Updated 5/2/2006 10:09 AM ET
Rex Evans, a student at Watson Junior High in Colorado Springs, suffers from involuntary jerking, which his parents believe was caused by atypical anti-psychotic drugs.
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Rex and his mother, Kricket Evans, at the dinner table at home. Rex has a movement disorder called tardive dyskinesia which causes him to grimace and make involuntary movements.
To study the growing use of atypical anti-psychotic medications among children, as well as the symptoms associated with their use, USA TODAY analyzed data from several public and private sources.
For information on illnesses and deaths potentially related to atypicals, USA TODAY studied the Food and Drug Administration's Adverse Event Reporting System database.
The database collects mandatory reports from manufacturers and voluntary reports from health professionals and consumers describing adverse drug reactions.
It uses the information to look for potential safety problems worthy of investigation. It includes information on the patient's age and gender, medications, symptoms and outcome. The data cannot be used to prove that a particular drug caused an adverse event, but the agency does label which drugs were considered the "primary" or "secondary" suspects.
USA TODAY's analysis focused on 1,373 cases received by the FDA from 2000 to 2004 in which one of the six atypical anti-psychotic drugs was coded as the primary suspect. These cases were used to count symptoms, diagnoses and deaths.
To learn about patterns in atypical use, USA TODAY asked Medco Health Solutions, a prescription-drug benefit manufacturer, to query its member database.
The company provided sample data on rates for atypical and non-atypical anti-psychotic prescriptions and other topics.
Finally, USA TODAY obtained data on pediatric atypical prescriptions from California and Illinois under Freedom of Information requests.
By Marilyn Elias, USA TODAY
Nancy Thomas remembers the bad old days when she had to wear long-sleeve clothes to church to cover bite marks all over her arms from her daughter Alexa's rages.
At age 8, Alexa was diagnosed with bipolar disorder. She was a violent child with sharp mood swings and meltdowns that drove her to tear up the house. Antidepressants and drugs for attention-deficit disorder had only made Alexa more aggressive, Thomas says.
A mix of medicines including so-called atypical antipsychotics — drugs approved only for adults — finally stabilized Alexa's moods. Now at 15, she is able to live a more normal life — as long as she takes the medication.
Even so, the Russellville, Mo., teen is paying a price: On one of the atypical antipsychotics, Alexa gained about 100 pounds in a year, putting her at risk for a host of health problems, including diabetes. It has taken her three years to lose a third of that extra weight; she is still struggling with the rest.
Atypicals are a new generation of antipsychotic drugs approved by the Food and Drug Administration for adult schizophrenia and bipolar disorder (manic depression). None of the six drugs — Clozaril, Risperdal, Zyprexa, Seroquel, Abilify and Geodon — is approved for kids, but doctors can prescribe them as "off-label" medications.
Psychiatrists say the drugs can be helpful for children with serious mental illnesses and have been known to save young lives. But diagnosis often is difficult, making appropriate prescribing tricky. And many experts, including behavioral pediatrician Lawrence Diller, author of Should I Medicate My Child?, say there is growing overuse of these powerful antipsychotics.
Schizophrenia is rare in children under 18: It strikes about 1 in 40,000, as opposed to 1 in 100 adults, according to the National Institute of Mental Health. Nobody knows exactly how many kids have bipolar disorder; psychiatrists don't even agree on criteria to diagnose the disease in childhood.
Research on how the drugs affect children is sparse, and experts increasingly are concerned that the drugs are being prescribed too often for children with behavior problems, such as attention-deficit disorder and aggression.
John March, chief of child and adolescent psychiatry at Duke University School of Medicine, prescribes the drugs to kids in some cases of serious illness when he thinks the benefits outweigh the risks. But he says prescribing them for behavior problems alone may be a mistake. "We have no evidence about the safety of these agents or their effectiveness in controlling aggression," he says. "Why are we doing this?"
At the same time, reports of deaths and dangerous side effects linked to the drugs are mounting. A USA TODAY study of FDA data collected from 2000 to 2004 shows at least 45 deaths of children in which an atypical antipsychotic was listed in the FDA database as the "primary suspect." There also were 1,328 reports of bad side effects, some of them life-threatening.
Drug companies are required to file any reports they have to the FDA, but consumers and doctors report such events on a voluntary basis. Studies suggest the FDA's Adverse Events Reporting System database captures only 1% to 10% of drug-induced side effects and deaths, "maybe even less than 1%," says clinical pharmacologist Alastair J.J. Wood, an associate dean at Vanderbilt Medical School in Nashville. So the real number of cases is almost certainly much higher.
"We're conducting a very large experiment on our children," March says.
Side effects that linger
Some parents tell stories of serious effects that linger long after their kids stop taking the drugs.
