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Association Between Childhood Trauma and Low Hair Cortisol in Depressed Patients and Healthy Control Subjects
CORRESPONDENCE Association Between Childhood Trauma and Low Hair Cortisol in Depressed Patients and Healthy Control Subjects To the Editor: hildhood trauma is associated with major depression and alterations of cortisol secretion and might thus be one important factor in the neurobiology of depression. Heim et al. found lower baseline cortisol in depressed patients with a history of childhood trauma (1). In contrast, in response to stress, depressed patients with childhood trauma showed increased adrenocorticotropic hormone and cortisol (2,3). This suggests that low baseline cortisol as a consequence of childhood trauma might facilitate disinhibition of central corticotropin-releasing factor leading to psychopathology (3). Low baseline cortisol has also been described in healthy individuals with a history of childhood trauma (1,4,5). However, not all studies concur (6–10). All previous studies have used point sampling of cortisol levels (blood, saliva). Recently, hair analysis for steroids has been introduced to the field of biopsychology, which allows for the retrospective assessment of cumulative cortisol levels over several months (11–13). Here, we present cortisol levels according to the presence or absence of childhood trauma in patients with major depression and healthy control subjects. We recruited 27 women and 16 men (mean age 41.7 years, SD 10.5 years) from specialized depression clinics at the University Medical Center Hamburg (Germany) with a diagnosis of major depressive disorder according to DSM-IV criteria and a minimum score of 18 points on the 17-item version Hamilton Rating Scale for Depression (mean 22.1 ⫾ 4.3). Two patients fulfilled the criteria for posttraumatic stress disorder (PTSD) according to the Mini International Neuropsychiatric Interview. Criteria for exclusion were dementia, schizophrenia spectrum disorder, bipolar disorder, substance dependence, serious medical conditions associated with adrenal dysfunction, steroid use, or well-known impact on hypothalamic-pituitary-adrenal (HPA) activity, pregnancy, and nursing. Twenty-three patients were free of psychotropic medication; 20 patients were treated with selective serotonin reuptake inhibitors (n = 7), selective norepinephrine reuptake inhibitor (n = 1), selective serotonin norepinephrine reuptake inhibitor (n = 4), mirtazapine (n = 3), agomelatine (n = 1), St. Johns Wort (n = 2), tranylcypromine (n = 1) and opipramol (n = 1). Forty-one age- and sex-matched healthy subjects (26 women, 15 men; mean age 41.2 years, SD 11.5 years) were recruited. Participants were free of former and present DSM-IV axis I disorders, had no physical illness, and were free of any medication. The study was approved by the local ethics committee, and written informed consent was obtained. Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ) (14). Childhood trauma was considered present (CTQ⫹) when at least one CTQ subscale (emotional, sexual, or physical abuse or emotional or physical neglect) was rated moderate–severe according to the cutoff scores described by Bernstein and Fink (15). Hair strands of a total diameter of approximately 3 mm were taken from the scalp and cut into 3-cm segments (reflecting the cumulative hormone secretion over a 3-month period) as described by Steudte et al. (16). Salivary cortisol was collected on 2 consecutive days at awakening and at 12:00 PM, 4:00 PM, and 10:00 PM. Salivary cortisol was determined by radioimmunoassay (DRG, Marburg, Germany).
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Demographic characteristics between patients and healthy control subjects were compared with univariate analysis of variance for continuous variables and χ2 tests for dichotomous variables. For salivary cortisol we calculated the area under the curve with respect to ground (17). Mixed analyses of variance were conducted to examine the effects of group (depression vs. healthy control subjects) and the effects of childhood trauma (CTQ⫹ vs. CTQ−) on cortisol values. There were no significant differences between groups on demographic variables except body mass index, which was controlled for in subsequent analyses. More patients than control subjects (24 of 43 patients vs. 7 of 41 control subjects) reported traumatic childhood experiences (p ⬍ .01). Among depressed patients, five traumatized individuals but none of the nontraumatized patients showed atypical symptoms (p ¼ .06). Analysis of covariance revealed lower mean hair cortisol concentrations (F1,71 ¼ 4.11, p ¼ .05) as well as lower mean salivary cortisol concentrations (F1,70 ¼ 4.95, p ¼ .03) in subjects
Figure 1. (A) Salivary cortisol. Analysis of covariance, adjusted for body mass index, significant effect of childhood trauma (F1,70 ¼ 4.95, p ¼ .03). (B) Hair cortisol. Analysis of covariance, adjusted for body mass index, significant effect of childhood trauma (F1,71 ¼ 4.11, p ¼ .05). Bars represent means (SEM). AUC, area under the curve; CTQ⫹, history of childhood trauma; CTQ−, no history of childhood trauma; DEP, depression.
