Newer drugs more helpful in first-time schizophrenia than older medications, study shows

December 10, 2000

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 over forty years ago.

The study of 200 young adults in China by a University of North Carolina at Chapel Hill psychiatrist working with Beijing and Harvard scientists is the first to directly compare treatment with clozapine, an 'atypical' anti-psychotic medication, with chlorpromazine in people who had an episode of schizophrenia for the first time. 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 was 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 Jeffrey A.Lieberman, MD, professor of psychiatry, pharmacology and radiology at 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 presents the findings Monday, December 11 to the 39th Annual Meeting of the American College of Neuropsychopharmacology in San Juan, Puerto Rico. Another finding of interest to schizophrenia theorists is the fact that patients in the study whose blood tests showed signs of exposure to the parasite toxoplasmosis had a poor response to treatment.

"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 interesting finding, the UNC psychiatrist says 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.

Unlike in China where today it is the second most widely used medication, clozapine was first introduced in the US in 1990 with restrictions. Studies showed it suppressed the immune system's white cells in about one percent of people who took it for more than six weeks. The FDA therefore decided it could only be used in America as a 2nd- or 3rd-line of treatment for people who were unresponsive to other medications, Lieberman explained.

"So we proposed to do a study in China. My Canadian-borne and American-trained colleague has a research program centered in one of the largest psychiatric hospitals in China, in Beijing. "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 Michael Phillips, MD, MPH, was in charge of the research in Beijing.

Lieberman noted that 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. 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. "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 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 (NIMH) 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 ten times that of the old medications and the questions remain as to their effectiveness in the real world and whether they are worth the higher price. "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.
Note to media: Jeffrey A. Lieberman, MD can be reached at 919-966-8990; email:
UNC School of Medicine contact: Leslie H. Lang, 919-843-9687,

University of North Carolina Health Care

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