Abstract
BackgroundAgitation in Alzheimer’s disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD.Methods and FindingsWe recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower −3.0; −8.3 to 2.2, p = 0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (−6.9; −12.2 to −1.6; p = 0.012) and 12 (−9.6; −15.0 to −4.3 p = 0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD.ConclusionsMemantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms.Trial RegistrationClinicalTrials.gov NCT00371059 Trial RegistrationInternational Standard Randomised Controlled Trial 24953404
Highlights
The worldwide prevalence of dementia, of which Alzheimer’s disease (AD) is the most common aetiology, was estimated as 24.3 million in 2005, doubling every 20 years due to increased longevity; prevalence is projected to reach 81?1 million by 2040. [1] Worldwide, dementia contributes 4.1% of all disabilityadjusted life years and 11.3% of years lived with disability [2].Neuropsychiatric symptoms are common in AD, with agitation affecting nearly 50% of people with AD over a month.[3,4] Symptoms persist for over six months in 80% of those with clinically significant symptoms, predicted by initial severity
Meta-analyses of drug treatments have confirmed modest benefits from antipsychotics, risperidone, olanzapine and haloperidol for agitation in AD over 6–12 weeks but with increased cognitive decline, cerebrovascular events, parkinsonism and death. [9,10] There is no compelling evidence for other medications, except for a recent trial of pain management for agitation in dementia which found that it was more efficacious than treatment as usual. [11,12,13,14] There is an urgent need to find safe and efficacious pharmacological therapies
This study aims to test the efficacy of memantine versus placebo in reducing clinically significant agitation, measured using the Cohen-Mansfield Agitation Score $45 (CMAI), [20,21] at 6 weeks after randomisation and secondarily at 12 weeks
Summary
The worldwide prevalence of dementia, of which Alzheimer’s disease (AD) is the most common aetiology, was estimated as 24.3 million in 2005, doubling every 20 years due to increased longevity; prevalence is projected to reach 81?1 million by 2040. [1] Worldwide, dementia contributes 4.1% of all disabilityadjusted life years and 11.3% of years lived with disability [2].Neuropsychiatric symptoms are common in AD, with agitation affecting nearly 50% of people with AD over a month.[3,4] Symptoms persist for over six months in 80% of those with clinically significant symptoms, predicted by initial severity. [15] A recent meta-analysis concluded that memantine significantly reduced total neuropsychiatric symptoms compared to placebo. This is difficult to interpret as the data was not from clinical populations selected for having clinically significant neuropsychiatric symptoms. [17] Analysis of three trials, indicated significant benefit for memantine versus placebo in the predefined ‘‘core’’ symptoms [18] (agitation, delusions and hallucinations)used to measure antipsychotics and memantine response in dementia and for agitation at 12 and 24/28 weeks. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD
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