Clinical Antipsychotic Trials Of Intervention Effectiveness Trial Research Articles

T125. INCIDENCE OF TREATMENT RESISTANCE SCHIZOPHRENIA IN A COMMUNITY SAMPLE USING THE TRRIP CONCENSUS

BackgroundEstimates of treatment resistant schizophrenia (TRS) vary due to lack of consensus definition. The Treatment Response and Resistance in Psychosis (TRRIP) consensus provides a rigorous prospective definition for TRS, but has not yet been applied to data. We provide the first prospective estimate of the incidence of TRS in a large community cohort using TRRIP.MethodsThe publicly available CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) data were mined using bespoke implementations of algorithms that operationalise the minimum TRRIP concensus criteria. Survival curves for transition to treatment resistance status (versus treatment responsive and censoring) were estimated. Inferential methods were used to establish baseline patient characteristics that are associated with TRS. Machine learning methods were also applied to estimate patient-level prediction of TRS status from baseline data.Results1369 patients were included in the analysis, with 992 patients at risk for developing TRS at baseline. A total of 48 cases of TRS were identified, yielding a crude incidence of 36.2 cases per 1000 person years. There were no strong associations with baseline demographics or clinical state at enrolment to the trial and the predictive modelling failed to identify any patient-level predictor of future TRS.DiscussionThe CATIE trial protocol excluded patients with retrospective evidence of TRS, however, prospectively applying the TRRIP consensus revealed that there were patients with TRS in the cohort. Our results suggest a small incidence, and that baseline clinical and demographic data is not a robust predictor of future resistance status. Analysis of individual TRRIP criteria reveals a significant unmet need for patients with poor treatment response, but who do not meet criteria for TRS, particularly in social and occupational functioning.

Effectiveness of antipsychotic drugs against hostility in patients with schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study – ADDENDUM

Introduction Aggressive behavior can be a dangerous complication of schizophrenia. Hostility is related to aggression. This study aimed to compare the effects of olanzapine, perphenazine, risperidone, quetiapine, and ziprasidone on hostility in schizophrenia. Methods We used the data that were acquired in the 18-month Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. We analyzed the scores of the Positive and Negative Syndrome Scale (PANSS) hostility item in a subset of 614 patients who showed at least minimal hostility (a score ≥ 2) at baseline. Results The primary analysis of hostility indicated an effect of difference between treatments (F 4,1487 = 7.78, P Discussion Our results are consistent with those of a similar post - hoc analysis of hostility in first-episode subjects with schizophrenia enrolled in the European First-Episode Schizophrenia Trial (EUFEST) trial, where olanzapine demonstrated advantages compared with haloperidol, quetiapine, and amisulpride. Conclusion Olanzapine demonstrated advantages in terms of a specific antihostility effect over the other antipsychotics tested in Phase 1 of the CATIE trial.

Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia

Tardive dyskinesia (TD) occurs in approximately 20% of patients exposed to long-term antipsychotic treatment and may be influenced by genetic predisposition, in addition to clinical risk factors. In this study, we implemented a two-step approach to identify susceptibility genes for TD. First, we performed a secondary analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) genome-wide association study (GWAS) dataset to identify candidate genes for TD severity. A total of 327 schizophrenia patients treated with antipsychotics who participated in the CATIE trial were included in a TD severity GWAS (approximately 495,000 SNPs). Cases were defined as demonstrating involuntary movements of a mild degree in two or more body regions or of a moderate to severe degree in at least one body region on at least two separate evaluations, whereas controls were completely free of abnormal involuntary movement on all evaluations. Using logistic regression and controlling for population stratification and relevant clinical risk factors, none of the associated SNPs reached GWAS significance; however, several promising SNPs were identified for follow-up investigation. In the second step, we performed an association study of the top 25 SNPs in an independent sample of 170 Jewish, Israeli, schizophrenia patients (retrospective, cross-sectional design). Association of the SNP rs3943552 T allele in the GLI2 gene with TD was observed in a subsample of Ashkenazi Jewish patients (N = 96, P = 0.018; P = 6.2 × 10⁻⁵ in the CATIE sample). The GLI2 gene encodes a transcription factor that participates in the development of the dopaminergic system during embryogenesis. Taken together, our findings support a possible contribution of GLI2 to TD susceptibility.

