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http://anp.sagepub.com/PsychiatryAustralian and New Zealand Journal ofhttp://anp.sagepub.com/content/47/9/828The online version of this article can be found at:DOI: 10.1177/0004867413488220 2013 47: 828 originally published online 1 May 2013 Aust N Z J PsychiatryKaran Makhija and Satish KarunakaranThe role of inflammatory cytokines on the aetiopathogenesis of depressionPublished by:http://www.sagepublications.comOn behalf of:The Royal Australian and New Zealand College of Psychiatrists can be found at: Australian and New Zealand Journal of Psychiatry Additional services and information for http://anp.sagepub.com/cgi/alerts Email Alerts: http://anp.sagepub.com/subscriptions Subscriptions: http://www.sagepub.com/journalsReprints.nav Reprints: http://www.sagepub.com/journalsPermissions.nav Permissions: What is This?- May 1, 2013 OnlineFirst Version of Record - Aug 28, 2013 Version of Record>> at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from Australian & New Zealand Journal of Psychiatry47(9) 828 839DOI: 10.1177/0004867413488220 The Royal Australian andNew Zealand College of Psychiatrists 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.navanp.sagepub.comAustralian & New Zealand Journal of Psychiatry, 47(9)IntroductionMajor depressive disorder (MDD) is a heterogeneous psychi-atric illness, with a lifetime prevalence of approximately 12% and20%inmenandwomenrespectively(Kessler etal.,2003).Itisalong-term,relapsingconditioninwhich 75% of patients experience more than one episode during their lifetime(Palazidou,2012).Itiscurrentlythethirdleading global burden of disease and expected to become the second leading cause in the next decade (Mathers and Loncar, 2006).There have been many theories regarding the aetiopatho-physiologyofdepression,themostwell-knownbeingthe monoaminehypothesis(Raedler,2011).However,this theory alone, fails to explain the heterogeneity inherent in MDD amongst different patients and its variable response to treatment, thus highlighting our lack of understanding of thiscomplexdisorder.Over30%ofpatientswithdepres-sion fail to respond to conventional antidepressants (Maes et al., 2009; Miller et al., 2009a). Some theories which try toexplainitspathophysiologyinclude:themonoamine hypothesis, based on a neurotransmitter deficiency of mon-oamines, namely serotonin and noradrenalin; the hypotha-lamicpituitaryadrenal(HPA)axisdysfunctiontheory, based on increased resistance to glucocorticoids and result-ingcortisolhypersecretion;theneurogenesishypothesis, based on a lack of adult neuronal growth leading to mood changes;andtheneuroinflammatoryormacrophage/cytokinetheory,basedonexternalpsychosocialstressors The role of inflammatory cytokines on the aetiopathogenesis of depressionKaran Makhija and Satish KarunakaranAbstractObjective: The primary focus of this review is to provide an overview of the role of inflammation in the development of depression. The article will describe how inflammatory cytokines contribute to depression via action on three major pathways in the brain: the neuroendocrine; neurotransmitter depletion; and neuroprogression pathways.Methods: An online literature search was carried out in July 2012. Original articles and reviews were selected if they discussed the role of inflammation on the development of depression.Results: There is a large body of current research on the role of inflammatory cytokines on the development of depres-sion. Cytokines have been found to interact with different pathways in the brain, and may contribute to the development of depression. Cytokines cause hypercortisolaemia by dysregulation of the hypothalamicpituitaryadrenal axis directly by activating it and indirectly by modifying glucocorticoid receptor sensitivity to cortisol leading to cortisol hypersecre-tion. Cytokines deplete central synaptic serotonin levels by reducing its synthesis and increasing its reuptake. They may also deplete neurotrophic factors which are believed to play a neuroprotective role against depression. Cytokines acti-vate cellular cascades that cause excitotoxicity and apoptosis and inhibit neurogenesis in the hippocampus.Conclusion: There is a growing body of correlative studies that suggest inflammatory cytokines may be a central fac-tor that can affect multiple neuronal pathways and have an additive effect on the development of depression. However, the fact that not all people with inflammatory conditions suffer from depression suggests that depression is not purely a result of elevated inflammatory cytokines. Depression may be a result of a complex pathology that remains an area of growing interest and importance.KeywordsCytokines, depression, immune response, infammationThe Towsnville Hospital, Douglas, AustraliaCorresponding author:Karan Makhija, The Townsville Hospital, 100 Angus Smith Drive, Douglas 4814, QLD, Australia. Email: [email protected] 488220ANP47910.1177/0004867413488220ANZJPArticlesMakhija and Karunakaran2013Review at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from Makhija and Karunakaran829Australian & New Zealand Journal of Psychiatry, 47(9)andinternalorganicinflammatoryconditionscausing depression via increased inflammatory cytokine production (Smith, 1991; Maes, 1993, 1995; Maes et al., 2009).Inflammatorycytokinesthatenterthebraincanaffecta numberofneuralpathwaysincludingthoseinvolvedwith mood.Thecytokinesmayaltertheabovementionedpath-ways to cause depressive symptoms. A number of correlative studies suggest a role for inflammation in the pathophysiol-ogy depression. The most consistent observations include:1.HigherratesofMDDdiagnosisinpersonswith inflammatory medical illnesses (Dickens et al., 2002; Graffetal.,2009;LoFermoetal.,2010;Pascoe et al., 2011; Krishnadas