What are the recommended dosing and titration guidelines for donepezil and memantine in moderate-to-severe Alzheimer’s disease?

Donepezil and Memantine for Alzheimer's Disease

Donepezil Dosing and Titration

Start donepezil at 5 mg once daily in the evening, just prior to retiring, and increase to 10 mg once daily after 4-6 weeks if well tolerated. 1, 2

• Take donepezil with food to minimize gastrointestinal side effects (nausea, vomiting, diarrhea), which occur with relative risks of 2.54,2.57, and 3.21 respectively at 10 mg versus 5 mg 1, 2
• The 10 mg dose provides superior cognitive and functional benefits compared to 5 mg, though average improvements do not reach the 4-point ADAS-cog threshold considered clinically significant 3, 1
• Benefits on cognitive function and activities of daily living can be maintained for approximately 21-81 weeks with donepezil 10 mg/day 1, 4
• An assessment period of 6-12 months is necessary to adequately evaluate treatment response using physician global assessment, caregiver reports, and functional/behavioral changes—not just brief mental status tests like MMSE 2, 5

Memantine Dosing and Titration

For moderate-to-severe Alzheimer's disease (MMSE 5-19), start memantine at 5 mg once daily and increase by 5 mg weekly in divided doses to reach the target of 20 mg/day (10 mg twice daily). 5

• In severe renal impairment (creatinine clearance ≈30 mL/min), reduce the target dose to 5 mg twice daily (10 mg/day total) 5
• Memantine at 20 mg/day shows statistically significant improvement in cognition for moderate-to-severe Alzheimer's disease 3, 5
• Common adverse effects include nausea, dizziness, diarrhea, and agitation, with discontinuation rates of 9-12% (comparable to placebo at 7-13%) 5

Combination Therapy: When and How

For patients with moderate-to-severe Alzheimer's disease who continue to decline after 3-6 months on donepezil monotherapy, add memantine while continuing donepezil. 2, 5

• Combination therapy produces statistically significant improvements over donepezil alone: approximately 3.4 points on the Severe Impairment Battery (cognition) and 1.4 points on activities-of-daily-living scales 5, 6
• The combination reduces marked clinical worsening (concurrent deterioration in cognition, function, and global status) from 20.4% to 8.7% in moderate-to-severe disease 6
• Combination therapy does not increase serious adverse events relative to either agent alone 5, 6
• Continue donepezil at 10 mg/day while titrating memantine to 20 mg/day; reassess response after 6-12 months of combination therapy 5

Evidence Quality and Magnitude of Benefit

• Donepezil has high-quality evidence from 24 studies showing statistically significant but modest improvements—approximately 20-35% of patients achieve clinically meaningful improvement, roughly equivalent to delaying cognitive decline by one year 3, 5
• In the DOMINO-AD trial, continuing donepezil in moderate-to-severe disease produced a 1.9-point improvement on SMMSE and 3.0-point advantage on functional scales compared to discontinuation, exceeding the minimum clinically important difference 5, 7
• Meta-analyses confirm combination therapy benefits in cognition (effect size 0.36-0.38), behavioral symptoms (effect size -0.88 to -0.91), and global function (effect size -0.59) 8, 6

Common Pitfalls to Avoid

• Do not prescribe donepezil for mild cognitive impairment—evidence shows no significant benefit in this population 1, 2
• Do not switch between cholinesterase inhibitors without cause—no convincing evidence demonstrates superiority of one over another; switching is only reasonable for intolerance 2, 5
• Do not discontinue donepezil prematurely in moderate-to-severe disease—continued treatment provides cognitive benefits exceeding clinically important thresholds 5, 7
• Do not expect dramatic improvement—realistic expectations include slowing decline or stabilization, not reversal of dementia 2, 5
• Do not start at high doses—gradual titration over 4-6 weeks improves tolerability and minimizes cholinergic side effects 1, 2
• Initial agitation may occur with donepezil but typically subsides after the first few weeks 2