Suicidal Threads

When sociologist Mike Tomlinson began combing through the health records of people in Northern Ireland, he wasn’t interested in suicide. He was on the hunt for links between poverty and international conflict. But he came across a startling trend. From 1998 to 2008, the rate at which men in their mid-30s to mid-50s were committing suicide rose alarmingly fast, more quickly than the rate for the rest of Northern Ireland’s population.

At first, that spike made no sense. A peace agreement reached in 1998 transformed Northern Ireland into a prosperous and tranquil place. Economic indicators had been surprisingly good. Suicide rates in neighboring countries were all gently falling. Nothing seemed to explain why so many of these men were killing themselves.

But Tomlinson found a hint in the men’s pasts. They had all grown up in the late 1960s and the 1970s, during some of the worst violence Northern Ireland had ever experienced. Called the Troubles, this warlike period brought religious and political fighting that pitted neighbor against neighbor. Children of the Troubles lived with terrorism, house-to-house searches, curfews and bomb explosions. Trauma early in life had rendered men more vulnerable to taking their own lives later, Tomlinson proposed in July in International Sociology.

“If you were younger then, you carry that through,” says Tomlinson, of Queen’s University Belfast. This idea, that something that happened long ago could have such a profound effect today, seemed to resonate with others. When he described his idea to a suicide prevention group in Northern Ireland, “they just lit on it, and said it speaks so much to what they were seeing.”

Tomlinson does not study the brain, but his work has led him to an idea that’s been under close scrutiny by people who do. Neuroscientists and psychologists now believe that childhood trauma, including violence and neglect, sears itself into the brain in ways that can have devastating effects later.

“It’s a known fact that individuals with early life adversity are at a higher risk of suicide,” says Gustavo Turecki, who directs the McGill Group for Suicide Studies in Montreal. A 2001 study in the Journal of the American Medical Association looking at more than 17,000 Californians found that harmful childhood experiences boost a person’s lifetime risk of attempting suicide by two to five times. Other studies reveal that people who experienced adversity during childhood make up anywhere from 10 to 40 percent of people who later display suicidal behavior.

All the evidence suggests that childhood trauma can lead to suicide. Now, Turecki says, scientists have to figure out why.

In the last few years, they have begun to turn up molecular scars from past abuse. Some researchers have discovered chemical tags that change genes’ behavior in ways that may contribute to suicide. And new evidence reveals that childhood trauma may throw off-kilter the hardware responsible for the brain’s response to stress. For a person struggling with suicidal thoughts, dealing with stress appropriately can be a matter of life or death. As more and more signs of these brain changes turn up, the scientific community is struggling to understand how they affect a person’s actions, thoughts and decisions — behaviors that sway a person’s likelihood of committing suicide.

“This is something we see in the clinic,” Turecki says. “People exposed to traumatic events seem to have a harder time adapting to life.”

The immediate goal, researchers say, is to better identify people who are likely to act on suicidal thoughts. But in the future, a deeper understanding of the brain scars left by abuse might point to better treatments for someone battling against suicidal behavior, and perhaps even ways to prevent such tragedy.

Something ‘truly biological’

Worldwide, about 1 million people take their own lives each year. And the number appears to be growing: In the last 45 years, the suicide rate has jumped by 60 percent.

Every suicide is different. But when scrambling to explain why people would take their own lives, researchers look for similarities, any common strands that might make some sense of the senseless.

Men are more likely to die from suicide than women, though women are more likely to attempt suicide, the stats show. Caucasians are more likely to commit suicide than African Americans. Smokers, substance abusers and people with extremely low cholesterol are all more likely to die by suicide than their counterparts. Genetics undoubtedly plays a role, because suicides are known to run in families. The chemical messenger serotonin, best known for its job in regulating mood, also seems to have a part: People who commit suicide are thought to have dampened serotonin signaling.

But no one knows whether these factors are causes of suicidal behavior or just innocent bystanders that happen to show up commonly in people who commit suicide. That distinction isn’t clear even for two of the strongest suicide predictors.

For one, most people who commit suicide are in the throes of an unmanaged psychiatric illness. And another, many of these people have recently experienced something very stressful, like public humiliation or a family problem, some precipitating factor that seems to send them over the edge. But attributing suicide solely to a stressor, or solely to a mental illness, is an oversimplified view, says psychiatrist J. John Mann of Columbia University and the New York State Psychiatric Institute in New York City. There must be much more to the story.

