Review Article, Jtsdt Vol: 12 Issue: 6

Critical Analysis of Classical and Novel Risk Factors to Post-traumatic Stress Disorders in military populations.

Elise Pearl¹, Adam Pearl^2,3, Muaaz Wajahath⁴, Kareem ElHage⁵, Ahmad Hasan⁶, Elias Nasser⁷, Khaled Saleh^2*

¹Department of Psychology, Eastern Michigan University, Ypsilanti, MI, USA

²John D. Dingell VA Medical Center, Detroit, MI, USA

³Department of Emergency Medicine, HCA Aventura Medical Center, MI, USA

⁴College of Human Medicine, Michigan State University, East Lansing, MI, USA

⁵Wayne State University, School of Medicine, Detroit, MI, USA

⁶Orthopedic Surgery, Detroit Medical Center, Detroit, MI, USA

⁷Southwestern Medical School, University of Texas, Dallas, TX, USA

*Corresponding Author: Khaled Saleh
John D. Dingell VA Medical Center, Detroit, MI, USA
E-mail: kjsaleh@gmail.com

Received: 19-Jul-2023, Manuscript No. JTSDT-23-107328; Editor assigned: 21-Jul-2023, PreQC No. JTSDT-23-107328 (PQ); Reviewed: 07-Aug-2023, QC No. JTSDT-23-107328; Revised: 10-Aug-2023, Manuscript No. JTSDT-23-107328 (R); Published: 17-Aug- 2023, DOI:10.4172/2324-8947.1000371

Citation: Pearl E, Pearl A, Wajahath M, Elhage K, Hasan A, et al. (2023) Critical Analysis of Classical and Novel Risk Factors to Post-traumatic Stress Disorders in Military Populations. J Trauma Stress Disor Treat 12:6.

Copyright: © 2023 Pearl E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Abstract

Keywords: PTSD; Military population; Prevention; Risk-assessment

Introduction

According to the Diagnostic Statistical Manual volume 5 (DSM 5), Post-Traumatic Stress Disorder (PTSD) is defined as a debilitating psychological reaction caused by having witnessed or experienced an intensely traumatic event [1]. Patients may experience anxiety, flashbacks, recurring nightmares, depression, and avoidance of reminders of the traumatic event [2]. In most individuals, these symptoms resolve within several weeks. However, in approximately 10–20% of individuals, symptoms may persist [3]. PTSD is independently associated with increased risk of migraines, hypertension, dermatitis, diabetes, Parkinson’s disease, cardiometabolic disease, [4-7] and drug and alcohol abuse [8] The incidence and prevalence of PTSD is common in United States (U.S.) veterans, with prevalence rates being even higher in Veterans Affairs healthcare settings. The lifetime prevalence of PTSD in Veterans varies by service era; five to 20% of service members from Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) are affected by PTSD [9], and 30% of Vietnam veterans have suffered from PTSD in their lifetime [10]. Upon exposure to traumatic events, 26-81% of men and 17-74% of women may develop PTSD [11] the impact of PTSD on a person’s physical and mental states leads to a diminished quality of life. The annual cost burden for PTSD treatment for service members is approximately $1.6 billion [10].

Symptoms of PTSD vary in severity and, in some instances, may lead to a chain of events culminating in suicide. The duration and intensity of combat exposure have been directly linked with PTSD and its severity [12]. When returning to civilian life, a veteran’s general health is undermined by the difficulty of reintegrating to society. They may find difficulty feeling a sense of belonging, social engagement, and self-capacity [13, 14], or they may experience mental health problems such as depression and anxiety [5, 15, 16]. Notably, studies have demonstrated a strong association between PTSD and suicidal ideation, attempts, and fatalities [17-21]. The progression of PTSD to ultimate suicide has not yet been fully investigated. A 30- fold increase in PTSD prevalence among people who died by suicide was reported by the National Violent Death Reporting System, 2005– 2014 [22]. Annual suicide rates in veterans with PTSD has increased by 30% since 2005 [23], and veterans screening positive for PTSD are four times more likely to experience suicidal ideations than their counterparts without PTSD [24].

Suicide is one of the leading causes of death worldwide, claiming 800,000 deaths annually [25]. Between 1999 and 2016, suicide rates among U.S. citizens increased by 25% [26]. In 2016, suicide became the second leading cause of death among people between ages 10-34 and the fourth leading cause between ages 35–54 [27]. During that same period from 1999 to 2016, the U.S. Department of Defense (DoD) reported that the rate of suicide-related deaths per 100,000 service members more than doubled, reaching a rate of 21.5/100,000 [28], which may be a result of the wars in Iraq and Afghanistan between the years of 2005 and 2009 [29]. In 2019, the United States Department of Veteran Affairs (VA) reported that an average of 20 veterans commit suicide daily [23]. From 2006-2020, more deaths of US active duty military personnel could be attributed to self-infliction (4,231), including suicide, than combat (2,729) or wounds sustained while serving (890) [30].

