Association between the polymorphic GRM3 gene and negative symptom improvement during olanzapine treatment

Purpose: The excitatory neurotransmitter glutamate has become an important area of focus for schizophrenia researchers. Polymorphisms in the type-three metabotropic glutamate receptor gene (GRM3) have been associated with the pathogenesis of schizophrenia. The purpose of this study was to determine whether a pharmacogenetic relationship exists between six polymorphisms of GRM3 and clinical improvement during olanzapine treatment in persons with schizophrenia. Method: Forty-two subjects meeting DSM-IV criteria for schizophrenia started olanzapine and were titrated to a fixed dose of 7.5-20 mg/day for 6 weeks. The Brief Psychiatric Rating Scale (BPRS) total score and the Scale for Assessment of Negative Symptoms (SANS) were completed at baseline and then weekly to assess psychopathology. Results: The principle finding of this study is that GRM3 polymorphisms were collectively significant predictors of negative symptom improvement in persons with schizophrenia treated with the atypical antipsychotic olanzapine. After controlling for baseline SANS scores, the genotypes as a whole were significant predictors of negative symptom improvement, accounting for approximately 28% of the variance in scores (F = 16.30, df = 29, p < 0.001). The single nucleotide polymorphism SNP1 (rs274622), located in a potential promoter region, had the most significant influence on SANS scores, but the effects of this locus could not be fully separated from the other polymorphisms. The mean decrease in SANS scores was 21% vs. 51% for SNP1 T/T + T/C and SNP1C/C subjects, respectively. Conclusion: These data suggest that polymorphisms in the GRM3 gene may be useful as predictors of negative symptom improvement in persons with schizophrenia treated with olanzapine.