12-week trial (essentially a Phase II trial). The results will determine the potential for a large-scale clinical trial (Phase III) to establish the utility of lithium in these patients.
详细描述
Symptoms of psychosis or agitation are common in Alzheimer's disease. These symptoms are associated with distress for the patient, an increased burden for caregivers, more rapid cognitive decline, greater risk of institutionalization and mortality, and increased health care costs. In a recent meta-analysis, caregiver education and behavior modification studies revealed a small to medium effect size in treating agitation in these patients. However, none of these studies were double-blind (difficult to achieve in such studies) and none had a control group that received the same amount of staff time as the intervention group, thereby biasing the results toward the active intervention.
Among the psychotropic medications that have been studied, only antipsychotics have shown superiority over placebo for the treatment of psychosis and agitation in patients with dementia.
However, most studies show only moderate superiority for antipsychotic over placebo and a few studies have been negative. The side effects of antipsychotic medications include sedation, extrapyramidal signs, tardive dyskinesia, weight gain, and the metabolic syndrome. A pooled analysis from 17 short-term trials showed that the mortality rate in patients with dementia receiving antipsychotic medications was 1.6 to 1.7 times as high (60-70% increase in mortality rate) as the mortality rate in patients receiving placebo. These findings led the FDA to issue a black-box warning for antipsychotic medication use in patients with dementia; a more recent meta-analysis reported a slightly lower odds ratio of 1.54 (54% increase in mortality rate).
Lithium has several different actions from anticonvulsants, though both are effective in bipolar disorder, especially mania. Lithium is not being proposed here to treat mania in AD though the investigators will monitor symptoms on the Young Mania Rating Scale. In patients with AD, lithium has been studied for its putative cognitive enhancing effects. A few reports suggest that chronic lithium use reduces the risk of dementia, but other data show increased dementia risk with lithium use. A placebo-controlled, single-blind lithium trial showed no cognitive effects in patients with AD, but a recent trial of lithium in 45 patients with mild cognitive impairment (MCI, which often leads to clinically diagnosable AD) showed a small advantage for lithium (n=24) over placebo (n=21) in attention and other cognitive domains. None of these studies with lithium were intended to treat psychosis or agitation in AD, and patients with these symptoms typically were excluded in these clinical trials.
There has been no systematic placebo-controlled trial of lithium to treat agitation/aggression with or without psychosis in AD even though lithium is a highly effective treatment for mania with psychosis and symptoms of agitation or aggression. Nonetheless, the published studies of lithium to treat cognitive decline in older patients show that low-dose lithium is safe in patients with MCI or AD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Patients were randomized to lithium or placebo, 1:1, stratified by site, for 12 weeks. Randomization, developed by the statistician and executed by the NYSPI pharmacy, was stratified within each site by the presence of psychosis (NPI score ≥4 on delusions or hallucinations) with randomization sequences balanced in blocks of four.
All study personnel and patients were masked to treatment assignment. After the final study visit, a psychiatrist independent of the study was unmasked and clinically treated the patient while study personnel remained blind.
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female adults.
- •Diagnosis of possible or probable AD by standard NIA criteria (McKahnn et al, 1984; McKhann et all, 2011)
- •Folstein MMSE 5-26 out of 30
- •Neuropsychiatric Inventory (NPI) agitation/aggression subscale score >
- •On each subscale (frequency X severity), a score higher than 4 represents moderate to severe symptoms.
- •Female patients need to be post-menopausal
- •Availability of informant; patients without an informant will not be recruited. Patients who lack capacity must have a surrogate.
排除标准
- •Medical contraindication to lithium treatment or prior history of intolerability to lithium treatment.
- •Contraindications to lithium in this study include: resting tremor causing functional impairment, history of falls in the last month, untreated thyroid disease or any abnormal thyroid function test (T3, T4, or TSH), creatinine level greater than 1.5 mg/100ml or a glomerular filtration rate less than 44ml/min/ 1.73m2; blood pressure > 150/90 mm Hg; heart rate < 50 bpm; unstable cardiac disease based on history, physical examination, and ECG.
- •Medications, in combination with lithium, known to have adverse renal effects, including therapeutic or higher doses of diuretics, i.e. hydrochlorothiazide greater than 25mg daily or furosemide greater than 10mg daily. Whenever feasible, patients receiving concomitant antidepressants or antipsychotics will be washed off these medications for at least 24 hours before starting lithium. Patients who do not wish to discontinue antipsychotics or antidepressants, typically because of family member/caregiver objection, will be allowed to enter the trial provided there is no contraindication to concomitant lithium use with that specific psychotropic medication. During the trial, patients will be permitted to receive lorazepam as needed up to 1 mg/day for anxiety/insomnia, and non-benzodiazepine hypnotics, e.g., zolpidem.
- •Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, or bipolar 1 disorder (DSM-IV TR criteria).
- •Current or recent (past 6 months) alcohol or substance dependence (DSM-IV TR criteria).
- •Current major depression or suicidality as assessed by the study psychiatrist.
- •Suicidal behavior or dangerous behavior with serious safety risk or risk of physical harm to self or others.
- •Parkinson's disease, Lewy body disease, multiple sclerosis, CNS infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder.
- •Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (small infarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion.
- •Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases will be excluded, but past history of successfully treated cancer will not lead to exclusion.
- •QTc interval > 460 ms at the time of baseline EKG is an exclusion criterion for treatment.
- •Hypernatremia as determined by serum sodium level > 150 meq/L.
研究组 & 干预措施
Lithium Treatment Group
The patient will be started on lithium 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on lithium blood level. Blood will be drawn at each study visit. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects).
Patients who develop side effects, e.g., tremor, falls, will have their dose reduced.
干预措施: Lithium (Drug)
Placebo Group
The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects).
Patients who develop side effects, e.g., tremor, falls, will have their dose reduced.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score
时间窗: Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain is the measure used that combines symptoms of agitation and aggression. Frequency X Severity rating score, range 0-12. Minimum score is 0, maximum score is 12. Higher score is a worse outcome and indicates more agitation and aggressive behavior.
次要结局
- Basic Activities of Daily Living (BADL)(Assessed at Week 0, Week2, Week 4, Week 6, Week 8, Week 10, Week 12)
- Clinical Responder Defined as a 30% Decrease in NPI Core Score (Sum Score of NPI Domains of Agitation/Aggression, Delusions and Hallucinations) Together With a Clinical Global Impression (CGI) Behavior Change Score of 1 or 2(Week 12)
- Simpson-Angus Scale(Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12)
- Clinical Global Impression (CGI) Behavior Change(Week 12)
- Young Mania Rating Scale(Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12)
- Treatment Emergent Signs and Symptoms(Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12)
- Zarit Caregiver Burden Interview(Assessed at Week 0, Week 4, Week 8, Week 10, Week 12)
研究者
Davangere P. Devanand
Professor of Clinical Psychiatry and Neurology
New York State Psychiatric Institute