MDS 2009: Memantine May Benefit Parkinson's Disease Dementia and Dementia With Lewy Bodies

Susan Jeffrey

June 18, 2009

June 18, 2009 — Results of a randomized phase 2 trial suggest that patients with dementia associated with Parkinson's disease (PDD) or dementia with Lewy bodies (DLB) may benefit from treatment with memantine (Ebixa/Abixa, Lundbeck), an agent already approved for use in moderate to severe Alzheimer's disease.

"This is the first positive randomized, placebo-controlled trial of memantine in patients with Parkinson's dementia and dementia with Lewy bodies," lead author Dag Aarsland, MD, from the Norwegian Center for Movement Disorders at Stavanger University Hospital, told Medscape Neurology; it showed a positive response with treatment on the primary end point of improvement on the Clinical Global Impression of Change (CGIC) in these patients.

"We are excited about this, and although it's a small study, the findings are very encouraging and should lead to follow-up studies with a larger number of patients to confirm them," he added.

Dr. Aarsland presented the results at the Movement Disorders Society's 13th International Congress of Parkinson's Disease and Movement Disorders. The study was published online June 10 in the Lancet Neurology to coincide with the presentation and will appear in the July issue.

This clinician-initiated study was supported by the Western Norway Regional Health Authority and Lundbeck. Memantine is also marketed as Namenda (Forest Pharmaceuticals), Axura/Akatinol (Merz Pharmaceutical), and Memox (Unipharm).

Common Dementias

DLB and PDD are common forms of dementia that have a major impact on quality of life, the authors write. "Only rivastigmine [Exelon, Novartis] is licensed for PDD, and there are no treatments for DLB," they note.

These 2 dementias are separate clinical entities, Dr. Aarsland noted, "but they are very similar in terms of what we know about clinical symptoms and pathological changes. Both dementias are dominated by Lewy bodies in the cortex of the brain, and also there are some Alzheimer's changes, although less pronounced than you would find in Alzheimer's disease."

Memantine, an N-methyl-D-aspartate (NMDA)–receptor antagonist, is already approved for use in moderate to severe AD, but the precise mechanism of improvement is not clear, he noted. "We know that the major mode of mechanism is that it normalizes glutamatergic neurotransmission," he said. "It might also influence in a positive way the dopaminergic transmission, which might be particularly relevant for this patient group."

It's possible that memantine may also have neuroprotective effects, "but that is more speculative," Dr. Aarsland added.

The current study was a parallel-group, 24-week randomized and placebo-controlled pilot study that included 75 patients with PDD and DLB from 4 centers in Sweden, Norway, and the United Kingdom. They were randomized to receive either 20 mg per day of memantine or placebo. The primary outcome was change on the CGIC scale; scores on this scale range from 1 to 7 points, with a lower score indicating a better outcome.

Of the 75 patients, 56 completed the study. All withdrawals were due to adverse events, but the proportion was similar between the treatment groups and in fact was slightly higher in the placebo group, Dr. Aarsland noted.

There was no particular pattern for dropouts, he added, with reasons including worsening of disease, urinary tract infection, and others. "The mean age of this group was 77 years old, so these are old, frail people with parkinsonism and dementia," he said. Analysis was by intention-to-treat, using the last observation carried forward.

At week 24, a significant difference between groups was found on the CGIC, with a mean difference of 0.7 points (95% CI, 0.04 – 1.39; P = .03). With the exception of improved speed on attentional tasks in the memantine group, specifically a quick test-of-cognition form, with a difference of 12.4 (P = .004), there were no significant differences between groups in secondary outcome measures.

Large-scale phase 3 studies are now needed to determine the real benefit of this treatment in these patients, Dr. Aarsland added. Their group is not involved in this ongoing work at this time, "so it's up to the company to provide more confirmative data from a larger trial," he said.

A "Welcome Addition"

In a Reflection and Reaction commentary accompanying the paper in Lancet Neurology, Murat Emre, MD, from the Istanbul Faculty of Medicine, in Turkey, calls this trial "a welcome addition in the treatment of patients with Lewy body–related disorders, in whom the options are scarce."

Dr. Emre points, though, to some limitations of the study, including a high attrition rate, a relatively low sample size for each of the 2 conditions studied, and background therapy with cholinesterase inhibitors, with which an interaction cannot be ruled out. In addition, there was an imbalance in this and other background therapies, including antipsychotics and antiparkinsonian drugs, between the groups.

Still, Dr. Emre writes, the effect size was "reasonably robust," mostly due to improvements in the patients with PDD.

"Although not conclusive, these results are encouraging, but they await confirmation before memantine can be added to the list of treatments for these patients," Dr. Emre concludes. "A larger, randomized placebo-controlled, multicenter trial including 199 patients with either DLB or PDD has just been completed, and the results are being analyzed. Should these results of Aarsland and colleagues be confirmed, the choices of treatment for physicians managing such patients might be expanded."

"Small but Significant" Change

Asked for comment on these findings, Steven J. Frucht, MD, from the movement-disorders division of the Neurological Institute of New York at Columbia University, said he would classify the change achieved by treatment in this trial as "small but significant."

"Whether or not this amounts to a noticeable difference in daily functioning remains to be seen," Dr. Frucht told Medscape Neurology. "Also, whether or not tolerability will be as good in a general population outside of a trial is a concern," he added, "but still, promising."

This investigator-initiated study was supported by Lundbeck and the Western Norway Regional Health Authority. Dr. Aarsland reports he has received honoraria and research support from Lundbeck, Novartis, GE Healthcare, and Merck-Serono. Disclosures for coauthors appear in the paper. Dr. Emre reports he has been on advisory committees for and received consultancy fees, honoraria, or study grants from Boehringer Ingelheim, Schering-Plough, Esai, Pfizer, Lundbeck, Merck-Serono, Noscira, and Novartis.

13th International Congress of Parkinson's Disease and Movement Disorders, Paris, France: Abstract LB-02. Presented June 10, 2009.

Lancet Neurol. 2009; Published online June 10, 2009. Abstract, Abstract

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