Pharmacogenetics of antipsychotics: focus on the glutamatergic system

A major drawback of the therapy with antipsychotics is the lack of efficacy and the occurrence of extrapyramidal symptoms in some patients that can limit therapy and compliance. Thus, the availability of a predictive tool for response to antipsychotics is desirable. The glutamatergic system may be relevant to the pathophysiology of psychosis and the effects of antipsychotic treatments. We analyzed a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol in a sample of 101 acutely ill psychotic patients. Antipsychotic effect was investigated using PANSS and motor side effects using ESRS. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures ANOVA, p = 0.0002), followed by a subsequent fast adaptation. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher ESRS scores (overall p = 0.01, haplotype p = 0.000001). We replicated this finding in two independent samples (n = 71 and n = 118) of schizophrenic patients treated with antipsychotics. This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment.