Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes.

Biomarkers which predict response to atypical antipsychotic drugs (AAPDs) increases their benefit/risk ratio. We sought to identify common variants in genes which predict response to lurasidone, an AAPD, by associating genome-wide association study (GWAS) data and changes (Δ) in Positive And Negative Syndrome Scale (PANSS) scores from two 6-week randomized, placebo-controlled trials of lurasidone in schizophrenia (SCZ) patients. We also included SCZ risk SNPs identified by the Psychiatric Genomics Consortium using a polygenic risk analysis. The top genomic loci, with uncorrected p<10-4, include: 1) synaptic adhesion (PTPRD, LRRC4C, NRXN1, ILIRAPL1, SLITRK1) and scaffolding (MAGI1, MAGI2, NBEA) genes, both essential for synaptic function; 2) other synaptic plasticity-related genes (NRG1/3 and KALRN); 3) the neuron-specific RNA splicing regulator, RBFOX1; and 4) ion channel genes, e.g. KCNA10, KCNAB1, KCNK9 and CACNA2D3). Some genes predicted response for patients with both European and African Ancestries. We replicated some SNPs reported to predict response to other atypical APDs in other GWAS. Although none of the biomarkers reached genome-wide significance, many of the genes and associated pathways have previously been linked to SCZ. Two polygenic modeling approaches, GCTA-GREML and PLINK-Polygenic Risk Score, demonstrated that some risk genes related to neurodevelopment, synaptic biology, immune response, and histones, also contributed to prediction of response. The top hits predicting response to lurasidone did not predict improvement with placebo. This is the first evidence from clinical trials that SCZ risk SNPs are related to clinical response to an AAPD. These results need to be replicated in an independent sample.

Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial.

Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.

Replication of SULT4A1-1 as a pharmacogenetic marker of olanzapine response and evidence of lower weight gain in the high response group.

AIM: Antipsychotic efficacy biomarkers have the potential to improve outcomes in psychotic patients. This study examined the effect of SULT4A1-1 haplotype status (rs2285162 [A]-rs2285167 [G]) on olanzapine response. PATIENTS & METHODS: We evaluated 87 olanzapine treated subjects from Phases 1, 1B and 2 of the CATIE trial for the impact of SULT4A1-1 status on change in Positive and Negative Syndrome Scale (PANSS) total score using two models of response. We also examined weight change. RESULTS: SULT4A1-1-positive status correlated with superior olanzapine response in Phase 1 (p = 0.004 for model 1 and p = 0.001 for model 2) and Phases 1B/2 (p = 0.05 for model 1 and p = 0.007 for model 2). SULT4A1-1-positive subjects gained significantly less weight per month on olanzapine, 0.15 lbs, than did SULT4A1-1-negative subjects, 2.27 lbs (p = 0.04). CONCLUSION: This study provides a second replication of superior olanzapine response in SULT4A1-1-positive subjects compared with SULT4A1-1-negative subjects. SULT4A1-1-positive subjects treated with olanzapine also gained less weight than SULT4A1-1-negative subjects.

Genotypic variation in the SV2C gene impacts response to atypical antipsychotics the CATIE study.

Pharmacogenetic (PGx) predictors of response would improve outcomes in antipsychotic treatment. Based on both biological rationale and prior evidence of an impact on Parkinson's disease, we conducted an association study for 106 SNPs in the synaptic vesicle protein 2C (SV2C) gene using genetic and treatment response data from the Clinical Trial of Antipsychotic Intervention Effectiveness (CATIE). We examined response to the atypical antipsychotics for Caucasian subjects in the blinded phases, Phases 1A, 1B, and 2, of CATIE with sample sizes as follows: olanzapine (N=134), quetiapine (N=124), risperidone (N=134), and ziprasidone (N=74). Response was defined as change in the Positive and Negative Syndrome Scale (PANSS) score using a mixed model repeat measures approach. Subjects homozygous for the T allele of rs11960832 displayed significantly worse response to olanzapine treatment, the only finding with study-wide significance (p=2.94×10(-5); false discovery rate=2.18×10(-2)). These subjects also displayed worse response to quetiapine with nominal significance (p=4.56×10(-2)). While no other SNP achieved study-wide significance, one SNP (rs10214163) influencing Parkinson's disease displayed nominally significant association with olanzapine and quetiapine response, while the second such SNP (rs30196) showed a statistical trend toward correlating with olanzapine and quetiapine response. Furthermore, both coding SNPs examined (rs31244 and rs2270927) displayed nominally significant correlations with treatment response: one for olanzapine (rs227092), and one for quetiapine (rs31244). The fact that multiple SNPs in SV2C may impact response to atypical antipsychotics suggests that further evaluation of SNPs in this gene as PGx predictors of antipsychotic response is warranted.

Sulfotransferase 4A1 Haplotype 1 (SULT4A1-1) Is Associated With Decreased Hospitalization Events in Antipsychotic-Treated Patients With Schizophrenia.

