EXPERT ANALYSIS AT THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF PSYCHIATRISTS
HUNTINGTON BEACH, CALIF. – Researchers are making significant headway in developing objective, reliable, and valid biomarkers to discriminate individuals with warzone post traumatic stress disorder from healthy controls, according to Dr. Charles R. Marmar.
“It’s clear that over the next four or five years we will identify very clear biological, psychological, and other behavioral risk and resilience profiles,” Dr. Marmar told attendees at the annual meeting of the American College of Psychiatrists.
Currently, clinicians largely rely on patient self-reports and clinical observations to diagnose PTSD in military personnel, said Dr. Marmar, professor and chair of the department of psychiatry at NYU Langone Medical Center and director of NYU’s Steven and Alexandra Cohen Veterans Center.
“The problem from the military and law enforcement perspective is that the majority of war fighters experience tremendous stigma in acknowledging their symptoms, particularly active duty military personnel,” he said. “A minority will exaggerate to avoid service or for compensation. Given that we’ve had nearly three million men and women serve in Iraq and Afghanistan, and the fact that we have no objective way yet of determining which ones continue to be fit for redeployment, which ones are in urgent need of help, and which ones deserve compensation, we need to develop better ways to determine if treatments are effective, to inform new treatment selection, and to define new targets for treatment.”
The scope of the problem is underscored in an analysis of data from 289,328 veterans entering VA Healthcare for the first time beginning on April 1, 2002 through March 31, 2006 (Am J. Pub. Health 2009;99[9]:1651-8) . Prior to the invasion of Iraq, the distribution of mental health problems was very similar among veterans as in the general population: depression being most common, and low rates of PTSD and alcohol and drug abuse. However, “with each quarter since the invasion of Iraq, there’s been an incubative growth in the prevalence of PTSD, which has now eclipsed depression,” Dr. Marmar said. “We have a toll, a generational effect which looks similar in magnitude with the Vietnam War, both in the number of men and women who serve and in the prevalence of PTSD, depression and alcohol- and drug-related disorders.”
In the general population, risk factors include female sex, child abuse, genetics, which in twin studies account for 30-40% of the risk, lower IQ and lower educational attainment, stressful life events in the prior and following year, and panic reaction at the time of event, such as racing heart, shaking, and sweating.
According to findings from the National Vietnam Veterans Readjustment Study , risk factors for chronic warzone PTSD include high school dropout rate, history of child abuse, high warzone exposure, serious warzone injury, killing combatants, prisoners, and civilians, peritraumatic dissociation, hostile homecoming, post-discharge trauma, and genetics. “These are the risk profiles, and they should give us some clues about where to look for biological factors,” Dr. Marmar said.
The risks of service are not limited to stress, anxiety, depression, alcohol and drug abuse, or traumatic brain injury (TBI). “If you compare men and women returning from Iraq and Afghanistan with no mental health issues to those who have a diagnosis of either PTSD, depression, or the combination, the [diagnosed] cases have 2.5 times the risk of tobacco use, hypertension, dyslipidemia, obesity, and type 2 diabetes,” he said. “These are people in their late 20s and early 30s. So the costs of warzone-related stress and depression are enormous on general health.”
Dr. Marmar presented preliminary findings from the ongoing PTSD Systems Biology Consortium, an effort by researchers at seven universities to establish biomarkers for PTSD. Funded by the Department of Defense, the National Institutes of Health, and other sources, the consortium is comprised of integrated cores including neurocognition, genetics, structural and functional brain imaging, endocrinology, metabolism, genomics, proteomics, metabolomics, and bioinformatics.
To date, the researchers have screened 2,215 veterans from service in Iraq and Afghanistan, all of whom have been deployed to war at least once. Cases were PTSD positive and had a CAPS (Clinician-Administered PTSD scale) score of 20 or greater. Controls were PTSD negative and had a CAPS score of less than 20. They excluded subjects with lifetime psychosis, bipolar disorder, or OCD, as well as alcohol dependence in the past eight months, and drug abuse in the past year. They also excluded veterans with TBI “because we’re trying to be very careful to see if we can get a biological signal comparing combat PTSD cases with controls,” Dr. Marmar noted.
Dr. Marmar presented preliminary findings from 52 PTSD cases and 52 controls that were matched for sex, ethnicity, and age. The sample was entirely men, their mean age was 34 years, and they had a mean of 14.8 years of education. The researchers covaried for depression and other known confounders. “It’s very difficult to disentangle the effects of PTSD and depression because 50% of the cases of warzone PTSD also meet criteria for current major depression, and over 80% meet criteria for lifetime depression,” he said.
