45 However, little evidence currently exists as to whether reduction of hippocampal volume is directly due to elevated levels of Cortisol, though it has been postulated that elevated Cortisol may influence

cognitive performance and mood state.46 MS patients are known to have a chronically activated HPA axis,47 and HPA axis activity correlates with progression ratings and cognitive impairment over 3 years.48 In addition, MRI studies28 have shown an association between depression in MS and temporal lobe atrophy (though not specifically hippocampal atrophy). Given the association between depression and both HPA activity and Inhibitors,research,lifescience,medical hippocampal atrophy, the chronic activation of the HPA axis in MS may be one source of these patients’ increased susceptibility to the development of depression. Steroid treatment Consistent with a role for the HPA axis in the mechanism of depression, exogenous corticosteroids have been shown to have powerful mood-altering effects. Inhibitors,research,lifescience,medical Corticosteroids are often used in high doses to treat exacerbations in MS. They are associated with a great number of side effects, including effects on mood.49 Their short-term Inhibitors,research,lifescience,medical use often produces an activated state characterized

by increased energy, decreased sleep, and variable euphoria, which can be quite destabilizing to a patient’s mood state. With initial dosing, longterm use, and discontinuation, steroid administration can result in new depressive symptoms as well as dramatic and even life-threatening worsening of mood in those already suffering from depression.50 The effects Inhibitors,research,lifescience,medical of steroids on mood regulation provides further support for a role of the HPA axis in precipitating depression. The role of inflammation in MS depression The increased incidence of depression in MS may be directly related to the inflammation which is the hallmark of this autoimmune disease. Alterations in the immune function

of depressed patients have been observed for many years, although the precise nature of the changes has been variable, with some reflecting suppression Inhibitors,research,lifescience,medical and others activation Dipeptidyl peptidase of the immune system.51-53 Recent work has demonstrated that depression is associated with an activation of inflammatory pathways, as evidenced by increases in C-reactive screening assay protein and other changes.54-57 In MS, depression scores are higher in patients with increased CSF white blood cell counts, in vitro interferon (IFN)-γ production, increased messenger ribonucleic acid (mRNA) for tumor necrosis factor (TNF)-α and IFN-γ, and central nervous system (CNS) inflammation as demonstrated by gadolinium-enhancing lesions on T1-weighted MRI.5,21,58 Cytokines Proinflammatory cytokines are chemical messengers that are produced by immunocompetent cells and mediate communication between cells of the immune system, and are elevated in MS.