Low cortisol, high DHEA, and high levels of stimulated TNF-α, and IL-6 in women with PTSD†
Corresponding Author
Jessica Gill
National Institute of Nursing Research, Bethesda, MD
National Institute of Nursing Research, National Institutes of Health, 10 Center Drive, 10/CRC 2-1339, Bethesda, MD 20892-1506Search for more papers by this authorMeena Vythilingam
National Institutes of Mental Health, Bethesda, MD
Search for more papers by this authorGayle G. Page
Johns Hopkins University, School of Nursing, Baltimore, MD
Search for more papers by this authorCorresponding Author
Jessica Gill
National Institute of Nursing Research, Bethesda, MD
National Institute of Nursing Research, National Institutes of Health, 10 Center Drive, 10/CRC 2-1339, Bethesda, MD 20892-1506Search for more papers by this authorMeena Vythilingam
National Institutes of Mental Health, Bethesda, MD
Search for more papers by this authorGayle G. Page
Johns Hopkins University, School of Nursing, Baltimore, MD
Search for more papers by this authorThis work was funded by the National Institutes of Health, National Institute of Nursing Research (NINR) Postdoctoral Fellowship: 8326927, Individual National Research Service Award (NRSA) F31 NR009166 funded through NINR, Institutional Training Grant funded through NINR T32 NR 07968: Health Disparities in Underserved Populations, The Freedom from Fear Sharon Davies Memorial Grant.
Abstract
Posttraumatic stress disorder (PTSD) has been associated with hypothalamic–pituitary–adrenal (HPA) axis and immune function alterations; however, few studies have simultaneously investigated these systems in participants with PTSD. In this study, HPA axis and immune function in 26 women with PTSD with and without major depressive disorder was compared to 24 traumatized controls and to 21 nontraumatized controls. Posttraumatic stress disorder was associated with low cortisol and higher levels of DHEA and greater production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) compared to traumatized and healthy controls. Women with PTSD and depression exhibited greater production of IL-6 and higher levels of dehydroepiandrosterone (DHEA) than those with PTSD, but without depression. These findings suggest dysregulated HPA axis and immune function in women with PTSD, and that comorbid depression may contribute to these abnormalities.
REFERENCES
- Altemus, M., Cloitre, M., & Dhabhar, F. S. (2003). Enhanced cellular immune response in women with PTSD related to childhood abuse. American Journal of Psychiatry, 160, 1705–1707.
- Altemus, M., Dhabhar, F. S., & Yang, R. (2006). Immune function in PTSD. Annals of the New York Academy of Sciences, 1071, 167–183.
- American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders ( 4th ed.). Washington, DC: Author.
- Baker, D. G., Ekhator, N. N., Kasckow, J. W., Hill, K. K., Zoumakis, E., Dashevsky, B. A., et al. (2001). Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraumatic stress disorder. Neuroimmunomodulation, 9, 209–217.
- Blake, D., Weathers, F. W., Nagy, L. M., Kaloupek, D. G., Gusman, F. D., & Charney, D. (1995). The development of a Clinican Adminsitered PTSD Scale. Journal of Traumatic Stress, 8, 75–90.
- Boscarino, J. A., & Hoffman, S. N. (2007). Consistent association between mixed lateral preference and PTSD: Confirmation among a national study of 2490 US Army Vietnam veterans. Psychosomatic Medicine, 69, 365–369.
- Breslau, N., Kessler, R. C., Chilcoat, H. D., Schultz, L. R., Davis, G. C., & Andreski, P. (1998). Trauma and posttraumatic stress disorder in the community: The 1996 Detroit Area Survey of Trauma. Archives of General Psychiatry, 55, 626–632.
- Charmandari, E., Tsigos, C., & Chrousos, G. (2005). Endocrinology of the stress response. Annual Review of Physiology, 67, 259–284.
- Davis, M. C., Zautra, A. J., Younger, J., Motivala, S. J., Attrep, J., & Irwin, M. R. (2008). Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: Implications for fatigue. Brain Behavior and Immunity, 22, 24–32.
- de Kloet, C. S., Vermetten, E., Bikker, A., Meulman, E., Geuze, E., Kavelaars, A., et al. (2007). Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder. Molecular Psychiatry, 12, 443–453.
