Take the case of Eric M., age 7.
His mother suspected something was wrong from the time he was 9 months old. She was troubled by Eric's frequent displays of anger and by his being in perpetual motion.
The problems worsened with time. By age 2, Eric started lashing out at other children. He would often get "out of control," biting other kids and pulling their hair. Age 3 brought no respite from his symptoms.
At age 4, Eric's pediatrician put him on Ritalin, a drug often prescribed for children with attention deficit hyperactivity disorder (ADHD). But according to his mother, he "looked gray, lost weight and was completely out of it." She took him off the drug within two weeks.
When Eric went to kindergarten, he behaved quite well. But when 3:30 rolled around, his mother said she had to brace herself. "He came home so wired," she says. However, if she sent him to his room, "he would carry on nonstop at the top of the stairs for two hours," she remembers. "I often felt I just couldn't stand that."
Then Eric seemed to calm down for just over a year. But in December of last year he took a sudden turn for the worse. His mother believes the change was triggered by the
family putting their home on the market.
Although they involved Eric in the process of looking for a new house, "something in him just snapped," says his mother. "He started having aggressive tantrums almost every day and the episodes were very bad. He was so out of control sometimes that we couldn't bring him back. And then one night he started banging his head against a sharp corner of a kitchen counter top, and I had to hold him tightly to keep him from injuring himself.
"After that, I knew there was nothing I could really do to help him," she states.
"I understood that I needed help."
The new therapist consulted by the family tried Eric on Prozac and several other drugs, but nothing worked, so she referred the boy to Hendren for further testing. The child was given a diagnosis for the first time -- bipolar disorder with mania. His mother explains it in lay terms as a "serious mood disorder."
The rest is the story of a toppling plant that got a badly needed stake. Hendren placed the 7-year-old in a study for Zyprexa, a drug prescribed for adults with psychotic thinking. The drug has not yet been approved for children. The medication has made a radical change in Eric and in his world.
"Now we can talk with him. He can tell us what's wrong. Eric could never do that before," explains his mother. "Now he sleeps through the night. Before he was up and down all night. He wakes up in the morning now, happy to go to school. I used to have to physically pull him out of bed, dress him and push him out the door. This is the answer to our prayers."
How does a mother feel about enrolling her 7-year-old son in a clinical trial for a drug not yet approved for children? "I would do anything to help him get better," she says.
"We have good days and not-as-good days," she continues, "but our lives are finally somewhat normal. The drug is making it possible to take the next step and work with Eric on developing social skills and better behavior."
Eric is not alone. As many as 12 to 13 percent of children and adolescents have a diagnosable mental disorder and 3 percent give early indications that the disorder is serious, according to Hendren. (An estimated 60 percent of those under 18 in correctional facilities have a diagnosable mental condition.) About 10 percent of young people have a psychiatric disorder that will respond to medication, he says, but only 2 percent are being treated with drugs.
That is largely because many physicians shy away from prescribing drugs that have not been adequately studied in children. The reasons for inadequate testing are fairly obvious. Unless a child is critically ill and seemingly without other options, parental concerns about possible harm to their child's health and well-being lead to difficulties in recruiting young people for drug trials. In addition, there are challenges in designing trials that are safe for young, developing bodies and minds, and that yield the needed information about safety and efficacy.
Children are not as homogenous a group as adults. What is safe for a child of six may not be safe for an infant or toddler, and may have a very different effect on a 12-year-old going through puberty. Researchers are concerned that the experimental drug will affect the growth and development of the child in some way. If that proves to be the case, the benefits must then be weighed against any potential risks.
And there are ethical concerns about conducting a double-blind study. "In this kind of study, some children get the drug and others get a placebo. But if you think the child could benefit from the drug, is it ethical to withhold it?" asks Hendren.
Since the answer is usually no, children's drug studies often use a "crossover" design, with a child being placed on a drug for four to eight weeks, then being given a short break or "wash-out period," to be followed by four to eight weeks on another drug or a placebo. There are sometimes up to three crossovers. Hendren says this kind of trial is popular with parents, who are asked -- along with teachers -- to rate each of the drugs.
