Rachel Yehuda, PhD

is Associate Professor, Icahn School of Medicine, Mount Sinai, New York, NY, and Director, Trauma and Recovery Services Clinic, James J. Peters Veterans Affairs Medical Center, Bronx.

is Professor of Psychiatry, Icahn School of Medicine, Mount Sinai, and Director, Mental Health Care Center, James J. Peters Veterans Affairs Medical Center.

In addition to psychosocial problems, there is a growing realization that PTSD may also lead to or exacerbate chronic medical health conditions. Several large cohort 

 demonstrate a prospective association between PTSD symptoms and cardio-metabolic disorders, such as myocardial infarction, stroke, type 2 diabetes mellitus, and coronary heart disease.

 The associations generally persist after adjusting for comorbid depression, which occurs in about half of all PTSD cases and findings are consistent across civilian and veteran samples.

The association between PTSD and medical illness appears to differ by race and ethnicity: black and Latino adults with PTSD are at greater risk relative to whites. The impact of sex and gender on this association also warrants further examination as many of the large prospective studies have been conducted using same-sex cohorts.

More recently, PTSD has been linked with autoimmune disorders and neurodegenerative diseases. 

 reported that patients with PTSD had a greater risk for thyroiditis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and lupus erythematosus. Findings from this retrospective cohort of more than 600,000 Iraq and Afghanistan veterans were not associated with age, race, or gender.

The temporal association between PTSD and autoimmune disorders has not been studied extensively. However, results from one longitudinal cohort 

 of women showed that the onset of trauma exposure and PTSD symptoms preceded the development of lupus erythematosus.

 The public health significance of understanding why and how trauma exposure/PTSD are linked to medical illness is enormous. Recent results from gene expression studies offer some intriguing research possibilities for investigation.

Is PTSD symptom severity associated with metabolic and inflammatory markers?

Genome-wide transcription studies of trauma exposure and PTSD have identified specific genes, as well as causal pathways that implicate dysregulation of the immune system. 

 undertook a mega-analysis using the results from 5 PTSD transcriptome studies. They observed that PTSD was associated with differential expression in genes that regulate innate immunity, cytokine production, and type I interferon signaling. The study included more than 225 cases and 300 controls, which allowed for sub-analyses by gender and trauma type.

Lower expression of cytokine-related genes was observed in men exposed to interpersonal trauma relative to women exposed to interpersonal trauma or men exposed to combat. Further work is needed to explore whether gene expression differences associated with gender and trauma-type, which may carry over to observed group differences in the expression of chronic medical illness.

These genome-wide studies complement an established body of research on PTSD biomarkers that have focused extensively on the stress response, including 

 of the hypothalamic-pituitary-adrenal (HPA) axis.

 Stress exposure initiates downstream release of endogenous glucocorticoids (GCs), which bind to GC receptors on target metabolic and immune system tissue (eg, adipose tissue, skeletal muscle, pancreas). Following stress exposure, increases in GC activity lead to immunosuppression, increases in metabolic activity, and negative feedback of the HPA axis to establish homeostasis. The link between PTSD and chronic illness may stem from the effects of long-term disruption in GC functioning-as observed in PTSD-which contribute to sustained low-grade inflammation that damages target organs.

Findings have not always been consistent in studies of cross-sectional associations between PTSD symptoms and inflammatory markers. A recent 

 demonstrated that PTSD is associated with higher interleukin 6 (IL-6), interleukin (IL)-1Î², tumor necrosis factor (TNF) Î±, and interferon (IFN)-Î³ relative to controls.

 Also relevant is the prospective association between elevated C-reactive protein, an inflammatory marker of cardiovascular disease risk and the development of PTSD in 

 Similarly, higher IL-6 levels measured within 24 hours of a motor vehicle accident 

 PTSD symptoms in children and adolescents.

While some inflammatory activity may relate to psychotropic medication use, comorbid depression, or even trauma exposure itself, there is little doubt that PTSD is associated with immune system functioning. For example, see 

 who report no group differences in some of these measures in combat-exposed veterans with and without PTSD; this suggests that trauma exposure by itself may lead to increased inflammatory activity.

Does behavior mediate the relationship between PTSD and chronic health problems?

It is important to understand whether the inflammatory signature associated with PTSD reflects an extension of trauma-related pathophysiology, or whether it is an inevitable outcome of the behaviors that are associated with PTSD (eg, tobacco use, physical inactivity, imprudent dietary choices, disrupted sleep). If the inflammatory signal is an extension of trauma-related consequences that associate with, or possibly even lead to, other medical illnesses, this would suggest that PTSD is part of a larger systemic illness linked to psychological trauma.

