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抑郁症标志物,文献综述

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doi:10.1111/pcn.12299Biochemicalmarkerssubtypingmajordepressivedisorder

HiroshiKunugi,MD,PhD,*HiroakiHori,MD,PhDandShintaroOgawa,PhD

DepartmentofMentalDisorderResearch,NationalInstituteofNeuroscience,NationalCenterofNeurologyandPsychiatry,Tokyo,Japan

Thepathophysiologyofmajordepressivedisorder(MDD)remainselusive,andthereisnoestablishedbiochemicalmarkerusedinthedailyclinicalsetting.ThissituationmayresultinpartfromtheheterogeneityofMDD,whichmightincludehetero-geneoussubgroupswithdifferentbiologicalmecha-nisms.Inthisreview,wediscussthreepromisingbiologicalsystems/markerstopotentiallysubtypeMDD:thedopaminesystem,thehypothalamic–pituitary–adrenalaxis,andchronicinﬂammatorymarkers.SeverallinesofevidencesuggestthatafacetofMDDisadopamineagonist-responsivesubtype.Focusingonthehypothalamic–pituitary–adrenalaxis,depressivespectrumdisordersshowhypercortisolismtohypocortisolism,whichcould

bedetectedbyhormonalchallengetests,suchasthedexamethasone/corticotrophin-releasinghormonetest.Finally,accumulatingevidencesuggeststhatatleastsomeMDDpatientsshowcharacteristicssimilartothoseofchronicinﬂammatorydiseases,includingneuroinﬂammatorymarkersandreducedtryptophanduetotheincreasedactivationofthetryptophan–kynureninepathway.Futurestudiesshouldexaminetheinter-relationsbetweenthesesystems/markerstosubtypeandintegratethepatho-physiologyofMDD.

Keywords:dopamine,hypothalamic–pituitary–adrenalaxis,inﬂammation,stress,tryptophan.

AJORDEPRESSIVEDISORDER(MDD)isacommondiseasewithalifetimeprevalenceof2–20%worldwide.1InJapan,the1-yearprevalenceofMDDwasestimatedtobeashighas2.9%.2MDDalsocomprisesaleadingcauseofsuicide.3MDDoftenaccompaniescollateralsocialdisadvantagesandisoneofthetop-rankeddiseasesintermsofthedisability-adjustedlifeyears.4However,thepatho-physiologyofMDDremainselusive;thereisnoestab-lishedbiochemicalmarkerusedinthedailyclinicalsettinganddiagnosisofMDDlargelydependsupontheclinicalinterview.Thissituationmayresultfrom

*Correspondence:HiroshiKunugi,MD,PhD,DepartmentofMentalDisorderResearch,NationalInstituteofNeuroscience,NationalCenterofNeurologyandPsychiatry,4-1-1,Ogawahigashi,Kodaira,Tokyo187-8502,Japan.Email:hkunugi@ncnp.go.jpAccepted27March2015.

theheterogeneityofMDD,thatis,itislikelytoincludeheterogeneoussubgroupswithdifferentbiologicalmechanismscontributingtotheirdisease.5Inthisreview,weshowrecentprogressonthreepromisingbiologicalsystemstopossiblysubtypeMDD:thedopaminesystem,thehypothalamic–pituitary–adrenal(HPA)axis,andinﬂammatorymarkers.

CENTRALDOPAMINE

Themonoaminehypothesisisoneofthemostwell-knownetiologicalhypothesesfordepression.Althoughtherearedifferentclassesofantidepressantswithdifferentmechanismsofaction,theygenerallyhavetheeffectsofinhibitingthereuptakeofneu-rotransmitters,includingserotonin,noradrenalineanddopamine,intotheneuronsviatransportersandofinhibitingtheirbreakdownbymonoamine

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oxidase,therebyincreasingthesemonoaminesinthesynapticcleft.Giventheﬁndingsfrominvitrostudiesthatﬁrst-lineantidepressants,suchasselectivesero-toninreuptakeinhibitors(SSRI)andserotoninnor-adrenalinereuptakeinhibitors(SNRI),inhibitthereuptakeofserotonin,themostimportantbiomarkerinMDDshouldbeserotoninlevelsinthebrain.However,evidenceonthereductionofbrainextracel-lularserotoninlevelsindepressedpatientsisnotconclusive.Indeed,post-mortembrainstudieshavenotconsistentlyobservedthatserotonin(oritsmetabolites)isreducedinpatientswithMDD.Forexample,Cheethametal.6examinedserotonin,itsmetabolite5-hydroxyindoleaceticacid(5-HIAA)concentrationsandserotoninturnover(5-HIAA/serotonin)inpost-mortembrainsofsuicidevictimswitharetrospectivediagnosisofdepressionandage-andsex-matchedcontrols,andfoundthatthesethreeindicesdidnotdiffersigniﬁcantlyinthefrontalandtemporalcortices,caudateandhippocampusbetweenthepatientsandcontrolsirrespectiveofthepatients’antidepressantmedicationstatus.

Theﬁndingsoncerebrospinalﬂuid(CSF)5-HIAAconcentrationsarealsocontroversial.7Inaddition,apartfromdepression,anumberofstudieshavereportedreducedCSF5-HIAAinindividualswhohaveahistoryofimpulsivebehaviors,suchassui-cidalattempts8andviolentacts,9irrespectiveoftheirdiagnosis(e.g.schizophreniaandpersonalitydisor-der).Itisthereforeconceivablethatreducedsero-toninisassociatedwithimpulsivityingeneral,ratherthandepressionperse.ThisideacorrespondswelltothefactthatSSRIareeffectiveatreducinganxiety,agitationanddepressedmoodbutnotnec-essarilysoforothersymptoms,includingavolition,psychomotorretardation,poorconcentrationandanhedonia.

