16 Forty-five percent of the IFN-α-treated patients developed major depression during the 12-week follow-up period. There were minimal differences in the severity of individual depressive symptoms between patients who became depressed during IFN-α treatment versus medically healthy depressed individuals, although IFN-α-treated depressed patients did exhibit more psychomotor retardation and weight loss, and the medically healthy depressed group experienced greater

feelings of guilt and thoughts of suicide.8 These results suggest that the depression induced by C59 wnt mouse cytokines Inhibitors,research,lifescience,medical is remarkably similar to depression seen in medically healthy depressed patients. Of note, the link between inflammation and depression may explain Inhibitors,research,lifescience,medical the frequent association between medical illnesses and depression.17 As shown in Table I, while there are many medical conditions associated with increased rates of depression, the majority of these illnesses are also associated with increased inflammation, including not only infectious diseases and cancer but

also cardiovascular disease and diabetes, both of which are now recognized to have an inflammatory component.18 Of note, when depression occurs in the context of medical illness, it has been Inhibitors,research,lifescience,medical associated with increased concentrations of inflammatory cytokines. For example, several studies have shown that depressed patients with cancer19-22 or cardiovascular disease23 have higher peripheral blood concentrations of IL6 and CRP. Moreover, depression scores have Inhibitors,research,lifescience,medical been shown to be strongly correlated with blood cytokine concentrations in these patients.24 Table I. Inflammatory and noninflammatory diseases associated with elevated rates of depression. *Particularly Inhibitors,research,lifescience,medical in the context of combined chemoradiation How do cytokines cause depression? Access to the brain Peripheral immune

activation, such as that seen with local infection, wounding and/or psychological stress, induces release of IL-1α, IL-1β, IL-6, and TNF-α.5,25-27 However, these cytokines are too large to freely pass through the blood-brain barrier, which raises the question of how a centrally mediated behavioral effect is achieved. Several pathways by which cytokine signals Rolziracetam can access the brain have been identified. Local release of cytokines can stimulate peripheral afferent nerve fibers such as the vagus that innervate peripheral tissues, ultimately leading to activation of microglia, which can produce cytokines in the brain. In addition, “leaky” regions in the blood brain barrier such as the circumventricular organs6,28 allow access of peripheral inflammatory mediators to the brain. Cytokines in the peripheral circulation can also cross the blood-brain barrier via saturable active transport molecules expressed on brain endothelial cells.