Evidence-based psychotherapies for PTSD address psychological symptoms, but it is not known whether they also affect the immune system. However, the presence of markers of inflammation and metabolic dysfunction (eg, elevated lipid profile, weight gain or increase in waist circumference, insulin resistance) in people with PTSD suggests a need for a more comprehensive approach to the biomedical consequences of trauma.

Does pharmacotherapy for PTSD affect inflammatory markers?

If PTSD is causally associated with disruption of the immune system, interventions that directly target inflammatory markers might result in improved psychological and biomedical outcomes. Many people with PTSD are treated with psychotropic medications, but to date, there have been only a few attempts to develop novel pharmacotherapeutic agents for PTSD. FDA-approved SSRIs are associated with reduced inflammation and may have both 

One study examined changes in inflammatory markers following treatment of PTSD with paroxetine.

 Findings from this open trial do not show a decline in Il-6 despite a decline in PTSD symptoms. In contrast, SSRI treatment of depression is associated with a decline in cytokines. Sertraline and transcranial direct current treatment of depression were associated with declines in 6 of 7 cytokines in a randomized clinical trial.

Some of the novel PTSD pharmacotherapy approaches currently under investigation may also have the added benefit of targeting the immune system. One of the exciting developments in pharmacotherapy involves the use of glucocorticoid-related drugs to either prevent the development of PTSD, augment the gains of psychotherapy, or treat symptoms of chronic PTSD.

 Glucocorticoids are primarily used in a variety of medical ailments because of their anti-inflammatory properties.

Ketamine, an NMDA-receptor antagonist, is under investigation for PTSD. Findings indicate that it influences cytokine production in animal models.

 Although controversial in some settings as a treatment option, cannabinoids have immunosuppressive properties.

 The anti-inflammatory properties of these agents may augment the potentially beneficial effects on psychological symptoms.

An intriguing possibility is whether these and other medications for PTSD exert direct benefits on symptoms as a result of their influence on the immune system. If so, it is critical to consider the broader implications of the inflammatory signature of PTSD and its psychiatric and medical comorbidities.

The link between PTSD and chronic illness has been established but the potential role of immune system markers in mediating this association is only beginning to be examined. As new psychotherapeutic and pharmacological treatments are developed, there is an opportunity to examine the relationships between inflammatory markers and symptoms as they change over time.

Future research should examine how and whether psychotherapy affects inflammatory markers, and also to determine the extent to which inflammation is reduced by medications that alleviate PTSD symptoms. It is possible that the growing interest in alternative therapies for PTSD such as meditation, yoga, acupuncture, and other interventions that increase physical activity or alter dietary intake may provide benefits through their anti-inflammatory effects.

It is also important to examine whether the association between PTSD and immune markers is part of a broader association between mental illness and poor health or whether there is specificity between trauma exposure and particular markers and disease outcomes. Moreover, it is important to identify the contributions of trauma type, sex, race, and ethnicity to these associations.

The authors report no conflicts of interest concerning the subject matter of this article.

 Koenen KC, Sumner JA, Gilsanz P, et al. 

Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice

 O’Donovan A, Cohen BE, Seal KH, et al. 

Elevated risk for autoimmune disorders in iraq and afghanistan veterans with posttraumatic stress disorder

 Roberts AL, Malspeis S, Kubzansky LD, et al. 

Association of trauma and posttraumatic stress disorder with incident systemic lupus erythematosus in a longitudinal cohort of women

 Breen MS, Tylee DS, Maihofer AX, et al. 

PTSD blood transcriptome mega-analysis: shared inflammatory pathways across biological sex and modes of trauma

 Yehuda R, Hoge CW, McFarlane AC, et al. 

 Passos IC, Vasconcelos-Moreno MP, Costa LG, et al. 

Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression

 Eraly SA, Nievergelt CM, Maihofer AX, et al. 

Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk

 Pervanidou P, Kolaitis G, Charitaki S, et al. 

Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident

 Lindqvist D, Wolkowitz OM, Mellon S, et al. 

Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress

 Galecki P, Mossakowska-WÃ³jcik J, Talarowska M. 

The anti-inflammatory mechanism of antidepressants: SSRIs, SNRIs

Prog Neuropsychopharmacol Biol Psychiatry

 Bonne O, Gill JM, Luckenbaugh DA, et al. Corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, insulin-like growth factor-1, and substance P in the cerebrospinal fluid of civilians with posttraumatic stress disorder before and after treatment with paroxetine. 

