On April 20, 1999, two high school seniors walked into Columbine High School and opened fire. It was the first mass-shooting in an American public school, an event that left 15 people dead and the world debating how it happened. Rebecca Brachman was a sophomore at the time, at a high school in New Jersey whose demographics mirrored Columbine’s. When the local school board asked students to come up with ways to prevent a similar tragedy in their town, many condemned gun access. Brachman took a different angle: mental health.

It’s common today to discuss the psychological state of attackers after a school shooting, but the topic was almost unheard of two decades ago. Brachman has always been a creative problem solver, though. In the first grade, when asked to circle half of the bunnies on a sheet of paper, she diligently circled the back half of each bunny. In high school, she’d seen some of her classmates somewhat unravel between middle school and freshman year, and she wondered whether something similar had happened in Colorado. What unbearable conditions might have caused the shooters to take such drastic measures?

The question sparked in Brachman a deep drive to understand—and improve—what she refers to as “the human condition.” Now a neuroscientist at Columbia University, she is among a burgeoning group of researchers attempting to makes sense of the complex relationship between stress and mental illness. Long-term stress is considered responsible for 60 percent of all human illness and disease, according to the American Institute of Stress. At its extremes, it can lead to mental breakdowns, depression, suicide—and possibly school shootings. But scientists have yet to determine how stress causes these ailments. It could be crippling the brain; it could be overwhelming the immune system. Maybe it’s some combination of the two.

Brachman wants to fix things either way. Her group at Columbia is investigating whether there are ways to change how both the brain and immune system handle stress—whether there’s a specific shot or procedure or pill to help people healthily regulate it. In essence, they’re looking for a stress vaccine. And their progress is promising.

* * *

As far back as 1936, scientists noted the connection between stress and ulcers, high blood pressure, allergic reactions, and other maladies. Analyzing the lives of children born to mothers who were pregnant during the Dutch Hunger Winter of 1944, a famine that affected more than 4.5 million people, researchers found that prenatal exposure to extreme stress led to long-term cognitive and mental-health issues, as well as addiction. Prenatal stress exposure has since been linked with ADHD in children as old as 15 years, increased risk for autism, greater impulsivity in boys and girls, and poorer task performance in boys. Exposure during the first trimester increases susceptibility to schizophrenia, while exposure during the second and third trimesters is linked with increased risk for depression, anxiety disorders, and bipolar disorder.

The full impact of stress depends on a variety of factors. It’s become evident in recent years that the younger a child, the greater the neurological impact, potentially because the developing brain is more malleable. The length of the exposure to stress is critical, too, as chronic stress is proving to be the strongest predictor of depression. (About 40 percent of the risk of depression is genetic, and stress is the most common trigger.)

How a person experiences stress is directly related to where and how they live. Every community has different expectations, so circumstances that feel incredibly stressful to someone in one place might seem normal to someone elsewhere. Even when people in similar situations experience the same types of stress, they might not develop the same reaction; there are now more than a dozen genetic mutations known to make people more susceptible to stress’s effects.

In recent years, scientists also have noted differences between the immune systems of depressed individuals and their mentally healthy peers. It’s unclear whether these differences are a cause or a consequence of depression, says Connie Hammen, a professor of clinical psychology at UCLA. If they are a cause, the immune system differences would be as important as genetic mutations, at least when it comes to determining how stress will affect someone.

* * *

For all its potential harm, stress is not all bad. “Stress as stress is functional,” says Sarah Pressman, an associate professor of psychology and social behavior at the University of California, Irvine. “You don’t want to feel calm and happy when a tiger jumps at you. You have to activate the right systems to make you run away [from danger].”

Monika Fleshner, a neuroimmunophysiologist at the University of Colorado, Boulder, has shown that short-term stress can even boost immunity. It's one of the body's natural defense systems. So, if the immune system is indeed critical to how the body processes chronic stress, short-term stress might help build the body’s defenses against stress itself.

Brachman doesn’t want to completely cut off a person’s stress response, as that could prove counterproductive. Instead, she’s seeking a way for people to stop the response before it turns dangerous—before it triggers mental illness. It’s a mission she landed on somewhat accidentally while completing a fellowship at the National Institutes of Health, where she researched how the immune system—specifically, a compromised immune system—is related to depression. She was particularly interested in whether depression influenced the immune system, or if the immune system helped trigger depression.

Working with 12 mice, her team transferred immune cells from depressive-like mice into new mice that had not been exposed to stress or displayed depressive behaviors. The team expected the new mice either to develop a typical physiological response to stress (inflammation, increased heart rate) or to show no changes. But when they actually stressed the new mice—by putting them in cages with more aggressive animals, forcing them to swim, and other standard lab methods—the results, and those of subsequent studies, showed the opposite: The new mice were more resilient to stress.

The immune cells from the depressed mice appeared to immunize the new mice against stress-induced depressive symptoms, as if they were a vaccine.

By the time Brachman’s results were published, in January 2015, she’d long since moved on to and completed a doctoral program at Columbia University, where she had begun collaborating with the neurobiologist Christine Denny.* In the course of her career, Denny had seen thousands of mice anesthetized with ketamine, the drug also known as special-K, for various studies, and recognized that there were lasting effects. Ketamine was by then also being used to treat depression in adults. Brachman and Denny decided to test whether ketamine had any effect on how mice react to stress. They gave the drug to lab mice, waited one week, then put those mice, as well as untreated mice, through stressful situations. The study results showed that for up to four weeks after the injection, the mice that were given ketamine were more social and less afraid than the control animals. They also exhibited fewer depressive-like symptoms after facing stressful situations.