Concerningothercatecholamines,suchasnor-adrenalineanddopamine,ﬁndingsfrompost-mortembrainstudiesandCSFstudiesindepressedpatientshavenotbeenuniform.However,thereisgoodevidenceforreducedhomovanillicacid(HVA:aprimarydopaminemetabolite)intheCSFofdepressedpatients.Asbergetal.10reportedsigniﬁ-cantlylowerCSFHVAlevelsin83patientswithmel-ancholia(includingbipolarones)incomparisonwith66healthyvolunteers.Reddyetal.11compared30drug-freepatientsand30age-andsex-matchedcontrols,andfoundthatdepressedpatientsshowedsigniﬁcantlylowerCSFHVAlevelsthancontrols.Kasaetal.12alsoreportedlowerCSFHVAlevelsinJapanesedepressedpatients(n=13),albeitsomeofthemwerebipolarones,comparedwithcontrols(n=16).Inaddition,ourrecentunpublisheddata(75patientswithMDDand87healthycontrols;thelargeststudytoourknowledge)showedthatCSFHVAlevelsweresigniﬁcantlylowerinMDDpatientswithaHamiltonRatingScaleforDepression(HRSD)scoreof13ormore,comparedwithcontrolsandpatientswithascoreoflessthan13,irrespectiveofantidepressantmedication.Furthermore,Peabodyetal.13reportedasigniﬁcantlypositivecorrelationbetweenHRSDscoresandCSFHVAlevelsin37maledrug-freeinpatientswithdepression.Althoughcontradictivenegativeresultshavealsobeenreported,14–16thesestudieswerelimitedbythesmallnumberofsubjectsandbeingunmatchedforsexdistributionbetweencasesandcontrols.Overall,themajorityofthestudieswitharelativelylargesamplesizereportedreducedCSFHVAlevels,suggestingthatdopamineplaysanimportantroleinthepathophysi-ologyofMDDandthatCSFHVAisasubtypingbiomarker.Also,reduceddopaminetransporterlevelsandincreasednumberofD2/D3receptorsintheamygdalaofthepost-mortembrainsamplesofpatientswithMDDwerereported,17suggestingdecreaseddopaminetransmission.

AlthoughplasmaHVAlevelswerereportedtosig-niﬁcantlycorrelatewithCSFHVAlevelsinhumansubjects,18itwasestimatedthatlessthan1%ofCSFHVAisderivedfromperipheralcirculationinmonkeys.19Inotherwords,over99%ofCSFHVAoriginatesfromthecentralnervoussystem.More-over,thehalf-lifeofHVAinCSFwasestimatedas16.9–46.2mininrats.20,21Therefore,CSFHVAisclearlymuchbetterthanplasmaHVAtoanalyzecentraldopaminemetabolism.

InvivoanimalstudiesusingmicrodialysishavedemonstratedthatmanyoftheSSRIincreaseextra-cellulardopamineaswellasserotoninintheprefron-talcortexeventhoughSSRIdonotinhibitthereuptakeofdopamineinvitro.Astricyclicantidepres-santsalsoincreaseprefrontaldopamine,thisactioncouldbecentraltotheantidepressanteffects.22OneofthepotentialmechanismsbywhichSSRIandSNRIincreaseprefrontaldopamineisthestimulationofdopaminereleasevia5-HT1Areceptorsbytheelevatedlevelsofserotonin.Anotheroneisthattheinhibitionofdopaminereuptakeviathenoradrena-linetransporterbySNRIleadstoanincreaseinextra-cellulardopaminelevelsbecausethenoradrenalinetransporter,butnotthedopaminetransporter,is

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mainlyresponsibleforthedopaminereuptakeintheprefrontalcortex.Itshouldbenoted,however,thattricyclicantidepressantsdonotincreasedopamineinthenucleusaccumbens,abrainregionknownasthe‘pleasurecenter’.22

Large-scaleclinicaltrials,suchastheSequencedTreatmentAlternativestoRelieveDepression(STAR*D),haverevealedthatasubstantialpropor-tionofpatientsfailtorespondto,orachieveremis-sionwiththecurrentﬁrst-lineantidepressants(i.e.SSRIandSNRI).23Inthesepatients,symptomssuchasavolition,psychomotorretardation,poorconcen-trationandanhedoniaarelikelytopersistevenafterdepressedmoodandanxietyhaveresolved.Asdopamine,particularlythatofthemesolimbicsystem,playsacentralroleinregulatingmotivation,psychomotorspeed,concentrationandemotionslikepleasure,itispostulatedthatatleastsomeofthetreatment-resistantpatientsareinahypodopaminergicstatewheremedicationssuchasdopaminereuptakeinhibitors,monoamineoxidaseinhibitorsanddopaminereceptoragonists,ratherthanserotonergicornoradrenergicagents,couldbeeffective.24Indeed,augmentationbyadopaminepartialagonist,aripiprazole,hasbeendemonstratedtobesuperiortostandardantidepressanttherapyinpatientswithMDD,particularlyinthosewhohadaninadequateresponsetostandardantidepressanttherapy.25,26Also,dopamineD2receptoragonists,suchaspramipexole,havebeendemonstratedtobeeffectiveintreatment-resistantdepressivedisorderandbipolardepression.27Ourgroupprovidedpre-clinicalandclinicalevidencesuggestingthatdopa-mineagonistsareeffectivefortreatment-resistantdepression.28,29

Collectively,dopamineplaysanessentialroleinthepathophysiologyofMDDandtheremightbeasubgroupof‘dopamineagonist-responsivedepres-sion’.30FutureresearchshouldfocusonwhetherCSFHVAconcentrationcouldbeabiomarkerforsuchasubtype.