A broad range of risk factors that are not yet fully understood are associated with significantly higher suicide risk. Some of these identifiable risks reside in genetic, psychological, social, and cultural conditions [31]. Guidelines have been established for the evaluation of suicide risk, suicide prevention, and for providing quality care to patients who are considered high-risk for suicide [32]. Unfortunately, the accuracy of identifying risk factors and patients at increased risk for suicidal ideation is still limited. Very few studies have proposed predictive models of the suicide risks. However, the predictive power of multivariate factors are inflated by chance findings [33, 34]. This review will examine the PTSD risk factors and their predictive power to provide up-to-date evidence-based understanding of the PTSD- suicide chain.

Traumatic stressors and PTSD

There are several theories regarding the causes of PTSD. However, PTSD cannot be diagnosed without experiencing exceptionally distressing events. The patient’s subjective perception of these events often determines the incidence, severity and prognosis of PTSD [35]. There are different ways in which traumatic stressors can be categorized. When considering who is inflicted, trauma can affect individuals, groups, communities and even generations [36]. Individual trauma refers to an event, series of events, or a set of prolonged circumstances that only affects one person, and could include illness, assault, and most commonly, physical injury. A study showed that more than half of ambulatory assault victims visiting the emergency room (ER) developed PTSD three months later [36]. In instances where a small group shares the same identify, such as first responders, military service members, or community members, group trauma may occur [36]. Mass trauma is an event, commonly natural or human-caused disasters, in which large numbers of individuals are witness to or experience widespread disruption of normal life activities as well as significant loss of property and lives. Mass traumas compromise the access to care and support, leading to poorer quality of life and mental health illnesses such as anxiety and depression [37]. Military personnel are exposed to all three trauma types as a result of combat and other war experiences.

Trauma can also be categorized by the mechanism of infliction (i.e., nature-cased or human-caused trauma), and different types of traumatic events have propensity to produce certain symptom clusters [38]. Human-caused trauma is broad, involves one-to- one relationships between humans, and includes wars, accidents, and interpersonal trauma. In a recent study, posttraumatic stress symptoms (PTSS) on active duty, retired military members, or family members of military personnel, were assessed using the DSM-5 criteria for PTSD [39]. Combat-related trauma led to more severe PTSS. Combat was also significantly linked with hyper arousal and intrusion symptoms, which tend to manifest somatically.

Interpersonal trauma correlates strongly with negative alterations in cognition and mood (NACM). Regarding specific interpersonal traumas and related symptoms, physical assault is associated with blame, childhood physical abuse is associated with avoidance/ numbing, and sexual trauma is significantly associated with avoidance and amnesia. Sexual trauma, during both adulthood and childhood, can also predict greater PTSS severity. Previous studies also demonstrated that interpersonal traumas are associated with higher rates of PTSD and total PTSS severity [39].

In addition, the exposure of military personnel to nature-caused trauma is substantial, as military personnel are often deployed to locations in a disaster relief supporting role. Disaster rescue and response personnel, which include police, firefighters, National Guardsmen and more, face mass violence as well as devastating effects on communities, and are thus at risk of death or injury, potential loss of fellow workers, and behavioral problems. The prevalence of PTSD in rescue workers ranges from zero to 34% and depression from 21- 53% [40]. In studies examining the effects of the World Trade Center disaster, most rescue workers only experienced normative to mild stress reactions, but some experienced worsening severe stress reactions [40]. Kim et al. examined the rates of PTSD between military personnel deployed to humanitarian assistance/disaster relief (HA/DR) deployments and those deployed to non- HA/DR fields, such as Unit Deployed Programs, unrelated to combat and training. Using data from the 2011 Health Related Behaviors Survey, it was determined that participating in HA/DR deployments, such as the Haiti earthquake and Deepwater Horizon Gulf oil spill, reduced PTSD symptoms by 3% (p < 0.1) and significantly reduced depression symptoms by 1% (p < 0.05) [41].

Trauma exposure and PTSD among military and veteran populations

Trauma exposure is also important to consider when conceptualizing the development of PTSD [37]. Acute trauma refers to a singular, traumatic event. Cumulative trauma describes repeated, prolonged trauma. Complex trauma, chronic trauma, and compounded trauma can be utilized for multiple trauma events, particularly among refugees and veterans that experience stress and violence for a sustained period of time. For PTSD to be diagnosed via the DSM-5 criteria there must be qualifying exposure to the trauma [42]. Research found that traumas such as witnessing injury or death and losing family or friends as well as reactions to trauma including dissociation were weak risk factors for PTSD [38].

