USA Today investigates hazards related to increased prescriptions of neuroleptics — also known as antipsychotics — given to children in the USA.
New antipsychotic drugs carry risks for children
Source: USA Today
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NancyThomas remembers the bad old days when she had to wear long-sleeveclothes to church to cover bite marks all over her arms from herdaughter Alexa’s rages.
At age 8, Alexa was diagnosed withbipolar disorder. She was a violent child with sharp mood swings andmeltdowns that drove her to tear up the house. Antidepressants anddrugs for attention-deficit disorder had only made Alexa moreaggressive, Thomas says.
A mix of medicines including so-calledatypical antipsychotics — drugs approved only for adults — finallystabilized Alexa’s moods. Now at 15, she is able to live a more normallife — as long as she takes the medication.
Even so, theRussellville, Mo., teen is paying a price: On one of the atypicalantipsychotics, Alexa gained about 100 pounds in a year, putting her atrisk for a host of health problems, including diabetes. It has takenher three years to lose a third of that extra weight; she is stillstruggling with the rest.
Atypicals are a new generation ofantipsychotic drugs approved by the Food and Drug Administration foradult schizophrenia and bipolar disorder (manic depression). None ofthe six drugs — Clozaril, Risperdal, Zyprexa, Seroquel, Abilify andGeodon — is approved for kids, but doctors can prescribe them as”off-label” medications.
Psychiatrists say the drugs can behelpful for children with serious mental illnesses and have been knownto save young lives. But diagnosis often is difficult, makingappropriate prescribing tricky. And many experts, including behavioralpediatrician Lawrence Diller, author of Should I Medicate My Child?,say there is growing overuse of these powerful antipsychotics.
Schizophreniais rare in children under 18: It strikes about 1 in 40,000, as opposedto 1 in 100 adults, according to the National Institute of MentalHealth. Nobody knows exactly how many kids have bipolar disorder;psychiatrists don’t even agree on criteria to diagnose the disease inchildhood.
Research on how the drugs affect children is sparse,and experts increasingly are concerned that the drugs are beingprescribed too often for children with behavior problems, such asattention-deficit disorder and aggression.
John March, chief ofchild and adolescent psychiatry at Duke University School of Medicine,prescribes the drugs to kids in some cases of serious illness when hethinks the benefits outweigh the risks. But he says prescribing themfor behavior problems alone may be a mistake. “We have no evidenceabout the safety of these agents or their effectiveness in controllingaggression,” he says. “Why are we doing this?”
At the same time,reports of deaths and dangerous side effects linked to the drugs aremounting. A USA TODAY study of FDA data collected from 2000 to 2004shows at least 45 deaths of children in which an atypical antipsychoticwas listed in the FDA database as the “primary suspect.” There alsowere 1,328 reports of bad side effects, some of them life-threatening.
Drugcompanies are required to file any reports they have to the FDA, butconsumers and doctors report such events on a voluntary basis. Studiessuggest the FDA’s Adverse Events Reporting System database capturesonly 1% to 10% of drug-induced side effects and deaths, “maybe evenless than 1%,” says clinical pharmacologist Alastair J.J. Wood, anassociate dean at Vanderbilt Medical School in Nashville. So the realnumber 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.
RexEvans’ parents are bitter about what happened to their son. Theybelieve the 13-year-old Colorado Springs boy was harmed permanently byan atypical antipsychotic he took several years ago. Rex now has aserious case of tardive dyskinesia (TD), suffering daily episodes ofinvoluntary 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.
Despitesuch reports, outpatient prescriptions for kids ages 2 to 18 leapedfivefold — from just under half a million to about 2.5 million — from1995 to 2002, according to a new analysis of a federal survey byVanderbilt Medical School researchers. This doesn’t includeprescriptions at psychiatric hospitals or residential treatment centers.
Andeven though the drugs are approved only for adults, the rate ofchildren treated with atypicals “is growing dramatically faster thanthe rate for adults,” says Robert Epstein, chief medical officer forMedco Health Solutions, pharmacy benefit managers.
