Overview of Cholinesterase Inhibitors in the Treatment of Alzheimers Disease

The use of cholinesterase inhibitors may preserve activities of daily living, slow progression of memory loss and improve behavioral and cognitive symptoms associated with Alzheimer's and related dementias. Treating Alzheimer's disease often takes great patience on the part of physicians as well as patients and caregivers. Response to drug may take weeks, sometimes months before caregivers may notice a difference in symptoms, if at all. The efficacy produced by cholinesterase inhibitors is not always clear-cut. For example, there is some evidence that donepezil may benefit moderate to severe Alzheimer's dementia in outpatients, however, the results have been conflicting in the nursing home population [17]. In addition, both donepezil and galantamine have not yet shown consistent results in improving behavioral and psychotic symptoms in patients with Alzheimer's disease. Improvement in psychosis is seen with rivastigmine which has shown improvements in behavioral symptoms in mild to moderate Alzheimer's dementia and in Lewy Body Dementia [17].

A recent meta-analysis by Trinh and colleagues looked at the efficacy of cholinesterase inhibitors relative to behavioral symptoms. In this study, they reviewed published literature from 1966-2001. A total of 29 parallel-group or crossover randomized, double-blind, placebo-controlled trials of outpatients with mild to moderate Alzheimer's disease were included in the study. Patients were treated for at least 1 month with a cholinesterase inhibitor. Among the assessment tools used during this study were the Neuropsychiatric Inventory, the Alzheimer Disease Assessment Scale, Activities of Daily Living and the Instrumental Activities of Daily Living. The study showed a small but significant improvement with use of cholinesterase inhibitors. There was no difference among the cholinesterase inhibitors as a class [18].

In a similar study, Lanctot and colleagues looked at efficacy and safety of donepezil, rivastigmine, and galantamine in a recent meta-analysis of randomized, double-blind, placebo-controlled, parallel-group trials. They concluded that there were significant therapeutic effects with the cholinesterase inhibitors although they often were accompanied by significant side effects [19]. Several large, multi-centered, double-blind, placebo-controlled studies have generally supported the use of cholinesterase inhibitors in improving cognition. Efficacy has been shown to last up to 1 year and beyond [20,21].

On the other hand, a recent analysis by Kaduszkiewicz and colleagues, looking at the efficacy of donepezil, rivastigmine, and galantamine in Alzheimer's disease, reached a different conclusion. This study included literature search of all published double-blind, randomized-controlled trials. The researchers concluded that there were methodological errors, which included having incomplete data, failing to correct for differences among comparisons, and using inappropriate methods in measuring outcomes which may have led to overestimation of efficacy in these trials. In addition, the modest benefits may have been overshadowed by the cholinergic adverse side effects of the cholinesterase inhibitors [22].

To this date, there has not yet been a randomized, double-blind, placebo-controlled trial comparing the efficacy of all of the cholinesterase inhibitors. The few studies available compared the efficacy between donepezil and ri-vastigmine [23], and two studies compared donepezil and galantamine [24, 25]. Each of the studies is sponsored by pharmaceutical companies with each sponsor favoring their own product. The methodological limitations in these trials are significant, including lack of adequate blinding, not having a long enough efficacy study, having small sample sizes, and not dosing the medications appropriately to their maximum daily dosage [26]. Due to the lack of evidence in comparison of efficacy among the cholinesterase inhibitors, there is still much debate on which cholinesterase inhibitor is most efficacious. Deciding which cholinesterase to use often depends on the side effect profile of the medications, pharmacokinetics, dosing schedule, patient tolerability, individual clinicians' personal preference, and which drug has been studied in which dementia. For example, rivastigmine recently won FDA approval for treating Parkinson's dementia.

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