- de Kloet, C. S., Vermetten, E., Lentjes, E., Geuze, E., van Pelt, J., Manuel, R., et al. (2008). Differences in the response to the combined DEX-CRH test between PTSD patients with and without co-morbid depressive disorder. Psychoneuroendocrinology, 33(3): 313–20.
- Dobie, D. J., Kivlahan, D. R., Maynard, C., Bush, K. R., Davis, T. M., & Bradley, K. A. (2004). Posttraumatic stress disorder in women veterans: Association with self-reported health problems and functional impairment. Archives of Internal Medicine, 164, 394–400.
- Elenkov, I. J. (2004). Glucocorticoids and the Th1/Th2 balance. Annals of the New York Academy of Sciences., 1024, 138–146.
- Foa, E. B., & Tolin, D. F. (2000). Comparison of the PTSD Symptom Scale-Interview Version and the Clinician-Administered PTSD Scale. Journal of Traumatic Stress, 13, 181–191.
- Ganzel, B. L., Eckenrode, J. J., Kim, P., Wethington, E., Horowitz, E., & Temple, E. (2007). Salivary cortisol levels and mood vary by lifetime trauma exposure in a sample of healthy women. Journal of Traumatic Stress, 20, 689–699.
- Goenjian, A. K., Yehuda, R., Pynoos, R. S., Steinberg, A. M., Tashjian, M., Yang, R. K., et al. (1996). Basal cortisol, dexamethasone suppression of cortisol, and MHPG in adolescents after the 1988 earthquake in Armenia. American Journal of Psychiatry, 153, 929–934.
- Gotovac, K., Sabioncello, A., Rabatic, S., Berki, T., & Dekaris, D. (2003). Flow cytometric determination of glucocorticoid receptor (GCR) expression in lymphocyte subpopulations: Lower quantity of GCR in patients with post-traumatic stress disorder (PTSD). Clinical & Experimental Immunology, 131, 335–339.
- Graves, D. T., & Kayal, R. A. (2008). Diabetic complications and dysregulated innate immunity. Frontiers in Bioscience, 13, 1227–1239.
- Heim, C., Owens, M. J., Plotsky, P. M., & Nemeroff, C. B. (1997). Persistent changes in corticotropin-releasing factor systems due to early life stress: Relationship to the pathophysiology of major depression and post-traumatic stress disorder. Psychopharmacology Bulletin, 33, 185–192.
- Heim, C., Newport, D. J., Wagner, D., Wilcox, M. M., Miller, A. H., & Nemeroff, C. B. (2002). The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: A multiple regression analysis. Depression and Anxiety, 15, 117–125.
- Hsiao, C. C. (2006). Difference in pre- and post-treatment plasma DHEA levels were significantly and positively correlated with difference in pre- and post-treatment Hamilton depression scores following successful therapy for major depression. Psychoneuroendocrinology, 31, 839–846.
- Inslicht, S. S., Marmar, C. R., Neylan, T. C., Metzler, T. J., Hart, S. L., Otte, C., et al. (2006). Increased cortisol in women with intimate partner violence-related posttraumatic stress disorder. Psychoneuroendocrinology, 31, 825–838.
- Kanter, E. D., Wilkinson, C. W., Radant, A. D., Petrie, E. C., Dobie, D. J., McFall, M. E., et al. (2001). Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder. Biological Psychiatry, 50, 238–245.
- Kessler, R. C., Sonnega, A., Bromet, E., Hughes, M., & Nelson, C. B. (1995). Posttraumatic stress disorder in the National Comorbidity Survey. Archives of General Psychiatry, 52, 1048–1060.
- Kimerling, R. (2004). An investigation of sex differences in nonpsychiatric morbidity associated with posttraumatic stress disorder. Journal of the American Medical Women's Association, 59, 43–47.
- Kinder, L. S., Bradley, K. A., Katon, W. J., Ludman, E., McDonell, M. B., & Bryson, C. L. (2008). Depression, posttraumatic stress disorder, and mortality. Psychosomatic Medicine, 70, 20–26.
- Koch, A. E., & Distler, O. (2007). Vasculopathy and disordered angiogenesis in selected rheumatic diseases: Rheumatoid arthritis and systemic sclerosis. Arthritis Research & Therapy, 9 (Suppl 2), S3.
