Study Compares Schizophrenia Treatments

A large, government-funded clinical trial comparing schizophrenia drugs highlights differences between these medications. But experts say that rather than pointing to a clear winner, the trial demonstrates the importance of choice in tailoring a treatment regimen for schizophrenic patients.

    Two articles published in the April issue of the American Journal of Psychiatry contain the second phase of results from the National Institute of Mental Health’s (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. The two trials examined the efficacy and tolerability of second-generation antipsychotic drugs among patients who had discontinued therapy in the first phase of the study. The results of the first phase were published in September 2005.

    The most groundbreaking results came from the arm of the trial that included Clozaril (clozapine), which was not part of the first phase. Patients on clozapine must be monitored closely by their doctors, because the drug is associated with some serious side effects including heart muscle inflammation and drastic drops in white blood cell counts, according to the NIMH.

    Doctors are often wary of using clozapine because of these side effects, said CATIE co-investigator J. Steven Lamberti of the University of Rochester Medical Center.

    But forty-four percent of the patients assigned to clozapine stayed on the drug through the end of the 18-month study. Only 18 percent of the patients re-assigned to the trial’s three other drugs – Seroquel (quetiapine), Risperdal (risperidone), and Zyprexa (olanzapine) – stayed on those drugs for the rest of the study.

    These results indicated that no patient should be considered a “poor responder,” someone who does not show significant improvements from medication, until he or she has tried clozapine, explained Stephen Marder, professor of psychology at the Semel Institute of the University of California Los Angeles. In contrast, people who respond very well to medication should try a different antipsychotic, with fewer side effects, before clozapine, he added.

    The second arm of the trials compared quetiapine, risperidone, and olanzapine with a newer drug, Geodon (ziprasidone). Unlike the other antipsychotics used in the CATIE trial, ziprasidone is not associated with weight gain and metabolic problems. All four of these drugs were included in the first phase of CATIE.

    Investigators thought that patients on ziprasidone would use that drug for the longest periods before changing therapies, Lamberti said.But patients stayed on risperidone and olanzapine for the longest periods. Olanzapine was also considered the most effective of the four at improving symptoms, even though it is associated with metabolic side effects.

    These results show that efficacy is more important than a patient’s ability to tolerate side effects, according to Lamberti.

    “No matter what, if a drug does not improve symptoms, then it is useless,” said Leslie Citrome, a professor of psychiatry at New York University’s medical school. “The balance between efficacy and tolerability is what individualized treatment is all about.”

    Taken together, the two paper’s outcomes demonstrate the importance of tailoring treatment to each patient’s individual needs, Lamberti explained.

    “There’s no clear better drug for everybody,” Marder said, adding that doctors and patients need access to “a broad range of choices.”

    But Citrome is concerned about the results that point to clozapine as the most effective choice for patients who already failed on another drug. Patients in this arm of the CATIE trial knew if they were assigned to clozapine, he explained, because the potential side effects require extra patient monitoring. What’s more, he explained, patients were only enrolled in this arm of the study if they expressed interest in taking clozapine.

    As a result, Citrome is worried that some patients who agreed to participate in the clozapine arm, but were assigned to one of the other three drugs in the trial, discontinued because they knew they were not receiving clozapine.

    “If they were dissatisfied with the therapeutic response with the drug from phase I, and were not randomized to clozapine, both the clinician and patient may have been inclined to discontinue earlier, as the expectation may have been ‘more of the same’ as in phase I,” he said.

    But Citrome added that the results are consistent with other literature about clozapine.