interferon - related depression is important in medicine and neurology , and the last decade has seen a spurt of research in the field . this article therefore summarizes the present state of knowledge about interferons and their role in depression in humans . interferon ( ifn ) activity was first discovered by isaacs and lindenmann in the year 1957 , when they came across a substance that interfered with the pathogenic activity of live influenza viruses in the chorioallantoic membranes of chick embryos that had previously been infected by heat - attenuated influenza viruses . ifns were the first cytokines to be discovered and the recombinant form of ifn- was the first cytokine to be approved , in 1986 , to treat hairy cell leukaemia [ 4 , 5 ] . ifn species are distinctively different from one another in their functional profile ; for example , they may exhibit antiviral and antiproliferative actvity , or they may stimulate antigen presenting cells . this variation in activity is species - specific , and in a given species the ifn secretion is specific to the cell of origin and the virus eliciting the response . ifns are classified as types i , ii , and iii ( table 1 ) , based on the cell surface receptors to which they bind . the ifn type - i family consists of the following : 13 different ifn- proteins coded by 14 ifn- genes ; ifn- , which is a product of the ifnb1 gene ; and 6 other single gene - coded ifns ( ifn- , ifn- , ifn- , ifn- , ifn- , and ifn- ) [ 7 , 8 ] . type i ifns can be produced by almost all cells in the body but are predominantly secreted by leukocytes ( ifn- ) and fibroblasts ( ifn- ) [ 7 - 9 ] . the type ii ifn family consists of ifn- , coded by the ifng gene that is predominantly secreted by t cells and natural killer ( nk ) cells . ifn-1 , ifn-2 and ifn-3  ( also known as il-29 , il-28a and il-28b , respectively ) and ifn-4 ( also known as ifnan ) form the ifn type - iii family of cytokines that are secreted by all nucleated cells in the body . other ifns have been described in animals , but are not described here because they are out of the scope of the present article . induction of types i and iii ifns ( ifn- , ifn- , and ifn- ; il-28a , il-28b , and il-29 ) occurs after viral infection whereas type ii ( ifn- ) is produced after stimulation with specific antigens such as staphylococcal enterotoxin a or b [ 4 , 9 ] . receptors for ifn family types i and ii are present on all cells in the body and receptors for ifn family type - iii are largely expressed on epithelial cells of the gastrointestinal and reproductive tracts , and on some immune cells [ 7 , 8 , 10 ] . the effector molecules involved in ifn downstream signalling that eventually results in their biological activity have not been completely defined in most cases , but one pathway that is strongly associated with ifn signalling is the  jak - stat pathway . in type - i and iii ifns , the activation of jak - stat leads to the formation of ifn - stimulated gene factor-3 ( isgf3 ) complex which translocates to the nucleus and binds to the promoter region of ifn stimulated genes to bring about their transcription [ 4 , 8 , 10 , 11 ] . type - i and type - ii ifns also follow another pathway resulting in the transcription of ifn stimulating genes ( isg ) by nuclear translocation and binding of stat1-stat1 homodimer to gas ( ifn--activated site ) elements on the promoter region of isgs . interferon ( ifn ) activity was first discovered by isaacs and lindenmann in the year 1957 , when they came across a substance that interfered with the pathogenic activity of live influenza viruses in the chorioallantoic membranes of chick embryos that had previously been infected by heat - attenuated influenza viruses . ifns were the first cytokines to be discovered and the recombinant form of ifn- was the first cytokine to be approved , in 1986 , to treat hairy cell leukaemia [ 4 , 5 ] . ifn species are distinctively different from one another in their functional profile ; for example , they may exhibit antiviral and antiproliferative actvity , or they may stimulate antigen presenting cells . this variation in activity is species - specific , and in a given species the ifn secretion is specific to the cell of origin and the virus eliciting the response . ifns are classified as types i , ii , and iii ( table 1 ) , based on the cell surface receptors to which they bind . the ifn type - i family consists of the following : 13 different ifn- proteins coded by 14 ifn- genes ; ifn- , which is a product of the ifnb1 gene ; and 6 other single gene - coded ifns ( ifn- , ifn- , ifn- , ifn- , ifn- , and ifn- ) [ 7 , 8 ] . type i ifns can be produced by almost all cells in the body but are predominantly secreted by leukocytes ( ifn- ) and fibroblasts ( ifn- ) [ 7 - 9 ] . the type ii ifn family consists of ifn- , coded by the ifng gene that is predominantly secreted by t cells and natural killer ( nk ) cells . ifn-1 , ifn-2 and ifn-3  ( also known as il-29 , il-28a and il-28b , respectively ) and ifn-4 ( also known as ifnan ) form the ifn