Memantine to Treat Social Impairment in Youths With Autism Spectrum Disorder: A Randomized Clinical Trial.

Researchers tested a medication called memantine in 42 young people with autism to see if it could help with social difficulties. After 12 weeks, more children taking memantine showed improvement compared to those taking a placebo pill (56% vs 21%). The medication was safe with few side effects. The study also found that children with higher levels of a brain chemical called glutamate responded better to the treatment, which could help doctors predict who might benefit most from this medication.

This randomized controlled trial evaluated memantine for treating social impairments in 42 youths with autism spectrum disorder (aged 8-17, IQ≥85) over 12 weeks. Significantly more participants receiving memantine met response criteria compared to placebo (56.2% vs 21.0%, OR=4.8, p=0.03). Response was defined as ≥25% reduction in Social Responsiveness Scale scores and clinician-rated improvement. The study also examined brain glutamate levels using proton magnetic resonance spectroscopy, finding that youths with ASD had elevated levels compared to healthy controls.

Importantly, those with abnormally elevated glutamate levels showed better treatment response to memantine (80.0% vs 20.0% for placebo, OR=16.0, p=0.007), suggesting glutamate levels may serve as a biomarker for treatment response. Memantine was well-tolerated with no significant increase in adverse events.

Memantine may be a viable treatment option for social impairments in autism, particularly for individuals with elevated brain glutamate levels. The potential biomarker could enable personalized treatment approaches. However, larger trials are needed to confirm efficacy and establish clinical implementation guidelines.

Small sample size (n=42) limits generalizability. Study limited to youths without intellectual disability (IQ≥85). Short 12-week treatment duration. Biomarker findings require replication in larger samples. Long-term safety and efficacy data not available.

Pharmacologic interventions for addressing social impairments in autism spectrum disorder (ASD) are lacking. Proton magnetic resonance spectroscopy (1H-MRS) studies in individuals with ASD have documented altered glutamate levels in the pregenual anterior cingulate cortex (pgACC). To evaluate the safety and efficacy of memantine for treating social impairments in youths with ASD and to explore pgACC glutamate levels as a potential biomarker for treatment response. This 12-week, placebo-controlled, double-blind, parallel-design randomized clinical trial was conducted between January 20, 2015, and July 11, 2018.

The study population comprised youths aged 8 to 17 years with ASD without intellectual disability (IQ≥85) recruited from ambulatory psychiatry clinics at an academic institution. Age- and sex-matched healthy control participants provided reference data for pgACC glutamate levels. Data analysis was conducted between January 7, 2020, and December 19, 2024. Participants with ASD were randomized to memantine or placebo, with dose titration up to 20 mg/d. 1H-MRS scans were acquired to assess pgACC glutamate levels.

Response was defined a priori as (1) a 25% or greater reduction in informant-rated Social Responsiveness Scale-Second Edition total scores and (2) a clinician-rated Clinical Global Impression-Improvement subscale (anchored for ASD) score of 2 or less. The association between pgACC glutamate levels and treatment response was explored using receiver operating characteristic (ROC) curve analysis. This study included 42 youths with ASD who initiated treatment (mean [SD] age, 13.2 [2.6] years; 32 males [76.2%]). Of these youths, 35 were included in the intention-to-treat efficacy analysis (n = 16 treated with memantine and 19 with placebo), and 33 completed the trial (n = 16 treated with memantine and 17 with placebo).

Significantly more memantine-treated participants met the response criteria compared with placebo-treated participants (9 of 16 [56.2%] vs 4 of 19 [21.0%]; odds ratio, 4.8 [95% CI, 1.1-21.2]; P = .03). Memantine was well tolerated and did not have significantly more adverse events compared with placebo. Mean (SD) pgACC glutamate levels were significantly higher in youths with ASD vs healthy control participants (95.5 [14.6] IU vs 76.6 [17.7] IU; standardized mean difference, -1.2 [95% CI, -1.8 to -0.6]; P < .001). Abnormally elevated pgACC glutamate levels (≥1 SD above that of healthy control participants) were observed in 20 of 37 participants (54.0%) with ASD and were associated with more treatment responders to memantine than placebo (8 of 10 [80.0%] vs 2 of 10 [20.0%]; odds ratio, 16.0 [95% CI, 1.8-143.2]; P = .007).

ROC curve analysis indicated that pgACC glutamate levels were highly efficient at identifying treatment responders. In this trial, memantine was well tolerated and significantly improved social impairments in youths with ASD. Elevated pgACC glutamate levels were associated with a favorable treatment response, supporting their potential as a biomarker for assessing memantine efficacy in individuals with ASD. ClinicalTrials.gov Identifier: NCT01972074.