These models have been tested on a limited basis in the context of susceptibility to TD in samples that we and other investigators have studied; the scope of such testing is constrained by the size of the samples. The additive effects of two genetic

variants on susceptibility to TD were first reported by Scgman et al.16 Patients who carried both the gly9 allele of the DRD3 ser9gly polymorphism and the ser23 allele of the 5-HT2C cys23ser polymorphism showed evidence of an additive effect Inhibitors,research,lifescience,medical of the two risk alleles, both of which had been shown to separately increase risk for TD. As shown in Figure 5,16 the highest, AIMS orofacial dyskinesia scores were observed in patients who carried both mutant risk alleles. Figure 5. Abnormal Involuntary Movements Scale (AIMS) orofacial dyskinesia scores among patients carrying: 5-HT2C-cys Inhibitors,research,lifescience,medical and DRD3-ser alleles (both wild type);

5-HT2C-cys and DRD3-gly (wild type + mutant); 5-HT2C-ser and DRD3-ser (mutant +wild type); or, 5-HT2C-ser … Studying gene-gene Inhibitors,research,lifescience,medical interaction and risk for TD, Segman et al17 selleck chemical examined the interactive contribution of a T→C polymorphism in the promoter region of the cytochrome P450 17α-hydroxylase gene (CYP17) and the ser9gly polymorphism of DRD3 that was previously shown to be associated with TD. CYP17 variability could influence susceptibility to TD because of effects on neuroprotective capacity or dopamine output through its role in the conversion of the neurosteroid, pregnanolone, to dehydroepiandrosterone (DHEA). A T→C transition Inhibitors,research,lifescience,medical (A2 allele) in the 5′ promoter region of the CYP17 gene creates an additional Spl type (CCACC box) promoter site, resulting in a functionally relevant, increase in transcription rate.18 Segman et al17 found that the T→C polymorphism was not in itself associated with TD. However, there was a significant excess of DRD3 gly allele carriers among carriers of the CYP17 CC genotype with TD compared with those without TD

(75.0% vs 14.3%; X 2=6.0, df=1, P=0.01). Significant differences were not observed among carriers Inhibitors,research,lifescience,medical of the CYP17TT genotype or CYP17TC genotypes with TD and carriers of these genotypes without TD. Two way analysis of variance Brefeldin_A (ANOVA) with age at first, antipsychotic treatment as covariate showed a significant main effect of DRD3 genotype on AIMS total score (F=14.9, df=1, 106, P=0.0002). There was no main effect, of CYP17 genotype on the AIMS score. There was a significant, interaction between DRD3 and CYP17 genotype on AIMS total score (F=4.2, df=2, 106, P=0.02). Figure 6 shows adjusted mean AIMS scores (derived from analysis of covariance [ANCOVA]) for the patients selleck chemicals grouped according to DRD3 and CYP17 genotype. Posthoc Newman-Keuls tests showed that the highest AIMS total (P<0.03) was in patients carrying the DRD3 gly9 allele and the CYP17 CC genotype. Figure 6.