Glutamatergic transmission in schizophrenia: from basic research to clinical practice

Abstract

Purpose of review: The past 20 years have seen the glutamatergic hypothesis go from theory to phase III trials of novel mechanism antipsychotics.

Recent findings: We review the recent literature on glutamatergic theory, covering assessment and genetic studies, as well as drug development in animals and humans.

Summary: Although evidence continues to accumulate in support of glutamate hypotheses, further research continues to be required and interactions with other key systems need to be explored.

FIGURE 1

Schematic model of the N-methyl-D-aspartate (NMDA) receptor complex and synaptic glutamate ( ), D-serine ( ), and glycine ( ) regulation and metabolism. The nonphysiologic NMDA antagonist PCP and ketamine site is also shown. DAOA, D-amino acid oxidase activator; PCP, phencyclidine. Reproduced from [2].

FIGURE 2

Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) outcomes for high-dose D-serine. Baseline (filled bars) and final (open bars) normalized MATRICS domains and overall mean composite (mean T-score of six tested domains) for (a) 30, (b) 60, and (c) 120 mg/kg. (d) Within group effect sizes for each dose. ^*P <0.05 in a paired t-test between baseline and final (a–c) or in a paired t-test for doses more than 60 mg/kg (d). ^#Significant (P <0.05) dose by time interaction for 30 vs. 60 mg/kg or more. Reproduced from [29^▪].