OBJECTIVE: To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predictor of hospitalization events due to the exacerbation of schizophrenia for patients treated with antipsychotic medications. Haplotypes were determined using single nucleotide polymorphism data. METHOD: The study included 417 white subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study with a DSM-IV diagnosis of schizophrenia. Patients were assigned to 1 of 4 atypical antipsychotics (olanzapine, quetiapine, risperidone, or ziprasidone) or to the first-generation antipsychotic perphenazine. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to measure if haplotype status impacted hospitalization events for these 5 treatments. Haplotype status was evaluated for its relationship to hospitalization events regardless of treatment and for the individual treatments, with or without previous exacerbation. Data for the CATIE study were collected from January 2001 to December 2004. The current post hoc analysis was performed between May 2011 and August 2011. RESULTS: In phase 1 of the trial, considering only the first hospitalization events, the haplotype had a significant impact on hospitalization events, with a hazard ratio for SULT4A1-1(-) versus SULT4A1-1(+) of 2.54 (P = .048). When prior exacerbation was included in the model for phase 1, the hazard ratio was 2.34 (P = .072) considering only the first hospitalization event and 2.71 (P = .039) considering all hospitalization events in the phase. When data for all phases were evaluated, SULT4A1-1(-) status was associated with increased hospitalization risk for subjects treated with olanzapine, with a hazard ratio of 8.26 (P = .041), and possibly for subjects treated with quetiapine, with a hazard ratio of 6.80 (P = .070). CONCLUSIONS: The SULT4A1-1 haplotype may be an important predictor of risk of hospitalization. SULT4A1-1(+) status was significantly associated with decreased risk of hospitalization when the subjects were treated with olanzapine.

Evidence for a SULT4A1 haplotype correlating with baseline psychopathology and atypical antipsychotic response.

AIM: This study evaluated the impact of SULT4A1 gene variation on psychopathology and antipsychotic drug response in Caucasian subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and a replication sample. PATIENTS & METHODS: SULT4A1 haplotypes were determined using SNP data. The relationship to baseline psychopathology was evaluated using linear regression of Positive and Negative Syndrome Scale (PANSS) total score. Drug response was evaluated using Mixed Model Repeat Measures (MMRM) for change in PANSS. RESULTS: For the CATIE sample, patients carrying a haplotype designated SULT4A1-1(+) displayed higher baseline PANSS (p = 0.03) and, when treated with olanzapine, demonstrated a significant interaction with time (p = 0.009) in the MMRM. SULT4A1-1(+) patients treated with olanzapine displayed improved response compared with SULT4A1-1(-) patients treated with olanzapine (p = 0.008) or to SULT4A1-1(+) patients treated with risperidone (p = 0.006). In the replication sample, SULT4A1-1(+) patients treated with olanzapine demonstrated greater improvement than SULT4A1-1(-) patients treated with olanzapine (p = 0.05) or than SULT4A1-1(+) patients treated with risperidone (p = 0.05). CONCLUSION: If validated, determination of SULT4A1-1 haplotype status might be useful for identifying patients who show an enhanced response to long-term olanzapine treatment. Original submitted 6 October 2010; Revision submitted 9 December 2010.

Estrogen receptor beta isoforms exhibit differences in ligand-activated transcriptional activity in an estrogen response element sequence-dependent manner.

Estrogen receptor beta (ERbeta) has been reported to have lower estradiol (E2)-induced transcriptional activity than human (h)ERalpha from estrogen response element (ERE)-driven reporters in transiently transfected cells. Conflicting data for activities of full-length and short hERbeta [hERbeta1, 530 amino acids (aa); and hERbeta1s, 477aa] have been reported. To test the hypothesis that hERbeta1 has higher transcriptional activity than hERbeta1s, we compared E2, 2,3-bis(4-hydroxyphenyl)propionitrile (a selective ERbeta agonist), and resveratrol-induced transcription by hERbeta1, hERbeta1s, and rat (r) ERbeta with hERalpha on different EREs in transiently transfected CHO-K1 and HEC-1A cells. Our results demonstrate for the first time that hERbeta1 has similar E2-induced activity to hERalpha and greater activity than rERbeta or hERbeta1s on a consensus palindromic ERE, either as a single or double copy; a minimal ERE; and the nonpalindromic pS2 ERE. 2,3-Bis(4-hydroxyphenyl)propionitrile showed greater efficacy with hERbeta1 and hERbeta1s than for rERbeta or hERalpha. We found that transcriptional differences between the ERbeta isoforms and ERalpha depend on the ERE sequence, confirming that the DNA sequence bound by ER is an allosteric effector of ER action. For the minimal 13-bp ERE and the pS2 ERE, the increase in transcriptional activity with hERbeta1 correlated with increased binding affinity. Coactivators steroid receptor coactivator-1 and cAMP response element binding protein-binding protein synergistically activated hERalpha and ERbeta transcription and showed reduced efficacy with rERbeta and hERbeta1s, suggesting a role for the N terminus of ERbeta1 in coactivator interaction. Collectively, these data indicate that the cellular expression of ERbeta isoforms may differentially impact ERE-regulated target gene expression in a ligand-dependent manner.