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Cambridge University Press
Online publication date:
May 2010
Print publication year:
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Book description

Antipsychotic medications are a key treatment for schizophrenia and sales of antipsychotic drugs approach $20 billion per year, with fierce marketing between the makers of the drugs. The U.S. National Institute of Mental Health sponsored the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project to provide independent information about the comparative effectiveness of medications. CATIE was the largest, longest and most comprehensive study of schizophrenia to date. Conducted under rigorous double-blind conditions, Antipsychotic Trials in Schizophrenia presents the definitive archival results of this landmark study. The core of the book consists of chapters focused on specific outcomes that set the CATIE findings in a wider context. Also included are chapters on the design, statistical analyses and implications for researchers, clinicians and policy makers. Psychiatrists, psychiatric researchers, mental health policy makers and those working in pharmaceutical companies will all find this to be essential reading.


'… important and timely …'

Source: Doody's

'This book is not just a reprint of all published CATIE papers - it takes us beyond the hype of the first publication by reminding us of the breadth and depth of the trial … This book will be of major interest to anyone involved in psychopharmacology. However, the richness of the use of social and cognitive end points means that there is a wealth of information for those who have no interest in antipsychotics but are interested in the lives and outcomes of people with schizophrenia.'

Source: The British Journal of Psychiatry

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  • Chapter 8 - Family outcomes
    pp 133-155
  • View abstract


    This chapter describes the development of the study designed to assess the effectiveness of antipsychotic drugs for persons with chronic schizophrenia. The protocol was developed by a team of academic investigators through an inclusive, iterative, and systematic process. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) program was designed to address a discrepancy between research demonstrating the efficacy of antipsychotic drugs and disappointing findings regarding their effectiveness and the ostensible superiority of second-generation antipsychotic (SGA) medications relative to first-generation antipsychotic drugs (FGA) medications. Some of the key study design decisions made by the Schizophrenia Protocol Development Committee, with input from various stakeholder groups, and their rationales are reviewed in this chapter. The study design was that of a practical clinical trial intended to evaluate the effectiveness of treatments in everyday settings to generate results intended to inform clinicians, administrators, policy makers, and patients.
  • Chapter 9 - Extrapyramidal side effects
    pp 156-172
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    The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia study sought to compare the effectiveness and cost-effectiveness of four second-generation antipsychotics and one first-generation antipsychotic in the treatment of schizophrenia. This study design posed several challenges for statistical analysis. The authors describe the stratified Phase 1/1A randomization, and explain the steps for comparing treatment groups within the stratified randomization structure. They describe strategies to perform treatment group comparisons that control the inflation of Type 1 error due to multiple pair-wise testing, and focus on the evaluation of multiple outcomes. The authors examine the advantages of using all-cause treatment discontinuation as the primary effectiveness outcome and the specific statistical issues for its analysis, and address the impact of missing data due to phase discontinuation on analysis of the secondary outcomes. The authors contrast the statistical methods employed to address this issue, and consider further methods.
  • Chapter 10 - Metabolic side effects and risk of cardiovascular disease
    pp 173-188
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    This chapter presents the rationale for the primary effectiveness outcome and results for the randomized phases of the study. Effectiveness studies of any treatments for a chronic disease such as schizophrenia must incorporate a longer term view of the treatments' effects. A primary goal of such effectiveness studies is to determine the durability of the treatments. These studies examine whether the treatments continue to provide therapeutic benefit over the course of illness. To ensure maximum generalizability, few patients should be excluded from effectiveness studies. As symptom reduction remains an important goal of antipsychotic treatment and is the typical outcome in antipsychotic drug trials, the chapter discusses the results of how olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone compared in their effects on the core psychopathology of schizophrenia. CATIE findings on effectiveness and symptom reduction are consistent with many careful meta-analyses.
  • Chapter 11 - Substance use in persons with schizophrenia: incidence, baseline correlates, and effects on outcome
    pp 189-206
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    In the United States, second-generation antipsychotics have become the most widely used drugs in the treatment of schizophrenia, with total annual costs of over $12 billion. While the main CATIE analysis showed that patients stayed on olanzapine longer than two other second-generation antipsychotics, none of four second-generation antipsychotics, showed any advantage over the first-generation antipsychotic perphenazine on measures of symptoms. The cost-benefit analysis presented here, which combines cost and benefit data in a single analysis, found perphenazine to be superior to each of the four second-generation antipsychotics with which it was compared. While cost-effectiveness analysis evaluates the health benefits per additional dollar expended using the measures of quality of life, cost-benefit analysis attempts to put monetary value on the health benefits of treatment and thus monetizes all outcomes. Antipsychotic medication costs were based on wholesale prices for the specific capsule strengths used in CATIE, adjusted downward for discounts and rebates.
  • Chapter 12 - Violence in schizophrenia: prevalence, correlates, and treatment effectiveness
    pp 207-236
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    This chapter reviews findings from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study as it compares the effects of olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone on psychosocial functioning as measured on the Quality of Life Scale (QLS). In assessing psychosocial functioning, it was hypothesized that improvement would be different among treatments. The CATIE study was initiated by the National Institute of Mental Health (NIMH) to determine the effectiveness of antipsychotic drugs. For the Psychosocial Functioning Study presented in this chapter, we hypothesized that there would be differences among olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone in improvement in psychosocial functioning as measured by the QLS total scale. The QLS is a clinician-rated scale of social functioning, interpersonal relationships, and psychological well-being, originally developed to measure schizophrenic deficit syndrome. Many diverse approaches to evaluate psychosocial functioning and quality of life for individuals with schizophrenia make comparisons across schizophrenia studies difficult.
  • Chapter 13 - Genetic investigations in the CATIE sample
    pp 237-254
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    This chapter describes the cognitive findings from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project, including analyses of the baseline cognitive assessments in 1,331 patients, one of the largest schizophrenia cohorts to be studied with neuropsychological measures, and the effects of treatment on these measures in over 800 patients randomized to five different antipsychotic treatments. The choice of tests for a neurocognitive battery is often controversial. Since the CATIE project promised to yield a rich database, it is important that the batteries of tests chosen for the project receive consensus approval from the leaders in schizophrenia and dementia research. The aim of the CATIE Neurocognitive Assessment Unit training program is for testers and investigators to achieve thorough understanding of the rationale and methods of the neurocognitive assessment protocol, and considerable preparation preceded the production of manuals and training materials.
  • Chapter 14 - Human subjects considerations
    pp 255-266
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    Several studies have already examined the differential effects of first-generation agents (FGAs) and second-generation antipsychotic medications (SGAs) on employment. The data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial provided an opportunity to prospectively examine the differential effect of FGAs and SGAs on employment outcomes. This chapter describes the results from Phase 1 of CATIE that examined the relationship between assignment to five different antipsychotic medications and two outcomes: employment and participation in psychiatric rehabilitation. It examines participation in psychiatric or psychosocial rehabilitation (PSR), which includes participation in vocational rehabilitation. The chapter analyzes the bivariate and multivariate relationships between potential baseline predictors with both employment measures and participation in PSR. Employment in the competitive economy is a primary goal of recovery-oriented behavioral health services. The chapter suggests that SGAs are no more likely to facilitate achievement of that goal than FGAs.
  • Chapter 15 - Population pharmacokinetics of antipsychotics
    pp 267-280
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    Research has shown that up to 83% of friends and family members of people diagnosed with schizophrenia experience financial, emotional, and practical burdens. In their pioneering study of family psychoeducation, Falloon and colleagues found that reductions in family burden associated with family psychoeducation were associated with improvements in patient clinical status and reductions in relapse over time. The design of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) permits investigation of the impact of random assignment to the first-generation antipsychotic perphenazine and four second-generation drugs on family outcomes over an 18-month study period. In addition, family members frequently take an active role in helping patients manage their medication and in other aspects of preventing relapse and promoting recovery. The findings of the CATIE study underscore the importance of involving family caregivers in treatment planning for their relatives with schizophrenia.
  • Chapter 16 - Implications for research design and study implementation
    pp 281-287
  • View abstract