Rex Evans' parents are bitter about what happened to their son. They believe the 13-year-old Colorado Springs boy was harmed permanently by an atypical antipsychotic he took several years ago. Rex now has a serious case of tardive dyskinesia (TD), suffering daily episodes of involuntary jerking movements and facial grimacing, says Erin Evans, his mother.
Antipsychotics are known to cause TD, but it's thought to be a rare effect for the newer atypicals.
Despite such reports, outpatient prescriptions for kids ages 2 to 18 leaped fivefold — from just under half a million to about 2.5 million — from 1995 to 2002, according to a new analysis of a federal survey by Vanderbilt Medical School researchers. This doesn't include prescriptions at psychiatric hospitals or residential treatment centers.
And even though the drugs are approved only for adults, the rate of children treated with atypicals "is growing dramatically faster than the rate for adults," says Robert Epstein, chief medical officer for Medco Health Solutions, pharmacy benefit managers.
Medco did an analysis of outpatient prescriptions for USA TODAY and found that, in a sampling of about 2.5 million of Medco's 55 million members, the rate of children 19 and under with at least one atypical prescription jumped 80% from 2001 to 2005 — from 3.6 per 1,000 to 6.5 per 1,000. And that only represents kids who are privately insured, not those in foster care or others on Medicaid.
"We know these are very strong medicines," Epstein says. "You'd want to be absolutely sure the child needs it."
The more serious risks
Because of the nature of the FDA data, they don't prove that these drugs caused the deaths or the side effects. Many side effects for which an atypical is listed as the "primary suspect" occurred in the normal course of using the drug, but the database also includes cases involving drug abuse, overdoses, suicides and homicides. Entries are sometimes cryptic, and the FDA enters verbatim — misspellings and all — what's reported on the form.
Still, the data "can be a useful signaling device" suggesting problems with a drug that warrant conclusive studies, says Jerome Avorn, a pharmacology specialist at Harvard Medical School and author of the book Powerful Medicines.
One-fourth of the cases in the database studied by USA TODAY did not list the patient's age. But in cases that listed an age under 18:
• A condition called dystonia was most often cited as an "adverse event" suffered by someone taking one of the drugs, with 103 reports. Dystonia produces involuntary, often painful muscle contractions.
• Tremors, weight gain and sedation often were cited, along with neurological effects such as TD. Symptoms of TD can vary from slight twitching to full-blown jerking of the body.
• A condition called neuroleptic malignant syndrome, with 41 pediatric cases over the five years, was the most troubling effect listed, says child psychiatrist Joseph Penn of Bradley Hospital and Brown University School of Medicine. It is life-threatening and can kill within 24 hours of diagnosis. It's been linked to drugs that act on the brain's dopamine receptors, which would include the atypicals, Penn says.
The FDA office of drug safety checks the database, "and we haven't been alerted to any particular or unusual concern," says Thomas Laughren, director of the agency's division of psychiatry products. "The effects (in kids) are similar to what we're seeing in adults. We have not systematically looked at the data for children" because the drugs aren't approved for them, he says.
The 45 deaths
Among the 45 pediatric deaths in which atypicals were the primary suspect, at least six were related to diabetes — atypicals carry warnings that the drugs may increase the risk of high blood sugar and diabetes. Other causes of death ranged from heart and pulmonary problems to suicide, choking and liver failure.
An 8-year-old boy had cardiac arrest. A 15-year-old boy died of an overdose. A 13-year-old girl experienced diabetic ketoacidosis, a deficiency of insulin.
More than half of the kids who died were on at least one other psychiatric drug besides the atypical antipsychotic, and many were taking drugs for other ailments.
The youngest, a 4-year-old boy whose symptoms suggested diabetes complications, was taking 10 other drugs.
The reports don't tell the child's general state of health or other factors that could predispose him to trouble. Also, neither Clozaril, which is rarely used, nor Abilify, the newest atypical, was listed as a primary suspect in any deaths.
All the drugmakers emphasize that their products are not approved for children, and they say the drugs are safe and effective for adults with schizophrenia or bipolar disorder who are monitored for side effects. Still, "there are worrisome questions here," says Avorn. Large, longer-term database studies could provide answers, he says.
There's some evidence that the drugs can help young schizophrenics and may be helpful in treating bipolar disorder in children, says Robert Findling, a child psychiatrist at University Hospitals of Cleveland.
But the data from controlled studies "are too few to guide treatment decisions" on bipolar disorder, concluded Findling's research team in a summary of pediatric studies published in the Journal of Clinical Psychiatry.
These antipsychotics are the most widely used class of drugs to treat disruptive kids who attack others and defy adults, Findling says. Again, there's a paucity of proof that the drugs help.
There are only a handful of carefully controlled, sizable studies testing the drugs for any pediatric disorder, and they're mostly short-term, says Benedetto Vitiello, chief of child and adolescent psychiatry at the national mental health institute. The most serious, widespread problem found to be caused by the medicines is weight gain, he says. The effect varies by drug, but kids typically put on twice the pounds they should in their first six months on atypicals.
