Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial.
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 [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.
Project description:AIM: To determine optimal sampling strategies to allow the calculation of clinical pharmacokinetic parameters for selected antipsychotic medicines using a pharmacometric approach. METHODS: This study utilized previous population pharmacokinetic parameters of the antipsychotic medicines aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone (including 9-OH risperidone) and ziprasidone. d-optimality was utilized to identify time points which accurately predicted the pharmacokinetic parameters (and expected error) of each drug at steady-state. A standard two stage population approach (STS) with MAP-Bayesian estimation was used to compare area under the concentration-time curves (AUC) generated from sparse optimal time points and rich extensive data. Monte Carlo Simulation (MCS) was used to simulate 1000 patients with population variability in pharmacokinetic parameters. Forward stepwise regression analysis was used to determine the most predictive time points of the AUC for each drug at steady-state. RESULTS: Three optimal sampling times were identified for each antipsychotic medicine. For aripiprazole, clozapine, olanzapine, perphenazine, risperidone, 9-OH risperidone, quetiapine and ziprasidone the CV% of the apparent clearance using optimal sampling strategies were 19.5, 8.6, 9.5, 13.5, 12.9, 10.0, 16.0 and 10.7, respectively. Using the MCS and linear regression approach to predict AUC, the recommended sampling windows were 16.5-17.5?h, 10-11?h, 23-24?h, 19-20?h, 16.5-17.5?h, 22.5-23.5?h, 5-6?h and 5.5-6.5?h, respectively. CONCLUSION: This analysis provides important sampling information for future population pharmacokinetic studies and clinical studies investigating the pharmacokinetics of antipsychotic medicines.
Project description:OBJECTIVE:Some atypical antipsychotics are associated with metabolic side effects, which are risk factors for gestational diabetes. The authors examined the risk of developing gestational diabetes associated with the continuation of treatment with aripiprazole, ziprasidone, quetiapine, risperidone, and olanzapine during pregnancy compared with discontinuation of these antipsychotic drugs. METHOD:Nondiabetic pregnant women who were linked to a live-born infant and enrolled in Medicaid (2000-2010) and who received one or more prescriptions dispensed for an antipsychotic drug during the 3 months before pregnancy were included in the analyses. Among 1,543,334 pregnancies, some expectant mothers at baseline were receiving treatment with aripiprazole (N=1,924), ziprasidone (N=673), quetiapine (N=4,533), risperidone (N=1,824), or olanzapine (N=1,425). For each antipsychotic drug, women with two or more dispensings ("continuers") were compared with women with no dispensings ("discontinuers") during the first half of pregnancy. A generalized linear model and propensity-score stratification were used to obtain absolute and relative risks of developing gestational diabetes, with adjustment for confounders. RESULTS:Women who continued antipsychotic treatment during pregnancy generally had higher comorbidity and longer baseline antipsychotic use. The crude risk of developing gestational diabetes among continuers compared with discontinuers, respectively, was 4.8% and 4.5% for aripiprazole, 4.2% and 3.8% for ziprasidone, 7.1% and 4.1% for quetiapine, 6.4% and 4.1% for risperidone, and 12.0% and 4.7% for olanzapine. The adjusted relative risks were 0.82 (95% CI=0.50-1.33) for aripiprazole, 0.76 (95% CI=0.29-2.00) for ziprasidone, 1.28 (95% CI=1.01-1.62) for quetiapine, 1.09 (95% CI=0.70-1.70) for risperidone, and 1.61 (95% CI=1.13-2.29) for olanzapine. CONCLUSIONS:Compared with women who discontinued use of an atypical antipsychotic medication before the start of pregnancy, women who continued treatment with olanzapine or quetiapine had an increased risk of gestational diabetes that may be explained by the metabolic effects associated with these two drugs.
