Unproven Psychiatric Drugs. In pediatricians’ offices across the country, millions of children and teenagers are part of a vast experiment.
Some have problems with aggression, or mania and depression. Some are preschoolers showing signs of attention deficit and hyperactivity.
These and other mental conditions are being treated with drugs not approved for, or fully understood in, youngsters.
Most of the data in this casual experiment go uncollected. And parents perhaps inclined to shield their children from a formal research study â€“ remain largely unaware of this nationwide informal one.
It is for these reasons, experts say, that more clinical research on children and psychiatric drugs is needed.
“I believe that good clinical research can be done in a way that doesn’t harm children or make guinea pigs of children, if it’s done thoughtfully and carefully,” says psychiatrist Mark Riddle.
Moreover, not doing such research, but prescribing medicines that have not been properly tested and approved for pediatric uses, may pose a bigger risk.
“I worry that the concerns about ‘protection, protection, protection’ to protect the individual child could in fact harm larger groups of children,” Dr. Riddle says.
Of all types of medicines available, only an estimated 20 to 30 percent have been labeled by the Food and Drug Administration for particular illnesses in children. (Other uses are considered “off-label.”)
Likewise, few psychiatric drugs are approved for pediatric uses, and generally for children at least school-age. These include stimulants such as Ritalin plus a new nonstimulant drug, Strattera, for attention-deficit/hyperactivity disorder. Also approved is the antidepressant Prozac for depression, and Prozac, Zoloft, Anafranil and Luvox for obsessive-compulsive disorder, or OCD.
The boom in off-label psychiatric prescriptions for children traces largely to the advent of more and better drugs for mental illness in adults. Doctors naturally have hoped to extend the benefits of those drugs to disturbed kids â€“ and frequently have been successful. But without scientific guidance, physicians often make an educated guess to determine what works best for children.
Calculating dosage, for instance, can vex doctors. “A lot of times it’s just kind of by crude extrapolation, based on body weight,” says psychiatrist James McCracken. “Many times it’s … more trial and error.”
While parents may fear that a child’s development will be altered by taking part in a drug study, using adult data to estimate how medicines should be given to kids is perilous for the same reason â€“ “precisely because both their bodies and their brains are changing more rapidly over time,” says Dr. McCracken, of the University of California, Los Angeles.
The brain develops until at least the early 20s, says Dr. Riddle. But development elsewhere in the body during those years is germane too, he says. For instance, the liver, where much of drug metabolism occurs, may be relatively much bigger in a child than in an adult: Compare a 60-pound child with a 3-pound liver to a 200-pound adult with a 4-pound one.
And the length of time a drug remains in the blood can greatly differ in children. “It’s often less,” says Dr. Riddle, of Johns Hopkins School of Medicine. “Those kinds of things we don’t know unless we do a study to find out.”
Also, drugs that work just fine in adults may not be best for children, notes psychiatrist Graham Emslie of the University of Texas Southwestern Medical Center at Dallas. An example of these is an older but effective class of drugs to fight depression in adults, known as tricyclic antidepressants (such as Elavil and Anafranil). But these appear to offer little benefit for children, Dr. Emslie says. The fact that such drugs were found ineffective in depressed youngsters, he says, indicates that in some way, their disorder is different.
Studies have also found that children under 5 need higher, not lower, doses of the anti-seizure drug Neurontin, for instance. And research has revealed dosage quirks in girls vs. boys on Luvox.
“There are a lot of examples of when you use a drug in children that the dose is too high, that there are adverse effects that you didn’t know about, that the drug affects children differently,” says Susan Cruzan, spokeswoman for the FDA, the federal agency responsible for drug safety and approvals.
Historically, little attention has been paid to the study of pharmaceuticals in children, because drug companies have viewed the very young as a limited market. But in fact, the use of medicines affecting the mind known as psychoactive or psychotropic drugs in children is booming.
One recent study suggested that the rate of use had doubled and perhaps even tripled from the late 1980s to the mid-1990s, with most of the growth occurring since 1991. During 1996, the last year of the research, 6 percent of the kids in the study had been given prescriptions for at least one psychiatric medication. In all, use of psychotropics in children had nearly reached the rates of adult use, the scientists concluded in January in the Archives of Pediatrics & Adolescent Medicine. The researchers, led by Julie Magno Zito of the University of Maryland, studied medical records annually for nearly 900,000 children and teens in three insurance programs across the United States.
Safety and benefit
According to another study led by Dr. Zito, published last year in Pediatrics, antidepressant use soared in the early 1990s at a time when the drugs’ effects in kids had hardly been studied.
“Community practitioners aren’t stopping or altering their practice simply because there’s a paucity of data to guide them,” says Dr. McCracken, director of child and adolescent psychiatry at UCLA’s Neuropsychiatric Institute. “They are forging ahead with large-scale prescription of these commonly used psychotropics in children, including all the way down into, in some cases, preschoolers.
“So to me, the scientific question now has become almost inarguable, that we have to do these studies in order to answer both the safety questions and, of course, the benefit questions.”
A flurry of recent studies have attempted to fill some of the gaps in scientific knowledge. Pediatric research has burgeoned over the last five years for the class of antidepressants that includes Prozac â€“ known as selective serotonin-reuptake inhibitors, or SSRIs â€“ used primarily to treat depression and anxiety disorders such as OCD in children. “And that’s very needed,” Dr. McCracken says of the surge in research.