Brachman’s results consistently showed that there are ways to build resilience to stress, by both injecting immune cells from another animal and giving a dose of ketamine prior to stress. This runs counter to the long-accepted notion that stress leads to illness because of risk factors such as genetic mutations, compromised immune systems, and prior exposures. Perhaps the relationship between stress and illness has more to do with a person’s level of resilience—and perhaps specific interventions could boost this.

Brachman’s hope is to create a drug that improves resilience so much that it inoculates people against stress, allowing even those most at risk of developing depression and other disorders to instead only enjoy stress’s benefits.

* * *

Brachman is not the first scientist to suggest vaccinating against stress. For decades, the Stanford University neuroscientist Robert Sapolsky has focused on muting the brain’s chemical response to stressful situations. In the most basic terms, Sapolosky’s approach cuts off the release of stress hormones when they’re starting to overwhelm the body. “We’ve proved that it’s possible,” he told Wired in 2010. He has since tested a version of the “vaccine” in rodents, and his research is ongoing.

The results of Brachman and Denny’s research on ketamine were repeated shortly after their study came out, when a study published in the Journal of Neuroscience showed the same protective potential of ketamine in rats, and added that the drug produces the same effects whether it is administered two hours, one week, or two weeks prior to a stressful event.

As Brachman finalized her NIH results paper, Georgia Hodes, of the Icahn School of Medicine at Mount Sinai, led a study investigating the link between increased immune system inflammation and depression in mice. The researchers determined that inflammation is not caused by stress; rather, stress comes first, and leaves people more susceptible to stress-related illness. They subsequently found that anti-inflammatories prevent stress-related depression in mice. In the same vein, researchers at the University of Colorado, Boulder, showed that anti-inflammatories help reduce fear in lab mice. But just like Brachman's immune and ketamine results, these are far from being replicated—or even tested—in humans.

Denny  has found one human study that supports her findings on ketamine, however. Published in an obscure journal in 2008, it’s a military study assessing the results of using ketamine when operating on soldiers who have been severely burned. Intense burns are considered one of the risk factors for post-traumatic stress disorder, and the doctors operating on the soldiers were concerned that using drug might leave them more susceptible to developing PTSD. But following up with soldiers showed the opposite. Receiving ketamine cut a soldier’s likelihood of developing PTSD nearly in half: Twenty-seven percent of those who received ketamine developed PTSD, compared to 46 percent of those who did not receive the drug.

Patients who received ketamine “had a lower prevalence of PTSD ... despite having larger burns, higher injury severity score, undergoing more operations, and spending more time in the ICU,” the authors wrote. Yet in a later military study ketamine had no impact on the likelihood of developing PTSD. This could have been due to the severity of the burns, to the timing of the dosage, or other factors, according to Denny. But whatever the cause for the different results, it was discouraging.

* * *

Denny and Brachman are currently studying the long-term effects of ketamine, the ideal timeframe to administer it, and whether similar compounds (and non-psychedelics) can produce the same effect. They have so far seen that the benefits of ketamine last at least a month, and that it’s significantly more effective when administered prior to stress than when used as a treatment for stress-related conditions. Giving the drug to a control animal, even if it's never exposed to stress, doesn't produce any cognitive changes, which indicates that ketamine would not be dangerous to administer as a precaution when people know that they are heading into potentially stressful events, such as a soldiers heading to a war zone. (The follow-up military study supports this, as it concluded that administering ketamine does not increase the likelihood of developing PTSD or other conditions.)

Miles Herkenham, the principal investigator in the functional neuroanatomy lab at the National Institutes of Health and Brachman’s advisor during her fellowship at the institution, said in an email that the NIH, too, is pursuing potential immune interventions for stress resilience, with a specific focus on the length of the preventative effects. As for mimicking the study in humans or moving towards actual drug development, he added, “‘Years off’ is one way of putting it.”

In an ideal world, a vaccine would allow first responders to return from disaster zones unaffected by the stress of their jobs and soldiers to return from war zones without the risk of debilitating conditions such as PTSD; it could prevent depression from developing when a person is out of work, and it could give children in extreme poverty a better shot at overcoming their upbringing. Still, a vaccine or vaccine-like drug of any sort would not be a cure-all. A vaccine “is only going to work on the biology; it’s really not going to change people’s ... basic ways of interacting and interpreting the world and themselves,” says Hammen, the UCLA psychology professor. “Kids who are exposed to abuse or other kinds of adversity often are exposed to terrible parenting and really dire learning conditions. … Just muting their biological response to stress really doesn’t fully prepare that child to deal with the world with all the tools that they need.”

According to Hammen, it would be more beneficial to focus on environmental interventions that have already be proven; she calls a discussion of an actual preventative drug for stress “extraordinarily premature.” For starters, she says, lab mice are not even representative of the general human population that would be treated by these proposed preventative approaches: Most of the mice are male, whereas “depression is primarily a disorder that female humans have. We have a long way to go before we can claim that something ... is going to be a useful vaccine for preventing depression. I think that’s just really a stretch.”

A stretch in the immediate future, but a potential long-term change in the way scientists approach mental illness. At the very least, Brachman and Denny have closed a few of what Brachman calls the “glaring holes” in researchers’ understanding of mental health—the problems that have fascinated Brachman since Columbine, and that lead one in four American adults to experience mental illness each year.

For so long, the approach has been to “wait for someone to get PTSD or depression and you try to deal with it,” says Denny. But that seems limited compared to how we handle many other diseases. “We don’t wait for someone to develop polio and then give them a polio vaccine,” she adds. To approach stress-induced mental illness as something that can be prevented, she and Brachman believe, would be so much more effective.


* This article originally stated that Brachman was still in Columbia's doctoral program at the time of her article's publication, and that she worked in a lab run by Denny. She and Denny both worked in a lab run by another neurobiologist, René Hen. We regret the error.