Donepezil for dementia due to Alzheimer's disease

BACKGROUND: Alzheimer's disease is the most common cause of dementia and is a primary degenerative disease of the brain of unknown cause. Onset is usually late in life with increasing impairment of memory, developing gradually into a global impairment of cognition, orientation, linguistic ability and judgement. The clinical course is accompanied by growing disability and dependency on care. One of the characteristic features of the disease is the widely variable rate of progression seen in different patients. Acetylcholine is an important neurotransmitter associated with memory, and abnormalities in cholinergic neurones (including cell loss) are among the many neurological and neurochemical abnormalities that develop in AD. One approach to lessening the impact of these abnormalities is to inhibit the breakdown of acetylcholine by blocking the relevant enzyme. Tacrine was the first compound approved as a treatment for AD in the US and worked in this way, but caused severe side effects. E2020 (donepezil, Aricept) is a second generation cholinesterase inhibitor and appears to be highly specific, with relatively few side effects. OBJECTIVES: The objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'donepezil', 'E2020' and 'ARICEPT'. Medline, PsychLIT and EMBASE electronic databases were searched with the above terms. Members of the Donepezil Study Group and Eisai Inc were contacted. SELECTION CRITERIA: All unconfounded, double-blind, randomised controlled trials in which treatment with donepezil was administered for more than a day and compared with placebo in patients with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers (JSB & DB), pooled where appropriate and possible, and the weighted or standardised mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat data were used. MAIN RESULTS: There are 4 included trials, covering treatment of 12 or 24 weeks duration in highly selected patients. The only information available on one trial (Gauthier 1998) is a conference abstract which reports no usable results. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. The results of three trials suggest a small beneficial effect of donepezil in improving cognitive function: at a 5mg/day dose, improvements measured -2.6 points (95%CI -3.5 -- -1.8) on weighted mean difference, in the midrange of the 70 point ADAS-Cog scale. The results of two trials show some improvement in global clinical state (assessed by an independent clinician) in those treated with donepezil compared to placebo. The patient's own rating of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/d (but not the 5mg/d) donepezil group compared with placebo, which may have resulted in some overestimation of beneficial changes at 10mg/d in progressively declining characteristics, as last available measures were used in analyses. A variety of adverse effects were recorded, but very few patients left a trial as a direct result of the intervention. REVIEWER'S CONCLUSIONS: In selected patients with mild or moderate Alzheimer's disease treated for periods of 12 or 24 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.