What is the best next step for a patient with Alzheimer's disease who has not shown improvement on donepezil (an acetylcholinesterase inhibitor) for three months?

Management of Alzheimer's Disease Not Responding to Donepezil Monotherapy

For a patient with Alzheimer's disease who has not improved after three months on donepezil, add memantine while continuing donepezil (Option B). 1, 2

Rationale for Adding Memantine to Donepezil

Three months is the appropriate timeframe to assess response to cholinesterase inhibitors, and beneficial effects are generally observed within this period. 1, 2 When a patient continues to decline on donepezil monotherapy, adding memantine represents an evidence-based escalation strategy rather than abandoning proven therapy. 2

Combination therapy with donepezil plus memantine is explicitly recommended by guidelines as "rational and safe" for patients who continue to decline on cholinesterase inhibitor monotherapy, with the goal of slowing cognitive decline. 1, 2

Evidence Supporting Combination Therapy

• The FDA label demonstrates that adding memantine to stable donepezil therapy in patients with moderate to severe Alzheimer's disease produces statistically significant improvements in both cognition (SIB score difference of 3.3 units) and activities of daily living (ADCS-ADL difference of 1.6 units) compared to donepezil alone at 24 weeks. 3

• Combination therapy produces significantly better outcomes than donepezil monotherapy across all domains, with improvements in neuropsychiatric symptoms and reduced caregiver distress particularly at 12 weeks of treatment. 4

• The combination is well-tolerated with no significant increase in serious adverse events compared to monotherapy. 4

Why Not the Other Options?

Option A (Add Sertraline) - Incorrect

Sertraline addresses depression, not the core cognitive and functional decline of Alzheimer's disease, and there is no evidence that adding an antidepressant improves cognitive outcomes in patients not responding to cholinesterase inhibitors unless behavioral symptoms or mood disorders are specifically present. 1, 2 Additionally, SSRIs carry a small but increased risk of intracerebral hemorrhage. 2

Option C (Switch to Memantine Alone) - Incorrect

Discontinuing donepezil that the patient is tolerating removes a proven therapeutic benefit. 2 Continuing donepezil while adding memantine is superior to memantine alone, with strong evidence demonstrating that patients with moderate to severe Alzheimer's disease benefit from continued donepezil treatment, with cognitive benefits exceeding the minimum clinically important difference. 1, 2 The landmark DOMINO-AD trial showed that patients who continued donepezil had MMSE scores that were 1.9 points higher and functional scores (BADLS) that were 3.0 points better compared to those who discontinued donepezil. 5

Option D (Switch to Rivastigmine) - Incorrect

There is no convincing evidence that one cholinesterase inhibitor is more effective than another, and switching between cholinesterase inhibitors is not supported by guidelines as a first-line strategy for non-responders. 1, 2 Switching is only reasonable if the patient cannot tolerate the current medication. 1

Practical Implementation

• Continue donepezil at the current dose (typically 10 mg/day) throughout memantine titration. 2

• Initiate memantine at 5 mg once daily and increase weekly by 5 mg/day in divided doses to reach the target dose of 20 mg/day (10 mg twice daily). 1, 3

• The full 20 mg/day dose of memantine is necessary for optimal therapeutic effect when combined with donepezil. 1, 2

• For patients with severe renal impairment (creatinine clearance ≈30 mL/min), reduce the target dose to 5 mg twice daily (10 mg/day total). 1

Assessment and Follow-Up

• Reassess response after 6-12 months of combination therapy using physician global assessment, caregiver reports, and evidence of behavioral or functional changes. 1, 2

• Realistic expectations should be set: treatment aims to slow decline rather than reverse it—stabilization or slower deterioration constitutes success. 1, 2

Common Pitfalls to Avoid

• Avoid premature discontinuation, as some patients may require up to 12 months to demonstrate benefit from combination therapy. 1, 2

• Avoid inadequate dosing—ensure memantine reaches the full 20 mg/day dose unless side effects prevent titration. 1, 2

• Monitor for side effects: Common adverse events with memantine include headaches, dizziness, confusion, and falls, though combination therapy is generally well tolerated. 2 Withdrawal rates due to adverse effects with memantine range from 9-12%, similar to placebo. 4

• Do not discontinue cholinesterase inhibitors in individuals who currently have clinically meaningful psychotic symptoms, agitation, or aggression until these symptoms have stabilized. 6