Memantine for the Treatment of Primary Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Controlled Trials

Houlin Hong¹, Jack Donlon², Martin Schaefer^{3

4}, Susanne Sarkar⁴, Dragana Bugarski-Kirola⁵, Mujeeb U Shad⁶, Wei Hou⁷, Matthias Kirschner^{8

9}, Sajoy P Varghese^{10

11}, Ludmil Mitrev¹², Valentina Echeverria^{13

14}, John Dibato¹⁵, Selene R T Veerman¹⁶, Rohit Aiyer¹⁷, Thomas N Ferraro¹⁸, Gerardo Villarreal¹⁹, Shafiqur Rahman²⁰, Trevor W Stone²¹, Maju M Koola²²

Affiliations

¹ Center for Systems and Community Design, CUNY School of Public Health and Health Policy, New York City, NY, USA.
² Cooper Medical School of Rowan University, Camden, NJ, USA.
³ Department of Psychiatry, Psychotherapy, Psychosomatics, and Addiction Medicine, Evang Kliniken Essen-Mitte, Essen, Germany.
⁴ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
⁵ Acadia Pharmaceuticals, Luzern, Switzerland.
⁶ Department of Psychiatry, University of Nevada, Las Vegas, NV, USA.
⁷ Department of Family, Population and Preventive Medicine, School of Medicine, Stony Brook University, Stony Brook, NY, USA.
⁸ Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
⁹ Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
¹⁰ VISN 23, Clinical Resource Hub, Minneapolis VA Medical Center, Minneapolis, MN, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA, USA.
¹² Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Cooper University Healthcare, Cooper Medical School of Rowan University, Camden, NJ, USA.
¹³ Facultad de Medicina y Ciencias, Universidad San Sebastián, Lientur, 1457, Concepción, Chile.
¹⁴ Research and Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, USA.
¹⁵ Cooper Research Institute, Cooper Medical School of Rowan University, Camden, NJ, USA.
¹⁶ Community Mental Health, Mental Health Service Noord-Holland Noord, Alkmaar, The Netherlands.
¹⁷ Sunny Hills Behavioral Health, Fullerton, CA, USA.
¹⁸ Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA.
¹⁹ Department of Psychiatry and Neuroscience, New Mexico Veterans Affairs Healthcare System, University of New Mexico, Albuquerque, NM, USA.
²⁰ Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD, USA.
²¹ Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.
²² Mental Health and Behavioral Services, Veterans Affairs New Jersey Health Care System, East Orange, NJ, USA. majumkoola@gmail.com.

PMID: 40748569
DOI: 10.1007/s40261-025-01465-4

Meta-Analysis

Memantine for the Treatment of Primary Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Controlled Trials

Houlin Hong et al. Clin Drug Investig. 2025 Sep.

. 2025 Sep;45(9):627-642.

doi: 10.1007/s40261-025-01465-4. Epub 2025 Aug 1.

Authors

Affiliations

¹ Center for Systems and Community Design, CUNY School of Public Health and Health Policy, New York City, NY, USA.
² Cooper Medical School of Rowan University, Camden, NJ, USA.
³ Department of Psychiatry, Psychotherapy, Psychosomatics, and Addiction Medicine, Evang Kliniken Essen-Mitte, Essen, Germany.
⁴ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
⁵ Acadia Pharmaceuticals, Luzern, Switzerland.
⁶ Department of Psychiatry, University of Nevada, Las Vegas, NV, USA.
⁷ Department of Family, Population and Preventive Medicine, School of Medicine, Stony Brook University, Stony Brook, NY, USA.
⁸ Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
⁹ Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
¹⁰ VISN 23, Clinical Resource Hub, Minneapolis VA Medical Center, Minneapolis, MN, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA, USA.
¹² Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Cooper University Healthcare, Cooper Medical School of Rowan University, Camden, NJ, USA.
¹³ Facultad de Medicina y Ciencias, Universidad San Sebastián, Lientur, 1457, Concepción, Chile.
¹⁴ Research and Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, USA.
¹⁵ Cooper Research Institute, Cooper Medical School of Rowan University, Camden, NJ, USA.
¹⁶ Community Mental Health, Mental Health Service Noord-Holland Noord, Alkmaar, The Netherlands.
¹⁷ Sunny Hills Behavioral Health, Fullerton, CA, USA.
¹⁸ Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA.
¹⁹ Department of Psychiatry and Neuroscience, New Mexico Veterans Affairs Healthcare System, University of New Mexico, Albuquerque, NM, USA.
²⁰ Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD, USA.
²¹ Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.
²² Mental Health and Behavioral Services, Veterans Affairs New Jersey Health Care System, East Orange, NJ, USA. majumkoola@gmail.com.

PMID: 40748569
DOI: 10.1007/s40261-025-01465-4

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

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Conflict of interest statement

Declarations. Conflicts of Interest: None. Ethics Statement: Institutional review board approval was not required for this meta-analysis. PRISMA guidelines were used. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. Code Availability: The meta-analysis was performed using RevMan 5.4. Availability of Data and Material: Studies included in this meta-analysis were openly available and sourced from PubMed, Cochrane Library, PsycINFO, EMBASE, or China Journal Net databases. Three authors provided original datasets. The data for this study are available upon request. The original datasets of certain studies are only available by contacting the corresponding authors of those studies. Author Contributions: Houlin Hong: Writing—Methodology, Software, Validation, Formal analysis, Investigation, Original draft preparation, Visualization. Jack Donlon: Writing—Investigation, Original draft preparation, Visualization. Martin Schaefer: Writing—Review and Editing. Susanne Sarkar: Writing—Review and Editing. Dragana Bugarski-Kirola: Writing—Review and Editing. Mujeeb U. Shad: Writing—Review and Editing. Wei Hou: Methodology, Validation, Formal analysis, Writing—Review and Editing. Matthias Kirschner: Writing—Review and Editing. Sajoy P. Varghese: Writing—Review and Editing. Ludmil Mitrev: Writing—Review and Editing. Valentina Echeverria: Writing—Review and Editing. John Dibato: Writing—Review and Editing. Selene R. T. Veerman: Writing—Review and Editing. Rohit Aiyer Writing—Review and Editing. Thomas N. Ferraro: Writing – Review and Editing. Gerardo Villarreal: Writing—Review and Editing. Shafiqur Rahman: Writing—Review and Editing. Trevor W. Stone: Writing – Review and Editing. Maju Mathew Koola: Conceptualization, Methodology, Investigation, Writing—Review and Editing, Visualization, Supervision. Two biostatisticians (HH and WH) completed the formal statistical analysis. Houlin Hong and Jack Donlon prepared the manuscript. All authors edited the manuscript with intellectual contributions and approved the final version of the manuscript. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs.

References

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Memantine for the Treatment of Primary Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Controlled Trials

Affiliations

Memantine for the Treatment of Primary Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Controlled Trials

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

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LinkOut - more resources

Full Text Sources

Medical