Article

Memantine for dementia.

University of Oxford, Department of Psychiatry, Cochrane Dementia and Cognitive Improvement Group,Radcliffe Infirmary, Oxford, Oxfordshire, UK, OX2 6HE.
Cochrane database of systematic reviews (Online) (Impact Factor: 5.7). 02/2006; DOI:10.1002/14651858.CD003154.pub5
Source: PubMed

ABSTRACT Memantine, a low affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia.
To determine efficacy and safety of memantine for people with Alzheimer's disease (AD), vascular (VD) and mixed dementia.
The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 8th February 2006. This register contains references from all major healthcare databases and many ongoing trial databases and is updated regularly. In addition, the search engines Copernic and Google were used to identify unpublished trials through inspection of the websites of licensing bodies like the FDA , EMEA and NICE and of companies' websites (Lundbeck, Merz, Forest, Suntori etc) and clinical trials registries.
Double-blind, parallel group, placebo-controlled, randomized trials of memantine in people with dementia.
Data were pooled where possible. Intention-to-treat (ITT) and observed case (OC) analyses are reported.
1. Moderate to severe AD. Two out of three six month studies show a small beneficial effect of memantine. Pooled data indicate a beneficial effect at six months on cognition (2.97 points on the 100 point SIB, 95% CI 1.68 to 4.26, P < 0.00001), activities of daily living (1.27 points on the 54 point ADCS-ADLsev, 95% CI 0.44 to 2.09, P = 0.003) and behaviour (2.76 points on the 144 point NPI, 95% CI 0.88 to 4.63, P=0.004), supported by clinical impression of change (0.28 points on the 7 point CIBIC+, 95% CI 0.15 to 0.41, P < 0.0001).2. Mild to moderate AD. Pooled data from three unpublished studies indicate a marginal beneficial effect at six months on ITT cognition (0.99 points on the 70 point ADAS-Cog, 95% CI 0.21 to 1.78, P = 0.01) which was barely detectable clinically (0.13 CIBIC+ points, 95% CI 0.01 to 0.25, P = 0.03) but no effect on behaviour, activities of daily living or OC analysis of cognition.3. Mild to moderate vascular dementia. Pooled data from two six month studies indicated a small beneficial effect of memantine on cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, P = 0.0002), and behaviour (0.84 95% CI 0.06 to 0.91, P = 0.03) but this was not supported by clinical global measures.4. Patients taking memantine were slightly less likely to develop agitation (134/1739, 7.7% versus 175/1873, 9.3% OR 0.78, 95% CI 0.61 to 0.99, P = 0.04). This effect was slightly larger, but still small, in moderate to severe AD (58/506 [12%] vs 88/499 [18%]; OR = 0.6, 95% CI 0.42 to 0.86, P = 0.005). There is no evidence either way about whether it has an effect on agitation which is already present.5. Memantine is well tolerated.
Memantine has a small beneficial effect at six months in moderate to severe AD. In patients with mild to moderate dementia, the small beneficial effect on cognition was not clinically detectable in those with vascular dementia and was detectable in those with AD. Memantine is well tolerated.

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    ABSTRACT: INTRODUCTION: Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. METHODS: In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. RESULTS: A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %). CONCLUSION: Extended-release memantine was efficacious, safe, and well tolerated in this population.
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    ABSTRACT: The N-methyl-D-aspartate receptor antagonist, memantine, is licensed for the treatment of moderate to severe Alzheimer's disease (AD). Memantine is administered both as a monotherapy and as an add-on therapy in patients already receiving acetylcholinesterase inhibitors. Several meta-analyses have been published that examine the efficacy of memantine in the treatment of AD, based on clinical trial data. However, different disease severities and concomitant medication use in the trial populations means that synthesis of this data is challenging with numerous methodological decisions required. The main objectives of this study were to review the methodologies of different meta-analyses, assess the impact of specific methodological approaches on efficacy results, and to help interpret previous meta-analyses results concerning the efficacy of memantine in moderate to severe stages of AD. The methodologies of five meta-analyses were reviewed in terms of the included trials, combination of data, choice of outcome, and analysis methods. Results were extracted and compared in line with the methodological approach taken. The most robust results were observed on cognition, activities of daily living, and overall assessment, where memantine showed a consistent benefit over placebo. The benefit of memantine on behavioral symptoms was also demonstrated, but results were more heterogeneous. Variability could not be explained by baseline severity and concomitant treatment alone. It is stressed that interpretation of meta-analysis results must be considered within the context of the methodological approach. Overall, results from individual clinical trials and from meta-analyses demonstrate that memantine represents a valuable treatment option in AD.
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