The nightmarish experience of post-traumatic stress disorder (PTSD) may be as old as danger itself. Survivors of natural disaster, criminal and domestic violence, and combat or granted formal psychiatric designation only in 1980. PTSD continues to pose a formidable challenge to treatment. Guidelines are derived more often from expert opinion than from trial results and only two medications were FDA-approved as of late 2018.
Now, drawing on a “brain bank” as well as a massive study of veterans, researchers at the School of Medicine are mapping PTSD’s genetic and neurobiological underpinnings. Their efforts could help predict who is susceptible, point the way to better treatments, and perhaps teach people how to cultivate resilience.
The aim of these studies is to move from the art to the science of psychiatry, says John Krystal, MD ’84, HS ’88, the Robert L. McNeil, Jr. Professor of Translational Research, professor of psychiatry and of neuroscience, chair of the Psychiatry Department, and director of the Clinical Neuroscience Division of the VA National Center for PTSD. To date, most PTSD research has been psychological, not biological, so the field has some catching up to do.
“Almost everything that we’re doing is the first of its kind,” Krystal says.
These studies are not merely groundbreaking, they’re vast in scale. So far, some 600,000 veterans have contributed DNA to the nationwide Million Veteran Program (MVP). With this database—one of the world’s largest—researchers can detect subtle signals across thousands of genes.
Joel Gelernter, MD, the Foundations Fund Professor of Psychiatry, professor of genetics and of neuroscience, is co-leading a study of this population to uncover genetic alterations that show up more often among trauma-exposed vets with PTSD. These data could one day help estimate individuals’ risk of PTSD based on their genes, allowing the military to predict that when exposed to combat, person ‘A’ has, say, a 20 percent risk of developing PTSD while person ‘B’ has only a 5 percent risk.
“Should that affect the role that the person is placed in by the military? Is this something we should tell the person, so that he or she can make a decision about the kind of stresses he’s willing to be exposed to?” Gelernter asks. “Those are open questions, but they’re things we’ll be facing—if not in the next year, in the next five years.” Further, he says, “the genetic information will also aid us in understanding the factors that underlie PTSD on the one hand and resilience on the other.”
In 1995, then-faculty member Douglas Bremner, MD, used MRI to discover the first evidence of changes in brain structure in PTSD—a shrunken hippocampus in a group of Vietnam War veterans diagnosed with the disorder. The hippocampus, one of several brain regions involved in PTSD, helps researchers interpret loci in the brain as vulnerable trauma or not.
Thanks to a brain-tissue repository, or “brain bank” of PTSD patients, researchers can now explore the differences between brains from people with PTSD and those without. The National PTSD Brain Bank is housed within the National Center for PTSD (NCPTSD) and the Boston VA Medical Center. The clinical neuroscience division of NCPTSD is based at the VA Connecticut Healthcare System and the Yale School of Medicine; it serves as the primary research laboratory for the National PTSD Brain Bank.
Instead of studying genetic alterations like Gelernter and his colleagues, Ronald Duman, PhD, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of neuroscience, is examining the activity of thousands of genes by measuring the mRNA transcripts and proteins those genes express in hotspot brain regions.
By comparing differences in gene expression in the brains of patients who were diagnosed during their lives from PTSD, those who had major depression, and those who did not receive a psychiatric diagnosis, researchers hope to illuminate where PTSD overlaps with other psychiatric disorders. They also hope to delineate subtypes that might respond differently to treatments.
With the RNA from tissue samples in each of five regions of 200 brains under study, Duman estimates that the project is amassing 50 million data points about the expression levels of 15,000 genes for each brain region of each subject. To analyze this massive amount of data, he is collaborating with the bioinformatics group in the laboratory of Hongyu Zhao, PhD, chair and Ira V. Hiscock Professor of Biostatistics, professor of genetics, and of statistics and data science. The project will gradually untangle networks of genes whose expression is altered in concert with PTSD, as well as identifying so-called hub genes that play an outsized role.
“If we understood the gene networks and biochemical changes that are critical for PTSD pathophysiology, then we could start to think about treatments that would actually target these networks and hub genes,” Duman says.
Given how few PTSD medications we currently have, new ones would be no small advance. But as we map the disorder’s genetic and protein correlates, we’re likely to learn more about the origins of resilience, too. In its way, resilience is as big a mystery as the frightening symptoms of PTSD. Why do some people manage to weather terrible traumas and return to a healthy baseline?
“Some of the factors that are going to be implicated in the risk and the vulnerability to PTSD aren’t just going to be things that help people be less anxious. They’re also going to be things that help people to cope and adapt and recover quickly,” Krystal says. “What we find in relation to the genetics of PTSD is likely to have implications not only to PTSD, but ... [for] how people face life challenges and grow from these experiences.”
That too should inform PTSD treatment. When successful, Krystal says, treatment pulls the patient away from rigid thinking—what some people call the “black hole” of trauma or depression—giving him or her the “capacity to approach the world in a much more adaptive and flexible way … learning to see the world as both dangerous and safe.”
“PTSD,” he adds, “has a lot to do with the capacity to bounce back.”