Trials Of Intervention Effectiveness Study Research Articles

Insomnia and inflammation in phase 1 of the clinical antipsychotic trials of intervention effectiveness study

Insomnia and inflammation are both common in schizophrenia. In the general population, insomnia is associated with inflammation. In n=519 subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, terminal insomnia was investigated as an indicator of inflammation using non-parametric ANCOVA. After controlling for potential confounders, insomnia was significantly associated with higher blood IL-6 (F=4.12, p=0.007) and leptin (F=9.67, p<0.001) with large effect sizes (d=1.03 and d=0.79, respectively). Findings suggest that the assessment of insomnia is relevant to studies of inflammation in schizophrenia, and germane to trials of adjunctive hypnotics and anti-inflammatory agents in these patients.

Total and differential white blood cell counts, inflammatory markers, adipokines, and incident metabolic syndrome in phase 1 of the clinical antipsychotic trials of intervention effectiveness study

ObjectiveThe metabolic syndrome is highly prevalent in patients with schizophrenia. We previously found that blood C-reactive protein (CRP), interleukin-6 (IL-6), and leptin levels were predictors of current metabolic syndrome in schizophrenia. In the present study, we investigated whether baseline levels of total and differential white blood cell (WBC) counts, inflammatory markers, and adipokines predicted incident metabolic syndrome in schizophrenia. MethodFor subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial who did not have metabolic syndrome at baseline (n = 726), WBC counts, inflammatory markers, and adipokines were investigated as predictors of incident metabolic syndrome over 12 months of antipsychotic treatment. Cox proportional hazards regression models, controlling for multiple potential confounding factors, were used to investigate these associations. Results39% of subjects (n = 280) had incident metabolic syndrome over 12 months. After controlling for potential confounders, baseline blood IL-6 (HR = 1.12, 95% CI 1.01–1.24, p = 0.031) and leptin (HR = 1.12, 95% CI 1.01–1.24, p = 0.038) were significant predictors of incident metabolic syndrome, and there was a trend-level association with CRP (HR = 1.09, 95% CI 1.00–1.19, p = 0.059). ConclusionsOur findings provide additional evidence that measurement of inflammatory markers and adipokines are germane to the clinical care of patients with schizophrenia. Specifically, these markers may identify—prior to treatment—patients with schizophrenia at heightened risk for incident adverse cardiometabolic effects of antipsychotics. Given the tremendous burden of cardiovascular disease morbidity and mortality in schizophrenia, vigilant screening for and treatment of metabolic risk factors in this patient population are warranted.

Inflammation, substance use, psychopathology, and cognition in phase 1 of the clinical antipsychotic trials of intervention effectiveness study

IntroductionSchizophrenia has been associated with aberrant blood levels of inflammatory markers. However, patients with comorbid illicit drug use have been inadequately studied with respect to immune function. Furthermore, associations between inflammatory markers, psychopathology, and cognition have been inconsistently considered. We investigated relationships between inflammatory markers, comorbid marijuana and cocaine use, and psychopathology and cognition in patients with schizophrenia. MethodFor subjects with available fasting data from the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, inflammatory markers were investigated as predictors of psychopathology and cognition in patients with and without comorbid marijuana or cocaine use, using linear regression models controlling for potential confounding factors. ResultsCompared to subjects with a negative urine drug screen (UDS), marijuana use was a predictor of higher lymphocytes and E-selectin, and lower leptin (p≤0.04 for each); cocaine use was a predictor of higher adiponectin (p=0.04). In subjects with marijuana use, lower WBC and higher IL-6 were predictors of higher PANSS total score (p<0.05 for each). In subjects with cocaine use, lower total and differential WBC were predictors of higher PANSS total score (p<0.04 for each). In younger, non-obese subjects with a negative UDS, higher monocytes and IL-6 were predictors of PANSS total score (p<0.04 for each). ConclusionsOur findings provide additional evidence that inflammation may be associated with psychopathology and cognition in some patients with schizophrenia. Furthermore, there is preliminary evidence for differential effects of comorbid marijuana and cocaine use on these relationships.