Antipsychotic‐associated all‐cause and cardiac mortality: what should we worry about and how should the risk be assessed?

Antipsychotic‐associated all‐cause and cardiac mortality: what should we worry about and how should the risk be assessed?

Antipsychotics and Schizophrenia: From Efficacy and Effectiveness to Clinical Decision-Making

To comprehensively review the 2 recent and large antipsychotic effectiveness trials for treatment of schizophrenia: the United Kingdom's Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), and the National Institute of Mental Health-initiated Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. We present a review of the rationale, methodology, and findings to date from the CUtLASS and CATIE schizophrenia trials, including all primary and secondary outcomes. The primary findings from both trials, CUtLASS and CATIE, suggest that first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) are equally effective in the treatment of schizophrenia. The exception is in treatment-resistant populations where clozapine exhibits superiority, compared with other SGAs. In the CATIE trial, there is a suggestion that olanzapine is superior in effectiveness, compared with other nonclozapine SGAs, although this seems to be mediated by past history of olanzapine use, and carries with it increased weight gain and metabolic adverse events. From a cost-effectiveness perspective, there is no evidence that SGAs are superior to FGAs, with findings suggesting the possibility that FGAs may be superior. Past efficacy trials have strongly supported the position that SGAs are superior to FGAs in the treatment of schizophrenia and in side effect profile. Two large independent effectiveness trials, CUtLASS and CATIE, have offered a strong challenge to these claims. Both suggest that SGAs, except clozapine in the treatment-resistant population, offer little, if any, clinical benefits, and, moreover, harbour their own significant side effects.

Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.

Experts Analyze Real Meaning of CATIE Study Findings

Experts Analyze Real Meaning of CATIE Study Findings

Policy Implications of CATIE

Back to table of contents Previous article Next article LetterFull AccessLetterRobert A. Rosenheck M.D.Douglas L. Leslie Ph.D.Jalpa A. Doshi Ph.D.Robert A. Rosenheck M.D.Search for more papers by this authorDouglas L. Leslie Ph.D.Search for more papers by this authorJalpa A. Doshi Ph.D.Search for more papers by this authorPublished Online:1 Jun 2008https://doi.org/10.1176/ps.2008.59.6.695AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Policy Implications of CATIETo the Editor: We contributed an article to the May issue's special section on interpreting the implications of CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) ( 1 ). As the section was being prepared for publication, the editor asked Richard Frank for a commentary on our article ( 2 ), which was also included in the CATIE special section. We are taking this opportunity to respond to Frank's commentary. We agree that caution should be exercised in the implementation of formulary policies and that full consideration must be given to the concerns of advocates and consumers. We also think that mental health services researchers and economists are responsible to taxpayers and other purchasers of health care for offering a balanced consideration of the value of public expenditures. We think four issues may deserve further clarification. First, Frank suggested that our appraisal of what is known may have been based too exclusively on the CATIE trial and that it may be premature to come to any conclusion about the cost-effectiveness of second-generation antipsychotics. However, the many studies we reviewed extend considerably beyond CATIE, which was only the most recent of a series of independent studies that have called into question the superiority of second-generation antipsychotics over older drugs. This perspective is perhaps most clearly reflected in the conclusion of the Texas Medication Algorithm Project authors, a distinguished group of schizophrenia experts, that second-generation antipsychotics should no longer be considered uniformly preferable to older drugs in the treatment of chronic schizophrenia ( 3 ). There are not likely to be additional large studies of these issues, so a broad consideration of current knowledge seems warranted. Second, Frank expresses concern that the high drop-out rate from CATIE at 18-months seriously limits what can be concluded about these drugs. However, CATIE, like several other large trials that we cited, was substantially longer and had higher follow-up rates, at equivalent time points, than most previous trials and thus is more informative than previous studies, many of which lasted only six weeks ( 4 ) or stopped collecting data after the first medication change. Third, Frank implies that we proposed placing strict restrictions on the use of second-generation antipsychotics. In fact, we suggested that a range of policy options be considered, most of which were not especially strict, and we sought to identify those that would be likely to be too precipitous or disruptive and thus should be avoided. Moreover, current practice is quite restrictive in that it relies predominantly on the five or six most expensive antipsychotics rather than on the full range of about 20 antipsychotic drugs currently available. One recent study showed that older drugs can offer new hope to patients who have failed to benefit from a second-generation agent ( 5 ). We believe that choices can be widened and costs lowered at the same time. Fourth, we quoted a state Medicaid official who commented on the influence of coalitions between left-leaning advocacy groups and conservative businesses to highlight the political difficulties involved in considering cost-containment initiatives that would keep up with emerging research findings. Neither advocates nor businesses are focused on the cost concerns to the taxpaying public, and we think that mental health researchers should not ignore these concerns.We agree that caution is warranted whenever health care policy is considered, but the need for caution should not, in itself, be a reason for inaction. The substantial public investment in government-funded studies such as CATIE can be justified only if new findings are carefully considered in developing policies that might better serve the public interest.

