What is the best approach to adjust medications for a patient with Alzheimer's disease who is not improving on donepezil (a cholinesterase inhibitor)?

Add Memantine to Donepezil

For a patient with Alzheimer's disease showing cognitive decline despite donepezil therapy (MMSE declining from 25 to 23), the best approach is to add memantine while continuing donepezil (Option B). This combination therapy provides additive benefits on cognition and function that exceed either medication alone.

Evidence Supporting Combination Therapy

The FDA label for memantine demonstrates that adding memantine to donepezil in patients with moderate to severe AD produces statistically significant improvements in both cognition (SIB scores) and activities of daily living (ADCS-ADL scores) compared to donepezil monotherapy over 24 weeks 1. The mean difference in ADCS-ADL was 1.6 units and in SIB was 3.3 units, both statistically significant 1.

The landmark DOMINO-AD trial confirmed that continuing donepezil in moderate-to-severe AD patients resulted in MMSE scores 1.9 points higher and functional scores 3.0 points better than discontinuation 2. Importantly, patients receiving memantine had MMSE scores 1.2 points higher than placebo 2. The efficacy of donepezil and memantine did not significantly differ in the presence or absence of the other, supporting additive effects 2.

Why Not the Other Options

Option A (Add Sertraline): Incorrect

• There is no evidence that adding an antidepressant improves cognitive decline in Alzheimer's disease 3
• Sertraline would only be appropriate if comorbid depression were present, which is not mentioned in this scenario 3

Option C (Switch to Memantine): Incorrect

• Switching means losing the demonstrated cognitive benefit of donepezil, which provides a 1.9-point advantage on MMSE over discontinuation 2
• The DOMINO-AD trial showed that continuing donepezil produced benefits exceeding the minimum clinically important difference of 1.4 points on MMSE 2

Option D (Switch to Rivastigmine): Incorrect

• No convincing evidence demonstrates that one cholinesterase inhibitor is more effective than another 4, 3
• While one trial showed rivastigmine had marginally better outcomes than donepezil in some measures, rivastigmine had significantly higher rates of adverse events, particularly nausea 4, 3
• Switching between cholinesterase inhibitors is only reasonable if the patient cannot tolerate donepezil 3

Clinical Implementation

Expected Outcomes

• Modest improvements or stabilization in cognition and function over 24-26 weeks can be expected with combination therapy 3, 1
• The combination is generally well tolerated, with adverse events occurring in 8-13% of patients 3
• Withdrawal rates due to adverse events are similar to placebo (8-12% vs 7-13%) 3, 1

Dosing Strategy

• Initiate memantine at 5 mg once daily and increase weekly by 5 mg/day in divided doses to a target of 20 mg/day (10 mg twice daily) 1
• Continue donepezil at current dose (typically 10 mg daily) 1

Important Caveats

• Set realistic expectations: The benefits represent slowing of decline rather than dramatic improvement 3
• The MMSE decline from 25 to 23 over 6 months (2 points) is consistent with expected progression (2-3 points per year average) 4, so combination therapy aims to slow this trajectory
• Assess response over 6-12 months, as this duration is necessary to evaluate potential benefit 5
• Monitor for adverse events including nausea, dizziness, diarrhea, and agitation 3, 1