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Overstimulation of the N -methyl-D-aspartate (NMDA) receptor by glutamate is implicated in neurodegenerative disorders. This 28-week study compared memantine, an NMDA-receptor antagonist, with placebo in persons with moderate-to-severe Alzheimer's disease. Among the patients who completed the study, memantine appeared to confer benefit in terms of activities of daily living and other measures; analysis of the last observation carried forward for the whole group supported this conclusion. Antiglutamatergic therapy may help in moderate-to-severe disease. Alzheimer's disease affects at least 15 million persons throughout the world. 1 , 2 The number of persons with Alzheimer's disease is increasing substantially as populations age. 3 As Alzheimer's disease advances, patients become progressively impaired in both cognitive and functional capacities, 2 , 4 and the burden on caregivers increases. Pharmacologic treatments are currently approved for treating mild-to-moderate Alzheimer's disease. 5 However, there are no treatments for the more advanced stages of Alzheimer's disease. Glutamate is the principal excitatory neurotransmitter in the brain. 6 , 7 Glutamatergic overstimulation may result in neuronal damage, a phenomenon that has been termed excitotoxicity. Such excitotoxicity ultimately leads to neuronal calcium . . .

The efficacy of memantine in Alzheimer’s disease (AD) has been investigated in multiple randomised, placebo-controlled phase III trials. Recently, the indication label for memantine in Europe was extended to cover patients with moderate to severe AD, i.e. Mini-Mental State Exam total scores below 20. The efficacy data for memantine in this patient subgroup has been summarised by a meta-analysis of 1,826 patients in six trials. Efficacy was assessed using measures of global status (Clinician’s Interview-Based Impression of Change Plus Caregiver Input), cognition (Alzheimer’s Disease Assessment Scale – Cognitive Subscale, or Severe Impairment Battery), function (Alzheimer’s Disease Cooperative Study Activities of Daily Living 19- or 23-item scale), and behaviour (Neuropsychiatric Inventory). Results (without replacement of missing values) showed statistically significant effects for memantine (vs. placebo) in each domain. Memantine was well tolerated, and the overall incidence rates of adverse events were comparable to placebo. This meta-analysis supports memantine’s clinically relevant efficacy in patients with moderate to severe AD.

To the Editor: Reisberg et al. (April 3 issue) 1 observed that the N- methyl-D-aspartate (NMDA) antagonist memantine 2 appears to be helpful in patients with moderate-to-severe Alzheimer's disease. There is evidence that an increased plasma homocysteine level is an independent risk factor for the development of Alzheimer's disease. 3 Homocysteine acts as an agonist at the NMDA receptor, mediates excitotoxicity, 4 and disturbs glutamatergic neurotransmission (with associated changes such as an impaired signal-to-noise ratio or long-term potentiation). Furthermore, elevated homocysteine levels are associated with decreased global cognitive performance in patients with Alzheimer's disease 3 as well as nondemented elderly persons. 5 Homocysteine may act as . . .

The uncompetitive N-methyl-D-aspartate (NMDA) antagonist memantine was tested against placebo in two randomized controlled trials. In total, 900 patients suffering from mild-to-moderate “probable” VaD (according to NINDS-AIREN criteria) were included. In these prospective, 2-arm parallel, multicenter trials conducted in the United Kingdom (MMM500) and in France (MMM300), patients suffering from “probable” vascular dementia (according to NINDS-AIREN criteria) were recruited. Active treatment in both trials was memantine at the standard daily dose of 10 mg b.i.d. The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) was a primary endpoint in both trials, and in both trials a statistically significant difference was seen between treatment groups after 28 weeks. In a pooled analysis of the data, various subgroups were examined. In a first analysis, patients were stratified by their severity of dementia (measured by the MMSE total scores at baseline). In this analysis, memantine was superior to placebo in all subgroups, but the magnitude of effect was clearly more pronounced in the more severely demented patients. A second analysis stratified the patients by the neuroradiological findings at baseline (“small vessel” versus “large vessel” type of VaD). The cognitive benefit by memantine treatment was larger for the small vessel group and, interestingly, also the decline in the placebo group was faster in the small vessel patients. In these trials, memantine at a dose of 10 mg b.i.d. was safe and very well tolerated with a frequency of dropouts due to adverse events that was close to placebo.

Although criteria for the diagnosis of vascular dementia (VaD) are established, the diagnostic concept is still controversial and there is no regulatory guidance for clinical drug development. Clinical trials in VaD present a number of pitfalls and challenges and, so far, no compound has received regulatory approval for this indication. The methodological issues of clinical VaD trials are discussed using the development of memantine for this indication as an example. In a pooled analysis of two placebo-controlled trials with the NMDA-antagonist memantine in VaD, the cognitive benefit by memantine treatment was more pronounced for patients with ‘small vessel disease’ than for those with other neuroradiological findings at baseline. In a subgroup of patients with ‘large vessel disease’ or macrolesions, there was less cognitive decline among the placebo patients. It may therefore be helpful to use predefined diagnostic subcategories in clinical studies in this indication. The findings further suggest that stroke or multiple infarctions may not be the primary reason for cognitive decline in VaD patients.