Treatment of Psychosis and Agitation in Alzheimer's Disease
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|ClinicalTrials.gov Identifier: NCT02129348|
Recruitment Status : Recruiting
First Posted : May 2, 2014
Last Update Posted : August 20, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Alzheimer's Disease Psychosis Agitation||Drug: Lithium Drug: Placebo||Phase 2|
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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.
Specific Aims and Hypotheses Specific Aim 1. To compare changes in agitation/aggression with or without psychosis in patients with AD who receive 12 weeks of randomized, double-blind treatment with lithium or placebo.
Primary Hypothesis. Over these 12 weeks, the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) will decrease significantly more on lithium than placebo.
Secondary Hypothesis. Over these 12 weeks, the proportion of responders on lithium will be significantly greater than the proportion of responders on placebo. Response is defined as a 30% decrease in NPI core score (defined as the sum of domains for agitation/aggression, delusions and hallucinations) plus a CGI Change score of much improved or very much improved (CGI based on these behavioral symptoms only). Exploratory hypothesis. Over these 12 weeks, the psychosis score, measured by the sum of the NPI domain scores for delusions and hallucinations, will decrease significantly more on lithium than placebo. Specific Aim 2. To evaluate the tolerability of low dose lithium by assessing emergent somatic side effects over the course of the 12-week trial on lithium compared to placebo. Specific Aim 3. To explore associations between improvement on lithium (decrease in agitation/aggression and psychosis scores) and serum brain-derived neurotrophic factor (BDNF) levels (baseline, 12 weeks), a SNP in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus, because these indices are associated with lithium response in bipolar disorder. The investigators do not postulate a specific mechanism of action for lithium in the investigators trial, but will evaluate these three potential predictors of lithium response with the aim of improving patient selection for personalized treatment. The investigators will examine BDNF serum levels as a biomarker correlate of lithium treatment by correlating change in BDNF levels with change in NPI agitation/aggression and psychosis scores.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||80 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Treatment of Psychosis and Agitation in Alzheimer's Disease|
|Study Start Date :||June 2014|
|Estimated Primary Completion Date :||January 2020|
|Estimated Study Completion Date :||January 2020|
Active Comparator: 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 real 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.
Other Name: lithium carbonate
Placebo Comparator: 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.
- Change in Neuropsychiatric Inventory (NPI) Score [ Time Frame: Screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]Assessment used to examine behavioral issues and disturbances in patients with dementia. Each behavior is assessed for frequency and severity by the rater.
- Clinical Global Impression (CGI) Global [ Time Frame: Screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]Used to assess a patient's overall functioning prior to, and after taking the study medication (Lithium or placebo).
- Clinical Global Impression (CGI) Behavior [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]Assessment used to determine changes in the patients behavior prior to, and after beginning study medication (Lithium or placebo).
- Young Mania Rating Scale [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]Used to assess manic symptoms experienced by the patient in the prior two days. Each mania item on the scale is rated for severity.
- Treatment Emergent Signs and Symptoms (TESS) [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]Scale used to assess if symptoms not present at screening emerge after treatment begins. Each symptom is assigned a "yes" or "no" response based on patient and caregiver report.
- Simpson-Angus Scale [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]Five point scale used to assess pseudoparkinsonism in patients. Symptoms assess include gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation.
- Basic Activities of Daily Living (BADL) [ Time Frame: Week 4, Week 8, Week 10, Week 12 ]Assesses if the patient can perform six basic ADLs on his own. These include bathing, dressing, toileting, transferring, continence, and feeding.
- Zarit Caregiver Burden Interview [ Time Frame: Week 0, Week 4, Week 8, Week 10, Week 12 ]Twenty-two item questionnaire, where the caregiver is asked to rank statements on a 5-point scale (never to nearly always).
- Clinical Dementia Rating Scale (CDR) [ Time Frame: Week 0, Week 12 ]Scale used to rate the severity of dementia symptoms raging from 0-3.
- Folstein Mini-Mental Status Exam [ Time Frame: Screening, Week 12 ]30 item questionnaire used to assess degree of cognitive impairment. Orientation, registration, attention/calculation, recall, language, repetitions and commands are assessed,
- Severe Impairment Battery [ Time Frame: Week 0, Week 12 ]Neuropsychological test used to assess a patient's cognitive ability. The patient is asked to complete small tasks such as drawing shapes and printing their name. They are also asked to remember certain names and objects, such as a cup and a spoon, and the evaluator's first name.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02129348
|Contact: DP Devanand, MD||646 774 8658 ext email@example.com|
|Contact: Gregory H Pelton, MD||646 774 8669 ext firstname.lastname@example.org|
|United States, Florida|
|University of Miami Miller School of Medicine||Recruiting|
|Miami, Florida, United States, 33136|
|Contact: Elizabeth Crocco, MD 305-355-9065 email@example.com|
|United States, Massachusetts|
|Belmont, Massachusetts, United States, 02478|
|Contact: Brent Forester, MD 617-855-3622 firstname.lastname@example.org|
|United States, New York|
|New York State Psychiatric Institute||Recruiting|
|New York, New York, United States, 10032|
|Contact: Laura Simon-Pearson, BA 646-774-8671 ext 8671 email@example.com|
|Contact: Jessica D'Antonio, BA 646-774-8674 ext 8674 firstname.lastname@example.org|
|Principal Investigator: DP Devanand, MD|
|Sub-Investigator: Gregory Pelton, MD|
|Sub-Investigator: Edward Huey, MD|
|United States, Texas|
|University of Texas Southwestern Medical Center||Recruiting|
|Dallas, Texas, United States, 75235|
|Contact: Mustafa Husain, MD 214-648-2806 email@example.com|
|Principal Investigator:||DP Devanand, MD||Columbia University|