Joshi Gagan, Gönenc Atilla, DiSalvo Maura, Faraone Stephen V, Ceranoglu Tolga Atilla, Yule Amy M, Uchida Mai, McDougle Christopher J, Wozniak Janet
Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital, Boston.
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
JAMA Netw Open. 2025 Oct 1;8(10):e2534927. doi: 10.1001/jamanetworkopen.2025.34927.
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.
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.
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.
针对自闭症谱系障碍（ASD）社交障碍的药物干预措施尚缺乏。对ASD个体进行的质子磁共振波谱（1H-MRS）研究已证明膝前扣带回皮质（pgACC）中的谷氨酸水平发生了改变。
评估美金刚治疗ASD青少年社交障碍的安全性和有效性，并探索pgACC谷氨酸水平作为治疗反应潜在生物标志物的可能性。
设计、地点和参与者：这项为期12周、安慰剂对照、双盲、平行设计的随机临床试验于2015年1月20日至2018年7月11日进行。研究人群包括从一所学术机构的门诊精神病诊所招募的8至17岁、无智力残疾（智商≥85）的ASD青少年。年龄和性别匹配的健康对照参与者提供了pgACC谷氨酸水平的参考数据。数据分析于2020年1月7日至2024年12月19日进行。
将ASD参与者随机分为美金刚组或安慰剂组，剂量滴定至20mg/d。进行1H-MRS扫描以评估pgACC谷氨酸水平。
预先将反应定义为：（1）知情者评定的《社会反应量表第二版》总分降低25%或更多；（2）临床医生评定的临床总体印象改善分量表（针对ASD进行锚定）得分≤2。使用受试者操作特征（ROC）曲线分析探索pgACC谷氨酸水平与治疗反应之间的关联。
本研究纳入了42名开始治疗的ASD青少年（平均[标准差]年龄为13.2[2.6]岁；32名男性[76.2%]）。在这些青少年中，35名被纳入意向性治疗疗效分析（n = 16名接受美金刚治疗，19名接受安慰剂治疗），33名完成了试验（n = 16名接受美金刚治疗，17名接受安慰剂治疗）。与接受安慰剂治疗的参与者相比，接受美金刚治疗的参与者达到反应标准的人数显著更多（16名中的9名[56.2%]对19名中的4名[21.0%]；优势比为4.8[95%CI，1.1 - 21.2]；P = 0.03）。美金刚耐受性良好，与安慰剂相比，不良事件并未显著更多。与健康对照参与者相比，ASD青少年的pgACC谷氨酸平均（标准差）水平显著更高（95.5[14.6]IU对76.6[17.7]IU；标准化平均差为 - 1.2[95%CI， - 1.8至 - 0.6]；P < 0.001）。在37名ASD参与者中的20名（54.0%）中观察到pgACC谷氨酸水平异常升高（高于健康对照参与者1个标准差以上），与接受美金刚治疗的治疗反应者相比，接受安慰剂治疗的更多（10名中的8名[80.0%]对10名中的2名[20.0%]；优势比为16.0[95%CI，1.8 - 143.2]；P = 0.007）。ROC曲线分析表明，pgACC谷氨酸水平在识别治疗反应者方面效率很高。
在本试验中，美金刚耐受性良好，显著改善了ASD青少年的社交障碍。pgACC谷氨酸水平升高与良好的治疗反应相关，支持其作为评估ASD个体中美金刚疗效的生物标志物的潜力。
ClinicalTrials.gov标识符：NCT01972074。