HPAAXIS(HYPERCORTISOLISMANDHYPOCORTISOLISM)

SincetheseminalworkofSelye,31awidevarietyofstresshasbeenassociatedwithanactivationoftheHPAaxis.MDDisinducedbychronicstress,andaccordinglyabnormalityinHPAaxisfunctionisoneofthemostextensivelystudiedbiologicalmarkersfordepression.32Stressorsofallsorts,bothphysicaland

psychological,activatetheHPAaxisbyincreasingtheproductionandreleaseofcorticotrophin-releasinghormone(CRH)andargininevasopressin(AVP)fromtheparaventricularnucleusofthehypothala-mus.Viatheportalveinsystem,CRH,inconcertwithAVP,stimulatesthepituitarytoproduceadrenocorti-cotropichormone(ACTH),whichenterstheblood-streamandactivatestheadrenalglandstoreleaseglucocorticoids(cortisolinprimates,includinghumans,andcorticosteroneinrodents).Glucocorti-coids,inturn,exertinhibitoryfeedbackeffectsmainlyatthehypothalamusandpituitaryglandstoinhibitthesynthesisandsecretionofCRHandACTH,respectively.ThehippocampusalsoconfersaninhibitoryeffectontheHPAaxis.NumerousstudieshaveassociatedmelancholicdepressionwithincreasedHPAaxisactivityasrevealed,forexample,byelevatedconcentrationsofCRHintheCSF,33increasedvolumesofadrenalgland34andpituitary,35andhigherratesofnon-suppressiontothedexa-methasone(DEX)suppressiontest(DST)andtheDEX/CRHtestasdescribedbelow.

ToquantifythedysregulationoftheHPAaxis,theDST,mostlyusing1mgofDEX,hasextensivelybeenstudiedsinceCarrolletal.36standardizeditasabio-logicalmarkerforthediagnosisofmelancholia.InaseriesofDSTstudies,cortisollevelsasmeasuredbytheDSTwereshowntobeincreasedindepressedpatients;37however,itssensitivitytodifferentiatedepressedpatientsfromhealthycontrolswasnotveryhigh38,39andelevatedcortisollevelswerenotspeciﬁctodepressivedisorderandwereobservedinvariouspopulationsunderstressfulconditions.40,41TheDSThasthusfailedtofulﬁlltheinitialpromiseasadiag-nostictoolfordepression,althoughthereremainsapossibleuseofthetestasasubtypingmarkerasdescribedlater.

ThentheDEX/CRHtest,whichcombinesDEXpre-treatmentwithCRHadministrationonthefollowingday,wasdevelopedinanattempttoenhancethesensitivityoftheDST.42,43InthestandardprotocoloftheDEX/CRHtest,arelativelyhighdose(i.e.1.5mg)ofDEXhasbeenused.ThemeritofthiscombinedtestisthatatthemomentofCRHinfusion,theHPAaxisisdownregulatedduetothenegativefeedbackeffectofDEX.Previousstudies,includingours,indi-catedthattheDEX/CRHtestdidshowrelativelyhighsensitivitytodetectMDDpatients.43–46UsingtheDEX/CRHtest,however,abnormalitiesintheHPAaxisfunctioninseveralotherpsychiatricdisorders,suchasbipolardisorder,panicdisorderandperson-

600H.Kunugietal.PsychiatryandClinicalNeurosciences2015;69:597–608

(a) Pharmacotherapy alone

1210Cortisol (μg/dL)86420

minPost-treatment(b) Pharmacotherapy + ECT

1210Cortisol (μg/dL)Pretreatment8Pretreatment64200

Post-treatmentminFigure1.Time-coursecurvesofcortisolresponsestothedexamethasone(DEX)/corticotrophin-releasinghormone(CRH)test

beforeandaftertreatmentin(a)thepharmacotherapygroup(n=23)and(b)thepharmacotherapy+electroconvulsivetherapy(ECT)group(n=12).TheX-axisrepresentstime(min)afterCRHinfusion.Errorbarsrepresentstandarderrorsofthemean.Abnormallyhighcortisolresponseswereimprovedafterinpatienttreatment,particularlyinthosepatientswhounderwentECTinadditiontopharmacotherapyascomparedtopharmacotherapyalone.AdaptedfromKunugietal.45

alitydisorders,havealsobeenreported,47–49indicat-ingagainthatabnormalresponseintheDEX/CRHtestisnotspeciﬁctoMDD.

