"Adverse baseline-to-end-point changes reached statistical significance for olanzapine and quetiapine for total cholesterol, triglycerides, non-HDL cholesterol, and ratio of triglycerides to HDL cholesterol. [ sic] With risperidone, levels of triglycerides increased significantly. Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group. Patients receiving quetiapine had modestly higher incidence rates of hyperglycemia and the metabolic syndrome and patients receiving olanzapine experienced the highest incidence rates (eTable 3). Pubertal status was unrelated to metabolic changes in any antipsychotic medication group."

In this short-term study of youth naïve to antipsychotic medications, aripiprazole, olanzapine, quetiapine, and risperidone were each associated with rapid and significant increases in body composition, whereas metabolic changes were less uniform. Effect sizes for body composition changes were large (eTable 2). Altogether, 10% to 36% of patients transitioned to overweight or obese status within 11 weeks.

"The lack of significant changes in weight and metabolic parameters in psychiatric comparison patients and short inpatient stays (10-18 days is equal to 14%-25% of treatment time) indicates that the observed alterations are not likely due to a newly developing or worsening psychiatric disorder or hospitalization.

"The results are concerning because they include fat mass and waist circumference, which are associated with the metabolic syndrome in adults treated with antipsychotic medications and heart disease in the general population. Moreover, abnormal childhood weight and metabolic status adversely affect adult cardiovascular outcomes."

"These data confirm prior findings that children and adolescents are highly vulnerable to antipsychotic medication–induced weight gain and metabolic adverse effects. The magnitude of weight gain is particularly concerning, as is the implication that metabolic adverse events may be underestimated in studies in which participants have had prior atypical antipsychotic medication exposure. Furthermore, the development of clinically significant hyperlipidemias and insulin resistance after only 12 weeks of treatment portends severe long-term metabolic and cardiovascular sequelae."

"These results challenge the widespread use of atypical antipsychotic medications in youth."

THE NEW YORK TIMES
October 28, 2009
Weight Gain Associated With Antipsychotic Drugs
By DUFF WILSON

Young children and adolescents who take the newest generation of antipsychotic medications risk rapid weight gain and metabolic changes that could lead to diabetes, hypertension and other illnesses, according the biggest study yet of first-time users of the drugs.

The study, to be published Wednesday in The Journal of the American Medical Association, found that 257 young children and adolescents in New York City and on Long Island added 8 to 15 percent to their weight after taking the pills for less than 12 weeks.

The patients, ages 4 to 19, added an average of one to one-and-a-half pounds a week.

“The degree of weight gain is alarming,” said Dr. Wayne K. Goodman, head of a Food and Drug Administration advisory panel on the drugs last summer and chairman of psychiatry at Mount Sinai School of Medicine in Manhattan. “The magnitude is stunning,” he said.

Although the drugs’ influence on weight and metabolism had been previously detected, Dr. Goodman, who was not involved in the study, said the speed and magnitude of the effects found in the study were greater than previously reported — findings he said were made possible by looking exclusively at new patients.

The four drugs in the study, the most popular antipsychotic medications, are industry blockbusters, with combined sales of $12.7 billion last year. And while all four caused weight gain, there were differences in the extent of the side effects. Among them, Zyprexa, made by Eli Lilly & Company, showed the most severe effects on weight and metabolism. The study’s authors, and an accompanying JAMA editorial, called for closer monitoring of patients taking the drugs, as well as additional long-term studies.

The drugs are prescribed for schizophrenia, bipolar disorder and a broad range of less serious psychological conditions. Their use by children and teenagers has been rising steadily. A 2008 study found that patients under 19 years old accounted for 15 percent of antipsychotic drug use in 2005, compared with 7 percent in 1996.

The study, financed by federal grants, is the largest yet published on childhood use of the drugs. And because it is also the largest study of first-time users of the drugs, whether children or adults, it provided an opportunity to analyze the cause and severity of near-term side effects.

As a result, the study goes further than previous research in distinguishing varying metabolic effects among the four drugs, according to Dr. Judith L. Rapoport, another expert who was not involved in the research.

“It’s by far the best documentation of not just weight gain and metabolic changes but also suggesting there might be differences among the drugs,” Dr. Rapoport, chief of the child psychiatry branch at the National Institute of Mental Health, said in an interview.