BIOL PSYCHIATRY 2013;74:e15–e17 & 2013 Society of Biological Psychiatry
e16 BIOL PSYCHIATRY 2013;74:e15–e17 with a history of maltreatment compared with subjects without childhood maltreatment (Figure 1). In contrast, the main effect of diagnosis and the diagnosis trauma interaction was not significant (p ⬎ .1). Sex, smoking status, antidepressant treatment, and atypical depression were not associated with cortisol concentrations and therefore omitted from the analyses (p ⬎ .1). Across groups, partial correlation analyses revealed a significant negative association of salivary cortisol area under the curve with CTQ sum score (r ¼ .35, p ⬍ .01). In summary, we found a significant association of childhood trauma with lower long-term cortisol secretion as measured by hair cortisol and lower diurnal salivary cortisol in depressed patients and healthy control subjects. In contrast, there was no effect of current depression on cortisol measures in our sample. Our study represents the first evidence of decreased long-term cortisol secretion as measured by hair analysis in individuals with a history of childhood trauma. Our results are compatible with a profound and lasting effect of childhood trauma on the HPA axis and in line with a recent longitudinal nonhuman primate study showing that early maternal separation led to reduced hair cortisol (18). Our findings also concur with a recent study by Steudte et al. (16), who found reduced hair cortisol in traumatized individuals with and without concurrent PTSD. Finally, our results are in accordance with Heim et al. (1) and with studies indicating lower baseline cortisol in healthy control subjects with childhood trauma (1,4,5). However, some studies did not find low cortisol after childhood trauma (6–10,19). Besides sampling methods, concurrent PTSD, atypical depression, and antidepressant medication could account for lower cortisol (20–23). In our study, excluding PTSD patients did not change the results, and neither atypical depression nor medication was associated with cortisol levels. Studies in maltreated children have consistently shown elevated basal cortisol (24), which might be followed by hypocortisolism as shown by a prospective study in victims of sexual abuse (25). Chronic hypocortisolism might then lead to an increased central corticotropin-releasing hormone drive, which then might sensitize to stress and depression (3). In sum, our study suggests that childhood trauma exhibits a profound and lasting effect on different measures of the HPA axis, independent of current psychopathology. Kim Hinkelmannan Christoph Muhtzb Lucia Dettenbornc Agorastos Agorastosd Katja Wingenfelda Carsten Spitzere Wei Gaof Clemens Kirschbaumf Klaus Wiedemannd Christian Ottea a
Department of Psychiatry and Psychotherapy, Charite University Medical Center, Campus Benjamin Franklin, Berlin; bDepartment of Psychosomatic Medicine; c Department of Medical Psychology; dDepartment of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg; eAsklepios Fachklinikum Tiefenbrunn, Rosdorf; and the fDepartment of Psychology, Technical University Dresden, Dresden, Germany. *Corresponding author E-mail: [email protected].
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Correspondence We thank the laboratory team of CK at the Technical University in Dresden for their efforts with the hair analysis. We also thank Mrs. Huwald and Mrs. Remmlinger-Marten for their technical assistance. Dr. Wiedemann served as a consultant to or has been on the Speakers’ boards of AstraZeneca, Bristol Myers Squibb, Janssen, Pfizer, Servier, and Wyeth. Dr. Otte has received honoraria fees for lectures from AstraZeneca, Berlin-Chemie, Lundbeck, and Servier. All other authors report no biomedical financial interests or potential conflicts of interest.
1. Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB (2001): Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry 158:575–581. 2. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, et al. (2000): Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284:592–597. 3. Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008): The link between childhood trauma and depression: Insights from HPA axis studies in humans. Psychoneuroendocrinology 33:693–710. 4. Gerritsen L, Geerlings MI, Beekman AT, Deeg DJ, Penninx BW, Comijs HC (2010): Early and late life events and salivary cortisol in older persons. Psychol Med 40:1569–1578. 5. Power C, Thomas C, Li L, Hertzman C (2012): Childhood psychosocial adversity and adult cortisol patterns. Br J Psychiatry 201:199–206. 6. van der Vegt EJ, van der Ende J, Huizink AC, Verhulst FC, Tiemeier H (2010): Childhood adversity modifies the relationship between anxiety disorders and cortisol secretion. Biol Psychiatry 68:1048–1054. 7. Carpenter LL, Carvalho JP, Tyrka AR, Wier LM, Mello AF, Mello MF, et al. (2007): Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment. Biol Psychiatry 62:1080–1087. 8. Klaassens ER, van Noorden MS, Giltay EJ, van Pelt J, van Veen T, Zitman FG (2009): Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 33:889–894. 9. Otte C, Neylan TC, Pole N, Metzler T, Best S, Henn-Haase C, et al. (2005): Association between childhood trauma and catecholamine response to psychological stress in police academy recruits. Biol Psychiatry 57: 27–32. 10. Elzinga BM, Roelofs K, Tollenaar MS, Bakvis P, van Pelt J, Spinhoven P (2008): Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects. Psychoneuroendocrinology 33:227–237. 11. Russell E, Koren G, Rieder M, Van Uum S (2012): Hair cortisol as a biological marker of chronic stress: Current status, future directions and unanswered questions. Psychoneuroendocrinology 37:589–601. 12. Dettenborn L, Muhtz C, Skoluda N, Stalder T, Steudte S, Hinkelmann K, et al. (2012): Introducing a novel method to assess cumulative steroid concentrations: Increased hair cortisol concentrations over 6 months in medicated patients with depression. Stress 15:348–353. 13. Stalder T, Steudte S, Alexander N, Miller R, Gao W, Dettenborn L, et al. (2012): Cortisol in hair, body mass index and stress-related measures. Biol Psychology 90:218–223. 14. Wingenfeld K, Schafer I, Terfehr K, Grabski H, Driessen M, Grabe H, et al. (2011): [The reliable, valid and economic assessment of early traumatization: first psychometric characteristics of the German version of the Adverse Childhood Experiences Questionnaire (ACE)]. Psychother Psychosom Med Psychol 61:e10–e14. 15. Bernstein DP, Fink L (1998): Childhood Trauma Questionnaire: A Retrospective Self-Report Manual. San Antonio, TX: The Psychological Corporation. 16. Steudte S, Kirschbaum C, Gao W, Alexander N, Schönfeld S, Hoyer J, et al. (2013): Hair cortisol as a biomarker of traumatization in healthy individuals and posttraumatic stress disorder patients. Biol Psychiatry 74:639–646. 17. Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH (2003): Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 28:916–931. 18. Feng X, Wang L, Yang S, Qin D, Wang J, Li C, et al. (2011): Maternal separation produces lasting changes in cortisol and behavior in rhesus monkeys. Proc Natl Acad Sci U S A 108:14312–14317.
Correspondence 19. Carvalho Fernando S, Beblo T, Schlosser N, Terfehr K, Otte C, Lowe B, et al. (2012): Associations of childhood trauma with hypothalamicpituitary-adrenal function in borderline personality disorder and major depression. Psychoneuroendocrinology 37:1659–1668. 20. Yehuda R, Seckl J (2011): Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis. Endocrinology 152:4496–4503. 21. Stetler C, Miller GE (2011): Depression and hypothalamic-pituitaryadrenal activation: A quantitative summary of four decades of research. Psychosom Med 73:114–126. 22. Hinkelmann K, Moritz S, Botzenhardt J, Muhtz C, Wiedemann K, Kellner M, et al. (2012): Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with
BIOL PSYCHIATRY 2013;74:e15–e17 e17 major depression: A longitudinal study. Psychoneuroendocrinology 37: 685–692. 23. Hinkelmann K, Muhtz C, Dettenborn L, Agorastos A, Moritz S, Wingenfeld K, et al. (2013): Association between cortisol awakening response and memory function in major depression. Psychol Med 27: 1–9. 24. Tarullo AR, Gunnar MR (2006): Child maltreatment and the developing HPA axis. Horm Behav 50:632–639. 25. Trickett PK, Noll JG, Susman EJ, Shenk CE, Putnam FW (2010): Attenuation of cortisol across development for victims of sexual abuse. Dev Psychopathol 22:165–175. http://dx.doi.org/10.1016/j.biopsych.2013.04.021
www.sobp.org/journal
C
0006-3223/$36.00
Demographic characteristics between patients and healthy control subjects were compared with univariate analysis of variance for continuous variables and χ2 tests for dichotomous variables. For salivary cortisol we calculated the area under the curve with respect to ground (17). Mixed analyses of variance were conducted to examine the effects of group (depression vs. healthy control subjects) and the effects of childhood trauma (CTQ⫹ vs. CTQ−) on cortisol values. There were no significant differences between groups on demographic variables except body mass index, which was controlled for in subsequent analyses. More patients than control subjects (24 of 43 patients vs. 7 of 41 control subjects) reported traumatic childhood experiences (p ⬍ .01). Among depressed patients, five traumatized individuals but none of the nontraumatized patients showed atypical symptoms (p ¼ .06). Analysis of covariance revealed lower mean hair cortisol concentrations (F1,71 ¼ 4.11, p ¼ .05) as well as lower mean salivary cortisol concentrations (F1,70 ¼ 4.95, p ¼ .03) in subjects
Figure 1. (A) Salivary cortisol. Analysis of covariance, adjusted for body mass index, significant effect of childhood trauma (F1,70 ¼ 4.95, p ¼ .03). (B) Hair cortisol. Analysis of covariance, adjusted for body mass index, significant effect of childhood trauma (F1,71 ¼ 4.11, p ¼ .05). Bars represent means (SEM). AUC, area under the curve; CTQ⫹, history of childhood trauma; CTQ−, no history of childhood trauma; DEP, depression.
