Use of memantine to treat Alzheimer's disease

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.

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.