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an online version of the magazine Spring/Summer 2004
Features
Childhood Trials Collage of boy and prescription drugs
 
  When my 7-year-old son became overly tearful, I enrolled him in a clinical study for anxiety. Testing psychiatric medication in children, I discovered, is an area shrouded in controversy.
BY MARY Ellen miller
 
 
 
 


My youngest son is a charming conversationalist. He is not shy. Without prompting and to the surprise of his mother, he offers a small, outstretched hand when introduced to adults, along with a polite, ‘Nice to meet you, Mr. X.’ He is popular among his peers, who inevitably greet him with an explosion of his name. Seth!


He is also sensitive and emotional. He has difficulty switching from one activity to another. And he worries. He worries when the gas gauge gets low on the minivan. Birthday parties make him so uneasy that he more often than not won’t attend. Just before he turned 7, he was brooding about death and the possibility that our graves might not be side by side.

Last winter, the worries started taking over his better half. Suddenly, in the middle of first grade, he refused to ride the bus to school. He cried every morning, and in order to part company with me, he had to be led away gently but firmly to perform some special job by a member of the school staff. Then the crying spells extended to recess, the hallways, and he began to dread going back to school at the start of the weekend.

Things came to a head just before Memorial Day. Seth was more upset than usual on the drive to school because, he fretted, he would be sent to the principal’s office if he cried. I assured him that was ridiculous.

But his tearfulness had become so disruptive to his class, it turned out to be true. Although I had had telephone and sidewalk consultations with the school guidance counselor, that morning I found myself face to face with her. She was worried that his classmates, now curious and concerned, would be less forgiving next year. Mrs. Miller, I think it’s time to get outside help for your son.

Such a statement can jolt even the most experienced and enlightened parent. You may believe rationally that anxiety and depression are bona fide illnesses, but in your heart you are looking for a cause and, probably, taking stock of yourself. Then, once you’ve accepted that your first-grader needs a therapist, you have to actually find one—one who’s good at an imperfect and “artful” science; one who practices near your home, is taking new patients and has appointments that fit into your life; and one who is compatible with your insurance company.

For me and Seth, a miracle occurred. The very next day, a co-worker forwarded an e-mail from Hopkins’ child psychiatry division about a clinical trial recruiting children with anxiety. I called immediately and passed the first eligibility test. The following week, Seth underwent an eight-hour assessment over two days that measured everything from his I.Q. and blood pressure to his fear of insects. To make sure the readings weren’t off, he was reassessed using a shorter version a week later. The results showed that Seth had ample “generalized anxiety disorder” to qualify for one of four arms of the study: medication only, cognitive behavioral therapy only, a combination of the two, or placebo. As it happened, he was randomized to the “pill only” group, which meant he’d receive either Zoloft, a drug that has successfully alleviated anxiety symptoms in children, or a sugar pill (placebo) containing no medication at all. And because this was a double-blind study, neither his doctors nor his parents would know which he was taking.

 

*****

 

Incredibly, three-fourths of prescription medications used to treat children have never been tested in children. As a result, most of the drugs approved by the Food and Drug Administration have labels that read, “Safety and effectiveness in pediatric patients have not been established.” Even ibuprofen bottles, until recently, were labeled “Ask your doctor” for dosing information for children under age 2.

For doctors who treat young children, this shortage of hard evidence about how their patients will respond to medications turns prescribing into a guessing game. Pediatricians solve the problem by using data from adults and adjusting the dose downward according to the weight of the child. It’s a practice that has occasionally gone awry: In the 1950s, many newborns died of “gray baby syndrome” because their immature livers couldn’t break down the antibiotic chloramphenicol that had been used widely in adults.

Still, despite such potentially devastating consequences, the public has remained reluctant to “experiment” with medications on children. If children couldn’t legally volunteer for research, the thinking went, they shouldn’t be used as subjects in research.

Slowly, however, as it became recognized that children are not small adults, the pediatric community called for changes to the system. In 1977, the American Academy of Pediatrics was the first to declare that it was more unethical for children to be exposed to drugs of unknown safety than to be enrolled into carefully controlled clinical trials. The true experiments, in other words, were taking place every time a child was prescribed an untested medicine.

Last to come around to this point of view have been the drug companies who fund so many of today’s costly clinical studies of medications. “The pharmaceutical industry has never really wanted to do trials in kids,” says Hopkins child psychiatrist John Walkup. “It’s a delicate patient population. And since doctors prescribe [drugs] off-label anyway, why should they? Why should they risk being held liable if something goes wrong?”

