Effect of N-methyl-D-aspartate receptor enhancing agents on cognition in dementia: an exploratory systematic review and meta-analysis of randomized controlled trials

Abstract

Multiple N-methyl-D-aspartate (NMDA) receptor enhancing agents have had promising effects on cognition among patients with dementia. However, the results remain inconsistent. This exploratory meta-analysis investigated the effectiveness of NMDA receptor enhancing agents for cognitive function. PubMed, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials (RCTs). Controlled trials assessing add-on NMDA receptor enhancing agent treatment in patients with dementia and using cognition rating scales were eligible and pooled using a random-effect model for comparisons. The standardized mean difference (SMD) was calculated in each study from the effect size; positive values indicated that NMDA receptor enhancing agent treatment improved cognitive function. Funnel plots and the I2 statistic were evaluated for statistical heterogeneity. Moderators were evaluated using meta-regression. We identified 14 RCTs with 2224 participants meeting the inclusion criteria. Add-on NMDA receptor enhancing agents had small positive significant effects on overall cognitive function among patients with dementia (SMD = 0.1002, 95% CI 0.0105-0.1900, P = 0.02860). Subgroup meta-analysis showed patients with Alzheimer's Disease and trials using the Alzheimer Disease Assessment Scale-cognitive subscale as the primary outcome had small positive significant effects (SMD = 0.1042, 95% CI 0.0076-0.2007, P = 0.03451; SMD = 0.1267, 95% CI 0.0145-0.2388, P = 0.2686). This exploratory meta-analysis showed a very small, positive, and significant effect on overall cognition function in patients with dementia. Studies with larger samples are needed to evaluate different cognitive domains and phases of dementia.

Figure 1

PRISMA flow diagram of the search and identification of included studies. Database: PubMed (n = 304), Cochrane Central Register of Controlled Trials (n = 208), Cochrane Database of Systematic Reviews (n = 7). Keyword: (Dementia OR Alzheimer*) AND (acetylcysteine OR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid OR AMPA OR benzoate OR CX516 OR D-cycloserine OR D-serine OR glutamine OR glutamate OR glutamate carboxypeptidase 2 OR GCP2 OR glycine OR glycine transporter type 1 OR GlyT1 OR glutamate receptor ionotropic kainate OR GRIK OR kynurenine aminotransferase OR KAT OR metabotropic glutamate receptor OR mGluR OR minocycline OR N-acetyl-aspartylglutamate OR NAAG OR N-methyl-d-aspartate OR NMDA OR pregnenolone OR sarcosine) AND controlled trial. Date: date available to August 7th, 2020.

Figure 2

Meta-analyses of (a) overall cognitive function, (b) diagnosis of dementia groups, (c) cognitive measure groups, (d) study design groups, (e) NMDAR enhancing agent groups, (f) drug pathway in enhancing glutamatergic neurotransmission groups, (g) duration of therapy groups, and (h) age range groups.

Figure 2

Meta-analyses of (a) overall cognitive function, (b) diagnosis of dementia groups, (c) cognitive measure groups, (d) study design groups, (e) NMDAR enhancing agent groups, (f) drug pathway in enhancing glutamatergic neurotransmission groups, (g) duration of therapy groups, and (h) age range groups.

Figure 3

Meta-regression of effects of NMDAR enhancing agents on overall cognitive function in relation to (a) baseline mean ADAS-cog total score, (b) proportion of men, and (c) mean age.

Figure 4

Funnel plots of overall cognitive function SMD.