Elsevier

Biological Psychiatry

Volume 42, Issue 8, 15 October 1997, Pages 669-679
Biological Psychiatry

Original Articles
The Corticotropin-Releasing Hormone Challenge in Depressed Abused, Depressed Nonabused, and Normal Control Children

https://doi.org/10.1016/S0006-3223(96)00470-2Get rights and content

Abstract

Hypothalamic–pituitary–adrenal (HPA) axis disturbances in depressed children with a history of abuse were examined. Thirteen depressed abused, 13 depressed nonabused, and 13 normal control children were given 1.0 μg/kg of human corticotropin-releasing hormone (CRH) intravenously. Blood samples for corticotropin (ACTH) and cortisol were obtained at nine intervals. When compared to depressed nonabused and normal control children, depressed abused children had significantly greater peak, total, and net ACTH secretion post-CRH. Increased ACTH secretion was only observed in depressed abused children experiencing ongoing chronic adversity (marital violence, emotional abuse, poverty, lack of supports). The pattern of findings of the depressed abused children experiencing ongoing adversity parallels the pattern of HPA axis dysregulation reported in animal studies of chronic stress. They add to a growing body of literature suggesting measures of past trauma and current adversity are important sources of variability in psychobiological correlates of major depression.

Introduction

Although disturbances of the hypothalamic–pituitary–adrenal (HPA) axis are among the more robust and consistent biological findings reported in samples of adults with depression (e.g., Holsboer 1995; Stokes and Sikes 1987), disturbances of the HPA axis are relatively rare in children (Ryan et al 1994). Hypercortisolemia (Dahl et al 1989, Dahl et al 1991; Kutcher and Marton 1991; Puig-Antich et al 1989), dexamethasone nonsuppression (see Casat et al 1989; Dahl et al 1992for a review), and blunting of corticotropin (ACTH) secretion after corticotropin-releasing hormone (CRH) infusion (Birmaher et al in press) are infrequently observed in depressed children.

For example, when the CRH challenge was administered to children with major depression (MDD) and normal controls, there were no differences between the two groups on any of the baseline or stimulation summary measures (Birmaher et al 1996). Depressed children with melancholia (n = 3) had a nonsignificant trend toward elevated cortisol at baseline. In addition, melancholic (n = 3) and inpatient (n = 10) depressed children secreted significantly less ACTH throughout the CRH challenge. Change in ACTH secretion in response to CRH was comparable among all groups, however. These results are in contrast to studies with adults, which typically report elevated cortisol at baseline and blunted ACTH secretion post-CRH infusion in depressed patients when compared to normal controls (e.g., Holsboer et al 1987; Lesch et al 1988; Rupprecht et al 1989).

Recent research has highlighted the importance of experiential (e.g., trauma) factors in explaining heterogeneity in the psychobiological correlates of depression (Halbriech et al 1989; Williamson et al 1995a; Yehuda et al 1995). As abuse history data were available for 62% (21/34) of the MDD and 63% (14/22) of the normal control children who participated in the CRH study described above (Birmaher et al 1996), secondary analyses were performed on the data as a preliminary test of the hypothesis that HPA axis disturbances are most prominent in depressed children with a history of trauma (e.g., abuse). Five MDD children were identified with a history of sexual abuse. When compared to the depressed and normal control children without a history of abuse, the depressed children with a history of abuse had blunted ACTH secretion post-CRH infusion, and a trend toward elevated cortisol at baseline (Kaufman et al 1993).

Similar finding were reported in another study in which the CRH challenge was administered to sexually abused and normal control children (DeBellis et al 1994a). Sixty-two percent of the sexually abused children in this study met criteria for dysthymia. When compared to normal controls, sexually abused children were found to have a blunted ACTH response to CRH, and normal basal and post-CRH cortisol values. In addition to these preliminary reports documenting HPA axis dysregulation in abused children, three other studies have reported abnormalities in the pattern of cortisol secretion in clinically heterogenous samples of abused children (Hart et al 1996; Kaufman 1991; Putnam et al 1991). In one of these reports (Kaufman 1991), cortisol secretion abnormalities were found to be significantly more likely among abused children who met criteria for MDD than in abused children without depressive symptomatology.

These initial reports suggest that, in contrast to the relative lack of HPA axis disturbances observed in cohorts of nontraumatized depressed children, depressed children with a history of abuse are likely to have altered HPA axis function. To further test the hypothesis that disturbances of the HPA axis are most prominent in depressed children with a history of trauma (e.g., abuse), a cohort of depressed children with a history of abuse was recruited and administered the CRH challenge. It was hypothesized that the depressed abused children, when compared to depressed nonabused and normal control children, would have increased basal cortisol values, and blunted ACTH and normal cortisol response post-CRH infusion.

Section snippets

Referral

Depressed children were recruited from the inpatient and outpatient clinics at Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center. Normal control children were recruited through advertisement and personal contacts. The depressed nonabused and normal control children were recruited to participate in a larger study on the psychobiology of childhood depression (PO5 MH 41712, Program Director, Neal Ryan, MD), and the depressed abused children were recruited to

Methods

The sleep/neuroendocrine laboratory where the tests were completed is furnished with many age-appropriate materials, including books, art supplies, board games, entertainment videos, and computer games. In the lab, children are given a lot of one-to-one attention from staff who have years of experience running biological studies with children, and the majority of children who participated in this and other studies in the lab rated the experience very positive (Townsend et al 1988; Nelson 1996).

Statistical Analyses

There were no problems with missing data. The following summary values were used to characterize children’s ACTH and cortisol responses to the CRH challenge: baseline, total post-CRH, peak post-CRH, and net response. The baseline values were computed by determining the mean of the three ACTH and cortisol specimens taken at −30, −15, and 0 min pre-CRH infusion. The total post-CRH scores were computed by determining the area under the curve (AUC) using the seven ACTH and cortisol specimens

ACTH Values

Table 2 portrays the means and standard deviations of the ACTH summary scores, and results of tests for group differences on these measures. As depicted in Table 2 there were no differences in the mean ACTH values at baseline. The depressed abused children, however, had significantly greater total, peak, and net ACTH response post-CRH than the children in the other two groups (p < .01, all comparisons). Overall the depressed abused children, when compared to the depressed nonabused and normal

Discussion

The response of the depressed abused children to the CRH challenge was opposite initial predictions. Based on prior examinations of the HPA axis in abused children (DeBellis et al 1994a; Kaufman et al 1993), the depressed abused children were expected to have blunted ACTH secretion post-CRH infusion. Instead, the depressed abused children in this study were found to have significantly augmented ACTH secretion. This finding was limited to the depressed abused children living under conditions of

Conclusions

Consistent with the work of others (Halbriech et al 1989; Williamson et al 1995b; Yehuda et al 1995) the analyses presented in this report highlight the importance of experiential (e.g., trauma) factors in explaining heterogeneity in the psychobiological correlates of depression. The data suggest that experiences of abuse, in combination with ongoing stressors and an absence of positive supports, promote significant dysregulation of the HPA axis system. More research is needed to understand how

Acknowledgements

This study was supported by two interlocking grants from the National Institute of Mental Health: 5K21 MH 01022 (P.I. Joan Kaufman, PhD) and PO5 MH 41712 (P.I. Neal Ryan, MD).

The authors would like to acknowledge the staff of the Clinical Core, Child and Adolescent Sleep Laboratory, Neuroendocrine Laboratory, and Data Analytic Core for their important contribution to this work. In addition, the authors wish to thank the children and families whose cooperation and support made this study

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