Add Memantine to Donepezil
For an Alzheimer's patient with declining cognition despite donepezil monotherapy, the best next step is to add memantine while continuing donepezil (Option B). This combination therapy provides superior cognitive and functional benefits compared to continuing donepezil alone.
Evidence Supporting Combination Therapy
The FDA-approved indication for memantine specifically includes patients with moderate to severe Alzheimer's disease already receiving donepezil 1. A pivotal 24-week trial demonstrated that adding memantine to stable donepezil therapy produced statistically significant improvements in both cognition (SIB score difference of 3.3 units) and activities of daily living (ADCS-ADL difference of 1.6 units) compared to donepezil monotherapy 1.
The American College of Physicians guidelines support this approach, noting that memantine added to donepezil showed statistically significant improvements in global assessment, quality of life, and caregiver burden in patients with moderate to severe disease 2.
Why Not the Other Options?
Adding Sertraline (Option A)
- There is no evidence that adding an antidepressant improves cognitive decline in Alzheimer's disease 2
- Sertraline would only be appropriate if the patient had comorbid depression, which is not mentioned in this scenario 2
Switching to Memantine Alone (Option C)
- This is contraindicated. The high-quality DOMINO trial demonstrated that discontinuing donepezil in patients with moderate to severe disease resulted in significantly worse outcomes 3
- Patients who stopped donepezil had SMMSE scores 1.9 points lower and BADLS scores 3.0 points worse compared to those who continued (both P<0.001) 3
- The cognitive benefits of continuing donepezil exceeded the minimum clinically important difference 3
Switching to Rivastigmine (Option D)
- While one trial showed rivastigmine had marginally better outcomes than donepezil in some measures, rivastigmine had significantly higher rates of adverse events, particularly nausea 2
- No convincing evidence demonstrates that one cholinesterase inhibitor is more effective than another 2
- Switching between cholinesterase inhibitors is only reasonable if the patient cannot tolerate donepezil, which is not the case here 2
Clinical Implementation
Start memantine at 5 mg once daily and titrate weekly by 5 mg/day in divided doses to the target of 20 mg/day (10 mg twice daily) 1. Continue donepezil at the current dose throughout this process 1.
Expected Outcomes
- Modest improvements or stabilization in cognition and function over 24-26 weeks 2
- The combination is generally well tolerated, with adverse events (nausea, dizziness, diarrhea) occurring in 8-13% of patients 2
- Withdrawal rates due to adverse events are similar to placebo (8-12% vs 7-13%) 2
Important Caveat
The benefits of combination therapy are statistically significant but modest 2. Set realistic expectations with the patient and family that this represents slowing of decline rather than dramatic improvement 2.