Special Section on Implications of CATIE: Lessons to Take Home From CATIE

The most surprising thing about the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) ( 1 ) is how surprised the field has been with the results. A common view has been that the second-generation antipsychotic drugs achieved the superiority of clozapine for positive symptoms, negative symptoms, and cognitive impairments, with a safety profile superior to clozapine and first-generation antipsychotics. Many studies sponsored by pharmaceutical companies have reported the advantages of the companies' second-generation antipsychotic, but little note has been taken of the fact that the Food and Drug Administration has not approved a superiority claim for any second-generation antipsychotic other than clozapine. In addition, little attention has been given to the failure of second-generation antipsychotics to demonstrate efficacy for primary negative symptoms ( 2, 3 ) (the avolitional component of schizophrenia described by Kraepelin), and the reports of efficacy of second-generation antipsychotics for cognitive impairments have not separated true efficacy from other explanations, such as less adverse cognitive effects with a second-generation antipsychotic compared with a high dosage of haloperidol ( 4 ).

A more critical approach would note the following issues. First, the first- and second-generation antipsychotics share the same therapeutic mechanism of action initiated at the dopamine D ₂ receptor. Second, serotonin antagonism has not been proven to enhance efficacy, although it may decrease adverse motor effects. The dopamine and serotonin antagonism mechanism is not essential for a drug to be classified as a second-generation antipsychotic (for example, amisulpride). Third, the mechanism for the superior efficacy of clozapine among treatment-resistant patients with schizophrenia is not established. Moreover, second-generation antipsychotics vary from each other substantially in their nondopamine pharmacological effects, which suggests that these additional actions do not account for class superiority.

There are few data to suggest that the efficacy of second-generation antipsychotics is superior to that of first-generation antipsychotics ( 5 ). Most of the data compare a second-generation antipsychotic to a first-generation antipsychotic, and haloperidol, at a substantial dosage, is the most common comparison drug in tests of second-generation compounds. When the data support superiority of second-generation antipsychotics, the differences are often very small and represent p value significance rather than clinical meaningfulness. Industry-sponsored studies provide most of the pre-CATIE data on comparisons between first- and second-generation antipsychotics, and analyses often used last observation carried forward, despite nonrandom differential attrition. In short, the data have not suggested substantial efficacy differences between these two classes of antipsychotics. Even when small advantages are observed, alternative explanations challenge superior efficacy reports. Finally, systematic meta-analytic studies done for the Cochrane Library (www.mrw.interscience.wiley. com/cochrane) routinely fail to document superiority claims. For a critical overview, which also considers adverse effects, see the article by Gardner and colleagues ( 6 ).

In short, in CATIE there was much reason to expect similar efficacy between the various second-generation antipsychotics and perphenazine (the first-generation antipsychotic comparison used in CATIE). There was also little reason to expect effectiveness differences between perphenazine and the second-generation drugs, because excessive dosing of the first-generation antipsychotic was avoided. In this context, CATIE, along with the United Kingdom's Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) ( 7, 8 ), has made two major contributions. First, these studies have generated comparative data in head-to-head comparison of antipsychotics with funding support from public sources. Second, and perhaps most important, the results have stimulated the first influential debate on the pharmacotherapy of schizophrenia since second-generation antipsychotics swept the market.