Background
Memantine, a low affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia.

Objectives
To determine efficacy and safety of memantine for people with Alzheimer's disease (AD), vascular (VD) and mixed dementia.

Search methods
The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 8 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 In addition, the search engines Copernic and Google were used to identify unpublished trials through inspection of the websites of licensing bodies like the FDA , EMEA and NICE and of companies' websites (Lundbeck, Merz, Forest, Suntori etc) and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.

Selection criteria
Double-blind, parallel group, placebo-controlled, randomized trials of memantine in people with dementia.

Data collection and analysis
Data were pooled where possible. Intention-to-treat (ITT) and observed case (OC) analyses are reported.

Main results
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 Pooled data from three unpublished studies indicate a marginal benefical effect at six months on ITT cognition (0.99 points on the 70 point ADAS-Cog, 95% CI 0.21 to 1.78, P = 0.01) which was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.

Authors' conclusions
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.

Memantine for dementia

Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an ml and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). Design: A 6-month, randomized, double-blind, placebocontrolled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Setting: Outpatients at 17 centers in the United States and Canada. Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD. Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo;P≤.05), and CIBIC+ (high dose vs placebo;P≤.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P≤.002) dose-dependent reductions in vocal Out-bursts, bursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P≤.02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

Objectives. To assess clinical efficacy and safety of memantine - an uncompetitive N-methyl-D-aspartate (NMDA) antagonist in moderately severe to severe primary dementia. Materials and methods. Dementia was defined by DSM-III-R criteria and severity was assessed by the Global Deterioration Scale (stages 5-7) and the Mini-Mental State Examination (< 10 points). Primary endpoints were the Clinical Global Impression of Change (CGI-C) rated by the physician, and the Behavioural Rating Scale for Geriatric Patients (BGP), subscore 'care dependence', rated by the nursing staff. Secondary endpoints included the modified D-Scale (Arnold/Ferm) Results. The ITT sample comprised 166 patients and 151 patients were treated per protocol. At 12-week ITT endpoint analysis, 82 received memantine 10 mg per day, 84 placebo. Dementia was in 49% of the Alzheimer type and in 51% of the vascular type (CT. Hachinski score). A positive response in the CGI-C was seen in 73% versus 45% in favour of memantine (stratifiec Wilcoxon p < 0.001) independent of the etiology of dementia. The results in the BGP subscore 'care dependence were 3.1 points improvement under memantine and 1.1 points under placebo (p 0.016). A coincident response of the two independent target variables was observed in 61.3% (memantine) versus 31.6% (placebo). Secondary endpoint analysis of the D-Scale assessing basic ADL functions support the primary results. Regarding the safety profile, no significant differences between treatment groups were observed. Conclusions. The results of this trial support the hypothesis that memantine treatment leads to functional improvement and reduces care dependence in severely demented patients.

Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine).

A new assessment of Activities of Daily Living has been developed specifically for use with people with dementia. The assessment is a carer rated instrument consisting of 20 daily-living abilities. The scale has 'face validity', assessing items rated as important by and using levels of ability generated by carers. It has 'construct' validity as demonstrated by principal components analysis. It has 'concurrent' validity in that it correlates well with observed task performance. It has good 'test-retest' reliability as measured by Cohen's Kappa and it correlates well with the Mini-Mental State Examination. Carers report that it is easy to use and it is relatively short. The authors believe the scale will be useful when assessing demented patients in the community or as part of clinical research trials.

