Memantine EFFICACYGortelmeyer and Erbler

In another placebo-controlled, randomized study, the authors studied the efficacy and tolerability of memantine in patients with mild-to-moderate dementia syndrome. After a one-week washout period, 88 patients received either memantine or placebo. Patients received 10 mg/day for the first three days, after which time the dose was increased to 20 mg/day for the remainder of the study period.

The investigators assessed the patients as follows:

  • at the psychopathological level: the [Sandoz] Clinical Assessment Geriatric Scale (SCAG), which measures cognitive, affective, and social functioning
  • the Clinical Global Impression (CGI), which assesses the risks and benefits of drug treatment in patients who are mentally ill
  • at the behavioral level: the GBS, which evaluates the patients’ functional capacity
  • at the performance level: the Activities of Daily Living (ADL) scale, which represents the patients’ ca-parity to carry out simple daily tasks

After 14 days of therapy, the SCAG score, which indicates global assessment of change in the patient’s condition, showed a statistically significant difference between the two groups in favor of memantine; the mean baseline for six weeks’ difference was -18.1 points with memantine and -6.4 points with placebo (P < .05).
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The total GBS score, which measures behavioral changes, also showed a decrease in dementia-associated symptoms. The differences between the two groups were significant after 14 days of therapy (P < .0001). The mean GBS score was 37.5 for the memantine group (base line mean score, 47) and 46.3 for the placebo group (baseline mean score, 47.2).

The analysis of the ADL assessment revealed superior results with meman-tine therapy for both the time required for performing the activity and the quality of the performance (P < .003). After six weeks of treatment, 26.8% of placebo patients versus 58.5% of mem-antine patients showed improvement in their initial condition.

Overall, this study showed a statistically significant alleviation of dementia-induced disturbances in both the behavioral and psychopathological measures and improvement in the quality of performing daily activities.

Orgogozo et al.

In another study of patients with mild-to-moderate vascular dementia, the investigators randomly selected 321 patients to receive either memantine or placebo, followed by a week-long washout period. The patients initially received a dose of 5 mg of memantine daily that was titrated up weekly by 5 mg until it reached 20 mg/day by week four. The assessments were performed at baseline and at weeks two, four, 12, 20, and 28.
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The ADAS-Cog was used to determine the primary efficacy endpoint for evaluating cognitive function. Scores ranged from 0 (best) to 70 (worst).

The CIBIC-Plus was used to rate global change, and a score of 1 to 7 was given for this assessment (1 = very much improved, 7 = very much worse). Secondary efficacy variables included the MMSE and the GBS scale.

The NOSGER was used to observe functional assessments.

At the end of the study period, the CIBIC-Plus scores in the intent-to-treat population with the LOCF were higher in the memantine group (60%) than in the placebo group (52%), although the difference between the two groups was not statistically significant (P = .227). The mean ADAS-Cog scores improved from the baseline value in the memantine group but deteriorated in the placebo group. In the intent-to-treat population assessment, the scores of the meman-tine patients improved by a mean of 0.4, whereas those of the placebo group decreased by a mean of 0.4. The MMSE scores, which were ana­lyzed for each protocol, declined in the placebo group but significantly improved in the memantine group (P = .003).

Both the GBS and NOSGER scales showed significant differences from baseline in favor of memantine (P = .04 and P = .07, respectively).

SAFETY PROFILE

The Reisberg study. Eighty-four percent of patients receiving memantine and 87% receiving placebo experienced ADEs, although most effects were mild to moderate in severity.15 However, the authors concluded that the events were either not related to, or were unlikely to be related to, memantine. Furthermore, ADEs were more common in the placebo group; 17% of the placebo group patients discontinued the study prematurely, compared with 13% in the memantine group. Agitation was the most common cause of premature withdrawal from the study in 32% of the placebo patients versus 18% of the memantine group. Other reported ADEs included urinary incontinence, urinary tract infections, insomnia, and diarrhea.

The Wilcock Study. Memantine was well tolerated in patients with mild-to-moderate vascular dementia. The most frequently seen ADEs in the memantine patients were dizziness (in 11% of patients taking memantine and in 8% taking placebo) and constipation (in 10% taking memantine and in 4% taking placebo). There was a slight increase in the number of reports of gastrointestinal and respiratory disorders in the memantine group but more reported psychiatric disorders in the placebo group. Overall, most ADEs during the study were rated as mild (52%) or moderate (39%) in severity.

The Orgogozo Study. Memantine was also well tolerated in this trial. Reported ADEs were comparable in both the memantine (76%) and the placebo (74%) groups. The most common ADEs included agitation, confusion, and dizziness. The serious ADEs reported were also comparable between the two groups (23% in the memantine group, 26% in the placebo group), the most severe being cerebrovascular events. None of the reported ADEs occurred at a significantly greater rate in the memantine arm. There were no drug-related deaths in either group.

Conclusion

Memantine belongs to a new class of agents and is the first drug approved for the treatment of patients with moderate-to-severe AD. The drug’s mechanism of action differs from that of other currently available AD therapies. Patients have tolerated the drug well and have experienced reduced symptomatic clinical deterioration when taking memantine therapy compared with placebo. The improvements have included cognitive, functional, and overall global progress. Most ADEs that occurred were mild to moderate in severity.
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Memantine is a promising medication for some patients. Although additional long-term and comparative studies are needed to assess its efficacy and safety, its benefits outweigh the risk of the disease progression.