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

1. Memantine treatment was more efficacious than placebo in improving social functioning in youths with autism spectrum disorder.

Evidence Rating Level: 2 (Good)

Study Rundown:

One characteristic of autism spectrum disorder (ASD) is deficits in social communication and interaction. Research suggests that glutamate, the brain’s primary excitatory neurotransmitter, is dysregulated in individuals with ASD. The pregenual anterior cingulate cortex (pgACC) is a brain region rich in glutamate neurotransmission and involved in social and emotional processing. Studies in youths with ASD have found elevated glutamate levels in the pgACC. Memantine hydrochloride is a glutamate-modulating agent that has shown potential in improving social communication and interaction in youths and adults with ASD. However, controlled clinical trials of memantine in youth are lacking. This study thus investigated the safety and efficacy of memantine for treating social impairments in youths with ASD and explored pgACC glutamate levels as a potential biomarker for treatment response. 

This 12-week randomized clinical trial included youths aged 8-17 years with ASD without intellectual disability (IQ≥85) in Boston. Participants were randomized 1:1 to receive memantine or placebo, with a maximum daily dose of 20 mg. Response was defined a priori as a >25% reduction in total scores on the informant-rated Social Responsiveness Scale–Second Edition and a clinician-rated score of <2 on the Clinical Global Impression–Improvement subscale anchored for ASD. In total, 35 participants were analyzed (n = 16 treated with memantine and 19 with placebo). More memantine-treated participants met the response criteria compared with placebo-treated participants and were 4.8 times more likely to meet the response criteria. Memantine was well tolerated, with no significant difference in adverse events compared with placebo. Mean pgACC glutamate levels were higher in youths with ASD vs healthy control participants. Abnormally elevated pgACC glutamate levels were associated with more treatment responders to memantine than placebo. 

Overall, this study found memantine to be well-tolerated and more efficacious than placebo in improving social functioning in youths with ASD. 

Click to read the study in JAMA Network Open 

Relevant reading: Blood and brain glutamate levels in children with autistic disorder

In-Depth [Randomized clinical trial]

This was a 12-week double-blind, parallel-design, randomized clinical trial conducted between January 20, 2015, and July 11, 2018, and included youths aged 8-17 years with ASD without intellectual disability (IQ≥85) recruited from ambulatory psychiatry clinics at an academic institution in Boston. Participants were randomized 1:1 to receive memantine or placebo. For the first four weeks, memantine was titrated to a maximum daily dose of 20 mg and then maintained at the maximum achieved dose until the end of the trial. pgACC glutamate levels were measured using 1H-MRS scans. Response was defined a priori as a >25% reduction in total scores on the informant-rated Social Responsiveness Scale–Second Edition and a clinician-rated score of <2 on the Clinical Global Impression–Improvement subscale anchored for ASD. 

Among the 42 participants who initiated treatment (mean [SD] age, 13.2 [2.6] years; 32 males [76.2%]), 35 were included in the intention-to-treat efficacy analysis (n = 16 treated with memantine and 19 with placebo). More memantine-treated participants met the response criteria compared with placebo-treated participants (9 of 16 [56.2%] vs 4 of 19 [21.0%]) and were 4.8 times more likely to meet the response criteria (odds ratio, 4.8 [95% CI, 1.1-21.2]). Memantine was well tolerated, with no significant difference in adverse events compared with placebo. Mean (SD) pgACC glutamate levels were 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]). Abnormally elevated pgACC glutamate levels (≥1 SD above that of healthy control participants) were observed in 20 of 37 participants (54.0%) 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]). ROC curve analysis showed pgACC glutamate levels were highly efficient at identifying treatment responders. Overall, this study found memantine to be well tolerated and more efficacious than placebo in improving social functioning in youths with ASD. Elevated pgACC glutamate levels were associated with a favorable treatment response, highlighting their potential role as a biomarker of memantine treatment response in this population. Some limitations of this study include a small sample size that was predominantly White and male, and the inability to control for confounding factors such as psychiatric comorbidities and medications that could affect glutamate levels. Future studies should confirm study findings in larger sample sizes and in broader populations with ASD to increase generalizability.

Image: PD

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