Time-coursecurvesofcortisolresponsestotheDEX/CRHtestinourMDDinpatientsbeforeandaftertreatment(pharmacotherapyandelectriccon-vulsivetherapy)areshowninFigure1.OurdatasuggestthattheDEX/CRHtestcanbeastate-dependentmarkerforMDD.45Consistently,hor-monalresponsestotheDEX/CRHtesttendtorestoreaftersuccessfultreatmentwithantidepres-sants.50,51IntheDSTstudies,conversionfromthenon-suppressortosuppressorwastemporallyasso-ciatedwithclinicalresponsestoantidepressants.52,53Ofnote,severalstudiesreportedthatpatientsremit-tedfromamajordepressiveepisodewhostillexhib-itedexaggeratedcortisolresponsestotheDEX/CRHtesthadagreaterriskforrelapsethantheircoun-terpartswhoshowedthenormalcortisolresponses.54–56TheseﬁndingssuggestthatHPAaxisabnormalitiesassessedbyDSTandDEX/CRHtestmayserveasabiomarkerfor‘biologicalcure’inaportionofMDDpatientswhoinitiallyshowedexag-geratedresponsetothetests.

AsMDDpatientsdonotalwaysshowelevatedHPAaxisfunction(hypercortisolism)orimpairednegativefeedbackintheaxis,HPAaxisabnormalitiescanbeusefulinsubtypingtheillness.Indeed,previousDSTaswellasDEX/CRHstudieshaveobservedpro-nouncedHPAaxishyperactivityinpsychoticdepres-sion.57Künzeletal.58examined235inpatientswithMDDbyusingtheDEX/CRHtestandfoundthatcortisolresponsespositivelycorrelatedwiththenumberofepisodes,depressionseverityandseveresomatic/vegetativesymptoms.Concordantly,base-linecortisolandACTHlevelswereelevatedinmel-ancholicMDDbutnotinnon-melancholictype.59Together,severeMDDofthemelancholicorpsy-chotictypeismorelikelytoshowhypercortisolism.However,severalresearchgroupsreportedthatdepressedpatientsasawholeshowedsimilar,60–63orevenattenuated,64–66cortisolresponsesascomparedtohealthycontrolsintheDEX/CRHtest.Inthesestudies,patientshadclinicalcharacteristics,suchasbeingoutpatients,61–63chroniccases,60depressivepatientswithpsychiatriccomorbidity,66orlong-termsick-leavepatients.64,65TheseinconsistentﬁndingsontheDEX/CRHtestindepressedpatientsarelikelytoresult,atleastinpart,fromtheheterogeneityoftheillness.Inlinewiththis,atypicaldepression,incon-trasttomelancholicdepression,issuggestedtorelatetohypocortisolismratherthanhypercortisolism.67,68Moreover,DSTstudieswithlowerdosesofDEX(e.g.0.5mg)havereliablyidentiﬁedhypocortisolismorenhancednegativefeedbackinseveralstress-relateddisorders,includingpost-traumaticstressdisorder,

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108Cortisol (μg/dL)6420Controls15:0015:1515:3015:4516:0016:15Hypercortisolism

PatientsNormal

Hypocortisolism

Figure2.Cortisolresponsepatternstothedexamethasone/

corticotrophin-releasinghormonetest.

chronicfatiguesyndromeandﬁbromyalgia.69–71Theseconditionsoftenaccompanydepressivesymp-tomsorcomorbidMDD.Moreover,itiswellknownthatsomaticdiseases,suchasAddison’sdiseaseandACTHdeﬁciency,bothofwhichshowinadequatecortisolsecretion,presentpsychiatricsymptomssimilartoMDD.

Toscrutinizetheroleofhypocortisolism,wehaveconductedaseriesofstudies.WhileweappliedtheDEX/CRHtesttohundredsofsubjects,wefoundapproximately10%ofthepopulationshowedexcessivelysuppressedresponsetothetest,thatis,cortisollevelsunderdetectionlimit(1μg/dL)throughoutthetest(Fig.2).Whenhypocortisolismwasexaminedforassociationwithdistresssymp-toms(assessedwiththeHopkinsSymptomCheck-list)72andcopingstyle(assessedwiththeWaysofCopingChecklist[WCCL]73)inanon-clinicalpopu-lation,wefoundthatenhancedsuppressorsshowedsigniﬁcantlyhigherscoresinobsessive–compulsive,interpersonalsensitivityandanxietysymptomsandsigniﬁcantlymorefrequentuseofavoidantcopingstrategy,comparedtotheotherindividuals(Fig.3).74Theseobservationsmayindicatethatindi-vidualswithhypocortisolismdonotcopewithstressinaneffectivewayduetothelackofcortisolandthustheysuffermoredistresssymptomsthantheothers.Subsequently,wecomparedpatientswithMDDwhoshowedhypercortisolismandthosewithhypocortisolismastotheirtemperamentandcharacterbyusingCloninger’sTemperamentandCharacterInventory(TCI)75andthecopingstyle.Wefoundthatpatientswithhypocortisolismshowedhigherrewarddependenceandlowercoop-erativenessinTCI.76Astocoping,depressedpatientsasawholedemonstratedsigniﬁcantlylessuseof

problem-solving,positivereappraisalandsocialsupportcopingstylesandmoreuseofself-blameandwishfulthinkingstyleswhencomparedtohealthyindividuals.77Moreover,patientswithhypocortisolismwereagainassociatedwithhigherescape-avoidanceinWCCL.Theseﬁndingssuggestthathyper-andhypocortisolismareassociatedwithcharacteristicclinicalpicturesthatcoulddelin-eatesubtypesofMDD.Interestingly,atypicaldepression,whichisreportedtobeassociatedwithhypocortisolismasdescribedabove,ischaracterizedbyrejectionsensitivityandpassivecoping.

Theoriginofhypocortisolismisunclear.However,priorexposuretotrauma,whichoftenoccursearlyinlife,issuggestedtobeassociatedwithincreasedsup-pressionofcortisol.78Similarly,Carpenteretal.79reportedthatnon-clinicalsubjectswithaself-reportedhistoryofmoderatetoseverechildhoodmaltreatmentwereassociatedwithdiminishedHPAaxisresponsetoapsychosocialstressor.

