Cytokines sing the blues: inflammation and the pathogenesis of depression

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1 Review TRENDS in Immunology Vol.27 No.1 Jnury 26 Cytokines sing the blues: inflmmtion nd the pthogenesis of depression Chrles L. Rison, Lucile Cpuron nd Andrew H. Miller Deprtment of Psychitry nd Behviorl Sciences, Emory University School of Medicine, 11 Woodruff Circle, Suite 4, Atlnt, GA 3322, USA Incresing mounts of dt suggest tht inflmmtory responses hve n importnt role in the pthophysiology of depression. Depressed ptients hve been found to hve higher levels of proinflmmtory cytokines, cute phse proteins, chemokines nd cellulr dhesion molecules. In ddition, therpeutic dministrtion of the cytokine interferon- leds to depression in up to 5% of ptients. Moreover, proinflmmtory cytokines hve been found to interct with mny of the pthophysiologicl domins tht chrcterize depression, including neurotrnsmitter metbolism, neuroendocrine function, synptic plsticity nd behvior. Stress, which cn precipitte depression, cn lso promote inflmmtory responses through effects on sympthetic nd prsympthetic nervous system pthwys. Finlly, depression might be behviorl byproduct of erly dptive dvntges conferred by genes tht promote inflmmtion. These findings suggest tht trgeting proinflmmtory cytokines nd their signling pthwys might represent novel strtegy to tret depression. So much is lost from the lives of people who suffer with mjor depression tht it ws perhps nturl for initil discoveries regrding mood disorders nd immunity to focus on yet nother loss in this cse, diminished functioning of the humorl nd cellulr rms of the cquired immune response [1]. Nevertheless, dt mssed over the pst 15 yers hve led to drmtic prdigm shift in which the erly focus on immunosuppression hs been subsumed within, nd supplnted by, n incresing recognition tht depressive disorders might be best chrcterized s conditions of immune ctivtion, especilly hyperctivity of innte immune inflmmtory responses. This profound chnge in our view of depression nd immunity hs not occurred in isoltion but rther is prt of lrger scientific movement built round n incresing pprecition tht inflmmtory processes re centrl to the pthogenesis of severl modern mldies, including crdiovsculr disese, dibetes nd cncer [2 4]. Indeed, much of the recent work linking depression with inflmmtion hs been prompted by the serch for potentil shred etiologicl mechnisms tht might explin the striking Corresponding uthor: Miller, A.H. (mill2@emory.edu). Avilble online 28 November 25 co-morbidity between these medicl illnesses nd mjor depression [5]. Evidence for incresed inflmmtion in depression Ptients with mjor depression who re otherwise mediclly helthy hve been repetedly observed to hve ctivted inflmmtory pthwys, s mnifested by incresed proinflmmtory cytokines, incresed cutephse proteins nd incresed expression of chemokines nd dhesion molecules [6 22]. Incresed serum nd/or plsm concentrtions of interleukin (IL)-6 nd/or C-rective protein hve been most frequently observed [6 15,17,19,2], lthough elevtions in IL-1-b nd tumor necrosis fctor (TNF)- hve lso been described, both in the peripherl blood circultion nd in the centrl nervous system (CNS; in prticulr, in the cerebrospinl fluid) [1,12,15 17,21,23 26]. In ddition to C-rective protein, other cute-phse proteins found to be elevted include - 1-cid glycoprotein, -1-ntichymotrypsin nd hptoglobin [11,15,22]. Incresed levels of chemokines nd dhesion molecules, including humn mcrophge chemottrctnt protein-1 (MCP-1), soluble intrcellulr dhesion molecule-1 (sicam-1) nd E-selectin, hve lso been described [18]. Although most studies hve compred inflmmtory mrkers in depressed versus nondepressed subjects, severl hve reported positive correltions between plsm concentrtions of vrious inflmmtory meditors nd depressive symptom severity [6,7,26]. Finlly, nscent literture suggests tht functionl llelic vrints of the genes for IL-1b nd TNF- increse