Memantine Dosing and Treatment for Moderate to Severe Alzheimer's Disease
Memantine is indicated for moderate to severe Alzheimer's disease with a target maintenance dose of 20 mg/day (10 mg twice daily), initiated at 5 mg once daily and titrated weekly in 5 mg increments over 4 weeks. 1
Standard Dosing Protocol
The FDA-approved titration schedule is:
- Week 1: 5 mg once daily 1
- Week 2: 10 mg/day (5 mg twice daily) 1
- Week 3: 15 mg/day (5 mg and 10 mg as separate doses) 1
- Week 4 and beyond: 20 mg/day (10 mg twice daily) - this is the effective dose demonstrated in controlled trials 1
The minimum interval between dose increases must be one week. 1 Memantine can be taken with or without food. 1
Dose Modifications for Special Populations
For severe renal impairment (creatinine clearance 5-29 mL/min):
- Target dose is 5 mg twice daily (10 mg/day total) 1
- This lower dose prevents accumulation due to reduced urinary elimination 1
For severe hepatic impairment:
- Administer with caution, though specific dose adjustments are not definitively established 1
Monotherapy vs. Combination Therapy
Combination therapy with a cholinesterase inhibitor (particularly donepezil) is superior to monotherapy and should be strongly considered. 2, 3 The landmark trial by Tariot et al. demonstrated that adding memantine to stable donepezil therapy in moderate to severe AD produced significant benefits across all domains: cognition (SIB), activities of daily living (ADCS-ADL19), global outcome (CIBIC-Plus), and behavior. 4 The combination is well-tolerated with no significant increase in adverse events compared to monotherapy. 2, 5
Clinical Efficacy Expectations
Memantine produces statistically significant but modest improvements in:
- Cognition: Measured by Severe Impairment Battery (SIB), though the magnitude may not reach clinically significant thresholds in all patients 6, 2, 5
- Global assessment: Demonstrated on CIBIC-plus scale 2, 5
- Quality of life: Particularly in moderate to severe disease 6, 2
- Behavioral symptoms: Notably reduced agitation compared to placebo 6, 2, 5
The evidence is strongest for moderate to severe AD; data for mild to moderate AD are equivocal. 7, 8
Safety Profile
Common adverse effects include:
- Dizziness, headache, confusion, and constipation (≥5% incidence) 1
- Gastrointestinal symptoms (nausea, diarrhea) 5
- Discontinuation rates due to adverse events are 7-12%, similar to placebo 5, 1
Important caveat: Conditions that raise urine pH (e.g., renal tubular acidosis, severe urinary tract infections, alkaline diet) decrease urinary elimination and increase plasma memantine levels. 1
Treatment Duration and Discontinuation Criteria
Consider discontinuing memantine if:
- Clinically meaningful worsening of dementia occurs over 6 months without other contributing medical or environmental factors 2, 5, 3
- No clinically meaningful benefit is observed at any time during treatment 2, 5
- Patient progresses to severe or end-stage dementia with dependence in most basic activities of daily living or limited life expectancy 2, 5
Exception: For patients with neuropsychiatric symptoms (psychosis, agitation, aggression), continue memantine if there has been clinically meaningful reduction in these symptoms, even with cognitive and functional decline. 2, 5
When discontinuing, use a gradual taper:
- Reduce dose by 50% every 4 weeks until reaching the initial starting dose 2, 5, 3
- This prevents potential withdrawal effects or symptom rebound
Missed Doses and Treatment Interruptions
If a single dose is missed, do not double the next dose; resume the regular schedule. 1 If memantine is stopped for several days, dosing may need to be resumed at lower doses and retitrated according to the standard schedule. 1
Clinical Trial Evidence Duration
Important limitation: Most controlled trials evaluated memantine for only 24-28 weeks, so evidence for long-term use beyond 6-7 months is limited. 6, 7 However, the benefits demonstrated were maintained throughout these study periods. 6