Theseobservationssuggestthatpriorexposuretotraumaandlong-termstresssensitizeindividualstostressandthentheircortisolresponsemayshifttowardsgreatersuppression,whichinturnmakespeopleunadaptabletostressors.Weproposeaschemaofhyper-andhypocortisolsubtypesofdepressivedisorder,asillustratedinFigure4.

Anotherkeymoleculethatshouldbementionedheremightbebrain-derivedneurotrophicfactor(BDNF),whichisconsideredtomediatethedetri-mentaleffectsoftheHPAaxisabnormalitiesonthebrain.Wehaveprovidedadetaileddescriptionelsewhere.80

INFLAMMATORYSUBTYPE

Recently,afacetofdepressivedisorderhasbeenrefor-mulatedasachronicinﬂammatorydisease,suchasdiabetes,coronaryheartdisease,andAlzheimer’sdisease,inwhichproinﬂammatorycytokines,includ-inginterleukin6(IL-6),interleukin1β(IL-1β)andtumornecrosisfactorα(TNF-α)playacentralroleinsustainingand/orinﬂatingthediseaseprocess.81,82Meta-analyticstudiesonproinﬂammatorycytokineshaveshownthatIL-1,IL-6andTNF-αlevelsinperipheralbloodareincreasedinMDD.83,84C-reactiveprotein,thebest-knownmoleculeforinﬂammation,hasalsobeenshowntobeelevatedinMDDbyameta-analysis.83

Possiblemechanismsofcytokine-induceddepres-sionincludeinductionofextrahypothalamicCRF

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(a)

302520Score151050

SomatizationObsessive–compulsiveInterpersonalsensitivityAnxietyDepression*********(b)

2.5

***2.0

1.5Score1.00.50.0

Problem-solving

Positivereappraisal

Social support

Self-blame

Wishfulthinking

Escape-avoidance

Figure3.(a)Distresssymptomsbycortisolresponsepatterns.Thisgraphshowscomparisonsof5dimensionsofdistress

symptomsassessedwiththeHopkinsSymptomChecklistbetweenthethreesuppressiongroups.Black,white,andborderlinebarsareincompletesuppressors(deﬁnedas‘dexamethasone(DEX)suppressiontest(DST)-Cortisol≥5orDEX/corticotrophin-releasinghormone(CRH)-Cortisol≥5′;n=55),moderatesuppressors(deﬁnedas‘DST-Cortisol<5and1≤DEX/CRH-Cortisol<5’;n=54),andenhancedsuppressors(deﬁnedas‘DST-Cortisol<5andDEX/CRH-Cortisol<1’;n=12),respectively.*P<0.05;**P<0.01.Errorbarsrepresentstandarderrorsofthemean.AdaptedfromHorietal.74,Incompletesuppressors(n=55);□,Moderatesuppressors(n=54);,Enhancedsuppressors(n=12).(b)Copingstylebycortisolresponsepatterns.Thisgraphshowscomparisonsofscoresonthe6subscalesoftheWaysofCopingChecklistbetweenthethreesuppressiongroups.Black,white,andborderlinebarsareincompletesuppressors,moderatesuppressorsandenhancedsuppressors,respectively.*P<0.05;**P<0.01.Errorbarsrepresentstandarderrorsofthemean.AdaptedfromHorietal.74,Incompletesuppressors(n=49);□,Moderatesuppressors(n=43);,Enhancedsuppressors(n=10).

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Cortisol’s actionsGluconeogenesis ↑Fatty acid release ↑Catecholamine systems ↑Stressor ⇒ HPA axis ↑ ⇒ cortisol ↑ ⇒ high tension; hard work ⇒ successful copingUnsuccessful or burnoutTreatmentDepression of melancholic typeRecoveryChronic depressionInability tocope with stressSensitization to stressHypocortisolismEarly maltreatmentRepeated exposure to stressChronic stressFigure4.Schemaonhyper-andhypocortisolsubtypesofdepressivedisorder.HPA,hypothalamic–pituitary–adrenal.

andAVP,developmentofglucocorticoidresistance,activationofindoleamine2,3-dioxygenase(IDO),andincreasedexpressionofserotonintransporter.81,85Amongthem,theactivationofIDOhasreceivedmuchattentionasitpotentiallysynthesizestheinﬂammationhypothesis,serotoninhypothesis,andtheHPAaxisalterationsinthecauseofdepression.IDOistheﬁrstandrate-limitingenzymethatdegradestryptophanalongthekynureninepathway,therefore,activationofIDOwouldresultindecreasedplasmatryptophan.Indeed,drasticfallinplasmatryptophanlevelswasreportedinhepatitisCandcancerpatientsreceivinginterferon-α.86,87However,plasmatryptophanconcentrationinpatientswithMDDhasnotunequivocallybeenreportedtobelowerwhencomparedwithcontrols.SomestudiesfoundsigniﬁcantdecreaseinplasmatryptophanlevelsinMDDpatientscomparedwithhealthycontrols,88–90whileothersobtainedcontra-dictivenegativeresults.91,92TheseinconsistenciesarelikelytoarisefromtheheterogeneityofMDD.Nev-ertheless,wehaverecentlyperformedameta-analysisandprovidedclearevidenceforreducedplasmatryp-tophaninMDD.93Inthisstudy,theeffectsizefortheobservationbecamegreaterwhensubjectswererestrictedtodrug-freepatients,whichisinlinewithmeta-analyticstudiesdemonstratingthatanti-depressanttreatmentreducesproinﬂammatorycytokines.94,95Inaddition,antidepressants,suchascitalopram,decreaseactivityoftryptophan2,3-dioxigenase(TDO),96anotherdegradingenzymeoftryptophantokynurenine.Ofnote,TDOishighlyexpressedintheliverandactivatedbyglucocorti-coids.97IndividualswhowereadministeredDEXshowedlowerplasmatryptophanconcentrationsthanbeforeadministrationinbothpatientsandcon-trols.98ItispossiblethatincreasedenzymaticactivityofTDOduetohypercortisolismispartlyinvolvedintheobservedreductioninplasmatryptophanlevelsinMDD.

