Lon S. Schneider, M.D.
N Engl J Med 2012; 366:957-959
Donepezil, the most frequently prescribed cholinesterase inhibitor for the treatment of Alzheimer’s disease, was marketed in 1997 on the basis of the results of 3-month and 6-month clinical trials showing that patients had improvements in cognitive test scores and in the ability to perform daily activities, and subsequent trials indicated that the drug had efficacy over the course of 1 to 2 years.About half of the patients who are prescribed cholinesterase inhibitors, however, discontinue them within a year, apparently because of a perceived lack of efficacy and adverse effects such as anorexia, weight loss, agitation, bradycardia, and syncope.
Cholinesterase inhibitors do not appear to mitigate the deteriorating clinical course of Alzheimer’s disease, and as patients continue to worsen, it is difficult to determine whether they are benefiting from them.Treatment guidelines, however, recommend continuing cholinesterase inhibitors only when they are thought to be having a worthwhile effect.
In the United Kingdom, where decisions about medication coverage are made by the National Health Service (NHS), physicians have three guidelines-based choices when their patients who are being treated with donepezil reach a moderately severe level of cognitive impairment and it is uncertain whether the drug is helping or harming: continue donepezil, discontinue it, or switch to memantine, an N-methyl-D-aspartate–receptor antagonist that is specifically indicated for the treatment of moderate-to-severe Alzheimer’s disease in both the United Kingdom and the United States. The NHS does not approve the addition of memantine to a cholinesterase inhibitor. In contrast, U.S. physicians typically add memantine to ongoing donepezil treatment, frequently when patients are still mildly impaired, without waiting for their condition to worsen to moderate-to-severe (the indication for which the drug is approved by the Food and Drug Administration [FDA]).
The randomized, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease trial (DOMINO; Current Controlled Trials number, ISRCTN49545035), reported by Howard et al. in this issue of the Journal, enrolled patients in the United Kingdom who had moderate-to-severe Alzheimer’s disease and who had been maintained on donepezil for an average of 2 to 3 years and compared the strategy of continuing the drug with that of discontinuing it. Concurrently, the trial compared starting memantine with not starting it. Over the 1-year follow-up period, continuing donepezil, as compared with discontinuing it, was associated with better scores on measures of cognitive ability and activities of daily living; adding memantine at the time donepezil was discontinued was better than not adding memantine; and adding memantine while continuing donepezil was not better than continuing donepezil alone.
The results of the DOMINO trial support findings from the only other randomized trial of the discontinuation of donepezil, but that trial enrolled patients who had less cognitive impairment and who had been treated for only 3 months.The results of a trial of discontinuation of therapy are difficult to interpret since the findings may have been due to a loss of the therapeutic effect of the drug or to withdrawal from the drug. In addition, the prior efficacy of donepezil in the DOMINO study sample had not been established, and patients may not have been benefiting. Regardless, the fact that the average score on the Standardized Mini–Mental State Examination was 1.9 points lower (indicating worse cognitive function) in the group that discontinued donepezil than in the group that continued the drug is potentially important because many of the patients were severely impaired, on the cusp for needing nursing home care, and slightly worse cognitive function could affect their ability to remain at home. Many patients, however, discontinue donepezil without obvious difficulty; and notably, only half the patients who were assigned to continue donepezil in this trial maintained their treatment for the entire 1-year study period, suggesting that many patients perceived that continuing the medication was not effective. Thus, the trial results may be viewed as supporting the decisions of patients, caregivers, and physicians who are reluctant to discontinue donepezil because they fear that there is more to lose than to gain. The results may also be viewed as supportive of those who decide to discontinue donepezil.
If the cognitive worsening with discontinuation of donepezil is due to withdrawal from the drug, then halving the donepezil dose before discontinuing it 4 weeks later may not make sense, since treatment with donepezil at a dose of 5 mg per day is nearly as effective as treatment at a dose of 10 mg per day.Despite its long plasma-elimination half-life of 70 to 80 hours, a more gradual tapering from the 5-mg dose may be needed, rather than an abrupt discontinuation of the 5-mg dose, to attenuate any withdrawal, since donepezil substantially increases brain acetylcholinesterase protein expression and activity, most likely in reaction to chronic inhibition.
Although memantine appears to be helpful for the treatment of moderate-to-severe Alzheimer’s disease when used aloneor when replacing donepezil,the results of the DOMINO trial do not support the typical use in the United States, and an FDA-approved use, as add-on therapy to established donepezil treatment. In contrast to the benefits observed in a 6-month U.S. trial,in the longer DOMINO trial, adding memantine to donepezil, as compared with continuing donepezil alone, was not associated with better cognition or function. The conflicting results of these two trials suggest the need for further study of the benefits and risk of using memantine as add-on therapy to donepezil in patients with moderate-to-severe cognitive impairment.
Results with donepezil in the DOMINO trial may not apply to the other marketed cholinesterase inhibitors, galantamine and rivastigmine, since the pharmacokinetic characteristics, mechanisms of cholinesterase inhibition, and other actions of these drugs differ from those of donepezil.7 Nor should the DOMINO results be interpreted as evidence of the efficacy of indefinite treatment with donepezil. More research is needed to assess the long-term benefits, the potential for harm and physiological tolerance, and the safe discontinuation of cholinesterase inhibitors as Alzheimer’s disease progresses.
From the Department of Psychiatry and the Behavioral Sciences and the Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles.