Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia.
Level 1 - systematic review of randomized trials
Systematic review of randomized controlled trials
PubMed 35608903 · doi:10.1002/14651858.CD009081.pub2
What was done
A Cochrane systematic review evaluated randomized controlled trials comparing discontinuation versus continuation of cholinesterase inhibitors, memantine, or both in people with dementia. Outcomes included cognitive, neuropsychiatric, and functional measures, adverse events, dropout, and mortality across short-term (up to 2 months), medium-term (3 to 11 months), and long-term (12 months or more) follow-up, with evidence certainty assessed using GRADE.
What was found
Seven trials comprising 759 participants with Alzheimer's disease were included (six evaluated cholinesterase inhibitor withdrawal and one evaluated donepezil or memantine withdrawal). Discontinuing cholinesterase inhibitors was associated with worse short-term cognitive function (standardised mean difference [SMD] -0.42, 95% CI -0.64 to -0.21; 4 studies; low certainty), uncertain medium-term cognitive function (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty), and worse cognitive function at 12 months (mean difference [MD] -2.09 SMMSE points, 95% CI -3.43 to -0.75; 1 study; moderate certainty). Functional status showed little short-term difference (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), uncertain medium-term effects (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty), and greater 12-month impairment (MD -3.38 BADLS points, 95% CI -6.67 to -0.10; 1 study; moderate certainty). Discontinuation was associated with worse neuropsychiatric symptoms in the short term (SMD -0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty) and medium term (SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty), but not at 12 months (MD -0.87 NPI points, 95% CI -8.42 to 6.68; 1 study; moderate certainty). Discontinuation had no clear effect on dropouts due to lack of efficacy or medical deterioration (OR 1.53, 95% CI 0.84 to 2.76; 4 studies), adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies), serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies), or mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; all low certainty).
Why it matters
Stopping cholinesterase inhibitors in Alzheimer's disease carries a risk of worsening cognitive, behavioral, and daily functioning outcomes. Deprescribing decisions must weigh these potential harms against the limited and predominantly low-certainty evidence base.
Limits
The total sample size was small (759 participants across 7 trials), and only a single trial evaluated outcomes at 12 months. All participants had Alzheimer's disease, meaning findings cannot be applied to other dementia types. No studies evaluated memantine-only withdrawal, and there were too few trials to determine if withdrawal effects differ by baseline disease severity. Several included studies were at unclear or high risk of selection, performance, detection, attrition, or reporting bias.
Cited by
- supports Sudden withdrawal of cholinesterase inhibitors can cause cognitive worsening due to compensatory upregulation of cholinesterase by the body.