title: Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials.
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.
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.|Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: R S E
authors.initials: RS
authors.lastname: Keefe
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Plitman
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: J K
authors.initials: JK
authors.lastname: Chung
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Caravaggio
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mimura
authors.affiliation: Multimodal Imaging Group-Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Graff-Guerrero
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.|Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Uchida
mesh_terms: D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004311:Double-Blind Method; D018683:Excitatory Amino Acid Agents / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018683:Excitatory Amino Acid Agents; D016194:Receptors, N-Methyl-D-Aspartate