175.3 Inflammation, Substance use, Symptoms, and Cognition in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study

Background: Schizophrenia has been associated with immune system dysfunction and aberrant blood levels of inflammatory markers. However, patients with comorbid illicit drug use have been inadequately studied with respect to immune function. Furthermore, associations between inflammatory markers, symptoms, and cognition have been inconsistently considered. We investigated relationships between inflammatory markers, comorbid marijuana and cocaine use, and symptoms and cognition in patients with schizophrenia. Methods: For subjects with available fasting data from the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, inflammatory markers were investigated as predictors of symptoms and cognition in patients with and without comorbid marijuana or cocaine use, using linear regression models controlling for potential confounding factors. Results: Marijuana use was a predictor of higher lymphocytes and E-selectin and lower leptin (P ≤ .04 for each). Cocaine use was a predictor of higher adiponectin (P = .04). In subjects with marijuana use, lower WBC and higher IL-6 were predictors of higher PANSS total score (P < .05 for each). In subjects with cocaine use, lower total and differential WBC were predictors of higher PANSS total score (P < .04 for each). In younger, non-obese subjects without substance use comorbidity, higher monocytes and IL-6 were predictors of PANSS total score (P < .04 for each). In older, alcohol-abstinent subjects, higher CRP was a predictor of greater impairments in processing speed, working memory, and global cognition (P < .04 for each). Conclusion: Our findings provide additional evidence that inflammatory markers be germane to the clinical care of some patients with schizophrenia, and are associated with symptoms and cognition. Furthermore, there is preliminary evidence for differential effects of comorbid marijuana and cocaine use on these relationships.

Total and differential white blood cell counts, inflammatory markers, adipokines, and the metabolic syndrome in phase 1 of the clinical antipsychotic trials of intervention effectiveness study

ObjectiveThe metabolic syndrome is highly prevalent in patients with schizophrenia, and is associated with a state of chronic, low-grade inflammation. We investigated relationships between total and differential white blood cell (WBC) counts, inflammatory markers, adipokines and the metabolic syndrome in patients with schizophrenia. MethodFor subjects with available data from the baseline/screening visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, WBC counts, inflammatory markers, and adipokines were investigated as predictors of the metabolic syndrome (and its components), using linear and binary logistic regression models, controlling for potential confounding effects of age, sex, race, smoking, fasting status, alcohol, and illicit drug use. ResultsAfter controlling for potential confounders, blood CRP, interleukin-6, and leptin were significant predictors of all five individual components of the metabolic syndrome (as both continuous and categorical outcome measures). Furthermore, total WBC (OR=2.31, 95% CI 1.58–3.41, p<0.01) and lymphocyte (OR=2.51, 95% CI 1.75–3.60, p<0.01) counts were the strongest predictors of current metabolic syndrome. ConclusionsOur findings provide the strongest evidence to date that measurement of total and differential WBC counts are germane to the clinical care of patients with schizophrenia, and that inflammation and adipokines are associated with metabolic disturbance in these patients.

Clinical and functional outcomes in people with schizophrenia with a high sense of well-being.

Optimal outcome in schizophrenia is thought to include remission of symptoms, functional recovery, and improved subjective well-being. The present study examined the characteristics of individuals with schizophrenia who report being satisfied with their life in general. Individuals with schizophrenia who participated in the Clinical Antipsychotic Trial of Intervention Effectiveness study were included in the present analysis. Approximately half of the individuals evaluated reported a high level of life satisfaction, even while many concurrently described themselves as at least moderately ill and experiencing moderate-severe symptoms and manifested severe functional deficits. Of all individuals evaluated, only about 1% experienced what was considered to be optimal outcome. Individuals with schizophrenia are able to experience a high level of life satisfaction, despite experiencing severe illness and functional deficits. Those involved in care should be aware that life satisfaction as an outcome is not necessarily associated with symptom remission and superior functioning.

