Add Memantine to Donepezil
For a patient with Alzheimer's disease showing continued decline on donepezil monotherapy (MMSE dropping from 19 to 12 over 6 months), the best approach is to add memantine 20 mg/day while continuing donepezil, as this combination therapy provides superior cognitive, functional, and behavioral outcomes compared to cholinesterase inhibitor monotherapy. 1, 2
Rationale for Combination Therapy
The American College of Physicians explicitly recommends that when patients fail to improve after 3 months on donepezil, the optimal strategy is to add memantine while continuing donepezil, as beneficial effects are generally observed within this timeframe 2
Combination therapy with donepezil plus memantine produces significant benefits on global clinical status measures, with improvements in neuropsychiatric symptoms and reduced caregiver distress, particularly evident at 12 weeks of treatment 1
Adding memantine to stable donepezil therapy provides additional benefit in patients with moderate to severe Alzheimer's disease, with a standardized mean difference of 0.36 for cognition 1
The FDA label demonstrates that memantine added to donepezil resulted in a mean difference of 3.3 units on the Severe Impairment Battery and 1.6 units on the ADCS-ADL scale compared to donepezil alone at 24 weeks 3
Why Not the Other Options
Switching to rivastigmine (Option D): There is no convincing evidence that one cholinesterase inhibitor is more effective than another, making switching between them unsupported by guidelines as a first-line strategy for non-responders 4, 2
Switching to memantine monotherapy (Option C): Continuing donepezil while adding memantine is superior to memantine alone, as discontinuing a cholinesterase inhibitor that the patient is tolerating removes a proven therapeutic benefit 2
Adding sertraline (Option A): Sertraline addresses depression, not the core cognitive and functional decline of Alzheimer's disease, and 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 2
Practical Implementation
Start memantine at 5 mg once daily and 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 (presumably 10 mg/day) while adding memantine 2
The combination of memantine and donepezil is well-tolerated with no significant increase in serious adverse events, and adverse event rates are similar between combination therapy and monotherapy groups 1
Reassess response after 6-12 months of combination therapy using physician global assessment, caregiver reports, and evidence of behavioral or functional changes 2
Expected Outcomes
Patients on combination therapy show improvements in cognition (measured by SIB and ADAS-Cog), activities of daily living (ADCS-ADL), and global clinical status (CIBIC-Plus) compared to donepezil monotherapy 3, 5
Realistic expectations include slowing decline rather than reversing it, with stabilization or slower deterioration constituting success 2
The assessment period for combination therapy is 6-12 months, during which the patient's response to treatment can be adequately assessed 2
Common Pitfalls to Avoid
Avoid premature discontinuation of treatment, as some patients may require up to 12 months to demonstrate benefit 2
Avoid inadequate dosing of memantine—the goal is to reach the full 20 mg/day dose unless side effects prevent titration 2
Do not discontinue donepezil prematurely, as 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 2