What is the preferred treatment for a geriatric patient with Alzheimer's disease, Namenda (memantine) or donepezil?

Donepezil vs Memantine for Alzheimer's Disease

For geriatric patients with mild to moderate Alzheimer's disease, start with donepezil 5 mg daily as first-line therapy; for moderate to severe disease, initiate donepezil first and then add memantine for superior outcomes. 1, 2

Disease Stage-Specific Treatment Algorithm

Mild to Moderate Alzheimer's Disease

• Initiate donepezil monotherapy as first-line treatment 3, 2
• Start with 5 mg once daily in the evening, taken with food to minimize gastrointestinal side effects 1, 2
• Increase to 10 mg daily after 4-6 weeks if tolerated 1, 2
• Donepezil produces a 2.7-point improvement on the ADAS-Cog scale compared to placebo 2
• Approximately 20-35% of patients show a 7-point improvement on neuropsychological tests, equivalent to reversing one year's cognitive decline 2
• Efficacy is maintained for up to 4.9 years 2

Memantine is NOT indicated for mild to moderate disease as monotherapy - it is specifically approved and effective for moderate to severe disease only 1, 4

Moderate to Severe Alzheimer's Disease

• Initiate combination therapy with both donepezil and memantine for optimal outcomes 1, 2
• Start donepezil first using the dosing schedule above, then add memantine after establishing stable donepezil therapy 2
• Memantine dosing: Start 5 mg once daily, increase weekly by 5 mg/day in divided doses to target of 20 mg/day (10 mg twice daily) 4
• Combination therapy produces significantly better outcomes than monotherapy across all domains including cognition, global function, neuropsychiatric symptoms, and caregiver distress 1, 2
• Adding memantine to stable donepezil provides additional cognitive benefit with a standardized mean difference of 0.36 1, 2

Evidence Supporting This Approach

Why Donepezil First

The American College of Physicians and American Academy of Neurology recommend donepezil as the initial agent based on:

• Consistent evidence of improving cognition and global function in mild to moderate disease 1, 2
• Simpler once-daily dosing with straightforward titration 5
• No hepatotoxicity unlike older agents (tacrine) 3, 2
• Well-established efficacy data spanning multiple years 2, 6

Why Add Memantine in Moderate to Severe Disease

Guidelines from the US, China, and Japan support combination therapy because:

• Memantine improves cognition and global assessment in moderate to severe disease 1
• Combination produces statistically significant improvements on the Severe Impairment Battery (SIB) and CIBIC-plus scale 1
• Memantine shows particular benefit for neuropsychiatric symptoms (psychosis, agitation, aggression) and may actually reduce agitation 1
• The combination is well-tolerated with no significant increase in serious adverse events 1

Adverse Effect Profile

Donepezil

• Primarily gastrointestinal: nausea, vomiting, diarrhea, anorexia 1
• More common with 10 mg dose but can be minimized by taking with food 1, 2
• May cause initial increase in agitation that typically subsides within a few weeks 7
• Low withdrawal rates due to adverse effects 1

Memantine

• Withdrawal rates of 9-12%, similar to placebo 1
• Common side effects: nausea, dizziness, diarrhea, agitation 1
• Generally well-tolerated as monotherapy or in combination 1

Combination Therapy

• No significant increase in serious adverse events compared to monotherapy 1
• Adverse event rates similar between combination and monotherapy groups 1

Critical Clinical Caveats

When to Continue Despite Decline:

• Continue donepezil or memantine if there has been clinically meaningful reduction in neuropsychiatric symptoms, even with cognitive and functional decline 1, 2

When to Consider Discontinuation:

• Clinically meaningful worsening over 6 months without other contributing factors 1, 2
• No clinical benefit observed during treatment 1, 2
• Progression to severe or end-stage dementia with dependence in most basic activities of daily living 1
• Use gradual discontinuation: reduce dose by 50% every 4 weeks until reaching initial starting dose 1

Common Pitfall to Avoid: Do not confuse donepezil's initial transient agitation (resolves within weeks) with sustained anxiety worsening 7. If agitation persists beyond the first few weeks, consider other factors such as disease progression or environmental stressors rather than attributing it solely to the medication 7.