Inthebrain,IDOisexpressedinastrocytesandmicroglias;however,downstreampathwaysofkyn-urenineareknowntobedifferentdependingonthesetwocelltypes.Inastrocytes,kynurenineiscon-vertedtokynurenicacid,whichhasneuroprotectiveeffectsthroughthepropertyofantagonizingglycine

604H.Kunugietal.PsychiatryandClinicalNeurosciences2015;69:597–608

Unhealthy lifestyle(diet, exercise)Chronic inflammationCytokines ↑StressGlucocorticoid ↑Noradrenaline ↑Tryptophan ↓IDO/TDOKynurenine ↑Serotonin ↓AntidepressantsMelatoninQuinolinateKynurenateNMDA receptorExcitotoxicityAltered dopamine systemNicotinic acid (Niacin)Psychiatric symptomsFigure5.Schemasynthesizingchronicinﬂammation,stressresponse,tryptophan–kynureninepathway,andmonoamines(sero-tonin,noradrenalineanddopamine)indepression.(→)Activation.(⊣)Inhibition.IDO,indoleamine2,3-dioxygenase;NMDAreceptor,N-methyl-D-aspartatereceptor;TDO,tryptophan2,3-dioxigenase.

coagonistsiteofN-methyl-D-aspartate(NMDA)receptor.99Inmicroglialcells,incontrast,kynurenineispredominantlyconvertedtoquinolinicacidor3-hydroxykynurenine,whichhasaneurotoxiceffectthroughthepropertyasanNMDAreceptoragonist99andisthoughttobeinvolvedinthepathogenesisofdepression.Ifmicrogliaisinvolved,thencytokinesinthebrainshouldbeincreased.Inlinewiththis,wehaverecentlyfoundhigherIL-6levelsintheCSFofMDDpatientscomparedwithcontrols.100ThisﬁndingprovidessupportforneuroinﬂammationandtheroleofmicrogliainMDD.Interestingly,CSFIL-6levelswereabithigherthanplasmaIL-6levelsinthesampleandthedifferencebetweenthepatientsandcontrolswasgreaterfortheformerthanthelatter.Furthermore,therewasnosigniﬁcantcorrelationbetweenCSFandplasmaIL-6levelsinoursubjects.100CSFIL-6levelsmightbeagoodbiomarkerforneuroinﬂammatorysubtypeofMDD.Figure5illus-tratesaschemasynthesizingchronicinﬂammation,stressresponse,tryptophan–kynureninepathway,

andmonoamines(serotonin,noradrenalineanddopamine)indepression.

FUTUREDIRECTIONS

HereweproposethatCSFHVA,hyper-/hypocortisolism,andCSFcytokineandplasmatryp-tophanarepossiblebiomarkersforsubtypingMDDandrelatedconditions.Thissubtypingmayleadtothedevelopmentofnewtreatmentstrategies,suchasdopamineagonists,CRH/AVPreceptorantagonists,andanti-inﬂammatoryagents,andtheirtailor-madeuse.Futurestudiesshouldfocusontherelationbetweenthesebiomarkersandintegratethem.Anotherimportantissuetomentionistheimpor-tanceofresearchonmoleculesofcentralorigin.Inthisrespect,theuseofCSFmightbemostrealistic.Perhapsthe‘omics’approach(i.e.genomics,proteomics,metabolomics,andsoon)ontheCSFsamplewillelucidatetheinter-relationshipsbetween

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moleculesandprovideanintegratedpictureofmoleculardynamicsinthebrainofMDDpatients.

ACKNOWLEDGMENTS

ThisstudywassupportedbytheIntramuralResearchGrantforNeurologicalandPsychiatricDisordersofNCNP(24-11)andaGrant-in-AidforScientiﬁcResearch(A)(25253075)fromtheJapanSocietyforthePromotionofScience(JSPS).Allauthorsdeclarethattheyhavenoconﬂictsofinterest.

REFERENCES

1.WeissmanMM,BlandRC,CaninoGJetal.Cross-nationalepidemiologyofmajordepressionandbipolardisorder.JAMA1996;276:293–299.

2.KawakamiN,TakeshimaT,OnoYetal.Twelve-monthprevalence,severity,andtreatmentofcommonmentaldisordersincommunitiesinJapan:PreliminaryﬁndingfromtheWorldMentalHealthJapanSurvey2002–2003.PsychiatryClin.Neurosci.2005;59:441–452.

3.BertoloteJM,FleischmannA,DeLeoD,WassermanD.Psychiatricdiagnosesandsuicide:Revisitingtheevi-dence.Crisis2004;25:147–155.