Veterans have a higher lifetime exposure to trauma compared to the general population [43]. A study on 2,463 treatment-seeking veterans with PTSD showed that 76% of the subjects had been exposed to four or more traumatic events in their lifetime. This number could be attributed to previous findings that military populations are more likely to have adverse childhood experiences than civilian populations [43]. The risk for PTSD increases when a person has experienced repeated traumas, such as those experienced by military personnel, compared to singular traumas [44]. Particularly, during deployment their lives are threatened constantly and many are ordered to fire upon enemy combatants [44]. Traumas have additive effects and may worsen PTSD symptom severity [37]. Prolonged exposure to combat is the most significant risk factor for PTSD in military personnel [9], and this exposure to combat correlates to PTSD severity [43]. For instance, in Vietnam theater veterans, greater combat exposure contributed to an increase in PTSD symptom severity [45].

Military sexual trauma and PTSD

As defined by the department of Veterans Affairs (VA), military sexual trauma (MST) refers to the exposure to sexual assault or repeated, threatening sexual harassment that a Veteran experienced during his or her military service [46]. Military personnel are more likely to experience sexual assault [43]. Rates of sexual assault have increased steadily, and “Department of Defense Annual Report on Sexual Assault in the Military, Fiscal Year 2018” stated that the fiscal year 2018 had 7,623 reported cases of sexual assault against service members and civilians compared to 6,172 reports in 2016 [47]. More than six percent of active duty women reported that they experienced sexual assault in 2017, an increase from 4.3% in 2016. A percentage of 0.7% remains stable for active duty men who have reported sexual assault.

The Department of Veterans Affairs’ National Center for PTSD found that sexual assault is more likely to lead to PTSD than other traumatic events [47]. It was found that 45% of the women who reported they were raped met the criteria for PTSD [47]. Previous experience with sexual assault was found to be associated with urgency/mixed and stress urinary incontinence, and this relationship could be mediated by PTSD [48]. 65% of the men who reported they were raped met the criteria for PTSD, which is higher than the 38.8% rate of PTSD development in men who were exposed to combat [47]. In a predominantly male sample of veterans, sexual trauma was shown to lead to more severe PTSD than combat trauma, aligning with previous data in the general population [43]. It is speculated that sexual trauma has such a large clinical impact because it can be unexpected, and the feelings of shame and secrecy, especially while struggling with stereotypical masculinity, can affect recovery.

Meanwhile, combat is an action that military personnel train for. The neurocognitive and physical preparedness can lessen the trauma’s effect. Thus, combat should not be the only trauma considered in military personnel, as sexual and other childhood/lifetime trauma are impactful as well and contribute to increased suicide risk as a result of the PTSD-suicide chain.

Risk factors of PTSD

Not every service member who experiences a traumatic stressor will ultimately develop PTSD. This highlights that there are other individual predisposing factors beyond the trauma itself that make some individuals more vulnerable to develop PTSD. Any factor that potentially contributes to variability in diagnosis and symptoms of PTSD would be considered a predictor or risk factor [49]. Understanding risk factors and susceptible individuals is imperative, as controlled clinical trials have shown that PTSD risk can be diminished greatly through early intervention [50].

The predictive risk factors of PTSD in military and veterans can be generally categorized as pre-, peri- and post-traumatic factors and these factors are categorized and listed in (Table 1). The pre- trauma risk factors include socio-demographic (i.e. age, gender, race, education, marital status, smoking, alcohol, etc.), military characteristics, and previous history of psychiatric illness and/or traumatic events. The peri-traumatic factors include the duration and intensity of trauma exposure and deployment-related stressors, whereas post-traumatic factors include rehabilitation, psychological and social support, and other comorbidities [49]. Additionally, several novel biomarkers that have been proposed to clinically predict the development and prognosis of PTSD (Table 2).

Table 1. Pre-, Peri-, and Post-Traumatic Risk Factors for PTSD in Military Personnel and Veterans

Table 2. PTSD Biomarkers Found in Literature

A data-driven machine learning approach by Schultebrauks et al. incorporated biological, clinical, and neurocognitive data pre- deployment from active-duty Army personnel to predict PTSD diagnosis and symptom trajectories developing 90-180 days after returning from a 10-month deployment from Afghanistan [44]. Data consisted of metabolic, epigenetic, inflammatory, endocrine, and blood tests as well as neurocognitive testing, self-reporting symptoms, and genome-wide association studies (GWAS) markers for Polygenic Risk Score. Certain biomarkers, neurocognitive functions, and self- reported symptoms were found to be predicting risk factors of deployment-related PTSD among military and veteran populations.

