Should donepezil (cholinesterase inhibitor) or memantine (N-methyl-D-aspartate receptor antagonist) be started first in a patient with Alzheimer's disease?

Start with Donepezil as First-Line Treatment

For patients with newly diagnosed Alzheimer's disease, initiate treatment with a cholinesterase inhibitor (donepezil) rather than memantine, regardless of disease severity. Memantine is reserved for moderate to severe disease and is typically added to cholinesterase inhibitor therapy rather than used as initial monotherapy.

Treatment Algorithm by Disease Severity

Mild to Moderate Alzheimer's Disease

• Start donepezil 5 mg once daily in the evening 1, 2
• Increase to 10 mg daily after 4-6 weeks if tolerated 2
• Donepezil demonstrates clinically meaningful improvements in cognition and global function, with efficacy maintained for up to 4.9 years 1
• Approximately 20-35% of patients show a 7-point improvement on neuropsychologic tests, equivalent to reversing one year's decline 1

Moderate to Severe Alzheimer's Disease

• Still initiate with donepezil first using the same dosing schedule (5 mg for 4-6 weeks, then 10 mg) 2
• Add memantine after establishing donepezil therapy 3
• Combination therapy (donepezil plus memantine) shows superior outcomes compared to cholinesterase inhibitor monotherapy in moderate to severe disease 3
• Consider increasing donepezil to 23 mg daily after at least 3 months on 10 mg for additional benefit in moderate to severe disease 2

Why Donepezil First

Cholinesterase inhibitors are the drug class with the best evidence of efficacy and represent first-line treatment across all stages of Alzheimer's disease 1, 4. The rationale includes:

• Donepezil is approved and effective for mild to moderate disease, where memantine lacks strong evidence 1
• Memantine's primary indication is moderate to severe disease, typically as add-on therapy 3
• Direct comparisons show cholinesterase inhibitors have broader applicability across disease stages 1

Memantine's Role

Memantine should be considered as:

• Add-on therapy to donepezil in moderate to severe disease for enhanced cognitive and functional benefits 3
• Particularly beneficial when neuropsychiatric symptoms (psychosis, agitation, aggression) are prominent 3
• Monotherapy only if cholinesterase inhibitors are contraindicated or not tolerated 1

Practical Dosing Considerations

Donepezil administration:

• Take in the evening, just prior to retiring 2
• Can be taken with or without food 2
• Taking with food reduces gastrointestinal side effects (nausea, vomiting, diarrhea) 1
• Initial agitation may occur but typically subsides after the first few weeks 1

Common pitfall: Advancing donepezil dose too quickly increases cholinergic side effects. The 4-6 week interval between 5 mg and 10 mg doses minimizes adverse events 2, 5.

Safety Profile

• Donepezil is not hepatotoxic, unlike tacrine 1, 6
• Adverse effects are mild, transient, and primarily cholinergic (gastrointestinal and nervous system) 6, 7
• No dose adjustment needed for elderly patients or those with renal/hepatic impairment 7
• Serious adverse event rates similar to placebo (4-10% vs 5-9%) in short-term trials 6

When to Add Memantine

Add memantine to ongoing donepezil therapy when:

• Disease progresses to moderate or severe stage (MMSE 5-13 or lower) 4
• Neuropsychiatric symptoms emerge or worsen 3
• Cognitive decline continues despite optimal donepezil dosing 3

The combination is well-tolerated and provides additive benefits in cognition, daily functioning, and behavioral symptoms 3.