Nowhere has this threat been more real than in the emotionally charged area of psychotherapeutic drugs. “A lot of the people who complain about giving medicine to these kids would rather teach them meditation, or pray about it. It’s not attention deficit hyperactivity disorder (ADHD), it’s ‘Boys will be boys.’ It’s not depression, it’s the divorce rate. It’s an issue that spans science, medicine, religion and politics, in a way that medicines for migraines and hypertension don’t.

“We realize that we are part of a maelstrom,” Walkup says. “We know that what we do is controversial and why. But we also realize that science is the only way out.”

 

*****

 

Mark Riddle
> Mark Riddle: “Compared to what we know in other disciplines, our knowledge [in child psychiatry] is way too limited.”
Seth was among the first volunteers in the Child/Adolescent Anxiety Multimodal Study (cams) sponsored by the National Institute of Mental Health. Eventually, the trial will enroll some 318 youngsters over a period of three years. Based at seven academic medical centers across the nation, it will attempt to pinpoint the best way of treating kids with anxiety. Studies, including those completed at Hopkins by Walkup and Mark Riddle, director of child and adolescent psychiatry, have shown that both medicine and behavioral therapy are effective. This study would treat some children with only medication, some with only cognitive behavioral therapy and some with a combination of the two approaches. And, as in any well-constructed clinical trial, one group of children would receive simply a pill containing sugar (a placebo), since the efficacy of an approach can only be demonstrated by comparing it to no treatment at all.

Seth was excited to be in the study and never once put up his usual fuss about the excursions away from our suburban cul-de-sac into the city. He enjoyed the little treats he was allowed, like experiencing the magic of inserting dollar bills into the soda and snack machines, and the attention lavished upon him by the staff. Our routine was to come in for weekly “med checks,” during which both of us would fill out a questionnaire customized to Seth’s particular fears. The psychiatrist would meet with us briefly to see how things were going, would sometimes adjust the dose, and then we’d get our new “prescription” at the investigational pharmacy. With the exception of some trepidation about doing the hula in front of his summer camp friends, Seth had relatively few setbacks during June, July and August, but I was holding my breath waiting for the start of second grade.

 

*****

 

Child psychiatry was born at Johns Hopkins. Its founding father, Leo Kanner, a medical graduate of the University of Berlin, was brought to Hopkins by Adolf Meyer in 1928. Eight years later, Kanner offered the first formal elective course in the subject here. But it wasn’t until the 1960s that the first NIH grant to study pediatric psychopharmacology was awarded. It went to one of Kanner’s students, Leon Eisenberg, the second director of the division.

Still, as late as 1983, when Mark Riddle finished his training in child psychiatry, the field was still considered “a boutique, very specialized, non-mainstream specialty.” Since then, some effective medications and therapies have come along for children, “but compared to what we know in other disciplines,” Riddle says, “like cardiology, oncology, orthopedics, our knowledge is still way too limited. Psychiatric disorders are common in kids and they can be disabling. If a child has anxiety and is socially inhibited for a long time, the disorder can affect development. You get into this work,” Riddle says, “and you realize, My gosh! There’s a lot of work to be done. There are a lot of kids and families out there suffering.”

Much of the controversy over prescribing psychotherapeutic drugs to children has stemmed from the nature of studies that have already taken place. One of the most urgent questions today has to do with whether giving antidepressants to children, particularly the class known as selective serotonin reuptake inhibitors (SSRIs), causes them to have suicidal thoughts. Last year, British health authorities banned the use of all the SSRIs except Prozac in kids under 18, citing evidence from unpublished studies suggesting an unacceptable risk of suicidal behavior in children and teenagers. The FDA quickly followed suit with its own probe, cautioning doctors against prescribing the same antidepressants.

Early in February, the agency held an advisory committee meeting to examine the risks and benefits of the drugs. Dozens of researchers, doctors and relatives of children who used the antidepressants testified. On one side of the aisle, bereaved parents, clutching photos of loved ones, blamed their children’s suicides on the very drugs meant to help them. Others credited the medications with saving their children’s lives and were booed by the crowd. A month later, the agency urged drugmakers to put new warning labels on the drugs.

Even Prozac, the only approved drug for children, has barely crossed the threshold of efficacy in some trials because too many kids taking placebos seemed to improve. “If you had a cancer treatment that you were testing against placebo and 70 percent got better with a placebo,” Walkup says, “you’d say, it’s probably not cancer. Depression is a very serious illness that’s associated with massive impairment, long-term dysfunction, risk for bipolar disorder, risk for suicide. You have a big, hunkin’ disorder like major depression and you say that 70 percent got better from placebo? That disorder is not what was in that trial.”

