Hong Houlin, Donlon Jack, Schaefer Martin, Sarkar Susanne, Bugarski-Kirola Dragana, Shad Mujeeb U, Hou Wei, Kirschner Matthias, Varghese Sajoy P, Mitrev Ludmil, Echeverria Valentina, Dibato John, Veerman Selene R T, Aiyer Rohit, Ferraro Thomas N, Villarreal Gerardo, Rahman Shafiqur, Stone Trevor W, Koola Maju M
Center for Systems and Community Design, CUNY School of Public Health and Health Policy, New York City, NY, USA.
Cooper Medical School of Rowan University, Camden, NJ, USA.
Clin Drug Investig. 2025 Sep;45(9):627-642. doi: 10.1007/s40261-025-01465-4. Epub 2025 Aug 1.
Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist with favorable safety and side effect profiles. There is a growing body of evidence for memantine as an adjunctive therapy for the positive, negative, and cognitive symptoms of schizophrenia.
This meta-analysis examined the efficacy of memantine as an add-on to treatment with antipsychotic(s) for the primary negative symptoms (PNS) of schizophrenia.
We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched for relevant publications in PubMed, Cochrane Library, PsycINFO, Embase, and China Journal Net databases from inception using the following search terms: memantine, schizophrenia, randomized controlled trials (RCTs), RCT, and clinical trial. Searches were limited to English- and Chinese-language articles to date. Standardized mean differences (SMDs) with 95% confidence intervals were calculated using RevMan 5.4 to assess the effect size. Risk of bias was assessed using RoB 2.0.
In total, 13 RCTs were identified (N = 681). Memantine was superior to placebo in treating negative symptoms, with an SMD of 0.79 (p = 0.0001, N = 631, 12 RCTs). Analysis of three studies whose corresponding authors provided original datasets showed an SMD of 2.16 (p = 0.25, N = 97) after adjusting for change in psychosis, depression, and extrapyramidal symptoms, suggesting that memantine is efficacious in treating PNS. Additionally, cognitive testing significantly improved, with an SMD of 0.66 (p = 0.0001, N = 395, eight RCTs). Positive symptoms were not significantly improved (SMD = 0.24, p = 0.1, N = 631, 12 RCTs).
To our knowledge, this is the first study showing a large effect size for treating PNS with memantine. Although statistical significance was not reached because of the small sample size (N = 97), the results were as expected because drugs such as memantine that act at NMDA receptors are unlikely to be effective as stand-alone treatments. Future RCTs should evaluate NMDAergic drugs in combination with complementary medications to optimize therapeutic effects for all three domains of schizophrenia psychopathology.
美金刚是一种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，具有良好的安全性和副作用特征。越来越多的证据表明美金刚可作为精神分裂症阳性、阴性和认知症状的辅助治疗药物。
本荟萃分析旨在研究美金刚作为抗精神病药物附加治疗对精神分裂症原发性阴性症状（PNS）的疗效。
我们遵循系统评价和荟萃分析的首选报告项目（PRISMA）指南，使用以下检索词从PubMed、Cochrane图书馆、PsycINFO、Embase和中国知网数据库创建以来检索相关出版物：美金刚、精神分裂症、随机对照试验（RCTs）、RCT和临床试验。检索仅限于截至目前的英文和中文文章。使用RevMan 5.4计算标准化均数差（SMD）及其95%置信区间以评估效应大小。使用RoB 2.0评估偏倚风险。
共纳入13项RCT（N = 681）。美金刚在治疗阴性症状方面优于安慰剂，SMD为0.79（p = 0.0001，N = 631，12项RCT）。对三位相应作者提供原始数据集的研究进行分析，在调整精神病性症状、抑郁和锥体外系症状的变化后，SMD为2.16（p = 0.25，N = 97），这表明美金刚在治疗PNS方面有效。此外，认知测试有显著改善，SMD为0.66（p = 0.0001，N = 395，8项RCT）。阳性症状未得到显著改善（SMD = 0.24，p = 0.1，N = 631，12项RCT）。
据我们所知，这是第一项显示美金刚治疗PNS有较大效应大小的研究。尽管由于样本量小（N = 97）未达到统计学显著性，但结果符合预期，因为作用于NMDA受体的药物如美金刚不太可能作为单一治疗有效。未来的RCT应评估NMDA能药物与补充药物联合使用，以优化对精神分裂症精神病理学所有三个领域的治疗效果。