- Kroboth, P. D., Salek, F. S., Pittenger, A. L., Fabian, T. J., & Frye, R. F. (1999). DHEA and DHEA: A review. Journal of Clinical Pharmacology, 39, 327–348.
- Kubany, E. S., Leisen, M. B., Kaplan, A. S., & Kelly, M. P. (2000). Validation of a brief measure of posttraumatic stress disorder: The Distressing Event Questionnaire (DEQ). Psychological Assessment, 12, 197–209.
- Laudenslager, M. L., Aasal, R., Adler, L., Berger, C. L., Montgomery, P. T., Sandberg, E., et al. (1998). Elevated cytotoxicity in combat veterans with long-term post-traumatic stress disorder: Preliminary observations. Brain Behavior and Immunity, 12, 74–79.
- Maes, M., Lin, A. H., Delmeire, L., Van Gastel, A., Kenis, G., de Jongh, R., et al. (1999). Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biological Psychiatry, 45, 833–839.
- McEwen, B. S. (2004). Protection and damage from acute and chronic stress: Allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Annals of the New York Academy of Sciences, 1032, 1–7.
- Meewisse, M. L., Reitsma, J. B., de Vries, G. J., Gersons, B. P., & Olff, M. (2007). Cortisol and post-traumatic stress disorder in adults: Systematic review and meta-analysis. British Journal of Psychiatry, 191, 387–392.
- Miller, R. J., Sutherland, A. G., Hutchison, J. D., & Alexander, D. A. (2001). C-reactive protein and interleukin 6 receptor in post-traumatic stress disorder: A pilot study. Cytokine, 13, 253–255.
- Neylan, T. C., Brunet, A., Pole, N., Best, S. R., Metzler, T. J., Yehuda, R., et al. (2005). PTSD symptoms predict waking salivary cortisol levels in police officers. Psychoneuroendocrinology, 30, 373–381.
- Ng, V., Koh, D., Mok, B., Lim, L. P., Yang, Y., & Chia, S. E. (2004). Stressful life events of dental students and salivary immunoglobulin A. International Journal of Immunopathology and Pharmacology, 17, 49–56.
- Olff, M., de Vries, G. J., Guzelcan, Y., Assies, J., & Gersons, B. P. (2007). Changes in cortisol and DHEA plasma levels after psychotherapy for PTSD. Psychoneuroendocrinology, 32, 619–626.
- Olff, M., Guzelcan, Y., de Vries, G. J., Assies, J., & Gersons, B. P. (2006). HPA- and HPT-axis alterations in chronic posttraumatic stress disorder. Psychoneuroendocrinology, 31, 1220–1230.
- Oquendo, M. A., Echavarria, G., Galfalvy, H. C., Grunebaum, M. F., Burke, A., Barrera, A., et al. (2003). Lower cortisol levels in depressed patients with comorbid post-traumatic stress disorder. Neuropsychopharmacology, 28, 591–598.
- Pervanidou, P., Kolaitis, G., Charitaki, S., Margeli, A., Ferentinos, S., Bakoula, C., et al. (2007). 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. Psychoneuroendocrinology, 32, 991–999.
- Pico-Alfonso, M. A., Garcia-Linares, M. I., Celda-Navarro, N., Herbert, J., & Martinez, M. (2004). Changes in cortisol and dehydroepiandrosterone in women victims of physical and psychological intimate partner violence. Biological Psychiatry, 56, 233–240.
- Raison, C. L., & Miller, A. H. (2003). When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. American Journal of Psychiatry, 160, 1554–1565.
- Rasmusson, A. M., Vasek, J., Lipschitz, D. S., Vojvoda, D., Mustone, M. E., Shi, Q., et al. (2004). An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology, 29, 1546–1557.
- Rohleder, N., Joksimovic, L., Wolf, J. M., & Kirschbaum, C. (2004). Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder. Biological Psychiatry, 55, 745–751.
- Schuld, A., Mullington, J., Friess, E., Hermann, D. M., Galanos, C., Holsboer, F., et al. (2000). Changes in dehydroepiandrosterone (DHEA) and DHEA-sulfate plasma levels during experimental endotoxinemia in healthy volunteers. Journal of Clinical Endocrinology & Metabolism, 85, 4624–4629.