Pre-traumatic risk factors

Gender: Females are at two to three times higher risk of PTSD compared to men [38, 51]; the lifetime prevalence of PTSD in females is 10-12% and males is five to six percent [51]. With the female population in uniform tremendously increasing and women now comprising 14% of the US Armed Forces [48], the gender-specific risk in PTSD development has been examined. Scores for PTSD symptoms such as re-experiencing trauma and anxious arousal have shown to be higher in women [51]. The difference has psychosocial and biological explanations according to author Olff [51]. Men and women experience different types of trauma, with women having greater exposure to high-impact trauma (sexual assault). Women also report less unit cohesion and lower military preparedness and have higher rates of depression [49]. In response to traumatic stress, women tend to use a tend-and-befriend response instead of a fight- or-flight response [51]. That is, women cope using an emotion- focused, defensive, and palliative method while men tend to be more problem-focused.

Olff et al. discussed the sex-specific mechanisms for the effects of oxytocin, which is associated with fear, social support, and stress responses, when administered in PTSD patients to reduce anxiety and fear expression by the amygdala [51]. As a result of an oxytocin treatment, men demonstrated increased inhibitory control of the ventromedial prefrontal cortex over the centromedial nucleus while women exhibited less excitatory dorsal anterior cingulate cortex projections to the basolateral nucleus. In addition, urinary incontinence (UI) symptoms are commonly reported in young to middle-aged female veterans, and a cross-sectional study of women veterans ages 20 to 52 found that PTSD is associated with urgency/ mixed (urgency and stress UI symptoms) [48]. Previous studies have demonstrated common biological pathways of urgency UI and mental health. Alterations in the serotonin process and hypothalamic- pituitary-adrenal axis has shown to contribute to the association [48].

Race: Race has demonstrated associations with PTSD in military personnel and veterans. In a meta-analysis of 32 full-text articles about PTSD risk factors for combat-related PTSD in military populations, Xue et al. found that non-white military service members were more likely to develop PTSD than white military service members [49]. There is little research explaining the greater risk in minority ethnic groups though Xue et al. postulated that minority individuals may experience higher levels of other risk factors or are assigned to more high combat roles [49]. Furthermore, the papers reviewed in the meta-analysis discerned the race variable to be dichotomous (white versus black/ethnic minority) so differences between minority groups could not be distinguished.

The National Vietnam Veterans Longitudinal Study follows up on a study conducted in the late 1980s on a nationally representative cohort of Vietnam theater veterans, era veterans, and civilians [45]. Conducted over a 25-year span, the study aimed to determine predictive variables of PTSD developed after war zone deployment. PTSD symptom presentation was shown to be predicted by negative homecoming reception. The study also found that the African American race significantly predicted PTSD severity and greater severity of symptoms. In a high trauma exposure African American community, an association was found between intergenic variant rs1433375 and alcohol use, a common PTSD comorbidity [52].

Age: The literature is mixed as to how age plays a role in PTSD development. The aforementioned Vietnam veterans’ longitudinal study found that boarding to Vietnam at a younger age predicted a substantial increase in symptom severity [45]. Similarly, Olff reported that trauma occurring at an earlier age has a greater impact, particularly type II trauma that interferes with neurobiological development and personality [51]. However, previous research by Guina et al. determined that the age at which the first trauma occurred does not have a strong correlation with PTSD severity [39]. Childhood abuse, adversity, or trauma were concluded to have weak predictive value for PTSD [38].

Age related changes in epigenetics have been studied and correlated with several diseases. To determine the association of epigenetic age with PTSD symptoms and diagnosis, Verhoeven et al. investigated the epigenetic age, or DNA methylation level, in white blood cells using Horvath’s algorithm within 2 cohorts of combat-exposed war veterans with PTSD and a control group of combat-exposed war veterans without PTSD [53]. Veterans with PTSD had significantly younger epigenetic age profiles, or relatively less accelerated DNA methylation, compared with veterans without PTSD, even when confounding factors such as race, BMI, smoking or alcohol behaviors, previous childhood trauma, or number of deployments, are not taken into account [53]. However, group differences are not significant when adjusting for current usage of antidepressants, thus the distinction in profiles may be partially mediated by antidepressants usage [53]. These results were surprising since age-related diseases and epigenetic age are independently associated with mortality and PTSD is also associated with a higher risk for mortality. However, previous research using the same Horvath’s algorithm aligned with the study’s findings. Epigenetic age could be used as a marker in PTSD vulnerability for military pre-deployment as epigenetic age was shown to be stable after follow-up testing on a subset of the cohort [53].

Social history: There is weak evidence to support the hypothesis that low socioeconomic status could be a risk factor for PTSD [38]. Considering other socio demographic factors, lower educational attainment is associated with higher risk for PTSD [49]. Military service members with higher education may have access to greater resources (e.g., psychotherapeutic support) and therefore be equipped with better coping methods. National Vietnam Veterans Longitudinal Study found that lower education level significantly predicts PTSD severity and an increase in symptoms severity [45]. As per the Vietnam veterans’ study, out of the 22 possible predictors tested, the only two that were not statistically significant were the relationship with the individual’s father as a child and alcohol problems at home as a child [45]. The meta-analysis conducted by Xue et al. determined that marital status had no effect on PTSD, which is contradictory to other studies [49]. Past research found that military personnel were at a higher risk for PTSD if divorced than if never married or married at that time. Smoking status was also concluded not to be related to PTSD in the meta-analysis, opposing previous research showing association between smoking and PTSD in Gulf War and Vietnam War veterans [49].

