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.

Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features

“…Some studies have attempted to target synaptic plasticity in adult schizophrenia patients, largely by targeting NMDAR function, with some positive effects on specific plasticity measures (e.g., [212,213] but see [214]). However, benefits have generally not extended to broader aspects of cognition [212,215]. If impaired synaptic plasticity disrupts the optimal tuning of local and long-range circuits, targeting plasticity deficits with pharmacological interventions and/or behavioral interventions intended to strengthen adaptive synapses earlier in development (e.g., support for school/extracurricular involvement, cognitive enhancement training, cognitive behavioral therapy) may provide more effective options for ameliorating the emergence of subsequent cognitive and/or psychotic symptoms [216–219].…”

Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

“…Current pathogenic models of schizophrenia emphasize hypofunction of the N-methyl-Daspartate (NMDA) receptor (Iwata et al, 2015;Kantrowitz and Javitt, 2010). There is growing evidence from genetic and animal studies that the metabotropic glutamate receptors 5 (mGluR5) critically modulates the NMDA receptor (Matosin et al, 2015a).…”

Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine

“…As such, numerous studies have attempted to improve cognition in schizophrenia by targeting the NMDAR, with relatively limited success. 75 The present results require replication in a larger sample of patients and in additional studies comparing patients to age-and gendermatched controls. Nevertheless, our findings raise the intriguing possibility that enhancing NMDAR signaling in schizophrenia may partially restore processes that are closely linked to electrical signaling across the NMDAR.…”