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.

Figures

Figure 1

Flowchart of patient inclusion.

Figure 2

(a) Before and after, dot plot representations of individual CVLT-II total free recall raw scores and the magnitude of change (denoted by straight lines connecting the dots representing individual measurement values) from the time of the baseline neuropsychological testing, before exposure to the study medication (T1) to the end of the 16-week trial (T2). The graphs in red (filled circles) and blue (open circles) represent the memantine and placebo groups, respectively. The symbol ‘*' denotes the P-value of <0.05 for the difference between T1 and T2 for the memantine group compared with the placebo group using MIXED models. Error bars represent mean and 90% confidence intervals. Note that the CVLT-II total free recall raw scores from 11 patients showed increases from T1 to T2, whereas this only happened for scores from 6 patients in the placebo group. Also, increases in score larger than 10 points only happened for the memantine group. (b) Bar graph representing the effect size (Cohen's d) for neuropsychological and adaptive functioning variables assessed in this study. The symbol ‘*' denote a treatment effect with P-values <0.05. The hashed bars represent primary measures or secondary measures associated with the primary hypothesis, whereas the solid bars represent secondary discriminant measures. The dashed horizontal lines represent the 0.2 level (at which an effect size is typically considered small), and the 0.5 level (moderate effect size). CVLT-II, California Verbal Learning Test-II; DAS-II, Differential Ability Scales-II; PAL, Paired Associate Learning; PPVT-III, Peabody Picture Vocabulary Test-3rd edition; RBMT, Rivermead Behavioral Memory Test-Children's version; SIB-R, Scales of Independent Behavior–Revised; SWM, Spatial Working Memory; TROG-II, Test of Reception of Grammar-2nd edition.