type - iii family of cytokines that are secreted by all nucleated cells in the body . other ifns have been described in animals , but are not described here because they are out of the scope of the present article . induction of types i and iii ifns ( ifn- , ifn- , and ifn- ; il-28a , il-28b , and il-29 ) occurs after viral infection whereas type ii ( ifn- ) is produced after stimulation with specific antigens such as staphylococcal enterotoxin a or b [ 4 , 9 ] . receptors for ifn family types i and ii are present on all cells in the body and receptors for ifn family type - iii are largely expressed on epithelial cells of the gastrointestinal and reproductive tracts , and on some immune cells [ 7 , 8 , 10 ] . the effector molecules involved in ifn downstream signalling that eventually results in their biological activity have not been completely defined in most cases , but one pathway that is strongly associated with ifn signalling is the  jak - stat pathway . in type - i and iii ifns , the activation of jak - stat leads to the formation of ifn - stimulated gene factor-3 ( isgf3 ) complex which translocates to the nucleus and binds to the promoter region of ifn stimulated genes to bring about their transcription [ 4 , 8 , 10 , 11 ] . type - i and type - ii ifns also follow another pathway resulting in the transcription of ifn stimulating genes ( isg ) by nuclear translocation and binding of stat1-stat1 homodimer to gas ( ifn--activated site ) elements on the promoter region of isgs . ifns are used for the treatment of viral hepatitis , hemato - proliferative disorders , and autoimmune disorders and malignancies because of their antiviral , antiproliferative , and immunomodulatory properties , respectively . the immunogenic property of ifn- has lead to the generation of ifn- conditioned dendritic cells to induce tumor cell death , and also to its use as an adjuvant to enhance the antitumor effect of other chemotherapeutic agents . table 2 lists the usa food and drug administration approved indications and other indications for interferon therapy [ 13 - 22 ] . pegylation of the ifn molecule increases the size of the molecule and thereby increases the time that the molecule persists in the body . pegylated ifn- , combined with ribavarin and protease inhibitors ( optional ) , is the most common choice of treatment for hepatitis c infection . pegylated ifn- is administered along with nucleotide analogues such as lamivudine , adefovir , entecavir , or tenofovir for chronic hepatitis b infections . many mechanisms are suggested to mediate ifn - related benefits ; because this is a considerably speculative area , only a few , brief examples are provided . ifn- may treat multiple sclerosis by inhibiting proinflammatory cytokines such as il-17 and osteopontin ; by increasing anti - inflammatory agents such as il-10 ; by attenuating leukocyte migration across the blood - brain barrier ; and by mediating tissue repair through stimulation of the release of trophic factors such as nerve growth factor . in chronic granulomatous disease , ifn- is suggested to convey benefits by stimulation of the release of superoxide and correction of impairments in oxidative metabolism . progression of malignant osteopetrosis is arrested by ifn- therapy putatively by improving osteoclast - mediated bone resorption and leucocytic superoxide production [ 25 - 27 ] . the neuropsychiatric adverse effects of ifns include depression , irritability , anxiety , agitation , loss of appetite , fatigue , sleep disturbance , and impaired cognition ; quality of life and functional abilities are consequently compromised . importantly , attributing all these changes exclusively to ifn treatment can be difficult because the conditions for which ifns are prescribed are often themselves associated with neuropsychiatric symptoms [ 28 - 30 ] . depression as a syndrome frequently complicates ifn therapy ; the prevalence is 30 - 70% . depressive symptoms are common in the early stages of treatment , but typically peak between 4 and 16 weeks . it is not always clear to what extent the risk is due to the ifn ( and specifically to the type of ifn ; e.g. ifn- vs. ifn- ) and to what extent the risk is due to the clinical condition for which the ifn was prescribed . therefore , risks are described separately in a later section . here , we note that , for example , a meta - analysis of randomized controlled trials ( rcts ) of ifns in multiple sclerosis found no increase in the risk of depression as an adverse outcome . other meta - analyses , for example coppola et al .   