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 Combination Therapy
Three months is the appropriate timeframe to assess response to cholinesterase inhibitors, and beneficial effects are generally observed within this period. 1 When a patient continues to decline on donepezil monotherapy, adding memantine represents an evidence-based escalation strategy rather than abandoning proven therapy. 1
Combination therapy with donepezil plus memantine is explicitly recommended by guidelines for patients who continue to decline on cholinesterase inhibitor monotherapy. 1 This approach is described as "rational and safe" with the goal of slowing cognitive decline. 1
Evidence Supporting This Approach
The FDA label for memantine demonstrates that in patients with moderate to severe AD already receiving stable donepezil therapy, adding memantine resulted in:
- Statistically significant improvements in cognition (SIB scores) with a mean difference of 3.3 units favoring combination therapy 2
- Significant benefits in activities of daily living (ADCS-ADL) with a mean difference of 1.6 units favoring combination therapy 2
- Superior global outcomes compared to donepezil monotherapy 2
A landmark randomized controlled trial of 404 patients confirmed that memantine added to stable donepezil therapy produced significant improvements across all outcome measures (cognition, function, global status, and behavior) and was well tolerated. 3
Why Not the Other Options?
Option A (Add Sertraline): Sertraline addresses depression, not the core cognitive and functional decline of Alzheimer's disease. 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 SSRIs should be reserved for patients with moderate to severe depression, as they carry a small but increased risk of intracerebral hemorrhage. 4
Option C (Switch to memantine monotherapy): Discontinuing donepezil that the patient is tolerating removes a proven therapeutic benefit. Continuing donepezil while adding memantine is superior to memantine alone. 1 Strong evidence demonstrates that patients with moderate to severe AD benefit from continued donepezil treatment, with cognitive benefits exceeding the minimum clinically important difference. 5
Option D (Switch to rivastigmine): There is no convincing evidence that one cholinesterase inhibitor is more effective than another. 4, 1 Switching between cholinesterase inhibitors is not supported by guidelines as a first-line strategy for non-responders and should only be considered if the patient cannot tolerate the current medication. 1
Practical 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). 2
- Continue donepezil at the current dose throughout memantine titration. 1
- Reassess response after 6-12 months of combination therapy using physician global assessment, caregiver reports, and evidence of behavioral or functional changes. 1
- The full 20 mg/day dose of memantine is necessary for optimal therapeutic effect when combined with donepezil. 1
Common Pitfalls to Avoid
- Avoid premature discontinuation: Some patients may require up to 12 months to demonstrate benefit from combination therapy. 1
- Avoid inadequate dosing: Ensure memantine reaches the full 20 mg/day dose unless side effects prevent titration. 1
- Set realistic expectations: Treatment aims to slow decline rather than reverse it—stabilization or slower deterioration constitutes success. 1
- Monitor for side effects: Common adverse events with memantine include headaches, dizziness, confusion, and falls, though combination therapy is generally well tolerated. 4, 3