4.LopezAD,MathersCD,EzzatiM,JamisonDT,MurrayCJ.Globalandregionalburdenofdiseaseandriskfactors,2001:Systematicanalysisofpopulationhealthdata.Lancet2006;367:1747–1757.

5.GillihanSJ,ParensE.Shouldweexpect‘neuralsigna-tures’forDSMdiagnoses?J.Clin.Psychiatry2011;72:1383–1389.

6.CheethamSC,CromptonMR,CzudekC,HortonRW,KatonaCL,ReynoldsGP.Serotoninconcentrationsandturnoverinbrainsofdepressedsuicides.BrainRes.1989;502:332–340.

7.CowenPJ,HarmerCJ.Isitallmonoamines?In:ParianteCM,NesseRM,NuttD,WolpertL(eds).UnderstandingDepression:ATranslationalApproach.OxfordUniversityPress,NewYork,2009;171–179.

8.BrownGL,EbertMH,GoyerPFetal.Aggression,suicide,andserotonin:RelationshipstoCSFaminemetabolites.Am.J.Psychiatry1982;139:741–746.

9.VirkkunenM,GoldmanD,NielsenDA,LinnoilaM.Lowbrainserotoninturnoverrate(lowCSF5-HIAA)andimpulsiveviolence.J.PsychiatryNeurosci.1995;20:271–275.

10.AsbergM,BertilssonL,MartenssonB,Scalia-TombaGP,

ThorenP,Traskman-BendzL.CSFmonoaminemetabo-litesinmelancholia.ActaPsychiatr.Scand.1984;69:201–219.

11.ReddyPL,KhannaS,SubhashMN,Channabasavanna

SM,RaoBS.CSFaminemetabolitesindepression.Biol.Psychiatry1992;31:112–118.

12.KasaK,OtsukiS,YamamotoM,SatoM,KurodaH,

OgawaN.Cerebrospinalﬂuidgamma-aminobutyricacidandhomovanillicacidindepressivedisorders.Biol.Psy-chiatry1982;17:877–883.

13.PeabodyCA,FaullKF,KingRJ,WhitefordHA,Barchas

JD,BergerPA.CSFaminemetabolitesanddepression.PsychiatryRes.1987;21:1–7.

14.GjerrisA,WerdelinL,RafaelsenOJ,AllingC,Christensen

NJ.CSFdopamineincreasedindepression:CSFdopa-mine,noradrenalineandtheirmetabolitesindepressedpatientsandincontrols.J.Affect.Disord.1987;13:279–286.

15.MolchanSE,LawlorBA,HillJLetal.CSFmonoamine

metabolitesandsomatostatininAlzheimer’sdiseaseandmajordepression.Biol.Psychiatry1991;29:1110–1118.

16.DeBellisMD,GeraciotiTDJr,AltemusM,KlingMA.

Cerebrospinalﬂuidmonoaminemetabolitesinﬂuoxetine-treatedpatientswithmajordepressionandinhealthyvolunteers.Biol.Psychiatry1993;33:636–641.

17.KlimekV,SchenckJE,HanH,StockmeierCA,Ordway

GA.Dopaminergicabnormalitiesinamygdaloidnucleiinmajordepression:Apostmortemstudy.Biol.Psychiatry2002;52:740–748.

18.DegrellI,NagyE.CorrelationsbetweencisternalCSFand

plasmaconcentrationsofHVA,MHPG,5-HIAA,DA,andNA.Biol.Psychiatry1990;27:1179–1182.

19.ElchisakMA,PolinskyRJ,EbertMH,PowersKJ,KopinIJ.

Contributionofplasmahomovanillicacid(HVA)tourineandcerebrospinalﬂuidHVAinthemonkeyanditspharmacokineticdisposition.LifeSci.1978;23:2339–2347.

20.MignotE,LaudeD,ElghoziJL.Kineticsofdrug-induced

changesindopamineandserotoninmetaboliteconcen-trationsintheCSFoftherat.J.Neurochem.1984;42:819–825.

21.ScheininH,ScheininM.Monoaminemetabolitelevels

inratCSF:Kineticstudies.Pharmacol.Toxicol.1987;61:167–171.

22.TandaG,CarboniE,FrauR,DiChiaraG.Increaseof

extracellulardopamineintheprefrontalcortex:Atraitofdrugswithantidepressantpotential?Psychopharmacology(Berl)1994;115:285–288.

23.RushAJ,TrivediMH,WisniewskiSRetal.Bupropion-SR,

sertraline,orvenlafaxine-XRafterfailureofSSRIsfordepression.N.Engl.J.Med.2006;354:1231–1242.24.DunlopBW,NemeroffCB.Theroleofdopamineinthe

pathophysiologyofdepression.Arch.Gen.Psychiatry2007;64:327–337.

25.KamijimaK,HiguchiT,IshigookaJetal.Aripiprazole

augmentationtoantidepressanttherapyinJapanesepatientswithmajordepressivedisorder:Arandomized,double-blind,placebo-controlledstudy(ADMIREstudy).J.Affect.Disord.2013;151:899–905.

606H.Kunugietal.PsychiatryandClinicalNeurosciences2015;69:597–608

26.WeberJ,Lyseng-WilliamsonKA,ScottLJ.Aripiprazole:In

majordepressivedisorder.CNSDrugs2008;22:807–813.

27.AikenCB.Pramipexoleinpsychiatry:Asystematicreview

oftheliterature.J.Clin.Psychiatry2007;68:1230–1236.