Medco did ananalysis of outpatient prescriptions for USA TODAY and found that, in asampling of about 2.5 million of Medco’s 55 million members, the rateof children 19 and under with at least one atypical prescription jumped80% from 2001 to 2005 — from 3.6 per 1,000 to 6.5 per 1,000. And thatonly represents kids who are privately insured, not those in fostercare 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
Becauseof the nature of the FDA data, they don’t prove that these drugs causedthe deaths or the side effects. Many side effects for which an atypicalis listed as the “primary suspect” occurred in the normal course ofusing the drug, but the database also includes cases involving drugabuse, overdoses, suicides and homicides. Entries are sometimescryptic, and the FDA enters verbatim — misspellings and all — what’sreported on the form.
Still, the data “can be a useful signalingdevice” suggesting problems with a drug that warrant conclusivestudies, says Jerome Avorn, a pharmacology specialist at HarvardMedical School and author of the book Powerful Medicines.
One-fourthof the cases in the database studied by USA TODAY did not list thepatient’s age. But in cases that listed an age under 18:
• Acondition called dystonia was most often cited as an “adverse event”suffered by someone taking one of the drugs, with 103 reports. Dystoniaproduces involuntary, often painful muscle contractions.
•Tremors, weight gain and sedation often were cited, along withneurological effects such as TD. Symptoms of TD can vary from slighttwitching to full-blown jerking of the body.
• A conditioncalled neuroleptic malignant syndrome, with 41 pediatric cases over thefive years, was the most troubling effect listed, says childpsychiatrist Joseph Penn of Bradley Hospital and Brown UniversitySchool of Medicine. It is life-threatening and can kill within 24 hoursof diagnosis. It’s been linked to drugs that act on the brain’sdopamine receptors, which would include the atypicals, Penn says.
TheFDA office of drug safety checks the database, “and we haven’t beenalerted 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 notsystematically looked at the data for children” because the drugsaren’t approved for them, he says.
The 45 deaths
Amongthe 45 pediatric deaths in which atypicals were the primary suspect, atleast six were related to diabetes — atypicals carry warnings that thedrugs may increase the risk of high blood sugar and diabetes. Othercauses 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 experienceddiabetic ketoacidosis, a deficiency of insulin.
More than halfof the kids who died were on at least one other psychiatric drugbesides the atypical antipsychotic, and many were taking drugs forother ailments.
The youngest, a 4-year-old boy whose symptoms suggested diabetes complications, was taking 10 other drugs.
Thereports don’t tell the child’s general state of health or other factorsthat could predispose him to trouble. Also, neither Clozaril, which israrely used, nor Abilify, the newest atypical, was listed as a primarysuspect in any deaths.
All the drugmakers emphasize that theirproducts are not approved for children, and they say the drugs are safeand effective for adults with schizophrenia or bipolar disorder who aremonitored for side effects. Still, “there are worrisome questionshere,” says Avorn. Large, longer-term database studies could provideanswers, he says.
There’s some evidence that the drugs can helpyoung schizophrenics and may be helpful in treating bipolar disorder inchildren, says Robert Findling, a child psychiatrist at UniversityHospitals 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 studiespublished in the Journal of Clinical Psychiatry.
Theseantipsychotics are the most widely used class of drugs to treatdisruptive kids who attack others and defy adults, Findling says.Again, there’s a paucity of proof that the drugs help.
There areonly a handful of carefully controlled, sizable studies testing thedrugs for any pediatric disorder, and they’re mostly short-term, saysBenedetto Vitiello, chief of child and adolescent psychiatry at thenational mental health institute. The most serious, widespread problemfound to be caused by the medicines is weight gain, he says. The effectvaries by drug, but kids typically put on twice the pounds they shouldin their first six months on atypicals.
In the first threemonths on the drugs, children add about 2 to 3 inches to theirwaistlines, says research psychiatrist Christoph Correll of ZuckerHillside Hospital in Glen Oaks, N.Y. A lot of this is abdominal fat,which increases the risk of diabetes and heart disease. Obese childrenare twice as likely as normal-weight children to have diabetes,according to a new University of Michigan study.
“Some patientsgain weight on Zyprexa and others do not,” says Calvin Sumner, amedical adviser to Eli Lilly Research Laboratories. Lilly makes thedrug, which has been associated with weight gains in adult studies.Sumner stresses that Zyprexa isn’t approved for kids.
