Perphenazine can cost no more than $50 a month compared with more than $600 for Zyprexa, depending on dose.

The biggest surprise: An overlooked generic drug called perphenazine -- around since the 1950s but seldom used -- proved as effective as all but one of a class of newer treatments called atypical antipsychotics that make up 90 percent of schizophrenia-related prescriptions today.

That one, Eli Lilly & Co.'s Zyprexa, worked slightly better but with a drawback: It was far more likely than leading competitors to cause severe weight gain, leading to high cholesterol, high blood sugar, even Type 2 diabetes.

The findings are striking considering that perphenazine can cost no more than $50 a month compared with more than $600 for Zyprexa, depending on dose. Indeed, the nation will spend about $10 billion this year on those atypical antipsychotics, said Dr. Thomas Insel, director of the National Institute of Mental Health, which funded the research.

A troubling finding: Three-quarters of patients switched medications because of inadequate symptom control or intolerable side effects.

There May Not Be a Magic Bullet

"Make no mistake, these treatments are effective and far better than no treatment at all," lead investigator Dr. Jeffrey Lieberman, of Columbia University and director of the New York State Psychiatric Institute, said Monday. But, "when it comes to the treatment of patients with chronic schizophrenia, the glass is only half full."

"There may not be a magic bullet for schizophrenia," said Insel. "We may need to find ways of combining treatments to get the maximal impact," just as multiple drugs are used for other disorders, such as high blood pressure.

Publication of the sobering first results in this week's New England Journal of Medicine may help doctors tease apart the trade-offs in picking which medicine to try for the 3.2 million Americans with schizophrenia.

Before the development of antipsychotics 50 years ago, most patients with schizophrenia -- characterized by hallucinations and disordered thinking -- were institutionalized. While the drugs have improved patients' care greatly, they aren't a cure, and side effects can affect how likely someone is to continue treatment.

First-generation drugs' chief concern was Parkinson's disease-like movement problems: tremor, rigidity, involuntary flailing. Zyprexa and its newer cousins rapidly gained popularity by promising an end to those problems, but have their own side effects. There had never been a direct comparison of all the leading treatments to see which works best long-term.

Weight Gain Is a Risk

The CATIE, or Clinical Antipsychotic Trial of Intervention Effectiveness, study enrolled 1,493 schizophrenia patients at 57 medical centers. Participants were randomly assigned to take one of five drugs -- Zyprexa, Seroquel, Risperdal, Geodon or perphenazine -- for 18 months, a period picked because therapy duration is a marker for schizophrenia control.

While 74 percent of patients switched drugs before the 18 months was up, only 64 percent of Zyprexa users did, giving it a slight edge. Also, 11 percent of Zyprexa users were hospitalized for schizophrenia symptoms, compared with 15 percent to 20 percent of those using the other drugs.

However, 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.

Weight gain is a risk with all atypical antipsychotics, but just 7 percent to 16 percent of users of Zyprexa's competitors gained the larger amount. No one knows why these drugs spur weight gain -- they could affect appetite, or the body's sensitivity to the diabetes-related hormone insulin.

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.

Dietary and Exercise Counseling

Dosage could have spurred Zyprexa's slightly better performance, cautioned Dr. Leslie Citrome, a New York University psychiatrist not involved in the research. The study's highest Zyprexa dose exceeds current label recommendations, and doctors today prescribe higher doses of the other antipsychotics than the study did, a factor drug companies noted.

Researchers still are analyzing how participants fared after switching drugs and additional factors. But the first findings suggest a hard-to-treat patient might need Zyprexa, while perphenazine might be a better choice if side effects are a bigger concern, Lieberman said.

"It clearly is an effective treatment and should not be disregarded just because it's older," he said.

Zyprexa should come with dietary and exercise counseling and be switched if excessive pounds threaten patients' physical health, cautioned Dr. Robert Freedman of the University of Colorado in an accompanying editorial.