the risk for depression nd re ssocited with reduced responsiveness to ntidepressnt therpy [27,28]. The ssocition between depression nd inflmmtion is pprent cross the dult lifespn [8,1,11,18] nd is evident even in the context of mild depressive symptoms tht do not meet criteri for mjor depression [29]. Indeed, even single depression-relted symptoms such s ftigue, insomni nd nger nd/or hostility hve been ssocited with evidence of inflmmtory ctivtion in otherwise helthy individuls [29 32]. Inflmmtion hs generlly been mesured t single time point; however, recent study found tht bnorml IL-6 production is pprent cross the circdin cycle in ptients with mjor depression [6]. In ddition to findings in mediclly helthy subjects, depression nd depressive symptoms (including ftigue nd cognitive dysfunction) hve been ssocited with inflmmtory mrkers in severl medicl illnesses, /$ - see front mtter Q 25 Elsevier Ltd. All rights reserved. doi:1.116/j.it

2 Review TRENDS in Immunology Vol.27 No.1 Jnury including crdiovsculr disese [33,34], cncer [9,35,36] nd postvirl infection [25,3]. Questions nd controversies: does ssocition imply cuslity? Although severl studies support the ide tht inflmmtory processes contribute to the pthogenesis of mjor depression, other studies hve filed to find n ssocition between the two [37,38] nd, in some cses, ssocitions hve been ttenuted or obvited when potentil mediting or moderting fctors (e.g. body mss index, gender or personlity) hve been included in the nlyses [8,13,14,39]. Some positive studies hve filed to find correltion between inflmmtion nd depressive severity [12,25] or hve found disprte nd occsionlly opposite correltions for different proinflmmtory meditors [7,12,16,26,34]. These inconsistencies indicte tht strong pronouncements bout the role of the immune system in depression might be premture nd suggest tht inflmmtion contributes to some, but not ll, cses of depression. Consistent with this, wide rnge of inflmmtory ctivity is typiclly observed within ny given smple of depressed subjects, nd ssocitions between inflmmtion nd groups of depressed subjects re often ccounted for by subset of individuls t the upper rnge of cytokine production nd/or relese [11]. Moreover, individul symptoms, especilly sleep disturbnce [4], hve been reported to contribute disproportiontely to the ssocition between depression nd inflmmtion. These points of controversy suggest venues of future reserch, including clrifiction of fctors most closely ssocited with immune ctivtion. Pthophysiologicl mechnisms: immunologicl pthwys to psychopthology A rich neuropsychitric literture ttests to fundmentl mechnisms tht conspire to cuse the syndrome of mjor depression. At neurobiologicl level, ltertions in neurotrnsmitter function involving serotonin, norepinephrine nd dopmine re well known to induce depression nd re primry trgets for currently vilble psychophrmcologicl (ntidepressnt) tretments [41]. Abnormlities in neuropeptide function re lso believed to contribute. Indeed, hypersecretion of the neuropeptide hormone corticotrophin-relesing hormone (CRH) hs been relibly demonstrted in depressed ptients [42]. CRH is the primry regultor of the hormonl response to stress [ctivtion of the hypothlmic pituitry drenl (HPA) xis nd the sympthetic nervous system]. Hypersecretion of CRH is considered to be the crucil biologicl substrte of the well-known link between psychosocil stress nd depression [42]. In ddition, the well-chrcterized hyperctivity of the HPA xis nd sympthetic nervous system in depression is believed to be secondry to CRH hyperctivity, in prt becuse of impired negtive regultion of CRH by glucocorticoids [43]. Altered CRH regultion by glucocorticoids is thought to be result of ltertions in the functioning of the glucocorticoid receptor [44]. Chnges in regionl brin ctivity hve lso been documented in depression nd involve bnorml metbolic ctivity in the prefrontl cortex nd ltered dopmine metbolism in the bsl gngli (cudte) [45,46]. There hs