Still, Walkup cautions against quick reactions. “Negative studies can be negative for a million reasons. There may be too many sites with too few patients and investigators who are not well trained. It may be because the outcome instruments have been conceptualized poorly. But that doesn’t necessarily mean the drug is bad.”

Child psychiatrists, however, worry that muddy data of this sort could erode the public’s confidence in them even further. With only about 7,500 to 8,000 practitioners to serve a population of more than 15 million children and adolescents with diagnosable psychiatric disorders, already the profession is battling a critical workforce shortage. And the cases keep piling up. Not only are the disorders being increasingly stripped of their stigma but the population under 18 is expected to grow by more than 40 percent in the next 50 years. “The goal for the Hopkins group is to have enough research dollars to answer the questions people want answered,” Riddle says.

 

*****

 

The first big, coordinated investment by the federal government to study psychiatric problems in youngsters began just 10 years ago, when the National Institute of Mental Health (NIMH) funded a multisite, four-arm clinical trial of Ritalin in children with attention deficit hyperactivity disorder (ADHD). Now, Hopkins is taking part in a second controversial study of the same disorder that will attempt to pinpoint the most effective treatment. This time, preschoolers with ADHD will receive intensive behavior management followed by medication. The results, not yet published, will be scrutinized within the profession.

“We’re not just trying to push drugs,” Riddle assures—his own research interests include the metabolic side effects of medications. “It’s risk and benefit, always. ADHD is a chronic problem, so these kids need to be kept on medicine for a while. Will they have growth problems as a result?

“The government has limited funds and wants more complicated studies, the kinds of studies we’re involved in—comparing psychotherapy to medicine, figuring out how to treat non-responders, figuring out how to treat kids with combination medicines. There are just a few of us here who have the credentials to do this stuff, and for years we’ve patched things together in order to get the leverage to do the next thing. Now we’re doing the studies we want to do.”

Over the next few months, child psychiatry at Johns Hopkins plans to launch another important clinical trial. Enrolled this time, will be a small group of children who have attempted suicide. “And this is a very difficult issue to study with a safe, straightforward, uncomplicated method,” Walkup says. “You can’t try to help children who’ve tried to take their own lives with a drug only vs. placebo study. [As a parent] would you sign up for that?” Instead the trial will treat some patients with medication, others with sophisticated psychotherapy, and the remainder with a combination of the two treatments.

Both Riddle and Walkup make clear that child psychiatry carries more than medications and talk therapy in its black bag these days. It’s just as important to give parents the support and skills they need.

“Parents can have trouble with kids who don’t have any problems,” Walkup explains. “They kind of wing it, they collect advice, they read books, they worry, they talk to their friends and neighbors and patch it together, and by the time they’re done with their kids, they’ve kind of figured out how to do it. But with kids with emotional problems, the mistakes you make along the way may add to the burden of the illness and the kids may accumulate additional disability. Most of the time, parents come in wondering if a medicine will be helpful. I say, Well it might be, but let me teach you about the disorder and empower you to manage it. And for most families, it’s that second part that they’re really interested in.”

Nevertheless, both Walkup and Riddle are heavily invested in clinical research in children with emotional problems. “What we need to serve kids best is solid information gathered in a very careful, thoughtful way about what works and what doesn’t,” Riddle says, “what’s harmful and what isn’t. People worry about kids being guinea pigs, and there should be concern about that, but if we just focus on that issue, research would come to a halt. It’s our obligation to make sure that kids aren’t harmed, and I think the mechanisms are in place to ensure safe and high-quality work.”

 

*****

 

Seth Miller
> Seth, now a second-grader, at the neighborhood playground.
At the end of Seth’s 12-week clinical trial, he had improved. He happily started school, then regressed to his crying jags but was righted fairly quickly. We were offered six months of follow-up treatment, but I couldn’t bear the burden of the appointments any longer. I couldn’t imagine how any parent, particularly a working parent, could manage the back and forthing. By the time we dropped out, the research team had recruited 16 kids, and all but one (too anxious to take the medication) had made it through the 12 weeks. How, I wondered, would they ever recruit 53?

Seth seems better. In February, on a day when school opened late due to snow and he was sent to a neighbor’s, he boarded the bus as if it had never been a problem.

And now, reader, you will want to know which arm of the study Seth was in. Did he receive medication or a placebo for his anxiety disorder? I regret to inform you that I am not at liberty to say. At least until the paper comes out in 2006.

 
 
 
 
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 A Remedy of Errors
 Childhood Trials
 Meat Muddle
 
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