April 18, 2023 | Post-traumatic stress disorder (PTSD) is difficult to diagnose under the best of conditions, including knowing the triggering issues and how an individual responds to stressful events. For the mostly young and “macho” men in the military who are exposed to combat and separated from their families for many months at a stretch the obstacles—and stakes—are even higher, according to Marti Jett, Ph.D., chief scientist for systems biology for the U.S. Army.
Identifying and properly treating PTSD is a matter of urgency, as is debunking the myth that admitting to having psychological issues comes at the cost of a promotion or military career, she says. Although having PTSD can feel stigmatizing, the condition can be debilitating and if left untreated the symptoms tend to get worse with time.
It is appropriate in the battlefield to have a startled response to loud sounds, but not in the city when a car happens to backfire, Jett points out. Other early-warning signs that a soldier is struggling with PTSD include uncontrolled anger, severe anxiety, and nightmares.
The diagnostic criteria, as spelled out in a chapter of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), is quite strict for PTSD, says Jett. One of the most definitive tools, called CAPS (Clinician-Administered PTSD Scale), is a 30-item structured interview that can be used to diagnosis a person’s current PTSD status, lifetime diagnosis, and overall PTSD symptoms. So, a survey asking a series of 20 questions corresponding to the key symptoms of PTSD is more commonly used, which uses a 5-point Likert scale (0 = "Not at all" to 4 = "Extremely").
Unfortunately, soldiers tend to answer each question with an automatic no, she adds. It is one reason the Army is interested in the development of a simple and objective PTSD screening tool that could be used at military bases three months after soldiers have returned home—one of the most vulnerable times for development of the mental health condition.
Soldiers stay on base together for three months following their deployment, awaiting reassignment to new and different locales, Jett explains. This point of separation from the bonds of brotherhood is a traumatic time because it also coincides with waning excitement at home about their return from theater and upset about changing family dynamics and house rules.
Four potential blood biomarkers of combat-elicited PTSD were found in a prospective longitudinal cohort study conducted over the past decade by the Walter Reed Army Institute of Research in conjunction with the PTSD Systems Biology Consortium, a network of government and academic laboratories, Jett reports. Results were recently presented at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, by Walter Reed Army Institute of Research scientist Stacy-Ann Miller.
The challenge in diagnosing PTSD is that the symptoms are wide-ranging and overlap with other conditions, including depression and acute stress disorder, making it hard to pin down, says Miller. It has also become clear that PTSD is a multidimensional condition with different subtypes, not all of which respond the same to treatment.
Recruitment and Retention
The clinical lead on the PTSD study was Charles Marmar, M.D., Lucius Littauer Professor of Psychiatry at New York University Langone’s Grossman School of Medicine. As an academic, he was able to reassure soldiers that any information they provided to investigators wouldn’t be shared with the military, Jett says.
Participants were thanked with small food items and received modest compensation, as allowed under guidance by the Food and Drug Administration (FDA), she adds. Nearly 1,800 soldiers signed up for the study, which was conducted over three, one-week periods at Fort Campbell.
Typically, between 125 and 150 individuals were evaluated per day—once 10 months before their deployment to Afghanistan, three days after their return, and again three to six months later—excepting those who returned earlier or later than the rest of their detachment, explains Jett. The clinical evaluation alone, which required 13 tubes of blood, took between 60 and 90 minutes.
The tubes variably held between a few microliters to 2 milliliters of blood, she continues, and were addressing specific analytes. A total of 3,000 blood draws were collectively performed on participants, leaving researchers with longitudinal data on about 1,000 people. Study results are expected to be published no sooner than the end of 2023.
Nearly 500 soldiers continue to participate in the study to this day and more likely would if recontacted, Miller notes. Funding limitations preclude that sort of outreach.
As presented at Discover BMB last month, the latest PTSD study succeeded in identifying four biomarkers of the condition out of 1,516 candidate metabolites: glycolytic ratio (a measure of how the body breaks down sugar to produce energy), arginine (an amino acid that plays a role in the immune and cardiovascular systems), serotonin (a chemical messenger that helps regulate mood, sleep and other functions), and glutamate (a chemical messenger that plays a role in learning and memory). These were all previously linked to stress, depression, anxiety, and mental health, says Miller.
