From Breakthroughs, 2010

Only relatively recently has it been recognized that many mental illnesses begin early in life. Studies have shown that among young adults with psychiatric disorders, 78 percent were diagnosed before the age of 18, and 58 percent before the age of 15. Epidemiologist E. Jane Costello, Ph.D., and her psychiatrist-epidemiologist husband, Adrian Angold, recipients of the 2009 NARSAD Ruane Prize for Outstanding Research in Child and Adolescent Psychiatric Research, run the Center for Developmental Epidemiology at the Duke University Medical Center. There, researchers with diverse approaches are working to understand the origins, course and prevention of mental illness across the lifespan.

A NARSAD Distinguished Investigator, Costello is the principal investigator of the center’s longest-running and most famous project, the Great Smoky Mountains Study. Based on the premise that following the same subjects as they grow up is the best way to learn about the prevalence and causes of psychiatric disorders, the study was initiated in 1993 with 1,420 representative youngsters, aged nine to 13, recruited from an 11-county area of western North Carolina.

The study’s findings are helping to reveal who gets mental illness, who gets treated, who needs treatment and doesn’t get it, how useful treatments are and what might be promising directions for future research and treatment.

Over the years, the focus of the project has broadened. “A lot of the things we’re looking at now,” Costello observes, “we couldn’t have dreamt of when we started. The technology didn’t exist. We can address issues at the level of the community, the family, the individual — of the brain, physiology and genome — in ways that 20 years ago couldn’t have happened.”

Identifying girls at risk: low birthweight links to depression at puberty

Many studies over the years have confirmed that twice as many women as men develop clinical depression. In 2007, Costello received a Distinguished Investigator grant from NARSAD to explore further one of the key findings of the Great Smoky Mountains Study: the startlingly high percentage of depression occurring at puberty in girls who had had low birth weights. Of the 6 percent of low-birth weight girls in the study, 38 percent developed major depressive disorder between the ages of 13 and 16, as compared to only 8 percent of girls who had had normal birth weight and 5 percent of normal- and low-birth weight boys.

Low birth weight has been linked to effects in the hypothalamo-pituitary-adrenal (HPA) axis, a hormonal system involved in many body processes. The hormonal changes of puberty have also been found to influence the HPA axis. The NARSAD-funded study showed that low birth weight and high levels of estrogen and testosterone independently predicted depression in teenage girls.

These results have led to an expanded genetic investigation, supported by the National Institute of Mental Health, and made possible by advances in genome studies. Costello explains that the small amount of blood in her study samples — 10 drops routinely collected every time the children were seen — was sufficient for hormone analysis, but would not have been nearly enough for genetic analysis, even as recently as five years ago. ”But that is no longer the case,” she says.

The blood that “sat in a freezer for years,” has now yielded a precious cargo. The cargo is 666,000 single nucleotide polymorphisms, or SNPs (pronounced “snips”). SNPs are single- “letter” variations in the genome that occur from one person to another. The SNPs from the Great Smoky Mountains Study are now in the process of being analyzed across the genome, in so-called genome-wide association studies.

“When that’s done,” Costello says, “we’ll put the gene data together with our developmental and psychiatric and environmental data and see what kind of stories we can come up with. Because we have so much environmental data on these children, we can map the environmental stresses onto the genes, look at which genes are expressed in which environments, or which particular polymorphisms are good or bad in specific environments.

Changing the environmental odds

In a very different context, Costello and her colleagues were able to observe how a serendipitous “real-world” event, a change in one community’s fortunes, in turn changed the community’s psychiatric dynamics. The region covered by The Great Smoky Mountains Study includes a Cherokee Indian reservation, and among the study group were 350 Cherokee children. In 1996, the Cherokees opened a gambling casino and, as Costello relates, the then tribal chief, “a very wise woman,” arranged that every member of the tribe would receive from birth a percentage of the casino’s profits. By the time the casino had been open for four years, the amount was about $6,000 a year.

Four years after the income supplements began, 14 percent of the Cherokee families in the study had moved above the federally defined poverty level. When the researchers compared the psychiatric profiles of the tribe’s children during the four years before and the four years after the casino opened, they discovered that the frequency of psychiatric symptoms had decreased among the children of families that had moved out of poverty and become comparable to that of children whose families had never been poor. “So just as environmental stresses can create mental illness,” Costello says, “so environmental interventions can remove them.”

Evidence that illness can begin as early as age two

A large study such as Costello’s Great Smoky Mountain Study that is sustained over long periods of time can address some of the really “big” questions that psychiatry has been trying to answer for many years. As co-leader of the study, Costello’s husband and collaborator Adrian Angold has focuced his attention on one of these: the question of when in life mental illness begins. Along with a colleague — Dr. Helen Egger, another NARSAD grantee and prizewinner — Dr. Angold has amassed scientific evidence for beginning the inquiry among children as young as two.

“What we are seeing,” Dr. Angold says, “are rates of disorder even for things we don’t think of as beginning early, like depression, that are not very different from what they are in later childhood or adulthood. We’re really going to have to start from scratch to figure out what we mean by mental illness in kids that young.”

Longitudinal studies like the Great Smoky Mountains Study are rare in the United States, where the five-year federal funding cycle can bring studies to an abrupt end. “Support from NARSAD and other foundations has been critical to keeping the study going over some difficult patches,” says Costello. “But now that we can link children’s life stories with their genes, we can open up a whole new world of developmental genetic epidemiology.” With her characteristic verve, she adds: “I wish I were 50 years younger”.