PTSD and Suicide Ideation in Veterans

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Re: PTSD and Suicide Ideation in Veterans

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PTSD and Death from Suicide

https://www.ptsd.va.gov/publications/rq_docs/V28N4.pdf


Understanding the causes of death from suicide has been the subject of scientific research for decades. In recent years, the increasing suicide rates among Veterans and active duty military members has brought predictors of suicide with specific relevance to these populations to the forefront of the research in this area
(e.g., PTSD). Most of this work has focused on PTSD and suicidal ideation or suicide attempt, and provided evidence for these associations (see Additional Citations for a brief summary of some well-done studies in this area). Research on predictors of suicidal behavior like ideation and attempts is critical; however, it does not necessarily provide information about the association between PTSD and death from suicide. This distinction is important because only about 15% of people who survive a suicide attempt go on to eventually die by suicide and, further, there are well-known differences in the risk factors for these events (e.g., gender). The more limited body of work on death from suicide is in part a result of challenges inherent to studying suicide in general (e.g., rarity of the event on a population level, difficulty in predicting who will die by suicide even in a high-risk sample, need for data collected prior to death) and, accordingly, a large portion of our knowledge in this area has come from epidemiologic studies using registry-based data. Interestingly, while some studies provide clear evidence that PTSD increases risk for death from suicide several studies have found evidence of a protective effect (i.e., PTSD decreases risk of death from suicide), thus resulting in a debate regarding the true magnitude and direction of this association. Further complicating this issue is the effect of comorbid psychopathology (e.g., depression) on this association, which has been inconsistently considered across studies. Depression in particular is known to be highly comorbid with PTSD and is also a strong risk factor for death from suicide and thus may act as a confounder, mediator, or modifier of this association, or any combination of the three. In this overview, we will summarize the state of the literature on the association between PTSD and death from suicide across civilian, active duty, and Veteran populations.

This guide to the literature focuses exclusively on risk factors for death from suicide and will not discuss the voluminous literature on risk factors for suicidal ideation, plans, or unsuccessful attempts. In the final sections, we discuss possible etiologic and methodologic causes of the disparate findings to date, and present possibilities for future research which may help elucidate this complex association.

Point: PTSD increases risk for death from suicide


Although few studies have examined the association between PTSD and suicide among civilian samples, the work that has been done has documented consistent evidence of a strong association, even while accounting for pre-existing psychiatric comorbidity (Gradus et al., 2010; Gradus et al., 2015). One study examined all suicide deaths from 1994–2006 using the Danish national healthcare and social registries, and found that persons with PTSD had 5.3 times the rate of death from suicide than persons without PTSD, after adjustment for gender, age, marital status, income, and pre-existing depression diagnoses (n = 208,918). A subsequent study examined death from suicide among all persons diagnosed with PTSD in Denmark from 1995–2011 and found that after adjustment for demographics and pre-existing comorbid psychiatric diagnoses, persons with PTSD had 13 times the rate of suicide than persons without PTSD (n = 22,716). The association between PTSD and suicide is particularly relevant to military members and Veterans, and given the availability of registry-based data on these populations most of the research in this area has been conducted within these populations. A handful of studies have documented an association between PTSD and suicide in active duty military members, but these studies did not examine comorbid psychopathology. In the entire active duty military population in 2005 (n = 2,064,183) and 2007 (n = 1,981,810) evidence of an association between PTSD and suicide was found in Army and Air Force members in both years, with effects ranging in magnitude from 1.9 to over 10. Sample sizes were too small to calculate an association for service members in the Marines or Navy (Hyman, Ireland, Frost, & Cottrell, 2012). Among US Army service members from 2001–2009 those who died by suicide (n = 874) were almost 13 times more likely to have received a diagnosis of PTSD compared to all Army service members in the same time period (Black, Gallaway, Bell, & Ritchie, 2011). These findings were corroborated in a smaller study of risk factors for suicide in the US Army from 2007–2008 (n = 255) in which persons with PTSD had 6 times the rate of suicide than those without PTSD (Bachynski et al., 2012). Using data from the Millennium Cohort Study (n = 151,560) that included current and former military personnel, LeardMann and colleagues (2013) found a sex- and age-adjusted association for PTSD and suicide of 1.8. Despite this evidence of an 80% increase in suicide risk among people with PTSD, this association was not statistically significant, likely due to sample size, and thus PTSD was not further examined in multivariate models.Some of the earliest and most expansive epidemiologic studies on PTSD and death from suicide have been conducted among Veterans, and these have used varying methods to examine comorbid psychopathology. Among Vietnam-era Veterans included in the Department of Veterans Affairs (VA) Agent Orange Registry (Bullman & Kang, 1994), Veterans with PTSD (n = 4,247) had an approximately 4 times higher suicide rate than Veterans without PTSD (n = 12,010), adjusting only for age and race. This study did not adjust for other psychiatric disorders analytically, but, in a separate analysis, did examine the association between PTSD and suicide among 3,246 Veterans who had no comorbid diagnoses, thus, controlling for comorbidity through restriction. Among these Veterans the suicide rate was almost 6 times as high as the expected rate in general population US males. Since this early study, several other epidemiologic studies have documented an association between PTSD and suicide in Veteran samples, primarily Veterans who use VA services, but with varying methods to assess comorbid psychopathology. Ilgen et al. (2010) examined the rate of suicide from fiscal year (FY) 1999 to FY 2006 among all Veterans who used VA care in FY 1999 (n = 3,291,891). Adjusting for age, male Veterans with PTSD had 1.8 times the rate of suicide than male Veterans without PTSD, while female Veterans with PTSD had 3.5 times the rate of suicide than female Veterans without PTSD. A subsequent study by Ilgen and colleagues (2012), examined all Veterans who received Veterans Health Administration (VHA) services during FY 2007 or FY 2008 (n = 5,772,282) and found a main effect for the association between PTSD and suicide among these Veterans, adjusting for sex, age, and VISN. Despite the contribution of this work to our understanding of this association, neither study examined the effect of comorbid psychiatric diagnoses on these associations. Further, it is unclear how this work might generalize to Veterans who do not use VA services. These studies were followed by work from Conner et al. (2013) that explicitly examined psychiatric disorder comorbidity and suicide in all male patients who used VA services in FY 1999 (n = 2,962,810). Patients with PTSD and any psychiatric comorbidity had 2.6 times the rate of suicide than those with no psychiatric diagnoses. Similar to the previous work by Bullman and Kang (1994), the authors then conducted analyses which were restricted to patients with PTSD diagnosis and no comorbidity and, thus, controlled for potential confounding by psychiatric comorbidity through restriction.

