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CATIE renews debate over old versus new antipsychotics

January 1, 2006
by GARY A. ENOS, CONTRIBUTING EDITOR
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Some experts warn against interpreting CATIE's fi ndings as an endorsement of the typicals

Some behavioral health leaders and government policymakers believe the first-phase results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) justify a look back at first-generation antipsychotics (“typicals”) as viable first-line treatments for schizophrenia. Yet two experts interviewed by Behavioral Healthcare suggest that the initial results perhaps should have these individuals looking forward instead, toward a next class of drugs that could improve on the efficacy of currently used antipsychotics without the side effects that plagued compliance with the conventional drugs.

Rather than emphasizing that the conventional antipsychotic perphenazine (brand name: Trilafon) showed results comparable with those of four newer antipsychotics in CATIE, professionals should be concerned that 74% of patients who received at least one dose of one of the studied drugs discontinued treatment prematurely, says the chairman of the University of Maryland School of Medicine's psychiatry department.

“None of these drugs are home runs,” says the university's Anthony F. Lehman, MD, MSPH. “If we had a treatment that was really great, more people would switch to it.”

The much-anticipated double-blind study comparing perphenazine with the newer antipsychotics olanzapine (brand name: Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon) was published in the September 22, 2005, New England Journal of Medicineas “Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia.” Jeffrey A. Lieberman, MD, of the Department of Psychiatry at Columbia University and colleagues randomized patients to one of the five drugs for purposes of identifying differences in overall effectiveness among the medications over an 18-month study period.

Besides the finding on treatment discontinuation, which generally occurred later for patients on olanzapine than for patients on one of the other drugs, researchers found some improvement over time for patients in all drug groups, as measured by scores on the Positive and Negative Syndrome Scale (PANSS). Improvement was initially greatest among patients on olanzapine, although the gap between olanzapine and the other medications narrowed over time, the researchers found.

On the all-important concern of side effects, while extrapyramidal effects such as tardive dyskinesia (TD) contributed to more treatment discontinuation among patients on perphenazine (8% of all patients taking perphenazine discontinued for this reason), olanzapine actually had the highest rate of overall treatment discontinuation from intolerable side effects (18% of patients on the drug). Effects consistent with possible development of metabolic syndrome were seen in the olanzapine group; 30% of this group gained 7% or more of their baseline body weight during the study period, according to researchers.

Dangerous Interpretations?

Dr. Lehman and Darrel Regier, MD, MPH, director of the Division of Research at the American Psychiatric Association (APA), share the view that despite the national media attention that the first-phase results received during the fall, the findings probably have had little effect on prescribing patterns to this point.

However, Dr. Regier says, the findings have had a “huge impact on conversations with state Medicaid offices.” National media reports and even an initial statement from the National Institute of Mental Health (NIMH) interpreted the results as an endorsement of first-generation antipsychotics as the most cost-effective option for treating people with schizophrenia. As a result, policymakers in some states want to waste no time in classifying perphenazine as the preferred medication for schizophrenia, Dr. Regier says.

“Folks are not waiting for phases two and three,” which will further explore the drugs’ effects, notes Dr. Regier. Some patients who in phase one discontinued treatment under one drug received another medication in subsequent phases. The study was conducted under NIMH's auspices between January 2001 and December 2004 at 57 sites.

Dr. Regier considers some state officials’ interpretation of the data to be hasty and dangerous for several reasons. First, the CATIE study looks at only one of the first-generation antipsychotics, and the researchers chose in perphenazine a drug with lower potency and lower risk of adverse effects than others in the class, he says: “They didn't bring in haloperidol, which was the most widely used of the typicals.”

In addition, Dr. Regier says, the 15% of the patient population with preexisting TD was excluded from being randomized to the perphenazine group in the study. “Patients with current tardive dyskinesia could enroll, but the randomization scheme prevented their assignment to treatment with perphe-nazine,” the journal article states.

“It was not a level playing field,” Dr. Regier says.

The first-phase results change nothing about the fact that as a class, the first-generation antipsychotics expose about 5% of the group prescribed them to extrapyramidal effects, Dr. Regier says: “Should we be forced into some cost-benefit equation on this? No, because the risk of TD is so great that it's not worth it.”

APA and other entities have taken a more cautious approach to the findings than what some state policymakers have apparently concluded. A statement from the National Council for Community Behavioral Healthcare (NCCBH) says that while the CATIE study suggests that socially stigmatizing movement disorders were not prevalent in patients on perphenazine, “a study that lasts only 18 months cannot determine this. Involuntary muscle movements typically manifest after years of taking a drug.”

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