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Antipsychotic Drugs Tied to Blood Sugar Trouble

Study finds adolescents taking them at much higher risk

TUESDAY, Nov. 27, 2001 (HealthDayNews) -- New research warns doctors who treat adolescents for schizophrenia and other psychotic illnesses to watch closely for signs of blood sugar trouble.

Scientists have found that a class of widely used antipsychotic medications significantly increases the risk of hyperglycemia, a dangerous surge in blood glucose. The findings, from researchers at Duke University and the Food and Drug Administration (FDA), appear as a letter in the Nov. 28 issue of the Journal of the American Medical Association.

The research involves a relatively new family of compounds called atypical antipsychotics, which include clozapine and its newer cousin, olanzapine. These drugs have long been known to promote weight gain and increase the risk of diabetes, or fan a smoldering case, although experts don't know why.

A paper this year in a Journal of Clinical Psychiatry supplement reports the FDA has been alerted to more than 140 cases of new-onset diabetes in patients taking clozapine. Three dozen cases involved ketoacidosis, a potentially deadly complication of elevated blood sugar. The paper also cited 19 case reports of diabetes associated with the use of olanzapine, sold as Zyprexa by Indianapolis-based Eli Lilly and Co.

But the problem hasn't been studied among patients in adolescence, when symptoms of some psychotic diseases, particularly schizophrenia, usually appear.

In the new research, Dr. Elizabeth Koller, an FDA medical officer, and colleagues culled the agency's MedWatch database for blood sugar trouble associated with clozapine and olanzapine.

They found 11 reports of runaway blood sugar in patients ages 13 to 18 taking clozapine between January 1993 and March last year. They also found nine reports of similar complications among teens taking olanzapine between January 1996 and May 2001.

Of the patients on olanzapine, seven had newly diagnosed hyperglycemia while two already were identified as diabetics. The sugar disorder developed within a week of taking the drug in two patients and within six months for eight others. (Data are missing for the ninth.)

Sugar control improved in four patients who stopped taking the drug or scaled back their dose. But one patient ultimately died of necrotizing pancreatitis, a condition in which cells in the pancreas die.

One youth taking clozapine also developed pancreatitis more than a month after stopping the drug. That patient survived.

Available information showed that eight of the clozapine patients with high blood sugar never had the problem before. Although the patients on olanzapine also were taking a wide range of other medications, those on clozapine took only one other medication.

Though diabetes linked to obesity is a growing problem among American teens, it is uncommon enough -- one case per 1,000 people under age 25 -- that uncontrolled blood sugar sticks out.

Assuming the number of reported adverse reactions to the two brain drugs accurately reflects their occurrence -- and researchers suspect many more cases weren't reported -- the researchers estimate the rate of hyperglycemia among young clozapine users is 10 times greater than among the general population. However, the rate for those taking olanzapine doesn't seem to be elevated, they conclude.

"The million-dollar question is whether the cases in the MedWatch database are the tip of the iceberg or not. We don't have a good sense for what percent of serious adverse events that occur in practice with marketed drugs are ever reported to the FDA," co-author P. Murali Doraiswamy, a Duke University psychiatrist, says in a statement.

"The connection between pancreatitis and these drugs is not fully known, but given its background rate is so rare, I suspect it's a drug toxicity," Doraiswamy says in an e-mail interview.

Tawny Bettinger, a brain drug expert at the University of Texas Southwestern Medical Center who has studied the effects of antipsychotics on blood sugar, says the problem is gaining attention among mental health experts. "They don't know the causes of it, or why it's happening," says Bettinger, who cites a number of case studies, including one she published, that have appeared in the last several years.

In her own work, Bettinger and her colleagues saw that a diabetic woman taking olanzapine quickly developed runaway blood sugar that previously had been under control with a careful diet. Once the woman started on the drug, even insulin and other sugar-quelling medications couldn't keep her glucose in check.

Fortunately, Bettinger says psychotic patients who suffer blood sugar disruptions on one medication can take a variety of other drugs.

Meanwhile, The Duke and FDA researchers write, "Atypical antipsychotic agents continue to have a role in treating pediatric psychotic disorders, although they are not currently labeled for pediatric use. Until systematic studies of the various agents are conducted to determine relative and absolute risk, physicians should consider monitoring patients for hyperglycemia."

Koller declined to discuss her study, and officials at the FDA could not be reached for comment on the findings.

Clozapine's better understood side effect is a potentially grave falloff in white blood cells, a problem called agranulocytosis that the FDA has recognized for some time. Patients starting on clozapine must undergo regular blood tests to watch for the condition.

Last July the drug was linked to dozens of cases of heart complications, including at least 28 deaths since the late 1980s. Novartis, which makes a brand-name version of the pill, has contested those figures. Even so, many mental health experts consider the compound a miracle drug for patients with otherwise untreatable psychosis.

In the United States, warning labels on atypical antipsychotics list the possibility of sugar problems in patients who use them, but they aren't "highlighted in any special way," Doraiswamy says. "In Japan, they have a much stronger warning that is highlighted and appears at the very first beginning of the label." However, Doraiswamy says, "It's difficult to further change the label in the United States without having a sense for whether this is a unique problem with one or two drugs or applies to the entire class."

What To Do

A recent report on mental illness from the U.S. Surgeon General says roughly 2.2 million Americans have schizophrenia, split evenly between men and women.

For more on the condition, try NARSAD, the National Alliance for Research on Schizophrenia and Depression or the National Institute of Mental Health.

To learn more about atypical antipsychotics, try About.com.

For more on hyperglycemia, check EndocrineWeb.com or the University of Pennsylvania.

SOURCES: Interviews with Tawny Bettinger, Pharm.D., assistant professor of psychiatry, University of Texas Southwestern Medical Center, Dallas; P. Murali Doraiswamy, M.D., (via e-mail), associate professor of psychiatry, Duke University, Durham, N.C.; Journal of Clinical Psychiatry; Nov. 28, 2001, Journal of the American Medical Association
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