CMAJ • August 29, 2006; 175 (5). doi:10.1503/cmaj.1060168.
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Letters

Use of memantine to treat Alzheimer's disease

Serge Gauthier*, Nathan Herrmann{dagger}, Florian Ferreri{ddagger} and Catherine Agokou{ddagger}

*Neurologist, Professor and Director, Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, Montréal, Que.; {dagger}Geriatric Psychiatrist, Professor of Psychiatry, Sunnybrook and Women's Health Sciences Centre, University of Toronto, Toronto, Ont.; {ddagger}Psychiatrist, Research Fellow, Clinical Psychopharmacology Unit, Allan Memorial Institute, McGill University Health Centre, Montréal, Que.

The regulatory approval of memantine for use in the symptomatic treatment of moderate to severe Alzheimer's disease has led to high hopes among patients and their families. However, many physicians are still unsure about how best to use this medication. This letter summarizes the available evidence.

Persistent activation of N-methyl-D-aspartate (NMDA) in the central nervous system has been considered to contribute to chronic neurodegeneration in Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a moderate-affinity, uncompetitive NMDA receptor antagonist.1

Memantine has been used for more than 10 years in Europe and more recently in the United States. In randomized controlled trials (RCTs)2–5 comparing the drug with usual care or placebo (see Table 1), memantine treatment has been associated with reduced rate of deterioration on global, cognitive and functional (activities of daily living [ADLs]) measures and also with behavioural improvements (particularly related to agitation). It has been suggested that memantine's properties related to agitation and aggression might reduce the need for antipsychotics.2 To evaluate this antipsychotic-sparing effect, a Canadian placebo-controlled RCT is under way in which outcomes such as cognition, ADLs and behaviour are being examined in patients with baseline agitation and/or aggression. Alternatively, combination therapy with memantine and cholinesterase inhibitors has been shown to increase the cognitive benefits.4,6 These results have been attributed to the distinct therapeutic mechanisms of these drugs.


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  		Table 1.

 

In Canada, memantine is licensed for use in the treatment of symptoms associated with moderate to severe Alzheimer's disease. Although licensed, memantine is currently reimbursed only in Quebec and there only as monotherapy. The dose recommended in the approved product monograph7 is 20 mg/d (10 mg twice a day). Memantine is mostly excreted through the kidneys; therefore, if creatinine clearance is known to be less than 60 mL • min-1 • 1.73 m-2, the dose prescribed should be no more than 10 mg/d. Furthermore, memantine is not recommended for patients with severe renal impairment. Data from prior use of memantine in Europe and the United States suggest a good safety profile, using a titration of 5 mg per week up to 20 mg/d in 2 divided doses. The most common side effects (occurring in 5% or more of patients) are dizziness, constipation, confusion and headaches; less common side effects (occurring in less than 5% of patients) are hypertension, somnolence and visual hallucinations. Families have reported that higher doses (e.g., 10 mg twice a day) can lead to worsening of confusion, which disappears at lower doses. There are no apparent additive side effects when memantine is combined with cholinesterase inhibitors.

For most patients who are receiving cholinesterase inhibitors and whose condition progresses to a more severe stage, the cholinesterase inhibitor is discontinued when memantine is started. Because of a risk of discontinuation syndrome (or withdrawal reaction) when cholinesterase inhibitors are stopped, a 1-month overlap between these 2 drug classes is suggested.9,10

Clinical efficacy may be evaluated by directly observing patients and questioning caregivers about the 5 domains of cognition, mood, behaviour, ADLs and social interaction. Caregivers can be asked to focus on the ability to participate in conversations, anxiety, and the behaviours of agitation and aggression.

Footnotes

Competing interests: Dr. Gauthier and Dr. Herrmann are the principal investigators in the ongoing Canadian randomized study comparing memantine with placebo, sponsored by Lundbeck Canada. Seven years ago, Dr. Gauthier was awarded (through a peer-reviewed process) a research chair funded by the Canadian Institutes of Health Research and Rx&D Canada's Research-Based Pharmaceutical Companies (via a pool of funds from different companies, including Lundbeck Canada). Both Dr. Gauthier and Dr. Herrmann have received speakers' honoraria and consultant fees from Lundbeck Canada. No competing interests declared for Florian Ferreri or Catherine Agbokou. None of the authors received any honoraria for writing this letter.


REFERENCES

  1. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006;5(2):160-70.[CrossRef][Medline]
  2. Gauthier S, Wirth Y, Möbius HJ. Effects of memantine on behavioural symptoms in Alzheimer's disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies. Int J Geriatr Psychiatry 2005;20:459-64.[CrossRef][Medline]
  3. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348(14):1333-41.[Abstract/Free Full Text]
  4. Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291(3):317-24.[Abstract/Free Full Text]
  5. Winblad B, Poritis N. Momeantine in severe dementia: results of the 9M-Best Study (Benefit and efficiacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14(2):135-46.[CrossRef][Medline]
  6. Dantoine T, Auriacombe S, Sarazin M, et al. Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer's disease who failed to benefit from previous cholinesterase inhibitor treatment. Int J Clin Pract 2006;60(1):110-8.[CrossRef][Medline]
  7. Ebixa, memantine HCl [product monograph]. In: Compendium of pharmaceuticals and specialties. Ottawa: Canadian Pharmacists Association; 2006. p. 729-33.
  8. Hartmann S, Mobius HJ. Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int Clin Psychopharmacol 2003;18(2):81-5.[CrossRef][Medline]
  9. Gauthier S. Managing discontinuation syndrome in patients with dementia. J Psychiatry Neurosci 2006;31:72.[Medline]
  10. Waldemar G. Tolerability of switching from donepezil treatment in patients with moderate to severe Alzheimer's disease [presentation]. 9th Congress of the European Federation of Neurological Sciences; 2005 Sept 17–20; Athens.



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Can. Med. Assoc. J., September 26, 2006; 175(7): 777 - 777.
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