The nation's leading schizophrenia (search) treatment doesn't work much better than an older, far cheaper drug, says a government study that is the most comprehensive comparison of therapies for the 3.2 million Americans with the devastating mental illness.

The study of five commonly used drugs highlights how difficult schizophrenia is to treat. Three-quarters of patients had to switch medications because of breakthrough symptoms or intolerable side effects.

Those taking Eli Lilly & Co.'s Zyprexa (search) did slightly better, staying on the medicine longer before switching and thus experiencing slightly fewer hospitalizations, researchers reported Monday.

However, Zyprexa was far more likely than leading competitors to cause some troubling side effects: severe weight gain associated with high cholesterol, high blood sugar and even Type 2 diabetes.

The big surprise was that older generic drug perphenazine (search) was just as effective as Zyprexa's main competitors — Seroquel, Risperdal and Geodon — and Zyprexa's advantage was modest, the study found.

That is a striking finding, considering that the newer drugs cost more than 10 times as much as perphenazine, used since the 1950s.

And it led the National Institute of Mental Health, which funded the work, to declare there's no clear winner. It said each drug has tradeoffs that must be considered for each patient.

"What works for one person may not work for another," said Dr. Jeffrey Liberman, director of the New York State Psychiatric Institute and the study's lead author.

The research is being published in this week's New England Journal of Medicine.

Zyprexa remains a reasonable choice, but it should come with dietary and exercise counseling and be switched if excessive pounds threaten patients' physical health, Dr. Robert Freedman of the University of Colorado wrote in an accompanying editorial.

"There is still a double-edged sword here," agreed Dr. Leslie Citrome, a New York University psychiatrist not involved in the study. He said doctors had begun shying away from Zyprexa because of recent bad publicity about the weight gain.

"It's important for clinicians to really keep an open mind and have everything available to them," Citrome said. But the study starkly illustrates that "we really need treatments that will work better," he added.

Schizophrenia, characterized by hallucinations, delusions, withdrawal and inability to feel pleasure, requires long-term treatment.

The choices are plagued with problems: Older drugs used to treat schizophrenia risk causing movement troubles such as rigidity, tremors or involuntary flailing. Newer antipsychotics such as Zyprexa, known chemically as olanzapine, avoid those troubles but come with a range of their own problematic side effects.

The new study, known as CATIE or Clinical Antipsychotic Trial of Intervention Effectiveness (search), enrolled 1,493 schizophrenia patients to compare leading treatments. Participants were randomly assigned to take one of five drugs, put into identical capsules so neither doctor nor patient knew which was being tested.

Overall, 74 percent patients switched drugs before the end of the 18-month study, a period picked because therapy duration is a marker for schizophrenia control.

Zyprexa had a slight edge: 64 percent of users switched. During that time, 11 percent of Zyprexa users were hospitalized for schizophrenia symptoms, compared with 15 percent to 20 percent of those using the other drugs.

On the other hand, Zyprexa users gained an average of 2 pounds a month, and 30 percent gained a significant amount — 7 percent or more of their baseline weight — accompanied by increases in cholesterol and diabetes-threatening high blood sugar.

Those problems are a risk for all newer antipsychotics, but just 7 percent to 16 percent of users of Zyprexa's competitors had such a dramatic weight gain.

Perphenazine, in contrast, didn't cause more of those anticipated movement troubles than the newer drugs — and the newer drugs overall had no substantial advantage, the study concludes.

Zyprexa, which garnered $2.4 billion in U.S. sales last year, can cost more than $12 a day, depending on dose; perphenazine can cost less than $1 a day.

Dosage could have been a factor in Zyprexa's slightly better performance, Citrome cautioned. The study's highest Zyprexa dose exceeds current label recommendations, while doctors today prescribe higher doses of the other antipsychotics than the study did.