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Randomized Controlled Trial
. 2025 Oct 1;8(10):e2534927.
doi: 10.1001/jamanetworkopen.2025.34927.

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

Gagan Joshi  1   2 , Atilla Gönenc  1 , Maura DiSalvo  1 , Stephen V Faraone  3 , Tolga Atilla Ceranoglu  1   2 , Amy M Yule  4 , Mai Uchida  1   2 , Christopher J McDougle  2   5 , Janet Wozniak  1   2
Affiliations
Randomized Controlled Trial

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

Gagan Joshi et al. JAMA Netw Open. .

Abstract

Importance: 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).

Objectives: 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.

Design, setting, and participants: 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.

Interventions: 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.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT01972074.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Joshi reported receiving speaker honoraria from the American Academy of Child and Adolescent Psychiatry, the American Physician Institute, the Asian College of Neuropsychopharmacology, the Kennedy Krieger Institute, the Neuroimmune Institute, New York University, Optum Health Education, and the Regional Council of Child and Adolescent Psychiatry of Eastern Pennsylvania and Southern New Jersey outside the submitted work. In addition, Dr Joshi reported receiving research support from Genentech, F. Hoffmann-La Roche Ltd, and the Demarest Lloyd Jr Foundation; providing consulting services (unpaid) to EuMentis Therapeutics; receiving royalties from Mass General Brigham Innovation for a licensed method for treating autism spectrum disorder; and having a patent pending (PCT/US2022/014878 for methods for treating autism spectrum disorder) outside the submitted work. Dr Faraone reported receiving consulting fees from Mentavi/ADHD, Axsome, Ironshore/Collegium, KemPharm/Corium, Noven, and Supernus; honoraria and personal fees for travel and accommodation expenses from Sandoz and Tris; royalties from Elsevier, Guilford Press, and Oxford University Press; and personal fees for travel and accommodation expenses from Medice outside the submitted work. In addition, Dr Faraone reported receiving grants from Mass General Hospital, Otsuka Pharmaceuticals, Oregon Health & Science University (OHSU), Supernus Pharmaceuticals, the European Commission, the National Institute of Mental Health (NIMH), the National Institute on Aging, the National Incident Management System, Noven, and the Upstate Foundation outside the submitted work. Dr Ceranoglu reported receiving grants from the Gerstener Family Foundation, the Brain Foundation, and the O’Sullivan Foundation as well as nonfinancial support from Niraxx Inc and the Autism Research Institute outside the submitted work. Dr Uchida reported receiving royalties for patents with Magazine House, Bunshun Shinsho, Jitsugyo no Nihonsha, Daiwa Shobo, and Kadokawa outside the submitted work. In addition, Dr Uchida reported providing consulting services to Guidepoint and Atheneum outside the submitted work. Dr McDougle reported receiving consulting fees from Acadia Pharmaceuticals and royalties from Oxford University Press and Springer Publishing outside the submitted work. Dr Wozniak reported receiving grants from the Baszucki Brain Research Foundation and OHSU outside the submitted work. In addition, Dr Wozniak reported the following relationships for their spouse: consulting and advising for Idorsia Pharmaceuticals Ltd, Alexza Pharmaceuticals, Azurity Pharmaceuticals Inc, Blackstone Life Sciences Advisors LLC, Covington & Burling LLP, Disc Medicine, Haleon PLC, Noctrix Health, PsychoGenics Inc, Quinn Emanuel Urquhart & Sullivan LLP, Taylor Wessing LLP, Cozen O’Connor, Fox Rothschild LLP, and Sterne Kessler Goldstein & Fox; editing, authoring, and publishing for UpToDate (Wolters Kluwer Health Inc); receiving research support from Baszucki, Merck & Co Inc, and the RLS Foundation; providing clinical or direct medical services to Teladoc Health Inc; and providing expert testimony for the International Law Firm of Winston & Strawn LLP. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow Diagram
TEAE indicates treatment-emergent adverse event.
Figure 2.
Figure 2.. Treatment Response Based on Pregenual Anterior Cingulate Cortex (pgACC) Glutamate Levels
Treatment response criteria were (1) a 25% or greater reduction in Social Responsiveness Scale–Second Edition School-Age Form score and (2) a Clinical Global Impression–Improvement subscale (anchored for autism spectrum disorder [ASD]) score of 2 or less. MD indicates mean difference; OR, odds ratio; SMD, standardized mean difference.
Figure 3.
Figure 3.. Treatment Response Based on Baseline Pregenual Anterior Cingulate Cortex (pgACC) Glutamate Levels
ABC-SW indicates Aberrant Behavior Checklist-Social Withdrawal; SRS-2, Social Responsiveness Scale–Second Edition School-Age Form; SRS-RRB, SRS-2 Restricted Repetitive Behaviors; SRS-SCI, SRS-2 Social Communication and Interaction.
See this image and copyright information in PMC

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