Neurocognitive Outcomes from Memantine: A Pilot, Double-Blind, Placebo-Controlled Trial in Children with Autism Spectrum Disorder

Abstract

Objective: Studies interrogating therapeutics which alter the excitation-inhibition balance in the treatment of autism spectrum disorder (ASD) have reported mixed results on social and behavioral outcomes. Methods: The aim of this randomized, double-blind placebo-controlled pilot trial was to evaluate neurocognitive effects of memantine over a 24-week trial. Twenty-three children ages 6-12 years old with ASD were randomized to memantine or placebo. Primary outcomes included measures of apraxia and expressive language with evaluations at midpoint (week 12) and endpoint (week 24). Secondary outcomes included memory and adaptive behavior measures. Exploratory outcomes included changes in overall cognitive functioning and behavior (e.g., Aberrant Behavior Checklist). Results: Results suggest that memantine was well-tolerated. Dropout rates were high across groups with only 14 participants completing the 6-month trial. Memantine was not associated with improvements in apraxia and expressive language. Treatment with memantine was associated with improvements in verbal recognition memory as measured by the Narrative Memory-Recognition (NEPSY-II) (F = 5.05, p = .03). In addition, exploratory analyses of changes in Intelligence quotient (IQ) suggest improvements on verbal IQ (d = 1.8). Conclusions: Results suggest future studies of memantine in ASD may benefit from shifting treatment targets from social and behavioral outcomes to exploration of effects of memantine on cognition, potentially as an adjunct to learning and educational interventions. ClinicalTrials.gov: NCT01372449.

Relationship Between MR Spectroscopy-Detected Glutamatergic Neurometabolites and Changes in Social Behaviors in a Pilot Open-Label Trial of Memantine for Adults With Autism Spectrum Disorder

“…This line of work could, in turn, have important implications for clinical care including improving accuracy of individual prognosis and individualizing treatments in ASD. Recent studies have suggested that memantine might better target cognitive outcomes in ASD rather than social (18). However, the findings from the current study begin to raise the question as to whether social outcomes might still be relevant in an optimally targeted subset of patients.…”

“…Memantine, a moderate affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist that attenuates glutamatergic excitation, is an FDA approved treatment for Alzheimer's disease and is known to improve communication abilities in this population (17). A few small studies have shown some effectiveness of memantine in the treatment of social and communication aspects of ASD (18)(19)(20). Considering these cognitive and behavioral outcomes and the impact of memantine on excitatory-inhibitory balance, there has been significant interest in the potential use of memantine to target core symptoms in patients with ASD.…”

“…Nonetheless, it is possible that differences in treatment response could be due to the heterogeneity in the nature of the excitatory-inhibitory balance between different patients with ASD, thereby causing a variation in response. Perhaps our understanding of the discrepancies between the small studies that documented evidence of beneficial effects of memantine in treating social and communication deficits associated with ASD and the negative larger clinical trial could be clarified with better understanding of aspects of the biological heterogeneity of the disorder (18)(19)(20)(21). In such a scenario, a biomarker to predict each individual patients' treatment response would be invaluable for increasing treatment efficacy and decreasing trial and error.…”

Genetics, Molecular Control and Clinical Relevance of Habituation Learning

“…A recent small double-blind trial focusing on neurocognitive measures found a beneficial effect of Memantine on verbal recognition memory and verbal intelligence quotient (VIQ). The authors further hypothesize that Memantine's effect more likely originates from cognitive enhancement than the reduction of behavioral problems [232].…”

Novel treatments in autism spectrum disorder

“…Although the primary endpoint was not met, exploratory analyses suggested possible clinically significant improvements in core ASD symptoms nonetheless [61]. A small recent RCT (2021) involving 24 participants did not find a difference on primary endpoints related to language and apraxia in ASD but did see some improvement in verbal memory and possibly IQ on secondary and exploratory analyses, although drop-out was high [62]. Additional trials of memantine are under investigation.…”