Up to 20% of the population exposed to a horror of a war, trauma or abuse may go on to develop post-traumatic stress disorder. PTSD, as it is better known, is a debilitating psychiatric disorder marked by flashbacks and nightmares. Till date the biological basis for PTSD was 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.
The team led by Dr. Kerry Ressler, associate professor at Howard Hughes Medical Institute (HHMI) from Emory University in Atlanta, looked at a group of 64 highly traumatized civilians (not veterans) treated at Atlanta’s Grady Memorial Hospital, some of whom developed PTSD. Ressler said, “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.”
The team, based the study on earlier evidence that the hormone-like molecule known as PACAP was important in the brain’s response to stress. They 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. Kessler said, “When we started we didn’t have any expectation that there was going to have a gender specificity to it… 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.”
Thereafter they repeated the experiment in a group of 74 traumatized women. Again, PACAP levels correlated with PTSD symptoms. These women all suffered form intrusive flashbacks, avoidance of trauma reminders and increased startle response. Ressler and his colleagues wrote in their report, published today in Nature, “These data may begin to explain sex-specific differences in PTSD diagnosis, symptoms and fear physiology.”
Earlier findings have shown that women 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, it pointed to a novel biological pathway underlying the brain’s response to fear.
Thereafter the team 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. This part of the gene responds to estrogen. The finding was replicated in an additional 439 subjects, and was not observed in men.
Dr. Steven Hamilton, associate professor of psychiatry and Carol Cochran Schaffner Endowed Chair in Mental Health at the University of California, San Francisco said, “Studies in diseases like panic disorder have previously shown that the genetic influences may differ by gender… 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,” This means that people are not necessarily born susceptible to PTSD but can acquire the vulnerability over time. The finding supports the idea that environmental and genetic all contribute to PTSD risk.
The next step by the team was to conduct the genetic study on mice. They 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.
Ressler said, “We hope some of these biomarkers may actually be predictive of who is at risk for PTSD.” He hopes that his research translates into new, more effective treatments or preventions that target specific fear pathways in the brain. Ressler said, “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 plans to study the genetics of 14,000 traumatized civilians, which will be the largest genomic study of PTSD to date.
Dr. Murray Stein, a professor of psychiatry and family and preventive medicine at the University of California, San Diego, in an accompanying editorial wrote that PTSD risk profile that “takes into account psychosocial and biological factors, much like those available for predicting the risk of coronary heart disease.” He wrote, “Even if PACAP is not it, this proof of principle study shows that developing a reliable biomarker for PTSD is not a pipe dream.”
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