ARTICLE IN BRIEF
In a longitudinal study among multiple generations of families, MRI showed cortical thinning in people at risk for major depression.
More than two decades ago, a team of scientists decided to study hundreds of people with major depression and follow them for years to understand hereditary aspects. Little did they know that they would amass information on three generations and use MRI to show cortical thinning in people at risk for major depression. But that is what they reported in the March 27 online edition of the Proceedings of the National Academy of Sciences.
What made this MRI study unique was that the scientists could study young people at high risk who had no history yet of depression.
The foresight to study the transmission of major depression began with Myrna Weissman, PhD, an epidemiologist at Columbia University College of Physicians and Surgeons. At the time, 91 families from the Greater New York area were recruited. Families with no history of depression also signed on for the study. Children at least six years old were interviewed and then followed five times for 25 years. They grew up and began having their own children and those children joined the study as well. The study now includes 800 people.
Seven years ago, Bradley S. Peterson, MD, director of Psychiatry MRI Research at Columbia and head of the child and adolescent psychiatry program, was invited to collaborate with Dr. Weissman, who thought that MRI technology was sensitive enough to detect whether there were cortical differences between those with and without a family history of depression. The scientists already had EEG records on some of the study recruits 10 years into the study, which showed hints of cerebral asymmetry in those who would later become anxious and depressed. MRI would allow them a window that was closed when they began the latest study in the early 1980s.
STUDY PROTOCOLS, RESULTS
In the current study, Dr. Peterson and colleagues reported on 131 individuals, 66 in the high-risk group — those with a family history of depression — and 65 in the low-risk group. There were 12 children in the high-risk group and 31 children in the low-risk group. Among their findings, the frequency of lifetime major depressive disorder was 56 percent for those in the high-risk group and 23 percent in those with no family history, a statistically significant difference. Anxiety disorders also seemed to track with the high-risk families, first showing up in adolescence and then paving the way for depression.
At the time of the MRI scanning, 25 percent of the high-risk individuals and 11 percent of low-risk individuals were in the throes of major depression. Dr. Peterson and his colleagues used MRI to measure cortical thickness millimeter by millimeter across the entire surface of the brain. There was significant thinning on the lateral surface of the right hemisphere, a 28 percent difference in the thickness between the high- and low-risk groups. Cortical thinning was present in high-risk people with no signs of depression. “We don't know what produces this unique effect on the right hemisphere,” said Dr. Peterson.
But they were able to correlate cortical thinning with cognitive problems in both groups. The more severe the thinning in the right hemisphere, the more problems people were experiencing with inattention and poor visual memory for social and emotional stimuli.
“We believe when you are born into a family with depressive illness it produces right hemisphere thinning whether the cause is genetic or environmental,” Dr. Peterson said. This right hemisphere thinning makes people vulnerable to depression by interfering with social and emotional processing, he said. But there is no evidence yet that these people are fated to develop anxiety or depression. This was the first MRI scan and the investigators plan to repeat scanning at some point in the future.
Those who had bilateral thinning were much more likely to have major depression. “Regardless of the cause, familial depression becomes hardwired into the tissue of the brain,” Dr. Peterson said. “What we have learned about the pathway from familial depression — from thinning to cognitive problems — suggests inroads into new treatments and ways that we may be able to prevent depression.”
Dr. Weissman agrees. By the second decade of the study, it was already clear that depression was transmitted from generation to generation, with a two- to five-fold increase in offspring of the depressed parents in the study. These same vulnerable children showed the first signs of illness before puberty with anxiety and then in late adolescence with more substance abuse than those without a family history of depression. Now that the first generation study members have grandchildren entering puberty, Dr. Weissman is finding that 40 percent have symptoms of mood or anxiety problems.
The researchers are now conducting genetic studies to look for risk genes in these families. “Depression is most definitely a biological disease,” said Dr. Weissman, but she added there are “environmental reasons why you may not get the illness. A person may not have been exposed to stressors that tip the scales on the side of depression.”
“If someone has a risk gene and cortical thinning,” she continued, “we may be able through psychotherapeutic approaches to reduce their risk for depression.”
“The magnitude of the finding is striking,” said Philip Shaw, MD, a staff clinician who specializes in child development at the National Institute of Mental Health intramural program. “To find such a dramatic cortical thinning in the right hemisphere of this at-risk population is extremely important. It says that this is where we should be focusing our attention.”
The depression study was funded by the National Institute of Mental Health.
• Peterson BL, Warner V, Weissman MM, et al. Cortical thinning in persons at increased familial risk for major depression. Proc Natl Acad Sci
2009; E-pub 2009 March 27.