lso been incresing interest in the role of neurl plsticity in depression, with specil emphsis on fctors tht influence neuronl growth nd survivl [47]. At the interfce between immunology nd behvior Given the primry fctors tht re ssocited with the pthophysiology of depression, it is intriguing tht peripherlly relesed inflmmtory cytokines cn ccess the brin nd influence ll of the relevnt pthophysiologicl domins (Figure 1). Becuse of the lrge size of cytokines nd their resultnt inbility to redily penetrte the blood brin brrier, ttention hs been pid to routes by which cytokines ccess the brin, including (i) entry through leky regions in the blood brin brrier, such s the circumventriculr orgns; (ii) binding to cytokinespecific trnsport molecules expressed on brin endothelium nd (iii) ctivtion of vgl fferent fibers which trnsmit cytokine signls to specific brin nuclei, such s the nucleus of the solitry trct, which then serves s rely sttion to other brin nuclei, including the prventriculr nucleus in the hypothlmus [48] (Figure 1c). Once in the brin, there is CNS cytokine network tht is mde up of cells (neurons nd glil elements) tht not only produce cytokines nd express cytokine receptors, but lso mplify cytokine signls, which in turn cn hve profound effects on neurotrnsmitter nd CRH function, s well s on behvior [43,49]. For exmple, studies in lbortory nimls provide compelling evidence tht inflmmtory cytokines induce syndrome of sickness behvior tht hs mny overlpping fetures with mjor depression, including nhedoni (n inbililty to experience plesure), norexi, impired sleep nd reduced locomotor ctivity [49]. Consistent with the pthophysiology of depression, these cytokine-induced behviorl chnges re ssocited with ltertions in the metbolism of serotonin, norepinephrine nd dopmine in brin regions essentil to the regultion of emotion, including the limbic system (mygdl, hippocmpus nd nucleus ccumbens), s well s the regultion of psychomotor function nd rewrd, including the bsl gngli [5,51]. In ddition to effects on neurotrnsmitter metbolism, inflmmtory cytokines hve profound stimultory effects on HPA xis hormones s well s CRH (mrna nd protein), in both the hypothlmus nd the mygdl, brin region tht hs n importnt role in fer nd nxiety [52 54]. These effects re, in lrge prt, medited by rich network of cytokines nd their receptors within HPA xis tissues which fcilitte the integrtion of cytokine signls [53]. Downstrem cytokine signl trnsduction pthwys, including mitogen-ctivted protein kinses (MAPKs) nd nucler fctor kb (NF-kB), lso disrupt glucocorticoid receptor signling [55,56], nd thus might contribute to ltered glucocorticoid-medited feedbck regultion of both CRH nd further proinflmmtory cytokine relese. In ddition, ctivtion of p38 MAPKs might contribute to ltertions in neurotrnsmitter function through effects on the serotonin trnsporter [57]. Induction of NF-kB in the brin following peripherl cytokine (IL-1) exposure hs been shown to medite mny of the behviorl effects of IL-1, including socil

3 26 Review TRENDS in Immunology Vol.27 No.1 Jnury 26 Depression ACTH PVN Pituitry Dorsl vgl complex 5HT DA CRH (d) (i) (ii) BDNF (iii) NTS Senso ry vgus (c) Stress Adrenl glnd Glucocorticoids (f) Motor vgus (e) Sympthetic NE ACh αar nd βar α7nachr TNF IL-1 IL-6 (b) Inflmmtion Pro-inflmmtory cytokines Chemokines Adhesion molecules Acute phse rectnts GR NFκB (g) JNK ERK p38 TLR () Mcrophge Infection, tissue dmge or destruction Figure 1. Stress immune interctions nd depression. () Activtion of NF-kB through Toll-like receptors (TLR) during immune chllenge leds to n inflmmtory response including (b) the relese of the proinflmmtory cytokines TNF-, IL-1 nd IL-6. (c) These cytokines, in turn, ccess the brin vi leky regions in the blood brin brrier, ctive trnsport molecules nd fferent nerve fibers (e.g. sensory vgus), which rely informtion through the nucleus trctus solitrius (NTS) [48]. (d) Once in the brin, cytokine signls prticipte in pthwys (indicted in