VA Researchers Find Sex-Based Differences in Disorder
By Annette M. Boyle
SAN FRANCISCO — Why are women so much more likely than men to develop post-traumatic stress disorder? The answer could be differences in the way men and women develop fear responses, according to VA researchers.
“Women with PTSD had greater fear-conditioning responses than did men with PTSD,” said Sabra Inslicht, PTSD, staff psychologist at the San Francisco VAMC (SFVAMC) and lead author of the study published in the Journal of Psychiatric Research. “This suggests that there may be differences in how men and women learn to fear.” 1
“In the general population, women are twice as likely as men to develop post-traumatic stress disorder,” added Sonja Batten, PhD, deputy chief consultant for specialty mental health at the VA.
Understanding how fear and arousal come to be associated with neutral environmental cues — i.e., fear conditioning — is central to treating PTSD, because researchers are finding that abnormal acquisition of conditioned fear may lead to development of the condition.
Up to 20% of veterans of the wars in Iraq and Afghanistan, 10% of Gulf War veterans and 30% of Vietnam veterans have developed PTSD, according to DoD statistics. As the number of women serving in the military rise, understanding the differences in developing and treating PTSD between men and women becomes increasingly important.
“Traditionally, studies on PTSD looked primarily at men or didn’t compare men vs. women, so our work aims to refine the basic science and inform treatment. If there are differences in fear conditioning or fear extinction, they may affect treatment,” Inslicht told U.S. Medicine.
The study included 18 men and 13 women, ages 18 to 65 and who had full or subsyndromal PTSD. Participants viewed computer-generated colored circles that were associated or not associated with a “highly annoying, but not painful” electrical stimulus. To control for differences in pain sensitivity, participants set their own level of stimulus. Researchers from the SFVAMC and the Northern California Institute for Research and Education measured skin conductance levels throughout the test to assess reactivity.
Women with PTSD were about 40% (0.71 compared with 0.51) more reactive than men to cues signaling threat. There were no differences in the response of men and women to cues for safety. Men diagnosed with PTSD had higher baseline skin conductance levels and greater response to novel cues during the conditioning phase.
These results suggest women with PTSD are more likely to develop a strong fear response and more likely to have stronger responses to associated stimuli once they are conditioned to respond fearfully. Previous studies have proposed that women have higher levels of perceived threat in general that make them more susceptible to PTSD, but this study indicates that men with PTSD have a greater level of general fear/arousal at baseline and during habituation.
“The heightened conditionability observed in this sample of women with PTSD stands in contrast to the sex differences in fear acquisition that has been found in some studies of healthy, non-trauma exposed humans in which females tend to either not differ from males or exhibit lower conditioned responding. One possible explanation for this difference is that greater fear conditioning in women could be a marker of vulnerability that is specific to those exposed to trauma who develop PTSD,” the authors wrote.
The researchers did not examine possible explanations for the gender differences identified in this study, but they did note that other research provides some insight and promising areas for future research.
“Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD,” the author pointed out.
Greater fear conditioning in women with PTSD could be attributable to “differences in brain structures in regions implicated in fear conditioning and fear extinctions between men and women,” Inslicht said.
Estrogen, which acts on multiple learning, fear conditioning, and other systems, may play a role, according to Inslicht.
“We did not look at stress or gender-specific hormones in our study. It is important to identify what, if any, role they have in fear conditioning and fear extinction,” she noted. Inslicht and her colleagues will be conducting additional research on the effect of hormones. She has previously published work showing an association between cortisol levels and vulnerability to stressful events.
Other hormones also might contribute to differences in fear conditioning between men and women. The authors suggest that pituitary adenylate cyclase-activating polypeptide (PACAP), in particular, might be a factor in greater fear conditioning in women with PTSD. PACAP modulates stress circuits in the brain and is moderated by estrogen. Other researchers have noted an association between higher PACAP levels and greater fear conditioning in traumatized women, but not men.
Or, the greater fear conditioning seen in women with PTSD compared to non-traumatized women might be a result of the trauma exposure rather than pre-existing vulnerability.
“We did not have a PTSD-free group in our study or a before/after comparison,” said Inslicht, so “we don’t know if the greater fear conditioning is in response to trauma or existed before.”
“The next important step is to look at fear learning and how people extinguish fear response,” added Inslicht. “How do they recover from fear conditioning over time? Are there gender differences there? How they extinguish fear will be key to recovery and treatment development.”
As a follow to this research, Inslicht is now investigating the effects of various pharmacological agents in fear extinction.
“There may be ways that we can enhance extinction learning — perhaps through medications or with other modifications to existing behavioral treatments,” she said.
- Inslicht SS, Metzler TJ, Garcia NM, Pineles SL, Milad MR, et al. “Sex differences in fear conditioning in posttraumatic stress disorder.” Journal of Psychiatric Research. 2013 (47): 64-71.