O lder adults experiencing memory and cognition deficits without substantial limitations in activities of daily living may be given a diagnosis of mild cognitive impairment.1 These patients often present with subjective memory loss, impairment of cognitive function and no change in their basic daily functioning. Mild cognitive impairment has recently been recognized as a distinct condition, with a prevalence that ranges from 3% to 42% and increases with age.2 Because of the growing proportion of older adults worldwide, the prevalence of this condition will only increase in the future.3 Each year, 3%-17% of people with mild cognitive impairment experience progression to dementia, 4-6 a rate that increases to between 11% and 33% by 2 years after the initial diagnosis.7 More than 4.6 million new cases of dementia are diagnosed each year, 3 and efforts to reduce this public health burden are essential. Strategies to delay the progression of mild cognitive impairment are being sought to meet this challenge.One strategy that has been hypothesized to delay the progression from mild cognitive impairment to dementia is the use of cognitive enhancers, agents that are often used to treat dementia. These medications include cholinesterase inhibitors (e.g., donepezil, rivastigmine and galantamine) and the N-methyl-d-aspartic acid receptor antagonist memantine.8 donepezil, rivastigmine and galantamine increase the concentration of acetylcholine at neurotransmitter sites, 9 enhancing the brain's cholinergic function. Galantamine also influences activity at nicotinic receptors, 9 whereas memantine modulates the neurotransmitter glutamate. We conducted a systematic review to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment.
Background/Objectives To examine the comparative effectiveness and safety of cognitive enhancers for Alzheimer's disease (AD). Design Systematic review and Bayesian network metaanalysis (NMA). Setting MEDLINE, EMBASE, Cochrane Library, CINAHL, Ageline (inception–March 2016). Participants Individuals with AD in randomized controlled trials (RCTs), quasi‐RCTs, and nonrandomized studies. Intervention Any combination of donepezil, rivastigmine, galantamine, or memantine. Measurements Two reviewers independently screened titles, abstracts, and full‐texts; abstracted data; and appraised risk of bias. Results Twenty thousand three hundred forty‐three citations were screened, and 142 studies were included (110 RCTs, 21 non‐RCTs, 11 cohort studies). NMA found that donepezil (Mini‐Mental State Examination: mean difference (MD) = 1.39, 95% credible interval (CrI) = 0.53–2.24), donepezil+memantine (2.59, 95% CrI = 0.12–4.98), and transdermal rivastigmine (2.02, 95% CrI = 0.02–4.08) improved cognition more than placebo. NMA found that donepezil (Alzheimer's Disease Assessment Scale–cognitive: MD = −3.29, 95% CrI = −4.57 to −1.99) and galantamine (MD = −2.13, 95% CrI = −3.91 to −0.27) improved cognition more than placebo. NMA found that donepezil+memantine (MD = −5.23, 95% CrI = −8.72 to −1.56) improved behavior more than placebo. NMA found that donepezil (MD = −0.32, 95% CrI = −0.46 to −0.19), donepezil+memantine (MD = −0.57, 95% CrI = −0.95 to −0.21), oral rivastigmine (MD = −0.38, 95% CrI = −0.56 to −0.17), and galantamine (MD = −3.79, 95% CrI = −6.98 to −0.59) improved global status more than placebo. NMA found that galantamine decreased the odds of mortality (odds ratio = 0.56, 95% CrI = 0.36–0.87). No agent increased risk of serious adverse events, falls, or bradycardia. Some increased risk of headache (oral rivastigmine), diarrhea (oral rivastigmine, donepezil), nausea (oral rivastigmine, donepezil, galantamine), and vomiting (oral rivastigmine, donepezil, galantamine). Conclusion An exhaustive review of the literature involving 142 studies demonstrated that cognitive enhancers in general have minimal effects on cognition according to minimal clinically important difference and global ratings. The drugs appear safe, but this must be interpreted cautiously because trial participants may have less comorbidity and fewer adverse effects than those treated with these drugs in clinical practice.
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