What are the indications, dosing regimens, and side‑effects of donepezil and memantine for treating Alzheimer‑type dementia?

Donepezil and Memantine for Alzheimer's Disease

Donepezil is a cholinesterase inhibitor indicated for mild-to-moderate Alzheimer's disease, started at 5 mg nightly and increased to 10 mg after 4–6 weeks; memantine is an NMDA receptor antagonist reserved for moderate-to-severe disease, typically added to donepezil at a target dose of 20 mg/day when patients continue to decline on cholinesterase inhibitor monotherapy. 1, 2

Indications by Disease Severity

Mild-to-Moderate Alzheimer's Disease (MMSE 10–26)

• Start donepezil monotherapy at 5 mg once daily in the evening, taken with food to minimize gastrointestinal side effects. 2, 3
• Increase to 10 mg daily after 4–6 weeks if tolerated; the higher dose provides greater cognitive and functional benefit, equivalent to delaying decline by approximately one year. 2, 3
• Approximately 20–35% of patients achieve clinically meaningful improvement (≥7-point gain on neuropsychological tests), while others experience stabilization rather than continued worsening. 3

Moderate-to-Severe Alzheimer's Disease (MMSE 5–19)

• Continue donepezil and add memantine when patients decline despite optimized donepezil therapy (10 mg/day for ≥3 months). 1, 2
• Combination therapy produces additional improvements of approximately 3.4 points on cognitive scales and 1.4 points on activities-of-daily-living measures compared to donepezil alone. 1, 4
• The American Academy of Neurology and American College of Physicians both recommend combination therapy as the evidence-based approach for moderate-to-severe disease. 1, 2

Dosing Regimens

Donepezil

• Initial dose: 5 mg once daily in the evening with food. 2, 3
• Titration: Increase to 10 mg daily after 4–6 weeks if well tolerated. 2
• Maintenance: Continue 10 mg daily; efficacy has been maintained for up to 4.9 years. 3
• No hepatic monitoring required (unlike tacrine, donepezil is not hepatotoxic). 2, 3

Memantine

• Initial dose: 5 mg once daily. 2
• Titration: Increase by 5 mg weekly in divided doses until reaching the target of 20 mg/day (10 mg twice daily). 2
• Renal adjustment: Reduce target to 10 mg/day (5 mg twice daily) in severe renal impairment (creatinine clearance ≈30 mL/min). 2
• Discontinuation: If stopping, taper by reducing dose 50% every 4 weeks. 1

Side Effects and Safety Profile

Donepezil

• Gastrointestinal effects (most common): nausea, vomiting, diarrhea, anorexia—occur more frequently with 10 mg dose (2.5–3.2-fold higher risk) but can be minimized by taking with food. 1, 2
• Cardiac effects: bradycardia may occur; assess for pre-existing conduction abnormalities before starting. 2
• Neuropsychiatric effects: nightmares have been reported; initial agitation may occur in the first few weeks but typically resolves. 1, 2
• Withdrawal rates: 5–20% discontinue due to adverse effects, comparable to placebo rates of 7–13%. 2
• No serious adverse events beyond expected cholinergic effects when compared to placebo. 2

Memantine

• Common side effects: nausea, dizziness, diarrhea, headache—occur at rates similar to placebo. 1
• Agitation: Although listed as a potential side effect, memantine actually reduces agitation compared to placebo in clinical trials. 1
• Withdrawal rates: 9–12% discontinue due to adverse effects, comparable to placebo rates of 7–13%. 1
• Combination therapy: Adding memantine to donepezil does not increase serious adverse events compared to monotherapy. 1, 4

Monitoring and Assessment Timeline

Initial Evaluation (Before Starting Treatment)

• Exclude reversible causes: delirium (infection, metabolic disturbance), major depression, anticholinergic medication effects. 2
• Document baseline cognitive function using validated instruments (ADAS-Cog, MMSE, or MoCA). 2
• Record baseline functional ability using ADL scales (IADL or ADCS-ADL). 2
• Obtain caregiver input regarding behavioral symptoms and functional changes. 2

