Correspondence
Biological Psychiatry
Glucocorticoid Functioning in Male Combat Veterans with Posttraumatic Stress Disorder and Mild Traumatic Brain Injury To the Editor: Before the wars in Afghanistan (Operation Enduring Freedom [OEF]) and Iraq (Operation Iraqi Freedom [OIF]), the cooccurrence of posttraumatic stress disorder (PTSD) and persistent postconcussive symptoms attributable to a history of mild traumatic brain injury (mTBI) was not considered to be a common phenomenon (1), but the large number of veterans with both conditions has brought to light a gap in our understanding of biological links between them. Surveys of OEF and OIF veterans suggest that PTSD and mTBI co-occur because the event that resulted in the brain injury was experienced as a life-threatening trauma (2,3). Another explanation is that similar biological factors give rise to persistent difficulties after mTBI and PTSD. Finally, it is possible that the same deficits or symptoms may be associated with different biological factors in mTBI versus PTSD. These alternative explanations could be parsed if there was greater understanding of biological correlates of the two conditions. There is a strong rationale for examining the neuroendocrinology of mTBI and PTSD because there are apparent similarities in the neuroendocrine sequelae of trauma exposure and brain injury. The immediate hormonal response to brain injury is similar to that associated with severe physical traumas, involving activation of the hypothalamic-pituitary-adrenal axis resulting in increased cortisol levels, followed by a decline to normal (4–8). We previously reported that male OEF and OIF veterans with PTSD had lower 24-hour urinary cortisol and higher glucocorticoid sensitivity on the in vitro lysozyme IC50DEX assay (i.e., the concentration of dexamethasone at which there is 50% inhibition of lysozyme activity) relative to combatexposed male veterans with no PTSD (9). Briefly, what is characteristic of this sample is that all participants were exposed to a criterion A combat-related trauma, but participants without PTSD had current and lifetime Clinician Administered PTSD Scale for DSM-IV (CAPS) (10) scores #20 and had never met criteria for PTSD. Participants with current PTSD had scores $40. By design, veterans reporting a loss of consciousness secondary to brain injury that lasted .10 min were excluded from participation in the study; however, 25% of the sample reported a brain injury with or without loss of consciousness for a shorter duration. Blood and urine sampling and processing procedures were described previously. Of the total sample of 122 male veterans, 32 reported one or more brain injuries with loss of consciousness lasting ,10 min and were designated as having a history of mTBI. The full group was classified by two dichotomous variables indicating the presence or absence of PTSD and the presence or absence of mTBI: 1) PTSD only, no mTBI (n 5 44); 2) mTBI only, no PTSD (n 5 15); 3) PTSD and mTBI (n 5 17); and 4) neither PTSD nor mTBI (n 5 46). To evaluate the influence of PTSD and mTBI on neuroendocrine measures, a series of linear regression equations was estimated. Each regression
analysis included three dummy variables that represented membership in one of the four above-defined groups. The reference group included veterans with neither PTSD nor mTBI. Current and lifetime (i.e., most severe) CAPS scores were evaluated using a series of 2 (PTSD group) 3 2 (mTBI group) analyses of variance. Self-reported history of mTBI was associated with neuroendocrine outcomes that were generally in the opposite direction than observed in participants with PTSD. Results of the regression analyses showed that the group of veterans with a past history of mTBI but no PTSD had higher lysozyme IC50-DEX values relative to the comparison group (β 5 .23, t 5 2.36, p 5 .02), indicative of lower glucocorticoid sensitivity; the groups with PTSD only or both conditions did not differ from the comparison group (p . .16), controlling for lymphocyte-tomonocyte ratio. This result persisted after controlling for potential confounding influences in separate regression equations including age (p 5 .89), presence of a major depressive episode (p 5 .86), alcohol use (p 5 .98) (i.e., scores on the Alcohol Use Disorders Identification Test), use of antidepressants (p 5 .20) or sedatives (p 5 .99), and regular use of prescribed or over-the-counter pain medications (p 5 .86). Results for the lysozyme IC50-DEX assay are depicted in Figure 1 by presence versus absence of the two conditions. Results for urinary cortisol analyses showed that the group with mTBI but no PTSD had higher 24-hour urinary cortisol levels relative to the comparison group (β 5 .30, t 5 3.06, p 5 .003), controlling for body mass index. Results persisted after controlling for age (p 5 .96), presence of a major depressive episode (p 5 .63), Alcohol Use Disorders Identification Test scores (p 5 .45), use of antidepressants (p 5 .47) or sedatives (p 5 .18), and regular use of prescribed or overthe-counter pain medications (p 5 .35). Combat veterans with mTBI also tended to have less severe current and lifetime PTSD symptoms whether comorbid with PTSD or not. Veterans who reported a history of mTBI were rated as having lower current Reexperiencing, Hyperarousal, and Total
Figure 1. Glucocorticoid sensitivity in veterans with or without posttraumatic stress disorder (PTSD) according to mild traumatic brain injury (mTBI) status.