Those with PTSD and no other psychiatric disorders had 1.6 times the rate of suicide than male Veterans without any psychiatric diagnoses. Subsequently, in the largest study to date focused specifically on PTSD and suicide, Conner and colleagues (2014) examined VHA patients from FY 2007–2008 (n = 5,913,648). In unadjusted analyses and demographically-adjusted analyses PTSD was associated with suicide with odds ratios that were all approximately 1.3. However, after adjustment for comorbid psychiatric diagnoses this association was reduced to 0.77, indicating a protective effect of PTSD on suicide. Counterpoint: PTSD is protective against death from suicide Given what we know about the potential negative, long-term consequences of PTSD and evidence of an association between PTSD and suicide, a study demonstrating a protective effect for the association between PTSD and suicide may seem counterintuitive or perhaps like a spurious finding. However, the 2014 study by Conner and colleagues is not the only one that has documented this association in this direction. A study of all US military personnel from 2001–2011 (n = 3,795,823) examined suicide during military service or post-separation and found a protective effect of PTSD across a range of time periods between diagnosis and death (effect estimates ranged from 0.63 to 0.82) compared to persons with no PTSD diagnoses (Shen, Cunha, & Williams, 2016). These estimates were adjusted for demographics, military variables, and comorbid psychopathology. In the Army STARRS study, the largest and most sophisticated study of risk factors for suicide among military members to date, a protective effect was found for the association between PTSD diagnosis during hospitalization and suicide after psychiatric hospitalization in 53,769 soldiers between 2004–2009 using novel machine learning methods that incorporated predictors from multiple domains including various forms of psychopathology (Kessler et al., 2015). The authors of the study do caution, however, that when building their models they prioritized the accuracy of the overall model, rather than the accurate estimation of each individual association, so the associations should be interpreted with caution. Among Veterans, Desai, Dausey, and Rosenheck (2008) found that among VA patients who were discharged from an inpatient unit between 1994–1998 (n = 1,057) PTSD was protective against death from suicide when adjusting for demographics and psychiatric comorbidity (adjusted risk ratio = 0.62). Similarly, in a study of all male Veterans discharged from VA inpatient units from FY 2005 to FY 2010 (n = 346,662) the association between PTSD and suicide was 0.66 for the year following discharge, after adjustment for demographics and psychiatric comorbidity (Britton et al., 2017). Zivin and colleagues (2007) examined PTSD and suicide among VA patients receiving treatment for depression from 1999–2004 (n = 807,694) and also found the association between PTSD and suicide to be protective (adjusted hazard ratio = 0.77).

Understanding disparate findings


Although most studies have documented that PTSD is associated with an increased risk for suicide, more than a few well-done studies have found a protective association. Why this is remains an open and important question. Potential explanations span etiologic and methodologic reasoning. A large and obvious discrepancy between the studies in each category has to do with the assessment of psychiatric comorbidity. Most of the studies that provide evidence of an association did not adjust for comorbidity, with the exception of the civilian research and the Veteran studies that adjusted through restriction. Studies that document an association without accounting for psychiatric comorbidity may report estimates that are inflated away from the null (due to lack of adjustment for these potential confounders); however, studies that did adjust for other psychopathology, particularly depression, provide compelling evidence of an association.Conversely, studies that documented a protective effect either adjusted for psychiatric comorbidity statistically or examined study populations with high levels of psychopathology. While it is hard to imagine that PTSD actually protects individuals from death from suicide, it is possible that such findings were the result of methodological choices or biases. For example, depression and its symptoms frequently co-occur with PTSD. In samples with high levels of comorbid PTSD and depression statistical adjustment for depression would obscure the part of the effect of PTSD on suicide that is due to this comorbidity. This adjustment would drive observed associations towards the null (e.g., that PTSD has no effect on death by suicide) and perhaps beyond it to demonstrate a protective effect. In fact, when strictly adhering to traditional epidemiologic methods, adjustment for a variable that is on the “causal pathway” between a predictor of interest and an outcome (i.e., PTSD -> Depression -> Suicide) is not recommended because these variables are thought to play an etiologically important role that is worthy of description rather than adjustment. In addition, in studies conducted entirely among samples with psychopathology (e.g., patients with depression or patients discharged from inpatient units), numerically smaller effects may be observed due to the use of a very high-risk study population. In these studies, the risk of suicide conferred by PTSD may not be enough to demonstrate an increased association, when compared to the very elevated suicide risk among a reference group with depression and/or other forms of psychopathology. The use of a high-risk reference group could make ratio measures of effect appear null or even protective if the predictor of interest has a weaker association with the outcome than the other risk factors that characterizes the study sample. Perhaps all results are evidence of different pieces of truth – that there are cross-population differences in the magnitude and direction of the association between PTSD and suicide. For that matter, there are likely within population differences in this association due to individual factors (e.g., gender or race/ethnicity – interestingly, the civilian studies which provide evidence for an association included a larger proportion of women than the active duty and Veteran studies). Epidemiologic research is critical for understanding the health of populations and documenting the need for resources. Yet, it is important to remember that one observed effect is an aggregation of likely varying effects that differ by people, places, and time included in one study. An important focus of future research will be to examine for whom PTSD is a risk factor for suicide and under what circumstances risk is potentiated. Further, future work will need to include rigorous and advanced methods to examine the many simultaneous and complicated roles of comorbid psychopathology can play in this association (e.g., marginal structural modeling, which allows for variables to be examined as confounders and modifiers simultaneously). Current novel applications of machine learning methods to understanding suicide risk are also a step in this direction (McCarthy et al., 2015).

Other data-driven methods that allow for the visualization of subpopulations for whom specific associations are particularly important (e.g., regression trees) may also result in a deeper understanding of the nuances of this association. In sum, there is conflicting evidence regarding the direction of the association between PTSD and death from suicide. While the majority of studies point to an increased risk of suicide associated with PTSD, the studies that do not corroborate these findings are too many to be discounted. Further research is needed to understand this potentially critical association.
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Re: PTSD and Suicide Ideation in Veterans

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What Are the Treatments for PTSD?

https://www.webmd.com/mental-health/wha ... disorder#1

Posttraumatic stress disorder (PTSD), a type of anxiety disorder, can happen after a deeply threatening or scary event. Even if you weren't directly involved, the shock of what happened can be so great that you have a hard time living a normal life.

People with PTSD can have insomnia, flashbacks, low self-esteem, and a lot of painful or unpleasant emotions. You might constantly relive the event -- or lose your memory of it altogether.

When you have PTSD, it might feel like you'll never get your life back. But it can be treated. Short- and long-term psychotherapy and medications can work very well. Often, the two kinds of treatment are more effective together.
Therapy

PTSD therapy has three main goals:

Improve your symptoms
Teach you skills to deal with it
Restore your self-esteem

Most PTSD therapies fall under the umbrella of cognitive behavioral therapy (CBT). The idea is to change the thought patterns that are disturbing your life. This might happen through talking about your trauma or concentrating on where your fears come from.

Depending on your situation, group or family therapy might be a good choice for you instead of individual sessions.

Cognitive Processing Therapy

CPT is a 12-week course of treatment, with weekly sessions of 60-90 minutes.

At first, you'll talk about the traumatic event with your therapist and how your thoughts related to it have affected your life. Then you'll write in detail about what happened. This process helps you examine how you think about your trauma and figure out new ways to live with it.

For example, maybe you've been blaming yourself for something. Your therapist will help you take into account all the things that were beyond your control, so you can move forward, understanding and accepting that, deep down, it wasn't your fault, despite things you did or didn't do.
Prolonged Exposure Therapy

If you've been avoiding things that remind you of the traumatic event, PE will help you confront them. It involves eight to 15 sessions, usually 90 minutes each.

Early on in treatment, your therapist will teach you breathing techniques to ease your anxiety when you think about what happened. Later, you'll make a list of the things you've been avoiding and learn how to face them, one by one. In another session, you'll recount the traumatic experience to your therapist, then go home and listen to a recording of yourself.

Doing this as "homework" over time may help ease your symptoms.


Eye Movement Desensitization and Reprocessing


With EMDR, you might not have to tell your therapist about your experience. Instead, you concentrate on it while you watch or listen to something they're doing -- maybe moving a hand, flashing a light, or making a sound.

The goal is to be able to think about something positive while you remember your trauma. It takes about 3 months of weekly sessions.
Stress Inoculation Training

SIT is a type of CBT. You can do it by yourself or in a group. You won't have to go into detail about what happened. The focus is more on changing how you deal with the stress from the event.

