NEWS

Study: New drugs help more in first-time schizophrenia than older medications

By LESLIE H. LANG
UNC-CH School of Medicine

CHAPEL HILL -- People diagnosed with first-episode schizophrenia may fare much better when treated with newer anti-psychotic drugs than with traditional medications that were first introduced more than 40 years ago, new research indicates.

A study of 200 young adults in China by a University of North Carolina at Chapel Hill psychiatrist working with Beijing and Harvard University scientists is the first to directly compare treatment with clozapine, an atypical anti-psychotic medication, with chlorpromazine in people who had a first episode of schizophrenia. None had ever been treated for the disorder with these medications.

In this double blind study, patients were randomized to receive treatment with one drug or the other. Neither they nor the researchers knew who received which one until the data were analyzed. The findings clearly tilted in favor of clozapine.

"We found that clozapine acts faster and produced fewer patients who drop out or stop treatment because of side effects," said Dr. Jeffrey A. Lieberman, professor of psychiatry, pharmacology and radiology at the UNC-CH School of Medicine. "This is the first time a study’s ever been done comparing the prototype of this new class of drugs with the old group in a large sample of patients."

Lieberman presented the findings Dec. 11 to the 39^th annual meeting of the American College of Neuropsychopharmacology in San Juan, Puerto Rico.

Patients in the study whose blood tests showed signs of exposure to the parasite toxoplasmosis responded poorly to treatment, the study found.

"Toxoplasmosis is a parasite borne by a number of domestic animals, most commonly by cats," Lieberman said. "There’s a theory that an infectious agent, a parasite or some other microorganism, can cause schizophrenia. And toxoplasmosis has an affinity for the nervous system, where it can lie dormant for a long time in its migration to the brain."

Given this finding, the UNC-CH psychiatrist said a potential treatment strategy for schizophrenia in a population with a high risk for toxoplasmosis may be using standard anti-psychotic medication along with one of the drugs typically used against the parasite.

In China, clozapine is the second most widely used medication; the medication was first introduced in the United States, with restrictions, in 1990. Studies showed it suppressed the immune system’s white cells in about 1 percent of people who took it for more than six weeks. The Food and Drug Administration, therefore, decided it could only be used in America as a second or third line of treatment for people who were unresponsive to other medications, Lieberman said.

"So we proposed to do a study in China. My Canadian-born and American-trained colleague has a research program centered in one of the largest psychiatric hospitals in China, in Beijing," he said. "We wanted to determine if outcomes would be better if we treated people who had never received treatment before for any psychosis and gave them these new medications."

Novartis, clozapine’s manufacturer, agreed to supply the medication and support the study. Over several years, Lieberman’s colleague Dr. Michael Phillips was in charge of the research in Beijing.

Since chlorpromazine’s introduction in 1953, more than 40 other compounds were developed by the pharmaceutical industry that did nothing to provide better efficacy or safety, Lieberman said. Of the newer atypicals, clozapine is the first and remains the gold standard for this class of drugs.

"We think using these new drugs as first-line medications increases the likelihood of recovering from the illness and reduces the likelihood of a second episode when they remain in treatment," he said.

"Patients who are at the beginning of their illness are extremely sensitive to treatment. That sensitivity makes them very responsive to the therapeutic effects of anti-psychotic drugs. They respond to all treatment including the newer and better treatments. However, they’re also more sensitive to side effects and this can become a real problem in terms of their willingness to continue their medication and the likelihood of them stopping."

In 1999, UNC-CH won a $42.1 million federal contract to determine the safety and effectiveness of atypical anti-psychotic drugs for treating people with schizophrenia and those with psychotic and disruptive behaviors often associated with Alzheimer’s disease.

The National Institute of Mental Health contract is the largest awarded by the agency. It places the university in charge of a multi-center, five-year effort aimed at definitively determining the value of atypical drugs represented by clozapine, risperidone, olanzapine and quetiapine. The contract includes 80 clinical sites nationally.

Now on the market, these drugs are proven effective in carefully controlled clinical studies typically co-sponsored by drug companies. The drugs differ from other anti-psychotic agents in that they act on multiple cell receptor sites in the brain, including receptors for dopamine, serotonin and norepinephrine instead of just dopamine.

However, the new drugs cost more than 10 times that of the old medications and the questions remain as to their effectiveness. "The NIMH wants to get definitive and objective results in terms of their effectiveness, results of significant magnitude in real-world settings that can inform public health policy," Lieberman said.

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Note: Contact Lieberman at (919) 966-8990 or jlieberman@css.unc.edu

School of Medicine contact: Leslie Lang, (919) 843-9687 or llang@med.unc.edu