There’s noproof atypicals cause diabetes, says Ramy Mahmoud of Janssen LP, makerof Risperdal. He says the FDA added a label warning of increaseddiabetes 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.
Thebrain system that the drugs work on develops through childhood andadolescence, says Cynthia Kuhn, a Duke University pharmacologist. “Wereally don’t know the impact of chronically perturbing that system inchildhood.”
Why atypicals get prescribed
Given all the potential problems, why would doctors prescribe these drugs to children to begin with?
Nobodydisputes that the lives of schizophrenic or severely manic children maybe saved by antipsychotics. “I use them myself for patients,” saysMarch, the Duke psychiatrist. “I have a 9-year-old who threatened tojump out of a second-story window if her mom didn’t give her the carkeys to drive down to the 7-Eleven to get a Coke. If I took her offantipsychotics, she’d disintegrate.”
But several factors can lead to misprescribing of antipsychotics.
Itcan be difficult to tell one behavioral disorder or illness fromanother in kids. For example, the aggression and irritability ofbipolar disorder can mimic attention-deficit hyperactivity disorder ordepression, the mental health institute says. Also, the environment canbe a key cause of symptoms that may be mistakenly diagnosed as mentaldisorders, says Diller, the behavioral pediatrician. Some events in achild’s life can trigger acting-out or other symptoms. Adults canexplain what happened to them; children, especially the youngest, maybe more reticent.
Doctors often face time pressures that preventthem from finding out what’s going on in kids’ lives, knowledge thatmight suggest alternative treatments, Penn says. For example, abuse ofdrugs such as methamphetamine, OxyContin and cocaine is fairly commonamong teens, he says. Kids begin acting strangely, hearing voices,becoming paranoid. The symptoms can mimic psychosis or behavioraldisorders, and doctors can end up giving these children unneededantipsychotic drugs, he says.
Insurance coverage rules mayencourage 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 Journalof 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.
Itcan take a couple of weeks just to get medical records and familyhistories, Penn says, but insurers often extend time if there’s a newmedicine started, which encourages drug dabbling for children who arenot ready to go home.
In the end, some parents say theirchildren have such severe behavior disorders or mental illness that thebenefits outweigh risks.
Parents of children such as AlexaThomas, who have bipolar disorder, say the atypicals often help. “Wewere very fortunate,” says Alexa’s mother, special-education directorfor the Russellville, Mo., school district. “The medication worked formy daughter. It doesn’t work for everybody.”
TheVanderbilt study of antipsychotic prescribing finds at least 13% ofpediatric prescriptions are for bipolar disorder. But there is someconcern about over-diagnosis and “jumping to this (bipolar) label tooquickly,” says psychiatrist Peter Jensen, head of the Center for theAdvancement of Children’s Mental Health at Columbia University.
SandraSpencer’s son, Stephen, was diagnosed as bipolar at age 6 and put onatypicals. He developed liver abnormalities and obesity, his mothersays. “He’s been on a smorgasbord of meds,” she says. None worked wellfor very long.
By the time he was in sixth grade, doctors saidthey weren’t sure Stephen was bipolar after all. Now 15, he is on lowdoses of an antidepressant and mood stabilizer. He’s being weaned offboth, says Spencer, executive director of the Federation of Familiesfor Children’s Mental Health, a support group.
She worries abouthow the drugs have affected Stephen, who is black: As littlepsychiatric drug research as there is on children, there’s least of allon minority kids. Some drugs are known to affect black adultsdifferently from whites. “He probably had ADHD all along,” Spencersays. “Psychiatry is so not an exact science.”
Childpsychiatrist Barbara Geller, a bipolar expert at Washington Universityin St. Louis, agrees: “The science is nowhere near where it is in otherbranches of medicine.”
So parents struggle to make the rightdecisions for very troubled kids. “There’s a lot of fear amongparents,” Spencer says. “You don’t know what the effects of these drugsare going to be. You’re at the mercy of your doctor.
“I have hadto make a lot of decisions, and they were fear-driven. You don’t haveenough information to make an intelligent decision.”
Contributing: Susan O’Brian