Adding Memantine to Donepezil for Worsening Alzheimer's Disease
For a 73-year-old woman with Alzheimer's disease experiencing worsening symptoms despite donepezil therapy, add memantine 20 mg/day while continuing donepezil. 1
Rationale for Combination Therapy
Combination therapy with donepezil plus memantine is the evidence-based approach for patients who continue to decline on cholinesterase inhibitor monotherapy, producing statistically significant improvements in both cognition (≈3.4-point increase on the Severe Impairment Battery) and activities of daily living (≈1.4-point increase) compared to donepezil alone. 1
This combination is explicitly recommended by the American Academy of Neurology and American College of Physicians as "rational and safe" with the goal of slowing cognitive decline in patients not responding adequately to monotherapy. 1
Continuing donepezil while adding memantine is superior to switching strategies—discontinuing a cholinesterase inhibitor that the patient tolerates removes a proven therapeutic benefit, and there is strong evidence that patients with moderate to severe Alzheimer's disease benefit from continued donepezil treatment. 1
Practical Implementation
Start memantine at 5 mg once daily and increase by 5 mg weekly in divided doses to reach the target of 20 mg/day (10 mg twice daily). 1
The full 20 mg/day dose is necessary for optimal therapeutic effect when combined with donepezil. 1
If the patient has severe renal impairment (creatinine clearance ≈30 mL/min), reduce the target dose to 10 mg/day total (5 mg twice daily). 1
Continue the current donepezil dose (typically 10 mg daily) without interruption while adding memantine. 1
Expected Timeline and Assessment
Allow 6-12 months of combination therapy before fully assessing treatment response, as this observation period is required to evaluate benefit adequately. 1
Response should be determined by physician global assessment, caregiver reports of functional and behavioral changes, and neuropsychological testing—brief mental status tests like MMSE are relatively insensitive to drug effects. 1
Realistic expectations include slowing decline rather than reversing it; stabilization or slower deterioration constitutes treatment success. 1
Safety Profile
Memantine's most common adverse effects are nausea, dizziness, diarrhea, and agitation, with discontinuation rates of 9-12% (comparable to placebo rates of 7-13%). 1
The combination of donepezil and memantine does not increase serious adverse events relative to either agent alone, supporting its use as a well-tolerated regimen. 1
Common Pitfalls to Avoid
Do not switch from donepezil to memantine monotherapy—memantine alone showed no significant improvement in mild-to-moderate Alzheimer's disease on cognitive measures. 1
Do not switch to another cholinesterase inhibitor (rivastigmine or galantamine) as a first-line strategy—no convincing evidence demonstrates that one cholinesterase inhibitor is more effective than another. 1
Avoid premature discontinuation; some patients may require up to 12 months to demonstrate benefit from combination therapy. 1
Ensure adequate dosing—do not stop titration of memantine before reaching 20 mg/day unless side effects prevent it. 1
Additional Considerations
Control vascular risk factors (hypertension, diabetes, hyperlipidemia), as rapid decliners may respond better to treatment when these are optimized. 1
Consider brain imaging (CT or MRI) if not recently performed to identify white matter changes or lacunar infarctions that may contribute to rapid decline. 1
Implement non-pharmacologic interventions alongside medication, including predictable routines, simplified tasks, safe environment modifications, and orientation aids (calendars, clocks, labels). 2