Each year, more than five million Americans suffer with post-traumatic stress disorder, or PTSD. Following terrible experiences — like rape, combat or disaster — PTSD can result in flashbacks, panic attacks and many other symptoms.
But many trauma victims don't develop PTSD and doctors don't have a biological test that they can rely on to diagnose who has the disorder — or to predict who is likely to get it.
Now, a team of researchers from the Emory University School of Medicine and the University of Vermont (UVM) have found that, in women, abnormal blood levels of a hormone called PACAP, produced in response to stress, are strongly linked to post-traumatic stress disorder.
Their study holds promise for developing blood and genetic tests that can identify those who have PTSD — "and this starts to give us tools to predict whether a patient is going to be susceptible to PTSD," says the University of Vermont's Victor May, a professor in the Department of Anatomy and Neurobiology, who helped lead the study.
The work might also eventually aid in developing treatments for the disorder and other anxiety diseases.
The results wered published in the February 24 issue of the journal Nature.
A PTSD biomarker
The hormone, called PACAP (pituitary adenylate cyclase-activating polypeptide), is known to act throughout the body of many animals, modulating central nervous system activity, metabolism, blood pressure, pain sensitivity and immune function. But the role of PACAP in the neurobiology of human fear and anxiety is little understood.
The new research shows that women, but not men, with high blood levels of PACAP display more of the symptoms of PTSD, such as difficulty discriminating between fear and safety signals and being easier to startle. In one group of people studied, most of whom had experienced significant trauma, women with above-average PACAP levels had PTSD symptom scores five times those of women with less-than-average PACAP levels.
"Few biological markers have been available for PTSD or for psychiatric diseases in general," says Kerry Ressler, associate professor of psychiatry and behavioral sciences at Emory University School of Medicine, and the first author on the paper. "These results give us a new window into the biology of PTSD."
A difference between women and men
This new study is also helping unravel the sex-specific differences in fear physiology. The researchers found that changes in PACAP are better correlated with PTSD in females than males; this is notable since females are at twice the risk for PTSD compared to men.
The researchers found that the PACAP system within stress-related portions of the brain appears to be regulated by both fear and the female sex hormone estrogen.
Which helps reveal the importance of another of the team's findings: they discovered a variation in the gene for the PACAP receptor that alters the gene's responsiveness to estrogen. This gene variation may explain why elevated PACAP is linked to PTSD risk in women only.
Ressler notes that despite comparable levels of trauma, women in the study with the more protective PACAP receptor gene variation have lower rates of PTSD than men, whereas those with the risk gene variation had higher rates of PTSD than men.
"What this says is that men and women who have been traumatized may arrive at PTSD by different biological pathways," he says.
PTSD prevention
And this study begins to point toward clinically useful information. "It may be possible to identify those people who may be susceptible to PTSD following traumatic stress experiences," says UVM's Victor May.
And the ability to forecast who is more likely to develop the disorder gives people and their physicians a better chance of avoiding it.
"For example, for people in severe high stress occupations or environments, as in the military services, we may be able to determine individuals who may be more prone for PTSD," May says, "and in averting or restricting their exposure, we may be able to avoid subsequent PTSD development."
Other applications of the new research, May says, could include better diagnosis of anxiety disorders versus other psychiatric illness, distinguishing head-injury symptoms from anxiety-induced ones, and faster response to patients with PTSD risk.
Research serendipity
The findings emerged from the Grady Trauma Project, a study of more than 1200 low-income Atlanta residents with high levels of exposure to violence and physical and sexual abuse, resulting in high rates of civilian PTSD. Beginning in 2005, interviewers asked patients in primary care, ob-gyn, and other clinic waiting areas of Grady Memorial Hospital in Atlanta to complete questionnaires on their life histories and to provide a saliva and blood sample for DNA and other analyses.
Ressler, a Howard Hughes Medical Institute Investigator who maintains a lab at Yerkes National Primate Research Center, is co-director of the Grady Trauma Project.
To explore how the PACAP pathway responds to stress and hormones, Ressler and colleagues from these institutions teamed up with researchers at the University of Vermont, who had been studying PACAP in animals.
Previous experiments by UVM's Jom Hammack, assistant professor of psychology, and Victor May, in the College of Medicine, showed that in rats experiencing stress, PACAP is increased ten-fold in a part of the brain called the BNST (bed nucleus of the stria terminalis), which scientists have shown is critical for anxiety behavior.
"But one of the lingering questions we had was: what if PACAP is important for anxiety-like behavior in rats and not in humans?" says May. And, like often happens in science, serendipity provided a way forward.
"It just happened that we were presenting a poster at the Society for Neuroscience meeting in Chicago," May says. "Jom Hammack was there to promote our poster and one of his good friends, Kerry Ressler, a psychiatrist—made a similar observation that PACAP appeared to be important in the work that he was doing related to fear in people."
"Three weeks later they had the blood shipped up here," May says, "Every vial had a code so I didn't know who the samples are from: the controls or PTSD, male or female." May took the samples and assayed them in his lab.
"I had all the numbers coming out of these assays—and since I couldn't decipher the code — all I could look at was assay numbers,"May recalls. "It was 10 in the morning. It was Friday. I had the spreadsheet. I pressed the button to send it over to Kerry and then I waited. At 3 in the afternoon, he sent me a note back: 'Eureka! It correlates with PTSD in females.'"
Following this study in Nature, Ressler says that it will be important to replicate the finding in separate population groups, including in veterans with PTSD. In addition, identifying when PACAP levels rise in the brain and blood during the development of PTSD will help determine whether drugs that act against PACAP could aid in treatment.
The UVM investigators' work on this study was supported in part with funding from the National Institutes of Health and UVM Neuroscience COBRE from the National Center for Research Resources.
More information
More about the Grady Trauma Project is available here: http://www.gradytraumaproject.com/index.html
An article about related research by Victor May and Jom Hammack at the University of Vermont is available here: http://www.uvm.edu/~uvmpr/?Page=News&storyID=17257
The research was supported by the National Institutes of Health, the American Foundation for Suicide Prevention and the Burroughs Wellcome Fund.