You might learn massage and breathing techniques and other ways to stop negative thoughts by relaxing your mind and body. After about 3 months, you should have the skills to release the added stress from your life.
Medications

The brains of people with PTSD process "threats" differently, in part because the balance of chemicals called neurotransmitters is out of whack. They have an easily triggered "fight or flight" response, which is what makes you jumpy and on-edge. Constantly trying to shut that down could lead to feeling emotionally cold and removed.

Medications help you stop thinking about and reacting to what happened, including having nightmares and flashbacks. They can also help you have a more positive outlook on life and feel more "normal" again.

Several types of drugs affect the chemistry in your brain related to fear and anxiety. Doctors will usually start with medications that affect the neurotransmitters serotonin or norepinephrine (SSRIs and SNRIs), including:

Fluoxetine (Prozac)
Paroxetine (Paxil)
Sertraline (Zoloft)
Venlafaxine (Effexor)

The FDA has approved only paroxetine and sertraline for treating PTSD.

Because people respond differently to medications, and not everyone's PTSD is the same, your doctor may prescribe other medicines "off label," too. (That means the manufacturer didn't ask the FDA to review studies of the drug showing that it's effective specifically for PTSD.) These may include:

Antidepressants
Monoamine oxidase inhibitors (MAOIs)
Antipsychotics or second generation antipsychotics (SGAs)
Beta-blockers
Benzodiazepines



It's OK for you to use a medicine off-label if your doctor thinks there's a reason to.

Medications might help you with specific symptoms or related issues, such as prazosin (Minipress) for insomnia and nightmares.

Which one or combination of meds is likely to work best for you depends in part on the kinds of trouble you're having in your life, what the side effects are like, and whether you also have anxiety, depression, bipolar disorder, or substance abuse problems.

It takes time to get the dosage of some medications right. With certain medications, you might need to have regular tests -- for example, to see how your liver is working -- or check in with your doctor because of possible side effects.

Medications probably won't get rid of your symptoms, but they can make them less intense and more manageable.

Disclaimer : This info is for educational / informational purposes only . See your doctor before making decisions on any treatments, or therapies.
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Re: PTSD and Suicide Ideation in Veterans

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"Brain fog" after COVID -19 recovery may indicate post-traumatic stress disorder

10/7/20


https://www.news-medical.net/news/20201 ... order.aspx

A new report suggests that lingering "brain fog" and other neurological symptoms after COVID-19 recovery may be due to post-traumatic stress disorder (PTSD), an effect observed in past human coronavirus outbreaks such as SARS and MERS.

People who have recovered from COVID-19 sometimes experience lingering difficulties in concentration, as well as headaches, anxiety, fatigue or sleep disruptions. Patients may fear that the infection has permanently damaged their brains, but researchers say that's not necessarily the case.

A paper co-authored by clinical professor and neuropsychologist Andrew Levine, MD, of the David Geffen School of Medicine at UCLA, and graduate student Erin Kaseda, of Rosalind Franklin University of Medicine and Science, in Chicago, explores the historical data on survivors of previous coronaviruses, which caused severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

The paper was published in The Clinical Neuropsychologist.

"The idea is to raise awareness among neuropsychologists that PTSD is something you might want to consider when evaluating persistent cognitive and emotional difficulties among COVID-19 survivors," said Dr. Levine.

"When we see someone for neuropsychological testing, we expect them to be at their best, relatively speaking," Dr. Levine said. "If we identify a psychiatric illness during our evaluation, and if we believe that condition's symptoms are interfering with their ability to perform at their best, we would want that treated first, and then retest them once it's under control."

If the symptoms are due, even partially, to a psychiatric condition such as PTSD, treatment will help manage those symptoms, and provide a clearer view of any underlying brain issues.

" Once they have treatment, and hopefully have some remission of their psychiatric symptoms, if the cognitive complaints and the deficits on neuropsychological tests are still there, then that's more evidence that something else is going on."

- Erin Kaseda, Graduate Student, Rosalind Franklin University of Medicine and Science

"It's going to be important for clinicians across the board to be keeping up with the literature that's coming out, to make sure they have the most up to date information as these survivors are starting to present for neuropsychological testing."

Kaseda began pursuing this question based on her experience working with patients with mild traumatic brain injury, such as concussion. "When these symptoms persist for months or years after the original injury, it's much more likely to be due to the presence of a psychiatric disorder," she said.

A review of data from the SARS and MERS outbreaks showed that those survivors had heightened risk for PTSD.

In the case of COVID-19, the symptoms of PTSD may arise in response to the invasive measures needed to treat the patients, including intubation and ventilation, which can be traumatic for fearful patients. Other times, delirium causes patients with COVID-19 to suffer hallucinations, and the memory of these terrifying sensations continues to plague the recovered patient.

In addition to patients who have been hospitalized, frontline health-care providers can be similarly affected due to the constant stress and fear they face at work. And for some people, the anxiety of living through a pandemic, being isolated from friends, and battling the constant fear of an invisible threat can deliver a similar blow to thinking and memory skills.

While a PTSD diagnosis might not sound like good news, there are many available treatments for the disorder, including psychotherapy and medications. By comparison, researchers are still working to understand the direct neurological effects of COVID-19. "Treatment options (for COVID) are still quite a way's out, because it's still an evolving situation," Kaseda said.

"We don't actually know anything yet from survivors of COVID-19," Kaseda said. "Until we have that data, it's very hard to say what actual percentage of patients are going to have cognitive complaints because of direct effects of the virus, because of medical intervention, or because of psychiatric concerns."
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Re: PTSD and Suicide Ideation in Veterans

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Post traumatic stress disorder as a risk factor for suicidal ideation in Iraq and Afghanistan War veterans

https://pubmed.ncbi.nlm.nih.gov/19626682/


Post traumatic stress disorder (PTSD) was examined as a risk factor for suicidal ideation in Iraq and Afghanistan War veterans (N = 407) referred to Veterans Affairs mental health care. The authors also examined if risk for suicidal ideation was increased by the presence of comorbid mental disorders in veterans with PTSD. Veterans who screened positive for PTSD were more than 4 times as likely to endorse suicidal ideation relative to non-PTSD veterans. Among veterans who screened positive for PTSD (n = 202), the risk for suicidal ideation was 5.7 times greater in veterans who screened positive for two or more comorbid disorders relative to veterans with PTSD only. Findings are relevant to identifying risk for suicide behaviors in Iraq and Afghanistan War veterans.
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Re: PTSD and Suicide Ideation in Veterans

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Study aims to understand the impact of COVID-19 pandemic on Canadian veterans and their spouses

10/15/20


https://www.news-medical.net/news/20201 ... ouses.aspx


Lawson Health Research Institute and the Centre of Excellence on Post-Traumatic Stress Disorder (PTSD) are partnering with a population at high risk of mental illness - Canadian Veterans and spouses of Canadian Veterans - to study how they have been impacted by the COVID-19 pandemic. Through online surveys, the project will hear directly from Veterans and their spouses to assess the pandemic's effects on their wellbeing over time. The team hopes results can be used by health care workers and policymakers to support Veterans and their families during both the current pandemic and future public health emergencies.

" With concerns about COVID-19 infection and drastic changes to everyday life, the pandemic is taking a toll on the health of Canadians. And it may be particularly distressing for those vulnerable to mental illness."

- Dr. Don Richardson, Lawson Associate Scientist and Director of the MacDonald Franklin Operational Stress Injury (OSI) Research Centre

Population studies show that Canadian Veterans are at double the risk of mental illness when compared to the rest of the population. They experience higher rates of depression, anxiety and loneliness. Spouses of Canadian Veterans are also at higher risk of distress, sometimes undertaking significant caregiving responsibilities that lead to less independence.

