There is much evidence that depression is a disease with damage accumulating in stress-sensitive systems over time.1 Damage is most likely to accrue in early life when the hypothalamic-pituitary-adrenal axis (HPAA) is more plastic. Animal models, with some support from human studies, demonstrate that exposure to prenatal and early life stressors bring about epigenetic changes in key genes involved in the regulation of the HPAA, leading to reduced feedback inhibition in the HPAA, prolonged stress responses, and ultimately depression.2,3 First-presentation depression (FPD) in early adult life is a unique point where the chronic stress, or the allostatic load, of early life adversity (ELA), possibly mediated by epigenetic mechanisms, may translate into a depressive state. This is an ideal time to examine and define specific aetiolopathological pathways to the depressive syndrome.
We thus wish to carefully phenotype a FPD group (n=100) in relation to ELA, and measure HPAA, epigenetic and neuroimaging markers. Measures will include salivary cortisol stress responses and diurnal secretory patterns; methylation of specific sites that modify glucocorticoid receptor (GR) and mineralocorticoid (MR) function; peripheral blood mononuclear cell (PBMC) responses to inflammatory provocation and immune suppression (GR mRNA, MR mRNA and cytokine production); and inflammatory biomarkers (IL6, TNFα, CRP and INFγ). Neuroimaging tests, found by our group to detect differences between depressed and control groups, will include fMRI using a cognitive-inhibition of emotion task, and volumetric and DTI analysis in targeted regions.
We will re-test the group at six months and one year later to track possible changes related to recovery or chronicity. Findings will be analysed to see if aetiopathological pathways within the depressed groups can be identified in an allostatic load/ELA model, and whether this will be reflected in the clinical phenotype. This analysis will also involve comparisons with a healthy group at baseline and 18 months.
