11,12,13 Signs of inflammation were found in schizophrenic brains,14 and the term “mild localized chronic encephalitis”

to describe a slight but chronic inflammatory process in schizophrenia was proposed.15 An inflammatory model of MD is “sickness behavior,” the reaction of the organism to infection and inflammation. Sickness behavior is characterized by weakness, malaise, listlessness, inability to concentrate, lethargy, decreased interest in the surroundings, and reduced food intake Inhibitors,research,lifescience,medical – all of which are depression-like symptoms. The sicknessrelated psychopathological symptoms during infection and inflammation are mediated by proinflammatorycytokines such as IL-1, IL-6, TNF-α, and IFN-γ. The active pathway of these cytokines from the peripheral immune Inhibitors,research,lifescience,medical system to the brain is via afferent neurons and through direct targeting of the amygdala and other brain regions after diffusion at the circumventricular organs and choroid plexus. Undoubtedly, there is a strong relationship between the cytokine and the neurotransmitter

systems, but the specific mechanisms underlying the heterogeneous disease MD are not yet fully understood. In humans, the involvement of cytokines in the regulation of the behavioral symptoms of Inhibitors,research,lifescience,medical sickness behavior has been studied by application of the bacterial endotoxin lipoploysaccharide (LPS) to human volunteers.16 LPS, a potent activator of proinflammatory cytokines, was found to induce mild fever, anorexia, anxiety, depressed mood, and cognitive impairment. The levels of anxiety, depression, and cognitive impairment were found Inhibitors,research,lifescience,medical to be related to the levels of circulating cytokines.17 Mechanisms that may contribute to inflammation and cause depressive states are: A direct influence of

proinflammatory cytokines on the serotonin and noradrenaline metabolism An imbalance of the type-1 Inhibitors,research,lifescience,medical – type-2 immune response leading to an increased tryptophan and serotonin metabolism by activation of indoleamine 2,3-dioxygenase (IDO) in the CNS, which is associated with: A decreased availability of tryptophan and serotonin A Histone demethylase disturbance of the kynurenine metabolism with an imbalance in favour of the production of the NMDA receptor agonist quinolinic acid (QUIN) An imbalance in astrocyte and microglial activation associated with increased production of QUIN. Effects of antidepressants on the immune function support this view. The mechanisms and the therapeutic implications will be discussed below. Inflammation, caused by infection or by other mechanisms, seems to play a role in schizophrenia and in MD. Type-1 and type-2 immune KU-55933 chemical structure responses in schizophrenia A well established finding in schizophrenia is the decreased in vitro production of IL-2 and IFN-γ,18,19 reflecting a blunted production of type-1 cytokines. Decreased levels of neopterin, a product of activated monocytes/macrophages, also point to a blunted activation of the type-1 response.