An older adult with Alzheimer disease on donepezil for 6 months has declined from an MMSE of 19 to 12; what medication change is most appropriate?

Add Memantine to Donepezil

For this patient with moderate-to-severe Alzheimer's disease (MMSE declining from 19 to 12) who has not improved on donepezil monotherapy for 6 months, the most appropriate medication change is to add memantine while continuing donepezil. 1, 2

Rationale for Combination Therapy

• Continuing donepezil is essential because discontinuing a cholinesterase inhibitor that the patient tolerates removes a proven therapeutic benefit, and evidence shows that patients with moderate-to-severe Alzheimer's disease benefit from continued donepezil treatment with cognitive benefits exceeding the minimum clinically important difference. 2, 3

• Adding memantine to stable donepezil therapy provides superior outcomes compared to donepezil monotherapy, with statistically significant improvements of approximately 3.4 points on the Severe Impairment Battery (cognition) and 1.4 points on activities-of-daily-living scales. 2, 4

• The patient's MMSE decline from 19 to 12 indicates progression from moderate to moderate-severe disease, which is precisely the population where combination therapy demonstrates the strongest evidence of benefit. 1, 3

Why Other Options Are Inappropriate

Switching to Memantine Monotherapy (Discontinuing Donepezil)

• This strategy lacks supporting evidence and would remove the proven cognitive benefits of donepezil that exceed the minimum clinically important difference in moderate-to-severe disease. 2, 3
• Memantine alone showed no significant improvement in mild-to-moderate Alzheimer's disease on cognitive measures, making monotherapy inferior to combination therapy. 2

Switching to Rivastigmine

• No convincing evidence demonstrates that one cholinesterase inhibitor is more effective than another, making switching between them unsupported as a first-line strategy for non-responders. 5, 2
• Switching is only reasonable when patients cannot tolerate the current medication, which is not the case here. 2

Adding Sertraline

• Sertraline is not indicated for cognitive decline in Alzheimer's disease, and there is no evidence supporting its use in this context unless behavioral symptoms or mood disorders are specifically present. 1, 2

Practical Implementation

Dosing Strategy

• Target memantine dose is 20 mg/day, achieved by increasing the dose by 5 mg weekly in divided doses to maximize therapeutic benefit. 2
• Continue donepezil at the current 10 mg/day dose while adding memantine. 2

Assessment Timeline

• Reassess response after 6-12 months of combination therapy using physician global assessment, caregiver reports, and evidence of behavioral or functional changes. 2
• The assessment period for combination therapy requires 6-12 months to adequately evaluate the patient's response to treatment. 2

Expected Outcomes

• Realistic expectations include slowing decline rather than reversing it, with stabilization or slower deterioration constituting treatment success. 2
• Beneficial effects of combination therapy are generally observed within 3 months, though the full assessment period extends to 6-12 months. 2

Common Pitfalls to Avoid

• Avoid premature discontinuation of donepezil based on perceived lack of improvement, as the DOMINO-AD trial demonstrated that continuing donepezil in moderate-to-severe disease resulted in SMMSE scores 1.9 points higher and functional scores 3.0 points better than discontinuation. 3
• Do not switch between cholinesterase inhibitors without evidence of intolerance, as this strategy lacks guideline support and removes a medication the patient is already tolerating. 5, 2
• Ensure adequate dosing of memantine by reaching the full 20 mg/day dose unless side effects prevent titration, as suboptimal dosing reduces therapeutic benefit. 2

Safety Considerations

• Memantine adverse effects include nausea, dizziness, diarrhea, and agitation, with discontinuation rates of 9-12% (comparable to placebo rates of 7-13%). 5, 1
• The combination of donepezil and memantine is well-tolerated with no significant increase in serious adverse events compared to monotherapy. 1
• Monitor for gastrointestinal side effects from donepezil, which can be minimized by taking the medication with food. 1