and zhuang et al . conclusions from individual rcts are hard to draw because these rcts would not have been adequately powered to study depression as an outcome . patients with a past history of major depression are at increased risk of ifn- related depression . the experience of certain depressive symptoms appears to predict an increased risk of depression as a syndrome ; these symptoms include psychomotor retardation , somatic symptoms , and insomnia . biochemical and other changes have also been associated with ifn- related depression ; examples include antiviral treatment - induced abnormal increase in the levels of interleukin-6 , interleukin-10 and soluble interleukin-2 receptor ( sil-2r ) , and exaggerated response of the hypothalamo - pituitary adrenal axis after the first ifn dose . possible genetic risk factors have been identified ; examples include polymorphism in the transcription initiation site of the serotonin reuptake transporter gene ( 5-ht transporter linked polymorphic region [ 5-httlpr])- presence  of short allele ( s ) ; c-1019 g polymorphism of the transcriptional control region of the 5-ht1a receptor gene ; ag poly-  morphism of the cyclo - oxygenase 2 ( cox2 ) gene ( rs4648308 ) ; gg polymorphism of the phospholipase a2 ( pla2 ) gene ( rs10798052 ) ; cc genotype of interferon alpha / beta receptor 1 ( ifnar1 ) . higher dose and longer duration of ifn treatment are also associated with a higher risk of ifn - related depression . finally , interferon treatment may interact with viral genotype , as in an increased risk of depression associated with hepatitis c viral genotype a [ 24 , 28 , 35 - 38 ] . ifn- treatment - related depression in multiple sclerosis ( ms ) is not completely attributable to interferon therapy as the prevalence of depressive and suicidal symptoms in patients with ms is high in comparison with the general population . ifn- therapy exacerbates depression in ms patients with a history of depression [ 39 - 42 ] . there does not appear to be significant literature on the association between ifn- treatment and depression as a treatment - emergent adverse effect . these are largely derived from animal models , are substantially speculative in nature , and are briefly outlined below . the interaction between immune , endocrine , and neuronal pathways is believed to play an important role in interferon - related depression . ifn therapy (  ,  ) induces hypothalamo - pituitary - adrenal axis hyperactivity to release corticotropin releasing hormone ( crh ) from the median eminence of the pituitary gland . crh also decreases serotonin and noradrenaline in the paraventricular nucleus , prefrontal cortex , hippocampus , and the central amygdala . these neuroendocrine and neurotransmitter changes are conventionally associated with risk of depression [ 28 , 44 ] . ifn- is suggested to modulate mood , behaviour , and the sleep - wake cycle by the activation of the proinflammatory cytokine network that comprises ifn - induced 15 kda protein , ubiquitin - specific proteinase 18 , guanylate binding protein 3 , interleukin 1 ( il1 ) , interleukin 6 ( il6 ) , and tumor necrosis factor  ( tnf- ) , caspase-4 , and caspase-8 or death - activating protein kinases [ 28 , 44 ] . the possible role of proinflammatory cytokines in depression has recently been reviewed by furtado and katzman . ifn- treatment - mediated induction of c - jun n - terminal kinases ( jnk ) , and p38 promote the expression of the beta isoform of the glucocorticoid receptor , which is an inactive form of the receptor to which glucocorticoid binding does not result in the inhibition of proinflammatory cytokine release and inhibition of crh release . these changes magnify the stress response and hence the risk of treatment - emergent depression . opioid receptor activation by ifn- and ifb- increases brain prostaglandin e2 levels , in turn increasing indolamine 2,3-dioxygenase ( ido ) . ido increases kynureninase ,  which inhibits kynurenine aminotransferase , resulting in excitotoxicity due to an imbalance between the nmda receptor agonists ( quinolinic acid and 3-hydroxykynurenine ) and antagonist ( kynurenic acid ) . this neurotoxic challenge causes a reduction in the density of serotonergic and adrenergic neuron , and loss of neurons in the hippocampus . these neurochemical and neurohistological changes predispose to depression [ 28 , 44 , 47 - 49 ] . in the adult mammalian brain , the dentate gyrus and the ventricular - subventricular zone on the lateral wall of the lateral ventricles harbor neural stem cells ( nsc ) . these nscs differentiate into neurons and neuroglial cells , and interference with this and related aspects of neuroplasticity is believed to predispose to depression . some of the mechanisms described earlier , such as release of corticosteroid hormones , dampen neuroplasticity in key structures such as the hippocampus and prefrontal cortex . additionally , proinflammatory cytokines such as ifn- inhibit neurogenesis by inhibiting neural stem cell differentiation [ 51 , 52 ] . zheng et al .   