ornge) known to be involved in the development of depression, including: (i) ltered metbolism of relevnt neurotrnsmitters such s serotonin (5HT) nd dopmine (DA) [5,51]; (ii) ctivtion of CRH in the prventriculr nucleus (PVN) nd the subsequent production nd/or relese of ACTH nd glucocorticoids (cortisol) [52,53] nd (iii) disruption of synptic plsticity through ltertions in relevnt growth fctors [e.g. brin-derived neurotrophic fctor (BDNF)] [59,6]. (e) Exposure to environmentl stressors promotes ctivtion of inflmmtory signling (NF-kB) through incresed outflow of proinflmmtory sympthetic nervous system responses [relese of norepinephrine (NE), which binds to (AR) nd b (bar) drenoceptors] (ornge). (f) Stressors lso induce withdrwl of inhibitory motor vgl input [relese of cetylcholine (ACh), which binds to the 7 subunit of the nicotinic cetylcholine receptor (7nAChR)] (blue) [73,77]. (g) Activtion of the mitogen ctivted protein kinse pthwys, including p38 nd Jun mino-terminl kinse (JNK), inhibit the function of glucocorticoid receptors (GR), thereby relesing NF-kB from negtive regultion by glucocorticoids relesed s result of the HPA xis in response to stress (blue) [55,56]. withdrwl nd decresed food intke [58]. NF-kB induction in the brin lso might contribute to ltertions in neuronl growth nd survivl, especilly through the induction of nitric oxide (e.g. vi inducible nitric oxide synthse, inos) nd, ultimtely, oxidtive stress, which hs been shown to lter promoter function for severl genes centrl to synptic plsticity [59,6]. Finlly, humns who re dministered cytokines exogenously for infectious diseses nd cncer show ltered function in brin regions relevnt to the development of depressive symptoms [54]. Interferon-: clinicl model of cytokine-induced depression To study the effects of innte immune cytokines on behvior in humns, severl investigtors hve seized upon the profound clinicl observtion tht high percentge of ptients who re dministered the cytokine interferon (IFN)- for the tretment of infectious diseses or cncer develop behviorl syndrome tht is strikingly similr to mjor depression (Figure 2). IFN- is potent inducer of proinflmmtory cytokines, including IL-6 nd, to lesser extent, IL-1 b nd TNF- [54]. Substntiting the fct tht the IFN--induced behviorl syndrome is indeed depression s encountered in other venues (e.g. mentl helth clinics) is tht IFN--induced depression: (i) is responsive to tretment with stndrd ntidepressnt therpy [61]; (ii) is ssocited with ltertions in serotonin metbolism, in prt relted to incresed ctivity of the metbolic enzyme indolemine 2,3, dioxygense, which degrdes tryptophn to kynurenine, which is then

4 Review TRENDS in Immunology Vol.27 No.1 Jnury () (b) (c) (d) ACC ACTH (pg ml 1 ) Cortisol (µg dl 1 ) Time following IFN-α injection (hr) b b MADRS score (d26) Trp (d d26) Free of mjor depression (%) Weeks of IFN-α therpy (e) fmri signl (ACC) Loction errors TRENDS in Immunology Figure 2. IFN-: modeling of cytokine-induced depression. Therpeutic dministrtion of IFN- is ssocited with depression in 3 5% of ptients, depending on the dose [61,62]. IFN--induced depression is ssocited with pthophysiologicl chnges tht overlp with those found in mediclly helthy depressed ptients, including ctivtion of neuroendocrine (HPA xis) pthwys (), ltertions in neurotrnsmitter metbolism (b), responsiveness to ntidepressnt tretment (c) nd ltertions in brin circuitry relevnt to informtion processing (d). () The initil injection of IFN- to ptients with mlignnt melnom is ssocited with mrked induction of ACTH nd cortisol, which ws significntly higher in ptients who eventully developed depression (blue) thn in those who never becme depressed during IFN- tretment (red)., significntly different from hours; P!.1; b, significnt difference between groups, P!.1. (b) The reltionship between the severity of depressive symptoms [s mesured by the Montgomery Asberg Depression Rting Scle (MADRS)] nd chnges in plsm tryptophn (TRP) concentrtions during