Although most people exposed to the horrors of war, trauma or abuse recover emotionally, up to 20 percent develop post-traumatic stress disorder -- a debilitating psychiatric disorder marked by flashbacks and nightmares.
The biological basis for PTSD remains unclear. But a new study offers clues about why some people rebound from horrific events while others relive them, and may lead to predictive tests and even treatments.
To tease out factors that contribute to PTSD risk and resilience, researchers led by Dr. Kerry Ressler, associate professor at Emory University in Atlanta, studied a group of 64 highly traumatized civilians (not veterans) treated at Atlanta's Grady Memorial Hospital, some of whom developed PTSD.
"In a lot of very impoverished, high-violence neighborhoods, we see high rates of trauma, and rates of PTSD can be as high as in veterans," Ressler said.
Based on previous evidence that the hormone-like molecule known as PACAP was important in the brain's response to stress, the researchers measured PACAP levels in the blood of their subjects. To their surprise, PACAP levels were higher in people with PTSD, and correlated with the severity of symptoms. But the boost was only significant in women.
"When we started we didn't have any expectation that there was going to have a gender specificity to it," Kessler said. "We were just looking and found a smaller effect, and then we split it by gender and found that the whole effect was in females."
The team repeated the experiment in a group of 74 traumatized women. Again, PACAP levels correlated with PTSD symptoms -- especially those considered essential for a diagnosis of PTSD: intrusive flashbacks, avoidance of trauma reminders and increased startle response.
"These data may begin to explain sex-specific differences in PTSD diagnosis, symptoms and fear physiology," Ressler and his colleagues wrote in their report, published today in Nature.
Women are known to have a higher risk of a range of anxiety disorders. But the finding of elevated PACAP in women with PTSD did more than offer a biological explanation for the gender difference; it pointed to a novel biological pathway underlying the brain's response to fear.
To better understand the relationship between PACAP and fear, Ressler and his colleagues studied the genes encoding PACAP and its receptor, PAC1. In addition to having elevated blood levels of PACAP, women with PTSD were more likely to have a variation in the PAC1 gene -- a particular part of the gene that responds to estrogen. The finding was replicated in an additional 439 subjects, and was not observed in men.
"Studies in diseases like panic disorder have previously shown that the genetic influences may differ by gender," said Dr. Steven Hamilton, associate professor of psychiatry and Carol Cochran Schaffner Endowed Chair in Mental Health at the University of California, San Francisco. "It is interesting to see that this seems to be the case for PTSD as well."
In both men and women with PTSD, the PAC1 gene was more likely to be modified by a process call "methylation," meaning people are not necessarily born susceptible to PTSD but can acquire the vulnerability over time. The finding supports the idea that environmental, genetic and so-called epigenetic factors all contribute to PTSD risk.
To confirm their discovery, Ressler and his colleagues studied PACAP signaling in mice trained to fear a particular sound. This so-called fear conditioning led to genetic changes, including a 1.5-fold boost in PACAP receptor expression, in regions of the brain involved in fear. Estrogen had a similar effect, according to studies done in rats.
Anyone can get PTSD -- including war veterans and survivors of assault, abuse, accidents and disasters. More than 10 percent of U.S. Army soldiers return from deployment with PTSD or major depression, according to a 2010 study published in the Archives of General Psychiatry. Some people can suffer from PTSD after the trauma or death of a loved one, even if they were not directly involved in the event.
"We hope some of these biomarkers may actually be predictive of who is at risk for PTSD," Ressler said.
Although psychotherapy and certain medications work for some, many people with PTSD develop chronic panic disorder, depression and even suicidal tendencies. Ressler hopes his research translates into new, more effective treatments or preventions that target specific fear pathways in the brain. But whether the PACAP pathway holds therapeutic promise needs to be confirmed in larger samples and in different types of trauma.
"At the early stages of a discovery there's always excitement but also apprehension as one waits for it to be replicated by others," Ressler said.
In an accompanying editorial, Dr. Murray Stein, a professor of psychiatry and family and preventive medicine at the University of California, San Diego, suggested the possibility of a PTSD risk profile that "takes into account psychosocial and biological factors, much like those available for predicting the risk of coronary heart disease."
"Even if PACAP is not it, this proof of principle study shows that developing a reliable biomarker for PTSD is not a pipe dream," Stein wrote.