Research reveals biological and chemical differences between the brains of people who have attempted suicide and those who are depressed.

The Suicidal Brain

Last week, the American Academy of Pediatrics issued a sobering new finding: Suicide is now the second-leading cause of death among teenagers, with nearly 2,000 taking their own lives annually. That contributes to a rising incidence of suicide among the wider population, which sees roughly 40,000 Americans take their lives each year. In 2014, there were 12.93 suicides per 100,000 people, up from 10.9 in 2005, and the U.S. Centers for Disease Control and Prevention lists suicide as the tenth leading cause of death nationally.

Those facts are known. Far less clear is what characteristics — physical, emotional, psychological — can signal suicide risk. The National Alliance on Mental Illness, an advocacy group, suggests for example that the majority of people who commit suicide suffer from depression or some other diagnosed mental illness. But not all clinically depressed people go on to take their own lives, and comparatively little is known about what distinguishes those who do — once thought to be around 15 percent, but now thought to be somewhere between 2 and 9 percent — and those who don’t.

“Suicide risk can only be reduced, not eliminated,” the AAP researchers noted in their recent report on teen suicide, “and risk factors provide no more than guidance.”

Getting beyond mere guidance, then, would seem to be crucial — and while we may never fully understand what tips someone over the edge, current research suggests that biology may hold at least some answers.

“Something is happening in the brain of these people,” said Fabrice Jollant, a psychiatrist at McGill University in Montreal. “It’s not doing its job properly.”

Jollant is one of several researchers who have been busy trying to make sense of suicide. His work and that of others has shown major differences between the brains of suicide attempters and depressed individuals who have never attempted suicide. In a 2008 study published in the American Journal of Psychiatry, for example, Jollant found that certain areas of the brain in formerly depressed men who had once attempted suicide reacted more strongly to seeing images of angry faces, compared to men who had a history of major depression, but had never attempted suicide.

“Even though these men were no longer suicidal or depressed, their brain responded very strongly compared to others,” Jollant said. “[The brain] was getting overactivated at angry faces, showing that [it] still responded unnaturally to its environment, even though the patient was healed psychologically.”

Jollant and his team observed that the right lateral orbitofrontal cortex — a region of the brain that is important for encoding the things people care about — lit up more often and more intensely in the men who had attempted suicide, showing they were particularly sensitive to the image. The finding aligns with past research that shows people who attempt suicide tend to react to stress more strongly than others. While healthy individuals can move past a negative experience, someone who is depressed or on the edge of suicide dwells excessively on the situation.

“Angry faces are a signal of social threat; someone’s angry at you,” Jollant explained. “Our interpretation is that [angry faces] are a signal of rejection [and] that’s standing out to these people when it doesn’t to anyone else.”

In an earlier study, Jollant had suicide-attempters participate in a computerized version of what’s known as the Iowa Gambling Task, and found that the decision-making part of their brains was impaired.

In the game, participants were presented with four virtual decks of cards and instructed to select individual cards from any deck of their choosing. Each selected card resulted in winning or losing game money, with a goal of winning as much as possible – but there was a catch: Two decks were stacked to favor small winnings, but even smaller losses, resulting in a net win over the course of the game. The other two decks were tweaked to provide big payoffs, but even greater losses — leading to a net loss in the long run.

Healthy subjects tended to figure out quickly which decks were long-term losers. “Most people test all the options. They lose several times, but at some point they understand that they have to leave those decks alone,” Jollant explaied. “It’s not only risky, it’s disadvantageous.”

But participants who were suicide attempters didn’t seem to distinguish between the decks. They didn’t learn from trial and error, and they continued selecting bad decks throughout the game. “It’s as if their brain isn’t processing the risk,” Jollant said.

MRI scans confirmed that something was amiss. The left lateral orbitofrontal cortex of the brain, which is associated with decision-making, lit up when healthy subjects chose the bad decks. But in suicide attempters, the region was markedly less active. This and past behavioral studies seem to suggest that decision-making is impaired in numerous psychiatric disorders.

The idea that certain biological markers can identify those who are prone to suicide isn’t new. Up until the 1980s, suicide was blamed generally on depression without any real understanding of the underlying neurochemistry. That changed when scientists noticed abnormally low levels of serotonin, a chemical that helps regulate mood, in the brain of individuals who were depressed or had committed suicide.

In a 1976 paper, Marie Asberg, a psychiatrist at the Karolinska Institute in Stockholm, noted that depressed patients with low levels of 5-HIAA, the primary metabolite of serotonin, attempted suicide significantly more often than depressed individuals with higher levels of 5-HIAA. She concluded, “The present investigation, albeit of a preliminary nature and based on a comparatively small sample, indicates that it may prove worthwhile to take biological issues into consideration in attempts to understand, and perhaps ultimately prevent suicide.”

Thus commenced a decades-long focus on serotonin’s association with suicide — though Jollant cautions that the issue is far more complex. “It’s not all about serotonin,” he said. “Yes, the system is implicated with suicide, but there are other factors at play.” Antidepressants — which boost serotonin levels in the brain — don’t work for everyone, for example, and some researchers even doubt their benefits for the severely depressed.

Yogesh Dwivedi, a psychiatrist at the University of Alabama at Birmingham, is among these researchers. In a 2014 overview published in the journal Dialogues in Clinical Neuroscience, Dwivedi suggested that there are observable differences at the cellular — and even molecular — level in the brains of those who commit suicide. Their levels of microRNA — molecules that help regulate gene expression — for example, are much lower than in those who die of natural deaths, Dwivedi observed. They also form entirely different shapes, or networks of microRNA, in the brain.

Dwivedi believes these unique molecular changes, which can appear when someone experiences severe stress at an early age, are one link in the chain of events that leads a person to commit suicide. When he replicated the structures of microRNA he saw in suicide victims in the brains of rodents, the animals themselves became depressed and anxious. “[Micro RNAs] in this form play a distinct role in suicidal behavior,” he said. “They’re another trait of suicide.”

Dwivedi is hoping to create a blood test that can identify these specific microRNA structures. The test could then help physicians identify if a patient is at a higher risk for suicide. “Scientists are learning more and more that there are very specific changes in the brain of those who commit suicide,” Dwivedi says. “And each of these factors contributes to that fatal decision.”

For all of this, advances in suicide research can seem sluggish — in part because those who are at highest risk are often excluded from studies. This is based on the premise that it would be unethical to allow them to participate in an experimental trial that may not work, instead of giving them already-proven treatment, like counseling or antidepressants.

But scientists like Jollant and Dwivedi continue to press on for answers.

In a recent pilot study with Marcelo Berlim at the Douglas Institute, Jollant observed that healthy subjects became even better at the Iowa Gambling Task after researchers stimulated the decision-making portion of their brains with low-voltage electric currents. The two scientists are now hoping to achieve similar results with individuals who are thought to be suicidal, with the long-term goal of making such individuals stronger in the face of life’s adversities.

Nadia Whitehead is a freelance journalist and science writer at Texas Tech University Health Sciences Center El Paso. Her work has appeared in Science, The Washington Post and NPR. Nadia is currently pursuing a master’s degree from Johns Hopkins University.