Association study of AKT1 polymorphisms with clozapine response

Abstract

Background: Clozapine is an effective antipsychotic especially in patients which have been refractory to treatment with other antipsychotic drugs. There is a significant variability in clinical response during treatment with clozapine. The Akt/glycogen synthase kinase (GSK) 3 signaling cascade has been strongly associated with the action of dopamine, serotonin and antipsychotics in different rodent models. We investigated whether AKT1 polymorphisms would predict clozapine response in schizophrenia patients. Methods: We evaluated eight polymorphisms (rs2498784, rs1130214, rs2494746, rs10149779, rs2494738, rs3730358, rs3803304 and rs2494731) in 208 schizophrenia patients who were refractory to typical antipsychotics. These subjects underwent six month treatment period with clozapine and they assessed prospectively using the Brief Psychiatric Rating Scale (BPRS). Response was defined as 20% BPRS reduction after six months from the baseline. In a second step of our analysis, we evaluated whether AKT1 genetic variants were correlated with the psychopathology alterations during clozapine treatment. We carried out these tests using the percentage change in the BPRS (total psychopathology), BPOS (positive symptomatology) and BNEG (negative symptomatology). Results: Our results indicate no association of AKT1 polymorphisms with clozapine treatment response in schizophrenia subjects with European Caucasian ethnic background. The rs10149779 polymorphisms presented a trend towards an association with clozapine response in subjects with African-American background (permuted P = .123). Our findings suggest that haplotypes comprised of AKT1 polymorphisms do not predict treatment response in subjects with both European Caucasian and African-American ethnic backgrounds. Moreover, rur results suggest that there is no association of AKT1 polymorphisms and BPRS, BPOS or BNEG change after six months of clozapine treatment. Conclusion: We have found no significant association of AKT1 polymorphisms with clozapine response in our sample. This result corroborates with previously published findings that showed that rs1130214 and rs3730358 polymorphisms were not predictors of response to risperidone treatment in first-episode schizophrenia subjects from a Japanese cohort or treatment response to chlorpromazine or clozapine in a Chinese sample. Taken together, our results further suggest that polymorphisms in the AKT1 gene are not associated with antipsychotic treatment response in schizophrenia patients.