found that ifn- administration upregulates endogenous ifn- production by activation of microglial cells , leading to inhibition of hippocampal neurogenesis . administration of minocycline , an inhibitor of microglial activation , reversed cns depression by reversing the effect of ifn- on hippocampal neurogenesis . currently , selective serotonin reuptake inhibitor ( ssri ) drugs such as citalopram and paroxetine are administered to treat depressive symptoms that arise after ifn therapy [ 54 , 55 ] . paroxetine treatment has been found to attenuate anxiety symptoms , depressive symptoms , and cognitive dysfunction , but other symptoms , such as fatigue , psychomotor retardation , insomnia and anorexia do not respond . in contrast , some data suggest that bupropion and modafinil may successfully treat neurovegetative symptoms such as insomnia , loss of appetite , and fatigue in the absence of mood and cognitive symptoms [ 28 , 57 ] . ifn- induced alteration in levels of monoamines in the brain , in areas such as the prefrontal cortex and hippocampus , may be attenuated by nonsteroidal anti - inflammatory drugs ( nsaids ) . these drugs are commonly used to treat flu - like symptoms associated with ifn- therapy and , as an additional benefit , are also known to augment the sustained virological response rate to ifn- therapy in hepatitis c infection [ 13 , 28 ] . the inflammatory hypothesis of depression notwithstanding , there are no suitable rct data on nsaids in the treatment of the primary symptoms of depression as an ifn - related treatment - emergent adverse effect . the only study relevant to the subject   examined indomethacin augmentation ( 75 mg / day ) vs no augmentation in metastatic malignant melanoma patients treatment with ifn- 2b . this study was small ( 47 evaluable patients ) and hence underpowered for examining depression outcomes , short ( most patients were treated for , apparently , 8 weeks , and so depression may not have had an adequate chance to develop ) , without a placebo control , did not describe how depression was diagnosed and evaluated , and actually found that confusion and depression was ( nonsignificantly ) more common in the indomethacin arm . given the well - established efficacy of ssris in this regard , it is hard to expect that nsaid rcts will be conducted in interferon - associated depression . ifn therapy decreases tetrahydrobiopterin ( bh4 ) , a cofactor required for the biosynthesis of serotonin , dopamine , epinephrine , and norepinephrine , thereby predisposing to depression . bh4 levels can be increased by blocking reactive oxygen species and reactive nitrogen species production , or by the administration of folic acid ,  l - methylfolate , or s - adenosyl methionine . these supplements have demonstrated varying degrees of success in the monotherapy or augmentation therapy of major depressive disorder , but treatment of ifn - related depression with these supplements has not so far been examined in randomized controlled trials and should therefore be considered as a possibility in the future . treatment - related depression and fatigue are the main causes of decreased treatment adherence to ifn regimes . measures to improve and prevent depression begin with providing the patient with support to cope with the chronic illness and the stigma attached to it , bringing about lifestyle changes , and equipping the patient with information about the adverse effects of ifn therapy . it is important to monitor the patient during the initial phase of ifn therapy for early detection of significant changes in mood ( however small ) in order to reduce their progression ; both psychosocial and pharmacological interventions may be implemented . udina et al .   conducted a systematic review and meta analysis to evaluate the safety and efficacy of ssris in preventing depression induced by ifn- therapy in chronic hepatitis c patients . they identified 7 relevant randomized controlled trials ( rcts ) and found that the prophylactic use of ssris reduced the odds of depression by 47% , relative to placebo . one rct found that prophylactic treatment with omega-3 polyunsaturated fatty acids reduced the risk of treatment - emergent depression in hepatitis c patients receiving ifn therapy . research on hepatitis c virus replication has led to the discovery of newer , directly acting antiviral agents that target viral proteases and polymerases . addition of these new antiviral drugs to an existing antiviral regimen ( telaprevir , semiprevir , faldaprevir and boceprevir ) or replacing the existing antiviral regimens with only direct - acting antiviral agents ( ledipasvir / sofosbuvir regimen and the ombitasvir /paritaprevir / ritonavir and dasabuvir regimen ) has shown greater efficacy by sustained viral clearance , and as the required duration of antiviral therapy is reduced the duration of depression is also reduced [ 29 , 61 , 62 ] . in other words , using alternatives to ifns would also reduce the risk of treatment - emergent depression in patients for whom such alternatives exist . ifn treatment , regardless of indication , is associated with a 30 - 70% risk of treatment - emergent depression ; there is probably an interaction between ifn and the indication for which the ifn is prescribed in the mediation of this risk . many neurohormonal , neurotransmitter , neurohistological , and other mechanisms have been suggested to underlie the risk . the risk of ifn - related depression is attenuated by prophylactic treatment with ssri drugs .