Researchers headed by a team at Indiana University School of Medicine have identified blood-based genetic markers of psychological stress that could help scientists develop improved, earlier diagnostics for post-traumatic stress disorder (PTSD) and other stress disorders, and offer up new leads for the development of drug or natural compound-based therapeutics. The 10-year study involving veterans visiting the Richard L. Roudebush VA Medical Center, identified hundreds of biomarkers that could potentially help to diagnose PTSD, as well as determine the severity of their stress and predict future hospitalizations. A number of the top candidates have previously been linked with psychiatric conditions.

“PTSD is a disorder that affects a lot of veterans, especially those involved in combat,” commented psychiatry professor Alexander Niculescu, MD, PhD, at the Indiana University School of Medicine. “They deserve our gratitude and the very best care, and we are making every effort to deliver that. It’s also an underappreciated and underdiagnosed disorder among the civilian population, whether it be the result of abuse, rape, violence, or accidents. Countless people are underdiagnosed with stress disorders, which may manifest themselves by drinking more, other addictions, suicide, or violence. Our research has broader relevance for not just veterans but the general public.”

Alexander Niculescu, MD, PhD, and researchers in the department of psychiatry at Indiana University School of Medicine have developed a new blood test for PTSD. [Indiana University School of Medicine]
Niculescu and colleagues at the department of psychiatry and VA Medical Center, together with collaborators at The Scripps Research Institute and University of California Irvine, published their findings in Molecular Psychiatry, in a paper titled, “Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs.”

Stress disorders such as PTSD are “prevalent, disabling, and underdiagnosed in both the military and civilian realm,” the authors stated. Such disorders manifest as mental and physical over-reaction to environmental cues that are perceived as potentially harmful, and which are provoked by past exposure to traumatic events. Stress disorders significantly affect quality of life and function. However, the authors added, “Owing to stigma and lack of objective tests, they are often underdiagnosed, sub-optimally treated, and can lead to self-medication with alcohol and drugs.”  In severe cases, stress disorders can lead to violence or suicide.

“Untreated pain and stress can lead to suicide, that’s how we became interested in these disorders, and decided to move upstream and see if we can better understand, treat, and prevent them,” Niculescu said. “We want to prevent the needless tragedy and suffering in people’s lives. By understanding in a biological way a patient’s illnesses and their mental health challenges, we could treat what they have better, preventing future episodes.”

The team’s study, carried out over a decade, involved a stepwise discovery, prioritization, validation, and independent cohort testing design, to search for blood-based genetic markers in participants in both low- and high-stress states. The study included three cohorts of patients. In the initial cohort of patients with psychiatric disorders the researchers carried out a broad search to identify changes in gene expression between participants’ self-reported low- and high-stress states. Next, the team prioritized a list of candidate markers, which involved comparison and analysis of their initial findings alongside existing, detailed studies of human gene expression in psychiatric disorders. Top biomarkers from the discovery and prioritization phases were then validated in an independent cohort of psychiatric subjects with high clinical stress rankings. In the fourth stage the candidate biomarkers from the first three stages were tested for their ability to predict high-stress state and future psychiatric hospitalizations with stress, in a separate cohort of psychiatric patients.

The team then assessed whether there was evidence that their biomarkers were involved in other psychiatric and related disorders, and they also looked more closely at the biological pathways that might be involved. The findings were also evaluated to see whether any of the biomarkers were targets of existing drugs, and so may enable drugs and natural compounds that might be repurposed for treating stress. “Given the negative impact of untreated stress on quality (and quantity) of life, the current lack of objective measures to determine the appropriateness of treatment, and the mixed results with existing medications, the importance of approaches such as ours cannot be overstated,” the team wrote.

Overall, more than 250 male and female veterans were involved in the study. The results highlighted 285 individual biomarkers associated with 269 genes, which could help to diagnose patients with PTSD, indicate stress severity, and the likelihood of future hospital admissions. One of the top biomarkers was FKBP5, a gene that is well recognized for its involvement in stress response, and “which serves as a de facto reassuring positive control,” the authors wrote. As part of the investigations the team also compared the biomarker findings telomere length (TL), which is another well-established biological marker of psychological stress. Their evaluation indicated that some of the newly identified predictive biomarkers, including NUB1, APOL3, MAD1L1, or NKTR were comparable or even better at predicting the state of stress and stress trait than either TL or FKBP5.

Interestingly, the scientists stated, “Over half of the top predictive biomarkers for stress also had prior evidence of involvement in suicide, and the majority of them had evidence in other psychiatric disorders, providing a molecular underpinning for the effects of stress in those disorders.” A number of the identified biomarkers are also targets of existing drugs, and so might be used for patient stratification or pharmacogenomic studies. It’s also possible that the findings could help scientists identify leads for developing new drugs and natural

“There are similar tests like this in other fields, like cancer, where a physician can biopsy the affected part of the body to determine the stage of disease,” Niculescu commented. But when it comes to mental health, biopsying the brain isn’t an option. Our research is applying similar concepts from other areas of medicine, but we’re engineering new ways that will allow us to track mental symptoms objectively, including stress, using blood, or so-called ‘liquid biopsies.'”

“Our work may lead to improved diagnosis and treatment for stress disorders such as PTSD, that result in decreased quality of life and adverse outcomes, including addictions, violence, and suicide,” the researchers concluded. “We think that one of the key uses of our research would be to test people before they have symptoms of an illness to see who’s at risk and possibly treat them early,” stated Niculescu, who is a practicing psychiatrist at the VA and Indiana University Health.

“It’s much better to prevent things for the person, and for the health care system, than to treat somebody who is in an acute crisis … If you treat a medical disorder in general, you improve someone’s quality of life; sometimes you save lives. But if you treat a mental health disorder, you can change somebody’s destiny. You can help change someone from being a person who suffers, is unhappy, is unemployed—maybe goes down the route of addiction, violence, or suicide—to somebody who can become a happy, well adjusted, productive member of society. That’s the challenge and the privilege—we can really change people’s destinies if we do our job.”

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