Medicating Young Minds

Sunday, Oct. 26, 2003 By JEFFREY KLUGER
STEVE LISS FOR TIME
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For kids with more serious symptoms, experts are worried that undermedicating is a bigger risk than overmedicating. "Say you've got a kid who's severely obsessive and literally can't leave the home because of the fears and rituals he's got to perform," says ucsf's Elliott. "Think about what anyone age 2 to age 16 has to learn to function in our society. Then think about losing two of those years to a disorder. Which two would you choose to lose?" Also on the side of intervention is the belief that treating more kids with mental illness could reduce its incidence in adults.

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Dr. Kiki Chang at Stanford University is trying to show that this is true with bipolar kids. He recently published a study in the Journal of Clinical Psychiatry that looked at kids from bipolar families who had only early signs of the disease. Pre-emptive doses of Depakote eased early symptoms in 78% of cases before the illness ever had a chance to take hold. "You can sit and watch it develop or intervene and possibly prevent the disorder," says Chang. While the researcher is excited about his results, he admits that treating kids who are not yet truly sick is controversial. "There's a chance some of the kids might not develop bipolar at all," says Chang. "We need to have more genetics, more brain imaging, more biological markers to know which direction the kids are going."

HOW CAN WE MEASURE THE RESULT?
Preventing symptoms, of course, is not everything. A sleeping child is completely asymptomatic, for example, but that's not the same as being fully functioning. If the drugs that extinguish symptoms also alter the still developing brain, the cure may come at too high a price, at least for kids who are only mildly symptomatic. To determine if this kind of damage is being done, investigators have been turning more and more to brain scans such as magnetic resonance imaging (MRI). The results they're getting have been intriguing.

MRIs had already shown that the brain volumes of kids with ADHD are 3% smaller than those of unafflicted kids. That concerned researchers since nearly all those scans had been taken of children already being medicated for the disorder. Were the anatomical differences there to begin with, or were they caused by the drugs? Attempting to answer that, Dr. F. Xavier Castellanos of the New York University Child Studies Center took other scans, this time using only kids with ADHD and comparing those who were taking medication with those who were not. Reassuringly, he discovered that they all shared the same structural anomaly, a finding that seems to exonerate the drugs.

Dr. Steven Pliszka, chief of child psychiatry at the University of Texas Health Center in San Antonio, went further. He conducted scans that picked up not just the structure but the activity of the brains of untreated ADHD children, and compared these images with those from children who had been medicated for a year or more. The treated group showed no signs of any deficits in brain function as measured in blood flow. In fact, he says, "we saw hints of improvement toward normal."

The news was less positive when it came to bipolar disorder. Chang has looked at the brains of kids treated with Depakote, and while his study is as yet unpublished, he says he noticed some anatomical differences that could result from treatment—and he wasn't necessarily happy with them. "We are seeing that medications do affect the brain acutely," he says. "Is that a good thing, a bad thing? We just don't know."

What nobody denies is that more research is needed to resolve all these questions—and that it won't be easy to get it started. The first problem is one of time. It was only in the early 1990s that the antidepressant Prozac exploded into pharmacies. It's hard to do a lifetime of longitudinal studies on a drug that's been widely used for just over a decade. And each time the industry invents a new medication, the clock rewinds to zero for that particular pill.

Even if it were possible to conduct extended studies, getting volunteers for the work is difficult. The attrition rate is high in any years-long research, especially so when the subjects are kids, who bore easily and, at any rate, eventually go away to college. On average, 40% of children will drop out of a long-term study before the work is done. And that assumes their parents will even sign them up in the first place. Some brain scans involve at least a little bit of radiation—something most parents are reluctant to expose their children to, particularly if those kids have no emotional disorders and are simply being used as a baseline to establish the look of a healthy brain. Getting good scans from kids who have diagnosable conditions isn't easy, as any radiologist who has ever tried to conduct a lengthy MRI on a child with ADHD can attest. "Holding still is not exactly what they do well," says Elliott.

Ethical questions hamstring research too. Any gold-standard study requires that some of the kids who are suffering from a disorder receive no drugs so that they can be compared with the kids who do. But if you believe the medications are helpful, how can you withhold them from a group of symptomatic children who need them? Despite such obstacles, research is moving ahead, if haltingly. The National Institute of Mental Health is conducting a study called the Preschool ADHD Treatment Study, in which researchers will track ADHD kids between 3 and 8 years old to determine the benefits and side effects of stimulant medications. Castellanos and N.Y.U. colleague Rachel Klein are taking things further, calling back subjects who were enrolled in an ADHD-treatment study that began in 1970 to scan their now late-30s and early-40s brains for the long-term effects of drugs. Castellanos is also planning a study of young rats treated with varying amounts of psychotropic drugs, conducting dosing and anatomical studies that cannot be performed on humans.