In the first three months on the drugs, children add about 2 to 3 inches to their waistlines, says research psychiatrist Christoph Correll of Zucker Hillside Hospital in Glen Oaks, N.Y. A lot of this is abdominal fat, which increases the risk of diabetes and heart disease. Obese children are twice as likely as normal-weight children to have diabetes, according to a new University of Michigan study.
"Some patients gain weight on Zyprexa and others do not," says Calvin Sumner, a medical adviser to Eli Lilly Research Laboratories. Lilly makes the drug, which has been associated with weight gains in adult studies. Sumner stresses that Zyprexa isn't approved for kids.
There's no proof atypicals cause diabetes, says Ramy Mahmoud of Janssen LP, maker of Risperdal. He says the FDA added a label warning of increased diabetes risk "to make people aware of the possibility."
One key question about atypicals is whether they will have long-term, unknown effects on the brains of children.
The brain system that the drugs work on develops through childhood and adolescence, says Cynthia Kuhn, a Duke University pharmacologist. "We really don't know the impact of chronically perturbing that system in childhood."
Why atypicals get prescribed
Given all the potential problems, why would doctors prescribe these drugs to children to begin with?
Nobody disputes that the lives of schizophrenic or severely manic children may be saved by antipsychotics. "I use them myself for patients," says March, the Duke psychiatrist. "I have a 9-year-old who threatened to jump out of a second-story window if her mom didn't give her the car keys to drive down to the 7-Eleven to get a Coke. If I took her off antipsychotics, she'd disintegrate."
But several factors can lead to misprescribing of antipsychotics.
It can be difficult to tell one behavioral disorder or illness from another in kids. For example, the aggression and irritability of bipolar disorder can mimic attention-deficit hyperactivity disorder or depression, the mental health institute says. Also, the environment can be a key cause of symptoms that may be mistakenly diagnosed as mental disorders, says Diller, the behavioral pediatrician. Some events in a child's life can trigger acting-out or other symptoms. Adults can explain what happened to them; children, especially the youngest, may be more reticent.
Doctors often face time pressures that prevent them from finding out what's going on in kids' lives, knowledge that might suggest alternative treatments, Penn says. For example, abuse of drugs such as methamphetamine, OxyContin and cocaine is fairly common among teens, he says. Kids begin acting strangely, hearing voices, becoming paranoid. The symptoms can mimic psychosis or behavioral disorders, and doctors can end up giving these children unneeded antipsychotic drugs, he says.
Insurance coverage rules may encourage the soaring use of antipsychotics for children, as well. "With some companies, the only thing they reimburse for is prescribing. There's little or no therapy," says Ronald Brown, editor of the Journal of Pediatric Psychology and a dean at Temple University.
Also, kids with serious mental health problems often have at least one hospitalization, but policies cover only a week or two.
It can take a couple of weeks just to get medical records and family histories, Penn says, but insurers often extend time if there's a new medicine started, which encourages drug dabbling for children who are not ready to go home.
In the end, some parents say their children have such severe behavior disorders or mental illness that the benefits outweigh risks.
Parents of children such as Alexa Thomas, who have bipolar disorder, say the atypicals often help. "We were very fortunate," says Alexa's mother, special-education director for the Russellville, Mo., school district. "The medication worked for my daughter. It doesn't work for everybody."
The Vanderbilt study of antipsychotic prescribing finds at least 13% of pediatric prescriptions are for bipolar disorder. But there is some concern about over-diagnosis and "jumping to this (bipolar) label too quickly," says psychiatrist Peter Jensen, head of the Center for the Advancement of Children's Mental Health at Columbia University.
Sandra Spencer's son, Stephen, was diagnosed as bipolar at age 6 and put on atypicals. He developed liver abnormalities and obesity, his mother says. "He's been on a smorgasbord of meds," she says. None worked well for very long.
By the time he was in sixth grade, doctors said they weren't sure Stephen was bipolar after all. Now 15, he is on low doses of an antidepressant and mood stabilizer. He's being weaned off both, says Spencer, executive director of the Federation of Families for Children's Mental Health, a support group.
She worries about how the drugs have affected Stephen, who is black: As little psychiatric drug research as there is on children, there's least of all on minority kids. Some drugs are known to affect black adults differently from whites. "He probably had ADHD all along," Spencer says. "Psychiatry is so not an exact science."
Child psychiatrist Barbara Geller, a bipolar expert at Washington University in St. Louis, agrees: "The science is nowhere near where it is in other branches of medicine."
So parents struggle to make the right decisions for very troubled kids. "There's a lot of fear among parents," Spencer says. "You don't know what the effects of these drugs are going to be. You're at the mercy of your doctor.
"I have had to make a lot of decisions, and they were fear-driven. You don't have enough information to make an intelligent decision."