A panel of 28 biomarkers for post-traumatic stress disorder (PTSD) has been identified in a study of combat veterans and shows promise for use as a screening tool, according to research published September 10 in Molecular Psychiatry. The findings could pave the way for an objective blood test for PTSD, which would be a first in psychiatry, researchers say.
For the study, the investigators examined war zone-exposed veterans of the Iraq and Afghanistan conflicts who had confirmed PTSD, as well as war zone-deployed veterans as healthy controls. The subjects were recruited from New York City-based Veterans Affairs (VA) medical centers and from other regional VA medical centers, veterans' service organizations, and the general community.
The researchers identified a range of biomarker types, drawn from routine lab markers, DNA methylation, metabolomics, microRNA, proteins, and physiological features. A diagnostic panel of 28 biomarkers -- all but one of which were derived from blood samples -- was validated in a cohort of 26 PTSD cases and 26 controls, with 81% accuracy, 85% sensitivity, and 77% specificity.
"The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD," wrote senior study author Dr. Charles Marmar, professor and chair of psychiatry at the New York University School of Medicine, and colleagues.
Diagnosing a common condition
Marmar and colleagues noted that combat-related PTSD is common -- 10.1% to 30.9% of veterans of wars in Vietnam, Afghanistan, and Iraq develop the condition over their lifetimes. Research can help transition mental health efforts toward clinical diagnostics, using lab tests to diagnose conditions based on physical measures instead of relying on patient self-reporting of symptoms and/or on interviews, which are subjective and prone to bias. The development of an objective screening tool such as a blood test would be a first in psychiatry, they said.
In the search for diagnostic biomarkers for PTSD, the researchers tested more than 1 million molecular, cellular, physiological, and clinical features from three cohorts of male veterans.
To select the biomarkers, they applied data-driven methods, other standard or published methodologies, and hypothesis-driven approaches based on previous genetic studies. They also reviewed PTSD-related literature.
The investigators analyzed blood samples for various molecular features, such as genetics, methylomics, proteomics, metabolomics, immune cell counts, cell aging, endocrine markers, microRNA, and cytokines. They quantified DNA methylation with a genome-wide unbiased approach, as well as a targeted sequencing-based approach.
Marmar and colleagues identified 343 potential biomarkers from a discovery cohort of 83 war zone-related PTSD cases and 82 war zone-exposed controls. Next, they reassessed about 30% of the study participants and narrowed down the number of biomarkers to 28, based on their performance and the ability of the markers to track changes in phenotype over time. The 28 biomarkers were validated in an independent cohort of 26 cases and 26 controls.
A systems biology approach
The researchers based their approach for developing the biomarker panel on how PTSD may affect the entire body, not just the brain. They reasoned that indicators, or signals, of the disorder may be found in genes, proteins, cells, tissues, and organism-level physiological changes. Identifying these signals could aid in diagnosing, treating, and providing a risk evaluation for PTSD.
The group took a systems biology approach, using comprehensive multiomic datasets, which helped them better comprehend the underlying disease network-associated biological processes involved in PTSD.
"The systems biology approach aims to characterize a large and diverse set of molecules within an illness or individual by examining entire biological systems, not just individual components," the authors wrote.
This made it possible to evaluate interactions that occurred among levels of cellular pathology, ranging from DNA to circulating metabolites.
The systems biology approach can yield a more comprehensive characterization of illnesses and reveal underlying biological dysregulation before clinical indicators develop or worsen, making it possible to identify better diagnostic markers and discover novel treatment targets, according to the authors. The circulating microRNA in the panel reflects the diverse pathology and comorbidities present in PTSD populations, including connections to metabolic diseases and cardiovascular conditions, they noted.
In the past, a lack of progress in the discovery of biological markers of PTSD has hampered accurate diagnosis, early identification of cases, staging and prognosis, stratification, personalized treatment, and new drug development. Previous PTSD biomarker research applied gene expression to predicting risk and making a diagnosis. There has been some success in identifying predictive and diagnostic markers, but research has been limited due to small sample sizes and a focus on individual molecular data types, the authors noted.
Studies of other patient populations are needed to determine the value of the biomarker panel and how it may be applied, they suggested.