Add Memantine to Donepezil
For a patient with Alzheimer's disease not improving after 3 months on donepezil with declining MMSE to 12, the best approach is to add memantine while continuing donepezil (Option B). 1, 2
Rationale for Combination Therapy
The American College of Physicians explicitly recommends that when patients with Alzheimer's disease fail to improve after three months on donepezil, the optimal strategy is adding memantine while continuing the cholinesterase inhibitor, as beneficial effects are generally observed within this timeframe and combination therapy provides additive benefits on cognition and function. 1, 2
Combination therapy with donepezil plus memantine is described as "rational and safe" in consensus guidelines, with the goal of slowing cognitive decline in patients who continue to deteriorate on cholinesterase inhibitor monotherapy. 1
The FDA label demonstrates that memantine added to donepezil in moderate to severe Alzheimer's disease produces statistically significant improvements in both cognition (SIB score difference of 3.3 units) and activities of daily living (ADCS-ADL difference of 1.6 units) compared to donepezil alone over 24 weeks. 3
A high-quality randomized controlled trial (DOMINO-AD) confirmed that continuing donepezil was associated with cognitive benefits exceeding the minimum clinically important difference (1.9 points on SMMSE) and significant functional benefits (3.0 points on BADLS) over 12 months, while memantine provided additional cognitive benefit (1.2 points on SMMSE). 4
Why Not the Other Options
Why Not Add Sertraline (Option A)
Sertraline addresses depression, not the core cognitive and functional decline of Alzheimer's disease, and 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
The American College of Physicians found no significant improvement in behavioral symptoms measured by the Neuropsychiatric Inventory with donepezil treatment, indicating that adding an antidepressant without documented behavioral or mood symptoms is not evidence-based. 5
Why Not Switch to Memantine Alone (Option C)
Switching to memantine means losing any residual benefit from donepezil, and the DOMINO-AD trial demonstrated that patients who discontinued donepezil had significantly worse cognitive (1.9 points lower on SMMSE) and functional outcomes (3.0 points worse on BADLS) compared to those who continued it. 4, 2
The American Academy of Family Physicians confirms that an assessment period of 6-12 months is necessary to evaluate potential benefit of cholinesterase inhibitors, and premature discontinuation should be avoided. 1
Why Not Switch to Rivastigmine (Option D)
There is no convincing evidence that one cholinesterase inhibitor is more effective than another, and switching between them is not supported by guidelines as a first-line strategy for non-responders. 1, 2
Rivastigmine has higher rates of adverse events, particularly nausea, compared to donepezil, making a switch less favorable than adding memantine. 2
Switching means losing any residual benefit from donepezil without evidence of superior efficacy with rivastigmine. 2
Clinical Implementation
Start memantine at 5 mg once daily and increase weekly by 5 mg/day in divided doses to reach the target dose of 20 mg/day (10 mg twice daily). 1, 3
Continue donepezil at the current dose (presumably 10 mg/day based on standard dosing for moderate disease). 1
Assess response over 6-12 months using physician global assessment, caregiver reports, and evidence of behavioral or functional changes, as this observation period is necessary to adequately evaluate potential benefit. 1, 2
Expected Outcomes and Safety
The combination provides modest but meaningful benefits, with realistic expectations including slowing decline rather than reversing it—stabilization or slower deterioration constitutes success. 1
Withdrawal rates for memantine are 9-12%, similar to placebo (7-13%), with adverse events including nausea, dizziness, diarrhea, and agitation. 2
The combination of memantine and donepezil has been shown to be safe with no significant increase in serious adverse events beyond expected cholinesterase inhibitor side effects. 3, 4
Common Pitfalls to Avoid
Do not prematurely discontinue donepezil, as some patients may require up to 12 months to demonstrate benefit from combination therapy. 1
Ensure adequate dosing of memantine to the full 20 mg/day dose unless side effects prevent titration, as inadequate dosing reduces therapeutic benefit. 1
Address unrealistic expectations before initiating combination therapy, explaining that the goal is slowing decline, not cure or reversal of symptoms. 1