Add Memantine to Donepezil
For a patient with Alzheimer's disease not improving after three months on donepezil, the best approach is to add memantine while continuing donepezil (Option B). 1, 2, 3
Rationale for Adding Memantine
Three months is sufficient to assess initial response to donepezil, as beneficial effects are generally observed within this timeframe, though full assessment typically requires 6-12 months. 1, 2
Adding memantine to ongoing donepezil therapy is the evidence-based approach for patients progressing despite cholinesterase inhibitor monotherapy. The DOMINO-AD trial specifically addressed this clinical scenario and demonstrated that continuing donepezil while adding memantine provides superior outcomes compared to switching strategies. 3, 4
Combination therapy with donepezil plus memantine showed cognitive benefits exceeding the minimum clinically important difference (SMMSE improvement of 1.9 points for continued donepezil plus additional 1.2 points for memantine). 4
Why Not the Other Options
Why Not Switch to Memantine Alone (Option C)
Discontinuing donepezil results in loss of treatment effect within 6 weeks, with significant deterioration in both cognitive function and activities of daily living. 5, 4
The DOMINO-AD trial demonstrated that patients who discontinued donepezil had SMMSE scores 1.9 points lower and BADLS scores 3.0 points worse (indicating greater impairment) compared to those who continued. 4
Why Not Switch to Rivastigmine (Option D)
There is no convincing evidence that one cholinesterase inhibitor is more effective than another. 1
One head-to-head trial comparing donepezil to rivastigmine showed statistically significant differences favoring rivastigmine in some measures, but rivastigmine had higher rates of nausea and more adverse events overall, with no differences in serious events. 1
Switching between cholinesterase inhibitors is not supported by guidelines as a first-line strategy for non-responders. 1, 2
Why Not Add Sertraline (Option A)
Sertraline addresses depression, not the core cognitive and functional decline of Alzheimer's disease. 1
There is no evidence that adding an antidepressant improves cognitive outcomes in patients not responding to cholinesterase inhibitors unless behavioral symptoms or mood disorders are specifically present. 1
Implementation Strategy
Start memantine at 5 mg daily, increasing by 5 mg weekly in divided doses to reach the target dose of 20 mg/day. 3
Continue donepezil at the current dose (typically 10 mg/day) while adding memantine. 2, 4
Reassess response after 6-12 months of combination therapy, using physician global assessment, caregiver reports, and evidence of behavioral or functional changes. 2, 3
Common Pitfalls to Avoid
Do not prematurely discontinue donepezil - the DOMINO-AD trial clearly showed that stopping donepezil leads to significant deterioration even when memantine is added. 4
Do not expect dramatic improvement - realistic expectations include slowing decline or stabilization rather than reversal, with combination therapy providing additive modest benefits. 1, 3
Ensure adequate memantine dosing - reach the full 20 mg/day dose unless side effects prevent titration, as inadequate dosing reduces therapeutic benefit. 3