"It's currently unknown how the pandemic will impact Veterans and their spouses, but it could result in particularly serious outcomes," says Dr. Anthony Nazarov, Associate Scientist at Lawson and the MacDonald Franklin OSI Research Centre. "We want to hear from all Canadian Veterans and their spouses, whether they're doing well or not and whether they're seeking care or not."

The study aims to recruit 1,000 Canadian Veterans and 250 spouses of Canadian Veterans. Participants will complete online surveys, available in both English and French, once every three months for a total of 18 months. They will be asked questions about their psychological, social, family-related and physical wellbeing, and any relevant changes to their lifestyle and health care treatment.

"Veterans who regularly access health care services could encounter significant changes, including a move to virtual care appointments. This could lead to increased caregiving responsibilities for spouses," says Dr. Nazarov. "Given the uncertainty surrounding the pandemic, these changes may persist well into the future, mandating a thorough assessment of patient satisfaction and treatment outcomes."

The team hopes results can be used to support the wellness of Veterans and their families during public health emergencies. This includes providing health care professionals and policymakers with information to guide emergency preparedness policies and health care delivery models. They hope results can also be used to recognize early signs of distress in order to target with early interventions.

"We are seeking to understand the impact of COVID-19 on Veterans and their families to identify if this global pandemic is leading to psychological distress or triggering historical traumas," says Dr. Patrick Smith, CEO of the Centre of Excellence on Post-Traumatic Stress Disorder. "The Centre's primary goal is to increase Canadian expertise related to military and Veteran mental health, suicide prevention and substance use disorders. This study can help us understand if the pandemic is having debilitating and life-altering effects, and help us address a potential mental health crisis."

Source:


Lawson Health Research Institute
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Re: PTSD and Suicide Ideation in Veterans

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➤ Risk factors for suicide among Veterans

https://www.research.va.gov/topics/suicide.cfm

Sexual dysfunction linked to suicidal thoughts—Sexual dysfunction is common in people with posttraumatic stress disorder (PTSD). In a 2020 study led by researchers with the San Diego VA Health Care System, a team assessed 138 Veterans and their partners before they began couples-based PTSD treatment. The assessment showed that, in male Veterans, decreased sexual pleasure and decreased frequency of sexual intercourse were linked with more recent suicidal thoughts.

In female Veterans, increased sexual frequency was marginally linked with increased suicidal thoughts. The researchers stressed the importance of assessing sexual function as a risk factor for suicide, and suggested therapists should consider the possibility that sexual functioning may be protective or predictive of suicidality depending on the person being treated and the context of the treatment.

Post-TBI symptoms linked to suicide attempts—Having traumatic brain injury (TBI) symptoms before deployment is associated with an increased risk of suicide attempt following deployment, according to a study published in 2020 that included a VA San Diego Healthcare System researcher.

The research team studied data on 7,677 soldiers deployed to Afghanistan in 2012. Of these, 103 attempted suicide. The team found that soldiers who had had post-concussive or TBI symptoms prior to deployment had a higher risk of suicide attempt than those without TBI symptoms. Therefore, detecting TBI symptoms could help target Veterans who would benefit from suicide prevention programs.

In a 2019 study of the effects of TBI on suicide attempts, a team of researchers funded by VA’s Mid-Atlantic MIRECC found that post-9/11 Veterans with a history of repeated TBIs were about twice as likely to report suicidal thoughts over the week before being surveyed, compared with Veterans who had had one TBI or none at all.

The findings were developed from interviews with more than 800 Veterans who had combat roles in Iraq and Afghanistan. About half of the interviewees reported at least one TBI. Nearly 20% of those with a history of multiple TBIs said they had recent suicidal ideation—thoughts of suicide—compared with 11% of Veterans with one TBI and 9% with no history of a TBI.

PTSD, however, was not consistently associated with suicidal ideation in Veterans with TBI.

Social determinants of health and suicide—Social determinants of health are economic and social conditions that can influence an individual's or group's health status. In a 2019 study, researchers at the VA Pittsburgh Healthcare System’s Center for Health Equity Research and Promotion used VA electronic health data to learn that seven adverse social determinants of health were strongly associated with thoughts of suicide and suicide attempts in Veterans, even after adjusting for mental health diagnoses.

The seven adverse social determinants of health were violence, housing instability, financial or employment problems, legal problems, familial or social problems, lack of access to health care and transportation, and nonspecific psychosocial needs. The team concluded that integrating social determinants of health into the electronic health record, using ICD-10 codes, could improve suicide prevention efforts.

Suicide risk common in patients with anxiety—In a 2019 study, a team of researchers with the Syracuse VA Medical Center found that 40% of surveyed Veterans with anxiety had at least one risk factor for suicide. The team surveyed 182 primary care patients who had anxiety symptoms but were not in psychotherapy specialty care.

The researchers found that suicide risk was more common in Veterans who also screened positive for depression than in those who had anxiety alone. The severity of anxiety symptoms did not affect Veterans’ suicide risk. The researchers believe primary care providers should assess suicide risk in patients with anxiety even when those patients are not seeking mental health treatment or when their anxiety symptoms do not rise to the level of a disorder.

Two genes may be linked to suicide attempts—Researchers with the Durham VA Medical Center and Duke University conducted a genome-wide association study, published in 2018, in which they examined the genomes of a large sample of Veterans to look for genetic variations that could be associated with a history of suicidal behavior. (A genome is the complete set of genetic information in a person or organism.)

The team found an association between suicide attempts and a gene called KCNMB2, which plays an important role in neuronal excitability. They also found evidence that may link another gene, ABI3BP, to both suicide attempts and suicidal thoughts. The researchers cautioned that additional work to replicate and extend their findings is needed.

Possible link between low cholesterol and suicide—Researchers at the Coatesville VA Medical Center in Pennsylvania found that lower cholesterol levels may be a biomarker for suicidal behavior. The 2017 study results indicated that Veterans with total cholesterol levels below 168 mg/dL appeared to be at higher risk of suicide than those with higher cholesterol levels. The researchers examined the medical records of 128 Veterans who received care at the Coatesville VA and who were included in a suicide prevention database.

Veterans in the study who experienced suicidal thoughts or attempts had cholesterol levels that were significantly lower than those who did not. Further analysis found that Veterans with suicidal behaviors were younger; leaner; and had more anxiety, more sleep problems, and higher education than those who were being seen for a health issue unrelated to suicide. The researchers cautioned against making a definitive link between low cholesterol and suicide risk.


➤ Predictors of suicidal behavior

Suicidal thoughts and behaviors, including suicide attempts and death by suicide, are commonly found at higher rates among people with psychiatric disorders. VA researchers have studied warning signs in hopes of being able to prevent suicide in Veterans and others.

Benzodiazepines may increase suicide risk—Benzodiazepines are sedative drugs commonly prescribed for conditions such as insomnia, anxiety, and dementia. They are also prescribed to people with PTSD and are often given to patients with chronic obstructive pulmonary disorder (COPD) to treat symptoms.

In a 2019 study, researchers from VA Puget Sound Health Care System in Seattle and the University of Washington found long-term use of benzodiazepines in COPD patients who also had PTSD more than doubled their risk of suicide. The researchers looked at the medical records of 44,555 Veterans who received VA care between 2010 and 2012. Of these, 23.6% received benzodiazepines for 90 days or longer. The researchers found that these patients had higher rates of psychiatric admissions. However, long-term use of benzodiazepines in this patient group did not increase the risk of death from all causes or from respiratory events.

Opioids are a key contributor to suicides and drug overdoses—Researchers from the VA Center for Clinical Management Research and the University of Michigan published a 2019 review article that found American adults died by suicide or drug overdose at more than twice the rate they did 17 years ago. The researchers also found that use of opioid medications was a key contributor to that rise in deaths. Opioids are a class of drugs used to treat moderate to severe pain.

