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Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials

Molecular Psychiatry volume 20, pages 1151–1160 (2015)Cite this article

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Abstract

Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=−0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=−0.03 to 0.11) (n=367–940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

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Acknowledgements

We thank Drs Michael Berk, Robert W Buchanan, Christopher Cain, Roy Chengappa, Deepak Cyril D’Souza, Erica Duncan and Fang Liu for kindly providing additional data. No funding support was obtained for this report.

Author Contributions

YI, HU, TS, RSEK, EP and SN led study design, literature review and interpretation and manuscript preparation. All authors have contributed to and approved the current version of the manuscript.

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  1. Y Iwata and S Nakajima: These authors contributed equally to this work.

Authors and Affiliations

  1. Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Y Iwata, S Nakajima, E Plitman, J K Chung, F Caravaggio & A Graff-Guerrero

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Y Iwata, S Nakajima & A Graff-Guerrero

  3. Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan

    Y Iwata, S Nakajima, T Suzuki, M Mimura & H Uchida

  4. Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, ON, Canada

    S Nakajima, A Graff-Guerrero & H Uchida

  5. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    R S E Keefe

  6. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    E Plitman, J K Chung & F Caravaggio

  7. Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    A Graff-Guerrero

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Competing interests

YI has received manuscript fees from Wiley Japan within the past 3 years. SN has received fellowship grants from the CIHR and Japan Society for the Promotion of Science, and manuscript fees from Dainippon Sumitomo Pharma and Kyowa Hakko Kirin. TS has received manuscript or speaker’s fees from Astellas, Dainippon Sumitomo, Eli Lilly, Elsevier Japan, Janssen, Meiji Seika, Novartis, Otsuka and Wiley Japan within the past 3 years. RSEK currently or in the past 3 years has received investigator-initiated research funding support from the Department of Veteran’s Affair, Feinstein Institute for Medical Research, GlaxoSmithKline, National Institute of Mental Health, Novartis, Psychogenics, Research Foundation for Mental Hygiene and the Singapore National Medical Research Council. He currently or in the past 3 years has received honoraria, served as a consultant, or advisory board member for Abbvie, Akebia, Amgen, Astellas, Asubio, AviNeuro/ChemRar, BiolineRx, Biogen Idec, Biomarin, Boehringer-Ingelheim, Eli Lilly, FORUM, GW Pharmaceuticals, Helicon, Lundbeck, Merck, Minerva Neurosciences, Mitsubishi, Novartis, Otsuka, Pfizer, Roche, Shire, Sunovion, Takeda, Targacept and WWCT. RSEK receives royalties from the BACS testing battery, the MATRICS Battery (BACS Symbol Coding) and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). He is also a shareholder in NeuroCog Trials and Sengenix. EP has received the Ontario Graduate Scholarship and the Canada Graduate Scholarship. FC has received the Ontario Graduate Scholarship and the Canada Graduate Scholarship. MM has received grants and/or speaker’s honoraria from Asahi Kasei Pharma, Astellas Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Meiji-Seika Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi Pharma and Yoshitomi Yakuhin within the past 3 years. AG has received research support from the following external funding agencies: the Canadian Institutes of Health Research (CIHR), US National Institute of Health, Ontario Mental Health Foundation, Brain and Behavior Research Foundation, Mexico ICyTDF, CONACyT, Ministry of Economic Development and Innovation of Ontario, Ontario AHSC AFP Innovation Fund and W Garfield Weston Foundation. HU has received grants from Astellas Pharmaceutical, Eisai, Otsuka Pharmaceutical, GlaxoSmithKline, Shionogi, Dainippon-Sumitomo Pharma, Eli Lilly, Mochida Pharmaceutical, Meiji-Seika Pharma and Yoshitomi Yakuhin and speaker’s honoraria from Otsuka Pharmaceutical, Eli Lilly, Shionogi, GlaxoSmithKline, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, Abbvie, MSD and Janssen Pharmaceutical within the past 2 years. Other authors have no financial or other relationship relevant to the subject of this manuscript.

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Iwata, Y., Nakajima, S., Suzuki, T. et al. Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. Mol Psychiatry 20, 1151–1160 (2015). https://doi.org/10.1038/mp.2015.68

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  • DOI: https://doi.org/10.1038/mp.2015.68

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