and Cavanagh, 2012).2.Higher levels of inflammatory markers, acute phase proteins,andcytokinessuchasC-reactiveprotein, tumour necrosis factor (TNF-), interleukin-6 (IL-6), interleukin-1 (IL-1), acute phase reactant proteins, andprostaglandinsintheserumandcerebralspinal fluid of individuals with MDD in the absence of any othermedicalcondition(Maes,1993;Songetal., 1994;Seideletal.,1995;Sluzewskaetal.,1996; Dowlati et al., 2010; Liu et al., 2011).3.Patients undergoing treatment with cytokines (inter-feron , IFN-) and IL-2 experience more frequent and more severe depressive symptoms than individ-uals with the medical conditions prior to commenc-ingcytokinetherapy(Bonaccorsoetal.,2001; Figure 1.Inflammatory pathways involved in the pathogenesis of depression. Genetic predispositions and lower PUFA levels may potentiate the effect of external stressors and medical illnesses to influence increased cytokine production either centrally or peripherally. Cytokines have a central role by acting via various pathways outlined above and affect neuroprogression, neuroendocrine and neurotransmitter depletion pathways. There are multiple interactions between these pathways suggesting the existence of a complex model for the development of depression.PUFA = polyunsaturated fatty acid, SNS = sympathetic nervous system, CNS = central nervous system, GR = glucocorticoid receptor, BDNF = brain derived neurotrophic factor,5HT = serotonin, HPA = hypothalamic-pituitary-adrenal. at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from 830ANZJP ArticlesAustralian & New Zealand Journal of Psychiatry, 47(9)Raisonetal.,2008;Myintetal.,2009;Krishnadas and Cavanagh, 2012;).4.Multiple classes of antidepressants have been asso-ciatedwithanegativeimmunoregulatoryeffect throughinhibitionofpro-inflammatorycytokines andstimulationofanti-inflammatorycytokines.It hasbeensuggestedthatthetherapeuticefficacyof antidepressantsmaybeduetoanegativeimmu-noregulatorymechanism(Xiaetal.,1996;Maes et al., 1999; Kubera et al., 2001).Bauneetal.(2012)intheSydneyMemoryand Aging Study suggested that cytokines may be aetiological factors in depression. They may be used as markers for depressive symptomsatdifferingstagesofthediseaseinelderly patients. Their study is the first to report that the chemokine IL-8isassociatedwithdepressivesymptomseverityat baseline and 2-year follow up (Baune et al., 2012).Inpatientswithknowninflammatorymedicalcondi-tions,theprevalenceofMDDis510-timeshigherthan that of the general population and these individuals tend to haveaworseprognosiswithahigherdisabilityrate (Krishnadas and Cavanagh, 2012). MDD is also associated withcentralnervoussystem(CNS)inflammatorycondi-tions,forexamplepeoplewithmultiplesclerosishave exhibited a prevalence rate of up to 50% after 14-year fol-low up (Lo Fermo et al., 2010). Additionally, a recent sys-tematicreviewofpost-strokedepressionreporteda conservativeprevalencerateof30%insurvivingpatients as discussed later (Pascoe et al., 2011). The review impli-catedinflammation-inducedcelldeathinmood-related brain regions as an explanation for post-stroke depression (Pascoe et al., 2011). MDD is also associated with periph-eral inflammatory conditions such as psoriasis, rheumatoid arthritis,andinflammatoryboweldisease,withconserva-tiveestimatedprevalenceratesbetween13and17% (Dickensetal.,2002;Graffetal.,2009;LoFermoetal., 2010; Krishnadas et al., 2011; Pascoe et al., 2011).Inflammatory conditions may not be a cause of depres-sion but may rather be part of a generalized physiological response to an underlying dysregulation in the immune sys-tem. For example, the presence of MDD was the only psy-chosocialvariablewhichindependentlypredictedworse short-term remission and increased negative long-term out-comes in patients with Crohns disease treated with inflixi-mab(Persoonsetal.,2005).Theauthorsstudysuggested thismaybeduetoanunderlyingimmunedysregulation andenhancedcytokineproductioninpatientswithMDD (Persoons et al., 2005).This review summarizes recent research on the relation-shipbetweeninflammatorycytokinesanddepressionvia: (1)alterationsinneuroendocrinefunction;(2)changesin neurotransmissionpathways;and(3)vianeuroprogression whichisdefinedasthecombinedeffectofneurotrophin depletion, neurodegeneration, neuronal apoptosis, decreased neurogenesis,andneuroplasticityonthedevelopmentof depression(Berketal.,2011).Figure1summarizesthe pathwaysdiscussedinthearticleandhowtheymayinter-relate in the pathogenesis of depression.MethodsAnonlineliteraturesearchwascarriedoutonlineinJuly 2012 using PubMed. Combinations of different search terms were employed to ensure maximum results; the terms used included major depressive disorder, depression, inflam-mation,inflammatory,immune,cytokines,hypo-thalamic-pituitary-axis,oxidativeandnitrosativestress, and antioxidant and omega-3. First, the titles of all the results were read to select articles which relevant to the topic of this review. Second, the abstracts of the selected articles were reviewed to further identify articles that were appropri-ate,andthefulltextsofthesearticleswerecollectedfor analysis.Thereferencesectionsofallthefulltextarticles were reviewed to collect additional articles that were missed in initial search. Original research and reviews were included tomaximizetheselectionofinformationincludedinthis review.AdditionalcontentwasincludedinJanuary2013 drawing on new literature relevant to this review.ResultsCytokines in the brainPro-inflammatorycytokines may affectCNSneural circuits tocauseacascadeofeventsthatcontributetothedevelop-ment of major depression. Until recently the CNS was thought to be restricted from the immune system. However it has been observed that cytokines may enter the CNS by de-novo syn-thesis by activated neurons, microglia, and