What is the next best step in management for a patient with Alzheimer's disease, on donepezil (a cholinesterase inhibitor) for 6 months with no improvement, a decline in Mini-Mental State Examination (MMSE) score from 19 to 12, and hippocampus atrophy on Magnetic Resonance Imaging (MRI)?

Add Memantine to Donepezil

For this patient with moderate-to-severe Alzheimer's disease (MMSE 12) who has progressed despite 6 months of donepezil therapy, the next best step is to add memantine while continuing donepezil (Option B). This combination therapy approach is supported by the highest quality evidence for patients transitioning from moderate to severe disease.

Rationale for Combination Therapy

Disease Severity Assessment

• The patient's MMSE decline from 19 to 12 indicates progression from moderate to moderate-severe Alzheimer's disease 1
• Hippocampal atrophy on MRI confirms neurodegenerative progression 2
• This clinical trajectory represents the critical transition point where combination therapy demonstrates superior outcomes 1

Evidence for Adding Memantine

Continuation of donepezil is essential. The DOMINO-AD trial, a landmark 52-week randomized controlled study of 295 patients with moderate-to-severe Alzheimer's disease (MMSE 5-13), demonstrated that patients who continued donepezil had SMMSE scores 1.9 points higher and functional scores (BADLS) 3.0 points better compared to those who discontinued donepezil—both exceeding minimum clinically important differences 3

Adding memantine provides additional benefit. In the same trial, patients receiving memantine had SMMSE scores 1.2 points higher and functional scores 1.5 points better than placebo 3. The FDA label confirms that combination therapy (memantine added to stable donepezil) in moderate-to-severe patients showed mean differences of 3.3 units on the SIB and 1.6 units on ADCS-ADL compared to donepezil monotherapy at 24 weeks 4

Combination therapy is superior to monotherapy. Guidelines from the American Academy of Neurology and American Geriatrics Society specifically recommend combination therapy with donepezil and memantine for moderate-to-severe Alzheimer's disease, as this produces significantly better outcomes than donepezil monotherapy across all domains 1

Why Not the Other Options

Option A (Add Sertraline) - Incorrect

• Sertraline is not indicated for cognitive decline in Alzheimer's disease 5
• There is no evidence of depression or behavioral symptoms requiring antidepressant therapy in this case 1

Option C (Add Rivastigmine) - Incorrect

• Adding a second cholinesterase inhibitor to donepezil is not evidence-based and would increase cholinergic side effects without additional benefit 5
• Switching between cholinesterase inhibitors is only considered when patients fail to respond to or cannot tolerate the first agent 5

Option D (Switch to Memantine Monotherapy) - Incorrect

• The DOMINO-AD trial definitively showed that discontinuing donepezil resulted in significantly worse cognitive (1.9 points lower SMMSE) and functional outcomes (3.0 points worse BADLS) 3
• Memantine monotherapy is less effective than combination therapy for patients already on donepezil 1, 4

Implementation Strategy

Dosing Protocol

• Continue donepezil at current dose (likely 10 mg/day) 1
• Initiate memantine at 5 mg once daily 4
• Titrate memantine by 5 mg/day weekly in divided doses to target of 20 mg/day (10 mg twice daily) 4

Expected Outcomes

• Cognitive stabilization or slower decline on standardized measures 4, 3
• Improved or maintained activities of daily living 4, 3
• Potential reduction in behavioral symptoms, particularly agitation 1

Safety Considerations

• Memantine adverse effects: Withdrawal rates of 9-12% (similar to placebo), with common effects including nausea, dizziness, diarrhea, and agitation 1
• Combination therapy tolerability: Well-tolerated with no significant increase in serious adverse events compared to monotherapy 1
• Donepezil side effects: Continue monitoring for gastrointestinal effects (nausea, vomiting, diarrhea), which can be minimized by taking with food 5, 6

Monitoring and Duration

• Assess response at 12 and 24 weeks using cognitive measures and functional assessments 5, 3
• Continue treatment as long as clinically meaningful benefit persists 1
• Consider discontinuation only if clinically meaningful worsening occurs over 6 months without other contributing factors, or if progression to severe/end-stage dementia with dependence in most basic ADLs 1