Abstract
ABT-925, a selective dopamine D3 receptor (DRD3) antagonist, was tested in schizophrenia. A DRD3 gene polymorphism results in an S9G amino-acid change that has been associated with lower risk of schizophrenia, higher affinity for dopamine and some antipsychotics, and differential response to some antipsychotics. The effect of S9G genotype on response to ABT-925 was examined. DNA samples (N=117) were collected in a proof-of-concept, double-blind, randomized, placebo-controlled study of ABT-925 (50 or 150 mg QD) in acute exacerbation of schizophrenia. A pre-specified analysis assessed impact of genotype (SS versus SG+GG) on change from baseline to final evaluation for the Positive and Negative Syndrome Scale (PANSS) total score using analysis of covariance with genotype, treatment and genotype-by-treatment interaction as factors, and baseline score as covariate. Significant genotype-by-treatment interaction (P=0.015) was observed for change from baseline to final evaluation for the PANSS total score. Within subgroup analyses showed significant improvement from placebo in the SG+GG group treated with ABT-925 150 mg. More favorable clinical outcomes were observed in patients treated with ABT-925 150 mg who carried the DRD3 G allele than in those who carried the DRD3 SS genotype.
Highlights
ABT-925 is a selective dopamine D3 receptor (DRD3) antagonist in vitro.[1]
Given the strong evidence of the role of dopamine in the etiology of schizophrenia and the potential of these genetic loci to affect drug response, we examined specific polymorphisms in DRD3, catechol-o-methyl transferase (COMT) and SLC6A3, and sought to determine whether subjects’ genotypes at specific loci were associated with a salutary response to ABT-925
A minimum receptor occupancy may be required for D3 antagonism to produce antipsychotic effects, as has been shown for the D2 receptor.[9,10]
Summary
ABT-925 is a selective dopamine D3 receptor (DRD3) antagonist in vitro.[1]. We recently reported that ABT-925 regimens of 50 and 150 mg QD were well tolerated, but did not significantly improve schizophrenia symptoms in acutely ill patients.[2]. Genetic polymorphisms at dopamine-relevant loci can increase sensitivity to dopamine and dopamine agonists[4] and may reveal subsets of schizophrenia patients in whom lower doses of D3 receptor antagonists could provide therapeutic benefit. A single-nucleotide polymorphism in the DRD3 gene results in a greater affinity of DRD3 for dopamine and some D3 receptor antagonists.[4] Associations between this Ser9Gly (S9G) single-nucleotide polymorphism and response to antipsychotics have been reported, treatment effects have been associated with each allele, reviewed in Arranz and de Leon.[5] A Val158Met (V158M) single-nucleotide polymorphism in the catechol-o-methyl transferase (COMT) gene reduces the ability of COMT to catabolize dopamine, and may affect subjects’ response to treatment with antipsychotics.[6,7] Polymorphisms in the dopamine transporter (SLC6A3) gene have been reported to affect transporter levels in the brain,[8] potentially modulating the levels of dopamine and affecting the response to antipsychotics. Given the strong evidence of the role of dopamine in the etiology of schizophrenia and the potential of these genetic loci to affect drug response, we examined specific polymorphisms in DRD3, COMT and SLC6A3, and sought to determine whether subjects’ genotypes at specific loci were associated with a salutary response to ABT-925
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