In September 2005, the National Institute of Mental Health published phase 1 results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a large-scale, double-blind trial comparing the relative effectiveness of five antipsychotics used to treat patients with schizophrenia: perphenazine, a conventional antipsychotic that has been commercially available since the 1950s, and four atypical agents—olanzapine, quetiapine, risperidone, and ziprasidone—that were introduced in the 1990s. The broad intention of the CATIE study is to determine if the atypical agents used offer any demonstrable clinical and public health advantages over the conventional agents. Concerns over costs and side effects (eg, pronounced weight gain and lipid disturbances) associated with the newer, atypical antipsychotics, as well as doubts about superior efficacy relative to older, conventional agents, served as an impetus to the trial.

The study design chosen for the CATIE study—that of a “large, simple” trial—sought to bypass the limitations of clinical studies that are conducted when pharmaceutical companies seek regulatory approval of a new medication. Studies done in pursuance of drug approval attempt to establish safety and efficacy in controlled clinical settings so as to determine if a drug works at all, and if its use entails specific side effects. Hence, they are typically placebo-controlled and short-term, enroll a small homogeneous population (eg, initially hospitalized patients with no psychiatric or medical comorbidities), forbid or restrict the use of concomitant medications, and take as their endpoints well-defined side effects and measures of core psychopathology. These restrictions heighten the risk that the study findings may not be widely applicable to patients outside the confines of the protocol.

Most clinical data for antipsychotics come from studies designed to test the efficacy and safety of the drugs under ideal conditions, in limited subgroups of patients. In contrast, practical clinical trials (PCTs) are designed to test the effectiveness of different treatment options under conditions that more accurately reflect actual clinical practice. Consequently, PCTs are able to provide information that can be utilized by healthcare providers and other decision makers. Characteristics of PCTs include a clinically relevant question, a representative sample of patients and practice settings, sufficient power to identify modest relevant effects, randomization to protect against bias, uncertainty regarding the outcome of treatment, assessment and treatment protocols that enact best clinical practices, simple and relevant outcomes, and limited subject and investigator burden. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program is an example of a PCT. The CATIE study illustrates how PCTs, when properly designed, might be helpful in informing clinical decision making. Because the CATIE study was designed to reflect the effectiveness of antipsychotics under naturalistic clinical conditions, its results should have particular applicability to the arena of clinical practice. This article provides a discussion of the differences between efficacy and effectiveness studies. In assessing the practical utility of results from the CATIE study, much can be learned on how to shape future studies of effectiveness so as to better generate data that are applicable to the “real world.”

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial was an effectiveness/”pragmatic” clinical trial designed to compare the efficacy, tolerability, and cost-effectiveness of four atypical antipsychotics (olanzapine, quetiapine, risperidone and ziprasidone) and a conventional antipsychotic (perphenazine) for an 18-month period in patients with schizophrenia. The study randomized 1,460 patients with fewer exclusion criteria than in most trials in hopes that this would allow for a more representative sample of outpatients in “real world” practice. Olanzapine demonstrated significant superiority in time to discontinuation for all cause and for lack of efficacy, as well as likelihood of hospitalization for relapse; however, it was associated with a significantly higher rate of metabolic side effects. Perphenazine exhibited comparable effectiveness with quetiapine, risperidone, and ziprasidone, and appeared to be as well tolerated as the atypicals. However, it had the highest rate of drop out due to extrapyramidal symptoms and was restricted to patients who did not have tardive dyskinesia (TD). This article examines the phase 1 CATIE results to guide the clinician in understanding how to interpret the findings, which were intended to be a guide for clinical practice. The nature of the patient population, the doses of drugs relative to one another, inclusion of patients who were treatment resistant, and exclusion of patients with TD from randomization to perphenazine were potential sources of bias in the study. In particular, the use of a higher-than-usual peak dose of olanzapine may have led to the superior results achieved with it. Practical suggestions are given for choice of antipsychotic medication in patients with chronic schizophrenia.

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.

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.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was undertaken to provide a valid assessment of the differences between conventional and atypical antipsychotics and among the atypicals themselves in patients with schizophrenia. The CATIE investigators reported that while none of the study medications were ideal, olanzapine was the most effective in terms of treatment discontinuation, and there were no significant differences in effectiveness between the conventional antipsychotic perphenazine and the atypicals quetiapine, risperidone, and ziprasidone. Each drug differed slightly in rates of side effects, with more patients discontinuing perphenazine due to extrapyramidal side effects and more patients discontinuing olanzapine due to weight gain and metabolic effects. In order for data from phase 1 of the CATIE study to be interpreted within the appropriate context, physicians must understand how aspects of study design and statistical methods affect interpretation, and how this trial weighs against other data in the literature. This article enumerates the factors that complicate our understanding of the CATIE results and compares these findings with those from previously published meta-analyses. It is clear that therapeutic and side effects of antipsychotics vary from person to person. The goal of schizophrenia management is to maintain pharmacotherapeutic efficacy and tolerability over the long-term in order to maximize treatment adherence and benefits. What should emerge from CATIE is a renewed commitment to tailor schizophrenia treatment to the individual patient for long-term management.