Adding Memantine to Existing Drug Treatment Helps Alzheimer's

Summarized by Robert W. Griffith, MD
April 8, 2004

Introduction

A group of drugs called cholinesterase inhibitors (e.g. donepezil, rivastigmine, and tacrine) have been used for a number of years to slow the progress of mild-to-moderate dementia. And recently a new type of drug, an NMDA receptor blocker called memantine, has been introduced in the United States for the treatment of more severe Alzheimer's (see the first link below).

Can these two types of drugs be used together, and if so, are they more effective? A study has been done that shows this is the case; it's been published in the Journal of the American Medical Association, and is summarized here.

What was done

The study was done in 37 clinics in the USA. Patients had to have a Mini-Mental State Examination score of 5 to 14 at baseline (indicating moderate-to-severe dementia) and be over 50. They had to have been taking donepezil for at least 6 months, and be on a stable dosage.

The participants underwent a battery of tests including a test of daily living skills. These evaluations were made on enrollment, and at weeks 4, 8, 12, 18, and 24 of the study.

After enrolling, the patients were assigned randomly to receive memantine (starting at 5 mg a day, and increased gradually to 20 mg a day by week 8) or placebo (dummy) tablets, for 24 weeks. They kept on their donepezil at their usual dose level.

The investigators decided at the outset that the main tests that they would use to determine the effectiveness of adding memantine would be the Severe Impairment Battery (SIB), which measures mental functioning, and the Activities of Daily Living Inventory (ADLI).

What was found

Just over 400 patients were enrolled in the study, and 322 (80%) of them completed the 24-week study - 150 on placebo and 172 on memantine. The reasons for people dropping out were similar in both groups: side-effects, a change of mind about participation, and failure to follow study procedures.

At the end of 24 weeks, the average SIB score for the patients on donepezil plus memantine had increased by 0.9, while the average score for those getting donepezil alone had decreased by -2.5. In other words, the memantine group was slightly better in mental functioning, while the placebo group had deteriorated. The difference between the groups was statistically significant, i.e. it hadn't occurred by chance alone.

Both the memantine and the placebo groups showed some deterioration on the Activities of Daily Living scale, but the deterioration was greater with the placebo; the average change in scores was -2.0 for memantine, and -3.4 for placebo. Again, this was a significant difference.

The other three tests used all showed significant benefits of memantine over placebo.

Side effects were reported in both groups, and were similar, except for somewhat more confusion and headache with memantine, compared with placebo. On the other hand, the memantine group had significantly fewer 'behavioral disturbances' and mental symptoms than the placebo patients, while diarrhea and incontinence of feces were less with memantine.

What this means

This study shows that adding memantine to a cholinesterase inhibitor drug - donepezil - has significant benefits for moderate-to-severe Alzheimer's patients. There are improvements (or lessened deterioration) in mental functioning, activities of daily living, behavior, and their overall medical condition. And there are no serious side effects.

The findings show that memantine can be a useful addition treatment for a patient already on donepezil. Whether the same results will be obtained with other anticholinergic drugs remains to be discovered. However, it seems likely this will be the case, based on reports coming from several years' availability of memantine in Europe.

Source

• Memantine treatment in patients with moderately to severe Alzheimer disease already receiving donepezil. PN. Tariot, MR. Farlow, GT. Grossberg,  et al., JAMA, 2004, vol. 291, pp. 317--324

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