Medication Management for Non-Responsive Alzheimer's Disease on Donepezil
Add memantine to the current donepezil regimen (Option B). This is the evidence-based approach for patients with Alzheimer's disease who continue to decline despite 6 months of cholinesterase inhibitor monotherapy.
Rationale for Combination Therapy
The American College of Physicians and American Academy of Family Physicians recommend continuing donepezil while adding memantine for patients not improving after 3-6 months on donepezil monotherapy 1, 2. This approach is superior to switching medications because:
- Discontinuing donepezil removes a proven therapeutic benefit that the patient is tolerating 2
- Combination therapy (donepezil plus memantine) provides additive benefits on cognition, activities of daily living, global outcomes, and behavior compared to monotherapy 3
- Patients with moderate to severe AD receiving both medications show statistically significant improvements: mean difference of 3.4 points on cognition (SIB scale) and 1.4 points on activities of daily living compared to donepezil alone 3
Evidence Against Alternative Options
Switching from donepezil to memantine (Option C) is not recommended because there is no convincing evidence that memantine monotherapy is superior to continuing a cholinesterase inhibitor that the patient tolerates 1, 2. Memantine alone showed no significant improvement in mild to moderate AD on cognitive measures 1.
Switching to rivastigmine (Option D) is not supported as there is no convincing evidence that one cholinesterase inhibitor is more effective than another 1, 2. Switching between cholinesterase inhibitors is only reasonable if the patient cannot tolerate the current medication 2.
Adding sertraline (Option A) is inappropriate unless specific behavioral symptoms or mood disorders are present, as antidepressants do not improve cognitive outcomes in patients not responding to cholinesterase inhibitors 2.
Implementation Strategy
Memantine dosing protocol:
- Start at 5 mg once daily 4, 5
- Increase by 5 mg weekly in divided doses 4, 5
- Target dose: 20 mg/day (10 mg twice daily) 4, 6, 5
- Continue donepezil at current dose (10 mg/day) 2, 7
For patients with severe renal impairment (creatinine clearance ≤30 mL/min): reduce target memantine dose to 10 mg/day (5 mg twice daily) 4, 2.
Expected Outcomes and Timeline
Reassess response after 6-12 months of combination therapy 2. Success is defined as:
- Stabilization or slower cognitive decline compared to pre-treatment trajectory 2
- Improvements in activities of daily living by 1.4-3.0 points on standardized scales 8, 3
- Reduction in neuropsychiatric symptoms if present 6, 3
The cognitive benefits of continuing donepezil in moderate to severe AD exceed the minimum clinically important difference (1.9 points on SMMSE and 3.0 points on functional scales over 12 months) 8.
Safety Profile
Common adverse effects of memantine include:
- Nausea, dizziness, diarrhea, and agitation 1, 4
- Discontinuation rates due to adverse effects: 9-12% (comparable to 7-13% with placebo) 1, 4
- When added to donepezil, memantine discontinuation rate was 7.4% vs 12.4% for placebo 3
Critical Pitfall to Avoid
Do not prematurely discontinue donepezil in patients with moderate to severe AD who are tolerating it, even if cognitive decline continues 8. The DOMINO-AD trial demonstrated that patients who discontinued donepezil had significantly worse cognitive and functional outcomes compared to those who continued, with differences exceeding clinically important thresholds 8.