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(Feb. 2006) -- Combining two antipsychotic drugs, clozapine and risperidone, offers no benefit in treating people with severe schizophrenia compared to the use of either drug alone, Canadian researchers report.

The findings cast doubt on the widespread practice of "polypharmacy" for schizophrenia, when two or more drugs are prescribed together.

"This study does not offer any support for antipsychotic polypharmacy," said study author Dr. William Honer, a professor of psychiatry at the University of British Columbia in Vancouver.

"The study is a very well-written report of a very meticulously conducted clinical trial, so it carries a lot of weight," added Dr. Leslie Citrome, a professor of psychiatry at New York University School of Medicine in New York City.

The findings appear in the Feb. 2 issue of the New England Journal of Medicine.

Schizophrenia is a chronic mental illness with symptoms that can include hallucinations, delusions and disordered thinking. The disease affects about 3.2 million Americans.

The treatment landscape for schizophrenia has been relatively static over the past 15 years, experts say. The antipsychotic medication clozapine represented a major advance when it was approved in the United States in 1990. Drugs released since then have not provided any significant improvement for symptoms, although some have different side-effect profiles, meaning they may be better tolerated by some patients.

"There has been an improvement in allowing us to match individual patients to individual medicines, but we are still frustrated at the inability to really control the symptoms of the illness in all patients," Honer said.

Even adequately treated with the available drugs, as few as 20 percent of patients see all of their symptoms resolve. And because so many people have such a poor response to single antipsychotic drugs, the practice has been to prescribe multiple antipsychotic drugs -- despite a lack of evidence that this is any more effective than using one drug alone.

"Current evidence for using more than one antipsychotic is limited to mainly anecdotal reports," Citrome said. "A lot of people do use more than one, and I think it's driven by our desperate need to get patients better. However, the evidence doesn't really support this strategy."

According to Honer, 25 percent to 50 percent of patients who are being prescribed one antipsychotic medication are taking also another one, and sometimes as many as five.

In the study, the researchers wanted to see if adding the antipsychotic drug risperidone in patients who had only a partial response to clozapine improved symptoms. Both drugs are widely used antipsychotics.

In all, 68 patients with schizophrenia and a poor response to clozapine were randomly assigned to receive clozapine plus a placebo or clozapine plus risperidone for eight weeks, followed by an additional, optional 18 weeks of clozapine plus risperidone.

At the end of the study period, the researchers found no statistically significant difference in symptom relief between the two groups. In other words, adding risperidone conferred no extra benefit.

"This indicates that antipsychotic polypharmacy is unlikely to produce a major effect," Honer said. "It doesn't say anything about other combinations [for example, an antipsychotic with an antidepressant]."

So, where does this leave patients struggling with schizophrenia?

There may also be other ways to make single medications more effective, such as optimizing the dose or making sure medications are being taken on schedule.

Beyond that, however, Honer said we're left "with the unexplored area of 'can we really come up with drugs that have different mechanisms that might really benefit people in ways that the current group of antipsychotics do not?'"

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Reviewed: 03/2006