CATIE highlights metabolic issues.

SANTA FE, N.M. -- Metabolic syndrome turns out to be the elephant in the room when antipsychotics are prescribed, according to clinicians who discussed the controversial Clinical Antipsychotic Trials of Intervention Effectiveness study at a psychiatric symposium sponsored by the University of Arizona.

Dr. Marvin S. Swartz, a CATIE investigator, reported that disproportionate numbers of the 1,460 patients with schizophrenia already had metabolic syndrome when they entered CATIE.

At baseline, 36% of men and 52% of women in a 509-patient sample met criteria for metabolic syndrome. Only 19.7% of men and 25% of women in a matched sample from the Third National Health and Nutrition Examination Survey had the condition (Schizophr. Res. 2005;80:19-32).

The individual components of metabolic syndrome--large waist circumference, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and high glucose--were all at significant levels in the schizophrenia patients compared with the matched sample.

Whereas extrapyramidal syndrome (EPS) was a major concern with first-generation antipsychotics, metabolic syndrome became a safety issue with the second-generation antipsychotic agents used in CATIE, according to Dr. Swartz, head of social and community psychiatry at Duke University in Durham, N.C.

Patients gained weight on most of the newer agents when these drugs were compared in the second phase of CATIE. "Olanzapine was somewhat more efficacious than the other drugs but also was associated with significant weight gain and metabolic changes," Dr. Swartz said.

He cited a substudy that found 27% of patients on olanzapine (Zyprexa) gained 7% or more of their body weight. Only 13% of patients on quetiapine (Seroquel) gained 7% or more as did an equal proportion on risperidone (Risperdal). Just 6% of patients on ziprasidone (Geodon) gained that much (Am. J. Psychiatry 2006;163:611-622).

Patients on olanzapine also had the biggest weight gain per month, 1.3 pounds, during the second phase of CATIE. While patients on quetiapine gained 0.1 pounds per month, those on risperidone lost 0.2 pounds per month. Ziprasidone was associated with the most weight loss: 1.7 pounds per month.

Changes in cholesterol and triglycerides were also significant, and followed similar patterns.

Average cholesterol increased 17.9 mg/dL with olanzapine and 4.8 mg/dL with quetiapine but decreased by 2.6 mg/dL with risperidone and 12.5 mg/dL with ziprasidone.

Average triglyceride levels went up 69.6 mg/dL with olanzapine and 15.5 mg/dL with quetiapine. They decreased by 27 mg/dL with risperidone and 29 mg/dL with ziprasidone.

Electrocardiograms showed QTc declines of 5.1 msec with olanzapine and 4.4 msec with risperidone, but increases of 1.9 msec with quetiapine and 1.3 msec with ziprasidone. The differences did not reach statistical significance, however.

Meanwhile, the one older antipsychotic in the trial, perphenazine (Trilafon), was well tolerated and performed generally as well as the newer medications in the first part of the trial, Dr. Swartz said. EPS was not a problem.

"This was big surprise; but people said when you use low doses, you are not going to get a lot of EPS," he said.

Clozapine was the most effective drug for patients who did not respond to their first antipsychotic, added Dr. Swartz, but along with olanzapine, it produced the most weight gain and metabolic effects.

"I don't think we can match people with these drugs without thinking about how to manage metabolic syndrome," Dr. H. George Nurnberg commented at the meeting, which also was sponsored by the University of Texas Southwestern Medical Center at Dallas and the University of New Mexico.

Family physicians would put many of them on statins, according to Dr. Nurnberg, director of clinical research programs in the psychiatry department at the University of New Mexico, Albuquerque. He suggested olanzapine might be a back-up drug for patients who do not respond to the other agents. Similarly, ziprasidone might be a back-up for patients who gain weight on another antipsychotic.

Dr. Stephen R. Marder called for frequent monitoring of weight gain and other metabolic side effects in patients on atypical antipsychotic medications.

"You can make the case that if patients were gaining 2 pounds per month; maybe they should have been discontinued sooner," said Dr. Marder, director of the psychosis section in the Neuropsychiatric Institute at the University of California, Los Angeles.

"With schizophrenia, the average individual dies 15 years sooner than the person who does not have schizophrenia," he added.

"It is a terrible problem we have to attend to. The reason is usually because of heart disease. Cardiovascular mortality in schizophrenia is increasing."

BY JANE SALODOF MACNEIL

Southwest Bureau