astrocytes, or indi-rectlyviathebloodbrainbarrier(BBB)(Krishnadasand Cavanagh,2012).Theseimmunotransmittersareproduced centrally in response to CNS and peripheral inflammation, as seeninautoimmunemultiplesclerosis,orsecondarytoan ischaemic insult as seen in post-stroke patients (Raison et al., 2008; Krishnadas and Cavanagh, 2012).Individuals on exogenous cytokine therapy have increased endogenouscytokineproductionandthisisassociatedwith thedevelopmentofdepressivesymptoms,withprevalence ratesbetween20and30%(Bonaccorsoetal.,2001;Myint et al., 2009; Karg et al., 2011). Patients with hepatitis C treated with IFN- have increased cerebral spinal fluid levels of IFN- and IL-6 and these were correlated with the concentration ofadministeredIFN-,butnotperipherallevelsofthese cytokines.ThissuggeststhatexogenousIFN-causedde-novosynthesisoftheseimmunotransmitters(Raisonetal., 2008).Thestudyalsofoundreducedserotoninmetabolite, 5-hydroxyindoleaceticacid(5-HIAA),whichwasthepri-mary predictor of depressive symptoms. IL-6 levels may have alteredserotoninmetabolism,therebyaccountingforthe at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from Makhija and Karunakaran831Australian & New Zealand Journal of Psychiatry, 47(9)depressive phenotype (Raison et al., 2008). It must be noted that the manifestation of these depressive symptoms, whilst similar to MDD, is a part of a sickness behaviour seen in patients on cytokine therapy and not that of psychiatric MDD.Peripheral cytokines can also signal the brain by gaining accessthroughtheBBBandconsequentlyaffectneural pathways.TheypenetratetheBBBbydifferentmecha-nisms, some of which include active transport, passive pas-sage through leaky regions in the BBB, and transmission along afferent vagal pathways (Miller et al., 2009a; Capuron and Miller, 2011; Krishnadas and Cavanagh, 2012). In two separatetrials,healthyvolunteerswereinjectedwith lipopolysaccharideandSalmonellatyphivaccine;these individuals developed symptoms of depression and anxiety andtheseveritycorrelatedwithincreasesinperipheral cytokinelevels(Reichenbertetal.,2001;Brydonetal., 2008).Oncecytokinesenterthebrain,throughprimary productionorsecondaryentry,theyhavetheabilityto affectcentralpathwaysthatmayleadtodevelopmentof major depression (Miller et al., 2009a).Higher rates of comorbid depression in infectious, auto-immune,andneurodegenerativediseasesarenotsuffi-cientlyexplainedbythepsychologicaldistressofthe starting disease (Pollak and Yirmiya, 2002). Therefore, the roleofbiologicalmechanismslikepro-inflammatory cytokinescannotbediscountedcompletelyintheaeti-opathogenesis of depression.Omega-3 polyunsaturated fatty acids (PUFA) depletion maybeassociatedwithdepressionduetoalossoftheir anti-inflammatoryeffect.Epidemiologicalstudiesshowed that lower dietary intakes of omega-3 PUFA are associated withhigherratesofdepression(Hibbeln,1998;Leonard andMaes,2012).Supplementationwitheicosapentaenoic acid, an omega-3 PUFA, in depression showed significant antidepressantactivity(LinandSu,2007).Apossible mechanism for the antidepressant effect of omega-3 lies in itsabilitytoattenuateproinflammatorycytokineproduc-tion. Eicosapentaenoic acid reduces the synthesis of prosta-glandinE2,IL-1,IL-6,TNF-,andIFN-(Leonardand Maes,2012).Subjectswithlowomega-3PUFAlevels show significantly higher stress-induced production of pro-inflammatorycytokinescomparedtosubjectswithhigher levelsofomega-3PUFA,andtheseareassociatedwith higheranxietyandperceivedstressratings(Leonardand Maes, 2012).Neuroendocrine disturbances, inflammation, and depressionHPA axis dysregulation in depression.Since the 1970s, it has been noted that up to 50% of patients with depression have raisedserumcortisolanddexamethasonenon-suppression (Carroll,1982).Depressivesymptomsareafrequentside effect of glucocorticoid treatment and a symptom of Cush-ings syndrome (Zunszain et al., 2011). Normally, the HPA axis is appropriately activated in the bodys response to envi-ronmental stress, but some depressed patients appear to have an abnormal negative feedback system in the setting of intact pituitary and adrenal sensitivity leading to excessive cortisol secretion (Lopez-Duran et al., 2009). Chronic hyperactivity may result in long-lasting problems and may explain some of the symptoms of MDD. There are a growing number of cor-relative studies that demonstrate elevated levels of both glu-cocorticoidsandinflammatorycytokinesindepressed individuals.Whenthisiscombinedwithcommunication mechanisms that exist between the endocrine, immune, and central nervous systems, it gives rise to the hypothesis that inflammatorymechanismsmayaffectneuroendocrinepro-cesses to cause depression (Zunszain et al., 2011).SomepatientswithMDDhaveraisedcorticotrophin-releasing hormone and its mRNA, which have been associ-atedwithmultipledepressivesymptomsincludingfear/anxiety, changes in sleep patterns, altering locomotor activ-ity, and food intake (Pace and Miller, 2009). Furthermore, hypercortisolismhasbeenassociatedwithincreasedpres-ence of distress symptoms and maladaptive coping styles, suggesting it may have a role in depression spectrum disor-ders (Kunugi et al., 2012).Glucocorticoid mechanism of action.The mechanism of glu-cocorticoidactionistobindtocytosolicglucocorticoid receptor(GR),causeaconformationalchangeinGR, resultinginitsdissociationfrominactivatingchaperone proteinsandsubsequenttranslocationintothenucleus. Once in the nucleus, GR acts directly as a transcription fac-tortoexpressanti-inflammatorygenes,oractindirectly with other co-repressor molecules to inactivate inflamma-tory signalling pathways, for example nuclear factor-kappa B (NF-B). Reduction in GR function may dysregulate the HPAaxisandishypothesizedtocontributetodepressive symptoms by a loss of inhibition of