Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia

Abstract

Rationale Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. Objectives The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. Methods Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients’ level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. Results Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. Conclusions These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects.

Effect of metabotropic glutamate receptor-3 variants on prefrontal brain activity in schizophrenia: An imaging genetics study using multi-channel near-infrared spectroscopy

“…Fourth, although the effects of each GRM3 SNP on brain activity in the prefrontal cortex are not fully understood (Bishop et al, 2015;Egan et al, 2004;Lencer et al, 2014;Marenco et al, 2006;Tan et al, 2007a;Xia et al, 2012), we divided participants into two SNP subgroups because of small sample size. Genotype group differences without any grouping may clarify the GRM3 effect on brain function.…”

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

“…The worsening was associated with GRM3 rs1468412, but the negative symptom improvement was associated with GRM3 rs6465084. In contrast, there were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment (Bishop, Reilly, 2015). This study provided direct pharmacogenetic associations of the GRM3 gene with working memory and the clinical response to antipsychotics in first-episode SZ.…”

“…These studies aid in discovering the DNA determinants of which influence drug efficacy and tolerability. Given that both type-2 and 3 metabotropic glutamate receptor gene (GRM 2 and 3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex activity in SZ patients (Bishop, Reilly, 2015, Egan, Straub, 2004, Harrison, Lyon, 2008, Joo, Shibata, 2001, Kordi-Tamandani, Dahmardeh, 2013, Mossner, Schuhmacher, 2008), it would be valuable to use pharmacogenomics to aid in finding the proper treatments for individual patients with different genetic profiles. In fact, a recent study examined the pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and SZ symptoms after treatment.…”

“…Both type-2 and 3 metabotropic glutamate receptor gene (GRM 2 and 3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex activity levels in SZ patients (Bishop et al, 2015, Chen et al, 2005, Egan et al, 2004, Harrison, Lyon, 2008, Joo et al, 2001, Kordi-Tamandani et al, 2013, Mossner et al, 2008). Administration of LY354740, a prototypical mixed mGlu2/mGlu3 agonist, effectively attenuated the disruptive effects of phencyclidine (PCP) on working memory, stereotypy, locomotion, and cortical glutamate efflux in the PCP model of SZ, at a dose that was without effects on spontaneous activity and corticolimbic dopamine neurotransmission (Moghaddam and Adams, 1998).…”

Risperidone-induced changes in DNA methylation from peripheral blood in first-episode schizophrenia parallel neuroimaging and cognitive phenotype

“…We obtained a replication data set involving participants from a prior study involving similar entry criteria (untreated first episode schizophrenia), treatment (4-6 weeks risperidone), and phenotyping [54] . This sample included four controls (2 men, 2 women; 2 African American, 1 Hispanic and 1 White; age range, 27-30) and three FESs (1 men, 2 women; 2 African American, 1 Hispanic; age range, ( Supplementary Table S1D).…”