Should Memantine and Donepezil Be Continued in Severe Dementia?
Yes, both memantine and donepezil should generally be continued in severe dementia, as continuation provides clinically meaningful cognitive and functional benefits that exceed minimum clinically important differences, though specific discontinuation criteria should guide individual decisions. 1
Evidence for Continuation in Severe Disease
Donepezil in Severe Dementia
The landmark DOMINO-AD trial demonstrated that continuing donepezil in patients with moderate to severe Alzheimer's disease (SMMSE scores 5-13) resulted in cognitive benefits of 1.9 points on the SMMSE and functional benefits of 3.0 points on the BADLS compared to discontinuation—both exceeding minimum clinically important differences (1.4 and 3.5 points respectively). 1 This represents robust evidence that donepezil maintains efficacy even as disease progresses to severe stages.
Additional evidence from extremely severe AD patients (MMSE 0-5) showed that continuation of donepezil resulted in a 0.4-point improvement versus a 0.5-point decline with discontinuation, suggesting benefit persists even in the most advanced stages. 2
Memantine in Severe Dementia
Memantine demonstrates statistically significant improvements in cognition (SIB), global assessment (CIBIC-Plus), and quality of life in moderate to severe AD, with particular benefits for reducing agitation. 3 The DOMINO-AD trial found memantine provided an additional 1.2-point benefit on SMMSE and 1.5-point benefit on BADLS when added to existing therapy. 1
Combination Therapy
The combination of memantine plus donepezil shows superior outcomes compared to either agent alone in moderate to severe disease, with significant improvements in cognition, daily functioning, and behavioral symptoms. 3 International guidelines from the US, China, and Japan (though not the UK) specifically recommend combination therapy for severe AD. 4
Specific Discontinuation Criteria
The 5th Canadian Consensus Conference provides clear guidance on when to discontinue these medications. 4
Discontinue Cholinesterase Inhibitors (including donepezil) if:
Clinically meaningful worsening of dementia over 6 months (changes in cognition, functioning, or global assessment) without other contributing factors like delirium or environmental changes 4
No clinically meaningful benefit observed at any time during treatment (no improvement, stabilization, or decreased rate of decline) 4
Severe or end-stage dementia defined as dependence in most basic activities of daily living, inability to respond to environment, or limited life expectancy 4
Intolerable side effects such as severe nausea, vomiting, weight loss, anorexia, or falls 4
Poor medication adherence that precludes safe use or prevents assessment of effectiveness 4
Discontinue Memantine if:
The same criteria apply as for cholinesterase inhibitors, with specific side effects including confusion, dizziness, and falls. 4
Critical Exception: Neuropsychiatric Symptoms
Do not discontinue cholinesterase inhibitors in patients with clinically meaningful psychotic symptoms, agitation, or aggression until these symptoms stabilize, unless the symptoms were worsened by the medication itself. 4
Patients who have experienced clinically meaningful reduction in neuropsychiatric symptoms (especially psychosis) with cognitive enhancers should continue treatment even if cognitive and functional decline is evident. 4 This represents a crucial clinical decision point where behavioral benefits outweigh cognitive trajectory.
Deprescribing Protocol When Indicated
If discontinuation is warranted based on the above criteria:
- Reduce dose by 50% every 4 weeks until reaching the initial starting dose 4
- After 4 weeks at starting dose, discontinue completely 4
- Reinitiate treatment if clinically meaningful worsening occurs that appears related to cessation 4
This gradual approach minimizes risk of precipitous decline.
Dosing Considerations in Severe Disease
Low-dose donepezil (5 mg/day) combined with memantine provides similar efficacy to high-dose donepezil (10 mg/day) with memantine for behavioral symptoms, cognition, and daily living abilities, but with significantly better sleep quality, quality of life, and lower adverse event rates (11.11% vs 27.87%). 5 This suggests that in severe disease, lower donepezil doses may optimize the risk-benefit ratio when combined with memantine.
Common Pitfalls to Avoid
Do not automatically discontinue medications when patients progress to severe dementia—the evidence shows continued benefit even in MMSE 0-5 range 2
Do not discontinue during acute behavioral crises—wait until neuropsychiatric symptoms stabilize before considering deprescribing 4
Do not abruptly stop medications—always use gradual dose reduction protocol to avoid rebound decline 4
Do not use mild cognitive impairment as an indication for continuation—these medications should be deprescribed in MCI 4
Quality of Evidence
The DOMINO-AD trial 1 represents the highest quality evidence for this question: a large (295 patients), multicenter, double-blind, randomized controlled trial specifically designed to address continuation versus discontinuation in moderate-to-severe disease. The 2020 Canadian Consensus Conference 4 provides the most recent and comprehensive guideline recommendations, synthesizing this evidence into actionable clinical criteria.