“What you see — and this is what the press gets locked into without looking beyond it — is an immediate precipitant. Job problems, scandal in the government, those kinds of things,” Mann says. “But in fact, people are dealing with psychological stressors all the time, and compared to that, the number of people who die by suicide is tiny. Why doesn’t that happen all the time if it’s cause and effect?”

Something different, above and beyond a mental illness or an intensely stressful situation, is present in the brains of people who commit suicide, Mann contends. “Something truly biological is happening,” he says.

Evidence now suggests that, in some cases, that something originates in traumatic early life experiences. The thread leading from a rough upbringing to suicide is quite strong.

Altered stress

Rats aren’t known to commit suicide, but a poor upbringing does have profound effects on their brains. Rats neglected by their mothers have brain changes that cause the animals to grow up with abnormal responses to stress, Michael Meaney of McGill University and his team found in a series of experiments in the 1990s. Turecki was intrigued by Meaney’s results. “We thought the same mechanism might make sense in humans,” Turecki says.

They turned out to be right. Turecki, Meaney and colleagues have now found changes in people similar to those seen in rats. And misbehaving genes in the brain seem to be behind both results.

By amassing a large collection of brain tissues from people who committed suicide, the researchers have been able to study genes, proteins and structures to look for similarities. One particular gene, found to behave abnormally in the neglected rats, caught the researchers’ interest. This gene’s activity level is low in people who suffered childhood adversity and later committed suicide, the team found. This wasn’t true for people who had normal childhoods and committed suicide or for people who died in accidents.

The gene in question makes a protein, called the glucocorticoid receptor, that decides when the body’s stress system has produced enough of the stress-signaling hormone cortisol and helps shut that system down. Without enough of this receptor, the body and brain can’t reset after a stressful event.

In people who committed suicide who also suffered childhood abuse, a chemical stop sign was affixed onto the gene in a certain part of the brain, Turecki and his team reported in Nature Neuroscience in 2009. This stop sign, presumably attached during childhood, might stymie current and future production of the glucocorticoid receptor. (The team has no way of knowing the timing for sure because they can study the brain only once a person has died.) Since publishing that finding, the researchers have turned up further evidence: This stop signal, a chemical tag called a methyl group, is also present on several different parts of the gene that encodes the glucocorticoid receptor, Turecki and colleagues reported July 1 in Biological Psychiatry.

And the sensitivity of glucocorticoid receptor production to trauma seems to start early. Karl Radtke of the University of Konstanz in Germany and colleagues found similar methyl tags on the gene in blood samples of children born to women who experienced domestic violence while pregnant. Though the researchers can’t say for sure what is happening in the children’s brains or when the methyl tags first appeared, the results, reported online last year in Translational Psychiatry, do suggest that trauma in the earliest stages of development can have a lasting influence.

Genetic effects of trauma during childhood aren’t restricted to the gluco­corticoid receptor, either. In a study comparing brain tissue of 25 people who died by suicide and experienced childhood trauma with 16 people who died suddenly without abuse, control regions for more than 300 genes had differing methyl tags, Turecki and colleagues reported in the July Archives of General Psychiatry.

It’s far from clear whether these genes have a role in suicide. Without large samples of people who experienced abuse without suicide, it’s impossible to get at any clear links.

But scientists are starting to figure out where to look next for possible clues.

A faulty axis

The glucocorticoid receptor is one small piece of the body’s larger stress system, which may be molded in many ways by abuse in early childhood. Called the HPA axis, this stress-response unit is made up of three pillars: the hypothalamus and pituitary gland in the brain and the adrenal glands on the kidneys. In response to a stressful situation, the HPA axis kicks into gear, churning out stress hormones that help a person get through challenging times. During childhood, this system is shaped by the environment. As children grow up, the HPA axis hardens into its final form. Some researchers, including Turecki, believe that a stress-response system permanently altered by early life trauma could lead to suicide later.

“To some degree, the message that you’re getting is that the environment is hostile,” Turecki says. “You’re being abused by people you’re supposed to trust, people who develop relationships of trust and attachment. When they’re abusing you, the message you’re getting is the world is one in which you can’t trust anyone. You’re always on alert.”