- Sondergaard, H. P., Hansson, L. O., & Theorell, T. (2002). Elevated blood levels of dehydroepiandrosterone sulphate vary with symptom load in posttraumatic stress disorder: Findings from a longitudinal study of refugees in Sweden. Psychotherapy and Psychosomatics, 71, 298–303.
- Sondergaard, H. P. & Theorell, T. (2003). A longitudinal study of hormonal reactions accompanying life events in recently resettled refugees. Psychother. Psychosom., 72, 49–58.
- Song, Y., Zhou, D., Guan, Z., & Wang, X. (2007). Disturbance of serum interleukin–2 and interleukin-8 levels in posttraumatic and non-posttraumatic stress disorder earthquake survivors in Northern China. Neuroimmunomodulation, 14, 248–254.
- Spivak, B., Shohat, B., Mester, R., Avraham, S., Gil-Ad, I., Bleich, A., et al. (1997). Elevated levels of serum interleukin-1 beta in combat-related posttraumatic stress disorder. Biological Psychiatry, 42, 345–348.
- Spivak, B., Maayan, R., Kotler, M., Mester, R., Gil-Ad, I., Shtaif, B., et al. (2000). Elevated circulatory level of GABA(A)–antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychological Medicine, 30, 1227–1231.
- Sternberg, E. M. (2006). Neural regulation of innate immunity: A coordinated nonspecific host response to pathogens. Nature Reviews. Immunology, 6, 318–328.
- Tucker, P., Ruwe, W. D., Masters, B., Parker, D. E., Hossain, A., Trautman, R. P., et al. (2004). Neuroimmune and cortisol changes in selective serotonin reuptake inhibitor and placebo treatment of chronic posttraumatic stress disorder. Biological Psychiatry, 56, 121–128.
- Vidovic, A., Vilibic, M., Sabioncello, A., Gotovac, K., Rabatic, S., Folnegovic-Smalc, V., et al. (2007). Circulating lymphocyte subsets, natural killer cell cytotoxicity, and components of hypothalamic–pituitary–adrenal axis in Croatian war veterans with posttraumatic stress disorder: Cross-sectional study. Croatian Medical Journal, 48, 198–206.
- von Kroet, R., Hepp, U., Kraemer, B., Traber, R., Keel, M., Mica, L., et al. (2007). Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. Journal of Psychiatric Research, 41, 744–752.
- Watson, I. P., Muller, H. K., Jones, I. H., & Bradley, A. J. (1993). Cell-mediated immunity in combat veterans with post-traumatic stress disorder. Medical Journal of Australia, 159, 513–516.
- Wessa, M., Rohleder, N., Kirschbaum, C., & Flor, H. (2006). Altered cortisol awakening response in posttraumatic stress disorder. Psychoneuroendocrinology, 31, 209–215.
- Woods, A. B., Page, G. G., O'Campo, P., Pugh, L. C., Ford, D., & Campbell, J. C. (2005). The mediation effect of posttraumatic stress disorder symptoms on the relationship of intimate partner violence and IFN-gamma levels. American Journal of Community Psychology, 36, 159–175.
- Woods, S. J., Wineman, N. M., Page, G. G., Hall, R. J., Alexander, T. S., & Campbell, J. C. (2005). Predicting immune status in women from PTSD and childhood and adult violence. Advances in Nursing Science, 28, 306–319.
- Yehuda, R., Teicher, M. H., Trestman, R. L., Levengood, R. A., & Siever, L. J. (1996). Cortisol regulation in posttraumatic stress disorder and major depression: A chronobiological analysis. Biological Psychiatry, 40, 79–88.
- Young, E. A., & Breslau, N. (2004). Cortisol and catecholamines in posttraumatic stress disorder: An epidemiologic community study. Archives of General Psychiatry, 61, 394–401.
- Zimmerman, M., Chelminski, I., & Young, D. (2004). On the threshold of disorder: A study of the impact of the DSM-IV clinical significance criterion on diagnosing depressive and anxiety disorders in clinical practice. Journal of Clinical Psychiatry, 65, 1400–1405.