Military history: Military characteristics play a crucial role in the development of combat-related PTSD [49]. In regard to occupation within the military, combat specialists had greater risk of PTSD than other job roles such as health specialists, service supply, and functional personnel. Military rank also contributed to PTSD; non-officers and supply personnel were more likely to be diagnosed with PTSD, likely due to their increased combat exposure. Other studies also reported that PTSD rates are higher in enlisted personnel than in officers. Branch of service was significant as well, with Army personnel being significantly more likely to report symptoms of PTSD compared to those in the Marines, Air Force, Navy, or Coast Guard.

Previous history of traumatic events and/or psychiatric illness

There is no significant relationship between history of stressful life events and threat appraisal (i.e., the fear for safety or well- being), though previous studies have found that prior stressors can cause an individual to be desensitized to the negative effects of future stressors [9]. However, previous deployment to a warzone can also lead to a higher perceived threat seeing as an individual can be more susceptible to the same stressors that they have previously experienced. The Vietnam longitudinal study reported that stressors occurring the year before deployment significantly predicted PTSD symptoms and increased symptom severity [45]. PTSD is also often associated with comorbid mental health conditions, and a GWAS meta-analysis found that PTSD is significantly genetically correlated with depression, schizophrenia, neuroticism, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD) [50]. Other studies support the link between PTSD and psychiatric disorders [54]. There was evidence of a significant association between PTSD and suicidality, with risk estimates higher in men, as was aggression through goal-oriented violence. Psychiatric comorbidities were found at higher rates in people with PTSD than those without, yet adolescents with ADHD or conduct disorder are not more likely to develop PTSD than those without them [54].

Previous epidemiological studies demonstrated that pre- existing pathology including chronic or major bodily disease and psychiatric disorders are highly associated with a PTSD diagnosis and psychiatric comorbidities after trauma exposure [38, 42]. Self- reported pre-deployment symptoms have been shown to have high predictive value for deployment-related PTSD. A machine-learning study determined that scores on the Generalized Anxiety Disorder Questionnaire, version 7 (GAD-7) are most predictive of PTSD symptom severity and sleep quality is the most important predictor to establish a provisional PTSD diagnosis [44]. A direct relationship was found between pre- and post-deployment PTSD symptom severity [9]. The chronic adverse responses to past stressors allow for symptom recurrence during new stressors occurring in deployment as individuals with pre-existing PTSD symptoms may perceive war events as more threatening.

PTSD also heavily impacts cognitive function. Researchers have questioned whether the resulting neurocognitive deficits are caused by the trauma or if pre-existing neurocognitive deficits cause individuals to be more susceptible to PTSD. There is possibility that higher neurological functioning could protect an individual from PTSD. The Fort Campbell Cohort Study examined active duty Army personnel pre-deployment to Afghanistan and multiple times post-deployment to determine if there were neurocognitive markers that identified individuals at risk for PTSD after deployment [54]. Aspects of executive functioning (i.e., sustained attention, processing speed, inhibitory control, working memory, and cognitive flexibility) were assessed prior to deployment. After controlling for confounding variables such as prior trauma exposure and age, impairments in sustained attention and inhibitory control were found to be significantly associated with PTSD symptom severity and stress trajectory (resilient or latent) after deployment. A study that utilized a machine-learning approach to determine PTSD risk factors also reported deficits in attention, but also found that pre-deployment cognitive flexibility is a PTSD predictor [44].

Peritraumatic factors and military characteristics

Longer duration of deployment and greater than two deployments has been shown to increase the risk for PTSD due to greater combat exposure [49]. Deployment experiences were also shown to be impactful in PTSD development [49]. Combat exposure was significantly associated with combat-related PTSD. Trauma severity was strongly associated with risk of developing PTSD, though the effect of the trauma severity was complex due to conceptual factors involved with measuring trauma severity. Discharging a weapon or witnessing an injury or death during deployment was also associated with PTSD. Deployment-related stressors overall significantly increased risk for PTSD development. These stressors include excessive heat or cold, family issues back home, boredom, lack of privacy, and leadership problems.

