Clinical and Research News
Experts Analyze Real Meaning of CATIE Study Findings
Psychiatric News
Volume 43 Number 11 page 28-28

Science without the industry spin. That's the idea behind a series of nine papers appearing as a special section in the May issue of the APA journal Psychiatric Services looking at the results of the landmark Clinical Antipsychotic Trials of Intervention effectiveness (CATIE).

Prior to the appearance of the first CATIE study results in the New England Journal of Medicine (September 22, 2005), the superiority of second-generation antipsychotics (SGA) over first-generation antipsychotics (FGA) was widely considered a given. Though the trial pitted a proxy FGA, perphenizine, against five SGAs, the primary question for many was which SGA was most efficacious.

So when results showed that, with the exception of clozapine, SGAs had only marginal superiority over perphenazine, the response from quarters with vested interests was not tepid; the pharmaceutical industry was loudest in attacking CATIE on methodological grounds.

"The CATIE trial was very controversial in no small part because it has a lot of potential impact on the public mental health system and Medicaid programs, because those systems have to make difficult decisions about how to use their psychotropic formularies," special section editor Marvin Swartz, M.D., told Psychiatric News. "Much of the commentary about CATIE began to happen in a partisan environment, and some of the most vocal commentators often seemed to represent the interests of the pharmaceutical industry.

"We thought it would be valuable to have a compendium of commentary on CATIE that was spin free and without any industry sponsorship," said Swartz, a professor of psychiatry at Duke University School of Medicine.

The Psychiatric Services series offers analysis and commentary by leading lights in mental health service research and includes an overview of CATIE findings; articles on implications for clinicians, public policymakers, and mental health researchers; and articles on the cost-effectiveness and the effect of CATIE on public mental health systems (see Cost Issues Occupy Intersection of Clinical, Policy Concerns).

A number of other articles and commentaries in the same issue, while not specifically examining CATIE, also address the subject of antipsychotic medication choice for patients with severe mental illness.

Journal editor Howard Goldman, M.D., said the section has been crafted for the journal's multidisciplinary readership.

"We felt it was important to inform our readers about what we thought were CATIE's lessons, particularly for the mix of clinicians, administrators, and researchers who are readers of our journal," he told Psychiatric News. "We wanted to have a mix of commentaries because there were so many concerns about how the findings have been spun, particularly by the makers of these agents that were compared, but also by advocacy groups to suit how they perceived the need for these agents."

Robert Rosenheck, M.D., the author of a paper on cost-effectiveness in the special section (and author of the original CATIE cost-effectiveness study) called the special section "APA at its best."

He added, "This edition of Psychiatric Services by itself redeems the investment by NIMH in CATIE. In this journal, the meaning of CATIE is revealed."


CATIE was conducted between January 2001 and December 2004 at 57 clinical sites in the United States. In phase 1 patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, or risperidone under double-blind conditions and followed for up to 18 months or until treatment was discontinued for any reason. Ziprasidone was approved for use by the Food and Drug Administration after the study began and was added to the study in January 2002.

If the initially assigned medication was not effective, subjects could choose to enter one of two trials in the following phase: randomization to open-label clozapine or a double-blinded SGA that was available but not assigned in phase 1; or double-blinded randomization to ziprasidone or another SGA that was available but not assigned in phase 1.

If the phase 2 study drug was discontinued, subjects could enter phase 3, in which clinicians helped subjects select an open-label treatment based on subjects' experiences in phases 1 and 2.

So what do commentators in Psychiatric Services say is the" take-home message" from CATIE?

"One important message is that the superiority of SGAs, as originally reported in industry trials, was overstated," Swartz told Psychiatric News. "That there was a remarkable upsurge in sales of these expensive drugs suggests that the field was not as critical of the source of the data as it could have been, since much of [the data were] from industry-sponsored trials."

One study in the series by Swartz and Marisa Elena Domino, Ph.D., using data from the Medical expenditure Panel Survey from 1996-1997 and 2004-2005 found that much of the growth in SGA prescribing was for off-label use in patients with conditions other than schizophrenia and for children.

Results from that study, titled "Who Are the New Users of Antipsychotic Medications?," would seem to be especially alarming in light of CATIE's overall finding of only modest superiority for SGAs over an FGA.

"Increasing understanding about the marginal efficacy and side-effect risks of newer and more expensive antipsychotic agents, even when prescribed as indicated, suggests that the dramatic increase in use warrants careful attention," Swartz and Domino concluded.


Yet despite the finding that, with the exception of clozapine, the SGAs studied in CATIE were on average only marginally more efficacious than perphenazine, Goldman and Swartz emphasized that what is true for the" average" patient may not be best for the individual patient in a clinician's office. And while CATIE findings have been damning for earlier industry-sponsored trials, most analysts agreed, they should not be construed to mean that SGAs ought not to be available.

William Carpenter, M.D., and Robert Buchanan, M.D., in "Lessons to Take Home From CATIE," emphasized the importance of designing pharmacotherapy for the individual patient to optimize the benefit-to-risk profile.

"First- and second-generation antipsychotic drugs are extensively similar in mechanism of action, efficacy for psychosis, and lack of efficacy for avolition and impaired cognition," they wrote. "However, adverse-effect profiles vary between drugs.... Rather than selecting drugs on the basis of unfounded expectations of superior efficacy, clinicians can focus on selecting drugs and optimizing dosages to minimize adverse effects without sacrificing efficacy."

For instance, tardive dyskinesia (TD) has been associated with FGAs, and the exclusion in CATIE of patients with TD from randomization to perphenazine was one methodological criticism cited by industry.

Carpenter and Buchanan argued in their paper, however, that while the risks of TD may be a good reason to avoid a high dose of FGAs, the evidence for differential risk is less compelling for a modest dose of low-affinity FGAs.

"Similarly, the metabolic effects of some second-generation antipsychotics can be decisive in considering risks," Carpenter and Buchanan wrote. "In either case, the clinician should detect earliest signs and take action while dyskinetic or metabolic effects are most reversible."

The May issue of Psychiatric Services can be accessed at<http://ps.psychiatryonline.org/content/vol59/issue5/index.dtl>.

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