Objective: Depression and fatigue are among the most common symptoms of multiple sclerosis (MS). These symptoms frequently co-occur and partially overlap in MS but their underlying biological substrates are unclear. In this study, we examined the relative role of cytokines and hypothalamic-pituitary-adrenal (HPA) axis activity for depression and fatigue in patients with relapsing-remitting MS (RRMS).Methods: HPA axis function and frequency of stimulated cytokine (IFNγ and TNFα) producing T cells was measured cross-sectionally in 44 female patients with RRMS. All subjects completed a neurological exam, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and self-report questionnaires. Results: Ten patients met diagnostic criteria for MDD. MS patients with comorbid MDDshowed normal morning but elevated evening salivary cortisol levels resulting in a flattened slope. While higher frequency of cytokine producing CD8+ T cells was also seen in MS patients with MDD, these markers were more closely associated with fatigue than depression. Conclusions:This study supports a role of HPA axis hyperactivity for major depression in MS. In addition, inflammatory and neuroendocrine factors may differentially mediate fatigue and depressive symptoms.

No abstract

No abstract

Summary Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS with a high prevalence of depression. Both MS and depression have been linked to elevated cortisol levels and inflammation, indicating disturbed endocrine-immune regulation. An imbalance in mineralocorticoid versus glucocorticoid signaling in the CNS has been proposed as a pathogenetic mechanism of depression. Intriguingly, both receptors are also expressed in lymphocytes, but their role for 'escape' of the immune system from endocrine control is unknown. Using steroid sensitivity of T cell function as a read-out system, we here investigate a potential role of mineralocorticoid receptor (MR) versus glucocorticoid receptor (GR) regulation in the immune system as a biological mechanism underlying MS-associated major depression. Twelve female MS patients meeting diagnostic criteria for current major depressive disorder (MDD) were compared to twelve carefully matched MS patients without depression. We performed lymphocyte phenotyping by flow cytometry. In addition, steroid sensitivity of T cell proliferation was tested using hydrocortisone as well as MR (aldosterone) and GR (dexamethasone) agonists. Sensitivity to hydrocortisone was decreased in T cells from depressed MS patients. Experiments with agonists suggested disturbed MR regulation, but intact GR function. Importantly, there were no differences in lymphocyte composition and frequency of T cell subsets, indicating that the differences in steroid sensitivity are unlikely to be secondary to shifts in the immune compartment. To our knowledge, this study provides first evidence for altered steroid sensitivity of T cells from MS patients with comorbid MDD possibly due to MR dysregulation.