the inflammatory path-ways (Zunszain et al., 2011).Cytokines and HPA axis dysregulation.Cytokines can cause hyperactivityoftheHPAaxis,withsubsequentelevated systemic cortisol levels (Maes et al., 1993b; Zunszain et al., 2011). Cytokines cause GR resistance to cortisol and result inlossofthenegativefeedbackovertheHPAaxis(Pace and Miller, 2009; Krishnadas and Cavanagh, 2012). Several molecular mechanisms have been identified to explain how cytokinescancauseafunctionalGRresistance.IL-6and TNF- prevent the entry of the cortisol-GR complex into the nucleusofneurons.Theyalsopreventthebindingofthe cortisol-GRcomplextotheDNAandinhibitDNAtran-scription (Pace et al., 2011). The cytokines act on pathways suchastheMAPK,NF-B,signaltransducersandactiva-torsoftranscription,andcyclooxygenase,andinhibitGR translocation into the nucleus and GR-mediated gene tran-scription,andreduceexpressionofintracellularGR(Zun-szainetal.,2011;KrishnadasandCavanagh,2012).The at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from 832ANZJP ArticlesAustralian & New Zealand Journal of Psychiatry, 47(9)result of inflammatory cytokines action on the HPA axis is functionalglucocorticoidresistanceresultinginsteroid insensitivityandcortisolhypersecretion(Zunszainetal., 2011;Schmidtetal.,2011).RestorationoftheHPAaxis abnormalities has been associated with clinical response to treatment (Zunszain et al., 2011; Kunugi et al., 2012).There may be a cyclic crosstalk between cytokines and glucocorticoids,implyingtheHPAaxishyperactivityand inflammation may be part of a common pathophysiological response.HPA axis hyperactivity is a marker of GR resist-ance and steroid insensitivity on target tissues, which may leadtoalossoftheglucocorticoidanti-inflammatory effect;also,inflammatorycytokinescancauseHPAaxis hyperactivitydirectlyorbyinducingGRresistance (Zunszainetal.,2011).Zunszainetal.(2011)proposeed thatelevatedcytokinesinthepresenceofglucocorticoid resistance may be a contributor to depressive symptoms, as opposedeitherprocessoccurringinisolation.Theysug-gested that chronic stressors cause persistent hypercortisol-aemiawhichcausesimmunecellstoundergoa compensatorydownregulationofGRactivity.Thislimits the ability of cortisol to inhibit the immune response even in the presence of high circulating cortisol levels. The result is a chronic low-grade inflammatory state which has been associated with infectious and autoimmune diseases as well as depression (Zunszain et al., 2011). There is also evidence inanimalandhumanstudiesthatadministrationofpro-inflammatorycytokinesleadstobehaviouralchangesthat correlatetoadepressivephenotype,includingdepressed mood,fatigue,disruptedsleep,anxiety,andsuicidalidea-tion (Raison et al., 2006; Pace and Miller, 2009).Neurotransmitters, inflammation,and depressionThemonoaminehypothesis.Themonoaminehypothesis states that a central synaptic deficiency of serotonin and/or noradrenalinecausedepressivesymptoms.Itisbelieved that there is a reduction in serotonin and noradrenaline neu-rotransmissionfromtheirmidbrainnucleiintheraphae nuclei and locus coeruleus, into the limbic, prefrontal cor-tex, and hippocampus (Palazidou, 2012).Cytokinesandreducedserotoninsynthesis.Inflammatory cytokinescanalterthesynthesisandreuptakeofcentral moodmodifyingneurotransmitterssuchasserotonin (MillerandTimmie,2008).Cytokinesmaylowercentral serotoninlevelsbyalteringtryptophan(aprecursorfor serotonin synthesis) metabolism. Maes et al. (1993a) found lowerplasmatrypthophanlevelsinpatientswithmajor depressionandhypothesizedthatthismaybeduetoan immuneresponse.IL-1andTNF-induceindoleamine 2,3-dioxygenase(IDO),anenzymewhichactivatesthe kynurenine pathway. The cytokines act via various inflam-matorysignallingcascades,suchasthesignaltransducer and activator of transcription 1a, interferon regulatory fac-tor-1,NF-B,andp38mitogenactivatedproteinkinase (MAPK)pathways(Milleretal.,2009a;Zunszainetal., 2011;KrishnadasandCavanagh,2012).Thekynurenine pathway is responsible for metabolizing dietary tryptophan away from serotonin (5HT) synthesis, and redirecting it to produce other metabolites, namely, kynurenine, 3-hydroxy-kynurenine, and quininolinic acid. The result is a reduction inserotoninsynthesis,andsubsequentcentralserotonin deficiency,andthepotentiationofdepressivesymptoms (Pace and Miller, 2009; Krishnadas and Cavanagh, 2012). Somestudiessuggestkynurenineandquininolinicacid affectmood,independentoftheireffectonserotonin,as discussed later (Miller et al., 2009a).Cytokines and increased serotonin reuptake.Selective sero-toninreuptakeinhibitorsactbyinhibitingserotoninreup-take from neural synapses and this is a mechanism by which theyarethoughttohavetheirantidepressanteffect.Cyto-kines oppose this effect by stimulating increased serotonin reuptake from synapses. Increased cerebral spinal fluid IL-6 levelsarecapableofactivatingtheIDOpathway,asdis-cussedabove,andalsotheMAPKpathway.TheMAPK pathway increases the activity of cell membrane transport-ersforserotonin,dopamine,andnorepinephrineintherat brain, causing increased reuptake of these neurotransmitters (Miller et al., 2009a). IL-1 and TNF- have also been asso-ciated with activation of the MAPK pathway and upregula-tion of serotonin transporters in the hippocampus (Bufalino etal.,2012).CytokineactivationoftheIDOandMAPK pathways deplete synaptic serotonin levels by reducing their synthesis and increasing reuptake respectively.Depletion of neurotrophic factors in depression.Brain volu-metric studies have shown decreased volumes in regions of thebrainassociatedwithmood.Itisbelievedthatthese changes are due to lower levels of neurotrophic factors that reduce neuroplasticity and neurogenesis and therefore pro-tection against depression. External stressors downregulate the production