What adjustment should be made to the medication regimen of a patient with Alzheimer's disease who is not improving on donepezil (a cholinesterase inhibitor), with a decreasing Mini-Mental Status (MMS) score?

Medication Adjustment for Alzheimer's Patient Not Improving on Donepezil

Add memantine to the current donepezil regimen (Option B). This is the most appropriate next step for a patient with declining cognitive function despite donepezil therapy.

Rationale for Adding Memantine

The combination of donepezil plus memantine is superior to donepezil monotherapy in patients with moderate to severe Alzheimer's disease. 1 The FDA label for memantine demonstrates that in patients already on stable donepezil therapy, adding memantine produced statistically significant improvements in both cognition (SIB scores) and activities of daily living (ADCS-ADL scores) compared to continuing donepezil alone. 1

• In a 24-week study of 404 patients with moderate to severe AD already on donepezil, adding memantine resulted in a mean difference of 3.3 units on the SIB scale and 1.6 units on the ADCS-ADL scale compared to placebo. 1

• The combination therapy showed that patients were more likely to demonstrate smaller decline or actual improvement compared to donepezil monotherapy. 1

Why Not the Other Options

Switching from donepezil to rivastigmine (Option D) is not recommended because there is no convincing evidence that one cholinesterase inhibitor is more effective than another. 2 While one trial showed rivastigmine had statistically significant benefits over donepezil in some measures, the American College of Physicians guideline states there is insufficient evidence to recommend switching between cholinesterase inhibitors as a primary strategy. 2

Switching from donepezil to memantine alone (Option C) is inferior to combination therapy. Continuing donepezil while adding memantine provides additive benefits, as the two medications work through different mechanisms (cholinergic enhancement versus NMDA receptor antagonism). 1, 3

Adding sertraline (Option A) is not indicated unless the patient has comorbid depression or behavioral symptoms that specifically warrant antidepressant therapy. The evidence provided does not support sertraline as a treatment for cognitive decline in Alzheimer's disease. 2

Evidence for Continuing Donepezil

Do not discontinue donepezil in patients with moderate to severe disease. A high-quality randomized trial of 295 patients demonstrated that continuing donepezil in moderate to severe AD resulted in SMMSE scores 1.9 points higher and BADLS scores 3.0 points lower (less impairment) compared to discontinuation—both exceeding minimum clinically important differences. 3

Implementation Strategy

• Continue current donepezil dose (typically 10 mg/day). 2, 4

• Initiate memantine at 5 mg once daily, increasing weekly by 5 mg/day in divided doses to reach the target dose of 20 mg/day (10 mg twice daily). 1

• Monitor for memantine side effects including dizziness, headache, and confusion during titration. 1

• Reassess cognitive and functional status at 12-24 weeks using standardized measures (MMSE or similar). 2

Common Pitfalls to Avoid

• Do not prematurely discontinue donepezil based on declining MMSE scores alone—the medication may be slowing decline rather than producing improvement, and discontinuation will accelerate deterioration. 3

• Do not switch between cholinesterase inhibitors without first trying combination therapy with memantine, as there is no evidence supporting superior efficacy of one cholinesterase inhibitor over another. 2

• Monitor for initial increase in agitation when continuing donepezil, which typically subsides after the first few weeks. 5, 4

• Be aware of dose-related gastrointestinal side effects (nausea, vomiting, diarrhea) with donepezil, particularly at the 10 mg dose, though these should already be established if the patient has been on therapy. 4, 6