Project description:BACKGROUND:According to the American Psychiatric Association Clinical Practice Guidelines for schizophrenia, second-generation antipsychotics may be specifically indicated for the treatment of depression in schizophrenia. We examined the impact of these medications on symptoms of depression using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), conducted between January 2001 and December 2004. METHOD:Patients with DSM-IV-defined schizophrenia (N = 1,460) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of 4 second-generation drugs (olanzapine, quetiapine, risperidone, or ziprasidone) and followed for up to 18 months (phase 1). Patients with tardive dyskinesia were excluded from the randomization that included perphenazine. Depression was assessed with the Calgary Depression Scale for Schizophrenia (CDSS). Mixed models were used to evaluate group differences during treatment with the initially assigned drug. An interaction analysis evaluated differences in drug response by whether patients had a baseline score on the CDSS of ? 6, indicative of a current major depressive episode (MDE). RESULTS:There were no significant differences between treatment groups on phase 1 analysis, although there was a significant improvement in depression across all treatments. A significant interaction was found between treatment and experiencing an MDE at baseline (P = .05), and further paired comparisons suggested that quetiapine was superior to risperidone among patients who were in an MDE at baseline (P = .0056). CONCLUSIONS:We found no differences between any second-generation antipsychotic and the first-generation antipsychotic perphenazine and no support for the clinical practice recommendation, but we did detect a signal indicating a small potential difference favoring quetiapine over risperidone only in patients with an MDE at baseline.
Project description:Persons with schizophrenia die earlier than the general population, in large part due to cardiovascular disease. The study objective was to examine effects of different antipsychotic treatments on estimates of 10-year coronary heart disease (CHD) risk calculated by the Framingham Heart Study formula.Change in 10-year risk for CHD was compared between treatment groups in 1125 patients followed for 18 months or until treatment discontinuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial.The covariate-adjusted mean change in 10-year CHD risk differed significantly between treatments. Olanzapine was associated with a 0.5% (SE 0.3) increase and quetiapine, a 0.3% (SE 0.3) increase; whereas risk decreased in patients treated with perphenazine, -0.5% (SE 0.3), risperidone, -0.6% (SE 0.3), and ziprasidone -0.6% (SE 0.4). The difference in 10-year CHD risk between olanzapine and risperidone was statistically significant (p=0.004). Differences in estimated 10-year CHD risk between drugs were most marked in the tertile of subjects with a baseline CHD risk of at least 10%. Among individual CHD risk factors used in the Framingham formula, only total and HDL cholesterol levels differed between treatments.These results indicate that the impact on 10-year CHD risk differs significantly between antipsychotic agents, with olanzapine producing the largest elevation in CHD risk of the agents studied in CATIE.
Project description:Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (-76%; confidence interval (CI), -83%, -66%; P < 0.001) and aripiprazole (-52%; CI, -62%, -39%; P < 0.001), but not for olanzapine (-9%; CI, -28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.
Project description:OBJECTIVE:The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes. METHOD:Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments. RESULTS:Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33-41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall). CONCLUSIONS:Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study.
Project description:Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 10(-8), q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 10(-7), q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 10(-7), q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.
Project description:Hallucinations are prevalent in schizophrenia and related psychotic disorders and may have severe consequences for the affected patients. Antipsychotic drug trials that specifically address the anti-hallucinatory effectiveness of the respective drugs in representative samples are rare. The aims of the present study were to investigate the rate and severity of hallucinations in acutely admitted psychotic patients at hospital admission and discharge or after 6 weeks at the latest, if not discharged earlier (discharge/6 weeks); and to compare the anti-hallucinatory effectiveness of risperidone, olanzapine, quetiapine, and ziprasidone with up to 2 years' follow-up.Adult patients acutely admitted to an emergency ward for psychosis were consecutively randomized to risperidone, olanzapine, quetiapine, or ziprasidone and followed for up to 2 years in a pragmatic design. Participants were assessed repeatedly using the hallucinatory behavior item of the Positive and Negative Syndrome Scale (PANSS).A total of 226 patients, 30.5% of those assessed for eligibility, were randomized and 68% were hallucinating at baseline. This proportion was reduced to 33% at discharge/6 weeks. In the primary analyses based on intention to treat groups of patients experiencing frequent hallucinations, the quetiapine and ziprasidone groups both had faster decreases of the mean hallucination scores than the risperidone group.Hallucinations are fairly responsive to antipsychotic drug treatment and differential anti-hallucinatory effectiveness may be found among existing antipsychotic drugs. If replicated, this could pave the way for a more targeted pharmacotherapy based on individual symptom profiles, rather than on the diagnostic category.ClinicalTrials.gov ID; NCT00932529.