Previous research found a significant association between threat appraisal during military deployment and an increase in PTSD symptoms from pre- to post deployment [9]. However, combat intensity was not the only factor impacting threat appraisal. A study consisting of 670 regular male and female active duty and 104 activated National Guard deployed soldiers found many predictors that had an effect on warzone threat appraisal and are associated with PTSD severity through mediation by threat appraisal [9]. Pre- deployment unit cohesion is linked to threat appraisal, though the indirect effect of pre-deployment unit cohesion on PTSD symptoms by way of perceived threat is statistically insignificant [9]. Unit cohesion during deployment plays a larger role in PTSD symptoms than the unit relationships present before deployment [9]. Soldiers feeling greater psychological preparedness, and thus more confidence in their ability to overcome challenges for the warzone, feel less threat appraisal regardless of actual physical readiness [9].

Post-traumatic factors

In military personnel, combat trauma can trigger PTSD development and post-deployment factors can affect PTSD severity. Possemato et al. assessed post-deployment factors such as social support and post-deployment stressors in 150 Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) veterans [55]. Unemployment, alcohol use, social support, and other post- deployment stressors,including reintegration efforts, independently predicted PTSD severity [49, 55]. The Vietnam longitudinal study also concluded that lower social support after deployment significantly predicted PTSD severity and an increase in symptoms severity [45]. A positive recovery environment with high levels of social care of support after deployment can promote feelings of self- reliance and self-security that protect against the development of PTSD [49]. However, Possemato et al. questioned the ability of these post-deployment factors to exacerbate or maintain PTSD severity over time [55]. Tortella-Feliu et al. also reported that many other past studies have identified post-traumatic factors, such as comorbid psychological problems [38]. However, none of these factors were shown to be as important in predicting development as those the early indicators of PTSD [38, 49].

Novel biomarkers

Though PTSD is a neuro-cognitive disease, it has been widely accepted that multiple biological systems are associated with the diagnosis and prognosis of PTSD. In 2012, the Department of Defense created the “PTSD Systems Biology Consortium’’ which aimed to use multiple -omics technologies to create a panel of PTSD biomarkers for PTSD diagnosis [56]. To identify and validate a set of multi- omic blood-based biomarkers, the study included male OEF/OIF veterans aged 20-50 with PTSD, matched controls without PTSD, and a validation cohort to corroborate the validity of the biomarkers. Out of 300 candidate biomarkers, a final set of 28 biomarkers was accurately assessed. These 28 biomarkers could potentially predict the susceptibility to PTSD and included DNA methylation markers, miRNAs, clinical lab values, physiological measurements, proteins, and metabolites. The 10 top biomarkers, in ascending order, methylation marker cg01208318, heart rate, methylation marker of PDE9A cg15687973, methylation marker cg20578780, mean platelet volume, hsa-miR-133a-3p, hsa-miR-192-5p, insulin, hsa-miR-9- 5p, and gamma-glutamyl-tyrosine. Four biomarkers in this final 28 set (cg01208318, cg17137457, lactate, and citrate) were found to be among the top 15 biomarkers in the Schultebrauks et al. machine learning study, previously mentioned [44].

Genomic related

MicroRNAs (miRNAs) impact the pathology of many neurological and psychiatric diseases. A profiling of miRNAs within whole blood plasma, extracellular vesicles (EV), and EV-depleted plasma (EVD) in male combat veterans with PTSD and their controls was conducted to determine an association between miRNAs in plasma to PTSD [10]. Concentration changes for two miRNAs between cases and controls were validated in an independent cohort. The miR-203a-3p (increased in EV) was found to have target genes that were involved in neural development, immune response, and neurotransmitter pathways, which are all impacted by PTSD and thus plays a role in comorbidities such as cancer, cardiovascular disease, diabetes, and metabolic disease. The other validated miRNA, miR- 339-5p (decreased in EVD plasma), is linked to dementia, in which PTSD is a risk for, and other common biological alterations seen in PTSD patients such as lysosome, lipid homeostasis, oxidative stress, and brain inflammation. Other studies investigating miRNAs did not confirm miR-203a-3p and miR-339-5p as biomarkers but found four other miRNAs (miR-133-3p, miR-9-5p, miR-192-5p, miR- 424-3p) as potential predictors involved in somatic comorbidities (cardiovascular disease, neurogenesis, liver and metabolic conditions, and inflammation, respectively) [56].

Genes associated with mitochondrial function have altered methylation or regulation in those with PTSD, and 20% of these genes are significantly correlated with PTSD symptom severity [57]. DNA methylation related to the mitochondria, cg17137457, on CPT1B gene might predict those who would develop PTSD [44]. Altered methylation of SHANK2 gene and expression of PDE9A are also biomarkers of PTSD [56]. A meta-analysis of GWAS consisting of more than 200,000 participants with either European or African ancestry was conducted to study the genomic interactions in PTSD [50]. Six genome-wide significant loci are found to be associated with PTSD. Two loci, which are both mapped to chromosome 6, are found in participants of European ancestry, and two more loci are found in only male participants of European ancestry. One locus is found in participants of African ancestry and another is found in only male participants of African ancestry. The six loci have target genes that could provide more information of the impacts PTSD has on biological systems such as neurocognition, neural development, synapses, beta-adrenergic receptors. Since many genes related to psychiatric traits are pleiotropic, the study validated that some of the genome-wide significant loci from the GWAS analysis were specific to PTSD when tested against the 3 genetic disorders most significantly correlated with PTSD.

