In addition to psychosocial problems, there is a growing realization that PTSD may also lead to or exacerbate chronic medical health conditions.
SIGNIFICANCE FOR THE PRACTICING PSYCHIATRIST
Find More About PTSD and Suicide
Dr. Floryis 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.Dr. Yehudais 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 studies demonstrate a prospective association between PTSD symptoms and cardio-metabolic disorders, such as myocardial infarction, stroke, type 2 diabetes mellitus, and coronary heart disease.1 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. O’Donovan and colleagues2 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 study of women showed that the onset of trauma exposure and PTSD symptoms preceded the development of lupus erythematosus.3 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. Breen and colleagues4 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 dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.5 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 meta-analysis 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.6 Also relevant is the prospective association between elevated C-reactive protein, an inflammatory marker of cardiovascular disease risk and the development of PTSD in trauma-exposed Marines.7 Similarly, higher IL-6 levels measured within 24 hours of a motor vehicle accident predicted PTSD symptoms in children and adolescents.8
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 Lindqvist and colleagues9 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 direct and indirect benefits for patients with PTSD.10
One study examined changes in inflammatory markers following treatment of PTSD with paroxetine.11 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.12
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.13 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.14 Although controversial in some settings as a treatment option, cannabinoids have immunosuppressive properties.15 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.
1. Koenen KC, Sumner JA, Gilsanz P, et al. Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice. Psychol Med. 2017;47:209-225.
2. O’Donovan A, Cohen BE, Seal KH, et al. Elevated risk for autoimmune disorders in iraq and afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry. 2015;77:365-374.
3. 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. Arthritis Rheumatol. 2017;69:2162-2169.
4. Breen MS, Tylee DS, Maihofer AX, et al. PTSD blood transcriptome mega-analysis: shared inflammatory pathways across biological sex and modes of trauma. Neuropsychopharmacol. 2018;43:469-481.
5. Yehuda R, Hoge CW, McFarlane AC, et al. Post-traumatic stress disorder. Nat Rev Dis Primers. 2015;1:15057.
6. Passos IC, Vasconcelos-Moreno MP, Costa LG, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2:1002-1012.
7. Eraly SA, Nievergelt CM, Maihofer AX, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71:423-431.
8. 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. Psychoneuroendocrinol. 2007;32:991-999.
9. Lindqvist D, Wolkowitz OM, Mellon S, et al. Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress. Brain Behav Immun. 2014;42:81-88.
10. Galecki P, Mossakowska-WÃ³jcik J, Talarowska M. The anti-inflammatory mechanism of antidepressants: SSRIs, SNRIs. Prog Neuropsychopharmacol Biol Psychiatry. 2018 3;80:291-294.
11. 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. J Clin Psychiatry. 2011;72:1124-1128.
12. 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. Psychopharmacol (Berl). 2014;231:1315-1323.
13. Yehuda R, Golier J. Is there a rationale for cortisol-based treatments for PTSD? Expert Rev Neurother. 2009;9:1113-1115.
14. 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. Biol Pharm Bull. 2017;40:1260-1267.
15. Katchan V, David P, Shoenfeld Y. Cannabinoids and autoimmune diseases: a systematic review. Autoimmun Rev. 2016 Jun;15(6):513-28. doi: 10.1016/j.autrev.2016.02.008. Epub 2016 Feb 11.