Sex-related differential response to dexamethasone in endocrine and immune measures in depressed in-patients and healthy controls.

Although sex differences in major depression have been reported repeatedly, the underlying mechanisms are still disputed. The rapidly changing gonadal steroid concentrations of the postpartum period or during menopause have been shown to be associated with depressive symptoms and to modulate the hypothalamic-pituitary-adrenal (HPA)-axis, which is implicated in depression. The sample comprised of 128 depressed in-patients (36.7% women) and 166 healthy controls (30.0% women). Blood was collected at baseline (at 6pm) and then 3 h as well as 21 h after ingestion of 1.5 mg dexamethasone for measurement of cortisol, ACTH and blood count. To further assess the function of the HPA-axis the dexamethasone/corticotrophin releasing hormone (Dex-CRH) test was performed in a subsample of 115 patients and 116 controls the following day. A significant interaction effect between sex, disease and ACTH concentrations over time after dexamethasone stimulation was observed, with men showing increased ACTH concentrations at baseline and after 21 h, while there was no difference after 3 h (p = .007). After separating for disease status this significant interaction effect was only observed in controls (p = .005). The cortisol response in the dex-CRH test was enhanced in female compared to male controls (p = .002). Leucocytes showed a stronger increase upon dexamethasone administration only in female compared to male controls (p = .023). These findings suggest a higher glucocorticoid receptor sensitivity following in-vivo glucocorticoid stimulation in healthy women that was absent in depressed patients. The sex-related differences in HPA-axis regulation and immune system function may contribute to the vulnerability of female sex to the development of depression.

Time-dependent effects of dexamethasone plasma concentrations on glucocorticoid receptor challenge tests.

Glucocorticoid challenge tests such as the dexamethasone suppression test (DST) and the combined dexamethasone/corticotropin-releasing hormone (dex-CRH) test are considered to be able to sensitively measure hypothalamic-pituitary-adrenal (HPA) axis activity in stress-related psychiatric and endocrine disorders. We used mass-spectrometry to assess the relationship of plasma dexamethasone concentrations and the outcome of these tests in two independent cohorts. Dexamethasone concentrations were measured after oral ingestion of 1.5mg dexamethasone in two cohorts that underwent a standard (dexamethasone at 23:00h) as well as modified (18:00h) DST and dex-CRH test. The first study population was a case/control cohort of 105 depressed patients and 133 controls in which peripheral blood mRNA expression was also measured. The second was a cohort of 261 depressed patients that underwent a standard dex-CRH test at baseline and after 12 weeks' treatment with cognitive-behavioral therapy or antidepressants. Dexamethasone concentrations explained significant proportions of the variance in the DST in both the first (24.6%) and the second (5.2%) cohort. Dexamethasone concentrations explained a higher proportion of the variance in the dex-CRH test readouts, with 41.9% of the cortisol area under the curve (AUC) in the first sample and 24.7% in the second sample. In contrast to these strong effects at later time points, dexamethasone concentrations did not impact cortisol or ACTH concentrations or mRNA expression 3hours after ingestion. In the second sample, dexamethasone concentrations at baseline and week 12 were highly correlated, independent of treatment type and response status. Importantly, a case/control effect in the Dex-CRH test was only apparent when controlling for dexamethasone concentrations. Our results suggest that the incorporation of plasma dexamethasone concentration or measures of earlier endocrine read-outs may help to improve the assessment of endocrine dysfunction in depression.