Using data from the Centers for Disease Control and Prevention, the researchers showed that the number of deaths from suicide and unintentional overdoses rose from 41,364 in 2000 to 110,749 in 2017. Suicides and overdoses from opioids accounted for more than 41% of such deaths in 2017, up from 17% in 2000. Opioids were implicated in more than two-thirds of all unintentional overdose deaths in 2017 and one-third of all overdose-related suicides.

The researchers believe addressing the problem will take investments in proven treatments for opioid addiction and additional research to identify and better treat Veterans at risk for opioid overdoses.

Suicidal thinking among Veterans—As part of the National Health and Resilience in Veterans study, more than 2,000 Veterans were surveyed on their prevalence of suicidal thinking. The study participants were asked twice, in 2011 and 2013, whether they had experienced suicidal thoughts in the two weeks prior to the survey. A minority, nearly 14%, reported they had.

The results of the 2016 study, led by VA's National Center for PTSD, determined that higher levels of psychiatric distress, physical health problems, and a history of substance misuse predicted chronic suicidal thinking in the study population.

In addition, because many Veterans reported having had suicidal thoughts in one survey but not the other, the researchers determined thoughts of suicide can come and go over time. The study authors said this finding underscored the need for ongoing monitoring of Veterans for suicidal thoughts, not just a one-time screening. Study researchers also found that being connected to others socially could keep some Veterans from thinking about suicide.

Substance use disorders and suicide risk—A team of researchers led by the VA Center for Clinical Management Research in Ann Arbor, Michigan, found in 2017 that Veterans with substance use problems have a higher risk of suicide than those without. They looked at health data for than 4.8 million Veterans and found drug and alcohol problems affected 8% of males and 3% of females in the study population. Veterans with a substance use disorder had more than twice the risk of suicide compared to those who did not.

The suicide rate was especially high among women Veterans with drug or alcohol problems. These women had greater than five times the rate of suicide than women Veterans who did not have substance abuse problems.

Exposure to suicide increases risk—Veterans and active-duty service members who have been bereaved by suicide may be at elevated risk of suicide, according to a 2017 study by researchers at the VA Eastern Colorado Health Care System and the University of Florida. The study's authors found that individuals who were particularly close to a person who died by suicide were at greater risk for future suicidal behaviors themselves.

The authors did not look at how service members and Veterans compared to the civilian population, nor did they study the degree to which service members or Veterans were exposed to suicide.

Insomnia and suicide
—A 2012 chart review study of 423 Veterans who died by suicide found that nearly half (173) of those Veterans had a sleep disturbance, such as insomnia, documented by a clinician. The study found that Veterans with a sleep disturbance died sooner after their final visit to a VA facility than those who did not. Researchers with the New York/New Jersey VA Health Care Network Center of Excellence for Suicide Prevention concluded that the presence of a sleep disturbance might pose a near-term risk of suicide. They suggested interventions to address sleep disturbances might be an important way to reduce suicide risk.

In 2016, researchers with the Center of Excellence for Suicide Prevention in Canandaigua, New York, found that cognitive behavioral therapy for insomnia and imagery rehearsal therapy were useful in treating nightmares in combat Veterans with PTSD. The researchers found that combining the two therapies was successful in reducing insomnia, nightmares, depression, and PTSD severity. The researchers said the combination of CBT-I and IRT was a promising treatment for Veterans with combat-related trauma and psychiatric morbidity.

Biomarkers of suicide—VA researchers at the Durham VA Medical Center and the Mid-Atlantic MIRECC found, in a 2014 study, that changes in the levels of certain amino acids in the body may contribute to suicide risk. The amino acids in question are important in regulating people's mood and behavior, although understanding their exact relationships to suicide will require further study.

In 2016, VA researchers at the Rocky Mountain MIRECC for Suicide Prevention in Denver, along with researchers in three other countries, found reduced activity in the enzyme ACMSD in people who have attempted suicide.

The enzyme is part of a chain of biochemical reactions called the kynurenine pathway, which is activated by inflammation. When it behaves sluggishly, it causes abnormal levels of two acids in the body, which could be measured in blood tests to help identify patients at high risk of suicide.


➤ Responding to suicide risk

While the studies described above and others help clinicians identify patients who are at risk of harming themselves, VA researchers are also considering ways to decrease that risk.

Uridine study—Uridine is a naturally occurring dietary supplement that shares similar brain mechanisms and neural effects with ketamine and lithium, two treatments commonly used to reduce suicidal thoughts. A team of VA researchers led by investigators at the Salt Lake City VA Medical Center is conducting a study to determine whether four weeks of taking uridine is an effective treatment for suicide compared to a group taking a placebo. They are recruiting 90 participants for this study, which is scheduled to be completed in 2023.

Firearms and older Veterans—Among U.S. Veterans, male Veterans aged 55 to 74 account for a disproportionate number of suicide deaths. For all Veterans, a majority of suicides are related to firearms. In a 2020 study, a team led by researchers at the Rocky Mountain MIRECC for Suicide Prevention interviewed 17 Veterans, aged 50 to 70, who were current or former firearm owners or users in order to learn about their experiences and beliefs about firearms.

The researchers identified six themes that could be used to develop safety interventions among older male Veterans. They learned the interviewees’ firearm experiences were usually facilitated by family members and took place at an early age; firearms serve an important social function; these Veterans believe not everyone should have access to firearms; they have preferences for who is involved in firearm safety discussions; and they perceive firearms as useful for protection.

The team hopes these findings may be useful in developing a personalized, effective intervention for Veterans in this age group.

WHO develops promising strategy—The World Health Organization (WHO), a United Nations body, has made suicide prevention a top priority on the global public-health agenda. WHO has developed a program called "brief intervention and contact," providing people who go to an emergency room following a suicide attempt with a one-hour educational session and regular contact with a health care professional after they are discharged.

A team of researchers with the White River Junction VA Medical Center in Vermont and Dartmouth College found in 2017 that this program was linked to significantly lower odds of suicide, based on a literature search. No other suicide prevention technique produced significant effects in reducing suicide, according to the research team. The team recommended additional research into this strategy.

Health-promoting behaviors may reduce suicidal thoughts in Veterans with PTSD
—Researchers with the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas, published a 2016 survey of more than 100 Iraq and Afghanistan Veterans with PTSD. They found that Veterans who routinely engaged in activities to foster good nutrition, physical activity, stress management, spiritual growth, health responsibility, and positive interpersonal relationships have a less pronounced link to suicidal thoughts.

The researchers believe that promoting these activities in Veterans with PTSD could help lower their suicide risk.
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Re: PTSD and Suicide Ideation in Veterans

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Diagnostic Biomarkers for Posttraumatic Stress Disorder (PTSD): Promising Horizons from Translational Neuroscience Research

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520791/


Abstract

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). Although its diagnostic features have been recently re-classified with the emergence of the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5), the disorder remains characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the etiology and maintenance of PTSD. Translational research spanning the past few decades has revealed several potential avenues for the identification of diagnostic biomarkers for PTSD. These include, but are not limited to, monoaminergic transmitter systems, the hypothalamic-pituitary-adrenal (HPA) axis, metabolic hormonal pathways, inflammatory mechanisms, psychophysiological reactivity, and neural circuits. The current review provides an update to the literature with regard to the most promising putative PTSD biomarkers with specific emphasis on the interaction between neurobiological influences on disease risk and symptom progression. Such biomarkers will most likely be identified by multi-dimensional models derived from comprehensive descriptions of molecular, neurobiological, behavioral, and clinical phenotypes.