Participants were classified as having PTSD, sub-threshold PTSD, or no PTSD, depending on their clinical diagnosis and symptoms, she explains. They were also classified according to their resilience to PTSD. The biomarkers were then compared among these groups.
As a reflection of miliary demographics, study participants were more than 95% male, says Miller. Investigators were therefore unable to conduct a subgroup analysis to detect any sex-specific patterns.
Based on the DSM-5 checklist of symptoms, PTSD was indicated when the cutoff score was between 31 and 33, and sub-threshold PTSD if the score was between 15 and 30, Miller says. For people who had scores below 15, researchers conducted a battery of other tests—e.g., Deployment Risk and Resiliency Inventory, Generalized Anxiety Disorder-7 assessment, Patient Health Questionnaire-9, Pittsburgh Sleep Quality Index, and presence of moderate-to-severe traumatic brain injury and alcohol use disorder—and used the information to sort them into the low or high resilience category.
Results indicated that individuals with PTSD or sub-threshold PTSD had significantly higher glycolytic ratio and lower arginine than those with high resilience, and people with PTSD also had significantly lower serotonin and higher glutamate (clinically correlated to depressive and anxiety symptoms) than those with high resilience. Individuals placed in the low resilience group were the ones who tended to “switch over” from the no PTSD to the sub-threshold or PTSD category starting three months post-deployment, Miller notes.
Data emerging from the study will help determine the true prevalence of PTSD in the military, even when soldiers are trying to ignore their true feelings, she says. As seen in the study, people who claim to be fine have molecular indicators saying otherwise.
In addition to blood high-throughput metabolomics, the research team has at least two other molecular panels—one based on proteins and the other nucleic acids—which look promising, says Jett. Details about the protein biomarkers will be published soon in Cell Reports Medicine, and a study on identified epigenetic markers published over two years ago in Molecular Psychiatry (DOI: 10.1038/s41380-020-00966-2).
Commercial and third parties still need to validate findings to date, says Miller. Discussions around regulatory requirements of the FDA have been underway for the past 18 months. Walter Reed investigators intend to submit their go-forward plans to the FDA and abide by its recommendations.
“We have probably four different types of panels we could use and so we are trying to choose the most reasonable one,” says Jett, meaning “the one that uses devices already approved by the FDA.” On the other hand, “the technology has moved so dramatically forward that it would be a shame to ignore some of the new ways that we could use the information we have.”
The military is applying the knowledge gained through clinical research to not only identify people with PTSD but also understand the subtypes, and who might respond to a particular therapy, Jett adds, citing 2018 headlines about how prazosin failed clinical trials for the condition. “The issue was not that it’s ineffective; it is very effective but only for a certain group of people” (New England Journal of Medicine, DOI: 10.1056/NEJMoa1507598).
The principal investigator—Murray A. Raskind, M.D., director of mental illness research for the VA Puget Sound Health Care System—also has the clinical experience to know if a patient is likely to respond to the treatment, she says. Prazosin is still frequently prescribed through the VA for the treatment of PTSD-related nightmares.
Meanwhile, the Walter Reed Army Institute of Research team has another ongoing study looking at stellate ganglion block, another popular PTSD treatment that is likewise known to be variably effective in different patient populations, says Jett. “Some people respond right away and maybe need a second injection, some people do so-so, and then there are people who don’t respond at all.”
The hope here is that clinicians will eventually be able to better match patients to treatments based on their molecular responses, she says. Personalized medicine is particularly important in treating PTSD since the hit-or-miss approach can be profoundly discouraging to patients.
If PTSD sufferers go unnoticed and untreated long enough it may literally be too late to intervene. As has been known for years now (Journal of Nervous and Mental Disease, DOI: 10.1097/01.nmd.0000168263.89652.6b), PTSD is significantly associated with suicidal ideation or attempts.