Many studies, both in animals and in people, have found that adversity early in life programs this stress system for a quick ramp-up, like an engine that roars to life at the lightest tap on the accelerator. What’s more, the engine keeps the RPMs redlined longer than it should.

Exactly how this system is sculpted by adversity in childhood is still unclear, but some animal experiments have yielded good leads. Changes in the structure and function of a brain region called the hippo­campus, which is known to be sensitive to the kind of stress experienced during trauma and is also involved in controlling the stress response, seem to be involved. Levels of molecular players that fluctuate along with stress, such as the protein BDNF and the chemical messenger glutamate, could also be disrupted. And some results hint that early stressors can even staunch the production of new nerve cells, which may somehow preclude a normal stress response later.

Jussi Jokinen of the Karolinska Institute in Stockholm and colleague Peter Nordström have been turning up evidence for HPA axis malfunctioning in people at risk of suicide. Recently, the team has found that a stress response, measured by cortisol in the blood, lingers too long in young adults with mood disorders such as depression who have attempted suicide, compared with others with mood disorders who have not attempted suicide. Another study has found that the cortisol-producing adrenal glands weigh more in people who committed suicide, suggesting that the enlarged organs have adapted to pumping out massive amounts of stress hormones.

From brain to behavior

As researchers move forward, the real challenge will be to identify the complex behaviors that may be the outward sign of suicide-associated brain changes.

Certain personality traits, such as anxiety, aggression, impulsivity and poor decision-making, show up in people exposed to childhood adversity. “We know there are alterations in executive function in kids who have been neglected,” says child psychiatrist David Brent of the University of Pittsburgh School of Medicine.

And such traits also appear in people who commit or consider committing suicide. Brent and his colleagues have recently found poor decision-making in adolescents who have previously attempted suicide. In a classic lab gambling task in which people picked cards from different decks, these volunteers kept choosing to draw from the losing deck of cards long after other people identified the winning deck. The study, led by Jeff Bridge of the Nationwide Children’s Hospital in Columbus, Ohio, was published in the April Journal of the American Academy of Child and Adolescent Psychiatry.

“What we have are different pieces of the puzzle,” Turecki says. It’s too early to draw clean lines from a hard childhood to a changed brain to behavior and on to suicide. And even if the relationship between early life and suicide were clear, the effect wouldn’t apply to everyone. But the results, though incomplete, are starting to paint a compelling picture that could explain some — not all — suicides.

Although there are many loose ends, the work so far suggests that in some cases, early childhood adversity changes the brain in a way that primes it for self-destructive behavior. Bigger studies of more diverse groups of people will help reveal how all these diverse lines of data fit together, says Brent. “These strands converge,” he says. “They converge on a person’s ability to balance the will to live and the wish to die.”

Often, when people come into a clinic or emergency room with signs of suicidal behavior, there’s no good way to figure out whether those people are truly a risk to themselves or not. With a deeper understanding of how brain changes early in life can usher in a greater risk of suicide, doctors may be better able to better judge whose life is in danger. Particular behaviors and ways of thinking might be good outward signs of what’s happening inside the brain, giving doctors clues about who needs the most help. “This is a story that’s just beginning,” Turecki says. “There’s so much still to learn.” 

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Marked early  Researchers have identified a number of molecules that may play a role in suicide or related mental problems. Amounts of these molecules in the body can be modified by life experiences and environment, often via chemical tags that affix to DNA and influence how a gene behaves. 

BDNF  The BDNF protein, which helps brain cells grow and survive, is diminished in people who commit suicide. Chemical tags called methyl groups may influence the activity of the gene for BDNF, slowing protein production.

TrkB  Low levels of this protein, which works with BDNF in the brain, have been linked to suicide. A DNA region that controls the gene for TrkB has more methyl tags in the brains of people who commit suicide. 

Polyamines  In people who commit suicide, gene activity controlling levels of polyamines — small molecules that help regulate cell growth and influence cell-to-cell communication in the brain — appears to be altered.

5-HTT  This protein slurps up serotonin, which helps nerve cells communicate and has been linked to suicide. A DNA region controlling activity of the gene for 5-HTT had more methyl tags in abused children than in others.