As PTSD is polygenic, similar to other psychiatric disorders, individual common SNP variants only contribute a small fraction of the genetic influence. As a result, an additive effect could provide more predictive value than individual genes and variants. The polygenic risk score (PRS) is derived from the total sum of risk variants and weighted by the corresponding effect-sizes determined from the summary statistics of PTSD GWAS [50, 58]. PRS was able to stratify patients into risk groups with each having distinct PTSD risk and severity levels. However, there is insufficient data to support clinical usage of PRS [58]. There are some aspects to consider regarding PRS and its development [58]. Future prediction models should include rare and low frequency variants and other complex structural polymorphisms rather than just SNPs. PRS should also take into consideration the different clinical presentations of PTSD as well as shared traits with other disorders and create genetic scores. Furthermore, different ancestries may have different SNP variants, but it is difficult to create PRS in ancestries other than European as many genomic studies have been conducted with only European subjects.

Metabolic dysfunction

Metabolic dysfunction is heavily associated with PTSD. Metabolites in the blood were identified by Mellon et al. to determine if there were profile distinctions in male combat veterans from OEF/OIF with and without PTSD [57]. A case-control study was conducted along with an additional smaller independent cohort to validate findings. There were significant metabolic profile differences in the subjects with PTSD and the control for both groups even when controlling for Major Depressive Disorder (MDD), BMI, blood glucose, hemoglobin A1C, smoking, and medication. The study identified many metabolites and metabolic pathways that differ between the cases and controls in men that could be PTSD biomarkers, but these changes are distinct from those distinguished in a previous study of male and female civilians with PTSD, suggesting that gender, types of trauma, and other variables such as comorbidities and medication can affect the metabolic profiles. However, lactate and eicosanoids are found to be highly predictive of PTSD. [44].

Lactate can contribute to PTSD symptoms through multiple pathways [58]. Lactate activates GPR81, a Gi coupled cell-surface receptor involved in lipid metabolism, cerebral energy metabolism, and neuronal activity. The enhanced concentrations of lactate may have anti-lipolytic effects so there are less available long chain fatty acids thereby decreasing energy metabolism. The elevated concentration has also shown to be associated with insulin resistance, a proven association of PTSD. The largest difference between the groups in a study conducted by Mellon et al. concerned increased levels of pyruvate and lactate, suggesting heightened levels of anaerobic glycolysis in the case group [57]. Previous research aligns with this notion as animal models with PTSD have decreased metabolites in the tricarboxylic acid (TCA) cycle. Furthermore, increased levels of lactate and pyruvate change the NADH/NAD ratio in the cell, and this disrupts biological clock genes, explaining the disordered sleep and glucocorticoid modifications that are associated with PTSD.

Regarding eicosanoids, no significant difference existed between participants with PTSD and controls for saturated fatty acid concentrations, but there was a significant decrease in concentrations of many unsaturated fatty acids in PTSD patients [57]. Long chain polyunsaturated fatty acids bind to nuclear peroxisome proliferator- activated receptors (PPAR) which then suppresses the expression of proteins and transcription factors that regulate the gene expression relating to inflammation, energy, intermediary metabolism, and other somatic health conditions seen in people with PTSD.

Mathematical models from literature for metabolism, HPA axis activity, and inflammation were consolidated to conduct metabolic control analysis (MCA) to determine if these metabolic abnormalities present in combat-related PTSD are independent or caused by regulation from a common source [61]. Corroboration was gained using correlational analysis and causal inference from the lab assay and metabolite data gathered from men aged 20 to 60 who served in OIF/OEF. MCA found mechanisms as to how HPA-axis alterations in wake of trauma exposure can lead to the metabolic dysfunction seen in PTSD patients, explaining conclusions from Schultebrauks et al. that citrate and glutamine are biomarkers of PTSD [44].

When a traumatic event occurs, stress hormones such as cortisol and catecholamine start gluconeogenesis to replenish the energy [61]. Gluconeogenesis requires the usage of pyruvate, and with an increased production of glucose, less pyruvate is available as a substrate for the conversion to acetyl CoA. Therefore, lower levels of citrate are available. The glucocorticoid (GC) activity from stress or trauma increases proteolysis on plasma proteins, and elevated insulin resistance contributes to the breakdown of proteins [61]. Protein breakdown is important to gluconeogenesis because alanine is converted to pyruvate, and glutamine and tyrosine play a vital role in the TCA cycle. These impaired levels of citrate and glutamine not only contribute to metabolic dysfunction but also the energy deficit commonly seen in PTSD. Yet, cortisol plays a significant role in gluconeogenesis and the response to trauma, and past research raised the potential of cortisol awakening response and hair cortisol being able to predict PTSD symptoms after deployment [44]. However, the machine learning approach study conducted by Schultebrauks et al. did not conclude that the plasma cortisol level is an important predicting factor [44].