of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and VGF nerve growth factor (Kuberaetal.,2011).BDNFisaneurotransmitterthat plays a major role in neuronal growth, survival, maturation, andsynapticplasticityintheadulthippocampus(Palazi-dou, 2012). VGF has a role in synaptic plasticity to reverse depressive-likebehaviourandenhancehippocampuspro-liferation (Thakker-Varia et al., 2007). Low serum BDNF levelshavebeenreportedindepressedindividualsand appeartocorrelatewithseverityofdisease(Palazidou, 2012). Chronic stress reduces BDNF synthesis by causing demethylationofhistonesattheBDNFpromoterregion (Tsankovaetal.,2006).Thisissupportedbyfindingsof decreased BDNF concentrations in response to stress, par-ticularly in the limbic regions that mediate mood (Shimizu etal.,2003).Anotherneurotrophicfactorisfibroblast at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from Makhija and Karunakaran833Australian & New Zealand Journal of Psychiatry, 47(9)growth factor ; reduced activity in the this system can also alterbraindevelopmentandpredisposeanindividualto develop depression (Turner et al., 2006).Antidepressanttherapyexhibitsneurogeniceffectsby stimulating the production of neurotrophic factors such as BDNF, the receptor for BDNF trkB, and neural growth fac-tor(Kuberaetal.,2011).Thisresultsinincreasedneuro-genic activity in the hippocampus and the prefrontal cortex, givingrisetoimprovingcognitiveflexibilityandsubse-quent increase in ability to cope with environmental chal-lenges that may otherwise potentiate a depressive episode (Schmidt et al., 2011). These studies suggest that reduced neurotrophicfactorlevelsmaycontributetodepressive symptoms and that antidepressant treatment reverses these symptoms by restoring neurotrophic factor activity. These studies support one part of the neuroprogression hypothesis model of depression, as defined earlier.PreliminarydatashowsthatadministrationofIL-1 receptorantagonistintothehippocampusofmiceblocks stress-inducedBDNFdepletion(Barrientosetal.,2003). IL-1andTNF-decreasehippocampalexpressionof BDNF and its receptor, resulting in decreased hippocampal neurogenesis (Wu et al., 2007; Miller et al., 2009a). These finding suggests that inflammatory mechanisms can reduce BDNFlevelsandpotentiatedepressivesymptomsvia altered neurogenesis.Neuroprogression, depression, and inflammationThereisevidencethatneuroprogressionmechanisms underlie the development of depression. The previous sec-tion addressed how neuroptrophin factor depletion is asso-ciated with depression; the following sections outline some of the other key mechanisms involved in neuroprogression, including neurodegeneration, neuronal apoptosis, decreased neurogenesis, and neuroplasticity.Neurogenic hypothesis of depression.According to the neu-rogenic hypothesis of depression, new neuronal connections are needed in the adult brain for adequate mood control and antidepressantefficacy(Petriketal.,2012).Researchinto this hypothesis has gained interest because of a number of correlative studies that showed that humans with depression have decreased volumes of selective brain regions, because of decreased adult neurogenesis and increased neurodegen-eration (Maes et al., 2009; Eisch and Petrik, 2012). Some of the areas in the brain affected include the anterior cingulate cortex,orbitofrontalcortex,andthehippocampus (Koolschijnetal.,2009).Thehippocampusisinvolvedin learning/memorycontext-dependentemotionalresponses (Fanselow, 2000), and mood control (Petrik et al., 2012). It is because of its role in mood control that the hippocampus hasbeenthesubjectofdepressionresearch.Interestingly, hippocampalvolumeisreducedinpatientswithmultiple episodes of depression but not with first-episode depressive symptoms (MacQueen et al., 2003; Palazidou, 2012). This impliesthathippocampaldysfunctionoccurpriortoany detectablestructuralchangesonimagingstudiesandthat repeatepisodescauseadditivedamagewhicheventually becomes grossly visible with chronicity.Neurogenic-neuroendocrineinteraction.EischandPetrik (2012) recently coined the term neurogenic interactome to describe a complex series of endocrine and neurochemi-calcascades,andreciprocalconnectionsbetweenbrain regions which influence adult neurogenesis and have down-stream effects on behaviour (Eisch and Petrik, 2012). They describe how intact neurogenesis in the hippocampus is key toinhibitionofthehypothalamusandregulationofthe HPA axis. This contributes to mood control and preventing the development of depressive symptoms (Eisch and Petrik, 2012; Petrik et al., 2012).Thefunctionalinhibitionofthehippocampusonthe HPAaxisissupportedbytherichnessofcorticosteroid receptors in the hippocampus (Reul and deKloet, 1986) and itsanatomicallinktothehypothalamusviathefornix (Palazidou, 2012). This inhibitory control is lost after dam-agetothehippocampus. ThereisresultantHPAaxisdys-function, leading to the cognitive and emotional symptoms of depression (Zunszain et al., 2011). This disinhibition of the HPA access may be due to impaired adult neurogenesis inthehippocampus.Animalmodelsrevealhowchronic stress (a surrogate for psychosocial precipitants for depres-sion) causes raised glucocorticoid levels and hippocampal shrinkagemanifestedbydendriticretraction,suppression ofadultneurogenesis,andincreasedneuronalcelldeath (Czeh and Lucassen, 2007).Persistent hypercortisolaemia acts via voltage-gated ion channelsfacilitatingcalciumentryintoneuronstofurther cause neuronal cell death (Palazidou, 2012). The antidepres-sant sertraline modulates GR expression and function, and thishasbeenassociatedwithenhancedneurogenesis (Anacker et al., 2011). Trials with GR antagonist mifepris-tone have shown relief of symptoms in psychotic depression after 48 days of treatment (Belanoff et al., 2002). In the rat brain, mifepristone