Medication for Mild Cognitive Impairment
No Benefit from Donepezil (Aricept) in 2009 Report
Jun 22, 2009
Mild Cognitive Impairment (MCI) is a condition in which brain function has declined enough to be recognized as not normal, but hasn’t declined enough to be considered dementia. In some countries, a similar or the same condition is called Cognitive Impairment Not Dementia (CIND).
The Significance of MCI
MCI had been thought of as early Alzheimer’s dementia. More recently, it is recognized that conditions other than Alzheimer's may cause MCI. Early estimates were that up to one in four people with MCI develop Alzheimer's in every year. These estimates were special cases that did not represent the wide variety in the MCI population. A recent meta-analysis estimated that less than nine percent of people with MCI convert to Alzheimer's each year. (Mitchell, 2009)
Still, if almost 10% develop Alzheimer's each year, a drug that could prevent or delay conversion would be a tremendous advance. It would have both economic and humanitarian benefit.
Aricept was hoped to be such a drug. It has shown enough benefit to be approved for treatment of Alzheimer's. While the amount of benefit is argued, it is possible that in MCI, it might actually delay progression to Alzheimer's. The market for such a drug is immense.
The Study
About 800 subjects were selected, all with confirmed memory complaints and MMSE of 24 or higher. Half were treated with Aricept, half with placebo. A few in each group were dropped from the study for safety and other reasons, leaving about 390 in each group. The study duration was about a year (48 weeks). The lead author was Dr. R. S. Doody, Baylor College of Medicine.
Results
A number of variables were measured. There were no significant differences in the treatment vs. the control groups over most variables. There were trivial differences in two. The patient global assessment variable did show a difference that arguably was more than trivial. It could be interpreted as indicating subjects treated with Aricept felt less disability than those receiving placebo.
Adverse effects were much more common in subjects treated with the real medication rather than placebo. Over 80% of donepezil-treated subjects had adverse events, compared to 69% of control subjects. Many of the adverse events were minor, but some had important effects on quality of life. Sixteen percent of drug-treated subjects had diarrhea, compared to 3% of controls. Thirteen percent had muscle spasms (compared to 2%). Eight percent had abnormal dreams (compared to 2%). Aricept also has the potential to dangerously lower heart rate.
The results were so unimpressive that Allan Brett, Professor of Medicine at the University of South Carolina, stated simply, “Clinicians should not prescribe donepezil for patients with mild cognitive impairment.” (Journal Watch [a professional newsletter], June 15, 2009)
Why Weren’t Results More Impressive?
The study was sponsored by the pharmaceutical companies that make and distribute Aricept. It is reasonable to think they expected a different outcome, a more clear benefit from the drug. The investigators suggested several reasons that Aricept may not have shown the anticipated benefit.
Donepezil increases acetylcholine in the brains of people with Alzheimer's. This is of benefit because the brains of people with Alzheimer's have a deficit in acetylcholine. But it is not clear the same is true in MCI, or, if there is a deficit, it is very important. So increasing acetylcholine may have nothing to do with stopping the basic underlying process that leads to Alzheimer's.
Subjects selected for the study may not have been representative of the total MCI population, in part due to selective absence of more subjects with more advanced disease.
Is the Controversy Over?
It’s unlikely. Another study showed a 25% reduction in risk of progression to Alzheimer's from Aricept treatment (Diniz, 2009). That study can be faulted due to possible publication bias and uneven criteria.
Patients, families, clinicians, insurance companies, and public policy makers need to continue to consider the real benefits compared to the risks of worse quality of life and potential heart and other adverse effects of treatment. And the dollar cost: one year of Aricept medication costs about $2,484, plus the cost of treating any adverse side effects, and the cost of clinician visits.
Sources
Mitchell, A. J., Shiri-Feshki, M., 2009, Acta Psychiatr Scand 119(4): 252-65.
Doody, R.S., 2009. Neurology 72(18): 1555-61
Dinez, B.S. et al., Eur Arch Psychiatry Clin Neurosci 259(4): 248-56
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