SEE COMMENTARY ON PAGE http://dx.doi.org/10.1016/j.biopsych.2015.02.003 ISSN: 0006-3223
Published by Elsevier Inc on behalf of Society of Biological Psychiatry e1 Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
Biological Psychiatry
Correspondence
CAPS scores compared with veterans without prior history of mTBI. Follow-up analyses on the current CAPS intensity and frequency scores revealed that the lower Reexperiencing and Hyperarousal scores in people with mTBI were attributed to lower frequency (p , .004), but not lower intensity (p 5 .06–.24). Insofar as PTSD has been shown to be associated with greater glucocorticoid sensitivity, the two conditions may have opposing effects when they are present in the same individual. Group contrasts comparing people with PTSD with people without PTSD on measures reflecting glucocorticoid receptor sensitivity may be diminished if the presence of TBI is not considered. Given the growing frequency of the comorbidity between mTBI and PTSD in OEF, OIF, and Operation New Dawn veterans, the results indicate that it is important to consider mTBI when evaluating neuroendocrine and symptom reports in investigations of PTSD. The results further suggest that TBI and PTSD may have distinct and even opposing biological and clinical profiles, which may inform treatment targets and the search for diagnostic markers for PTSD. Janine D. Flory Clare Henn-Haase Linda M. Bierer Amy Lehrner Iouri Makotkine Charles R. Marmar Rachel Yehuda
Acknowledgments and Disclosures This work was supported by the U.S. Department of Defense Grant Nos. W911NF-09-1-0298 (RY) and W81XWH-09-2-0044 (CRM) and National Center for Advancing Translational Sciences, a component of the National Institutes of Health, Grant No. UL1TR000067. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. We thank Dr. Owen Wolkowitz for scientific collaboration and for support from Department of Defense Grant No. W81XWH-10-1-0021 that permitted additional recruitment. The authors report no biomedical financial interests or potential conflicts of interest.
e2
Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
Article Information From the James J. Peters Veterans Affairs Medical Center (JDF, LMB, AL, RY), Bronx; Departments of Psychiatry (JDF, LMB, AL, IM, RY) and Neuroscience (RY), Icahn School of Medicine at Mount Sinai; and Steven and Alexandra Cohen Veterans Center for the Study of Posttraumatic Stress and Traumatic Brain Injury (CH-H, CRM), Department of Psychiatry, New York University School of Medicine, New York, New York. Address correspondence to Janine D. Flory, Ph.D., James J. Peters Veterans Affairs Medical Center, 526 OOMH PTSD 116/A, 130 West Kingsbridge Road, Bronx, New York 10468; E-mail: Janine.Flory@ mssm.edu.
References 1. 2.
3.
4.
5.
6. 7.
8. 9.
10.
McAllister TW (2009): Psychopharmacological issues in the treatment of TBI and PTSD. Clin Neuropsychol 23:1338–1367. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL (2008): Combat duty in Iraq and Afghanistan, mental health problems and barriers to care. US Army Med Dep J:7–17. Schneiderman AI, Braver ER, Kang HK (2008): Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: Persistent postconcussive symptoms and posttraumatic stress disorder. Am J Epidemiol 167:1446–1452. Tanriverdi F, Ulutabanca H, Unluhizarci K, Selcuklu A, Casanueva FF, Kelestimur F (2008): Three years prospective investigation of anterior pituitary function after traumatic brain injury: A pilot study. Clin Endocrinol 68:573–579. Tanriverdi F, Unluhizarci K, Kelestimur F (2010): Pituitary function in subjects with mild traumatic brain injury: A review of literature and proposal of a screening strategy. Pituitary 13:146–153. Woolf PD (1992): Hormonal responses to trauma. Crit Care Med 20: 216–226. Cernak I, Savic VJ, Lazarov A, Joksimovic M, Markovic S (1999): Neuroendocrine responses following graded traumatic brain injury in male adults. Brain Inj 13:1005–1015. Richmond E, Rogol AD (2014): Traumatic brain injury: Endocrine consequences in children and adults. Endocrine 45:3–8. Yehuda R, Flory JD, Bierer LM, Henn-Haase C, Lehrner A, Desarnaud F, et al. (2015): Lower methylation of glucocorticoid receptor gene promoter 1F in Peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry 77:356–364. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, et al. (1995): The development of a ClinicianAdministered PTSD Scale. J Trauma Stress 8:75–90.