The lead researcher, Dr. Christoph U. Correll of Zucker Hillside Hospital in Queens and the Feinstein Institute for Medical Research in Manhasset, N.Y., said researchers had saved their blood work for future study of the molecular basis of the different drugs’ metabolic effects.

“People should think twice before they actually prescribe the medications,” Dr. Correll said in a phone interview. The drugs studied are in a class known as atypical antipsychotics, which are second-generation psychiatric drugs that in some cases regulate the receptors in the brain that interact with the mood-altering hormones serotonin and dopamine.

Abilify and Risperdal are the only two of the four drugs approved as pediatric treatments, for the severe mental conditions schizophrenia and bipolar disorder — and in Risperdal’s case, for some children with autism. More than 70 percent of atypical antipsychotics’ use in young children and teenagers has been off-label prescriptions for nonpsychotic conditions like attention deficit hyperactivity disorder, according to Stephen Crystal, a Rutgers University professor who studies the drugs.

Dr. Rapoport said Lilly’s Zyprexa drug, introduced in 1996, had been so heavily marketed that it was in widespread use before physicians began to recognize the severity of its side effects a few years ago. Zyprexa has continued selling in the range of nearly $3 billion a year in the United States even as concerns emerged about its tendency to cause patients to gain weight.

Abilify, from Bristol-Myers Squibb, showed the least metabolic effects among the four drugs in the study. “It’s considered a very good but weaker drug,” Dr. Rapoport said.

The other two drugs in the study, whose weight-related side effects fell between Zyprexa and Abilify, were Risperdal and Seroquel. Seroquel, from AstraZeneca, had United States sales of $2.2 billion in the first six months of this year, according to IMS Health, a research company. Abilify had sales of $1.9 billion during that period; Zyprexa, $1.5 billion; and Risperdal, from Johnson & Johnson, $660 million.

A Lilly spokesman, Jamaison R. Schuler, said the new research echoed Lilly’s own findings and previous studies about weight gain and metabolic changes that led to a label warning being placed on Zyprexa in October 2007. But in an interview, he said the drug was still essential to sparing children a lifetime of psychological suffering.

“It’s important to recognize that severe mental illnesses, including schizophrenia and bipolar 1 disorder, often strike during adolescence and are devastating,” Mr. Schuler said.

In an editorial accompanying the study in the journal, Dr. Christopher K. Varley and Dr. Jon McClellan, child psychiatrists at Seattle Children’s Hospital and the University of Washington school of medicine, wrote that “ominous long-term health implications” arise from weight gain and changes in blood fat levels early in life. “These results challenge the widespread use of atypical antipsychotic medications in youth,” they wrote.

Dr. Varley said in a phone interview Monday that doctors had been loath to use the older antipsychotic medicines, like Thorazine and Haldol, because of neurological side effects. But he said the new data indicated that the newer ones should be prescribed more cautiously.

“In the course of less than 12 weeks, the weight gains are startling,” he said. “If you look at Zyprexa, the kids are gaining a pound and a half a week. Even with the drug Abilify, which is one that was not so prone to weight gain, kids still gained a pound a week. In addition, they had evidence in a very short period of time of other metabolic problems.”

The study covered 272 patients visiting clinics in Brooklyn, Queens and Long Island from 2001 to 2007. Fifteen patients who stopped taking their medicine were used as a control group. Their weight stayed level. The 257 patients who stayed on their drugs took detailed tests, including a fasting blood test to check for high glucose levels.

Their mean weight at the start of the study period was 118 pounds. But after about 11 weeks, those who took Zyprexa had gained 18.7 pounds; Seroquel, 13.4 pounds; Risperdal, 11.7 pounds; and Abilify, 9.7 pounds.

Their waists typically expanded three inches with Zyprexa, and two inches with the others.

All but Abilify showed rapid and significant increases in one or more metabolic markers, which can presage adult obesity, hypertension and Type 2 diabetes. The metabolic markers included glucose, insulin, triglycerides and cholesterol.

The authors noted that the study had limitations. Patients were not randomly assigned, so the baseline starting weights differed. Clinicians, given the choice, started heavier patients on Seroquel and those with the lowest fat mass on Zyprexa, who then gained the most, the data show. Also, the study did not control for dosing or other medications, which can affect outcome.


Copyright 2009 The New York Times Company