fear

A Common Drug Could Take the Sting Out of Trauma

Scientists are puzzling out a promising new approach to PTSD.

Crystal Ponti

Image: David McNew / Getty

"I want to jump out of planes, shoot guns, and blow things up," Sgt. Casey Leimbach told his military recruiter right before his senior year of high school. It was an innocent declaration, and one that would turn into a reality with surprising speed. Leimbach enlisted immediately after graduation and served nine years in the 17th Infantry and 501 st Airborne, including two tours of Afghanistan. He recalls unpredictability; nights of grueling patrols, days without sleep, and the untimely passing of fellow soldiers he considered brothers. There was no average day in the face of the enemy. When offered an early retirement, eleven years short of the twenty-year mark, he accepted. He had seen enough, and needed a change.

Transitioning from active duty to civilian life can be tricky for combat veterans. For Leimbach, it meant leaving a familiar role, one he had poured his heart and soul into, for a life that seemed out of touch with all he had experienced—moments that replayed over and over again in his mind.

"When I got out, I really struggled that first year," Leimbach says. "I kind of fell into this rut that I think a lot of combat veterans, especially those who have seen some heavy action, find themselves in. I was depressed. I was angry."

An estimated 8 percent of Americans, roughly 24.4 million people, struggle with post-traumatic stress disorder (PTSD) at any given time, including 1 in 3 troops returning home. Leimbach would receive an official diagnosis, but not before falling into a perpetual cycle of denial and self-destruction. PTSD threatened to consume his life.

Psychotherapy (such as cognitive-behavioral therapy, or CBT), medications, or both are currently the main forms of treatment for PTSD. Unfortunately, a treatment that works for one person might not work for another, and many people complain that despite treatment, their symptoms persist. Given the intensity and ubiquity if this condition, it's imperative that the medical field find a more effective means of treating PTSD, and those at risk of developing it—soldiers like Leimbach and many others.

Findings from a recent study, conducted at NYU Langone Medical Center in collaboration with Harvard and Emory Universities and other organizations, offer new promise. This new research suggests that the manipulation of a specific gene could prevent the onset of PTSD in trauma victims. The gene, known as FKBP5 (FK506 binding protein 5), is the same one responsible for trauma-related memory formation.

"Most people have been exposed to a life-threatening event at some point, but roughly 10 percent will go on to receive a diagnosis like PTSD," says Isaac Galatzer-Levy, the lead investigator on the study and an assistant professor in the Department of Psychiatry at NYU Langone and its Steven and Alexandra Cohen Veterans Center. A major focus of Galatzer-Levy's research: the factors that play a role in why people respond differently to traumatic events, such as combat, physical and sexual assault, and car accidents. Most people are resilient and recover quickly, he explains, while others continue to struggle years after an event has taken place. For those who cannot shake off the emotional response, they keep on responding as if they're in danger. This is what he calls "a failure to extinguish."

PTSD is characterized by a number of symptoms—intrusive thoughts, nightmares, hyperarousal, among others—that involve having strong responses to subtle cues from your environment. In his earlier work with combat veterans, Galatzer-Levy describes one solider being triggered by garbage along the highway. "His job in Iraq was to drive a Humvee around looking for enemy combatants and scanning every piece of garbage along the road… a place where improvised explosive devices were often hidden. So now every piece of garbage along the road is a potential threat cue, even after he returns home, and causes this intense physiological response."

To better understand these biological processes, Galatzer-Levy and his team analyzed preexisting data from two studies on fear conditioning, a simple behavioral paradigm in which humans and animals learn to predict aversive events from environmental cues, and fear extinction, a decline in fear response to the same cues after being exposed to them in a nonthreatening manner. One study was conducted on animals and the other included 724 human subjects.

Three fear responses were seen in both the animals and human subjects: 1) resilient/quick to extinguish (signs of fear or stress were gone immediately or quickly), 2) slow to extinguish (signs of fear or stress lingered, but eventually the subject showed no signs of fear or stress), and 3) failure to extinguish (signs of fear or stress persisted indefinitely). In humans, Galatzer-Levy discovered that there were different versions of the FKBP5 gene—the gene that helps form memories around traumatic events. The humans who were unable to extinguish and continued to have a startled response to stimuli had a version of the FKBP5 gene that seemed to be causing the fear response to persist.

When we're stressed, a class of compounds known as glucocorticoids are released to help the body cope with the increased physical and mental demands. Cortisol, the most well-known glucocorticoid, plays a vital function. Cortisol travels through the body to the brain regions that are involved in an initial response to a threat or danger. It also connects to important regions that help form new memories about that event. The FKBP5 gene determines whether this process is completed—cortisol binding in the brain functions differently if there is a variance in that gene. When the process doesn't complete itself, people's ability to calm down in the face of a trigger—their fear-extinction mechanism—is compromised.

In the animal study, mice were given a high dose of a drug called dexamethasone, an inexpensive, common oral steroid, which appeared to break the blood-brain barrier, alter the expression of the FKBP5 variant, and allow fear to rapidly extinguish. "That has a lot of promise, because it indicates that we may be able to intervene with people in really a critical window to alter their trajectory of response to a potentially traumatic event… before new memories about that event form," Galatzer-Levy says.

For chronic sufferers of PTSD, administering dexamethasone in conjunction with exposure therapy—triggering the traumatic event in a safe environment so that a critical window of possible intervention is reopened—appears promising. This was not part of the current study, and more research is required.

"Overall, these studies suggest that particular deficits in glucocorticoid signaling in the face of stress may impair resilience to stress," says John Krystal, a professor of neuroscience and chair of the Yale department of psychiatry who was not involved in the research. "In these cases, as suggested by Galatzer-Levy and colleagues, administration of drugs that impact glucocorticoid levels may enhance resilience, perhaps in part by promoting fear extinction."

Some experts caution that blocking the formation of fearful memories is not the same thing as preventing PTSD. "Our bodies probably encode traumatic memories following trauma exposure for good reason. What we want to help people with is how not to be negatively controlled by their traumatic memories," says Rachel Yehuda, a professor of psychiatry and neuroscience and the director of the Traumatic Stress Studies Division at the Mount Sinai School of Medicine.

Galatzer-Levy acknowledges this concern, but is quick to point out that fear extinction is something we do all the time, which in turn affects gene expression. "When you're preparing yourself for danger or a stressful situation, you might rehearse or talk to other people, or even take a drug," he says. "You might take a beta blocker, for instance, because you have anxiety about giving a speech or going for a job interview. What are you doing when you take that drug? You're dampening the initial autonomic response and, on some level, you're manipulating the expression of genes involved in the processes."

His team is now conducting a clinical trial at Bellevue Hospital's emergency room in New York City, where they're offering mugging and accident victims a single oral dosage of dexamethasone, consistent with the dose that worked in animals, to see if it successfully prevents the development of PTSD. The team is also performing additional investigative studies in human populations. "You have this sensitive period when memories are forming and the brain is changing in response to stress, and what we're trying to do is give people a gentle push in one direction," Galatzer-Levy says.

After attending two weeks of intensive cognitive-behavioral therapy for PTSD in Washington state, Leimbach felt something click. "I went home and, although I wouldn't say I felt free of it, I had this understanding that the biggest player in this wasn't going to be therapy. It was going to be me," he says. He knows there will be terrible days, especially anniversaries of events that happened overseas, but refuses to quit.

"Don't suck it up because you think there's people out there who have it worse than you. Go talk to somebody," he says. "To get stuck in the mindset that you'll be fine is really not an acceptable excuse to not go get help."