Memantine is not an effective treatment for dementia in adults older than 40 years with Down syndrome, according to findings from a randomized, placebo-controlled study.
In fact, all of the 173 participants in the Memantine for Dementia in Adults Older than 40 Years with Down Syndrome (MEADOWS) trial, regardless of whether they received placebo or active treatment, experienced declines in cognition and function during the 52-week study. Moreover, although the rates of decline did not differ significantly between the groups, they were slightly lower in the placebo group, senior author Dr. Clive Ballard of King’s College London (England) and his colleagues reported online in the January 10 issue of The Lancet.
Dr. Clive Ballard
The findings suggest that therapies that are effective for Alzheimer’s disease in other patient populations are not necessarily effective in those with Down syndrome.
After adjustment for baseline score, participants in the placebo group and treatment group experienced mean changes in scores on the Down syndrome attention, memory, and executive function scales (DAMES) of -1.9 and -5.6 at 52 weeks, respectively. There also was no difference in the mean changes in scores between the placebo and memantine groups in part I of the Adaptive Behavior Scale (-1.7 and -10.7, respectively), which measures independent functioning, or part II (0 and 1.0, respectively), which measures challenging behavior (Lancet 2011 Jan. 10 [doi:10.1016/S0140-6736(11)61676-0]).
The results were similar regardless of the presence of dementia, which had been diagnosed in 35% of individuals in each group at the time of randomization.
The rate of serious adverse events also did not differ significantly between the placebo and treatment groups at 7% and 11%, respectively.
The findings have implications for research strategy in development of treatments for cognitive decline and dementia in individuals with Down syndrome, the investigators said.
Dementia is very prevalent in this population, with nearly 40% of those with Down syndrome receiving a diagnosis of dementia after age 60 years. Additionally, clinically significant Alzheimer’s disease–like pathological features are "almost ubiquitous" by age 40 years in those with Down syndrome.
"Although there is therefore a rationale for the efficacy of pharmacological treatments for Alzheimer’s disease in people with Down’s syndrome, there are some key differences in pathological features that should not be overlooked. For example, people with Down’s syndrome have lifelong overproduction of amyloid-beta compounded with dysregulation of many genes, most of which are not associated with Alzheimer’s disease," the investigators explained, adding that differences in the neuropathologic features of people with Down syndrome compared with Alzheimer’s disease might affect responses to pharmacologic therapies.
The N-methyl-d-aspartate glutamate receptor antagonist memantine (Namenda) is licensed for the treatment of moderate to severe Alzheimer’s disease and showed promise in two studies in a Down syndrome model in mice. But in the current study it was found to confer no benefit, regardless of whether a formal diagnosis of dementia was available, they said.
Study participants were men and women with Down syndrome aged 40 years or older or individuals of any age with Down syndrome and an established diagnosis of dementia. They were enrolled at four learning disability centers throughout the United Kingdom and Norway. The randomization process involved a computer-generated allocation sequence that ensured balanced allocation based on the prognostic factors of sex, presence of dementia, age group, DAMES score, and center. The investigators escalated the dose of memantine over 8 weeks from 5 mg per day to the optimal therapeutic dose of 10 mg per day with fixed titration.
"The findings of this study are robust and represent an important step in the evidence base for treatment of people with Down syndrome with cognitive decline," the investigators wrote, concluding that research into specific therapies for this patient population needs to be based on an understanding of underlying pathologic processes.
In particular, an adequately powered randomized controlled trial of cholinesterase inhibitors is needed to determine if this class of drug has any role in the treatment of Down syndrome patients with dementia. Cholinesterase inhibitors are approved in the United Kingdom for people with dementia in the context of Down syndrome, but very little evidence exists to support this guidance, they said.
This study was funded by Lundbeck and sponsored by King’s College London. Dr. Ballard reported receiving consultancy and speaking fees from Lundbeck, Janssen, Novartis, and Acadia and grants from Lundbeck and Acadia. Other study authors reported receiving consultancy fees, speaking fees, honoraria, and/or grants from Lundbeck, Novartis, and/or Roche, as well as serving on the advisory board for Lundbeck, providing paid expert testimony for Novartis and Eisai, and receiving funding from the Alzheimer’s Society and the Henry Smith Trust. Detailed disclosures are available with the full text of the article at www.thelancet.com.