What is the recommended dosage of memantine (N-methyl-D-aspartate receptor antagonist) for a geriatric patient over 65 years old with moderate to severe dementia, possibly with comorbid conditions such as hypertension, diabetes, or cardiovascular disease, and impaired renal function?

Memantine Dosage for Moderate to Severe Dementia

The recommended dosage of memantine for moderate to severe dementia is 20 mg/day (10 mg twice daily), initiated at 5 mg once daily and titrated upward in 5 mg increments weekly until reaching the target dose. 1

Standard Dosing Regimen

Titration Schedule:

• 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 target therapeutic dose 1

The minimum interval between dose increases must be one week 1. This 20 mg/day dosage has been demonstrated effective in controlled clinical trials for moderate to severe Alzheimer's disease, vascular dementia, and mixed dementia 2.

Dose Adjustments for Renal Impairment

For patients with severe renal impairment (creatinine clearance 5-29 mL/min):

• Target dose: 10 mg/day (5 mg twice daily) 1, 3
• This reduced dosing is necessary because memantine area under the curve increases by 115% in severe renal impairment 3
• Predicted steady-state concentrations with 5 mg twice daily in severe renal impairment (84 ng/mL) are comparable to those achieved with 10 mg twice daily in patients with normal renal function 3

For mild to moderate renal impairment:

• No dose adjustment is required 1, 3
• Patients with moderate renal impairment (creatinine clearance 30-49 mL/min) show only a 60% increase in drug exposure, which remains within acceptable therapeutic ranges 3

Hepatic Impairment Considerations

Memantine should be administered with caution in patients with severe hepatic impairment, though specific dose adjustments are not definitively established 1. Clinical judgment is required in this population.

Evidence for Efficacy at 20 mg/day

The 20 mg/day dose demonstrates:

• Statistically significant improvements on the Severe Impairment Battery (SIB) for moderate to severe Alzheimer's disease 2, 4
• Significant benefits on global assessment measures (CIBIC-plus scale) across all severity levels of Alzheimer's disease and vascular dementia 2
• Quality of life improvements in 3 of 4 studies, with significant summary estimates 2
• Reduced caregiver burden and improved resource utilization 2

However, it is important to note that while improvements are statistically significant, they may not reach clinically important thresholds on cognitive scales like ADAS-cog (which requires ≥4 point change for clinical significance) 2.

Combination Therapy with Cholinesterase Inhibitors

When combining memantine with donepezil:

• The same 20 mg/day target dose applies 5
• Combination therapy (memantine 20 mg/day plus donepezil) shows superior outcomes compared to donepezil monotherapy in moderate to severe AD 5
• Benefits include improvements in cognition (SIB), activities of daily living (ADCS-ADL19), global outcomes (CIBIC-Plus), and behavioral symptoms 5
• Low-dose donepezil (5 mg/day) combined with memantine may offer better tolerability with similar efficacy to high-dose donepezil (10 mg/day) combinations, particularly regarding sleep quality and adverse event rates 6

Safety Profile

Withdrawal rates due to adverse effects are 9-12% with memantine versus 7-13% with placebo 2, 4. Common adverse effects include:

• Nausea, dizziness, diarrhea, and agitation 2
• Confusion, dizziness, and falls (particularly relevant for discontinuation decisions) 2

The medication is generally well-tolerated, with discontinuation rates actually lower than or comparable to placebo in most trials 2, 1.

Practical Administration Points

• Memantine can be taken with or without food 1
• If a single dose is missed, do not double the next dose 1
• If multiple doses are missed over several days, resume at lower doses and retitrate 1
• For oral solution formulations, do not mix with other liquids 1

When to Continue Treatment

Continue memantine even with cognitive decline if:

• There has been a clinically meaningful reduction in neuropsychiatric symptoms (psychosis, agitation, aggression) 2, 4
• These behavioral benefits persist despite progression of cognitive and functional impairment 2

This dosing approach prioritizes both efficacy and safety, with clear adjustments for the most common comorbidity affecting drug clearance (renal impairment) in geriatric patients.