Duration of Antipsychotic Drug Therapy in Real-World Practice: A Comparison with CATIE Trial Results

Background Duration of drug therapy is a key measure of drug effectiveness in schizophrenia. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial found that only olanzapine achieved a longer time to all-cause-discontinuation (TTAD) than a standard therapy comparator. This study compares the TTAD achieved when using alternative antipsychotics to treat patients with schizophrenia in real-world practice settings. Methods A total of 219,504 episodes of antipsychotic therapy initiated in the years 2000 to 2002 were identified using data from the California Medicaid (Medi-Cal) program. To capture the full range of treatment scenarios facing clinicians, four episode types were included: restarting therapy using the drug used in the preceding episode; restarting therapy using a different medication (delayed switches); switching therapy without a break in therapy; and augmentation. TTAD and changes in therapy were analyzed using ordinary least squares and logistic regressions and Cox proportional hazards models. Results Atypical antipsychotics consistently achieved longer TTAD and reduced switching rates relative to conventional antipsychotics. Differences in TTAD favoring atypical antipsychotics were 13 to 15 days in restart episodes; 28 to 36 days for delayed switching episodes; 41 to 52 days in switching episodes; and 59 to 63 days for augmentation ( P < 0.0001 for all estimates). Differences between the atypical antipsychotics were smaller than reported in other studies and may not be clinically significant. Conclusions This study confirms two results from the CATIE study: Patients with schizophrenia frequently do not achieve stable, long-term drug therapy regardless of the specific drug used, and olanzapine achieved longer TTAD than conventional drugs. However, this study also found that patients treated with risperidone and quetiapine also achieved longer TTAD than patients treated with conventional antipsychotics.

CATIE'S LESSONS

CATIE'S LESSONS

Latest CATIE Analysis Shows Patient Response Suggests Pathway

Latest CATIE Analysis Shows Patient Response Suggests Pathway

Cost-Effectiveness Measures, Methods, and Policy Implications from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for Schizophrenia

Sales of atypical antipsychotics have expanded rapidly as their use for treatment of schizophrenia and other illnesses has increased. The CATIE trial was designed to evaluate the cost-effectiveness of these medications. Cost-effectiveness analysis in CATIE examined the benefits and costs of treatments and attempted to determine whether one treatment would result in better outcomes and lower costs than another one. While the data from CATIE on cost-effectiveness have not been analyzed yet, it is still possible to consider the potential implications of the analysis, including how the roles of researchers and stakeholders should be considered in deciding optimal clinical practices and public policies.