Project description:To investigate whether differential influence on the QTc interval exists among four second generation antipsychotics (SGAs) in psychosis.Data were drawn from a pragmatic, randomized head-to-head trial of the SGAs risperidone, olanzapine, quetiapine, and ziprasidone in acute admissions patients with psychosis, and with follow-up visits at discharge or maximally 6-9 wk, 3, 6, 12 and 24 mo. Electrocardiograms were recorded on all visits. To mimic clinical shared decision-making, the patients were randomized not to a single drug, but to a sequence of the SGAs under investigation. The first drug in the sequence defined the randomization group, but the patient and/or clinician could choose an SGA later in the sequence if prior negative experiences with the first one(s) in the sequence had occurred. The study focuses on the time of, and actual use of the SGAs under investigation, that is until treatment discontinuation or change, in order to capture the direct medication effects on the QTc interval. Secondary intention-to-treat (ITT) analyses were also performed.A total of 173 patients, with even distribution among the treatment groups, underwent ECG assessments. About 70% were males and 43% had never used antipsychotic drugs before the study. The mean antipsychotic doses in milligrams per day with standard deviations (SD) were 3.4 (1.2) for risperidone, 13.9 (4.6) for olanzapine, 325.9 (185.8) for quetiapine, and 97.2 (42.8) for ziprasidone treated groups. The time until discontinuation of the antipsychotic drug used did not differ in a statistically significant way among the groups (Log-Rank test: P = 0.171). The maximum QTc interval recorded during follow-up was 462 ms. Based on linear mixed effects analyses, the QTc interval change per day with standard error was -0.0030 (0.0280) for risperidone; -0.0099 (0.0108) for olanzapine; -0.0027 (0.0170) for quetiapine, and -0.0081 (0.0229) for ziprasidone. There were no statistically significant differences among the groups in this regard. LME analyses based on ITT groups (the randomization groups), revealed almost identical slopes with -0.0063 (0.0160) for risperidone, -0.0130 (0.0126) for olanzapine, -0.0034 (0.0168) for quetiapine, and -0.0045 (0.0225) for ziprasidone.None of the SGAs under investigation led to statistically significant QTc prolongation. No statistically significant differences among the SGAs were found.
Project description:Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the relationship between the GRM7 variants and the risk of schizophrenia is still uncertain, and there are significant individual variations in response to the antipsychotic drugs. In order to identify susceptible gene and drug-response-related markers, 2413 subjects in our research were chosen for determining drug-response-related markers in schizophrenia. The rs1516569 variant (OR?=?0.95, P?<?3.47?×?10-4) was a significant risk factor, and a single-nucleotide polymorphism of GRM7 gene- rs9883258 (OR?=?0.84, P?=?2.18?×?10-3) has been determined as potential biomarkers for therapeutic responses of seven commonly used antipsychotic drugs (aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone and ziprasidone) in Chinese Han population; Significant associations with treatment response for several single-nucleotide polymorphisms in every antipsychotic drugs, such as rs779746 (OR?=?1.39, P?=?0.03), rs480409 (OR?=?0.73, P?=?0.04), rs78137319 (OR?=?3.09, P?=?0.04), rs1154370 (OR?=?1.51, P?=?0.006) have been identified in our study. Hence our research elucidates that GRM7 variants play the critical role of predicting the risk of schizophrenia and antipsychotic effect of seven common drugs.