New York Times December 24, 2002 Health Lab Monkeys May Reveal the Secrets of Childhood Depression By MARY DUENWALD A rhesus monkey, only 4 months old, has been pried from the shoulders of its sedated mother and let into a small steel cage. Within minutes the fright in its little brown eyes softens into curiosity, and stepping tentatively, the monkey makes its way across the cage. But when a man with a white hood over his head strides in and stops two feet away, the baby freezes. It pulls its body close to the bars and quietly looks the other way, appearing to ignore the man until, two minutes later, he leaves. This is a very inhibited response, says Dr. Judy Cameron, a neurobiologist and the director of the University of Pittsburgh's primate laboratory, watching the monkey through an opening in a curtain. Obviously, the intruder caused this animal a great deal of anxiety. Other young monkeys, placed in the same situation, act braver, Dr. Cameron knows from having observed more than 150 of them. Some at least exhibit their fear by grimacing with bared teeth. Others smack their lips in a gesture of submission. The bravest open their mouths wide, a threatening _expression_ for a monkey, and may even lunge toward the intruder. That this little female would be so utterly passive makes her typical of a small subset of Dr. Cameron's laboratory population — 8 percent to 10 percent — that show high anxiety. More important, for Dr. Cameron's purposes, the baby monkey can be compared to a highly anxious or depressed human child. Monkeys as fearful as this one produce less growth hormone than the average monkey does when injected with substances that bring on the hormone's release, Dr. Cameron has found by testing blood samples. Though scientists do not believe that the growth hormone causes depression, it seems to be a marker. The same blunted response has been found in depressed adolescents. This means not only that rhesus monkeys provide a good model for studying depression in children but also that some biological underpinnings of the disorder may be in place years before adolescence. Though scientists have long suspected this, finding the early signs of depression in human children has been difficult because they do not seek treatment until symptoms arise, like lack of motivation, lethargy, concentration problems and irritability. Adolescent depression was long disregarded by scientists because dark moods and dreary thoughts were assumed to be natural parts of being a teenager. But in the last 25 years, scientists have come to realize that some 14- to 18-year-olds — about 8 percent — suffer from clinical depression. Their symptoms can be different; young people are likely to exhibit very low energy or a lack of enthusiasm rather than outright sadness. Still, adolescent depression has come to be seen as essentially the same disorder as adult depression. Now researchers are putting a spotlight on teenage depression, hoping that by learning how the disorder takes root, they can find ways to keep it from growing into a debilitating and lifelong problem for 9.5 percent of adults. The monkey studies, it is hoped, will add to the effort to discern which aspects of brain function are involved in adolescent depression. In monkeys, depression is difficult to diagnose because, obviously, the animals cannot talk about feelings. Anxiety, though, is fairly easy to measure by observing behavior. The kinds of anxious behavior the monkeys demonstrate — not only inhibition when facing a stranger but also increased fearfulness and vigilance — are like the actions of children with anxiety, Dr. Cameron said. In children, anxiety and depression are closely related and are thought to arise from the same biological mechanisms. Now, we can do all sorts of studies with the anxious monkeys that are harder to do in humans, Dr. Cameron said. We can observe their behavior every day. We can take blood samples and look at their hormones. We can assess how they respond to stress. We can ask what's different about their brains. And ultimately, we can search for genes that underlie their anxiety. Dr. Cameron and her colleagues are careful to say they do not believe adolescent depression is strictly a biological disorder. It may begin with a genetic liability, but when the early episodes of depression happen, it probably has to do with psychosocial stressors, said Dr. Neal D. Ryan, a psychiatrist and a leader of a 20-year study of adolescent depression at the University of Pittsburgh. The kinds of stress that can bring about depression in adolescence, psychiatrists have found, can include both negative experiences and the lack of positive experiences — the death of a family member, for example, and perhaps a dearth of love, warmth or support from others. We'd like to understand the biological piece not because we think it's all of the story or even most of the story, said Dr. Ronald E. Dahl, a psychiatrist