Introduction


Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that occurs after a psychological traumatic life event and increases individual vulnerability to adverse health outcomes (1). PTSD is heterogeneous, often presenting across different symptom domains, including re-experiencing, avoidance/numbing, and hyper-arousal symptoms (2). While extensive work has successfully identified psychological, genomic, and biological risk factors that are associated with PTSD in trauma survivors (3–5), the identification of discrete diagnostic biomarkers for PTSD remains elusive. The lack of diagnostic biomarkers for PTSD is not due to a lack of intensive study, but rather likely due to the complexity of PTSD and the complex set of rules by which we classify individuals according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), as illustrated by the recent description of 636,120 different ways in which an individual can be diagnosed with PTSD (6). Furthermore, PTSD is associated with significant mental health (e.g., major depression, substance and alcohol abuse, panic disorder, suicide) and general medical (e.g., diabetes, cardiovascular disease(7, 8) comorbidities, which can obscure the search for diagnostic biomarkers for PTSD. Given that DSM criteria are not based on the underlying biology, PTSD research could benefit significantly from the new approach to mental health diagnoses using the Research Domain Criteria (RDoC; (9)). One of the tenets of this approach is dimensional analyses of neurobiological metrics and symptoms, rather than diagnostic classification. The putative biomarkers listed in this review are reflective of the extant literature, but can also serve RDoC objectives in future studies by linking PTSD symptoms to relevant biological underpinnings.

The vast heterogeneity inherent in PTSD symptom presentation makes it highly unlikely that a valid, singular biomarker will be identified for PTSD (10, 11). However, comprehensive biological phenotyping of the factors associated with PTSD may yield a parsimonious diagnostic model with which to diagnose PTSD in the future. The current review will highlight several biomarkers associated with PTSD symptomatology and vulnerability, in addition to underscoring how individual factors, such as one’s co-morbid diagnoses and gender, must be considered as they can profoundly influence biology and thus influence our search for true biomarkers of PTSD. Specifically, we will emphasize monoamine, neuroendocrine, inflammatory, genetic, epigenetic, psychophysiologial, neuroanatomical and neuroactivational phenotypes associated with PTSD to illustrate the potential efficacy of using multi-dimensional phenotypic data to characterize unique profiles of PTSD.

Monoamine Systems in PTSD

PTSD is characterized by increased sympathetic nervous system (SNS) tone that is coincident with augmented levels of catecholamine secretion (12). Urinary and central levels of norepinephrine (NE) are heightened in individuals with PTSD (13) and in child trauma victims (14), and peripheral and central levels of NE in response to threatening stimuli are also elevated in PTSD (15, 16). Recent evidence suggests that this increase in NE in PTSD is due to attenuated levels of the NE transporter within the brainstem locus coeruleus (17). PTSD has also been associated with decreased expression of peripheral α2-adrenergic receptors; receptors that underlie an autoreceptor-driven mechanism that serves to inhibit synaptic transmitter release (18). Further, facilitation of NE release via blockade of pre-synaptic α2-adrenergic receptors with the antagonist, yohimbine, can produce panic attacks and an increase in anxiety- and trauma-related symptoms in individuals with PTSD (19, 20). A prospective study of motor vehicle accident survivors indicates that urinary levels of NE were associated with increased development of PTSD one-month following trauma, but only in men (21), indicating that gender may be important for characterizing catecholaminergic biomakers of PTSD. Increased catecholamines, however, are also coincident with panic attacks and other fear-related psychopathology (22), indicating that increased sympathetic activation is not a specific biomarker of PTSD, but rather of a common neurobiological feature of fear- and anxiety-related disorders.

Alterations in the serotonergic system have also been implicated in the pathophysiology of PTSD. Individuals with PTSD show decreased levels of paroxetine binding, suggesting that levels of the serotonin (5-HT) transporter (5-HTT) are attenuated in PTSD (23) and involved in the manifestation of arousal and avoidance symptoms (24). Empirical evidence has shown that 5-HTT expression within the amygdala is attenuated in PTSD, and is significantly associated with higher anxiety and depressive symptoms (25). Brainstem and forebrain levels of the 5-HT1A receptor are higher in individuals with PTSD (26), similar to what has been described in depression (27). Likewise, reductions in central 5-HT1B receptors in trauma-exposed individuals are associated with increased PTSD and depression symptoms (25). Taken together, these data indicate that alterations within serotonergic system could reveal putative biomarkers for depressive symptoms common to both PTSD and major depression (26). The effectiveness of selective serotonin reuptake inhibitors (SSRIs; e.g., sertraline) for reducing the symptoms of PTSD (28–30), major depression, and other psychiatric conditions with which PTSD is highly comorbid (2, 22), further suggest that more careful examination of serotonergic phenotypes is warranted to better disentangle the specificity of biomarkers for PTSD- and depression-specific phenotypes.

One way in which to elucidate the specificity of monoaminergic biomarkers on PTSD symptomology is to concurrently characterize sympathetic and serotonergic function within the same individuals. Using a repeated-measures design, Southwick and colleagues (1997) found that both yohimbine and meta-Chlorophenylpiperazine (m-CPP) treatment increased panic attacks, anxiety, and trauma-related symptoms in veterans diagnosed with PTSD (20) in a manner that suggested at least two different biological sub-types of PTSD; thus, underscoring the need for more robust phenotyping of biological factors including the monoaminergic transmitter systems.

Neuroendocrine Biomarkers of PTSD

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is present in PTSD and has been extensively characterized (Figure 1; for review see (31). Evidence suggests that individuals with PTSD have attenuated levels of basal cortisol (31) and that a low level of cortisol in trauma survivors is associated with increased risk for subsequent development of PTSD (32, 33). However, findings on baseline cortisol levels have been mixed, and a recent meta-analysis concluded that there are no consistent differences between PTSD and controls (34). Similarly, equivocal results exist surrounding the cortisol response to acute cognitive stressors, as reports show heightened or no differences in cortisolresponse to a stressor (35, 36). In part, these discordant HPA results appear to be due to different sampling methods, the diurnal rhythm of cortisol release, and confounding analyses that have disregarded the influence of sex on HPA activity (37).

Rather than focus on baseline cortisol, a more promising approach is to measure cortisol reactivity to a challenge. Blunted cortisol reactivity to acute stress exposure is associated with increased prospective risk for PTSD (38). Low cortisol levels in PTSD have been coupled to enhanced glucocorticoid negative feedback inhibition of the HPA axis as evidenced by increased suppression of cortisol levels following a dexamethasone suppression test (39). This enhanced HPA negative feedback in PTSD is coincident with: (1) augmented levels of peripheral and central corticotropin-releasing hormone (CRH) (40, 41), (2) elevated glucocorticoid receptor (GR) levels (42), (3) increased glucocorticoid sensitivity (43), and (4) decreased levels of FKBP5 (44), a co-chaperone of GR that inhibits ligand binding and nuclear translocation of GRs. A recent prospective study indicates that augmented baseline GR levels and diminished FKBP5 mRNA levels are associated with increased risk for PTSD symptoms following trauma (45).

While extensive work has alluded to HPA-based biomarkers of PTSD, it is clear that additional neuroendocrine factors influence PTSD vulnerability and symptomology (Table 1; Figure 1). For example, menstrual cycle phase (46, 47) and pregnancy (48) influence PTSD symptom expression profile and psychophysiology in women, suggesting that ovarian steroid hormones are important modulators of PTSD susceptibility and symptom presentation. Indeed, low levels of estradiol are associated with impaired fear extinction in PTSD (49), and high levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a peptide implicated in stress-related behavior and physiology (50–52), are associated with PTSD only in women (53). Furthermore, central levels of the anxiolytic neuroactive steroid allopregnanolone, a potent modulator of GABAergic inhibition, are decreased in women with PTSD (54). Low levels of testosterone in men, on the other hand, have prospectively been associated with increased rates of PTSD (55) and increased risk for PTSD (56). These data, along with epidemiological studies strongly suggesting that female sex is a risk factor for psychopathology (including PTSD; (57) and reinforce the need to better understand the influence of gonadal steroid hormones in men and women with PTSD.

