The largest study to date analyzing the cost-effectiveness of
second-generation antipsychotic medications (SGAs) compared with
first-generation antipsychotics (FGAs) has determined that treatment with the
FGA perphenazine (Trilafon) is associated with, on average, a savings in total
health care costs of $300 to $600 per month compared with SGAs.
Furthermore, the study found that the difference in total monthly health
care costs was due entirely to differences in the cost of the medications.
The new analysis, from the National Institute of Mental Health's Clinical
Antipsychotic Trials of Intervention Effectiveness (CATIE), was reported by
Robert Rosenheck, M.D., director of the VA's Northeast Program Evaluation
Center and a professor of psychiatry, epidemiology, and public health at Yale
Medical School, and his CATIE co-investigators in the December American
Journal of Psychiatry. The team analyzed data comparing six antipsychotic
medications—the FGA perphenazine versus the SGAs clozapine (Clozaril),
olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and
ziprasidone (Geodon)—on measures of health costs, symptom improvement,
and several measures of effectiveness that address "health-related
quality of life."
What is likely to stir debate is the study's overall conclusion that
treatment with an FGA, rather than an SGA, is associated "with no
significant differences in measures of effectiveness," including symptom
and quality-of-life ratings. That debate will likely be spurred by an
unusually frank editorial accompanying the publication of the study, which
questions the study's methods, results, and conclusions (see box on page
The CATIE protocol compared the real-world effectiveness of the
antipsychotics through four phases of the complex study over a total treatment
period of up to 18 months. Outcome data from phase 1 and phase 2 of the
protocol have been previously reported (Psychiatric News, October 21,
2005; April 21). Phase 3 and 4 data have yet to be published in peer-reviewed
Briefly, in phase 1, patients were randomly assigned to take one of the six
antipsychotic medications above (except clozapine, which was only offered in
phase 2). Patients who had tardive dyskinesia (TD) at baseline were prevented
from assignment to perphenazine, which was thought at the time the study was
designed to carry a higher risk of developing TD. Mirroring clinical practice,
clinicians were encouraged to maximize dosing of each of the medications,
increasing dose until either an effective dose was reached, the top of the
dose range was reached, or intolerable side effects appeared.
If a patient and/or their physician believed an assigned drug was not
effective, even after maximizing dosing, or if intolerable side effects
appeared, the patient could be switched to another study drug. Each drug trial
could last up to 14 weeks. Patients who did well on an assigned drug could
remain on that drug in a follow-up phase for the remainder of the 18 months of
Phase 1 results showed that patients stayed on olanzapine longer (with a
median time to discontinuation of 9.2 months) than any of the other drugs
before switching. No difference was found between perphenazine and
risperidone, quetiapine, or ziprasidone.
Phase 2 of the study generally found that clozapine, despite its risks, was
more effective than other second-generation antipsychotics. But if clozapine
was not an option, olanzapine and risperidone appeared to be the next-best
The CATIE cost-effectiveness analysis used as its two primary outcomes
total health costs and quality-adjusted life year (QALY) ratings.
Total health costs (defined as costs of total health services use plus
medications) were documented each month with a self-report questionnaire. The
investigators tracked an exhaustive list of possible services, including
inpatient, outpatient, and community mental health treatment and residential
assistance services. Costs of various medical or surgical outpatient visits as
well as emergency-room visits were also included.
Monthly medication costs were based on published average wholesale prices.
For those patients covered by Medicaid or cared for in the VA system, monthly
medication costs were adjusted to reflect the steep discounts and rebates on
medication prices often negotiated between those two systems of care and drug
The QALY ratings take into account health-related quality of life that
includes both "health gains," such as beneficial effects of
treatment, and "health losses," such as those associated with side
The CATIE team performed four rigorous analyses, either including or
excluding patients with TD at baseline, and including or excluding patients
randomly assigned to ziprasidone, which was approved by the Food and Drug
Administration and added to the CATIE protocol after the study began.
The December AJP report presents an "intent-to-treat"
analysis of cost-effectiveness, in which all costs, symptom scores, and QALY
ratings are analyzed based on a patient's initially assigned drug. Any changes
that occurred over time were attributed to the effects of the initial drug
assignment, regardless of whether the patient remained on that drug for the
entire study period or switched medications.
Other analyses tracked patients who switched medications during the study
(only 25.9 percent of patients remained on their initially assignment). One of
those analyses, a report by Susan Essock, Ph.D., et al., appears in the same
issue of AJP.
Average monthly medication costs (see top graph) for patients initially
assigned to perphenazine were lower than medication costs for patients
initially assigned to any of the four SGAs. In addition, drug costs for
patients initially assigned to olanzapine were significantly higher than for
patients assigned to quetiapine, risperidone, and ziprasidone. There were no
statistically significant differences, however, in total health care costs
between SGA groups.
There were no statistically significant differences between the groups of
patients initially assigned to any of the five antipsychotics in the
proportion of patients who received inpatient care each month or in costs per
month for inpatient, residential, or outpatient health services.
Total health care costs for patients initially assigned to perphenazine
were $300 to $600 per month per patient, lower than for any of the SGAs (see
Significant improvements in Qaly ratings were observed from baseline to 18
months for patients assigned to all five medications. Perphenazine was
associated with higher (that is, better) QALY ratings than the other agents,
but only one comparison was statistically significant: perphenazine was
associated with higher ratings than was risperidone.
The CATIE investigators pointed out that CATIE was not long enough to
detect any differences in costs that would be attributable to the long-term
development of differential adverse effects, such as TD while taking an FGA,
or the development of metabolic syndrome, diabetes, or cardiovascular disease
while taking an SGA.
This lack of data on long-term costs, Rosenheck and colleagues cautioned,"
limits the conclusions regarding cost-effectiveness that can be drawn
at this time."
The CATIE investigators also cautioned that the relevance of their findings
to FGAs other than perphenazine or to patients with schizophrenia materially
different from the patients studied "is unknown." For example, the
CATIE findings cannot be extrapolated to "first-episode patients,
refractory patients, the elderly, those with unstable medical problems,
long-term institutionalized patients, patients who refuse to take medication,
or patients with diagnoses other than schizophrenia."
Despite all of their cautions, the CATIE team anticipated that some people
will try to use the study results to change existing policy regarding access
to antipsychotic medications within managed formularies.
"This study," they emphasized, "would clearly
not justify policies that would unconditionally restrict access to
any particular medication or that would thoughtlessly force patients or
doctors who are satisfied with a current treatment to change to a [different]
treatment just because it might be less expensive."
And while "[t]hese results should encourage consideration of older
intermediate-potency drugs like perphenazine when a medication change is
indicated," the CATIE investigators noted, "the coming
availability of generic second-generation antipsychotics will undoubtedly
alter the cost profiles described here."
"Cost-Effectiveness of Second-Generation Antipsychotics and
Perphenazine in a Randomized Trial of Treatment for Chronic
Schizophrenia" is posted at<www.ajp.psychiatryonline.org>.▪