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
"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
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
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
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
"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
"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
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
"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