reversed corticosterone-induced loss in neurogenesis and survival (Mayer et al., 2006). This may be themechanismbywhichmifepristonerelieveddepressive symptoms in humans. These findings support the hypothesis thatpersistenthypercortisolaemiacausedepressivesymp-toms by interacting with GR in the hippocampus to cause a loss of neurogenesis and increased cell death.Inflammation and the neurogenic theory of depression.If the neurogenichypothesisofdepressionisavalidhypothesis forthedevelopmentofmajordepression,thenthenext question is, What inflammatory mechanisms inhibit neu-rogenesisandtherebyleadtodepressivephenotypes? Inflammatorychangeshavebeenimplicatedinneuronal at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from 834ANZJP ArticlesAustralian & New Zealand Journal of Psychiatry, 47(9)celldeathviaexcitotoxicmechanisms.Excessglutamate signalling induces neuron excitotoxicity, resulting in struc-tural changes in the brain that have been studied in disor-ders such as stroke, neurodegenerative diseases, and, most recently,depression(Leeetal.,2002).IL-1bindstothe IL-1 R1 receptor in the hippocampal neurons and induces phosphorylationoftheN-methyl-D-aspartate(NMDA) receptor(Vivianiet al.,2003).Thispotentiatesthe recep-tors activity and increases Ca2+ influx into the neuron with consequentialneuronalcelldeath(Vivianietal.,2003). IL-1 has also been shown to reduce expression of the pre-synapticglutamatetransporter,leadingtoareductionin glutamate reuptake, excess synaptic glutamate, and subse-quent NMDA-mediated excitotoxicity (Hu et al., 2000).The kynurenine pathway byproducts 3-hydroxy-kynure-nine and quininolinic acid, contribute to neurotoxicity and neurodegeneration(Christmasetal.,2011).3-Hydroxy-kynureninecausesincreasedoxidativestressandcontrib-utes to neuron apoptosis. Quininolinic acid causes oxidative stressandisanNMDAreceptoragonistcontributingto excitotoxicneurotoxicity(MyintandKim,2003). Additionally, TNF- leads to a change in the conformation ofthe-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, facilitating calcium influx into the neuron, and consequent glutamate activated excito-toxicity (Stellwagen et al., 2005).Inflammatory cytokines inhibit neurogenesis by causing cell death directly via excitotoxic mechanisms and apopto-sis in the hippocampus, and indirectly via interaction with neuroendocrine pathways, namely hypercortisolaemia.Theoxidativeandnitrosativestress(O&NS)pathways.A new hypothesis centres around the generation of free radi-cals in the setting of antioxidant scarcity, leading to further neuroprogression and depression. Inflammation and mito-chondrial metabolism generate highly reactive oxygen spe-cies (ROS) and reactive nitrogen species (RNS). ROS/RNS maycausedamagetofattyacids,membranelipids(lipid peroxidation), DNA, proteins, and mitochondria, with con-sequent cellular dysfunction, apoptosis, and tissue destruc-tion(Maesetal.,2011).Thereisevidencethat proinflammatory cytokines such as IL-1 and TNF- poten-tiatetheeffectsoffreeradicals.Theimplicationisthat cytokinesmaystimulatetheneuroprogressionofdepres-sion via the O&NS pathway (Maes et al., 2012).Normally, free radicals are balanced by protective anti-oxidants,antioxidantenzymes,andproteins.Examplesof antioxidants include coenzyme Q10, vitamins C and E, and glutathione. Antioxidantenzymesincludesuperoxidedis-mutase(SOD)andglutathioneperoxidaseandproteins include albumin, transferrin, haptoglobins, and ceruloplas-min.Aloweredantioxidantcapacityimpairsprotection against the free radicals and allows for the damage to cel-lular structures. Organs like the brain are particularly vul-nerabletotheO&NSneuronaldamageand neurodegenerationbecauseofahighmetabolicrateand lower antioxidant levels (Maes et al., 2011).Oxidative stress can alter the immunogenicity of ubiqui-touscellularproductstoinduceanautoimmuneresponse. O&NSpathwaysmaychangethechemicalstructuresof innatemoleculestocreateneoepitopesthatarehighly immunogenic.Theresultisanimmunoglobulinmediated autoimmuneresponseagainstthefattyacidsandprotein neoepitopes (Maes et al., 2011; Leonard and Maes, 2012).CurrentevidencesupportstheO&NShypothesisas depression is associated with decreased antioxidant levels, increasedO&NSactivity,andincreasedcellulardamage and autoimmune response secondary to O&NS. In depres-sion,thereisasignificantdecreaseinantioxidantlevels such as tryptophan, tyrosine, albumin, zinc, vitamin E, and glutathione(Maesetal.,2000).Manystudiesshowan increased level of ROS and RNS production in depression; however, the values are higher in the acute phase of depres-sionandnormalizewhenthedepressionbecomesmore chronic (more than 2 years duration) (Maes et al., 2011)The decrease in antioxidant levels and increase free radi-cal result in oxidative damage and apoptosis and may explain thevolumetricchangesinthebrainofdepressedsubjects. Malondialdehyde (MDA) is a byproduct of polyunsaturated fatty acid peroxidation and is used as a measure for lipid per-oxidation and oxidative stress. Multiple studies have found increasedMDAlevelsinthebloodofpeoplewithdepres-sionscomparedwithhealthysubjects(Ozcanetal.,2004; Galecki et al., 2009). These levels were reduced with treat-ment with antidepressants. There is increased oxidative dam-age to DNA by ROS in depression, as the molecular marker for DNA damage is significantly increased in patients with recurrent depressive episodes (Forlenza and Miller, 2006).Thereisevidencethatdepressionisassociatedwith increasedautoimmuneresponsetoneoepitopesgenerated secondarytoO&NSpathways.Depressedsubjectshave raised plasma IgG autoantibodies against low-density lipo-proteinsandIgM-mediatedimmuneresponsesagainst phosphatidylinositol (PI) as compared to healthy subjects. TheIgM-mediatedresponseagainstPIwassignificantly