Older Schizophrenia Drug Called More Cost-Effective Than Newer Ones

NEW YORK, Dec. 1 -- The older anti-psychotic drug, Trilafon (perphenazine), is significantly cheaper and no less effective than four newer medications for the treatment of chronic schizophrenia, according to researchers here.

The finding -- controversial before the ink was dry -- came from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, a prospective randomized trial that compared Trilafon with four so-called second generation medications. These were Zyprexa (olanzapine), Geodon (ziprasidone), Seroquel (quetiapine fumarate), and Risperdal (risperidone).

The main result of the study, published last September, was that Zyprexa had the lowest rate of discontinuation, but that Trilafon was comparable to the other three and "not that much less effective than olanzapine," reported Jeffrey Lieberman, M.D., of Columbia University, the principal investigator.

But an additional paper, in the December issue of the American Journal of Psychiatry, now suggests that the older drug is more cost-effective than the newer drugs in terms of their "human benefit," reported Robert Rosenheck, M.D., of Yale.

Dr. Rosenheck said during a telephone press conference that rates of discontinuation are a marker for "what we genuinely care about -- (patients') health, their quality of life, their well-being."

Using a range of measures of quality of life, derived from interviews of participants during the study, Dr. Rosenheck and colleagues found that all five drugs were roughly equivalent in improving patients' well-being, but that Trilafon cost between and less per month.

"The bottom line of the study is that the older drug is substantially less expensive -- by between ,600 and ,000 a year -- and no less effective," Dr. Rosenheck said.

But in an unusual development, the study was sharply criticized in an editorial signed by the journal's editor in chief, Robert Freedman, M.D., among others. The report was published, the editorial said, despite "severe reservations," including:

• Questions about the randomization of the study. In the study design, patients with tardive dyskinesia were not randomized to Trilafon, which the editorial suggested may limit the generalizability of the results.
• Concerns about the sensitivity of one of the measures used by Dr. Rosenheck and colleagues, the quality-adjusted life-year (QALY). "Most troubling to the reviewers was that there was no difference in QALY outcome between treatments," Dr. Freedman and colleagues said. "Failure to find difference does not mean that there is no difference."

Dr. Freedman and colleagues also said the 18-month follow-up of the CATIE trial -- "although extensive for a study, is short for the lifetime of care for schizophrenia" and may not have taken into account some long-term consequences of the disease, including tardive dyskinesia.

During the press conference, Dr. Rosenheck shot back that the CATIE trial was subject to a "clear orthodox randomization" and that not allowing patients with tardive dyskinesia to be treated with Trilafon was one of the strengths of the study.

"You can't examine the onset of tardive dyskinesia in patients who already have it," he said. The condition is associated more with the older antipsychotics than the newer drugs.

The practice did not affect the main result of the study, Dr. Lieberman said, because those patients were excluded from the analysis. He agreed that -- for the current study -- the exclusion could "potentially" limit the generalizability of the result.

But, he noted, the affected population is less than one in 10 patients treated with antipsychotic drug, so that "it's a small subgroup that you can't necessarily generalize the results to."

Dr. Rosenheck said the QALY measure -- a standard in health economics studies -- was "sensitive enough to show that the groups were getting better -- it just didn't show there were any significant differences."

The main concern of the editorial and the peer reviewers, Dr. Rosenheck said, was that health insurance companies will use the study to limit access to some drugs. "Most of the reviewers skipped over the science entirely," he said.

But both he and Dr. Lieberman agreed that the study does not suggest that doctors should limit what drugs they will use. "What it does say is that the proportion of medications that are prescribed for chronic schizophrenia is not congruent to the pattern of effectiveness," Dr. Lieberman said.

One effect, however, could be to put the older drugs back on the table for many physicians. The results "should encourage consideration of older intermediate potency drugs like perphenazine when a medication change is indicated," Dr. Rosenheck and colleagues concluded in their report.

And Thomas Insel, M.D., director of the National Institute for Mental Health, which sponsored the study, said in a statement, "The results from CATIE should encourage doctors to reconsider the use of perphenazine as another choice for patients with schizophrenia."

Many of the researchers involved in the CATIE study, as well as several of those who wrote the editorial, reported possible conflicts, which were mainly previous consulting arrangements with pharmaceutical companies.

The study was one of two secondary analyses of the CATIE data published in the December issue of the American Journal of Psychiatry. The other, from a team led by Susan Essock, Ph.D., of New York's Mount Sinai School of Medicine, focused on the promise and perils of switching antipsychotic medications.