Namenda vs Aricept for Alzheimer's Disease
For moderate to severe Alzheimer's disease, use both medications together—the combination of memantine (Namenda) and donepezil (Aricept) provides superior outcomes compared to either drug alone. 1, 2, 3
Mechanism and FDA Indications
Donepezil (Aricept) is a cholinesterase inhibitor that prevents the breakdown of acetylcholine, approved for mild, moderate, and severe Alzheimer's disease 4. Memantine (Namenda) is an NMDA receptor antagonist that works through a completely different mechanism, approved for moderate to severe Alzheimer's disease 5.
Disease Stage-Specific Recommendations
Mild to Moderate Alzheimer's Disease
- Start with donepezil alone at 5 mg daily in the evening, taken with food 6, 7
- Increase to 10 mg daily after 4-6 weeks if tolerated 7
- Donepezil shows consistent evidence of improving cognition (ADAS-cog) and global function (CIBIC-plus) in this population 6, 8
- The cognitive benefit averages 2.02 points on ADAS-cog at 24 weeks for 5 mg dose and 2.92 points for 10 mg dose 6
Moderate to Severe Alzheimer's Disease
- Use combination therapy with both donepezil and memantine 6, 1
- This recommendation is supported by guidelines from the US, China, and Japan (though not the UK) 6
- The combination produces significantly better outcomes than donepezil monotherapy across all domains 2, 3:
Key Evidence for Combination Therapy
The landmark DOMINO-AD trial demonstrated that continuing donepezil in moderate to severe disease provides cognitive benefits of 1.9 SMMSE points and functional benefits of 3.0 BADLS points compared to discontinuation (both exceeding minimum clinically important differences) 9. When memantine is added to stable donepezil therapy, patients gain an additional 1.2 SMMSE points and 1.5 BADLS points 9.
A separate randomized controlled trial of 404 patients already on donepezil showed that adding memantine produced statistically significant improvements on the Severe Impairment Battery (0.9 vs -2.5 points, p<0.001), activities of daily living (-2.0 vs -3.4 points, p=0.03), and global assessment (p=0.03) 3.
Practical Dosing
Donepezil
- Start 5 mg once daily in the evening with food 7
- Increase to 10 mg after 4-6 weeks 7
- Initial agitation may occur but typically resolves within weeks 7
Memantine
- Start 5 mg daily, titrate to target dose of 20 mg daily 5
- Can be taken with or without food 5
- Adjust dose in severe renal impairment (CrCl 5-29 mL/min) 5
Adverse Effects
Donepezil causes primarily gastrointestinal side effects (nausea, vomiting, diarrhea, anorexia), more common with 10 mg dose 6, 8. Withdrawal rates due to adverse effects are low 8.
Memantine has withdrawal rates of 9-12% (similar to placebo at 7-13%) 6, 1. Common side effects include nausea, dizziness, diarrhea, and agitation (though memantine may actually reduce agitation) 6. The combination is well-tolerated with no significant increase in serious adverse events 1, 3.
When to Discontinue
Consider stopping treatment if 1:
- Clinically meaningful worsening occurs over 6 months without other contributing factors
- No clinical benefit is observed during treatment
- Progression to severe or end-stage dementia with dependence in most basic activities of daily living
Exception: Continue memantine if neuropsychiatric symptoms (psychosis, agitation, aggression) have meaningfully improved, even with cognitive and functional decline 1.
When discontinuing, reduce dose by 50% every 4 weeks until reaching the initial starting dose 1.
Critical Clinical Pearls
- Never discontinue donepezil abruptly in moderate to severe disease—the DOMINO-AD trial showed significant deterioration when stopped 9
- The combination works through complementary mechanisms and does not cause pharmacokinetic interactions 5
- Benefits are maintained at 52 weeks, confirming long-term efficacy 6, 9
- Memantine shows particular benefit for behavioral symptoms and caregiver distress at 12 weeks 6, 1