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A new study released during the week of October 26, 2009, found that children on widely used psychiatric drugs can quickly gain an alarming amount of weight, with many put on nearly 20 pounds and become obese within just 11 weeks. “Sometimes this stuff just happens like an explosion. You can actually see them grow between appointments,” said Dr. Christopher Varley, a psychiatrist with Seattle Children’s Hospital who called the study “sobering.”

Weight gain is a known possible side effect of the anti-psychotic drugs which are prescribed for bipolar disorder and schizophrenia, but also increasingly for autism, attention deficit disorders and other behavior problems. The new study in mostly older children and teens suggests they may be more vulnerable to weight gain than adults. The study also linked some of these drugs with worrisome increases in blood fats including cholesterol, also seen in adults. Researchers tie these changes to weight gain and worry that both may make children more prone to heart problems in adulthood.

The research is the largest in children who had just started taking these medicines, and provides strong evidence suggesting the drugs, not something else, caused the side effects, said lead author Dr. Christoph Correll of North Shore-Long Island Jewish Health System in Glen Oaks, New York.  But because these drugs can reduce severe psychiatric symptoms in troubled children, “We’re a little bit between a rock and a hard place,” he said.

The authors of the study said their results show that children on the drugs should be closely monitored for weight gain and other side effects, and that when possible, other medicines should be tried first.

The study appears in the Journal of the American Medical Association. It involved 205 New York City-area children from 4 to 19 years old who had recently been prescribed one of the drugs; the average age was 14. Depending on which of four study drugs children used, they gained between about 10 and 20 pounds on average in almost 11 weeks; from 10% to 36%t became obese.

The drugs are Abilify, Risperdal, Seroquel and Zyprexa. Of the four, Seroquel and Zyprexa are not yet approved for children, and they had the worst effects on weight and cholesterol. However, a government advisory panel recently voted in favor of pediatric use for the two drugs, and the Food and Drug Administration often follows its advisers’ recommendations.

The drugs’ makers said these problems are known side effects but emphasized the drugs’ benefits in helping patients cope with serious mental illness.

The four drugs have been considered safer than older anti-psychotic drugs, which can cause sometimes permanent involuntary muscle twitches and tics. That has contributed to widespread use of the newer drugs, including for less severe behavior problems, a JAMA editorial said.

The number of children using these drugs has soared to more than 2 million annually, according to one estimate.

Doctors “should not stretch the boundaries” by prescribing the drugs for conditions they haven’t been proven to treat, said Varley, co-author of the editorial.

Why these drugs cause weight gain is uncertain but there’s some evidence that they increase appetite and they may affect how the body metabolizes sugar, said Jeff Bishop, a psychiatric pharmacist at the University of Illinois at Chicago. The drugs also can have a sedation effect that can make users less active.

Recently plaintiff lawyers stated that marketing executives at British drug maker AstraZeneca PLC for years blocked efforts by company scientists to raise concerns that the antipsychotic drug Seroquel caused weight gain and other problems. Internal documents that were released as part of ongoing lawsuits against the company brought by patients alleging they were harmed by the blockbuster drug for schizophrenia and bipolar disorder.

Some of the internal e-mails and other documents, released on May 19, 2009 to the AP, demonstrate efforts to keep public information about Seroquel positive amid a spirited debate between the company’s scientists and its marketing executives.

AstraZeneca spokesman Tony Jewell said that since the drug was approved in late 1997, the label or detailed package insert has stated that diabetes, high blood sugar and weight gain have been observed in patients in clinical studies.

He noted that the FDA in the past several years has approved Seroquel as safe for new uses bipolar mania, then bipolar depression and then an extended-release version.

Other internal e-mails and planning documents suggest the company pondered uses for which Seroquel was not approved by the FDA, including in dementia patients, though none of the documents indicate the company actually marketed the drug for those uses.

Doctors are allowed to prescribe drugs for unapproved uses, but drug makers can’t promote them for those uses.
A strategic plan dated 2000 suggested a “key success factor” would be to “broaden Seroquel use on and off label,” specifically targeting educational programs “to share off label data.”

