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

Memantine Treatment for Moderate to Severe Alzheimer's Disease

Memantine 20 mg/day (administered as 10 mg twice daily) is the recommended treatment regimen for moderate to severe Alzheimer's disease, with demonstrated efficacy on cognition, activities of daily living, and global outcomes. 1

Dosing Regimen and Titration

The FDA-approved dosing schedule requires gradual titration to minimize adverse effects and optimize tolerability 1:

• Week 1: Start with 5 mg once daily
• Week 2: Increase to 10 mg/day (5 mg twice daily)
• Week 3: Increase to 15 mg/day (5 mg and 10 mg as separate doses)
• Week 4 and beyond: Target dose of 20 mg/day (10 mg twice daily)

The minimum interval between dose increases is one week, and 20 mg/day represents the dose proven effective in controlled clinical trials 1. Memantine can be taken with or without food 1.

Clinical Efficacy Evidence

Memantine demonstrates statistically significant benefits across multiple outcome domains in moderate to severe Alzheimer's disease 2, 3:

• Cognitive function: Improvements on the Severe Impairment Battery (SIB), with treatment groups showing mean improvements of 0.9 points versus declines of -2.5 points in placebo groups (p<0.001) 4
• Activities of daily living: Slower functional decline on the ADCS-ADL19 scale, with memantine groups declining by -2.0 points versus -3.4 points for placebo (p=0.03) 4
• Global assessment: Significant benefits on CIBIC-Plus scores (4.41 vs 4.66 for placebo, p=0.03) 4
• Quality of life: Reduced agitation and improved behavioral symptoms compared to placebo 2

International guidelines from the UK, US, China, and Japan consistently recommend memantine for severe dementia, with three of these countries (excluding the UK) also recommending combination therapy for severe AD 5.

Combination Therapy Approach

Memantine combined with a cholinesterase inhibitor (particularly donepezil) produces superior outcomes compared to cholinesterase inhibitor monotherapy in moderate to severe Alzheimer's disease. 2, 3

The landmark combination therapy trial demonstrated that adding memantine to stable donepezil therapy resulted in 4:

• Better cognitive outcomes (SIB improvement)
• Better functional outcomes (ADCS-ADL19)
• Better global outcomes (CIBIC-Plus)
• Excellent tolerability with only 7.4% discontinuation due to adverse events versus 12.4% for placebo

The American Academy of Neurology recommends this combination for patients with moderate to severe AD, noting significant improvements in cognition, daily functioning, and behavioral symptoms 2.

Special Population Dosing

Renal impairment: For severe renal impairment (creatinine clearance 5-29 mL/min), reduce the target dose to 5 mg twice daily (10 mg/day total) 1.

Hepatic impairment: Use memantine with caution in severe hepatic impairment, though specific dose adjustments are not provided 1.

Genitourinary conditions: Be aware that conditions raising urine pH decrease urinary elimination of memantine, potentially increasing plasma levels 1.

Treatment Duration and Discontinuation Criteria

Consider discontinuing memantine under the following circumstances 2, 3:

• Clinically meaningful worsening of dementia over 6 months without other contributing factors
• No observable clinical benefit during treatment
• Progression to severe or end-stage dementia with dependence in most basic activities of daily living

Important exception: Continue memantine in patients with neuropsychiatric symptoms (psychosis, agitation, aggression) if there has been clinically meaningful reduction in these symptoms, even if cognitive and functional decline continues 2.

When discontinuation is necessary, use a gradual taper: reduce the dose by 50% every 4 weeks until reaching the initial starting dose 2, 3.

Safety and Tolerability Profile

Memantine demonstrates excellent tolerability with 1, 4:

• Discontinuation rates due to adverse events: 7.4-10.1% (comparable to placebo at 11.5-12.4%)
• No individual adverse reaction causing discontinuation in ≥1% of patients at rates greater than placebo
• Well-tolerated both as monotherapy and in combination with donepezil 2
• Significantly less agitation compared to placebo groups 2

The drug is contraindicated only in patients with known hypersensitivity to memantine or its excipients 1.

Practical Administration Details

If a patient misses a single dose, do not double the next dose—simply resume the regular schedule 1. If multiple days are missed, dosing may need to be resumed at lower doses and retitrated using the standard schedule 1.