Biological Psychiatry
Glucocorticoid Functioning in Male Combat Veterans with Posttraumatic Stress Disorder and Mild Traumatic Brain Injury To the Editor: Before the wars in Afghanistan (Operation Enduring Freedom [OEF]) and Iraq (Operation Iraqi Freedom [OIF]), the cooccurrence of posttraumatic stress disorder (PTSD) and persistent postconcussive symptoms attributable to a history of mild traumatic brain injury (mTBI) was not considered to be a common phenomenon (1), but the large number of veterans with both conditions has brought to light a gap in our understanding of biological links between them. Surveys of OEF and OIF veterans suggest that PTSD and mTBI co-occur because the event that resulted in the brain injury was experienced as a life-threatening trauma (2,3). Another explanation is that similar biological factors give rise to persistent difficulties after mTBI and PTSD. Finally, it is possible that the same deficits or symptoms may be associated with different biological factors in mTBI versus PTSD. These alternative explanations could be parsed if there was greater understanding of biological correlates of the two conditions. There is a strong rationale for examining the neuroendocrinology of mTBI and PTSD because there are apparent similarities in the neuroendocrine sequelae of trauma exposure and brain injury. The immediate hormonal response to brain injury is similar to that associated with severe physical traumas, involving activation of the hypothalamic-pituitary-adrenal axis resulting in increased cortisol levels, followed by a decline to normal (4–8). We previously reported that male OEF and OIF veterans with PTSD had lower 24-hour urinary cortisol and higher glucocorticoid sensitivity on the in vitro lysozyme IC50DEX assay (i.e., the concentration of dexamethasone at which there is 50% inhibition of lysozyme activity) relative to combatexposed male veterans with no PTSD (9). Briefly, what is characteristic of this sample is that all participants were exposed to a criterion A combat-related trauma, but participants without PTSD had current and lifetime Clinician Administered PTSD Scale for DSM-IV (CAPS) (10) scores #20 and had never met criteria for PTSD. Participants with current PTSD had scores $40. By design, veterans reporting a loss of consciousness secondary to brain injury that lasted .10 min were excluded from participation in the study; however, 25% of the sample reported a brain injury with or without loss of consciousness for a shorter duration. Blood and urine sampling and processing procedures were described previously. Of the total sample of 122 male veterans, 32 reported one or more brain injuries with loss of consciousness lasting ,10 min and were designated as having a history of mTBI. The full group was classified by two dichotomous variables indicating the presence or absence of PTSD and the presence or absence of mTBI: 1) PTSD only, no mTBI (n 5 44); 2) mTBI only, no PTSD (n 5 15); 3) PTSD and mTBI (n 5 17); and 4) neither PTSD nor mTBI (n 5 46). To evaluate the influence of PTSD and mTBI on neuroendocrine measures, a series of linear regression equations was estimated. Each regression
analysis included three dummy variables that represented membership in one of the four above-defined groups. The reference group included veterans with neither PTSD nor mTBI. Current and lifetime (i.e., most severe) CAPS scores were evaluated using a series of 2 (PTSD group) 3 2 (mTBI group) analyses of variance. Self-reported history of mTBI was associated with neuroendocrine outcomes that were generally in the opposite direction than observed in participants with PTSD. Results of the regression analyses showed that the group of veterans with a past history of mTBI but no PTSD had higher lysozyme IC50-DEX values relative to the comparison group (β 5 .23, t 5 2.36, p 5 .02), indicative of lower glucocorticoid sensitivity; the groups with PTSD only or both conditions did not differ from the comparison group (p . .16), controlling for lymphocyte-tomonocyte ratio. This result persisted after controlling for potential confounding influences in separate regression equations including age (p 5 .89), presence of a major depressive episode (p 5 .86), alcohol use (p 5 .98) (i.e., scores on the Alcohol Use Disorders Identification Test), use of antidepressants (p 5 .20) or sedatives (p 5 .99), and regular use of prescribed or over-the-counter pain medications (p 5 .86). Results for the lysozyme IC50-DEX assay are depicted in Figure 1 by presence versus absence of the two conditions. Results for urinary cortisol analyses showed that the group with mTBI but no PTSD had higher 24-hour urinary cortisol levels relative to the comparison group (β 5 .30, t 5 3.06, p 5 .003), controlling for body mass index. Results persisted after controlling for age (p 5 .96), presence of a major depressive episode (p 5 .63), Alcohol Use Disorders Identification Test scores (p 5 .45), use of antidepressants (p 5 .47) or sedatives (p 5 .18), and regular use of prescribed or overthe-counter pain medications (p 5 .35). Combat veterans with mTBI also tended to have less severe current and lifetime PTSD symptoms whether comorbid with PTSD or not. Veterans who reported a history of mTBI were rated as having lower current Reexperiencing, Hyperarousal, and Total
Figure 1. Glucocorticoid sensitivity in veterans with or without posttraumatic stress disorder (PTSD) according to mild traumatic brain injury (mTBI) status.
