Older Drug Is Best for Schizophrenia

Despite the development of numerous modern drugs to treat schizophrenia, the older, less expensive option, clozapine, is still the most effective treatment, according to a new study released today.

The study found that clozapine was able to control some of the symptoms of schizophrenia and that a higher percentage of patients could take it for extended periods.

But even clozapine’s side effects were so serious that only 40% of patients in the trial could stay on the drug.

“None of the medications are sufficient for treatment of this disorder,” said Dr. Thomas R. Insel, director of the National Institute of Mental Health, which funded the study. “We have to find a new generation of medicines.”

The findings, reported in the American Journal of Psychiatry, came from a major federal study designed to outline the best protocols for treating the estimated 3.2 million Americans suffering from one of the most severely debilitating mental disorders.

People with schizophrenia suffer from hallucinations and delusions, often hearing voices in their heads.

They also have thought impairments -- they are often unable to hold a thought for more than a few seconds, for example. Patients often say they have “a poverty of thought, as if their brain has stopped working and they are dead inside,” Insel said.

All of the drugs now in use can minimize or eliminate the hallucinations and delusions, but none improve thought processes.

Only about 10% of schizophrenics are able to hold a job, and fewer than 10% are married, Insel said.

The $45-million Clinical Antipsychotic Trials of Intervention Effectiveness were designed to compare various drugs for treatment and to determine which drugs were best if the first one failed. Eventually, the researchers hope to find the best treatment path for patients.

First, researchers enrolled 1,493 patients with long-standing schizophrenia and randomly assigned them either to receive one of four so-called second-generation antipsychotics -- olanzapine (trade-named Zyprexa), quetiapine (Seroquel), risperidone (Risperdal) or ziprasidone (Geodon) -- or to receive an older drug, perphenazine.

The results from that phase, released in September, were “sobering,” said Dr. Carol A. Tamminga of the University of Texas Southwestern Medical School, who wrote an editorial accompanying today’s studies.

Only 26% of the patients were able to stay on their drug for the full 18 months of the study. The rest quit because they didn’t think the drug helped or they couldn’t tolerate the side effects.

“All the drugs are helpful, but they are helpful only if people stay on them,” Insel said.

None of the drugs stood out in the study. Olanzapine was slightly better, but it also had a higher level of side effects, including weight gain, diabetes and other problems.

In the second phase, reported today, patients for whom the first drugs didn’t work were randomly assigned a different drug.

This time the researchers included clozapine, a drug that is rarely used now because intensive medical monitoring is required to prevent potentially life-threatening side effects.

Dr. Joseph P. McEvoy of Duke University Medical Center and his colleagues reported that clozapine was substantially more effective than the others.

Twenty out of 45 patients who received it were able to stay on clozapine for the length of the study, compared with only eight of 45 who received one of the other drugs.

These patients were seriously ill, McEvoy said, “so 40% [success with clozapine] isn’t bad. But the other agents really don’t offer much promise for patients.”

Added Tamminga: “The evidence, clearer than many clinicians might have believed, is that clozapine is the only rational alternative” if one of the new drugs doesn’t work.

In a separate part of the trial, patients who could not tolerate the side effects with their first drug and who were not willing to take clozapine were randomly assigned to receive a different second-generation drug.

Dr. T. Scott Stroup of the University of North Carolina at Chapel Hill and his colleagues reported that 74% of the patients stopped taking their drugs before the end of the study.

About 35% of the patients who took olanzapine or risperidone were able to tolerate the drugs, compared with 23% of those who took ziprasidone and 16% of those who received quetiapine.

“This is a very serious illness, and the medications all have substantial limitations,” Stroup concluded.