Motivational deficits and cognitive test performance in schizophrenia.

Motivational and cognitive deficits are core features of schizophrenia, both closely linked with functional outcomes. Although poor effort and decreased motivation are known to affect performance on cognitive tests, the extent of this relationship is unclear in patients with schizophrenia. To evaluate the association between intrinsic motivation and cognitive test performance in patients with schizophrenia. Cross-sectional and 6-month prospective follow-up study performed at 57 sites in the United States, including academic and community medical treatment centers, participating in the Clinical Antipsychotic Trials of Intervention Effectiveness study. The primary sample included 431 stable patients with a DSM-IV diagnosis of schizophrenia currently receiving a stable medication regimen. Cognitive performance and intrinsic motivation were evaluated using a comprehensive neuropsychological test battery and a derived measure from the Heinrichs-Carpenter Quality of Life Scale, respectively. Symptom severity and functional status were also assessed. The primary outcome variable was global neurocognition. Individual domains of cognition were also evaluated for their association with motivation. Level of intrinsic motivation was significantly and positively correlated with global cognitive test performance, a relationship that held for each domain of cognition evaluated (correlation range, 0.20-0.34; P < .001). This association was found to be reliable after statistically accounting for positive, negative, depressive, and overall symptom severity (P < .05) and after accounting for community functioning (P < .001). The relationship between motivation and cognitive performance also remained significant after controlling for antipsychotic dose (P < .05). Prospective increase in motivation during the 6-month follow-up was also found to be significantly related to improvement in global cognitive performance (P < .05). The present findings provide strong support for a robust and reliable relationship between motivation and cognitive performance and suggest that test performance is not purely a measure of ability. Future studies assessing cognition in patients with schizophrenia should consider potential moderating variables such as effort and motivation. Implications for the assessment and interpretation of cognitive impairment based on neuropsychological test measures in schizophrenia are discussed, especially in the case of clinical trials for cognition-enhancing treatments. clinicaltrials.gov Identifier: NCT00014001.

Neurocognitive Functioning of Individuals With Schizophrenia: Using and Not Using Drugs

Research on neurocognition in schizophrenia, using modest samples and self-rated assessments, reports drug use contributes to improved rather than impaired cognitive function. We have sought to replicate these findings in a large sample of patients that had their drug-use status confirmed by laboratory assays and evaluated the potential differences in cognitive function between patients with positive and negative results. Nine hundred and seventy four schizophrenia patients completed neuropsychological and laboratory tests at screening/baseline of the Clinical Antipsychotic Trials of Intervention Effectiveness study. Radioimmunoassay (RIA) of hair tested for cannabis, cocaine and methamphetamine. Many patients screened positive for drug use (n = 262; 27%), and there were no differences between patients with positive and negative results in terms of cognitive function after adjusting for multiple inference testing, except patients with positive RIA for methamphetamine demonstrated increased processing speed (corrected, P = .024). Moderator models were employed to explore potential subgroup differences in this pattern of results. At low medication dosages, patients with positive RIA for cocaine demonstrated decreased processing speed compared with patients with negative RIA for cocaine (uncorrected, P = .008). And for any other drugs with low psychopathology, patients with positive RIA demonstrated decreased working memory compared with patients with negative RIA (uncorrected, P = .006). No positive effects of cannabis on cognitive function were observed, and drug use was not associated with improved neurocognition across most of the subgroup characteristics explored in this sample of schizophrenia patients.

Drug and alcohol trajectories among adults with schizophrenia: Data from the CATIE study

ObjectiveThe primary aim is to describe drug and alcohol trajectories in adults with schizophrenia. MethodGrowth mixture models were used to examine disordered and non-disordered use and abstinence in the Clinical Antipsychotic Trials of Intervention Effectiveness study. ResultsFive classes – always abstinent; fluctuating use, abuse, and occasional abstinence; occasional (ab)use; stopped (ab)use; abusing – fit best. Overlap exists between always abstinent drug and alcohol classes; less overlap exists across other classes. ConclusionThere is heterogeneity in drug and alcohol use among adults with schizophrenia. The lack of overlap between classes, save always abstinent, suggests modeling drug and alcohol use separately.

