What is the recommended dosing schedule for memantine (Namenda) in adults with moderate to severe Alzheimer disease, how should the dose be adjusted in renal impairment, what are the common adverse effects, and what alternative therapies are available?

Memantine (Namenda) for Moderate to Severe Alzheimer's Disease

Dosing Schedule

Start memantine at 5 mg once daily and titrate upward in 5 mg weekly increments to a target dose of 20 mg daily (10 mg twice daily), as this is the FDA-approved regimen shown to be effective in controlled trials. 1

Standard Titration Protocol

• Week 1: 5 mg once daily 1

• Week 2: 10 mg daily (5 mg twice daily) 1

• Week 3: 15 mg daily (5 mg and 10 mg as separate doses) 1

• Week 4 and beyond: 20 mg daily (10 mg twice daily) – the therapeutic target dose 1

• The minimum interval between dose increases must be one week 1

• Memantine can be taken with or without food 1

• An extended-release formulation (28 mg once daily) is available and may improve adherence, though it has not been directly compared to immediate-release in clinical trials 2

---

Renal Dose Adjustment

In severe renal impairment (creatinine clearance 5–29 mL/min), reduce the target dose to 5 mg twice daily (10 mg total daily). 1

• No dose adjustment is needed for mild to moderate renal impairment (CrCl >30 mL/min) 1
• Memantine is predominantly renally eliminated (48% unchanged in urine), and severe renal impairment increases AUC by 115% and half-life by 95% 1
• Use the Cockcroft-Gault equation to calculate creatinine clearance 1

---

Hepatic Impairment

• No dose adjustment is required for mild to moderate hepatic impairment (Child-Pugh Class A or B) 1
• Use memantine with caution in severe hepatic impairment, as pharmacokinetics have not been evaluated in this population 1
• The hepatic CYP450 system does not play a significant role in memantine metabolism 1

---

Common Adverse Effects

Memantine is generally well tolerated, with discontinuation rates due to adverse events (9–12%) comparable to placebo (7–13%). 3, 1

Most Frequent Adverse Events

• Gastrointestinal: Nausea, vomiting, diarrhea (4–18% of patients) 3, 4, 1
• Neurological: Dizziness (6.1% vs 3.9% placebo), headache (5.5% vs 4.3% placebo) 3, 1
• Behavioral: Agitation is listed as a potential side effect (4–18%), but memantine actually reduces agitation compared to placebo (RR 0.81,95% CI 0.66–0.99) 3, 4

Important Safety Considerations

• Memantine improves sleep architecture and reduces sleep fragmentation, unlike cholinesterase inhibitors which commonly cause insomnia 4
• No individual adverse reaction led to discontinuation in ≥1% of patients at rates higher than placebo 1
• Memantine is well tolerated both as monotherapy and in combination with donepezil 3, 5

---

Clinical Efficacy

Memantine produces statistically significant improvements in cognition (measured by Severe Impairment Battery) and global assessment (CIBIC-plus) in moderate to severe Alzheimer's disease, though the clinical meaningfulness of these changes may be modest. 3, 6

• Memantine improves ADAS-cog scores by approximately 1–3 points, with changes ≥4 points generally considered clinically significant 7
• Combination therapy with memantine plus a cholinesterase inhibitor (typically donepezil) produces superior outcomes compared to cholinesterase inhibitor monotherapy across all domains: cognition, function, behavior, and global status 3, 5
• Memantine shows particular benefit for neuropsychiatric symptoms, significantly reducing Neuropsychiatric Inventory scores by 1.84 points (95% CI 1.05–2.76) 4
• Benefits on quality of life, caregiver burden, and behavioral symptoms are documented, with notable improvements in caregiver distress at 12 weeks 3

---

Alternative and Combination Therapies

Cholinesterase Inhibitors

For moderate to severe Alzheimer's disease, combination therapy with donepezil (10 mg daily) plus memantine (20 mg daily) is recommended, as this produces significantly better outcomes than donepezil monotherapy. 3

• Donepezil monotherapy is the first-line treatment for mild to moderate Alzheimer's disease: start at 5 mg daily in the evening with food, increase to 10 mg daily after 4–6 weeks if tolerated 3
• Donepezil improves ADAS-cog by 2.02 points (5 mg dose) to 2.92 points (10 mg dose) at 24 weeks 3
• Common donepezil adverse effects include gastrointestinal symptoms (nausea, vomiting, diarrhea), bradycardia, and nightmares 3

Other Cholinesterase Inhibitors

• Galantamine and rivastigmine are alternative cholinesterase inhibitors for mild to moderate disease 7
• Rivastigmine trials showed a 3-point improvement on ADAS-cog (−3.06,95% CI −4.48 to −1.65) 7
• Do not combine two cholinesterase inhibitors, as this increases cholinergic side effects without additional benefit 3

Non-Pharmacologic Interventions

• Caregiver-focused educational interventions show consistent small benefits on caregiver burden and depression in moderate dementia 7
• Cognitive training, exercise interventions, and multidisciplinary care coordination may provide adjunctive benefits 7

Ineffective Therapies

• Aspirin, statins, NSAIDs, gonadal steroids, and dietary supplements have no proven benefit for cognitive or physical function in dementia 7
• Sertraline is not indicated for cognitive decline in Alzheimer's disease 3

---

Treatment Duration and Discontinuation

Continue memantine as long as the patient demonstrates clinically meaningful benefit, particularly for neuropsychiatric symptoms, even if cognitive decline persists. 3, 6

Criteria for Discontinuation

Consider stopping memantine if: 3, 6

• Clinically meaningful worsening of dementia over 6 months without other contributing medical or environmental factors
• No clinically meaningful benefit observed at any time during treatment
• Progression to severe or end-stage dementia with dependence in most basic activities of daily living
• Development of intolerable side effects
• Poor medication adherence

Discontinuation Protocol

• Taper gradually by reducing the dose by 50% every 4 weeks until reaching the initial starting dose 3, 6
• Abrupt discontinuation is not recommended

Special Exception

• For patients with neuropsychiatric symptoms (psychosis, agitation, aggression), continue memantine if there has been clinically meaningful reduction in these symptoms, even with evidence of cognitive and functional decline 3, 6

---

Drug Interactions

• Conditions that raise urine pH (e.g., renal tubular acidosis, severe urinary tract infections, alkaline diet) decrease urinary elimination and increase memantine plasma levels 1
• Drugs using the same renal cationic secretion system (hydrochlorothiazide, triamterene, metformin, cimetidine, ranitidine, quinidine, nicotine) may alter memantine levels 1
• Memantine does not affect donepezil pharmacokinetics or acetylcholinesterase inhibition 1
• Memantine does not interact with warfarin, bupropion, or drugs metabolized by CYP450 enzymes 1

---

Monitoring

• Assess treatment response at 12 and 24 weeks using cognitive measures (e.g., MMSE, ADAS-cog) and functional assessments 3
• Monitor renal function, particularly in elderly patients or those with baseline renal impairment 1
• Evaluate for gastrointestinal side effects, dizziness, and changes in behavioral symptoms 3, 1