Memantine: An NMDA Receptor Antagonist for Moderate to Severe Alzheimer's Disease
Memantine is a prescription medication that acts as an NMDA (N-methyl-D-aspartate) receptor antagonist primarily used for treating moderate to severe dementia in people with Alzheimer's disease, showing modest improvements in cognition, global function, and quality of life. 1
Mechanism of Action
- Memantine works as a low to moderate affinity uncompetitive NMDA receptor antagonist that binds preferentially to NMDA receptor-operated cation channels 1
- It is hypothesized to exert therapeutic effects by blocking excessive glutamate activity at NMDA receptors, which may contribute to the symptomatology of Alzheimer's disease 1
- There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease 1
Clinical Efficacy
- Memantine improves cognition and global assessment in moderate to severe Alzheimer's disease, though the magnitude of effect may not reach clinical significance in all domains 2
- Studies demonstrate statistically significant improvements on the Severe Impairment Battery (SIB) and CIBIC-plus scale (global assessment) for patients with moderate to severe Alzheimer's disease 3
- Limited evidence shows improvement in quality of life, with less agitation reported in treatment groups compared to placebo 4, 3
- For mild to moderate Alzheimer's disease, data from trials are equivocal, with some meta-analyses indicating beneficial effects on global status and cognition 5, 6, 7
Treatment Approach
Monotherapy vs. Combination Therapy
- Memantine can be used as monotherapy or in combination with cholinesterase inhibitors 4, 8
- Combination therapy with memantine plus a cholinesterase inhibitor (particularly donepezil) has shown superior outcomes compared to cholinesterase inhibitor therapy alone 8, 9, 10
- In a well-designed study, patients receiving memantine plus donepezil showed significant benefits on measures of cognition, activities of daily living, global outcome, and behavior compared to donepezil alone 9
Dosing
- Treatment is typically initiated at 5 mg once daily and increased to 10 mg once daily after 1 week, with further titration as needed 1
- Dosage should be reduced in patients with severe renal impairment 1
Adverse Effects
- Common adverse events include dizziness, headache, confusion, and constipation 1
- Withdrawal rates due to adverse effects range from 9-12% in treatment groups (compared to 7-13% in placebo groups) 3
- Memantine is generally well tolerated, with adverse events occurring with a similar incidence to that reported with placebo 10
Treatment Duration and Discontinuation
- Consider discontinuation if clinically meaningful worsening of dementia occurs over 6 months without other contributing factors 4, 3
- Consider discontinuation if no clinical benefit is observed during treatment 3
- Consider discontinuation if the patient progresses to severe or end-stage dementia with dependence in most basic activities of daily living 3
- When discontinuing, use a gradual approach, reducing dose by 50% every 4 weeks until reaching the initial starting dose 4, 3
Important Clinical Considerations
- For patients with neuropsychiatric symptoms (psychosis, agitation, aggression), continue memantine if there has been a clinically meaningful reduction in these symptoms, even with cognitive and functional decline 4, 3
- Memantine should be used with caution in patients with seizures, urinary problems, or kidney issues 1
- Drug interactions may occur with other NMDA antagonists (amantadine, ketamine, dextromethorphan) and medications that make urine alkaline 1