IFN- therpy for cncer. TRP is the primry mino cid precursor of serotonin, mjor regultor of limbic brin circuitry tht subserves emotion. Decreses in TRP were significntly correlted (RZK.5, P!.5) with increses in depression severity scores during IFN- tretment. (c) Ptients who received the serotonin reuptke inhibitor proxetine, commonly used ntidepressnt, before nd during IFN- therpy for mlignnt melnom (red tringles), were significntly more likely to remin free of depression during IFN- dministrtion thn plcebo-treted control group (blck squres). (d) Significntly greter ctivtion (yellow nd ornge) of the dorsl ACC, s mesured by functionl mgnetic resonnce imging (fmri) during tsk of visuosptil ttention ws found in IFN--treted ptients compred with controls. (e) A significnt liner reltionship ws found between ctivtion of the ACC nd the number of tsk-relted errors in IFN--treted ptients (red strs) but not in control subjects (blck tringles). Incresed ACC ctivtion in response to reltively low tsk error rtes hs been ssocited with cognitive styles tht predispose to nxiety nd depression, suggesting tht IFN--induced chnges in ACC function might represent cognitive pthwy to psychopthology [65]. Reproduced, with permission, from () Ref. [63], (b) Ref. [62], (c) Ref. [61] nd (d,e) Ref. [65]. metbolized to quinolinic cid [62]; nd (iii) is ssocited with ltertions in CRH function s mnifested by n exggerted drenocorticotropic hormone (ACTH) nd cortisol response to the first dministrtion of IFN- in ptients who ultimtely develop depression [63]. In ddition, using positron emission tomogrphy, IFN- hs been shown to lter metbolic ctivity in the bsl gngli [64], possibly representing disruption of bsl gngli circuitry involving dopmine nd subserving hedonic tone (i.e. the cpcity to experience plesure nd rewrd), s well s psychomotor speed. IFN- hs lso been found to lter fundmentl informtion processing in the dorsl prt of the nterior cingulte cortex (ACC), s reveled by functionl mgnetic resonnce imging. In comprison with control subjects, IFN--treted ptients exhibited incresed ACC ctivity in response to tsk with low error rte, possibly representing n incresed sensitivity to negtive events or conflict [65]. Similr ltertions hve been demonstrted in popultions t risk for mood nd nxiety disorders, including subjects with high-trit nxiety, neuroticism nd obsessive compulsive disorder. Tken together, these dt demonstrte tht cytokine (IFN-) dministrtion to humns replictes multiple pthologies centrl to depression, thereby providing support for the notion tht endogenous cytokines tht medite innte immune responses cn contribute to the stte of depression. Stress nd immunity: crucil link in the cytokine depression chin Inflmmtion is the sine qu non of pthology, so it is understndble tht proinflmmtory cytokines might contribute to depression in the context of medicl illness, thus potentilly ccounting for the five tenfold greter prevlence of depression in individuls with wide rnge of medicl disorders [5]. Nevertheless, it is not s redily pprent wht might drive incresed inflmmtion in ptients with mjor depression who re presumbly physiclly helthy. One possibility is the impct of stress on the immune response (Figures 1 nd 3). Psychologicl stress is common risk fctor for the development of mjor depression in every culture exmined, nd most initil episodes of mjor depression re preceded by n identifible stressor [66]. Consistent with the notion tht stress might provide link between depression nd inflmmtion, incresing dt indicte tht psychologicl stress ctivtes proinflmmtory cytokines nd their signling pthwys in the periphery nd CNS. In lbortory nimls, vriety of psychologicl stressors (e.g. restrint, open-field exposure or socil isoltion) increse concentrtions of proinflmmtory cytokines, including IL-1b nd TNF-, in brin regions involved in emotionl regultion, s well s in the periphery [6,67]. Moreover, behviorl chnges induced in rodents by socil isoltion cn be reversed by intrcerebroventriculr dministrtion of the soluble IL-

