Abstract
Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (βrange = −0.057 to −0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; βrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (β = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: β = −0.059, P = 0.043; nucleus accumbens: β = −0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.
Highlights
Major depressive disorder (MDD) is the leading cause of disability worldwide [1] and affects ~6% of the adult population globally per year [2]
There were no False discovery rate (FDR)-significant associations with hair cortisol, increased hair cortisone concentrations were significantly associated with MDD case–control status (β = 0.115, PFDR = 0.002), total QIDS scores (β = 0.089, PFDR = 0.014), and QIDS depression severity (β = 0.071, PFDR = 0.038)
While we found no associations with hair cortisol, increased hair cortisone concentrations were significantly associated with total Childhood Trauma Questionnaire’ (CTQ) scores (β = 0.083, P = 0.017) and with two subscales of the CTQ: higher reported total emotional abuse (β = 0.087, PFDR = 0.034) and total physical neglect (β = 0.090, PFDR = 0.034)
Summary
Major depressive disorder (MDD) is the leading cause of disability worldwide [1] and affects ~6% of the adult population globally per year [2]. Since there are no previous studies of long-term glucocorticoid exposure with both global/regional brain morphology and white matter microstructure phenotypes, Depression status and symptoms We measured both the lifetime incidence of MDD (case/control status) and current depression symptoms and symptom severity. There have been no prior studies of the association between hair glucocorticoids, structural neuroimaging phenotypes and deprescontrol status was ascertained using the research version of the Structured Clinical Interview for DSM disorders (SCID) [39] and diagnostic criteria were based on the ‘Diagnostic and Statistical Manual of Mental Disorders’ (DSM-IV-TR) Using this definition, the sample had N = 317 MDD cases and N = 676 controls. We investigated hair glucocorticoid associations with (i) MDD case/control status and depressive symptoms, (ii) childhood adversity and current-life stress and (iii) structural neuroimaging-derived phenotypes from the two.
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