In results from the clinical diagnostic evaluation, PTSD cases, compared with controls, were significantly more likely to have current anxiety (7% vs. 0%, respectively; P = .041); lifetime anxiety (9.6% vs. 0%; P = .022); current major depressive disorder (51.5% vs. 1.9%; P<.001); lifetime MDD (84.6% vs. 23.1%; P<.001); and lifetime alcohol abuse dependence (63.5% vs. 25%; P = .001). There was also a non-signficant trend toward lifetime substance abuse/dependence (13.5% vs. 3.9%; P = .081).
Results from the neurocognitive assessments revealed that PTSD positive men had a significantly lower estimated IQ, compared with their PTSD negative counterparts (a mean of 99.3 vs. 107.9, respectively; P = .031). Other significant differences between the two groups were observed in tests of auditory and working memory, specifically digit span (8.67 vs. 10.04; P = .02), and the visual memory sum (9.1 vs. 10.67; P = .01).
One of the consortium collaborators developed a test to compare reward and punishment learning. For the test, “the subject is required to understand what the meaning of a symbol is in a task, and they have no prior knowledge [of the meaning],” Dr. Marmar explained. “They’re either rewarded for guessing correctly or punished for guessing incorrectly.” So far, the healthy controls “are performing much better in identifying the symbols when they’re rewarded, compared with the PTSD cases, and there’s no difference in punishment,” he said. “So there’s impaired reward learning and intact punishment learning in PTSD cases compared to controls, which likely reflects underlying disturbances in dopamine reward circuitry.”
Investigators in the neurogenetics core hypothesized that DNA variants in stress-response genes identified from previous medical studies will be associated with PTSD. These included FKBP5, COMT, APOE, BDNF, PACAP/PAC1R, and OPRL1. Initial analysis revealed that there were a greater number of BDNF allele frequencies among cases, compared with controls (P = .008). “It would appear that BDNF variants confer resilience for combat-related PTSD,” Dr. Marmar said.
The researchers also found a single nucleotide polymorphism never previously described on Chromosome 4. “It’s in a region between genes, probably a micro-RNA regulatory gene on the 4th chromosome,” he said. “That gene in our sample was associated with higher levels of PTSD. In addition, fMRI studies found that carrying this allele was associated with weaker activation of prefrontal cortical areas in the brain to empirical faces tasks.”
The endocrine core found that PTSD cases had lower ambient cortisol levels, compared with controls (P = .051). They also had significantly greater cortisol suppression following dexamethasone administration, compared with controls (P = .013). “This is evidence that there is increased glucocorticoid receptor sensitivity in PTSD expressing as elevated cortisol suppression,” Dr. Marmar said.
Investigators from the structural imaging core found no significant differences in overall hippocampal volume or in the five major hippocampal subfields between PTSD cases and controls, nor in difference in the volume of other brain structures previously implicated in PTSD, such as the amygdala and the thalamus. However, the researchers are finding some differences between cases and controls on functional imaging, including increased spontaneous activity in the amygdala and the insula, and decreased spontaneous activity in the precuneus. “The overall findings on fMRI are that there’s increased activity in the regions [of the brain] associated with fear and decreased connectivity between the frontal cortex and the amygdala,” he said. “This is consistent with the model of dysregulated fear activity in PTSD.”
Researchers have also observed that many markers of metabolic syndrome are significantly elevated between PTSD cases and controls, including fasting glucose (P = .001), weight (P = .03), and resting pulse (P = .003). “When you covary for depression, these findings remain,” Dr. Marmar said. “It’s important to note that these are men mostly in their early 30s recently returned from war and recently in military training, physically fit to be deployed to war.”
He closed his presentation by noting that mounting evidence from animal and human studies suggests evidence of mitochondrial dysfunction in PTSD. In the current analysis, researchers observed a reduced abundance of citrate and other mitochondrial metabolites in PTSD cases compared with controls, as well as an increased abundance of “premitochondrial” metabolites such as pyruvate and lactate. “These findings stand when you covary for depression and for metabolic syndrome,” Dr. Marmar said.
“We believe that these may be very important potential future candidate biomarkers to differentiate PTSD cases from controls.”
The next step in this effort, he added, is to replicate the consortium’s overall findings in a cross-validation sample of 50 male cases and 50 male controls. “We also have a sample of 40 female cases and 40 controls to see if the markers are the same or different,” he said. The researchers are also conducting a prospective study of 1,200 active duty military personnel, who will be evaluated before and after deployment.
For now, some clinicians wonder what should be done for men and women who carry the PTSD risk alleles, or carry the endocrine or metabolism vulnerability to develop complications from combat exposure. “That’s a very sensitive national question,” Dr. Marmar said. “People want to serve their country. The answer may be to allow service but to have a more nuanced approach to what people’s roles should be within the military, to match individuals’ stress resilience with the responsibilities they have.”
Dr. Marmar reported that he had no relevant financial conflicts.
On Twitter @dougbrunk