 Brunoni AR, Machado-Vieira R, Zarate CA, et al. Cytokines plasma levels during antidepressant treatment with sertraline and transcranial direct current stimulation (tDCS): results from a factorial, randomized, controlled trial. 

 Yehuda R, Golier J. Is there a rationale for cortisol-based treatments for PTSD? 

 Tan S, Wang Y, Chen K, et al. Ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice.

 Katchan V, David P, Shoenfeld Y. Cannabinoids and autoimmune diseases: a systematic review. 

2016 Jun;15(6):513-28. doi: 10.1016/j.autrev.2016.02.008. Epub 2016 Feb 11.

Articles

In addition to psychosocial problems, there is a growing realization that PTSD may also lead to or exacerbate chronic medical health conditions.

Is PTSD a Systemic Disorder?

PTSD filled a nosological gap by providing a way to characterize the long-lasting effects of trauma exposure.

 This led to a plethora of previously lacking scientific observations. Now the existence of PTSD is being called into question because some of the original assumptions that helped make the case for it have proved to be incorrect.

 However, it is possible to update some of the flawed assumptions of PTSD without rescinding the diagnosis. There is no reason to throw the baby out with the bathwater.

It is true that when advocates argued for the centrality of trauma exposure as a cause of PTSD, they lacked the perspective that PTSD is only one of many possible outcomes following trauma exposure-including resil­ience.

 However, the diagnosis is not invalidated by the fact that trauma exposure does not always-but sometimes does-result in PTSD.

 In medicine, diagnoses are not invalidated when not all persons express symptoms associated with a pathogen. Not all persons who are infected with Mycobacterium tuberculosis get clinically manifested pulmonary disease. Yet this does not call into question the role of the bacterium. Nor do we call into question the diagnoses of pulmonary tuberculosis because it shares symptoms with pneumonia  and sarcoidosis.

The PTSD construct is valid independent of symptoms of overlapping disorders.

 The argument that “symptom overlap” calls the PTSD diagnosis into question reflects a fundamental misunderstanding of the purpose of diagnostic categories-which is to organize symptoms around a common cause to effectively provide the needed intervention. Treating specific symptoms outside the framework of a diagnosis is problematic.

 The idea here is that one arguably treats behavioral manifestations of panic attacks that come “out of the blue” differently from similar physiological reactivity provoked by traumatic reminders in PTSD. The PTSD diagnosis implies a failure of homeostatic mechanisms involved in stress recovery.

 In the absence of trauma exposure, some of the same symptoms might reflect a different neurobiological process and treatment intervention.

We agree that the diagnosis of PTSD almost entered a cul-de-sac when it initially postulated-back in the days before functional neuroimaging in psychiatric research-that symptoms resulted from an organic brain change occurring secondary to stress-induced arousal. Fortunately, advances in neuroscience disconfirmed this, while providing the constructs for a more nuanced way of understanding enduring brain ef­fects resulting from environmental per­turbations-including gene-environment interactions, epigenetic mod­ifications, and other molecular mechanisms.

 These advances have not only explained mechanisms involved in enduring stress effects but have also revealed individual differences that explain why long-term illness develops in only some traumaexposed persons.

 That initial theories about pathophysiology may have been erroneous does not jeopardize the validity of the PTSD construct any more than the concept of schizophrenia was jeopardized when its cause was considered to be the “schizophrenogenic mother.”

So too, the “errors” that can be made in the diagnosis of PTSD underscore the need for better training. Also, there is every reason to believe that scientific advances will yield PTSD biomarkers that differentiate this condition from others, particularly, those with overlapping symptoms. Progress in this area has already been made, and the yield from the rapid develop­ment of methodologies for unbiased genome-wide genotyping, gene expression, and molecular approaches are only beginning to be realized.

 Soon it will be more difficult for those who have never seen PTSD clinically to dismiss the “validity” of the PTSD diagnosis.

What is it that really bothers people? Could it be the high price tag of caring for persons disabled with PTSD? Could it be resentment that some persons fake symptoms for secondary gain?

“Malingerophobia” is a strong fear for doctors, but being able to fake an illness does not invalidate it as a diagnostic entity.

 Could it be that if we continue to assert that trauma exposure really can result in a mental health syndrome, our society will need to shoulder some of the responsibility for primary prevention and start making the world safer from violence, accidents, and disasters that threaten our citizens?