Regarding comorbid conditions, somatic health-related markers such as insulin resistance [56] and a lipid panel with LDL cholesterol data seem to be relevant to predicting PTSD [44]. Levels of hypoxanthine, a purine derivative naturally produced, were elevated in the PTSD cases. This chemical leads to accumulation of cholesterol and atherosclerosis, both of which are risk factors for cardiovascular disease, which is associated with PTSD [57].

Cardiovascular disease is typically screened using biomarkers such as insulin resistance, prediabetes, and metabolic syndrome (MetS) [4]. Previous studies showed increased MetS as well as increased amounts of fasting insulin and malfunctioning glucose tolerance in people with PTSD, but these studies focused on civilian populations [4]. A case-control study on young male veterans returning home from Operation Iraqi Freedom and Operation Enduring Freedom studied the relationship between combat-related PTSD and risk for cardio metabolic disease [4]. The study found an increase in insulin resistance, which is measured through fasting insulin and HOMA-IR, even when controlling for increased BMI, smoking, and antidepressant use. Moderate to severe PTSD symptoms significantly predicted increased HOMA-IR, MetS, and thus cardio metabolic disease, in young male warzone veterans. These results are supported by previous studies on older individuals and civilian populations (cite studies). Other animal models have concluded bidirectional processes to explain the effects. Biological mediators of insulin resistance and lipid panel alludes to early prevention for the disease in PTSD patients.

Inflammatory and immune response

A study was conducted to measure pro-inflammatory cytokine levels in male war veterans with PTSD against a control group of male war veterans without PTSD [59]. Values of Interleukin (IL) - 6, Tumor Necrosis Factor (TNF)-α, IL-10, Interferon-γ, and high- sensitivity C-reactive protein (CRP) were measured and combined into a single total pro-inflammatory score. Study participants with PTSD had a significantly higher total pro-inflammatory score than the control participants when age, smoking, BMI, medication, and biological comorbidities were considered. However, within the PTSD experimental group, no significant correlations were found between the total pro-inflammatory score and Clinical Administered PTSD Scale current and lifetime, Early Trauma Inventory, and Beck Depression Inventory scores. This lack of significant correlation between inflammation and symptom severity of PTSD prompted the researchers to speculate that an increased inflammatory state may be a potential marker of vulnerability for PTSD rather than a result of trauma or symptoms, though this does not have substantial evidence as inflammation is present in other psychiatric disorders.

A subsequent study sought to understand the relationship between inflammation and PTSD symptom severity [60]. To achieve this, circulating platelets, white blood cells (WBCs), and red blood cells (RBCs), all of which are involved in inflammation, were measured in male veterans with and without PTSD. Male war veterans with PTSD were found to have higher counts of platelets, WBCs, and RBCs, even when smoking and BMI were considered. The elevated levels contribute to the pro-inflammatory state seen in PTSD patients, suggesting a possible explanation as to why veterans and military personnel have a higher incidence rate of PTSD. Indeed, other studies have identified platelet volume as a biomarker for PTSD [57]. There is a positive correlation between platelet count and lifetime PTSD symptom severity [60].

In addition, the HPA-axis is also involved with the pro- inflammatory state associated with PTSD [61]. Increasing glucocorticoid receptor sensitivity can increase the pro-inflammatory response, leading to up regulation of the HPA axis and subsequent immune response dysregulation. Monocytes, basophil, and C-reactive protein are important predictors [44]. This result supports the findings of higher plasma levels of CRP in those with PTSD and pre-developed leukocyte sensitivity to GCs is associated with PTSD development after deployment for those without comorbid depression [44].

Conclusion

It is imperative that the risk factors predicting PTSD are fully understood. Many factors contribute to the diagnosis of PTSD, including genetic, psychological, and social conditions. It has been repeatedly demonstrated that, out of the many risk factors that have been studied, depression most strongly correlates to PTSD. However, the difficulty in diagnosing and treating PTSD has been shown through the identification of non-traumatic variables that can also contribute to its diagnosis. Interestingly, it has been shown that impairments in neurocognition more specifically abnormalities in the prefrontal cortex – play a strong role in the development of PTSD. Furthermore, various biomarkers have been shown to correlate with PTSD, including decreased metabolites of the TCA cycle, low levels of unsaturated fatty acids, inflammatory biomarkers, and many more. The complexity of PTSD cannot be understated, and many efforts must be made to further our understanding of the disease in order to prevent its progression to suicide.

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