What are Aricept (donepezil) and memantine used for in Alzheimer-type dementia?

Indications for Aricept (Donepezil) and Memantine in Dementia

Aricept (donepezil) is used to improve cognition and function in mild to moderate Alzheimer's disease, while memantine is used for moderate to severe Alzheimer's disease, and combining both medications provides superior outcomes in moderate to severe disease compared to either drug alone. 1

Donepezil (Aricept) - Mild to Moderate Alzheimer's Disease

Primary indication: Donepezil is the first-line treatment for mild to moderate Alzheimer's disease, demonstrating consistent evidence of improving cognition and global function. 1

Cognitive Benefits

• Produces an average cognitive benefit of 2.02 points on ADAS-cog at 24 weeks with the 5 mg dose and 2.92 points with the 10 mg dose. 1
• These improvements represent statistically significant and clinically meaningful changes in cognitive function. 1

Dosing Strategy

• Start with 5 mg once daily in the evening, taken with food, to minimize side effects. 1, 2
• Increase to 10 mg daily after 4-6 weeks if the initial dose is tolerated. 1
• Taking with food reduces gastrointestinal and potentially behavioral side effects. 2

Common Side Effects

• Primarily gastrointestinal effects: nausea, vomiting, diarrhea, and anorexia, more common with the 10 mg dose. 1
• May cause initial increase in agitation in some patients, but this typically subsides after a few weeks and should not be confused with sustained anxiety worsening. 2
• Low withdrawal rates due to adverse effects overall. 1

Memantine - Moderate to Severe Alzheimer's Disease

Primary indication: Memantine is indicated for moderate to severe Alzheimer's disease, where it improves cognition, global assessment, and behavioral symptoms. 1, 3

Cognitive and Functional Benefits

• Produces statistically significant improvements on the Severe Impairment Battery (SIB) and CIBIC-plus scale for patients with moderate to severe disease. 1
• Achieves approximately 2-3 points improvement on the SIB (0-100 scale) versus placebo. 3
• Shows particular benefit for quality of life, with less agitation reported compared to placebo. 1

Behavioral Symptom Management

• Significantly reduces the frequency of agitation compared to placebo across multiple randomized trials. 1
• This agitation-reducing effect has been confirmed in multiple independent studies. 1

Safety Profile

• Well tolerated both as monotherapy and in combination with donepezil. 1, 3
• Withdrawal rates due to adverse effects are 9-12% in treatment groups, comparable to placebo rates of 7-13%. 1, 3
• Common side effects include nausea, dizziness, diarrhea, and headache, but these do not lead to higher discontinuation than placebo. 1

Important Limitation

• Not recommended for mild to moderate Alzheimer's disease, as it shows no significant improvement in activities of daily living or behavioral symptoms in this population, with minimal cognitive gain. 3

Combination Therapy - Moderate to Severe Alzheimer's Disease

For moderate to severe Alzheimer's disease, combination therapy with both donepezil and memantine produces significantly better outcomes than donepezil monotherapy across all domains. 1

Superior Efficacy Evidence

• Adding memantine to stable donepezil therapy provides additional cognitive benefit with a standardized mean difference of 0.36. 1, 4
• Combination therapy produces significant improvements in cognition, daily functioning, and behavioral symptoms compared to donepezil alone. 1, 5
• Shows improvements in neuropsychiatric symptoms and reduced caregiver distress, particularly at 12 weeks of treatment. 1

Clinical Worsening Prevention

• Significantly fewer patients on combination therapy show marked clinical worsening (concurrent deterioration in cognition, function, and behavior) compared to monotherapy. 4
• In moderate to severe disease: 8.7% with combination versus 20.4% with donepezil alone showed marked worsening (p = 0.0002). 4
• In moderate disease: 5.9% with combination versus 15.0% with donepezil alone showed marked worsening (p = 0.006). 4

Safety of Combination

• Well-tolerated with no significant increase in serious adverse events compared to monotherapy. 1, 4
• Adverse event rates are similar between combination therapy and monotherapy groups. 1

Treatment Monitoring and Discontinuation

Assessment Timeline

• Assess response at 12 and 24 weeks using cognitive measures and functional assessments. 1

When to Consider Discontinuation

• Clinically meaningful worsening of dementia over 6 months without other contributing factors. 1
• No clinical benefit observed during treatment. 1
• Progression to severe or end-stage dementia with dependence in most basic activities of daily living. 1

Discontinuation Method

• Use a gradual approach, reducing dose by 50% every 4 weeks until reaching the initial starting dose. 1

Exception for Behavioral Symptoms

• Continue memantine if there has been clinically meaningful reduction in neuropsychiatric symptoms (psychosis, agitation, aggression), even with cognitive and functional decline. 1

Common Pitfalls to Avoid

• Do not add a second cholinesterase inhibitor to donepezil - this is not evidence-based and would increase cholinergic side effects without additional benefit. 1
• Do not use memantine for mild to moderate disease unless combined with a cholinesterase inhibitor in moderate disease. 3
• Do not attribute initial agitation with donepezil to treatment failure - counsel patients and caregivers that this typically resolves within the first few weeks. 2
• Do not use sertraline for cognitive decline in Alzheimer's disease - there is no evidence to support its use in this context. 1