correlated to symptoms of depression such as sadness and fatigue (Maes et al., 2007; Leonard and Maes, 2012).Thereisevidencethatantidepressantscancounterthe effectsofO&NSbyhavinganantioxidant-likeeffectand thismaybeanotherwaytheyachievetheirtherapeutic effect (Maes et al., 2011; Leonard and Maes, 2012). There are numerous hypotheses with growing evidence to support the idea that depression is a result of neuroprogression. The various pathways that lead to neuroprogression are closely linkedtoinflammationandproinflammatorycytokines. The most recent O&NS pathway highlights how inflamma-tiongeneratesfreeradicalsthatmaycauseneuroprogres-sionviatwomainmechanisms;directlybycellular destruction and indirectly by the inhibition of immune tol-erance and activation of autoimmune mechanisms. at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from Makhija and Karunakaran835Australian & New Zealand Journal of Psychiatry, 47(9)GeneticsSome studies have implicated the serotonin transporter gene (SLC6A4) as a common gene affecting both depression and immunefunction.However,thereareconflictingfindings linking polymorphisms in this gene to predispose individu-alstodepressivesymptoms.Suetal.(2009)reportedthat participants with a specific haplotype at SLC6A4 had both increaseddepressivesymptomsandelevatedplasmaIL-6; however, they acknowledged that other studies reported no significantdifferencesbetweendepressivesymptomsand polymorphisms of SLC6A4 (Su et al., 2009).Polymorphisms in the human serotonin transporter gene promoter region (5-HTTLPR), leading to the short (SS) allele, have been associated with an increased likelihood or vulnerabilitytodevelopdepressionafterstressfullife events(Caspietal.,2003),chronicillness(Otteetal., 2007), or IFN- administration (Bull et al., 2009).Onestudyanalysedcytokineconcentrationsinhealthy individuals with and without the SS allele to determine any variancewhichmayaccountforthepredispositionto depression (Fredricks et al., 2010). They found that healthy individualswiththeSSpolymorphismhadahigherIL-6/IL-10 ratio at baseline and after stress testing. This was sug-gestive of a chronic proinflammatory state under both rest-ingandstressfulsituations.Theauthorshypothesizethat thesegeneticvariationscauseachronicproinflammatory stateandtherebyincreasetheseindividualsvulnerability todevelopdepression,actingasapredisposingfactor (Fredricks et al., 2010).Studies investigating the relationship of IL-1 gene pol-ymorphismsanddepressionhavereportedinconsistent results.EarlystudiesassociatedepressionwiththeT/T genotypethatcauseshigherIL-1concentrations(Rosa etal.,2004);however,laterstudieslinkedthelowIL-1 producer, C/C genotype, with depressive symptom severity (Hwang et al., 2009). Yet another study found that a combi-nationoftheCandTallelesatdifferentlocationsinthe genewasassociatedwithrecurrentmajordepressiveepi-sodes via enhanced binding to transcription factors, result-ing in increased production of IL-1 (Bufalino et al., 2012). Additionally,patientswithspecificpolymorphismsofthe IL-1genewerelesslikelytorespondtoantidepressant treatment,supportingtheideathatimmunegenesare important not only in the aetiology of depression, but also in efficacy of treatment (Su et al., 2010).Polymorphismsintheenzymesphospholipase-A2 (PLA2)andcyclooxygenase-2(COX2)wereassociated with increased risk of developing IFN--induced depression in patients with hepatitis C. They found that polymorphisms in these enzymes led to a reduction in polyunsaturated fatty acids (PUFAs) docohasexaenoic acid and eicosapentaenoic acid, which are believed to play a protective role in depres-sion(Suetal.,2010).Thesegeneticpolymorphismand reductioninPUFAsrenderedindividuals3-timesmore likely to develop IFN--induced depression than those with-out these genetic polymorphisms (Su et al., 2010).The degree of inconsistency and lack of reproducibility of the genetic links between inflammation and depression warrantsfurtherresearchinthisfield.Depression,like hypertension and diabetes, is a complex disorder involving environmental factors that interact with genetic predisposi-tions and is likely to involve multiple genes and unlikely to betheresultofadefectinanysinglegene(Blochand Singh,2007). Thediscoveryofasetofgeneswhichmay predispose an individual to developing depression or resist-ance to treatment would be clinically valuable as these indi-vidualsmaybenefitfromtailoredprophylactictreatment (Bufalino et al., 2012).Psychosocial stressors and inflammatory cytokinesPsychosocial stress can directly activate peripheral and cen-tralinflammatorycascadeswhichmayactaspathwaysto triggerorperpetuatedepressivesymptoms.Individual healthyvolunteersexposedtopublicspeakingandother stressorswerefoundtoexhibitincreasedDNAbindingof the chief inflammatory transcription factor NF-B in periph-eralmononuclearcells(Bierhausetal.,2003).NF-Band IL-6responsetopsychosocialstressorsareexaggeratedin patients with depression as compared to non-depressed indi-viduals (Pace et al., 2006). Psychosocial stressors may also induceO&NSpathwaysdirectlyasevidencedinmenand animalstudies(LeonardandMaes,2012).Stress-induced productionoftheseCNScytokinesismediatedthrough microglia (Frank et al., 2007). It may also be due to activa-tion of the sympathetic nervous system, which is active dur-ingacutestress.Stress-inducedcatecholamineshavebeen showntoincreasecytokineexpressioninthebrainofrats (Johnsonetal.,2005).Alpha-adrenergicantagonistscan blockstress-inducedrisesinperipheralIL-6levelsin humans,suggestingapossiblelinkbetweenpsychosocial stressleadingtoSNSactivation,cytokineproduction,and the resulting depressive symptoms (Mazzeo et al., 2001).Potential applicationsA number of retrospective studies report depressed patients with poor response to conventional antidepressant