5 28 Review TRENDS in Immunology Vol.27 No.1 Jnury 26 Divorce S t r e s s Nturl disster Poverty Interpersonl conflict Berevement Job loss Genetics Mjor depression Pst experience Infection Autoimmune disorder Cncer Tissue trum I n f l m m t i o n Chemotherpy Surgery TRENDS in Immunology Figure 3. Acute nd chronic immune nd inflmmtory processes, combined with relevnt contributions from immunogenetics (such s polymorphisms in cytokine genes) nd pst immune experiences (such s prior infections nd vccintion history) (ornge) interct with cute nd chronic stressors combined with relevnt contributions from psychitric genetics (such s polymorphisms in neurotrnsmitter trnsporter genes) nd pst emotionl experiences (such s dversity in erly life) (yellow) to promote the syndrome of mjor depression (brown). A dignosis of mjor depression is bsed on the presence of five of the following symptoms: depressed mood, nhedoni, ftigue, guilt nd/or worthlessness, suicidl idetion, impired concentrtion nd/or memory, psychomotor retrdtion nd/or gittion nd disturbnces of sleep or ppetite. Symptoms must persist for t lest two weeks nd cuse significnt functionl impirment [91]. 1 receptor ntgonist (IL-1r) [68]. Proinflmmtory cytokine ctivtion lso ppers to medite other stressrelted biochemicl chnges in the brin. For exmple, TNF- is required for the production of nitric oxide within the CNS following immobiliztion stress [6], nd IL-1-b hs key role in the inhibition of the expression of brinderived neurl growth fctor in the hippocmpus of rts following socil isoltion [69]. Consistent with these findings is the fct tht stress-induced neuronl cell loss in rodents is linked to incresed concentrtions of TNF- nd NF-kB [6]. In humns, cute stress (e.g. lbortory stressor) nd chronic stress (including lck of socil support) hve both been ssocited with incresed production nd/or relese of proinflmmtory cytokines nd decreses in ntiinflmmtory cytokines such s IL-1 [7 72]. Recent work indictes tht psychosocil stress lso ctivtes NFkB in peripherl blood mononucler cells of helthy volunteers [73]. Interestingly, stress-induced ctivtion of proinflmmtory cytokines might provide some insight into the decreses in cquired immune responses found in both stress nd depression. For exmple, stress-induced decreses in the IgM nd IgG ntibody responses to immuniztion with keyhole limpet hemocynin were found to be ttenuted significntly if rts were pretreted with IL-1r [74]. Combined with dt suggesting tht TNF- cn significntly disrupt T-cell signling, these findings suggest tht overctivtion of innte immune responses following stress nd during depression might come t the expense of decresed cellulr nd humorl cquired immune responses [43]. Stress system ctivtion might promote cytokine production through severl mechnisms (Figure 1). Despite suppressing certin immune processes, ctivtion of the sympthetic nervous system hs been linked in severl studies to proinflmmtory ctivtion in the periphery, which might, in turn, influence inflmmtory processes in the CNS [43]. For exmple, stress-induced ctivtion of NF-kB in peripherl blood mononucler cells ppers to be dependent on norepinephrine nd cn be brogted by 1-drenoceptor blockde [73]. Similrly, b- drenoceptor stimultion hs been shown to increse gene expression nd protein production of TNF-, IL-1b nd IL- 6 in myocrdil cells [75], nd chronic b-blockde reduces plsm levels of IL-6 in concert with symptomtic improvement in ptients with congestive hert filure [76]. Vgl withdrwl in response to stress might lso promote inflmmtion, given the evidence tht vgl ctivity inhibits NFkB ctivtion (nd the relese of TNF from mcrophges) vi cholinergic signling through the -7 subunit of the nicotinic cetylcholine receptor [77]. Indeed, decresed vgl tone, s mnifested by reduced hert rte vribility, hs been ssocited with incresed inflmmtory mrkers in women with coronry rtery disese [78]. Stress nd depression hve both been ssocited