Medical Therapy for Alzheimer's Disease

Abstract & Commentary

By Michael Lin, MD, PhD, Associate Professor of Neurology and Neurosciences, Weill Cornell Medical College. Dr. Lin reports no financial relationships relevant to this field of study.

Synopsis: Continuation of combination therapy with donepezil and memantine appears to have a long-term beneficial effect for patients with moderate-to-severe Alzheimer's disease.

Source: Howard R, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. New Engl J Med 2012;366:893-903.

Despite initial improvement on current alzheimer's disease (AD) medications, patients inevitably decline again, and families frequently ask whether it is worth it to continue the medication. This study from the United Kingdom provides data supporting continued therapy.

The Donepezil and Memantine in Moderate-to-Severe Alzheimer's Disease (DOMINO) study was a double-blind, randomized, placebo-controlled, multicenter trial with a two-by-two factorial design. Two hundred ninety-five community-dwelling patients with moderate-to-severe AD (Mini-Mental State Exam score 5-13) who had already been receiving donepezil for at least 3 months (87% were for >1 year) but not memantine, were randomized to one of four arms: 1) continue donepezil and start memantine placebo, 2) discontinue donepezil and start memantine placebo, 3) discontinue donepezil and start memantine, or 4) continue donepezil and start memantine. Primary outcomes were MMSE score (0-30, higher better) and Bristol ADL scale (0-60, higher worse).

After 52 weeks of follow-up, continuation of donepezil was associated with better cognition (average MMSE 1.9 points higher, 95% confidence interval [CI] 1.3-2.5, P < 0.001) and function (average BADLS 3.0 lower, 95% CI 1.8-4.3, P < 0.001) than discontinuation. Institution of memantine was also associated with better cognition (average MMSE 1.2 points higher, 95% CI 0.6-1.8, P < 0.001) and function (average BADLS 1.5 points lower, 95% CI 0.3-2.8, P = 0.02). The combination of donepezil and memantine appeared better than either alone at intermediate time points, but differences were not statistically significant. On secondary measures, memantine improved neurobehavioral symptoms (4.0 point reduction in neuropsychiatric inventory, 99% CI 0.6-7.4, P = 0.002), and donepezil continuation came close to significance (2.3 point reduction in NPI, 95% CI -1.1-5.7, P = 0.08).  


Several points are worth noting. This study specifically examined the effect of discontinuing donepezil, making it directly relevant to the question of whether benefit is sustained with continued therapy. Moreover, the magnitude of benefit an entire year later (~2 point improvement on MMSE) is still approximately the same as the benefit typically seen at 3-6 months in studies examining the initiation of donepezil. The study design and long follow-up are strengths, and these points favor continued therapy. In addition, both donepezil and memantine should be considered to help reduce neurobehavioral symptoms in patients with moderate-to-severe AD. Finally, although this study did not replicate a previous report that combination therapy with both donepezil and memantine was superior to either alone, recruitment in the current study was less than originally planned, and statistical significance might have been reached with a larger sample size. Combined treatment with both donepezil and memantine is still likely to remain standard practice in moderate-to-severe AD.