Accuracy of self-report, biological tests, collateral reports and clinician ratings in identifying substance use disorders among adults with schizophrenia.

Identifying substance use disorders among adults with schizophrenia presents unique challenges but is critical to research and practice. This study examined: (a) the accuracy of assessments completed using various approaches in identifying substance use disorders, (b) their ability to discriminate between disorders of abuse and dependence, and (c) the benefits of using multiple indicators to identify substance use disorders. Data are from the Clinical Antipsychotic Trials of Intervention Effectiveness study. The sample comprised 1,460 community-based adults with schizophrenia, 15.8% (n = 230) of whom were positive for a current (past month) drug or alcohol use disorder using the Structured Clinical Interview for DSM-IV Disorders (SCID). Clinician ratings, self-report, collateral reports, and results of hair and urine tests were compared to SCID diagnoses. Congruence with SCID diagnoses was good across approaches and evidence for superiority of one approach over another was limited. No approach discriminated between abuse and dependence. There was limited benefit of using multiple indicators. Findings suggest that the decision regarding the "best" approach for identifying substance use disorders among adults with schizophrenia may be made through consideration of practical issues and assessment purpose, rather than selection of the approach that yields the most accurate diagnostic assessment.

Gluten-Free Diet: Imprudent Dietary Advice for the General Population?

As of April 20, 2012, Amazon.com listed 4,765entriesforthetopic“gluten-free.”AGooglesearchatthesametime for “gluten-free diet” produced more than 4.2 millionresults. The number-one reason consumers cite for buyinggluten-freeproductsisthattheyareperceivedtobehealthierthan their gluten-containing counterparts.

Assessing illicit drug use among adults with schizophrenia

Accurate drug use assessment is vital to understanding the prevalence, course, treatment needs, and outcomes among individuals with schizophrenia because they are thought to remain at long-term risk for negative drug use outcomes, even in the absence of drug use disorder. This study evaluated self-report and biological measures for assessing illicit drug use in the Clinical Antipsychotic Trials of Intervention Effectiveness study (N=1460). Performance was good across assessment methods, but differed as a function of drug type, measure, and race. With the Structured Clinical Interview for DSM-III-R as the criterion, self-report evidenced greater concordance, accuracy and agreement overall, and for marijuana, cocaine, and stimulants specifically, than did urinalysis and hair assays, whereas biological measures outperformed self-report for detection of opiates. Performance of the biological measures was better when self-report was the criterion, but poorer for black compared white participants. Overall, findings suggest that self-report is able to garner accurate information regarding illicit drug use among adults with schizophrenia. Further work is needed to understand the differential performance of assessment approaches by drug type, overall and as a function of race, in this population.

Making a Difference

Making a Difference

Association of Allelic Variation in Genes Mediating Aspects of Energy Homeostasis with Weight Gain during Administration of Antipsychotic Drugs (CATIE Study)

Antipsychotic drugs are widely used in treating schizophrenia, bipolar disorder, and other psychiatric disorders. Many of these drugs, despite their therapeutic advantages, substantially increase body weight. We assessed the association of alleles of 31 genes implicated in body weight regulation with weight gain among patients being treated with specific antipsychotic medications in the clinical antipsychotic trials in intervention effectiveness study, we found that rs2237988 in Potassium Channel Inwardly Rectifying Subfamily J Member 11 (KCNJ11), rs13269119 in Solute carrier family 30 member 8 (SLC30A8), and rs9922047 in fat mass and obesity associated (FTO) were associated with percent weight gain. We also observed the significant interaction of rs11643744 by treatment effect on the weight gain.

Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia.

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.