Also, the development of Strattera, the first nonstimulant approved for ADHD, resulted from extensive studies in children as well as adults, he says.
“The good news here is that there’s a lot going on, and for the most part the research has been of high quality,” Dr. McCracken says. “Rather than people being frightened by the increase in studies, I would hope that they would see that this is in all children’s best interests.”
Probably the best tested of psychiatric drugs in children are those that seem to have caused the most public hand-wringing stimulants like Ritalin for ADHD.
“That’s one place where we have a lot of clinical observation over 30 years,” Dr. McCracken says. “So we feel pretty comfortable with giving the stimulants a very good to excellent long-term safety grade.”
But Ritalin is not approved yet for use in children under age 6. Data for this group are still minimal, says Dr. McCracken, whose team is taking part in a large, federally funded study of the drug in preschoolers.
Ritalin for tots
A 2000 report by Dr. Zito in The Journal of the American Medical Association, examining prescriptions in the three insurance groups during the early 1990s, found that 12 percent of children ages 2 to 4 were given stimulants, and most of the prescriptions were for Ritalin or related drugs.
“Again, community practitioners are forging ahead using the medicine more and more, but without the solid evidence you would expect for a medical treatment,” Dr. McCracken says.
Meanwhile, for other drugs including those used to treat autism, bipolar disorder and schizophrenia few placebo-controlled studies have been conducted in children of any age.
Particularly ripe for more research, experts agree, is the use of so-called atypical antipsychotic drugs. In children they are commonly prescribed for aggression and have been used for other ailments “well beyond the adult indication of psychosis,” Dr. McCracken says.
A few studies have found the atypical antipsychotic Risperdal effective for treating aggression in specific groups of kids â€“ such as those with mental retardation or autism. But there’s still a gap in understanding such drugs in children, even when they are being used for psychosis, Dr. McCracken says. “We’re so far behind our adult-research colleagues in this regard, it’s a little humbling.”
Certain ill effects, meanwhile, of the atypical antipsychotic Zyprexa may occur more frequently in younger populations, scientists reported in December in the Journal of the American Academy of Child & Adolescent Psychiatry. A side effect known as tardive dyskinesia, in which a person suffers involuntary movements, could occur more often among those 9 and younger than among adults on the drug, the study suggested. And among those 19 and younger, sedation, weight gain and aberrations in liver function were more common than in adults.
“If you’re talking 20-pound weight gains in kids over four to five weeks, it’s a huge problem,” says Dr. Emslie, noting that the added pounds can influence a child’s long-term development.
Long-term consequences of many drugs aren’t well-understood in part because studies tend to be short-term shorter than the typical duration of an illness.
“Most illnesses we see don’t just last six to eight weeks or whatever the course of the usual study is,” says Dr. Emslie. The illnesses instead tend to be chronic or recurring, says Dr. McCracken, and “can end up covering a large chunk of childhood or adolescent development.”
Dr. Zito’s recent study found that among kids ages 10 to 14, total stimulant use surpassed that in the 5- to 9-year-old group suggesting that the drugs are being used for longer periods in childhood.
Yet performing long-term research carries extra ethical baggage, says Dr. Emslie for instance, the practice of keeping kids who need treatment on an ineffective pill, or placebo.
“Unless you have placebo as a baseline, it’s very hard to see what the effects of the medicine are,” says Dr. Emslie, director of child and adolescent psychiatry at UT Southwestern.
As researchers try to learn about medicines’ effects further into the future, new issues are emerging even about drugs that have been tested and approved for children. For instance, very preliminary evidence suggests that Prozac and other SSRI antidepressants might slightly diminish some children’s growth. But because stunted growth has not been widely reported, the significance of the finding remains unclear.
And, researchers note, children who are depressed and do not receive treatment may also lag behind peers in growth. “We know that stress of various kinds can influence physiological function, including growth. It becomes a complicated question to try to research,” Dr. McCracken says.
“This is exactly why you need a placebo-controlled study,” Dr. Emslie points out.
Clinical research in children can be knotty in other ways, too. For instance, it’s not always clear that younger children thoroughly understand what a clinical trial entails. “We do our best to inform them,” Dr. McCracken says. But even by using techniques such as kid-friendly language, a young child’s grasp of a study is “clearly at a different level.”
It’s important for the public to scrutinize the whole process, says Dr. Riddle, director of child and adolescent psychiatry at Hopkins’ medical school. “I think that the critics of research are correct to shine a light on the enterprise and to try to be sure that kids aren’t being used just to help somebody make money. I do think that there are problems in that area.”
For instance, he says, it can be difficult to recruit subjects for clinical trials â€“ and drug companies, which finance a substantial and growing portion of such research, pay scientists per head. Such an approach could incline researchers to include children who don’t strictly fit a study’s entry criteria.
“I don’t know if there’s a better way to do this,” Dr. Riddle adds.
Finding kids to take part in a clinical trial can be the hardest part of doing one, Dr. McCracken agrees. “One issue is that often you’re studying a treatment that’s already available in the community, so it’s not as if the child is getting access to a new or necessarily improved treatment.”
On the other hand, some parents actually seek out trials because they are a vital avenue for getting their children access to specialized mental health care. “One of the things that continues to strike me,” Dr. McCracken says, “is how many people we enroll whose kids have pretty severe psychiatric illness but who have received next to no treatment.”