An additional avenue of exploration with regard to PTSD and putative biomarkers is the expression and regulation of metabolic hormones in individuals with PTSD. Neuropeptide Y (NPY) is an orexigenic peptide neurotransmitter (58) that also shows anxiolytic properties via antagonism of CRH and noradrenergic systems (59). Trauma exposure (60) and PTSD (59) are associated with attenuated peripheral levels of NPY and, conversely, resilience to trauma is associated with increased NPY levels (61). Ghrelin, an orexigenic peptide secreted from the stomach (58), displays fear-enhancing effects in rodents (62) and could serve as a biomarker of trauma exposure and PTSD. More recently, individuals with PTSD have shown a hyperinsulinemic response to an oral glucose challenge (63). Finally, peripheral endocannabinoid levels (64) are reduced and central cannabinoid CB1 receptors (65) are increased in PTSD.

In summary, it is clear that significant progress has been made in identifying and characterizing PTSD-related neuroendocrine perturbations. However, the majority of these neuroendocrine factors have been studied in isolation in traumatized populations exhibiting PTSD signs and symptoms and, as such, it is important to characterize multi-level neuroendocrine profiles of PTSD accounting for parallel trauma-related neuroendocrinological changes, their interaction, and the relationship to stress exposure or resilience. For example, increases in dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) have been linked to PTSD symptom expression, but are also associated with decreased levels of affective symptoms and PTSD severity (66, 67). Thus, it has been suggested that the ratio of these adrenal hormones to cortisol might be important for resilience to stress and recovery from PTSD (68, 69). Furthermore, elucidating the complex interaction of neuroendocrine factors (i.e. allopregnanlone/estradiol/NPY effects on cortisol) on the regulation of the HPA axis will likely expand our ability to further describe PTSD-specific and may prove beneficial in characterizing biological sub-profiles of PTSD (Figure 1). For instance, avoidance symptoms in male veterans with PTSD (70) may be related to arginine vasopressin (AVP) levels, and as such, may serve as a biomarker for increased aggression in men with PTSD (71).

Biomarkers of Heightened Inflammation in PTSD

The high comorbidity between PTSD, physical illness (7), and inflammation (spanning cardiovascular (72) and metabolic disease; (73) has led to investigations of the relationship between inflammatory markers and PTSD symptomology (Table 2). Pro-inflammatory cytokines (i.e. proteins), including interleukin (IL)-6 (74), IL-1β (75), and IL-2 (76) are elevated in individuals with PTSD and peripheral levels of inflammatory markers correlate positively with PTSD symptomology (Figure 1) (77). C-reactive protein (CRP) levels are also elevated in individuals with PTSD (78–80). More specifically, increased CRP levels have been reported with exacerbated PTSD symptoms and impaired inhibition of fear-potentiated startle (FPS) in the presence of a safety signal (79); a psychophysiological biomarker for PTSD described in a later section of this review (81).

In addition, individuals with PTSD also show altered immune cell sensitivity to glucocorticoids that results in increased inflammation (82). Lysozyme enzyme activity is more sensitive to dexamethasone in PTSD (43), indicating that innate immune efficiency is higher in individuals with PTSD. Enhanced monocyte sensitivity to glucocorticoids in individuals with PTSD is also coincident with hypocortisolemia and can lead to increased cytokine production (83). The transcriptional factor, nuclear factor-κB (NF-κB), lays upstream of cytokine activation (84) and is activated by exposure to psychosocial stress (85) as well as noradrenergic activity (85), and thus may be critically sensitive to immune changes following trauma exposure. Individuals with PTSD show augmented NF-κB gene expression (86) and NF-κB activity (87).

Overall, the cross-sectional data linking PTSD to a pro-inflammatory state further support the notion that PTSD is associated with chronic inflammation (Table 2), and suggest that inflammation may serve as a possible therapeutic target for alleviating PTSD symptoms. However, increased inflammation is a hallmark of depression (88) and other adverse health outcomes that are comorbid with PTSD (7, 72, 73, 89), thus complicating the view that immune factors may serve as diagnostic biomarkers for PTSD specifically. This point is further highlighted by other reports that have described no differences, or decreases in pro-inflammatory markers, such as CRP, in individuals with PTSD (90–92). Factors such as gender should also be considered in our examination of immunological biomarkers, as there are clear sex differences in immune system function and risk for infection (93). Finally, it is still unclear whether increased inflammation is a consequence of trauma exposure and PTSD, or whether a baseline pro-inflammatory state increases individual vulnerability to PTSD after trauma exposure. As such, baseline inflammation may serve as biomarker of PTSD vulnerability, as recent evidence from a prospective study indicates that pre-deployment levels of CRP significantly predict post-deployment PTSD (94).

Genetic and epigenetic biomarkers of PTSD

Genetic loci within genes critical for the neuroendocrine regulation of the HPA axis and emotional behavior have been associated with increased risk for PTSD (see review (5). However, these genetic loci have been associated with other psychiatric conditions as well, indicating that these genetic polymorphisms are not specific to PTSD, but rather may serve as biomarkers for stress-induced psychopathology in general or common underlying symptoms. There are several recent genomic reviews of PTSD (e.g., (95)) and the disorders with which it is co-morbid and, as such, will not be discussed at length in the current review. We will simply note that the emerging genetic and epigenetic findings related to PTSD risk versus resilience have focused on modulators of HPA axis function (prior to and following trauma - e.g., FKBP5; PACAP.

Psychophysiological biomarkers of PTSD


Hyperarousal symptoms, which include some of the longstanding, hallmark symptoms of PTSD, can be strongly influenced by an individual’s autonomic response following trauma; the output of the autonomic nervous system can be indexed non-invasively via psychophysiological assessments of peripheral targets, such as heart rate (HR), blood pressure (BP), skin conductance (SC), respiration rate (RR), muscle contractions using electromyography (EMG; e.g., startle), and body temperature. However, the use of these psychophysiological measures as biomarkers of PTSD may rely heavily on the timing and context in which they are collected. For instance, while some reports indicate that HR in the immediate aftermath of trauma exposure is predictive of later PTSD development (96), others suggest this is not the case (97, 98). These equivocal findings suggest that a more robust and controlled measurement of psychophysiological data may be necessary (99). Indeed, HR and SC changes in response to a challenge have been repeatedly associated with a diagnosis of PTSD (100–104).

Exaggerated startle response, a hyperarousal symptom that remains central to DSM-based PTSD diagnosis, is readily assessed by psychophysiology. Increased HR (SC and EMG less so) reactivity to startling loud tones has been found to reliably differentiate PTSD from Non-PTSD (105). Heightened HR reactivity to loud tones does not appear to be pre-existing, but rather is acquired with the development of PTSD (106, 107). Whereas heightened HR reactivity to loud tones appears to be an acquired marker, there is accumulating evidence that heightened SC reactivity to loud tones is a pre-trauma risk marker for posttraumatic stress (108, 109). Exaggerated arousal can manifest as sleep disturbances, which are frequently observed in PTSD (110, 111); however the diagnostic specificity of these disturbances are not yet understood.

