What is the recommended treatment regimen for moderate to severe Alzheimer's disease using Memantine?

Memantine Treatment for Moderate to Severe Alzheimer's Disease

For moderate to severe Alzheimer's disease, initiate memantine at 5 mg once daily and titrate weekly in 5 mg increments to the target dose of 20 mg daily (10 mg twice daily for immediate-release or 28 mg once daily for extended-release formulation). 1

Dosing Regimen

Immediate-Release Formulation

• Start at 5 mg once daily and increase by 5 mg weekly until reaching the target dose of 20 mg/day (10 mg twice daily) 1
• The titration schedule follows this pattern: Week 1 (5 mg once daily) → Week 2 (10 mg/day as 5 mg twice daily) → Week 3 (15 mg/day as 5 mg and 10 mg in separate doses) → Week 4 (20 mg/day as 10 mg twice daily) 1
• Can be taken with or without food 1
• If doses are missed for several days, resume at lower doses and retitrate 1

Extended-Release Formulation

• Extended-release memantine 28 mg once daily is an alternative that improves adherence through simplified dosing 2, 3
• This formulation provides higher total daily exposure and has demonstrated efficacy in patients already taking cholinesterase inhibitors 2
• Capsules can be opened and sprinkled on applesauce for patients with swallowing difficulties 3

Special Population Dosing

• For severe renal impairment (creatinine clearance 5-29 mL/min), reduce target dose to 5 mg twice daily (10 mg/day total) 1
• Use caution in severe hepatic impairment 1
• Conditions that raise urine pH may increase memantine plasma levels 1

Clinical Efficacy

Cognitive and Functional Benefits

• Memantine demonstrates statistically significant improvement in cognition measured by the Severe Impairment Battery (SIB) and global assessment on the CIBIC-plus scale 4, 5
• Combination therapy with cholinesterase inhibitors provides additional benefits on cognition, activities of daily living, global outcome, and behavior compared to cholinesterase inhibitor monotherapy 4
• The extended-release 28 mg formulation showed significant improvements in cognition (SIB), global status (CIBIC-Plus), neuropsychiatric symptoms (NPI), and verbal fluency when added to cholinesterase inhibitors 2

Quality of Life Considerations

• Limited evidence shows improvement in quality of life, caregiver burden, and resource utilization 4, 5

Safety Profile

• Common adverse events include nausea, dizziness, diarrhea, headache, and agitation 4, 1, 2
• Withdrawal rates due to adverse effects are 9-12% in treatment groups, comparable to placebo rates of 7-13% 4, 5
• Memantine is safe and well tolerated for at least one year of continuous treatment 6
• The extended-release formulation shows similar tolerability with headache (5.6%) and diarrhea (5.0%) being most common 2

Duration and Discontinuation Criteria

When to Consider Discontinuation

• Discontinue if clinically meaningful worsening of dementia has occurred over the past 6 months without other contributing medical or environmental factors 4, 5
• Discontinue if no clinically meaningful benefit has been observed at any time during treatment 4, 5
• Discontinue in severe or end-stage dementia characterized by dependence in most basic activities of daily living, inability to respond to environment, or limited life expectancy 4, 5

Important Exception for Neuropsychiatric Symptoms

• Continue memantine in patients with neuropsychiatric symptoms (psychosis, agitation, aggression) if there has been clinically meaningful reduction in these symptoms, even with evidence of cognitive and functional decline 4, 5

Discontinuation Protocol

• When stopping memantine, reduce dose by 50% every 4 weeks until reaching the initial starting dose 4, 5
• This gradual tapering approach minimizes potential withdrawal effects

Clinical Pitfalls to Avoid

• Do not mix memantine oral solution with other liquids 1
• Do not use memantine for indications other than Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, or vascular dementia 4
• Do not abruptly discontinue—always taper gradually 4, 5
• Monitor for conditions that alkalinize urine, as these decrease urinary elimination and increase plasma levels 1