133 The first report on the sickness behavior-inducing effect of cytokines was published by Smedley and colleagues, who treated patients with advanced locally recurrent breast ATM Kinase Inhibitor cancer with a high dose (160 MU/week) of IFN-α.15 Within 1 h of administration, they observed influenzalike symptoms, which 1 week later were superseded by lethargy, anorexia, and nausea, with a consequent loss of weight in most patients. Other side effects included profound somnolence, confusion, and paresthesia. Low-dose IFN-α therapy Inhibitors,research,lifescience,medical (3-5 MU three times a week) induces less severe psychiatric symptoms such as irritability and depression accompanied by impaired concentration,

lack of motivation, sleep disturbances, and decreased libido.134 Depressive symptoms induced by IFN-α or IL-2 therapy were described to be related to a decreased tryptophan availability.135 Not only sickness behavior, but also schizophrenia-like Inhibitors,research,lifescience,medical symptoms including agitation, cognitive impairment, disorientation, delusions, and hallucinations are induced by IL-2 and IFN-α.136,137 Denicoff

and colleagues were the first to report dose- and time-related psychiatric Inhibitors,research,lifescience,medical side effects in cancer patients treated with recombinant IL-2 that ranged from brief to severe agitation and combat iveness, requiring antipsychotic therapy.138 Besides the observation in patients suffering from malignancies or chronic inflammatory diseases, experimental data in healthy humans confirmed that

cytokines, Inhibitors,research,lifescience,medical particularly TNF-α and IL-6, induce depressed mood, anxiety, and memory impairment.139 Major depression The observations described above led to the hypothesis that sickness behavior may serve as a model for the immune-related pathophysiology of major depression (MD).132 In fact, there is a large body of evidence for an altered immune response in depressed patients. As described above, IFN-γ is a characteristic marker of Th1 cells. IFN-γ is produced in higher amounts by lymphocytes of patients with MD than by those of healthy controls,140 and higher plasma levels of IFN-γ in depressed patients, accompanied by lower plasma tryptophan availability, Inhibitors,research,lifescience,medical were described.141,142 This gives additional evidence for a possible link between the Th1 -like cytokine IFN-γ and the IDO-related Megestrol Acetate reduction in 5-HT availability in the CNS of depressed patients. Given a functional relationship among the Th1 -dominated immune system, the serotonergic system, and MD, antidepressant therapy should be adequate to induce a Th1 to Th2 shift. There are indeed some reports demonstrating the potency of antidepressants to significantly reduce the IFN-γ/IL-10 ratio in vitro143 and to suppress the Th1 response in patients.144 The most frequently investigated immune parameter in patients suffering from MD is IL-6. Most of the publications report a marked increase of in vitro IL-6 production145 or serum IL-6 levels in depressed patients.