Abstract 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, RBFOX 1; 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.
Abstract 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 Leu260 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 Ser168 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.
The complex Na3{NiII(nmp)}3S3BTAalk) (1) (nmp2– = deprotonated form of N-(2-mercaptoethyl)picolinamide; H3S3BTAalk = N 1,N 3,N 5-tris(2-mercaptoethyl)benzene-1,3,5-tricarboxamide, where H = ...dissociable protons), supported by the thiolate-benzenetricarboxamide scaffold (S3BTAalk), has been synthesized as a trimetallic model of nickel-containing superoxide dismutase (NiSOD). X-ray absorption spectroscopy (XAS) and 1H NMR measurements on 1 indicate that the NiII centers are square-planar with N2S2 coordination, and Ni–N and Ni–S distances of 1.95 and 2.16 Å, respectively. Additional evidence from IR indicates the presence of H-bonds in 1 from the approximately −200 cm–1 shift in νNH from free ligand. The presence of H-bonds allows for speciation that is temperature-, concentration-, and solvent-dependent. In unbuffered water and at low temperature, a dimeric complex (1 A ; λ = 410 nm) that aggregates through intermolecular NH···OC bonds of BTA units is observed. Dissolution of 1 in pH 7.4 buffer or in unbuffered water at temperatures above 50 °C results in monomeric complex (1 M ; λ = 367 nm) linked through intramolecular NH···S bonds. DFT computations indicate a low energy barrier between 1 A and 1 M with nearly identical frontier MOs and Ni–ligand metrics. Notably, 1 A and 1 M exhibit remarkable stability in protic solvents such as MeOH and H2O, in stark contrast to monometallic NiII(nmp)(SR)− complexes. The reactivity of 1 with excess O2, H2O2, and O2 •– is species-dependent. IR and UV–vis reveal that 1 A in MeOH reacts with excess O2 to yield an S-bound sulfinate, but does not react with O2 •–. In contrast, 1 M is stable to O2 in pH 7.4 buffer, but reacts with O2 •– to yield a putative NiII(nmp)(O2)− complex from release of the BTA-thiolate based on EPR.
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.
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.
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).
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.
Abstract 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.
Summary Background Pulmonary rehabilitation (PR) is recommended for patients with respiratory disease who feel limited by breathlessness. Poor attendance wastes finite resources, increases waiting ...times and is probably associated with poorer clinical outcomes. We investigated what factors, identifiable from routine hospital data, predict poor attendance once enrolled in a pulmonary rehabilitation programme (PRP). Methods Retrospective case note study of 239 patients (60% male) of mean (S.D.) age of 66.6 (8.7) years, mean FEV1 39.6 (14.6)% predicted, who attended a 6 (short) or 18 (long) week, 18 session, outpatient PRP. Attendance data was analysed using linear multiple regression analysis with the log transformed odds ratio of attendance as the dependant variable. Results Overall median attendance was 16 out of 18 sessions. Being a current smoker ( p <0.05), attending a long PRP ( p <0.05), more previous hospital admissions ( p <0.01), higher Medical Research Council (MRC) dyspnoea score ( p <0.01) or enduring a long journey ( p <0.001) were independent risk factors for low attendance. Lower body mass index (BMI) and distance from PR centre were of borderline importance ( p <0.1) but age, gender, co-morbidity, respiratory diagnosis, FEV1 and St. Georges Respiratory Questionnaire Score at baseline did not predict later attendance ( p >0.2). Conclusions Attendance at PRPs is independently influenced by smoking status, the degree of breathlessness, frequency of hospital admissions, length of the programme and journey time.
Medicine Lake Volcano (MLV), located in the southern Cascades ∼
55 km east-northeast of contemporaneous Mount Shasta, has been found by exploratory geothermal drilling to have a surprisingly silicic ...core mantled by mafic lavas. This unexpected result is very different from the long-held view derived from previous mapping of exposed geology that MLV is a dominantly basaltic shield volcano. Detailed mapping shows that <
6% of the ∼
2000 km
2 of mapped MLV lavas on this southern Cascade Range shield-shaped edifice are rhyolitic and dacitic, but drill holes on the edifice penetrated more than 30% silicic lava. Argon dating yields ages in the range ∼
475 to 300 ka for early rhyolites. Dates on the stratigraphically lowest mafic lavas at MLV fall into this time frame as well, indicating that volcanism at MLV began about half a million years ago. Mafic compositions apparently did not dominate until ∼
300 ka. Rhyolite eruptions were scarce post-300 ka until late Holocene time. However, a dacite episode at ∼
200 to ∼
180 ka included the volcano's only ash-flow tuff, which was erupted from within the summit caldera. At ∼
100 ka, compositionally distinctive high-Na andesite and minor dacite built most of the present caldera rim. Eruption of these lavas was followed soon after by several large basalt flows, such that the combined area covered by eruptions between 100 ka and postglacial time amounts to nearly two-thirds of the volcano's area. Postglacial eruptive activity was strongly episodic and also covered a disproportionate amount of area. The volcano has erupted 9 times in the past 5200 years, one of the highest rates of late Holocene eruptive activity in the Cascades. Estimated volume of MLV is ∼
600 km
3, giving an overall effusion rate of ∼
1.2 km
3 per thousand years, although the rate for the past 100 kyr may be only half that. During much of the volcano's history, both dry HAOT (high-alumina olivine tholeiite) and hydrous calcalkaline basalts erupted together in close temporal and spatial proximity. Petrologic studies indicate that the HAOT magmas were derived by dry melting of spinel peridotite mantle near the crust mantle boundary. Subduction-derived H
2O-rich fluids played an important role in the generation of calcalkaline magmas. Petrology, geochemistry and proximity indicate that MLV is part of the Cascades magmatic arc and not a Basin and Range volcano, although Basin and Range extension impinges on the volcano and strongly influences its eruptive style. MLV may be analogous to Mount Adams in southern Washington, but not, as sometimes proposed, to the older distributed back-arc Simcoe Mountains volcanic field.
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.
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.
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).
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.
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.
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.
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).
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.
Estrogen receptor β (ERβ) has been reported to have lower estradiol (E2)-induced transcriptional activity than human (h)ERα from estrogen response element (ERE)-driven reporters in transiently ...transfected cells. Conflicting data for activities of full-length and short hERβ hERβ1, 530 amino acids (aa); and hERβ1s, 477aa have been reported. To test the hypothesis that hERβ1 has higher transcriptional activity than hERβ1s, we compared E2, 2,3-bis(4-hydroxyphenyl)propionitrile (a selective ERβ agonist), and resveratrol-induced transcription by hERβ1, hERβ1s, and rat (r) ERβ with hERα on different EREs in transiently transfected CHO-K1 and HEC-1A cells. Our results demonstrate for the first time that hERβ1 has similar E2-induced activity to hERα and greater activity than rERβ or hERβ1s 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 hERβ1 and hERβ1s than for rERβ or hERα. We found that transcriptional differences between the ERβ isoforms and ERα 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 hERβ1 correlated with increased binding affinity. Coactivators steroid receptor coactivator-1 and cAMP response element binding protein-binding protein synergistically activated hERα and ERβ transcription and showed reduced efficacy with rERβ and hERβ1s, suggesting a role for the N terminus of ERβ1 in coactivator interaction. Collectively, these data indicate that the cellular expression of ERβ isoforms may differentially impact ERE-regulated target gene expression in a ligand-dependent manner.
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