SEE COMMENTARY ON PAGE http://dx.doi.org/10.1016/j.biopsych.2015.02.003 ISSN: 0006-3223
Published by Elsevier Inc on behalf of Society of Biological Psychiatry e1 Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
Biological Psychiatry
Correspondence
CAPS scores compared with veterans without prior history of mTBI. Follow-up analyses on the current CAPS intensity and frequency scores revealed that the lower Reexperiencing and Hyperarousal scores in people with mTBI were attributed to lower frequency (p , .004), but not lower intensity (p 5 .06–.24). Insofar as PTSD has been shown to be associated with greater glucocorticoid sensitivity, the two conditions may have opposing effects when they are present in the same individual. Group contrasts comparing people with PTSD with people without PTSD on measures reflecting glucocorticoid receptor sensitivity may be diminished if the presence of TBI is not considered. Given the growing frequency of the comorbidity between mTBI and PTSD in OEF, OIF, and Operation New Dawn veterans, the results indicate that it is important to consider mTBI when evaluating neuroendocrine and symptom reports in investigations of PTSD. The results further suggest that TBI and PTSD may have distinct and even opposing biological and clinical profiles, which may inform treatment targets and the search for diagnostic markers for PTSD. Janine D. Flory Clare Henn-Haase Linda M. Bierer Amy Lehrner Iouri Makotkine Charles R. Marmar Rachel Yehuda
Acknowledgments and Disclosures This work was supported by the U.S. Department of Defense Grant Nos. W911NF-09-1-0298 (RY) and W81XWH-09-2-0044 (CRM) and National Center for Advancing Translational Sciences, a component of the National Institutes of Health, Grant No. UL1TR000067. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. We thank Dr. Owen Wolkowitz for scientific collaboration and for support from Department of Defense Grant No. W81XWH-10-1-0021 that permitted additional recruitment. The authors report no biomedical financial interests or potential conflicts of interest.
e2
Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
Article Information From the James J. Peters Veterans Affairs Medical Center (JDF, LMB, AL, RY), Bronx; Departments of Psychiatry (JDF, LMB, AL, IM, RY) and Neuroscience (RY), Icahn School of Medicine at Mount Sinai; and Steven and Alexandra Cohen Veterans Center for the Study of Posttraumatic Stress and Traumatic Brain Injury (CH-H, CRM), Department of Psychiatry, New York University School of Medicine, New York, New York. Address correspondence to Janine D. Flory, Ph.D., James J. Peters Veterans Affairs Medical Center, 526 OOMH PTSD 116/A, 130 West Kingsbridge Road, Bronx, New York 10468; E-mail: Janine.Flory@ mssm.edu.
References 1. 2.
3.
4.
5.
6. 7.
8. 9.
10.
McAllister TW (2009): Psychopharmacological issues in the treatment of TBI and PTSD. Clin Neuropsychol 23:1338–1367. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL (2008): Combat duty in Iraq and Afghanistan, mental health problems and barriers to care. US Army Med Dep J:7–17. Schneiderman AI, Braver ER, Kang HK (2008): Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: Persistent postconcussive symptoms and posttraumatic stress disorder. Am J Epidemiol 167:1446–1452. Tanriverdi F, Ulutabanca H, Unluhizarci K, Selcuklu A, Casanueva FF, Kelestimur F (2008): Three years prospective investigation of anterior pituitary function after traumatic brain injury: A pilot study. Clin Endocrinol 68:573–579. Tanriverdi F, Unluhizarci K, Kelestimur F (2010): Pituitary function in subjects with mild traumatic brain injury: A review of literature and proposal of a screening strategy. Pituitary 13:146–153. Woolf PD (1992): Hormonal responses to trauma. Crit Care Med 20: 216–226. Cernak I, Savic VJ, Lazarov A, Joksimovic M, Markovic S (1999): Neuroendocrine responses following graded traumatic brain injury in male adults. Brain Inj 13:1005–1015. Richmond E, Rogol AD (2014): Traumatic brain injury: Endocrine consequences in children and adults. Endocrine 45:3–8. Yehuda R, Flory JD, Bierer LM, Henn-Haase C, Lehrner A, Desarnaud F, et al. (2015): Lower methylation of glucocorticoid receptor gene promoter 1F in Peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry 77:356–364. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, et al. (1995): The development of a ClinicianAdministered PTSD Scale. J Trauma Stress 8:75–90.