BIOL PSYCHIATRY 2013;74:e15–e17 & 2013 Society of Biological Psychiatry
e16 BIOL PSYCHIATRY 2013;74:e15–e17 with a history of maltreatment compared with subjects without childhood maltreatment (Figure 1). In contrast, the main effect of diagnosis and the diagnosis trauma interaction was not significant (p ⬎ .1). Sex, smoking status, antidepressant treatment, and atypical depression were not associated with cortisol concentrations and therefore omitted from the analyses (p ⬎ .1). Across groups, partial correlation analyses revealed a significant negative association of salivary cortisol area under the curve with CTQ sum score (r ¼ .35, p ⬍ .01). In summary, we found a significant association of childhood trauma with lower long-term cortisol secretion as measured by hair cortisol and lower diurnal salivary cortisol in depressed patients and healthy control subjects. In contrast, there was no effect of current depression on cortisol measures in our sample. Our study represents the first evidence of decreased long-term cortisol secretion as measured by hair analysis in individuals with a history of childhood trauma. Our results are compatible with a profound and lasting effect of childhood trauma on the HPA axis and in line with a recent longitudinal nonhuman primate study showing that early maternal separation led to reduced hair cortisol (18). Our findings also concur with a recent study by Steudte et al. (16), who found reduced hair cortisol in traumatized individuals with and without concurrent PTSD. Finally, our results are in accordance with Heim et al. (1) and with studies indicating lower baseline cortisol in healthy control subjects with childhood trauma (1,4,5). However, some studies did not find low cortisol after childhood trauma (6–10,19). Besides sampling methods, concurrent PTSD, atypical depression, and antidepressant medication could account for lower cortisol (20–23). In our study, excluding PTSD patients did not change the results, and neither atypical depression nor medication was associated with cortisol levels. Studies in maltreated children have consistently shown elevated basal cortisol (24), which might be followed by hypocortisolism as shown by a prospective study in victims of sexual abuse (25). Chronic hypocortisolism might then lead to an increased central corticotropin-releasing hormone drive, which then might sensitize to stress and depression (3). In sum, our study suggests that childhood trauma exhibits a profound and lasting effect on different measures of the HPA axis, independent of current psychopathology. Kim Hinkelmannan Christoph Muhtzb Lucia Dettenbornc Agorastos Agorastosd Katja Wingenfelda Carsten Spitzere Wei Gaof Clemens Kirschbaumf Klaus Wiedemannd Christian Ottea a
Department of Psychiatry and Psychotherapy, Charite University Medical Center, Campus Benjamin Franklin, Berlin; bDepartment of Psychosomatic Medicine; c Department of Medical Psychology; dDepartment of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg; eAsklepios Fachklinikum Tiefenbrunn, Rosdorf; and the fDepartment of Psychology, Technical University Dresden, Dresden, Germany. *Corresponding author E-mail: [email protected].
www.sobp.org/journal
Correspondence We thank the laboratory team of CK at the Technical University in Dresden for their efforts with the hair analysis. We also thank Mrs. Huwald and Mrs. Remmlinger-Marten for their technical assistance. Dr. Wiedemann served as a consultant to or has been on the Speakers’ boards of AstraZeneca, Bristol Myers Squibb, Janssen, Pfizer, Servier, and Wyeth. Dr. Otte has received honoraria fees for lectures from AstraZeneca, Berlin-Chemie, Lundbeck, and Servier. All other authors report no biomedical financial interests or potential conflicts of interest.
1. Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB (2001): Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry 158:575–581. 2. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, et al. (2000): Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284:592–597. 3. Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008): The link between childhood trauma and depression: Insights from HPA axis studies in humans. Psychoneuroendocrinology 33:693–710. 4. Gerritsen L, Geerlings MI, Beekman AT, Deeg DJ, Penninx BW, Comijs HC (2010): Early and late life events and salivary cortisol in older persons. Psychol Med 40:1569–1578. 5. Power C, Thomas C, Li L, Hertzman C (2012): Childhood psychosocial adversity and adult cortisol patterns. Br J Psychiatry 201:199–206. 6. van der Vegt EJ, van der Ende J, Huizink AC, Verhulst FC, Tiemeier H (2010): Childhood adversity modifies the relationship between anxiety disorders and cortisol secretion. Biol Psychiatry 68:1048–1054. 7. Carpenter LL, Carvalho JP, Tyrka AR, Wier LM, Mello AF, Mello MF, et al. (2007): Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment. Biol Psychiatry 62:1080–1087. 8. Klaassens ER, van Noorden MS, Giltay EJ, van Pelt J, van Veen T, Zitman FG (2009): Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 33:889–894. 9. Otte C, Neylan TC, Pole N, Metzler T, Best S, Henn-Haase C, et al. (2005): Association between childhood trauma and catecholamine response to psychological stress in police academy recruits. Biol Psychiatry 57: 27–32. 10. Elzinga BM, Roelofs K, Tollenaar MS, Bakvis P, van Pelt J, Spinhoven P (2008): Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects. Psychoneuroendocrinology 33:227–237. 11. Russell E, Koren G, Rieder M, Van Uum S (2012): Hair cortisol as a biological marker of chronic stress: Current status, future directions and unanswered questions. Psychoneuroendocrinology 37:589–601. 12. Dettenborn L, Muhtz C, Skoluda N, Stalder T, Steudte S, Hinkelmann K, et al. (2012): Introducing a novel method to assess cumulative steroid concentrations: Increased hair cortisol concentrations over 6 months in medicated patients with depression. Stress 15:348–353. 13. Stalder T, Steudte S, Alexander N, Miller R, Gao W, Dettenborn L, et al. (2012): Cortisol in hair, body mass index and stress-related measures. Biol Psychology 90:218–223. 14. Wingenfeld K, Schafer I, Terfehr K, Grabski H, Driessen M, Grabe H, et al. (2011): [The reliable, valid and economic assessment of early traumatization: first psychometric characteristics of the German version of the Adverse Childhood Experiences Questionnaire (ACE)]. Psychother Psychosom Med Psychol 61:e10–e14. 15. Bernstein DP, Fink L (1998): Childhood Trauma Questionnaire: A Retrospective Self-Report Manual. San Antonio, TX: The Psychological Corporation. 16. Steudte S, Kirschbaum C, Gao W, Alexander N, Schönfeld S, Hoyer J, et al. (2013): Hair cortisol as a biomarker of traumatization in healthy individuals and posttraumatic stress disorder patients. Biol Psychiatry 74:639–646. 17. Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH (2003): Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 28:916–931. 18. Feng X, Wang L, Yang S, Qin D, Wang J, Li C, et al. (2011): Maternal separation produces lasting changes in cortisol and behavior in rhesus monkeys. Proc Natl Acad Sci U S A 108:14312–14317.
Correspondence 19. Carvalho Fernando S, Beblo T, Schlosser N, Terfehr K, Otte C, Lowe B, et al. (2012): Associations of childhood trauma with hypothalamicpituitary-adrenal function in borderline personality disorder and major depression. Psychoneuroendocrinology 37:1659–1668. 20. Yehuda R, Seckl J (2011): Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis. Endocrinology 152:4496–4503. 21. Stetler C, Miller GE (2011): Depression and hypothalamic-pituitaryadrenal activation: A quantitative summary of four decades of research. Psychosom Med 73:114–126. 22. Hinkelmann K, Moritz S, Botzenhardt J, Muhtz C, Wiedemann K, Kellner M, et al. (2012): Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with
BIOL PSYCHIATRY 2013;74:e15–e17 e17 major depression: A longitudinal study. Psychoneuroendocrinology 37: 685–692. 23. Hinkelmann K, Muhtz C, Dettenborn L, Agorastos A, Moritz S, Wingenfeld K, et al. (2013): Association between cortisol awakening response and memory function in major depression. Psychol Med 27: 1–9. 24. Tarullo AR, Gunnar MR (2006): Child maltreatment and the developing HPA axis. Horm Behav 50:632–639. 25. Trickett PK, Noll JG, Susman EJ, Shenk CE, Putnam FW (2010): Attenuation of cortisol across development for victims of sexual abuse. Dev Psychopathol 22:165–175. http://dx.doi.org/10.1016/j.biopsych.2013.04.021
www.sobp.org/journal