• A boy younger than 3 was treated with two anti-psychotics at a therapeutic preschool for kids with severe behavior problems. Stewart got a full family history, discovering his teen mother had a series of abusive boyfriends. "He was acting out due to that, but nobody took the time to find out what was going on at home," says Stewart, who worked with the mom to improve conditions. "She settled down." The child was taken off atypicals and is doing fine.
• A 12-year-old boy with out-of-control rage "we're talking smearing poop all over the 'quiet room' " was treated at Stewart's center. Intensive therapy identified the sources of his rage and taught the boy how to cope. He returned home, off all meds.
• A teen girl seemed to be intractably violent. "She was trying to stab pencils in people's eyes," Stewart says. It turned out she had been raped and experienced other severe trauma. She was weaned off anti-psychotics and counseled. Now in her late teens, she's living independently and doing well with no psychiatric drugs.

One of the most disturbing, potentially dangerous trends linked to atypicals is called "polypharmacy": routinely giving kids several psychiatric drugs, says child psychiatrist Joseph Penn of Bradley Hospital and Brown University School of Medicine in Providence. "We know very little about the interaction of these drugs, the effects they could be having on kids," he says.

The benefits of prescribing multiple drugs may outweigh risks in some cases, but Penn says he is appalled at how many times he has seen the mega-powerful atypicals prescribed to children suffering from insomnia when they're taking other medicines.

"I've seen hundreds of cases," he says, "and often parents don't seem to have been told about the many less risky prescription and non-prescription options out there."

Sometimes medical conditions or drugs for attention-deficit hyperactivity disorder cause the insomnia. Rather than attacking causes, doctors add an atypical to the mix, he says.

More research needed

There has been little carefully controlled, long-term research on children taking most psychiatric drugs, including the atypical anti-psychotics. The FDA is trying to get more pediatric research on the atypicals, says Thomas Laughren, the agency's director of the psychiatry products division.

The FDA has asked five pharmaceutical companies that make the drugs to test them in children with schizophrenia and bipolar disorder, the uses they're approved for in adults. Under law, they can get a six-month extension on their patents for doing these studies.

Also, the drug companies are doing their own pediatric studies on children with disorders as diverse as ADHD, autism, conduct disorder and Tourette's syndrome.

Janssen LP has applied to the FDA for approval to use its atypical anti-psychotic, Risperdal, in the treatment of symptoms of autism, says Ramy Mahmoud, vice president of medical affairs for Janssen.

The National Institute of Mental Health also is conducting pediatric studies, but the research is primarily funded and supervised by pharmaceutical companies.

Even if the companies win approval, it won't guarantee safety or effectiveness of the drugs in children, says David Graham of the FDA Office of Drug Safety, who emphasizes he doesn't speak for the agency. "You basically know the drug isn't cyanide. You don't know much else," says Graham, who was the whistle-blower in the 2004 Vioxx heart disease scandal. Industry-funded trials are four to five times more likely than independent studies to show effectiveness for a drug, he says.

According to a research review published in February, 90% of drug-company-funded studies come up with findings that support the company's drug.

In head-to-head research testing more than one atypical anti-psychotic drug, the outcomes are contradictory, coming down on the side of whichever company is paying for the research. (The research included studies of Risperdal, Zyprexa, Clozaril and Geodon, but none on Seroquel or Abilify.)

"It appears that whichever company sponsors the trial produces the better anti-psychotic drug," writes lead author Stephan Heres of the Technical University of Munich in the American Journal of Psychiatry.

And the short-term, smaller studies required of companies rarely detect any but the most glaring problems, Graham says.

"The American public is operating under the illusion that a drug is safe just because it's approved by the FDA," says Jeffrey Lieberman, chairman of psychiatry at the Columbia College of Physicians and Surgeons in New York. Studies lasting a few weeks to a few months, with a couple of thousand patients total, won't reveal all that's wrong with a drug, he says.

Laughren agrees that "it's very difficult to answer every question we'd like to answer with these studies, because obviously they're not huge. Sometimes bad things that happen are going to be discovered only when a drug is used more widely."

He says he, too, shares concern about the anti-psychotics prescribed for children without proof of safety or effectiveness. Much more pediatric information on the atypicals will be available within five years, he says.

Recommended changes

Others favor fundamental changes to get the needed facts about drug safety. Lieberman thinks one solution would be for the FDA to be given a new legal authority: the right to require drug companies seeking to gain approval of a drug to contribute to a collective pool at the National Institutes of Health. The NIH could supervise larger safety and effectiveness studies of medicines after they're on the market.

A national electronic medical records database that would capture all bad side effects of drugs, and require ages and diagnoses, could do a lot to protect children from careless prescribing and reveal the effects of anti-psychotics, Duke's March says.

