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.