with reduced hert rte vribility [79]. Finlly, chronic stress promotes the development of glucocorticoid resistnce, which hs been ssocited with incresed cytokine production nd which might lso relese the sympthetic nervous system from inhibitory control, further promoting inflmmtory ctivtion [43]. Evolutionry perspectives The reltionship between depression nd ctivtion of innte immune responses might hve its roots in the evolutionry dvntges of behviorl repertoire tht enbles diversion of crucil energy resources to the metbolic demnds of fever during times of pthogen exposure. In ddition, pthophysiologicl chnges centrl to depression might protect inflmmtory responses from negtive regultion by neuroendocrine (glucocorticoid) responses [48,8] (Box 1). Thus, depression might hve been necessry behviorl ccoutrement to erly, endogenous ntibiotic strtegies tht hve been rendered unnecessry in modern times. Tretment implictions Becuse prdigm shifts within medicine re judged (finlly) by their clinicl utility, it is encourging tht importnt tretment implictions hve lredy emerged from our nscent understnding of the role of inflmmtion in the pthogenesis of mjor depression. Indeed, dt incresingly suggest tht inflmmtory processes contribute to the therpeutic effects of the currently vilble ntidepressnts nd could provide trgets for novel phrmcologicl nd nonphrmcologicl tretment strtegies.

6 Review TRENDS in Immunology Vol.27 No.1 Jnury Box 1. Evolutionry impertives for the depression inflmmtion link The discovery tht depression shres n underlying physiology with inflmmtion nd stress system ctivtion provides novel perspective on why vulnerbility genes for mjor depression might hve been retined in the humn gene pool despite the negtive impct of depression on morbidity nd mortlity. Although current dptive theories focus on the potentil benefits of depressive symptoms themselves (i.e. serving s signls to increse id from, or decrese competition with, others), viewing depression s requisite behviorl counterprt of immune ctivtion suggests tht the high prevlence of mood disorders cme bout not s result of providing hidden socil benefits but becuse these disorders re pleiotropiclly linked to genes tht directly, or indirectly, promote enhnced inflmmtory responses nd, hence, survivl in times of stress. Despite posing risk for depression, such llelic vrints might hve simultneously improved overll fitness by incresing resistnce to pthogen ssult before the dvent of modern snittion nd ntibiotic therpy [48]. Consistent with this hypothesis is the observtion tht mny symptoms of depression (e.g. psychomotor retrdtion, ftigue nd nhedoni) promote the conservtion of essentil energy resources tht re dptive in the context of subserving the metbolic demnds of endogenous ntibiotic strtegies such s fever [48]. The benefits of heightened inflmmtory ctivity in response to infection might lso help to explin common neuroendocrine bnormlity found in mjor depression. In hierrchicl socil species (including humns), psychosocil stress in mles is frequently ccounted for by dominnce struggles in which the risk of wounding, especilly in subordintes, is high. This presents individuls with the prdox of needing HPA xis ctivtion (nd the relese of glucocorticoids) to provide energy for the stressful encounter, while voiding the incresed dnger of wound infection presented by glucocorticoid-induced immunosuppression. Studies using socil disruption prdigm in rodents suggest tht this impsse is resolved through the induction of glucocorticoid resistnce, which correltes with ssumption of subordinte behviorl profile following defet nd with the number of wounds received in fighting with ggressive intruder mice [8]. Interestingly, depression in humns is highly ssocited with both socil defet (especilly in mles) nd with endocrine nd immune tissue resistnce to glucocorticoids. These considertions suggest tht, rther thn hrboring hidden dptive fetures, mjor depression is disese fueled in the modern world by