"We know so little about what's happening to all the kids who are getting these powerful anti-psychotics," he says.

March also thinks more private insurers ought to insist that aggressive children with short fuses try non-drug therapies proven to help before doctors jump in with anti-psychotics. These pills can seem like an appealing "quick fix," he says, so they're popular.

For foster children with mental health problems, medication is a mainstay, says Ira Burnim, legal director at the Bazelon Center for Mental Health Law, an advocacy group for those with mental disabilities. There's proof that the most effective care is "wraparound," he says, meaning that caseworkers touch base regularly with a child's school, doctor, foster and perhaps birth families, in addition to ensuring therapy or medication as needed.

"Now they're medicating many kids instead of giving them the services they need. But there's very little time spent with psychiatrists and not much attention paid to side effects from these heavy drugs," Burnim says.

States vary in how much wraparound care they provide for foster kids, "but a typical pattern is patches here and there," Burnim says. "They rely heavily on medications like the anti-psychotics. This costs more than wraparound in the long run, and it's less safe for the kids."

March considers the widespread use of anti-psychotics on children without proof of safety or effectiveness "a very large experiment." Many kids are getting the short end of the stick, he says. "We're not even gathering good data on the outcome of the experiment. It's the worst of all possible worlds."

• 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."

Misdiagnosis common

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."

The vigilant medical monitoring that is needed by foster children on anti-psychotics "is still unusual, unfortunately" in the USA, says Moira Szilagyi, a Rochester, N.Y., pediatric endocrinologist who specializes in foster children.

There are no numbers collected nationally, but Paul Vincent of the Child Welfare Policy and Practice Group believes there has been an upswing in the use of atypicals by foster kids in the past few years. His Montgomery, Ala., firm consults for state child welfare agencies, reviewing many of their health services.

Some state data obtained by USA TODAY through Freedom of Information Act requests appear to support his observations.

• In California, Med-Cal prescription claims for atypicals for kids in foster care increased 77% between 2001 and 2005, to 70,879. The actual number is probably higher because the state does not get complete data from managed-care providers, which cover the majority of foster children.
• In Illinois, the number of children covered under the state's public health care program not just foster children who had an atypical prescription went up 39% between fiscal years 2003 and 2005, to 17,746.

Kids as young as 4 are getting prescriptions for anti-psychotics, Vincent says, sometimes from unqualified counselors. "They aren't psychiatrists or even psychologists. I have considerable worry about the accuracy of these diagnoses."

The safety of these drugs is of most concern to Andrea Moore, a Coral Springs, Fla., attorney. Judges appointed her to represent foster kids a few years ago. Several children she represented started lactating after taking anti-psychotics, a recognized side effect of the drugs. A 12-year-old girl with a history of heart problems became short of breath on Geodon, an atypical that can cause arrhythmias. "The doctor prescribing it did not even have her medical history," Moore says.

Geodon has a proven "modest" effect on heart rhythms in adults, says Ilise Lombardo, medical director for the U.S. Geodon team at Pfizer Inc., maker of the drug. The clinical impact of this rhythm change is unknown but is being studied in adults, she says; safety and effectiveness studies in kids are underway, too. The drug's label says patients with certain heart problems shouldn't take it.

In February, Florida's health care agency ordered an independent investigation into why the number of Medicaid children taking anti-psychotics nearly doubled in the past five years. The numbers jumped from 9,500 to 17,900.

A new Florida law adds some protections for foster children, but it has loopholes, Moore says. "I'm still hearing about problems with overprescribing and under-monitoring."

The findings are worrisome "because it looks like these medications are being used for large numbers of children in a setting where we don't know if they work," said lead author Dr. William Cooper, a pediatrician at Vanderbilt Children's Hospital.

The increasing use of anti-psychotics since the mid-1990s corresponds with the introduction of costly and heavily marketed medications such as Zyprexa, made by Eli Lilly and Co. and used to treat schizophrenia, and Risperdal. The packaging information for both says their safety and effectiveness in children have not been established.

Anti-psychotics are intended for use against schizophrenia and other psychotic illnesses.

However, attention deficit disorder is sometimes accompanied by temper outbursts and other disruptive behavior. As a result, some doctors prescribe anti-psychotics to these children to calm them down a strategy some doctors and parents say works.

The drugs, which typically cost several dollars per pill, are considered safer than older anti-psychotics at least in adults but they still can have serious side effects, including weight gain, elevated cholesterol and diabetes.

The researcher’s analyzed data on youngsters age 13 on average who were involved in annual national health surveys. The surveys involved prescriptions given during 119,752 doctor visits. The researchers used that data to come up with national estimates.

Cooper said some of the increases might reflect repeat prescriptions given to the same child, but he said that is unlikely and noted that his findings echo results from smaller studies.