The fact that many persons choose not to continue mental health treatment for PTSD after they become service-connected is often used to “prove” that the injury was never really there and that the diagnosis was only a vehicle for compensation. Anyone who works with veterans or civilians battling the courts in an attempt to obtain compensation for PTSD would understand that severity of PTSD would be high during this process. It is stressful to recount explicit details of traumatic material-even with appropriate support, corrective information, and anxiety-reduction techniques in therapy. Imagine needing to do so in the context of an adversarial process in which the veracity of one’s report of trauma or level of distress is questioned. It is unfortunate that some veterans link the experiences of seeking compensation with mental health treatment at the VA and do not return. It is also true that the compensation- seeking process promotes avoidance behavior, accounting for more drop­outs. Because there are still barriers to care, it is important not to draw conclusions about the prevalence, sever­ity, or reality of any mental illness based on treatment-seeking behavior. Indeed, only a minority of those with PTSD seek any treatment.

A constructive solution to the problem of the high cost of PTSD-related disability is to invest in the development of novel PTSD treatments and strategies for its prevention. One of the benefits of asserting that PTSD is not a result of brain damage secondary to stress exposure is that this opens up many new vistas for intervention. The validity of PTSD does not depend on its being a permanent condition-this is another assumption that could be corrected without even altering the  diagnostic criteria. When treatment options based on a more precise characterization of the cause and biology of PTSD become available, the price tag associated with PTSD disability will be reduced. Rescinding the di­agnosis will stand in the way of these  developments.

It seems disingenuous, invoking  DSM-V to use the convenience of having been wrong about some things to obliterate a diagnosis that has been so on-target in so many ways for so many trauma survivors. It is not clear why the dialogue is set up in a binary manner to either confirm or deny the existence of PTSD as currently formulated. The question going into DSM-V is whether we can restructure a more precise diagnosis that will be more resis­tant to the superficial criticisms currently used to challenge its existence. Once we acknowledge that PTSD is a specific type of response to trauma, many of the conceptual “problems” related to refining Criterion A, bracket creep, or symptom overlap dissipate.

The issues regarding PTSD have faced other diagnoses that are also sometimes difficult to delineate as a result of symptom overlap or because some patients fall into the cracks of often arbitrary and dichotomously parsed diagnostic criteria. That PTSD has become the whipping post for the challenges that emerging knowledge brings to the classification of mental disorders suggests it has had a strong cultural impact . . . let’s not shoot the messenger.

1. Yehuda R, McFarlane AC. Conflict between current knowledge about posttraumatic stress disorder and its original conceptual basis. Am J Psychiatry. 1995; 152:1705-1713.
  2. Weathers FW, Keane TM. The Criterion A problem revisited: controversies and challenges in defining and measuring psychological trauma. J Trauma Stress. 2007;20:107-121.
  3. Spitzer RL, First MB, Wakefield JC. Saving PTSD from itself in DSM-V. J Anxiety Disord. 2007;21:233-241.
  4. McHugh PR, Treisman G. PTSD: a problematic 
  diagnostic category. J Anxiety Disord. 2007;21:211-222.
  5. North CS, Suris AM, Davis M, Smith RP. Toward validation of the diagnosis of posttraumatic stress disorder. Am J Psychiatry. 2009;166:34-41.
  6. Elhai JD, Grubaugh AL, Kashdan TB, Frueh BC. 
  Empirical examination of a proposed refinement to DSM-IV posttraumatic stress disorder symptom criteria using the National Comorbidity Survey Replication data [published correction appears in J Clin Psychiatry. 2008;69:1985]. J Clin Psychiatry. 2008;69:
  597-602.
  7. McFarlane AC, Yehuda R. Clinical treatment of posttraumatic stress disorder: conceptual challenges raised by recent research. Aust N Z J Psychiatry. 2000;34:940-953.
  8. Yehuda R. Post-traumatic stress disorder. N Engl J Med. 2002;346:108-114.
  9. Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007;56:19-32.

10. Koenen KC, Nugent NR, Amstadter AB. Geneenvironment interaction in posttraumatic stress disorder: review, strategy and new directions for future research. Eur Arch Psychiatry Clin Neurosci. 2008; 258:82-96.
  11. Malhi GS, Lagopoulos J. Making sense of neuroimaging in psychiatry. Acta Psychiatr Scand. 2008; 117:100-117.
  12. Banati R, Hickie IB. Therapeutic signposts: using biomarkers to guide better treatment of schizophrenia and other psychotic disorders. Med J Aust. 2009;190 (suppl 4):S26-S32.
  13. Pilowsky I. Malingerophobia. Med J Aust. 1985; 143:571-572.
  14. Kessler RC. Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry. 2000;61(suppl 5):4-14.
  15. Spinazzola J, Blaustein M, van der Kolk BA. Posttraumatic stress disorder treatment outcome research: the study of unrepresentative samples? J Trauma Stress. 2005;18:425-436.
  


