What is the best medication adjustment for a geriatric patient with Alzheimer's disease (AD) who is not improving on donepezil (a cholinesterase inhibitor), as evidenced by a decreased Mini-Mental Status Examination (MMSE)?

Add Memantine to Donepezil

For a patient with Alzheimer's disease showing continued decline on donepezil (evidenced by decreasing MMSE), the best medication adjustment is to add memantine while continuing donepezil (Option B). 1, 2

Rationale for Adding Memantine

The American Academy of Neurology explicitly recommends combination therapy with donepezil plus memantine for patients who continue to decline on cholinesterase inhibitor monotherapy. 1 This represents an evidence-based approach to slowing cognitive decline in patients not responding adequately to monotherapy. 1

• The American College of Physicians confirms that beneficial effects of cholinesterase inhibitors are generally observed within 3 months, making this an appropriate timeframe to assess response and escalate therapy. 3, 2

• Continuing donepezil while adding memantine is superior to switching to memantine alone because discontinuing a cholinesterase inhibitor that the patient is tolerating removes a proven therapeutic benefit. 1, 2

Evidence Supporting Combination Therapy

Combination therapy with donepezil and memantine produces significant benefits on global clinical status measures and improvements in neuropsychiatric symptoms, with reduced caregiver distress particularly evident at 12 weeks of treatment. 1, 4

• FDA-approved clinical trials demonstrate that adding memantine to stable donepezil therapy provides additional benefit in patients with moderate to severe Alzheimer's disease, with a mean difference of 3.3 units on the Severe Impairment Battery (SIB) and 1.6 units on the ADCS-ADL scale at 24 weeks. 5

• The combination is well-tolerated with no significant increase in serious adverse events, and adverse event rates are similar between combination therapy and monotherapy groups. 1, 4

Why Not the Other Options

Switching donepezil to rivastigmine (Option D) is not supported as a first-line strategy for non-responders. 2 There is no convincing evidence that one cholinesterase inhibitor is more effective than another, and switching between them is only reasonable if the patient cannot tolerate the current medication. 3, 2

• While one study showed that some patients who failed donepezil responded to rivastigmine, this was an open-label trial without placebo control, and switching should only be considered after combination therapy has been attempted. 6

Switching donepezil to memantine (Option C) removes the established benefit of the cholinesterase inhibitor. 1, 2 Strong evidence demonstrates that patients with moderate to severe Alzheimer's disease benefit from continued donepezil treatment, with cognitive benefits exceeding the minimum clinically important difference. 2

Adding sertraline (Option A) addresses depression, not the core cognitive and functional decline of Alzheimer's disease. 2 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. 2

Implementation Strategy

Start 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). 5 The full therapeutic dose should be the goal unless side effects prevent titration. 1

• Continue donepezil at the current dose (typically 10 mg/day) while adding memantine. 2, 5

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

Expected Outcomes and Timeline

Realistic expectations include slowing decline rather than reversing it, with stabilization or slower deterioration constituting success. 1, 2 Some patients may require up to 12 months to demonstrate benefit. 1

• Combination therapy shows improvements in cognition, daily functioning, and behavioral symptoms in patients with moderate to severe Alzheimer's disease. 4

• Benefits on global assessment, quality of life, and caregiver burden have been demonstrated with memantine. 3

Common Pitfalls to Avoid

Avoid premature discontinuation of treatment, as some patients may require up to 12 months to demonstrate benefit. 1 An assessment period of 6-12 months is necessary to evaluate potential benefit. 3, 2

Avoid inadequate dosing of memantine—the goal is reaching the full 20 mg/day dose for maximum therapeutic benefit. 1, 2 Withdrawal rates due to adverse effects with memantine are only 9-12% in treatment groups, similar to placebo (7-13%). 3, 4

Do not discontinue donepezil in a patient who is tolerating it, as this removes established therapeutic benefit. 1, 2 The FDA label demonstrates that discontinuation of donepezil results in loss of treatment effect within 6 weeks. 7