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.

The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression.

OBJECTIVE: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. METHODS: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). RESULTS: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01). CONCLUSIONS: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment.

Epigenetics in posttraumatic stress disorder.

Reported exposure to traumatic event is relatively common within the general population (40-90%), but only a fraction of individuals will develop posttraumatic stress disorder (PTSD). Indeed, the lifetime prevalence of PTSD is estimated to range between 7% and 12%. The factors influencing risk or resilience to PTSD after exposure to traumatic events are likely both environmental, such as type, timing, and extent of trauma, and genetic. Recently, epigenetic mechanisms have been implicated in mediating altered risk for PTSD as they can reflect both genetic and environmental influences. In this chapter, we describe the accumulating evidences for epigenetic factors in PTSD highlighting the importance of sensitive periods as well as methodological aspects such as tissue availabilities for such studies. We describe studies using a candidate gene approach focusing mainly on key players in the stress hormone regulation that show epigenetic alterations both in humans and in animal models for PTSD. We also summarize the results of epigenome-wide studies reporting associations with PTSD. For the above, we focus on one epigenetic mechanism, DNA methylation, as it is so far the best studied for this disorder. Finally, we describe how epigenetic mechanisms could be responsible for the long-lasting effects of gene-environment interactions observed in PTSD.