Ian Gotlib has spent years compiling a growing catalog of clues that could help to identify children who are at increased risk for developing depression later in life. The list includes everything from size differences in structures tucked deep within the brain to a predilection for sorrowful faces.

Psychology professor Ian Gotlib confers with students in his office. (Image credit: Misha Bruk)

The Stanford professor of psychology is convinced that if psychologists can learn to spot these “predictors of depression” early, they may one day be able to prevent a mental disorder that affects more than 16 million Americans every year from happening in the first place.

“The average number of discrete episodes of depression over a lifetime is five or more,” said Gotlib, who is also the David Starr Jordan Professor in Stanford’s School of Humanities and Sciences. “If we can prevent the first episode, we can prevent a significant negative cascade.”

The signs Gotlib seeks are subtle. They are hidden in the children’s brains and bodies, in their genes and the subconscious, or automatic, ways they respond to stress. They also manifest early – often years before the children ever exhibit symptoms that would warrant a clinical diagnosis of depression. No one really knows just how early the signs can appear, so Gotlib’s lab began studying hair from expectant mothers.

Like tree rings or light from a distant galaxy, the strands of hair are time capsules. Each centimeter of hair captures about one month’s average cortisol production. A 4- to 5-centimeter hair sample, collected before a baby is born and once more a few weeks after birth, can provide monthly cortisol levels for a woman’s entire nine-month pregnancy.

Graduate student Lucy King studies the predictors of depression in Ian Gotlib’s lab. (Image credit: Misha Bruk)

Often called the “stress hormone,” cortisol is released by our bodies during times of emotional and physical duress to help regulate our moods, motivations and fears. Gotlib and others have shown that early life stress can alter cortisol levels, which in turn can reduce the size of the hippocampus, part of the brain that plays an important role in learning and memory. A smaller hippocampus has been linked to greater risk of depression, anxiety, suicidal behavior and other mental disorders in later life. A recent study in Developmental Science, led by Kathryn Humphreys, an assistant professor at Vanderbilt University and a former postdoctoral fellow in Gotlib’s lab, found that hippocampal growth is especially sensitive to stress during the first five years of a child’s life.

Gotlib now seeks to understand how maternal cortisol levels during pregnancy affect a developing infant’s brain from in utero to at least 18 months of age by monitoring and measuring their responses in stressful situations.

Researchers in Gotlib’s lab are also assessing whether parental warmth and sensitivity make a difference by recording everything the baby hears. Using software to separate adult speech from baby babble and extraneous noise, they can paint a sonic picture of the parent-child bond. “We can get basic measures of how many adult words are spoken near the infant and how many times the infant vocalized in response,” said Stanford graduate student Lucy King, who is involved in the project.

By combining data about cortisol exposure in the womb, infant neuroimaging and parental behavior, Gotlib’s lab aims to disentangle the complex web of factors that can influence a child’s psychobiological responses to stress and their risk for depression in later life.

“We want to know, what are the relative effects of the pre-birth versus postnatal environments on infant brain development?” King said. “And can enrichment postnatally remediate the effects of a negative prenatal environment?”

In other words, can the actions of a parent or caretaker help assuage the marks of early life stress and shield a child against developing emotional difficulties like depression in adulthood?

A shift in understanding

It’s a provocative question, and one that was unthinkable when Gotlib was a graduate student at the University of Waterloo in the 1970s. Back then, there was little research into the predictors of depression, which was largely considered an adult disorder. “In fact, there was a school of theorists who thought that depression in children was impossible,” Gotlib said. “But there’s a growing recognition now that depression is occurring at increasingly earlier ages.”

It is now known that while many people don’t experience their first depressive episode until early adulthood, the foreshadowing of depression can appear much earlier – especially in women, who are twice as likely as men to be depressed.

This shift in understanding is due in large part to Gotlib, who has spent the past 30 years studying what drives depression. In one of the largest and longest-running longitudinal studies of its kind, Gotlib’s lab compared 100 young daughters (ages 10 to 14) of mothers with a history of depression with a matched sample of daughters whose mothers had never been depressed.

Results from the study, which began in 2005 and is still ongoing, confirmed that teenage girls whose mothers have experienced clinical depression are at higher risk of eventually developing depression themselves. “It turns out that 10 years later, 60 percent of the daughters of depressed mothers have now experienced an episode of depression,” Gotlib said.

By itself, this finding isn’t new – psychologists long ago noticed that depression tends to run in families. What Gotlib found “striking and alarming” in the new study, however, was that despite never having experienced depression or exhibited depressive symptoms themselves, the daughters of depressed mothers resembled depressed adults in many other ways –cognitively, behaviorally, physiologically, even genetically.

A stress index

For instance, like depressed adults, the daughters of depressed mothers gravitated toward sad faces when given a choice between focusing on a happy or a sad face on a computer screen. The girls also secreted higher levels of cortisol both in response to stress and throughout the day. In addition, they had smaller hippocampi, likely because hippocampal development was being compromised by the high levels of cortisol their bodies produced.

Perhaps most surprising, the daughters of depressed mothers had shorter telomeres – end caps on chromosomes that help protect DNA during cell replication. Its length is an indicator of biological age – which can differ from a person’s chronological age – and may be a better index of overall health. Gotlib’s group was the first to show that telomeres in daughters with a family history of depression were prematurely shortened: The telomeres of 10-year-old girls whose mothers had a history of depression resembled those of 18-year-olds. “They’re aging faster biologically,” Gotlib said.

Gotlib had initially assumed that there would be no differences between the two groups of girls because neither cohort had experienced a depressive episode yet. It soon became clear, however, that the daughters of depressed mothers had already diverged from their counterparts in significant and worrisome ways by the time they entered the study. “In a sense, we were already late,” Gotlib said. “At 10 years old, these children already have what some people would call early signs of depression. They were already exhibiting abnormalities.”

The surprising findings prompted Gotlib’s lab to turn their attention to infants. “We thought we’d see cortisol start to rise in the teenage girls closer to the beginnings of a depressive episode, but we saw elevated cortisol levels years before, which raises the question, are these high levels evident years before that?” Gotlib said. “The infants study is our best shot to see when these factors emerge.”

Next steps

In addition to studying possible predictors of depression in utero and infants, Gotlib’s lab is also conducting another decade-long study that follows 220 mentally healthy boys and girls from late childhood (ages 8 to 11) into their early teenage years (ages 13 to 18). By studying and following healthy children through puberty, Gotlib hopes to identify factors that predict the onset of mental disorders and uncover clues about why women are at higher risk than men.

“If we can identify what that risk profile looks like, then we can develop prevention programs that target those mechanisms that we think are contributing to the development of depression and suicidal behaviors,” Gotlib said.

Gotlib is also a member of Bio-X, the Maternal & Child Health Research Institute, the Precision Health and Integrated Diagnostics Center and the Wu Tsai Neurosciences Institute. He is also a faculty affiliate at the Stanford Center on Longevity.

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