    This chapter summarizes the features of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial that are relevant to interpretation of extrapyramidal side effects (EPS) findings. CATIE was designed to address the overall effectiveness of second-generation antipsychotic (SGA) versus a mid-potency first-generation antipsychotic drugs (FGA), perphenazine, based on treatment discontinuation. Using measures of dystonia, Parkinsonism, akathisia, and tardive dyskinesia (TD), the analysis of incidence rates and continuous measures from CATIE shows no substantial or statistically significant differences between modest doses of the intermediate potency FGA perphenazine and four SGAs in patients with chronic schizophrenia requiring maintenance antipsychotic treatment. The conclusion that must be drawn from the CATIE study is that there were no significant differences in primary outcome measures of acute EPS and TD overall, while at the same time perphenazine was shown to be not different in overall effectiveness compared with olanzapine, risperidone, quetiapine, and ziprasidone.
  • Chapter 17 - Conclusion and implications for practice and policy
    pp 288-306
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    Multiple factors contribute to high levels of cardiovascular (CV) risk in schizophrenia patients including lifestyle habits. The additive CV effects of cigarette smoking, hypertension, total cholesterol, and high density lipoprotein (HDL) cholesterol have been found to predict the risk of major cardiac events over a 10 year period. These effects can be calculated with empirically derived CV risk algorithms. By the time the initial Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) analysis of metabolic syndrome prevalence was performed in 2005, there was already a signal that schizophrenia patients had 2-4 times higher prevalence than that expected from general population estimates. The CATIE schizophrenia trial data illustrate the possibility for improving metabolic health by switching patients from more offending medications, and for avoiding long-term CV consequences by preferential use of agents with metabolically benign profiles. Management of schizophrenia requires acknowledgment that CV disease remains a primary cause of excess mortality.


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