PTSD filled a nosological gap by providing a way to characterize the long-lasting effects of trauma exposure.1 This led to a plethora of previously lacking scientific observations. Now the existence of PTSD is being called into question because some of the original assumptions that helped make the case for it have proved to be incorrect.2-4 However, it is possible to update some of the flawed assumptions of PTSD without rescinding the diagnosis. There is no reason to throw the baby out with the bathwater.

PTSD Is a Valid Diagnosis: Who Benefits From Challenging Its Existence?

Posttraumatic stress disorder develops in response to experiencing, witnessing or even learning about a terrifying event. The event--or trauma--is usually life-threatening, or at least capable of producing bodily harm, and it typically involves either interpersonal violence or massive disaster (e.g., rape, assault, torture, terrorism, car or plane crashes, earthquake, tornado, or flood). Traumatic events have in common the ability to elicit intense and immediate fear, helplessness, horror and distress. These subjective responses lead to a cascade of adverse psychological reactions that can result in the symptoms of PTSD and the resultant disability that is associated with this condition.

The diagnosis of PTSD did not appear in the DSM until 1980. This reflected the reluctance of the mental health field to recognize that the psychological effects of traumatic experiences could be long lasting. Prior to 1980, stress-related symptoms were generally viewed as transient and not requiring intensive treatment. This was in keeping with the pervasive feeling that, with time, people ought to be able to "get over" the effects of a traumatic experience and "move on" without noticeable impairment. According to the 

, people who developed long-term symptoms following trauma were perceived as constitutionally vulnerable (Yehuda and McFarlane, 1995). The diagnosis of PTSD was meant to pave the way for an improved understanding of the long-term, and possibly even permanent, impact of trauma exposure. Ultimately, systematic testing of hypotheses about the relationship between trauma exposure and long-term symptoms has led to a better understanding of the causes of PTSD and its longitudinal course and biologic basis. 

Posttraumatic stress disorder defines a rather specific syndrome in which trauma survivors are unable to get the traumatic event out of their minds. Three symptom clusters are associated with PTSD: 1) reexperiencing symptoms refers to distressing images, unwanted memories, nightmares or flashbacks of the event that cause distress and attendant physical symptoms such as palpitations, shortness of breath and other panic symptoms; 2) the avoidance of reminders of the event, including people, places or things associated with the trauma and becoming emotionally numb, constricted or generally unresponsive to the environment; and 3) hyperarousal, which is reflected in physiological symptoms such as insomnia, irritability, impaired concentration, hypervigilance and increased startle responses. To meet DSM criteria for PTSD, symptoms in each of the three domains must not only be present, but also must be severe enough to cause substantial impairment in social, occupational or interpersonal domains. Furthermore, symptoms must be present for at least one month. 

Posttraumatic stress disorder is the fourth most common 

 disorder, afflicting 7% to 14% of the population at some time in their lives (Yehuda, 2002). Although exposure to trauma is thought to be the major cause of PTSD, there is a marked discrepancy between the number of people exposed to trauma and the number of people who develop PTSD. If one considers the prevalence of PTSD solely among individuals who have been exposed to a potentially traumatic event as defined by the 

, it would become clear that only about 9% of men and 20% of women who are so exposed develop this disorder (Kessler et al., 1995).

The nature of the trauma experienced seems to be a highly significant factor in determining whether PTSD will develop. Events involving interpersonal violence, such as torture, rape, assaultive violence and combat, are more potent elicitors of PTSD than experiences such as motor vehicle accidents and natural disasters. The former events produce PTSD in as many as 50% to 75% of trauma survivors, whereas the latter types of events often result in PTSD 

The majority of people experience acute stress symptoms following trauma, but the development of posttraumatic stress disorder is the exception rather than the rule. Some investigators hypothesize that PTSD develops following increased nervous system response to trauma. Why only a minority of individuals experience this response, what their risk factors are and when should they be treated is the subject of ongoing research.

Rachel Yehuda, PhD

Articles

Is PTSD a Systemic Disorder?

PTSD Is a Valid Diagnosis: Who Benefits From Challenging Its Existence?

Changes in the Concept of PTSD and Trauma