Dementia is a syndrome of acquired deficits in multiple domains of cognition. These cognitive impairments can affect a person's memory, language, judgement, behaviour and ability to perform everyday activities. The clinical development of the disease is associated with increasing disability and dependency on carers, although this progressive deterioration is highly variable in different patients with dementia (Ritchie et al, 2017).
Alzheimer's disease is a primary degenerative cerebral disease of unknown origin and is the most common cause of dementia in older people (Apostolova, 2016). Acetylcholine is a vital neurotransmitter associated with memory, and abnormalities in cholinergic neurons, in which acetylcholine is the neurotransmitter, are clearly identified in the pathological changes in the brains of people with Alzheimer's disease. The drug donepezil inhibits the breakdown of acetylcholine by reversibly inhibiting the enzyme acetylcholinesterase, thereby reducing the impact of these abnormalities (Alzheimer's Society, 2020). The recommended dose of donepezil is 5 mg once a day, increasing to 10 mg per day after 1 month of treatment. Due to the increasing approval and accessibility of this drug worldwide, closer consideration of the available evidence is required to assess the efficacy and safety of this intervention (Alzheimer's Society, 2020).
Objective
The objectives of Birks and Harvey's updated Cochrane systematic review were to determine the clinical efficacy and safety of donepezil in people with mild, moderate or severe dementia due to Alzheimer's disease (Birks and Harvey, 2018). Furthermore, it aimed to compare the efficacy and safety of varying doses of donepezil and to assess the effect of donepezil on healthcare resource use and costs.
The primary efficacy outcomes considered for this review were cognitive function (as measured by psychometric testing), activities of daily living, behavioural disturbance, clinical global impression, quality of life, death and acceptability of treatment (as measured by withdrawal from trial). The safety outcomes were the number of incidences of adverse effects leading to participant withdrawal and the overall incidence of adverse effects. Lastly, direct and indirect costs were also considered.
Methods
In this updated review (Birks and Harvey, 2018), the authors searched for randomised double-blinded trials that investigated people with dementia due to Alzheimer's disease receiving donepezil treatment. Trials in which donepezil was administered for 12 weeks or longer and compared with a placebo group or those comparing two different doses of donepezil were considered. Participants included those with a probable diagnosis of Alzheimer's disease according to internationally accepted criteria, such as those in the International Classification of Diseases (ICD)-10 and the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). Studies were excluded if the method included withdrawal design, if the allocation to treatment or control was not randomised or if treatment allocation could have led to biased participant allocations.
For this update, the reviewers searched at least 12 electronic databases and trial registries for relevant trials, up to 20 May 2017. Papers were considered for this review irrespective of language, date and publication status. Selected studies were appraised for risk of bias using the using the Cochrane Handbook for systematic reviews of interventions (Cochrane Training, 2019). Quality of evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (Siemieniuk and Guyatt, 2020).
Results
Thirty studies with data available for 8 257 participants with a mean age of 75 years were examined in this updated review, and this included four newly added studies. All trials included used randomised, double-blind designs, and most were of a duration of 6 months or less. Participants in 21 studies had mild to moderate disease, those in five studies had moderate to severe disease, and those in four trials had severe disease. The overall quality of the evidence was moderate due to various study limitations.
According to the finding, 10 mg/day donepezil when compared to a placebo at 24–26 weeks of treatment was associated with better outcomes for cognitive function (17 studies) and activities of daily living (three studies) and better clinician-rated global impression scores (six studies). However, there was no difference between donepezil and the placebo in terms of behavioural symptoms (five studies) or quality of life (two studies). Participants were more likely to experience an adverse event (10 studies) or withdraw from the trials prior to conclusion (12 studies) if they were receiving donepezil.
In three studies, 5 mg/day donepezil was compared with 10 mg/day donepezil over 26 weeks. The lower dose was associated with fewer instances of withdrawal from the study or adverse events. In these dose-comparative studies, the higher dose showed some benefits for cognitive function, but not for activities of daily living or clinician-rated global impression scores.
In two trials, a dose of 23 mg/day donepezil (slow release) was compared with 10 mg/day donepezil. There was no difference in efficacy outcomes between the doses, but participants on the higher dose were more likely to withdraw from the study prior to conclusion or experience an adverse event.
There was no evidence of differences between donepezil and placebo in terms of patient total healthcare resource use.
Four studies only included participants with severe dementia, but the results reported were similar to those of studies that included only participants with mild or moderate disease.
Conclusions
The evidence suggests that people with mild, moderate or severe dementia may experience a small benefit in cognitive function, activities of daily living and clinician-rated global impression scores when treated for a period of 12–24 weeks with donepezil at a dose of 10 mg/day. These benefits were only marginally greater than those conferred by a dose of 5 mg/day. However, the higher rates of dropout and adverse effects with higher doses may indicate that the side effects of this medication remain a clinical challenge.
Implications for practice
This review highlights that clinicians in this area of practice should support further research to identify the maximum duration of treatment with donepezil for those with Alzheimer's disease-related dementia, weighed against effectiveness. Furthermore, research is warranted to establish indicators that may assist in determining when treatment is no longer beneficial. Continued developments in the effectiveness of cholinesterase inhibitors illustrate the need for treatment and management to be informed by best practice, which may be facilitated by clinicians working in a multidisciplinary team.