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.