Seroquel was AstraZeneca’s No. 2 drug in sales last year, with revenue of $4.5 billion.

U.S. District Judge Anne C. Conway in Orlando, Florida, who has been coordinating pretrial details of nearly 6,000 federal Seroquel lawsuits, recently ordered them returned to the federal courts where they were filed.

First, she is settling issues such as which of the many documents plaintiff lawyers obtained through pretrial discovery should be available for use in those trials and open to the public. AstraZeneca has claimed its documents are confidential but agreed to release hundreds in February and 400 more on May 20, 2009.

In a chain of e-mails in one document, a scientists’ safety evaluation committee in June 2000 recommended removing “limited” before the words “weight gain” in the list of Seroquel side effects, because many patients gained significant weight.

Marketing staff suggested trying other explanations, such as whether patients took other drugs that could be blamed. One marketing executive, Medical Affairs Manager Richard Owen, then wrote that such a change “is potentially damaging to Seroquel.”

The change in the drug’s label was finally made in 2002. That was after Barry Arnold, the vice president for clinical drug safety, complained repeatedly to the physician in charge of Seroquel drug safety about “Commercial (executives) having such an influence.”

Later in 2002, Simon Hagger, global brand manager for Seroquel, e-mailed nearly 20 marketing staffers to say “we are under clear instruction from the highest level within AstraZeneca at this time not to discuss details surrounding trial 41,” outside the company. That patient study, concluded that year, found elevated levels of blood sugar.

AstraZeneca, the world’s fifth-biggest drug maker, has been trying to get Seroquel approved in the U.S. for treating patients with depression and anxiety disorder, a group that includes more than 20 million people.

In April, a panel of FDA scientific advisers said Seroquel’s side effects, including weight gain, high blood sugar and potential heart problems, were too troubling to make it a first choice against depression or anxiety. On a split vote, the panel said Seroquel could be used as an added therapy for patients taking other medicines but not getting relief from depression. The FDA has yet to issue a final ruling.

“Going back almost 20 years, AstraZeneca has conducted 118 studies on the safety and efficacy of Seroquel,” company spokesman Jewell said, adding some studies continue.

AstraZeneca faces roughly 15,000 lawsuits over Seroquel, about 60% of them in state courts. The first state trial is set to begin in Delaware on June 29. No federal trials have been held yet.

Recent trail data from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s disease (CATIE-AD), reveals that elderly patients with Alzheimer’s disease who are treated with second-generation antipsychotics should be monitored closely for weight gain and lipid abnormalities.

The 36-week trial included 421 outpatients with Alzheimer’s disease who were treated for delusions and aggression. The average patient age was 78 years and 56 % were female. The findings are reported in the online edition of the American Journal of Psychiatry.

Seventy-two patients had no exposure to the study drugs, while the remaining subjects were assigned to treatment with Zyprexa (generic: olanzapine), Seroquel (generic: quetiapine), and Risperdal (generic: risperidone); and they could switch antipsychotic medication during the trial.

Female subjects gained an average of 0.14 pounds per week and body mass index increased by 0.03 per week, Dr. Lon S. Schneider at the University of Southern California, Los Angeles, and associates report. Changes in weight and BMI among males were not statistically significant.

The duration of antipsychotic use by women was significantly associated with weight gain. “The prevalence of significant weight gain was 10 percent, 17 percent, and 20 percent among patients with less than 12 weeks, 12 to 24 weeks, and greater than 24 weeks of use compared to 7 percent with no use,” Schneider’s team reports.

The effect on weight was significant for olanzapine and quetiapine, but less so for risperidone. Olanzapine was also significantly associated with increased waist circumference and decreased HDL cholesterol, the “good” cholesterol.

The metabolic changes that correlated with treatment with a second-generation antipsychotic drug were of similar magnitude to those observed in younger people with schizophrenia, the team notes.

The results from a previous analysis of the CATIE-AD data indicated that the drugs did not improve patients’ function and quality of life and did not decrease their need for care.

The worsening cardiac and metabolic risks among these Alzheimer’s patients are “particularly concerning,” they add, and likely explain the increased risk of mortality seen with these drugs.