Effects of glutamate positive modulators on cognitive deficits in schizophrenia

A systematic review and meta-Analysis of double-blind randomized controlled trials

Y. Iwata, Shinichiro Nakajima, T. Suzuki, R. S E Keefe, E. Plitman, J. K. Chung, F. Caravaggio, Masaru Mimura, A. Graff-Guerrero, Hiroyuki Uchida

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1151-1160
Number of pages10
JournalMolecular Psychiatry
Volume20
Issue number10
DOIs
Publication statusPublished - 2015 Oct 29

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Meta-Analysis
Glutamic Acid
Schizophrenia
Randomized Controlled Trials
Cognition
Placebos
Antipsychotic Agents
Allosteric Site
Synaptic Transmission
Pharmaceutical Preparations
Glycine
Confidence Intervals
Acids
Population
aspartic acid receptor
Cognitive Dysfunction
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Effects of glutamate positive modulators on cognitive deficits in schizophrenia : A systematic review and meta-Analysis of double-blind randomized controlled trials. / Iwata, Y.; Nakajima, Shinichiro; Suzuki, T.; Keefe, R. S E; Plitman, E.; Chung, J. K.; Caravaggio, F.; Mimura, Masaru; Graff-Guerrero, A.; Uchida, Hiroyuki.

In: Molecular Psychiatry, Vol. 20, No. 10, 29.10.2015, p. 1151-1160.

Research output: Contribution to journalArticle

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