In order to examine further explore hyper-reactivity following trauma, Pitman and colleagues (112) modified an imagery procedure originally developed to study phobias (113). In this method, psychophysiological data are recorded from participants while listening to a script of their actual traumatic event. This method has been used with divergent PTSD populations, including several combat populations (114–116) and a heavily traumatized civilian population (117). In all trauma survivors, PTSD patients exhibit a stronger HR and SC response to scripts than non-PTSD trauma survivors. In studies using script-driven imagery, SC was found to be the most sensitive measure of hyperarousal in PTSD. In 1998, Keane and colleagues (101) published the results of the largest study (multi-site VA Cooperative Study with Vietnam veterans) to date examining the utility of psychophysiological measures in diagnosing PTSD. The study employed script-driven imagery coupled to psychophysiological recordings. While this study did not find a perfect correlation between interview-based PTSD diagnosis and psychophysiological reactivity, they concluded that psychophysiological data did provide useful and objective assessment of the disorder. Recent re-analyses of script-driven imagery data collected in the 1990s have shown high specificity for PTSD (i.e., 90% of individuals without PTSD classified correctly) (102), and high concordance with subjective distress (118), but sensitivity to PTSD diagnosis remained at approximately 60% (102). Simply talking about autobiographical trauma appears to have similar effects as script-driven imagery in increasing physiological arousal (118). These methods are currently being standardized as common data elements, in order to promote generation of large datasets using the same approach. Technological advances have afforded the opportunity to employ physiological indices that can be easily obtained in most clinical settings and may prove beneficial in the diagnosis and treatment evaluation of PTSD. A recent application of these methods using virtual reality techniques to provide immersive trauma-related imagery during recording of psychophysiological responses showed utility of this approach in tracking treatment outcomes (119).

The findings described previously support the notion that the etiology and maintenance of the fear-related symptoms of PTSD can be characterized according to the principles of fear conditioning (120, 121). Given the richness of the translational literature, the neural underpinnings of fear conditioning are well understood, and PTSD research can capitalize on these findings (122). Fear conditioning is based on a simple Pavlovian conditioning model in which a neutral conditioned stimulus (CS, for example, a light) is paired with an aversive unconditioned stimulus (US, for example, electric shock). After a number of pairings, an association is formed such that the CS alone elicits a conditioned response (CR, for example, a fear response). Following initial acquisition, conditioned fear is subject to consolidation, extinction, and reconsolidation, all of which may be disturbed in PTSD (123–125). Fear conditioned responses can be measured with peripheral outcomes such as SC (123) or EMG startle responses (81). These psychophysiological measures can be used to index both the increase in fear during conditioning, as well as the reduction of fear during extinction, or the repeated presentation of the CS without the US. In addition, these measures can be used in differential conditioning studies using a CS+ cue predicting danger (US), and a CS− predicting safety from the US; these have shown that PTSD, but not depression, is associated with a reduced ability to inhibit fear-potentiated startle responses to safety signals (81). Similarly, retention of the extinction memory has been tested using SC 24 hours after fear extinction, and PTSD subjects have exhibited reduced levels of extinction recall (125). Taken together, these studies indicate the fear responses to traumatic memories may be serve as biomarkers specific for dysregulated fear in PTSD.

Neuroanatomical and neuroactivational biomarkers of PTSD

Neuroimaging data gathered during the last decade demonstrate that PTSD is associated with greater amygdala activation compared to controls (126). Functional magnetic resonance imaging (fMRI) studies have shown that trauma-relevant words increase amygdala activation in PTSD subjects more than in controls (127–130). Exaggerated fear responses observed in PTSD may be due to a weakened inhibitory control of the amygdala by the medial prefrontal cortex (mPFC). A large number of imaging studies have indicated that this inhibitory neurocircuit is dysregulated in patients with PTSD (126, 128, 130). A recent meta-analysis of imaging studies during emotion processing in PTSD, social anxiety, and specific phobia indicated that the rostral anterior cingulate cortex (ACC) is less active in PTSD patients relative to controls; an effect not found in other anxiety disorders (131).

Neuroimaging studies using fear conditioning paradigms demonstrate that fear acquisition and extinction of fear activate the prefrontal cortex (PFC), specifically the ventromedial (vmPFC) (132). For example, activation of the vmPFC (which includes the rostral ACC; rACC) is decreased in PTSD patients during an extinction recall in fMRI task (133). The vmPFC also differs in shape and size in PTSD patients (134). To date, one of the most replicated neuroanatomical findings in PTSD has been reduced hippocampal volume (135, 136). Early studies of twins discordant for trauma exposure suggested that smaller hippocampal volume likely confers individual vulnerability to PTSD(137), however, a recent prospective study found that hippocampal reductions were acquired with trauma exposure (136). Finally, methods using higher resolution imaging techniques have indicated that reductions in specific subregions of the hippocampus, such as the cornu ammonis 3 (CA3) and dentate gyrus, are associated with PTSD symptoms (138). Studies of neural activation have used several fMRI paradigms to activate the mPFC; the simplest and most commonly used tasks involve response inhibition. In such tasks, the participant is presented with a stimulus indicating that a response is required, for example, to press a button when a letter appears on the monitor. This is referred to as a “Go” signal. On a minority of trials, however, the participant is required to withhold a response during a “NoGo” signal (the Go/NoGo task). The Go/NoGo task has been used in subjects with PTSD with functional magnetic resonance imaging (fMRI) and it reliably indicates decreased activation in the rostral vmPFC and rACC in PTSD subjects compared to controls (139, 140). Weakened mPFC control of the amygdala may be a risk factor for trauma-related psychopathology: a recent study of children with depressed parents found a lack of ACC activation to the emotional Stroop, using both fear-relevant words depicting physical threat as well as social threat (141).

Summary and Conclusions

To date, an array of putative biomarkers associated with PTSD risk and symptom progression have been identified across distinct biological domains, including, but not limited to, alterations and differences in monoaminergic systems, neuroendocrinology, inflammation, genomics, psychophysiology, and neuroanatomy. However, the heterogeneity inherent in PTSD symptom presentation, and the common comorbidity with other psychiatric and general medical conditions represent formidable obstacles in the identification of valid biomarkers specifically for PTSD when considered as a diagnostic categorization (10, 11). Indeed, the likelihood of characterizing one biological marker associated with the suggested 636,120 different ways in which an individual can present with PTSD (6) is vanishingly small. Rather, it is more prudent that future studies develop a cross-dimensional, comprehensive biological and psychological phenotypic profile in individuals with PTSD to: (1) characterize biomarkers for specific clusters of symptoms and/or (2) uncover divergent biological profiles of PTSD using more complex statistical techniques (142). In order to be compatible with the RDoC approach, biomarkers should be dimensional as well as transdiagnostic—in effect, not biomarkers specific to PTSD as a DSM disorder, but biomarkers of features associated with PTSD. For example, physiological measures of fear responses would be relevant to other fear-related disorders such as phobias in addition to PTSD. Similarly, deficient prefrontal activity could be associated with PTSD symptoms, as well as addiction, and could clarify common bases for comorbid disorders.

In order to begin collecting comprehensive phenotypes necessary for such analyses, the importance of studying the interaction between biological factors (e.g., cellular, molecular, genetic, neurotransmitter, endocrine; Figure 1) needs to be emphasized; most notably as they relate to physiology and behaviors underlying complex biological phenotypes within PTSD. It is important to note that biology is dynamic. Thus, it is critical for the field to understand that biomarkers might be relevant at one time point (HR immediately following trauma exposure) and not at another (143). Lastly, the implications of characterizing diagnostic biomarkers for PTSD must be carefully considered to ensure that the benefits outweigh the costs (144).

In summary, the available biological and translational data point to promising new horizons for diagnostic biomarkers of PTSD symptoms. It is most likely that such biomarkers will represent a panel of several measures that will combine molecular with behavioral and clinical information to increase specificity and sensitivity of these tools.
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