What is the next step for a patient with Alzheimer's disease who has not shown improvement on donepezil (Aricept) after three months?

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

Rationale for This Recommendation

The American College of Physicians explicitly states that beneficial effects of cholinesterase inhibitors are generally observed within 3 months, and this timeframe is appropriate for assessing response. 2 Since your patient has not improved after this period, escalation of therapy is warranted rather than switching or adding non-cognitive medications.

Combination therapy with donepezil plus memantine is the evidence-based approach for patients who continue to decline on cholinesterase inhibitor monotherapy. 1 This recommendation is supported by:

• FDA-approved data showing that adding memantine to stable donepezil therapy provides additional benefit in moderate to severe Alzheimer's disease, with a mean difference of 3.3 units on the Severe Impairment Battery and 1.6 units on activities of daily living scales at 24 weeks. 3
• The combination produces statistically significant improvements in cognition, daily functioning, behavioral symptoms, and global clinical status. 4
• Combination therapy is well-tolerated with no significant increase in serious adverse events compared to monotherapy. 4

Why Not the Other Options?

Option A (Add Sertraline) - Incorrect

• 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, 5
• This option would only be appropriate if comorbid depression was documented, which is not mentioned in this scenario. 5

Option C (Change to Memantine Monotherapy) - Incorrect

• Continuing donepezil while adding memantine is superior to memantine alone. 3
• There is strong evidence that patients with moderate to severe Alzheimer's disease benefit from continued donepezil treatment, with cognitive benefits exceeding the minimum clinically important difference. 6
• Discontinuing a cholinesterase inhibitor that the patient is tolerating removes a proven therapeutic benefit. 2

Option D (Switch to Rivastigmine) - Incorrect

• No convincing evidence demonstrates that one cholinesterase inhibitor is more effective than another. 2, 1
• While one trial showed rivastigmine had marginally better outcomes than donepezil in some measures, rivastigmine had significantly higher rates of adverse events, particularly nausea. 5
• Switching between cholinesterase inhibitors is only reasonable if the patient cannot tolerate donepezil, which is not the case here. 5

Implementation Strategy

Dosing Protocol

• Start memantine at 5 mg once daily. 3
• Increase by 5 mg weekly in divided doses to reach the target dose of 20 mg/day (10 mg twice daily). 1, 3
• Continue donepezil at the current dose throughout memantine titration. 1

Expected Outcomes

• Reassess response after 6-12 months of combination therapy using physician global assessment, caregiver reports, and evidence of behavioral or functional changes. 1
• Expect modest improvements or stabilization in cognition and function over 24-26 weeks rather than dramatic improvement. 5, 4
• The combination shows benefits in neuropsychiatric symptoms and reduced caregiver distress, particularly at 12 weeks of treatment. 4

Important Caveats

Setting Realistic Expectations

• The benefits of combination therapy are statistically significant but modest. 5
• Set realistic expectations with the patient and family that this represents slowing of decline rather than reversal. 5
• Stabilization or slower deterioration constitutes success. 1

Tolerability

• The combination is generally well tolerated, with adverse events occurring in 8-13% of patients. 5
• Withdrawal rates due to adverse events are similar to placebo (8-12% vs 7-13%). 5
• Most gastrointestinal side effects can be minimized by taking medications with food and gradual dose titration. 1

When to Discontinue

• Consider discontinuation if clinically meaningful worsening occurs over 6 months without other contributing factors. 4
• Consider discontinuation if no clinical benefit is observed during the 6-12 month assessment period. 4
• If slowing decline is no longer a goal (severe or end-stage dementia), treatment is no longer appropriate. 2