treatment were more likely to have raised inflammatory markers, TNF- and IL-6, prior to treatment (Maes et al., 1997; Miller et al., 2009b). Schmidt et al. (2011) suggested the use of a panel of biomarkers, including inflammatory molecules to diagnose, create biological subtypes of depression and predict response to treatment in order to optimize clinical outcomes. There is alsosomeevidenceforthebenefitofadjuvantpharmaco-logicaldrugs,suchastheadditionofcelecoxib(aCOX2 inhibitor)toreboxetineandfluoxetinetoachievinghigher ratesofimprovementindepressivesymptomsthanthe at UNIV FED DO RIO DE JANEIRO on September 11, 2013 anp.sagepub.com Downloaded from 836ANZJP ArticlesAustralian & New Zealand Journal of Psychiatry, 47(9)respective antidepressants alone (Muller et al., 2006). Similar findingswerereportedinpsoriasispatientsreceivingthe TNF-antagonistentercept;theyexperiencedgreater improvements in depressive symptoms compared with pla-cebo-treated patients and this difference was independent of any improvement in psoriasis activity (Tyring et al., 2006). Evidenceanalysedinthisreviewsupportsfurtherresearch may be warranted to biologically subtype depression based on variations in inflammatory markers.DiscussionThere is a large and growing body of evidence for the role of inflammatory mechanisms interacting with neural path-ways involved in mood, which may underlie the develop-ment of depressive symptoms. However, it is important to appreciatethatthemajorityofpeoplewithinflammatory conditions do not suffer from depression, and the majority of people with depression do not have inflammatory condi-tions.Thisservestoremindusthatinflammationalone does not cause depression and is certainly not necessary for depression to occur. Also, if depression were an inflamma-tory illness, it may be reasonable to hypothesize that anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) or steroids may alleviate depressive symp-toms;however,thereisevidencethatNSAIDsactually attenuate the antidepressant response to selective serotonin reuptake inhibitors (Gallagher et al., 2012).The question that arises is, What role does inflammation actuallyplayindepression?KrishnadasandCavanagh (2012)suggestthatinflammationmayactasatriggerina cascade of events that culminates in a depressive phenotype. Raison and Miller (2011) propose that inflammation contrib-utes to depression in only a subset of patients and that inflam-mationisnotanabsolutedepressogenicprocess.They suggestthenotionofasuper-networkwithimmune response amplification, constituting of different mechanisms through which inflammation may act to precipitate a depres-sive phenotype. Some of these mechanisms include glucocor-ticoidinsensitivity,reducedparasympatheticsignalling,and reduced BDNF levels (Raison and Miller, 2011; Krishnadas and Cavanagh, 2012). Inflammatory processes may affect a combination of pathways in a subset of susceptible patients to trigger the development of a depressive phenotype.Many studies at present are correlative in nature; how-ever, correlation is not causation. Further research is needed to demonstrate a causative link between inflammatory pro-cesses and depression.ConclusionTheroleofinflammationintheaetiopathogenesisof depression may be conceptualized in terms of a psychiatric formulationfocusedonthebiologicalmodelofdisease, dividedintopredisposing,precipitating,perpetuating,and protectivefactorsthatalladduptocausedepression. Various genetic polymorphisms and a chronic pro-inflam-matorystatemaypredisposesusceptibleindividualsto develop depression as well as predict a failure to respond to treatment.Cytokinesaffectthreemajorneuralpathways involved in the aetiopathogenesis of depression. These dis-turbances may precipitate and perpetuate and a loss in neu-roprotectivemechanismsthatalleventuateinthe developmentofmajordepression.Thesemechanisms include: the neuroendocrine pathway, by causing HPA axis dysregulationandcortisolhypersecretion;theneurotrans-mitter pathway, by reducing synaptic serotonin availability and depleting central neurotrophin levels to reduce its neu-roprotective effect and loss of neurogenesis; and the neuro-progressionpathway,bycausingalossofhippocampal neurogenesis and volume which in turn causes more HPA axis dysregulation. External and/or internal stressors induce proinflammatorycytokineproductionwhichinturnpre-cipitatesandperpetuatesdepressivesymptomsviatheir action on multiple neuronal and neuroendocrine pathways. Despitethelargebodyofcorrelativeandexperimental research implicating inflammation in the aetiopathogenesis ofdepression,moreresearchisneededtodeterminethe extenttowhichinflammatorycytokinescontributeto depressive symptoms and exact the mechanisms by which theseoccur.Currently,thereisstillnoconsensusona pathophysiologicalmodelofdepression,butratherthe existence of multiple observations and empirical data that provide, at best, hypotheses on the mechanisms underlying this complex disease. By understanding these mechanisms further,inthefuture,wemaybeabletocreatebiological subtypes of depression and tailor treatment more optimally for patients with depression.AcknowledgementsWe would like to thank Dr Jason Lee for his advice regarding this review.FundingThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.Declaration of interestThe authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.ReferencesAnacker C, Zunszain P, Cattaneo A, et al. (2011) Antidepressants increase humanhippocampalneurogenesisbyactivatingtheglucocorticoid receptor. Molecular Psychiatry 16: 738750.BarrientosR,SprungerD,CampeauS,etal.(2003)Brain-derivedneu-rotrophic factor mRNA downregulation produced by social isolation inblockedbyintrahippocampalinterleukin-1receptorantagonist. 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