n evolutionry mismtch between current conditions nd our ncestrl environment. This lso suggests surprising hypothesis: to the degree tht inflmmtory processes re rendered less essentil by culturl inventions (i.e. improved medicines or lws ginst physicl violence), genes tht promote mjor depression should decrese in frequency s the survivl benefits of immune ctivtion become outweighed by disdvntges, including n incresed risk of mjor depression in the context of psychologicl stress. Consistent with their bility to meliorte cytokineinduced depression [61], ntidepressnts hve been shown in nimls nd humns to inhibit the production nd/or relese of proinflmmtory cytokines nd to stimulte the production of nti-inflmmtory cytokines (such s IL-1) [81]. These effects might contribute to therpeutic efficcy, given recent dt tht ntidepressnt-like effects of desiprmine in the forced swim test (n niml model frequently used to evlute ntidepressnt efficcy) depend on the bility of the drug to inhibit CNS production of TNF- [82]. In humns, vriety of ntidepressnt strtegies (including mediction, electroconvulsive shock therpy nd psychotherpy) pper to ttenute inflmmtory ctivity in concert with improvements in depressive symptoms, suggesting tht reductions in inflmmtion might contribute to tretment response [16,17,19,23,24,83]. An inflmmtory perspective on depression lso provides novel insights into indequcies in our current tretment options. For exmple, ptients with history of nonresponse to ntidepressnts hve been found to exhibit incresed plsm concentrtions of IL-6 nd cute-phse proteins when compred with tretmentresponsive ptients [2,22]. Similrly, ptients with evidence of incresed inflmmtory ctivity before tretment hve been reported to be less responsive to ntidepressnts, lithium or sleep deprivtion ( potent short-term mood elevtor) [17,21,22,84]. Moreover, work by our group nd by others suggests tht in the context of cytokine exposure, ntidepressnts might only ddress selected symptom domins (e.g. depressed mood nd nxiety), while leving severl symptoms reltively unffected (e.g. ftigue or psychomotor slowing) [85,86]. Interestingly, this pttern of symptom response hs lso been observed in the ntidepressnt tretment of mediclly helthy ptients with depression [87]. These observtions suggest tht inhibition of proinflmmtory cytokine signling represents vible strtegy for the tretment of depression, especilly in ptients with evidence of incresed inflmmtory ctivity before therpy who might be less likely to respond to conventionl gents. In support of this ide, studies in lbortory nimls demonstrte tht cytokine-induced sickness syndromes (which overlp symptomticlly with depression) cn be meliorted or reversed by dministering specific cytokine ntgonists (e.g. IL-1r) or ntiinflmmtory cytokines (e.g. IL-1) directly into the brin [68,88]. Moreover, cytokine ntgonists pper to hve ntidepressnt-like effects, even in the bsence of n immune chllenge. For exmple, in rodents intrcerebroventriculr dministrtion of IL-1r prevents memory deficits following the psychologicl stress of socil isoltion [68], nd ntibodies to TNF- demonstrte ntidepressnt effects on the forced swim test when dministered vi the intrcerebroventriculr route [82]. In humns, ntgonists of TNF- (i.e. etnercept, infliximb) hve been reported to reduce depressive symptoms in the context of treting vriety of utoimmune conditions [89,9]. Interestingly, in these ptients, improvements in mood often pper to precede improvements in the underlying disese stte. Conclusion A gret mount of compelling dt suggest tht inflmmtory innte immune responses might contribute to the development of depression, in prt through complex interctions with stress-responsive pthwys involving the neuroendocrine nd utonomic nervous systems. The role of the immune system in the pthophysiology of depression probbly derives from evolutionry impertives, nd presents intriguing nd unique therpeutic

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