Insights from interferon-α-related depression for the pathogenesis of depression associated with inflammation

Interferon-alpha (IFN-alpha) is a pleiotropic cytokine that is administered as a therapeutic in highly prevalent medical conditions such as chronic hepatitis C and B virus infection, melanoma and lymphoma. IFN-alpha induces, to a clinically relevant degree, concentration, memory, drive and mood disturbances in almost half of all patients. For this reason, IFN-alpha is increasingly being replaced by more specifically acting drugs. In the past decades, IFN-alpha has offered a valuable insight into the pathogenesis of major depression, particularly in settings associated with inflammation. IFN-alpha, triggers immune responses, hypothalamo-pituitary-adrenal axis abnormalities and disturbances of brain metabolism resembling those in other depression states. IFN-alpha stimulates indoleamine-2,3 dioxygenase-1, activating the kynurenine pathway with reduced formation of the neurotransmitters serotonin and dopamine, excessive formation of the NMDA agonist quinolinic acid, and reduced formation of the NMDA antagonist kynurenic acid. In addition, IFN-alpha disturbs neurotrophic signaling and impedes neurite outgrowth, synaptic plasticity, endogenous neurogenesis and neuronal survival. Consequently, IFN-alpha-related depression may represent a model for the neurodegenerative changes that are noticed in late-life major depression. Indeed, the observation that brain responses in IFN-alpha-related depression resemble idiopathic depression is supported by the existence of common genetic signatures, among which of note, a number of neuronal survival and plasticity genes have been identified. In view of the high incidence of depressive symptoms, IFN-alpha-related depression is an attractive model for studying links between neuronal plasticity, neurodegeneration and depression. We predict that in the latter areas new targets for anti-depressant therapies could be identified, which may deepen our understanding of idiopathic major depression. (C) 2014 Elsevier Inc. All rights reserved.