By Paul Nicolaus
June 19, 2019 | New findings could lead to a blood test that is able to help diagnose post-traumatic stress disorder (PTSD) with greater accuracy. The biomarker gene expression signatures identified could also be a gateway toward more precise prevention and treatment measures, researchers say.
The disorder can occur following shocking or dangerous events, such as car accidents, natural disasters, military combat, or sexual assault. Exposure to trauma isn't necessarily a rarity, either.
Over half of adults experience at least one trauma in their lives, according to the National Center for PTSD, and (based on the U.S. population) roughly 7-8% will develop the condition at some point.
The notion that most people who experience a trauma do not wind up developing PTSD is highly misunderstood in the general public and even among physicians, explained Larry Amsel, an assistant professor of clinical psychiatry at Columbia University, a research psychiatrist at the New York State Psychiatric Institute, and an attending psychiatrist at New York Presbyterian Hospital.
PTSD-like symptoms, such as nightmares, are a common response to trauma and can last for weeks or even a month or two, but they tend to go away. PTSD is not an illness of having those symptoms. PTSD occurs, rather, when those symptoms do not go away. "It's a failure of getting back to your baseline after a trauma," Amsel told Diagnostics World.
Because undiagnosed stress disorders can lead to poor sleep, anxiety, anger, violence, and even suicide, proper assessment and early diagnosis are essential. It can be difficult to diagnose, however, because no two people respond to the same situation in the same way, explained Teresa McMahon, vice president of clinical operations at Vantage Health System.
"In psychiatry currently, we have to rely on what the patients are telling us and on our clinical impression in order to make a diagnosis," Alexander Niculescu told Diagnostics World, "and that's not an ideal way of doing things." The Indiana University professor of psychiatry and medical neuroscience and his colleagues are making progress, however.
A study published in Molecular Psychiatry (doi: 10.1038/s41380-019-0370-z) followed over 250 veterans at the VA Medical Center in Indianapolis to pinpoint molecules that can help track stress intensity. The researchers, led by Niculescu, tested participants in low- and high-stress states and analyzed blood samples for changes in expression of genes that could serve as biomarkers for stress.
They were able to narrow the focus down to 285 individual biomarkers that can help diagnose people with PTSD, determine the severity of stress, and predict future hospitalizations.
As part of the study, which was supported by an NIH Director's New Innovator Award and a VA Merit Award, the researchers used a step based on the convergent functional genomics approach that Niculescu's group has developed over the last two decades. It takes a list of candidate genes or biomarkers and uses convergent evidence from other studies as a way of prioritizing the findings that are most relevant and reproducible.
"In essence, we leverage our data with all the other data that’s been published in the field," Niculescu said, as a way of ensuring that the markers carried forth into validation and testing have reproducibility in other data sets and have relevance to the disorder.
Because the other studies used for this convergent approach were carried out in civilian populations and animal model studies, the researchers believe that the markers found, prioritized, and validated are "broadly relevant" beyond just military veterans and "applicable to stress paradigms across different populations."
A Step in the Right Direction
It's a methodologically complex paper, according to David Spiegel, professor and associate chair of psychiatry & behavioral sciences and director of the Center on Stress and Health at Stanford University School of Medicine, but the idea is basically this: "classical genetics of disease have involved gene structure but not so much gene function."
There are some cases where that's enough, like Huntington's disease, where a defect in one gene will cause a person to have this disorder later in life. The gene is so damaged that when it needs to work, it can't, and one gene is enough to cause a major disease. It has been a much more complex picture with psychiatric disorders, on the other hand, where a number of genes seem to be involved.
"Stress is a more complex and interesting situation because it's an intersection of gene and environment," Spiegel told Diagnostics World, whereas the environment doesn't matter very much with a disease like Huntington's. "You get it, or you don't."
What's different, he added, is the developing field of epigenetics. "It's fine if you have these genes or you don't, but if they don't get expressed and used, they may not have any effect even if there is a defect." What the researchers are looking at in this paper is gene expression—not gene structure. Rather than looking for mutations, they're looking for the likelihood that stress affects the expression of certain genes, which can, in turn, lead to adverse outcomes.