NIMH-Funded Pragmatic Trials: Moving On

NIMH-Funded Pragmatic Trials: Moving On

Genome-wide association study of antipsychotic-induced QTc interval prolongation

QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug specific genome-wide association studies (GWAS) with 492K SNPs to search for genetic variation mediating antipsychotic induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study.Our candidate gene study suggests the involvement of NOS1AP and NUBPL (p-values =1.45×10−05 and 2.66×10−13, respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a q-value <0.10, (p-value =1.54×10−7, q-value =0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds including drugs, environmental toxins, and endogenous metabolites across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic induced QT prolongation.

Comparison of the metabolic and economic consequences of long‐term treatment of schizophrenia using ziprasidone, olanzapine, quetiapine and risperidone in Canada: a cost‐effectiveness analysis

Second-generation antipsychotic agents have varying propensities to cause weight gain, elevated lipid levels and associated long-term complications. This study evaluates the cost-effectiveness of four second-generation antipsychotic agents used in Canada for the treatment of schizophrenia (ziprasidone, olanzapine, quetiapine, risperidone) with a focus on their long-term metabolic consequences. Using data from the Clinical Antipsychotic Trials of Intervention Effectiveness Study, a semi-Markov model was developed to predict the incidence and associated costs of type 2 diabetes, cardiovascular complications (e.g. angina, myocardial infarction, stroke, cardiovascular disease death), and acute psychiatric hospitalizations in patients with chronic schizophrenia treated over 5 years. Incremental costs per quality-adjusted life year (QALY) gained were calculated from the perspective of the Canadian provincial ministries of health. Scenario and probabilistic sensitivity analyses were performed. The total average cost of treatment with ziprasidone was $25,301 versus $28,563 with olanzapine, $26,233 with quetiapine and $21,831 with risperidone. Ziprasidone had the lowest predicted number of type 2 diabetes cases and cardiovascular disease events, and the highest QALY gains. Patients receiving quetiapine had the highest predicted number of hospitalizations. Ziprasidone was less costly and resulted in more QALYs compared with olanzapine and quetiapine. Compared with risperidone, ziprasidone was more costly and had higher QALYs, with an incremental cost per QALY gained of $218,060. Compared with olanzapine and quetiapine, ziprasidone produced savings to the health care system. Although ziprasidone generated incremental expenditures versus risperidone, it resulted in more QALYs. Based on this analysis, ziprasidone treatment possesses cost and therapeutic advantages compared with olanzapine and quetiapine.

Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K SNPs, from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study. Outcomes included twelve indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. Twenty-one SNPs satisfied this criterion. The top finding indicated a SNP in MEIS2 mediated the effects of risperidone on hip circumference (q =.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q =.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

Inflammatory Markers in Schizophrenia: Comparing Antipsychotic Effects in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study

C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are systemic inflammatory markers (IM) that positively correlate with cardiovascular (CV) risk. Despite the known CV effects of atypical antipsychotics, there is limited prospective data on IM changes during treatment. The IM outcomes were compared between antipsychotic treatment groups in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial phase 1 with subjects with laboratory assessments at baseline and 3 months (n = 789). There were significant treatment differences in CRP, E-selectin, and ICAM-1 at 3 months, with a differential impact of baseline values on the CRP and ICAM-1 results. In overall comparisons, quetiapine and olanzapine had the highest median levels for CRP, and olanzapine for E-selectin and ICAM-1. Olanzapine was significantly different after baseline adjustment than perphenazine (p = .001) for E-selectin, and in those with low baseline CRP (<1 mg/L), olanzapine was significantly different than perphenazine (p < .001), risperidone (p < .001), and ziprasidone (p = .002) for CRP. Perphenazine had the lowest 3-month ICAM-1 levels in subjects with baseline ICAM-1 above the median, but the differences were not statistically significant versus olanzapine (p = .010), quetiapine (p = .010), and risperidone (p = .006) after controlling for multiple comparisons. The 18-month repeated measures CRP analysis confirmed the significantly higher values for olanzapine in those with low baseline CRP. This analysis provides further evidence for differential antipsychotic metabolic liabilities as measured by changes in systemic inflammation. C-reactive protein might emerge as a useful target for CV risk outcomes in schizophrenia patients.