Tardive Dyskinesia Circa 2006

Tardive Dyskinesia Circa 2006

Baseline Use of Concomitant Psychotropic Medications to Treat Schizophrenia in the CATIE Trial

This study examined the prevalence and correlates of concomitant psychotropic medications and use of anticholinergic drugs to treat schizophrenia.Concomitant medication use was studied at baseline for participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial.Of the 1,380 patients with baseline medication data, 82 percent were taking psychotropic medications. Of this group, 6 percent were taking two antipsychotics (one first generation and one second generation); 38 percent, antidepressants; 22 percent, anxiolytics; 4 percent, lithium, and 15 percent, other mood stabilizers. The strongest predictors of taking several medications were having anxiety or depression, being female, and taking second-generation antipsychotics. Conversely, African Americans and those with better neurocognitive functioning were less likely to be taking several concomitant psychotropic medications. In some cases symptoms that were likely targets of polypharmacy, such as depression, remained prominent, suggesting only partial response.Concomitant use of psychotropic medications to treat people with schizophrenia is common. Empirical data demonstrating the effectiveness of many of these agents for this population are lacking.

Metabolic Findings From the CATIE Trial and Their Relation to Tolerability

The overall effectiveness of antipsychotics for the management of schizophrenia is restricted by their side-effect profiles, particularly over an extended treatment period. Intolerable side effects can reduce patient adherence to medication and often lead to treatment discontinuation. Some side effects that result from antipsychotic use are precursors to the metabolic syndrome, which is prevalent among individuals with schizophrenia and represents a significant source of cardiovascular risk. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study assessed the efficacy of the atypical antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone relative to the conventional drug perphenazine. Additional assessments included the metabolic effects of these agents in patients with schizophrenia and the incidence of negative side effects. No significant differences were found between treatment groups for time to discontinuation due to intolerability, but the rates of side effects significantly differed (P=.04). For metabolic parameters, olanzapine was associated with greater and significant adverse effects on weight, lipids, and glucose metabolism versus the other antipsychotics tested. The CATIE results show that important distinctions exist among currently available atypical antipsychotics. Physicians should be aware of the propensity of these drugs to increase the risks of cardiovascular disease and diabetes in treated patients and tailor individual treatment decisions accordingly. This article highlights the metabolic findings from the CATIE schizophrenia study, and explores the differences shown by atypical antipsychotics, with regard to metabolic side effects that increase cardiovascular risk.

Implications of the CATIE Trial on Treatment: Extrapyramidal Symptoms

Development of extrapyramidal symptoms (EPS), particularly tardive dyskinesia (TD), has long been a troubling side effect for patients taking antipsychotics. Atypical antipsychotics have been hailed as an improvement over conventional antipsychotics, offering similar efficacy with more favorable EPS profiles. In the recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, which compared the conventional antipsychotic perphenazine with atypical antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone in patients with schizophrenia, no significant differences in time to treatment discontinuation due to intolerability were observed between treatment groups. However, perphenazine was associated with a higher rate of patients experiencing EPS as well as a significantly higher rate of discontinuation due to EPS, despite the fact that patients with TD at baseline were excluded from the perphenazine group. Unfortunately, due to short treatment duration, the CATIE study did not have the assay sensitivity to detect differences in TD risk among any of the drugs. Thus, the atypical antipsychotics remain the first line of treatment for most patients, with specific drug selection based on benefit-risk profiles that best fit the individual patient's needs. Frequent monitoring, while noting a patient's subjective experience, remains the best strategy for choosing therapy to maximize symptom relief and minimize the impact of EPS and other side effects over the long- term. This article explores the reported results of the CATIE trial regarding EPS and emphasizes the differentiation of the atypicals from perphenazine on EPS and how these results should be incorporated into daily practice for the clinician.