Childhood Trauma, HPA Axis Activity and Antidepressant Response in Patients with Depression

Naghmeh Nikkheslat, Anna P. Mclaughlin, Caitlin Hastings, Zuzanna Zajkowska, Maria A. Nettis, Nicole Mariani, Daniela Enache, Giulia Lombardo, Linda Pointon, Philip J. Cowen, Jonathan Cavanagh, Neil A. Harrison, Edward T. Bullmore, Carmine M. Pariante, Valeria Mondelli

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Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n=42), treatment non-responder (n=80) and untreated depressed (n=41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.
Original languageEnglish
JournalBrain Behavior and Immunity
Early online date30 Nov 2019
Publication statusE-pub ahead of print - 30 Nov 2019


  • Childhood trauma
  • Cortisol response
  • Glucocorticoid resistance
  • HPA axis hyperactivity
  • Inflammation
  • Major depressive disorders
  • Treatment resistant depression


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