/pdf/assessment-of-activities-of-daily-living-in-dementia-2waqkx11is.pdf

Assessment of Activities of Daily Living in Dementia: Development of the Bristol Activities of Daily Living Scale

Background and Purpose — Based on the hypothesis of glutamate-induced neurotoxicity (excitotoxicity) in cerebral ischemia, this study examined the efficacy and tolerability of memantine, an uncompetitive N -methyl-d-aspartate antagonist, in the treatment of mild to moderate vascular dementia. Methods — In this multicenter, 28-week trial carried out in France, 321 patients received 10 mg/d memantine or placebo twice a day; 288 patients were valid for intent-to-treat analysis. Patients had to meet the criteria for probable vascular dementia and have a Mini-Mental State (MMSE) score between 12 and 20 at inclusion. The 2 primary end points were the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and the global Clinician’s Interview Based Impression of Change (CIBIC-plus). Results — After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo. In the intention-to-treat population, the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score had declined by 1.6 points, ie, a difference of 2.0 points (95% confidence interval, 0.49 to 3.60). The response rate for CIBIC-plus, defined as improved or stable, was 60% with memantine compared with 52% with placebo ( P =0.227, intention to treat). Among the secondary efficacy parameters, which were analyzed in the per-protocol subset, MMSE was significantly improved with memantine compared with deterioration with placebo ( P =0.003). The Gottfries-Brane-Steen Scale intellectual function subscore and the Nurses’ Observation Scale for Geriatric Patients disturbing behavior dimension also showed differences in favor of memantine ( P =0.04 and P =0.07, respectively). Memantine was well tolerated with a frequency of adverse events comparable to placebo. Conclusions — In patients with mild to moderate vascular dementia, memantine 20 mg/d improved cognition consistently across different cognitive scales, with at least no deterioration in global functioning and behavior. It was devoid of concerning side effects.

Efficacy and Safety of Memantine in Patients With Mild to Moderate Vascular Dementia: A Randomized, Placebo-Controlled Trial (MMM 300)

Although a great number of psychometric tests and rating scales for the assessment of psychogeriatric patients is available, there is still an urgent need, in research and practice, for a clinical rating instrument that meets the following main requirements: (1) applicable to institutionalized and community patients and covering a wide range of behavioral pathology; (2) acceptable and easy to use for professionals and lay persons alike; (3) covering a wide range of behavior relevant to daily functioning but independent of sex or social status of the individual assessed. The NOSGER contains 30 items of behavior, each rated on a 5-point scale according to frequency of occurrence. Item scores are summarized into 6 Dimension scores (memory, instrumental activities of daily life, self-care, mood, social behavior, and disturbing behavior) which are clinically relevant in dementia, depression, and other psychiatric disorders of old age. Validation studies with a preliminary version of the NOSGER indicated good acceptance of the scale, high inter-rater and test-retest reliability, and high correlations of all NOSGER Dimension scores with results of a variety of established assessment instruments. The NOSGER is currently being used in a number of European and North American centers and should turn out to be a useful instrument for longitudinal studies in psychogeriatrics.

A new behavioral assessment scale for geriatric out- and in-patients: the NOSGER (Nurses' Observation Scale for Geriatric Patients).

The NOSGER is an assessment instrument used in psychogeriatrics, consisting of 30 observable items of behaviour and measuring impairments in six areas: memory, IADL (instrumental activities of daily living), ADL (activities of daily living), mood, social behaviour and disturbing behaviour. Data collected in the course of validation studies were reanalysed to calculate tentative normative scores and to assess the scale's sensitivity to change. Cutoff scores for elderly normal subjects living in the community are estimated around 10 for ADL and around 15 for memory and IADL disturbances. Cutoff values for the three non-cognitive NOSGER dimensions are not yet available. Sensitivity to change (over 3 months) was shown to be relatively highest for memory, IADL and disturbing behaviour and lowest for ADL in a group of patients with mild to moderate dementia. Correlations between NOSGER change scores and physicians- overall assessments of treatment efficacy in a drug study were highest for social behaviour, IADL and mood, suggesting that non-cognitive factors were at least as important to determine doctors- assessments of change as changes in cognitive areas of behaviour. Further studies are on their way to supplement the present data set.

Lothar Tremmel

Papers

A new behavioral assessment scale for geriatric out- and in-patients: the NOSGER (Nurses' Observation Scale for Geriatric Patients).

Clinical experience with the nosger (nurses' observation scale for geriatric patients): Tentative normative data and sensitivity to change

Nurses' Observation Scale for Geriatric Patients (NOSGER) 1991