Depression is different in kids
Their unique symptoms, responses to antidepressants may explain link between drugs, suicidal tendencies.
By Sharon Begley / Wall Street Journal

After more than a year of debate, the link between antidepressant use and a higher risk of suicidal tendencies in some children is convincing, government regulators say. That has scientists probing an urgent new question: Why kids and not adults?

A growing number of discoveries suggest that depression in young people isn't simply a scaled-down version of depression in adults. The symptoms and the responses to antidepressants are different, indicating different biological activity. Teen brains, scientists are finding, are very different than adult brains.

Instead of feeling deeply and chronically unhappy, teens diagnosed with depression feel bored, moody and irritable.

"It isn't the consistently down, sad, depressed feeling that adults have," said Carol Glod of McLean Hospital in Belmont, Mass. Glod is leading brain-imaging studies of depression in young people.

Adults with depression typically have severe sleep disturbances, including frequent awakening, abnormal brain waves and a dream-state sleep that comes later in the sleep cycle. Depressed children under 12, however, rarely have these symptoms. "The symptom profile is strikingly different," said psychiatrist Harold Koplewicz of New York University Medical Center.

These symptomatic differences, experts say, must reflect differences in the underlying biochemistry of the disease in adults and children. One indication is that an older class of antidepressants, called tricyclics, are no more effective than a placebo in young people but are fairly effective in adults. Even the class of antidepressants at the heart of the controversy - called SSRIs, for Selective Serotonin Reuptake Inhibitors - seem somewhat less effective in young patients.

When it comes to the biological underpinnings of depression in young people and adults, "the differences far outnumber the similarities," said Robert A. King of the Yale University Child Study Center. "We don't even know if depression that begins in childhood is the same disease as adult-onset depression."

Concern that antidepressants may raise the risk of suicidal thoughts and behavior in young people suffering from depression has been growing for more than a year.

After analyses of published and unpublished studies in which children and adolescents took SSRIs for depression, the Food and Drug Administration concluded that 3.8 percent of young people taking one of the drugs became suicidal. Of those on a placebo, 2.1 percent became suicidal. That represents an increase in risk of 80 percent.

None of the young patients in the trials committed suicide. Nevertheless, "it seems likely that the effect is real," psychiatrist David Brent of the University of Pittsburgh Medical Center writes in the current issue of the New England Journal of Medicine. Brent serves on the FDA advisory panel that voted 15-8 last month to recommend a prominent "black box" warning on SSRIs indicating the drugs increase the risk of suicidal thinking and behavior in a small number of young people. The FDA on Friday ordered that all antidepressants carry the warnings. Brent was among those who voted against requiring it, because he said it could scare doctors and parents away from drugs that have helped many young patients suffering from depression.

No one has a definitive answer about why adolescent depression is different. But research is focusing on a handful of possibilities involving the brain's chemistry and structure.

Several studies suggest that the antidepressants called SSRIs stimulate the birth of neurons in the brain. Boosting this "neurogenesis" might have different effects on a developing brain than a mature one. The creation of neurons in the brain had been assumed to be beneficial. In depressed adults, the hippocampus - the part of the brain responsible for learning, memory and emotion - is typically shrunken. By restoring it to full size, and presumably full health, depression might be lifted.

But in young people with depression, the hippocampus isn't shrunken. It may be that the influx of new neurons is somehow detrimental to adolescents. Some scientists wonder whether the new neurons could destabilize fragile brain circuits in children suffering from mental illness.

In another key difference, young patients with depression usually don't show elevated levels of the stress hormone called cortisol. In adults, in contrast, scientists are discovering more and more evidence that depression is caused by abnormally high levels of cortisol flooding the brain.

Cortisol shrinks the hippocampus. But scientists don't understand why depressed adults have higher levels of cortisol than depressed teens do. The human brain isn't fully mature for two decades. The way it matures suggests reasons that young people might be vulnerable to the worst side effects of SSRIs.

Using a new imaging technology called proton magnetic resonance spectroscopy, David Rosenberg and colleagues at Wayne State University's School of Medicine have been peering into the brains of children and adolescents suffering from major depression.

From the gray smudges on the scans, they discovered that in the brains of many of 9- to 17-year-old patients, the left side of the prefrontal cortex - the seat of higher thought, analysis and planning - is clearly larger than the right side. In adults with depression, in contrast, the left prefrontal cortex is often shrunk. While the significance of the difference isn't clear, it adds to the evidence that depression leaves different marks on young brains and adult ones.

The brain's prefrontal cortex is the last region to mature. It isn't fully functional until the late teens or early 20s. This region is responsible for controlling impulses and inhibiting dangerous thoughts, including self-destructive ones. "It acts to inhibit intrusive and impulsive thoughts," said Yale neuroscientist George Alexander. "Because their frontal cortex is still developing, kids have less to bring to bear on regulating impulsive acts."

As a result, young people are more prone to act on their impulses, including self-destructive ones, than adults are, scientists say.