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CATIE renews debate over old versus new antipsychotics

January 01, 2006

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.”

How Should Prescribers Proceed?

Although some interpretations of the phase one results are advising that prescribers and purchasers turn back to the typicals, Dr. Lehman says that the pharmaceutical industry's marketing machine is conducting its own efforts, using the Internet to cite reasons the field should dismiss the CATIE findings.

In not finding vast differences in effectiveness or side effects among the antipsychotics studied, CATIE so far has made its greatest contribution in affirming that prescribers and their patients have choices, Dr. Lehman believes.

“Practitioners shouldn't just exclude the older agents in their thinking,” Dr. Lehman says. “There had been a push at one time to say that it was unethical for prescribers to use the first-generation antipsychotics.” Dr. Lehman characterizes that line of reasoning as essentially a marketing ploy.

In an editorial accompanying the September 22 journal article, Robert Freedman, MD, of the Department of Psychiatry at the University of Colorado Health Sciences Center, reminds readers that both the first- and second-generation antipsychotics have troublesome side effects as a group, and that metabolic problems seen in some patients on atypicals can be far more life-threatening than TD and other extrapyramidal symptoms.

While Dr. Freedman believes it is reasonable to prescribe atypicals such as olanzapine and clozapine (Clozaril) for patients who have not experienced a clinical remission of their illness, he adds, “However, it is also prudent to switch treatment from these drugs to one of the others if a metabolic syndrome is threatening the patient's general health.”

Dr. Lehman focuses on the high treatment discontinuation rates evident in phase one, and observes that both classes of antipsychotics fall short in that they address only the positive symptoms of the illness: “Underlying neurocognitive impairments are not affected in a regular way, and this accounts for a lot of the disability.”

A new wave of medications is likely to arrive at some point to address this, Dr. Lehman says. A number of other receptor areas besides those for dopamine and serotonin justify being studied, including glutamate receptors, according to Dr. Regier. Other promising approaches include wider use of cognitive-behavioral interventions, as well as more exploration of “cognitive remediation” techniques that treat the brain as a muscle and essentially offer “brain exercises” to patients, Dr. Lehman says.

So while prescribers and policymakers may be advised to look to the future for better treatments, they shouldn't forget that for some patients, a good plan for now might draw from either the present or the past. As Dr. Freedman states in the closing of his journal editorial, “The value of CATIE is that it provides solid evidence to help clinicians and their patients make the difficult decisions needed to optimize the treatment of schizophrenia with the compounds currently available.”

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