and an investigator for the Pittsburgh study. It's because there probably is this interaction between biological systems and stress; we'd like to get insights into the brain systems involved. The ultimate goal is to find ways to nip depression in the bud. Our hypothesis is that there is some degree of plasticity in these brain systems, and that to intervene early in anxiety and depression may have greater potential than intervening late, Dr. Dahl said. Only about 2 percent of children under the age of 12 suffer from depression. Childhood, it seems, is relatively protective, Dr. Ryan said. And then there's a clear increase in depression at puberty. Then, once you've had one episode, there is sort of a kindling effect. It makes the next depression even easier to get, and that continues through adulthood. About 70 percent of adolescents with depression go on to have recurring episodes, he said. Vulnerability to depression mushrooms when children begin producing significant amounts of reproductive hormones. At puberty, too, suddenly twice as many girls as boys have the problem. The same female-to-male ratio holds through adulthood. This interaction with maturation may offer clues to depression, Dr. Ryan said. It suggests that one of the things you're going to look at is the effects of steroids on the brain. But, he added: The social roles of sexually mature females are different from the social roles of immature females. There's lots more interesting stuff going on than just estrogen causing depression. Although growth hormone is a marker for depression, it is probably not directly involved in the disorder, Dr. Ryan said. Rather, the growth hormone seems to be under the control of certain neurotransmitters — substances released by brain cells — that also affect behavior. Cortisol is also regulated differently in adolescents who have depression. This hormone probably has a more direct effect, Dr. Ryan said. The body releases cortisol in varying amounts throughout the day to help provide energy. Cortisol levels in the blood are typically high in the morning, but wane toward evening. The adrenal glands will secrete extra cortisol if needed for more energy and in response to stress. Dr. Ryan and others have found that in depressed teenagers, in the late afternoon, cortisol levels do not regularly drop as low as they do in other teenagers. This may not be just an empty phenomenon, Dr. Ryan said. The regulation of cortisol is certainly one of the important aspects of how we control stress, he said, adding that it is related to developing other psychiatric disorders. In the last five years, with the advent of functional magnetic resonance imaging, researchers have also been able to look at brain differences in depressed adolescents. Recently, for instance, Dr. Wayne Drevets, the laboratory chief of neuroimaging and mood and anxiety disorders at the National Institute of Mental Health in Bethesda, Md., has found that a part of the brain's prefrontal cortex just behind the forehead is smaller than average and abnormally structured in mothers with depression, as well as in their children and adolescents. It may be that the children have inherited some biological vulnerability to having these structural and functional differences in the brain, Dr. Drevets said. The amygdala, deep in the middle of the brain, is another area that is smaller and functions differently in people with depression. This part of the brain is involved in regulation of emotion, response to stress and recognition of fear. In a study conducted by Dr. Drevets, Dr. Dahl and others, children with both anxiety and depression demonstrated abnormal activity in the amygdala when they were shown pictures of people with fearful _expression_s on their faces. The hippocampus, another part of the midbrain, also looks somewhat different in people with depression. Both the hippocampus and parts of the prefrontal cortex seem to be involved in thought processes having to do with rewards — anticipating, striving for and feeling satisfaction about earning rewards. Scientists would like to understand how operations in both these brain areas might correlate with the abnormal way in which depressed adolescents often think about rewards. Depressed adolescents typically lose their motivation to seek rewards, Dr. Dahl said. They may, for example, feel no desire to attend a party. Yet if they are given rewards anyway, they enjoy them. If you take them to the party, they'll have a pretty good time, Dr. Dahl said. Depressed adults, in contrast, lose both the motivation to seek rewards and any feeling of satisfaction upon receiving them. I think that's actually a hint about one part of depression, Dr. Dahl said. The capacity to enjoy rewards probably is intact at least early in the course. Kids are still able to brighten up quickly. Perhaps, Dr. Dahl said, it may be possible to minimize
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