Response Assessment

• Early assessment: Evaluate at 4–6 weeks for tolerability and dose titration. 2
• Full efficacy evaluation: Conduct comprehensive assessment at 6–12 months using physician global impression, caregiver reports, and detailed cognitive testing. 2, 3
• Do not rely solely on brief mental-status tests (e.g., MMSE), as they are relatively insensitive to treatment effects; incorporate caregiver-reported functional and behavioral changes. 2

Continuation Criteria

• Continue therapy when cognitive function stabilizes or declines more slowly than the pre-treatment trajectory. 2
• Continue when caregivers report stable or improved activities of daily living and manageable behavioral symptoms. 2
• For patients with neuropsychiatric symptoms (psychosis, agitation, aggression), continue memantine if there has been clinically meaningful reduction in these symptoms, even with cognitive and functional decline. 1

Discontinuation Criteria

• Stop if intolerable side effects persist despite dose adjustment. 2
• Stop if decline continues at the pre-treatment rate after 6–12 months without other contributing factors. 1, 2
• Stop if the patient progresses to severe or end-stage dementia with dependence in most basic activities of daily living. 1

Common Pitfalls and How to Avoid Them

Premature Discontinuation

• Do not stop donepezil before 6–12 months unless side effects are intolerable; some patients require up to 12 months to demonstrate benefit. 2
• Beneficial effects typically become apparent within 3 months, but full assessment requires longer observation. 2

Inadequate Dose Titration

• Do not remain on donepezil 5 mg indefinitely; attempt escalation to 10 mg after 4–6 weeks when tolerated, as the higher dose provides greater benefit. 2
• Ensure memantine reaches the full 20 mg/day target (or 10 mg/day in severe renal impairment) for optimal therapeutic effect. 2

Switching Between Cholinesterase Inhibitors

• Do not switch from donepezil to another cholinesterase inhibitor (rivastigmine or galantamine) as a first-line strategy for non-responders; no evidence demonstrates superiority of one agent over another. 1, 2
• Switching is reasonable only when the patient cannot tolerate the current medication. 2

Adding a Second Cholinesterase Inhibitor

• Do not add a second cholinesterase inhibitor to donepezil; this is not evidence-based and would increase cholinergic side effects without additional benefit. 1
• When patients fail to respond to donepezil after 3–6 months, the correct escalation is to add memantine, not another cholinesterase inhibitor. 1, 2

Over-Reliance on Brief Cognitive Tests

• Do not use MMSE scores alone to assess treatment response; incorporate comprehensive functional assessments and caregiver reports of behavioral changes. 2

Unrealistic Expectations

• Counsel patients and caregivers that these medications slow decline rather than reverse dementia; stabilization or slower deterioration constitutes treatment success. 2, 3
• The overall effect is comparable to delaying cognitive decline by approximately one year. 3

Special Considerations

Neuroimaging

• Structural brain imaging (CT or MRI) is recommended but not an absolute prerequisite for starting donepezil; its primary purpose is to detect treatable lesions (subdural hematoma, tumor, normal-pressure hydrocephalus). 2
• Do not delay symptomatic therapy awaiting imaging when acute reversible causes have been clinically excluded. 2
• Expedite imaging when focal neurological deficits, recent head trauma, new severe headache, seizures, or anticoagulation/bleeding risk are present. 2

Drug Interactions

• Monitor closely when donepezil is combined with cimetidine, theophylline, warfarin, or digoxin. 2
• Assess for cardiac conduction abnormalities (sick-sinus syndrome, significant bradycardia), as cholinesterase inhibitors can exacerbate bradyarrhythmias. 2

Behavioral Symptoms

• Implement non-pharmacologic interventions (predictable routines, environmental simplification, use of calendars/clocks) alongside medication. 2
• If agitation persists beyond 3–4 weeks, exhaust non-pharmacologic strategies before considering antipsychotic medication. 2