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Post by Former NIMH Director Thomas Insel: Depression, Daughters, and Cellular Aging

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Depression is prevalent—6.9 percent of Americans have been affected in the past 12 months.1 Depression is serious—according to the Global Burden of Disease study it accounts for the second largest medical source of years lost to disability in the U.S.2 And depression can be fatal—the suicide rate for people hospitalized for depression exceeds 6 percent.3 Can we predict risk for depression? There are no genetic tests or imaging tests that can be used to predict individual risk. But a longitudinal study from Ian Gotlib and colleagues at Stanford University is worth watching.

This study has followed healthy (with no psychiatric diagnosis) daughters of mothers who have had multiple episodes of depression and a matched sample of healthy daughters of never depressed mothers. Although the high-risk daughters—those whose mothers have depression—showed no signs or symptoms of depression when they were first evaluated between ages 10 and 14, Gotlib notes that 60 percent have developed depression by age 18. In a paper published this month in Molecular Psychiatry, Gotlib and his colleagues report that 10- to 14-year-old-girls at risk for depression have shorter telomeres, relative to daughters of mothers who have never been depressed.4 Telomeres are the caps at the end of our chromosomes. They are essential for chromosomal stability and they naturally shorten with aging (findings recognized by the Nobel Prize in 2009). Indeed, telomere shortening is one of the most reliable signs of cellular aging.

How could healthy 10- to14-year-old girls show signs of aging? The answer is not entirely clear but a second observation may provide an explanation. The same girls with shortened telomeres had increased stress reactivity, indicated by a steeper spike in the hormone cortisol in response to a simple stress test. Does the heightened stress reactivity lead to shorter telomeres? While there is an abundant literature linking developmental stress to risk for depression, we don’t know if stress reactivity is the mechanism for apparent cellular aging or if both stress reactivity and cellular aging reflect some other underlying process.

Beyond suggesting a risk biomarker for early identification of depression, this finding indicates a troubling early sign of risk for premature biological aging and possibly age-related chronic diseases, such as cardiovascular disease. Investigating the cause and timing of decreased telomere length—to what extent it may result from abnormalities in stress responses or is genetically influenced, for example—will be important for understanding the relationship between cellular aging, depression, and other medical conditions.

What can be done to reduce the risk of depression? In previous experiments, girls at risk for depression exhibited different patterns of brain activation during experimental mood regulation. In ongoing experiments, the Gotlib team is using neurofeedback to help these girls retrain their brain circuits and hopefully their stress responses. It will be a few years before we will know how much this intervention reduces risk for depression, but anything that prevents or slows the telomere shortening may be an early indication of success.

1 U.S. Dept. of Health and Human Services, Substance Abuse and Mental Health Services Administration. National Survey on Drug Use and Health, 2012.

2 US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA. 2013 Aug 14;310(6):591-608.

3 Nordentoft M, Mortensen PB, Pedersen CB. Absolute risk of suicide after first hospital contact in mental disorder. Arch Gen Psychiatry. 2011 Oct;68(10):1058-64.

4 Gotlib IH et al. Telomere length and corticol reactivity in children of depressed mothers. Mol Psychiatry. 2014 Sep 30. doi: 10.1038/mp.2014.119.