From Breakthroughs, 2010

“When we understand populations at risk, periods of risk, all situations of risk,” says three-time NARSAD Distinguished Investigator Myrna Weissman, Ph.D., “then we can develop more rational interventions for psychiatric disorders.”

Weissman has studied the distribution of psychiatric disorders across national borders, races and generations; among different communities and social classes; in men, women and children. She is recognized throughout the psychiatric community for her groundbreaking 25-year, three- generation study of depression, and is particularly interested in the impact of stress upon those who are already susceptible to becoming depressed.

The most consistent worldwide epidemiological finding about depression is that it is twice as prevalent in women as in men. Studies show that the periods of greatest risk for some women may coincide with the periods of major hormonal changes in their lives. NARSAD Independent Investigator Claudio Soares, M.D., Ph.D., a faculty member of the psychiatry and obstetrics/ gynecology departments at McMaster University, Canada, studies hormonal fluctuations in women across the reproductive life cycle and their effect on mood and depression.

Myrna Weissman: Lowering the incidence of depression by treating depressed mothers

Today, Weissman says, the study of disease incidence in large populations is moving toward what she calls translational epidemiology. “We have the clinical observations, but to be able to translate them into treatments and preventive measures, we have to understand them biologically. To do that, we have to collaborate with people in a variety of disciplines.” Weissman’s current collaborations are helping to tease apart the interweaving strands of environmental and genetic factors that underlie the trajectory of depression.

Stress is an environmental factor that can trigger depression in genetically susceptible people. “And,” says Weissman, “what could be more stressful to a child than a depressed mother?” Parental depression, she says, is among the most well documented risk factors for childhood anxiety, disruptive behavior disorders and major depressive disorders. Among its many findings, her long-term study revealed that grandchildren descended from two generations affected by depression had a 60 percent risk of developing a psychiatric disorder sometime around 12 years of age.

Weissman contributed to the recent, multicenter STAR*D clinical trial (Sequenced Treatment Alternatives to Relieve Depression) conducted by the National Institute of Mental Health. Her goal was to find out whether treating depressed mothers and getting them better would help their distressed children get better. The answer was yes.

The study, which involved 151 mother-child pairs in eight primary care and 11 psychiatric outpatient clinics, showed that when there was remission of maternal depression after three months of treatment with antidepressant medication, there was an overall 33 percent remission in depressive and anxiety symptoms in the children. Conversely, the children of mothers who did not respond to treatment got steadily worse. Weissman hopes that these findings will encourage practitioners to institute more vigorous treatment of depressed mothers, especially, she says, “when there are so many questions about the appropriate and safe treatment of psychiatric disorders in children.”

Cortical thinning and depression risk

In another collaboration, Weissman teamed up with brain imaging specialists to uncover a dramatic correlation between thinning of the cortex and increased familial risk for depression. This was observed in families who took part in her multi-generational study. The cortex is the area of the brain responsible for higher thinking and functioning. The research showed that those at high risk of developing depression had a 28 percent thinning of the right cortex compared to control subjects.

Because the results were so dramatic, Weissman wanted to follow through, and, with the help of geneticists, see if genetic variations among her test families would correlate with the observed cortical thinning. To do so, she turned to NARSAD. “You have to have a funding agency that trusts you and is flexible. The kind of flexibility and trust NARSAD provided was extraordinary. To do the study, we had to get DNA samples from our families, and that takes time. For example, we had to wait for one family’s annual reunion. In another case, a son was in Iraq. In another, the grandmother, believe it or not, is a long-distance trucker! We had to wait until she got to the east coast.

“We were awarded the grant in 2005, but NARSAD let us extend the study. We’ve now finished collecting over 300 samples and we’re starting to analyze the data. NARSAD has stepped to the plate whenever we’ve wanted to do something we thought was innovative and exciting and didn’t think anyone else would fund.”

Weissman has been widely honored for the depth and breadth of her work. In addition to her epidemiological studies, earlier in her career she participated in the development of interpersonal psychotherapy (IPT), now in wide use. In 1994, NARSAD awarded her its Selo Prize (since renamed the Falcone Prize) for her contributions to research on affective disorders. She, in turn, established the Klerman Award for clinical research by NARSAD Young Investigators, named for her late husband, Gerald Klerman, M.D., with whom she worked at Yale.

Claudio Soares: Tracking the effects of stress across generations

Before his 2005 appointment to McMaster University, first in his native Brazil and then at Harvard, Claudio Soares examined depression risk for women during menopause and the perimenopause, the period of transition into menopause. He has been involved in tailored treatments for women during this critical time, sometimes combining antidepressants with estrogen, and has found that the use of estrogen may help patients to respond to antidepressants and achieve better overall quality of life.

Despite the later controversy over the safety of estrogen therapy, Soares’ research contributed to a better understanding of estrogen’s effects on mood and behavior. He thinks it is likely that treatments for menopausal depression in the near future might employ drugs called SERMS: selective estrogen receptor molecules. “These are smart molecules that could target specific estrogen receptors in the brain, but bypass those in the breast or other unwanted areas. They could have the same benefits of estrogen but with minimal side effects or cancer risks.”

At McMaster, Soares heads the Mood Disorders Division and the Women’s Health Concerns Clinic, where, in a large study called MAVAN (for Maternal Adversity, Vulnerability And Neurodevelopment), women and their children are being followed from the women’s’ early pregnancies through the first few years of their children’s lives. The oldest of the children are now approaching age five.

“The idea was to establish a cohort of whom half are healthy moms and the other half are moms who, while not necessarily clinically depressed, have shown depressive symptoms or had psychosocial stressors or a family history of mental illness,” says Soares. “It turns out that within the ‘adversity’ group, the majority have developed depressive symptoms.” Data from the study show stress hormone levels in mothers actually predicting changes (behavioral, hormonal) in their children.

Based on the MAVAN model, Soares got the idea to look at a population with a ready-made source of stress: immigrants, who universally must cope with adjustment to an unfamilair place. Specifically, he wanted to look at how much stress during pregnancy would increase the risk of allergies in the babies. “One of the hypotheses,” he says, “is that you have a sort of transgenerational impact on allergies or allergic development, and you can actually affect the threshold for allergic development in kids.” In 2009, Soares received a NARSAD Independent Investigator grant with which he is now going back to the original MAVAN cohort to compare the data from his immigrant children to see how allergies in MAVAN children correlate with their moms’ mental health in pregnancy.

“The first NARSAD grant,” Soares says, “was the tipping point in my career that made it possible to support myself as a new researcher in the U.S. The second gave me reassurance that I was doing something meaningful in the area of women’s mental health. This grant is probably the most influential one since it involves the effect of stress across generations. We’re looking forward to reporting on the results.”