Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial

Abstract

Down syndrome (DS) is the most common genetic cause of intellectual disability. The N-methyl-D-aspartate (NMDA) receptor uncompetitive antagonist, memantine hydrochloride (memantine), has been shown to improve learning/memory and rescue one form of hippocampus synaptic plasticity dysfunction in the best-studied mouse model of DS available, the Ts65Dn mouse. Given the status of memantine as a treatment for Alzheimer's disease (AD) approved by the Food and Drug Administration, the preclinical evidence of potential efficacy in Ts65Dn mice, and the favorable safety profile of memantine, we designed a study to investigate whether the findings in the mouse model could be translated to individuals with DS. In this pilot, proof-of-principle study we hypothesized that memantine therapy would improve test scores of young adults with DS on measures of episodic and spatial memory, which are generally considered to be hippocampus dependent. Accordingly, in this randomized, double-blind, placebo-controlled trial, we compared the effect of 16-week treatment with either memantine or placebo on cognitive and adaptive functions of 40 young adults with DS using a carefully selected set of neuropsychological outcome measures. Safety and tolerability were also monitored. Although no significant differences were observed between the memantine and placebo groups on the two primary outcome measures, we found a significant improvement in the memantine group in one of the secondary measures associated with the primary hypothesis. Only infrequent and mild adverse events were noted.

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial

“…The combined intervention of EGCG and cognitive training for 12 months seem to ameliorate functional integration of cortical and subcortical brain networks in this population. Although other statistically underpowered studies have reported preliminary data suggesting that cognitive and adaptive skills in Down's syndrome might be treated through pharmacological intervention, 9,30 this study is the first well-powered trial that shows improvement in adaptive behaviour (functional academics) and brain-related changes in young adults with Down's syndrome. However, more research is needed to clarify the nature of the beneficial association between the EGCG and cognitive training intervention (ie, synergistic or additive).…”

Assessing Cognitive Improvement in People with Down Syndrome: Important Considerations for Drug-Efficacy Trials

“…Some of these factors are obvious but, even here, are not always recognized when making group assignments. An example of the matched-pairs design in a clinical trial of people with DS is highlighted in a study led by Costa (Boada et al 2012). Here, the researchers evaluated whether the NMDA open-channel blocker memantine could improve measures of episodic memory relative to placebo.…”

“…The brain is one of the primary sites of action for T 4 /T 3 during development and adulthood (Kester et al 2004). The clinical significance of adult-or acute-onset hypothyroidism on cognitive function (e.g., episodic memory) and mental health has been established in the general population, and exclusion criteria for the participation of individuals with DS in drug-efficacy trials often specify removing those with active thyroid problems (e.g., Boada et al 2012). However, the impact of congenital hypothyroidism on later adult cognition and behavior-and its bearing on DS clinical trial enrollment-has received less attention.…”

New Innovations: Therapies for Genetic Conditions

“…Vitamin E has a suggested utility in Alzheimer's disease, and a clinical trial is currently underway studying whether it slows the cognitive decline of older adults with Down syndrome [14,15]. Memantine, a glutamine antagonist also used in Alzheimer's disease, may provide limited cognitive improvement in verbal memory [16]. Lithium and baclofen are also under investigation, having been shown to improve cognitive performance in a Down syndrome mouse model [17][18][19].…”