"They were methodologically complex but rigorous in first identifying gene expression patterns that seem to differentiate people high and low in stress, and then see whether they predicted poor outcomes to stress, like psychiatric hospitalization," Spiegel explained.
There have been previous attempts to identify specific genes associated with PTSD risk or PTSD symptoms that are associated with known systems related to trauma, and "cortisol would be the classic example," Spiegel said. The researchers noted that they "have a positive control with an FKBP5, which is a co-chaperone for cortisol that affects receptor sensitivity and had been associated with vulnerability to PTSD. So they found that gene but a bunch of others as well."
Whereas previous studies have been more hypothesis-driven about particular genes that are thought to be related to the functioning of known stress response pathways, like cortisol, "this one is more bottom up," he said, where the researchers are attempting to determine which genes are overexpressed in people who have high stress or who have poor response to stress.
One intriguing aspect is that the researchers noted the discovery of some genes nobody thought of before, Spiegel said, "but they've also discovered bad genes like FKBP5 show up in their method, too, making it more likely that they're finding things that are, indeed, salient to stress response."
Do the biomarkers identified in this research have the potential to lead to more accurate diagnosis of PTSD? In theory, yes, said Spiegel. There is potential to confirm subjective reports of being stressed, he explained, and there is also potential to predict vulnerability to adverse outcomes of stress. A high expression of some of these genes could be a predictor of risk.
"So it's a good step in the right direction," he added, but "there need to be more confirmatory studies documenting that they've identified genes that are, in fact, strong predictors of stress."
He also noted that because the researchers are identifying genes within a group of highly stressed individuals, this is not yet at a point where it would be useful for population screening.
Bringing Precision Medicine to Psychiatry
The recently published study, which included Indiana University and VA researchers as well as collaborators at The Scripps Research Institute and the University of California Irvine, is part of a series of studies conducted over the last decade, which includes research on suicide and pain.
"We are developing genomic tools to more objectively assess psychiatric disorders, to predict the risk of future worsening, to match people with the correct medications, to monitor response to treatment, and last but not least to identify new drug targets and repurpose drugs for psychiatric indications," Niculescu said.
His group hopes the tests developed at the Indiana University School of Medicine can eventually be implemented in clinical settings. (He is listed on a patent application filed by Indiana University and is a co-founder of MindX Sciences, a start-up that has licensed the technology for future development.)
The goal, according to Niculescu, is to turn the field of psychiatry into a 21st-century medical specialty that uses objective assessments and blood tests as a way of practicing a more precise way of delivering clinical care.
"To me, biomarkers are the bread and butter of all of medicine," said Amsel, and psychiatry has been looking for a biomarker that can serve as an objective measure to support a diagnosis.
Laboratory tests and objective measures, whether it's imaging or blood tests, have supplanted, to a large extent, the 19th-century doctor who focused on medical history and physical exam. "Psychiatry has to this day not gotten there," he explained, because there isn't the same sort of physiological knowledge in place as there is in regards to, say, the kidney.
"Kidney physiology is a fascinating thing," he continued. "It's like this amazing piece of engineering." It can sort out tiny harmful molecules from the blood while leaving all the good molecules in, and it can pull out the right amount of water to maintain balance. "It's an amazing organ. But it's all physics, and it's all understandable in terms of physics."
"So I can tell you exactly how a kidney produces urine, but I cannot tell you how the brain produces a thought," he added, "because it's the most complicated of all the organs."
There are brain imaging and genetic studies that are starting to sort out PTSD, he added, but generally speaking, this research hasn't led to definitive findings just yet. Picturing the potential is intriguing, though, and there's no one more interested in this realm of research than the military community, Amsel pointed out.
Imagine giving soldiers a blood test to determine who would get PTSD following combat. "The army would love to have that," he said, because it would allow them to "sort through those people who are going to be sick their whole lives versus those people who can handle a combat situation, come home, and have a good life."
"One of the things that's very important from a public health perspective, from a medical perspective, from an army perspective, is being able to identify those people who will be susceptible to a trauma," Amsel added. That would be an interesting marker in addition to a marker for those who have PTSD.
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.