In the world of mental health, only the class of drugs called stimulants has been studied adequately with children, and has been determined to be effective and fairly safe, according to the psychiatrist. But there have been few studies, even with this class of drug, that lasted longer than two to three months. The best known stimulants are Ritalin, Dexedrine and Cylert and they are most often used to treat young people with ADHD, a condition that causes them to have trouble focusing and screening out external stimuli. Hendren says that half of those diagnosed as kids will continue to have symptoms into adulthood, but that experience has shown that the drugs continue to be effective for years at similar doses.
He explains that for other often prescribed psychiatric drugs, physicians must extrapolate from adult studies, or rely on an exchange of information with their colleagues. Among these are the mood stabilizers Lithium, Tegritol and Depakote; anti-depressant drugs such as Prozac and Zoloft; adrenergic stimulating agents such as Catapres and Tenex that are prescribed for anxiety and sleep disturbances; and
atypical neuroleptics (formerly called antipsychotics) such as Risperdal and Zyprexa for older children who are overwhelmed with anxiety, or are unable to control impulses and are poorly behaved.
But the FDA has recently undergone major policy changes, requiring all new drugs for those under 18 to undergo the same rigorous testing required for adult medications. This will mean years of testing each new agent on hundreds of children.
The FDA requires three distinct stages of drug investigation in humans before granting its approval. Phase I involves 20 to 100 participants over a period of several months, and primarily tests the safety of the medication. Phase II -- which can last from several months to two years -- includes up to several hundred volunteers, and looks at whether the drug actually has the intended beneficial effect on a condition. Phase III requires several hundred to several thousand volunteers, tests for safety, dosages and effectiveness, and lasts from one to four years.
So how can you be absolutely sure that your sick child will not be used as a "guinea pig" in drug research? Although many adults fear involvement in medical research, stemming from such fiascos as the Tuskegee Study, Nazi "medical" trials, and even insufficiently tested drugs given to military personnel involved in the Gulf War, today institutional review boards (IRBs) stand ready to protect human interests in research and to make sure that the therapy itself causes no foreseeable harm. Any organization or individual conducting research involving human beings must submit all protocols to an IRB.
The IRBs review all studies before volunteers are recruited, and also make sure that all consent forms can be understood by those who participate. In the case of trials involving minors, consent forms must be signed by a parent or guardian, and "assent" forms by the child who is involved. The children's forms are not legal documents, but demonstrate that the child understands what's going on and wishes to participate. Volunteers are assured that they can withdraw from the trial at any time without penalty.
But why would a child "assent" to participate in a drug trial that may involve hours spent in the hospital and even overnight stays, repeated blood tests and other needles? The question has been asked and the answers recorded many times.
If you're feeling that today's kids are exceptionally jaded, you may believe that kids do it for the food and toys they're often given as rewards, or for the attention lavished upon them or the money that's sometimes offered for completion of the study. Or you may think they volunteer because a doctor or parent pushed them to do it. But the fact is that most children who agree to participate in a clinical trial do so for a very simple reason: They want to help other kids who may be sicker than they are, and who may even need the new medicine in the future to stay alive.
Hendren's group will participate in several Phase III drug trials for children and adolescents over the next six months. The researchers are also using MRI to identify regions of the brain that may not be functioning as they should and are beginning to match psychiatric drugs to the biological problem. Right now, physicians prescribe such drugs by "educated trial and error," the psychiatrist says.
"As we gain a better understanding of the biological basis of mental disorders, we can begin to identify problems earlier," Hendren states. "Our aim is to identify and treat the child at a younger age and to try to improve the long-term outcome of the disorder."
Note: A special thank you to Dr. George Lambert, who organized a
two-day conference, "The State of the Art of Clinical Pediatric Pharmacology and Pharmacology Research in Children" at UMDNJ-Robert Wood Johnson Medical School. Much of the information for this article came from speakers at that