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 cognitive decline on donepezil monotherapy (MMSE decreased from 25 to 23 over 6 months), the best medication adjustment is to add memantine while continuing donepezil (Option B). 1, 2, 3

Rationale for Combination Therapy

• Combination therapy with donepezil plus memantine is explicitly recommended by the American Academy of Neurology for patients who continue to decline on cholinesterase inhibitor monotherapy, representing an evidence-based approach to slowing cognitive decline 2

• 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 2, 3

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

Evidence Supporting This Approach

• FDA-approved clinical trials demonstrate that adding memantine to stable donepezil therapy provides additional benefit in moderate to severe Alzheimer's disease, with statistically significant improvements in cognition (mean difference 3.3 units on SIB) and activities of daily living (mean difference 1.6 units on ADCS-ADL) at 24 weeks 4

• Combination therapy 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

• 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

Why Not the Other Options

Why Not Switch to Rivastigmine (Option D)

• There is no convincing evidence that one cholinesterase inhibitor is more effective than another, making switching between them unsupported by guidelines as a first-line strategy for non-responders 5, 2, 3

• Switching means losing any residual benefit from donepezil, and rivastigmine has higher rates of adverse events, particularly nausea 3

• Switching between cholinesterase inhibitors is only reasonable if the patient cannot tolerate the current medication, which is not the case here 2

Why Not Switch Donepezil to Memantine (Option C)

• Discontinuing donepezil removes a proven therapeutic benefit in a patient who is tolerating the medication 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

Why Not Add Sertraline (Option A)

• Sertraline 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

• The clinical scenario describes cognitive decline (decreased MMSE), not depression or behavioral symptoms 5

Clinical Implementation

• 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) 4

• The full therapeutic dose of 20 mg/day should be the goal unless side effects prevent titration 2

• Assess response over 6-12 months, as this observation period is necessary to evaluate potential benefit 2, 3

Expected Outcomes

• Realistic expectations include slowing decline rather than reversing it, with stabilization or slower deterioration constituting success 2

• Memantine shows statistically significant improvement in cognition scores for moderate to severe Alzheimer's disease, with benefits on global assessment, quality of life, and caregiver burden 3

• Withdrawal rates for memantine are 9-12%, similar to placebo (7-13%), with adverse events including nausea, dizziness, diarrhea, and agitation 1, 3

Common Pitfalls to Avoid

• Avoid premature discontinuation of treatment, as some patients may require up to 12 months to demonstrate benefit 2

• Avoid inadequate dosing of memantine—the goal is reaching the full 20 mg/day dose for maximum therapeutic benefit 2

• Do not discontinue donepezil in a patient who is tolerating it, as this removes established therapeutic benefit 2