Combination Therapy for Alzheimer Disease

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

Introduction

Memantine has recently been introduced in the United States for the treatment of moderate-to-severe Alzheimer's disease (see the first link below). It's an N-methyl-D-aspartate (NMDA) receptor antagonist that has been shown in well-controlled studies to be safe and effective in improving the symptoms of patients with moderate or severe Alzheimer's.

The cholinesterase inhibitors (donepezil, rivastigmine, tacrine, galantamine) have been used for a number of years to delay progression of symptoms in mild-to-moderate dementia. As memantine has a different mechanism of action to these drugs, it was a logical step to study its combined use with a cholinesterase inhibitor (i.e. donepezil) in a randomized, double-blind setting. The results have been published in JAMA.

Method

Participants were recruited from 37 clinics in the USA. Patients had to have a Mini-Mental State Examination score of 5 to 14 at baseline, be over 50, an MRI compatible with the diagnosis of Alzheimer disease, and have been taking donepezil for 6 months, at a stable dose (5-10 mg daily) for the last 3 months.

At baseline, the patients were randomized to receive memantine (starting at 5 mg daily, increased gradually to 20 mg daily by week 8) or placebo, for 24 weeks.

The primary efficacy variables were the change from baseline in the Severe Impairment Battery (SIB) and a modified Activities of Daily Living Inventory (ADLI). Three additional tests were conducted to provide secondary variables. Assessments were made at baseline and at weeks 4, 8, 12, 18, and 24.

Results

Of 404 patients enrolled at baseline, 201 received placebo and 203 received memantine. A total of 322 (80%) completed the study - 150 placebo and 172 memantine patients. The reasons for discontinuation were similar in both groups.

Using the 'last-observation-carried-forward' endpoint analysis, significant changes in mean scores favored memantine for both the SIB (0.9 vs. -2.5, p<0.001) and ADLI (-2.0 vs. -3.4, p=0.03). Almost identical results were obtained using the 'observed cases' endpoint analysis, i.e. only the results from the patients that completed the study. All three secondary efficacy variables showed significant benefits of memantine over placebo.

Adverse events were similar in both groups, except for more than double the frequency of confusion and headache with memantine, compared with placebo (8% and 6% compared with 2% and 3%, respectively). On the other hand, the memantine group had significantly fewer behavioral disturbances and psychiatric symptoms than the placebo patients, and diarrhea and fecal incontinence were lessened with memantine.

Comment

This study shows that addition of memantine to a cholinesterase inhibitor - donepezil - in moderate-to-severe Alzheimer patients has significant benefits on changes in cognitive function, activities of daily living, behavior, and overall clinical status. The findings confirm the previous benefits of memantine, and show that this drug can be usefully added to a regimen of a specific anticholinergic drug. Whether the results can be extrapolated to all anticholinergic drugs remains unproven; however, it seems probable that this is 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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