Introduction

There are effective drugs available to treat mild-to-moderate Alzheimer's disease - the cholinesterase inhibitors, such as tacrine, rivastigmine, donepezil, and galantamine. However, there aren't any effective treatments for more advanced cases. As glutamate is the main excitatory neurotransmitter in the brain, and glutamatergic over-stimulation has been found to lead to neurodegeneration, attention has recently been directed at one of the receptors it stimulates, the N-methyl-D-aspartate (NMDA) receptor. A clinical trial of an NMDA-receptor antagonist, memantine, in patients with advanced Alzheimer disease has recently been reported in the New England Journal.

Method

Patients over 50 with probable Alzheimer's were recruited at 32 US centers; they had to have a Mini-Mental State Examination (MMSE) score between 3 and 14, a stage of 5 or 6 on the Global Deterioration Scale, and a stage of 6a or above on the Functional Assessment Staging test. Those with vascular dementia or non-Alzheimer causes for dementia were excluded, as well as those on specified medications for conditions such as Parkinson's disease or epilepsy.

The subjects were randomized to receive memantine or placebo, in a double blind fashion, for 28 weeks. Two chief efficacy variables were used: the Clinician's Interview-Based Impression of Change Plus Caregiver input (CBIC-Plus) global score at 28 weeks, and the change from baseline to week 28 in the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) modified for severe dementia (ADSC-ADLsev). Secondary endpoints included the Severe Impairment Battery and the MMSE.

Results

A total of 252 patients were enrolled - 126 each assigned to placebo and memantine, respectively. Their mean age was 76 years, and 67% of them were women. Seventy-one discontinued before the end of the 28-week period, so that the mean duration of treatment was 24 weeks. Reasons for discontinuation were the same in the two groups - e.g. 'adverse events' in 22 (17%) placebo patients and 13 (10%) in memantine patients.

The patients given memantine had better results on the CIBIC-Plus scale; the difference was significant for those treated for the full 28 weeks (p=0.03) and borderline-significant for the whole collective, where results from the last assessment in those discontinuing early were included (p=0.06). Significantly positive results in favor of memantine were shown by the ADCS-ADLsev scale, with p=0.003 for the full 28-week completers, and p=0.03 for the whole collective. Results were also significant for the Severe Impairment Battery, but not for changes in the MMSE.

Adverse events were reported in the majority of patients, but these were rarely severe, and they were not related, or unlikely to be related, to study medication. Agitation, urinary incontinence, urinary tract infection, insomnia, and diarrhea were all reported, but were equally common in both placebo and memantine groups.

Comment

This study shows that an NMDA antagonist is able to improve, or at least alleviate, the symptoms of severe Alzheimer disease. Certainly there was a slowing in the inevitable deterioration expected in such patients. The novel approach offered by this type of neuropharmacology offers new hope for progress in out attempts to treat this disease, and should be seen as a considerable step forward. The authors of this report suggest that future studies should be done with memantine and a cholinesterase inhibitor given in combination.

Memantine is available as Axura® in European countries. It is not yet available in the USA.