Zyprexa Trial in Schizophrenia ‘Prodome’ Yields Only Hints

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A two-year study of Zyprexa (olanzapine) in patients thought to have early signs of schizophrenia had mixed results, researchers reported.

On one hand, daily Zyprexa appeared to blunt symptoms and delay the onset of full-blown schizophrenia, according to Thomas McGlashan, M.D., of Yale and colleagues in the multicenter Prevention Through Risk Identification, Management, and Education (PRIME) project.

On the other hand, patients taking Zyprexa had large weight gains and the dropout rate in the study was so high that no definitive conclusions about the efficacy of the drug could be drawn, the researchers reported in the May issue of the American Journal of Psychiatry.

The basis of the trial itself was controversial - the idea that it is possible to find people with early signs of schizophrenia and treat them before the full-blown disease develops. And it turned out to be difficult to enroll enough participants. After more than three years of recruiting, the researchers were forced to stop at 60 patients with so-called prodromal symptoms.

Of those, only 17 finished the first year of the study and only 12 completed it, Dr. McGlashan and colleagues reported.

The study, carried out at two centers in the U.S. and two in Canada, randomized the 60 participants to Zyprexa (at between 5 mg and 15 mg a day) or placebo for one year. For the second year, the participants were followed without treatment.

They were mainly adolescent males “displaying symptoms similar to those seen in psychosis but less severe and restrained by intact insight,” the researchers reported. However, the value of considering them be “prodromal” was shown by the fact that by the end of the first year 26.7% of the 60 patients had converted to psychosis, while after two years 35% had converted.

In the treatment year, Zyprexa patients had a lower rate of conversion to psychosis than the placebo patients - 16.1% versus 37.9%. The difference approached but did not reach statistical significance.

Placebo patients were about 2.5 times more likely to convert to psychosis than Zyprexa patients, a hazard ratio that also approached statistical significance.

In the following year, with no treatment, conversion rates were also not significantly different - 33.3% versus 25.0%.

Nevertheless, Dr. McGlashan said, the study is a valid proof of concept. “There really is this high-risk state, or syndrome, that you can detect,” he said. “The treatment made a difference.”

One significant difference in the groups during the treatment year was in weight gain - patients taking Zyprexa gained an average of 19.3 pounds (8.79 kg), compared with slightly more than half a pound (0.30 kg) for the placebo group.

The researchers estimated that the number needed to treat - the reciprocal of the absolute risk reduction - is 4.5. On the other hand, patients taking the drug will gain an average of 13% of their body weight in a year, which may later increase their risk of metabolic syndrome.

The study, they concluded, demonstrated that the benefits of identifying and treating people with the schizophrenia “prodrome” outweigh the risks - at least by enough to justify future clinical trials. These should be conducted in academic centers with programs for early detection and intervention in psychosis with Zyprexa or other antipsychotic medications so that definitive recommendations on the use of antipsychotics to treat a prodromal phase of schizophrenia can be made.

They suggested that “future studies should use larger study groups and longer assessment times to determine whether a medication could prevent psychosis onset if continued for longer than one year. Power should be enhanced by determination of further markers of risk for psychosis or collaboration among multiple sites and pooling of participants. This would improve the identification of the truly at-risk subset of any clinically “prodromal” group.

The study was financed by Eli Lilly, of Indianapolis, maker of Zyprexa, and by the National Institutes of Health in Bethesda, Md.

Source: American Journal of Pychiatry

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