28.ChibaS,NumakawaT,NinomiyaM,YoonHS,Kunugi

H.Cabergoline,adopaminereceptoragonist,hasanantidepressant-likepropertyandenhancesbrain-derivedneurotrophicfactorsignaling.Psychopharmacology(Berl)2010;211:291–301.

29.HoriH,KunugiH.Theefﬁcacyofpramipexole,adopa-minereceptoragonist,asanadjunctivetreatmentintreatment-resistantdepression:Anopen-labeltrial.ScientiﬁcWorldJournal2012;2012:372474.

30.HoriH,KunugiH.Dopamineagonist-responsivedepres-sion.Psychogeriatrics2013;13:189–195.

31.SelyeHA.Syndromeproducedbydiversenocuous

agents.Nature1936;138:32–36.

32.HolsboerF.Thecorticosteroidreceptorhypothesisof

depression.Neuropsychopharmacology2000;23:477–501.33.NemeroffCB,WiderlovE,BissetteGetal.Elevatedcon-centrationsofCSFcorticotropin-releasingfactor-likeimmunoreactivityindepressedpatients.Science1984;226:1342–1344.

34.RubinRT,PhillipsJJ,SadowTF,McCrackenJT.Adrenal

glandvolumeinmajordepression.Increaseduringthedepressiveepisodeanddecreasewithsuccessfultreat-ment.Arch.Gen.Psychiatry1995;52:213–218.

35.MacMasterFP,KusumakarV.MRIstudyofthepituitary

glandinadolescentdepression.J.Psychiatr.Res.2004;38:231–236.

36.CarrollBJ,FeinbergM,GredenJFetal.Aspeciﬁclabora-torytestforthediagnosisofmelancholia.Standardiza-tion,validation,andclinicalutility.Arch.Gen.Psychiatry1981;38:15–22.

37.CarrollBJ.Thedexamethasonesuppressiontestformel-ancholia.Br.J.Psychiatry1982;140:292–304.

38.AranaGW,BaldessariniRJ,OrnsteenM.Thedexametha-sonesuppressiontestfordiagnosisandprognosisinpsy-chiatry.Commentaryandreview.Arch.Gen.Psychiatry1985;42:1193–1204.

39.BraddockL.Thedexamethasonesuppressiontest.Fact

andartefact.Br.J.Psychiatry1986;148:363–374.

40.CeulemansDL,WestenbergHG,vanPraagHM.The

effectofstressonthedexamethasonesuppressiontest.PsychiatryRes.1985;14:189–195.

41.MellsopGW,HuttonJD,DelahuntJW.Dexamethasone

suppressiontestasasimplemeasureofstress?Br.Med.J.1985;290:1804–1806.

42.HolsboerF,vonBardelebenU,WiedemannK,Müller

OA,StallaGK.Serialassessmentofcorticotropin-releasinghormoneresponseafterdexamethasoneindepression.ImplicationsforpathophysiologyofDSTnonsuppression.Biol.Psychiatry1987;22:228–234.43.HeuserI,YassouridisA,HolsboerF.Thecombined

dexamethasone/CRHtest:Areﬁnedlaboratorytestforpsychiatricdisorders.J.Psychiatr.Res.1994;28:341–356.

44.KunugiH,UrushibaraT,NankoS.CombinedDEX/CRH

testamongJapanesepatientswithmajordepression.J.Psychiatr.Res.2004;38:123–128.

45.KunugiH,IdaI,OwashiTetal.Assessmentofthe

dexamethasone/CRHtestasastate-dependentmarkerforhypothalamic-pituitary-adrenal(HPA)axisabnor-malitiesinmajordepressiveepisode:Amulticenterstudy.Neuropsychopharmacology2006;31:212–220.

46.WatsonS,GallagherP,SmithMS,FerrierIN,YoungAH.

Thedex/CRHtest:IsitbetterthantheDST?Psychoneuroendocrinology2006;31:889–894.

47.SchreiberW,LauerCJ,KrumreyK,HolsboerF,

KriegJC.Dysregulationofthehypothalamic-pituitary-adrenocorticalsysteminpanicdisorder.Neuropsycho-pharmacology1996;15:7–15.

48.RinneT,deKloetER,WoutersL,GoekoopJG,

DeRijkRH,vandenBrinkW.Hyperresponsivenessofhypothalamic-pituitary-adrenalaxistocombineddexamethasone/corticotropin-releasinghormonechal-lengeinfemaleborderlinepersonalitydisordersubjectswithahistoryofsustainedchildhoodabuse.Biol.Psy-chiatry2002;52:1102–1112.

49.WatsonS,GallagherP,RitchieJC,FerrierIN,YoungAH.

Hypothalamic-pituitary-adrenalaxisfunctioninpatientswithbipolardisorder.Br.J.Psychiatry2004;184:496–502.

50.BaghaiTC,SchuleC,ZwanzgerPetal.Evaluationofa

salivarybasedcombineddexamethasone/CRHtestinpatientswithmajordepression.Psychoneuroendocrinology2002;27:385–399.

51.HatzingerM,HemmeterUM,BaumannK,BrandS,

Holsboer-TrachslerE.ThecombinedDEX–CRHtestintreatmentcourseandlong-termoutcomeofmajordepression.J.Psychiatr.Res.2002;36:287–297.

52.HolsboerF,LieblR,HofschusterE.Repeateddexametha-sonesuppressiontestduringdepressiveillness:Normalisationoftestresultcomparedwithclinicalimprovement.J.Affect.Disord.1982;4:93–101.

53.GredenJF,GardnerR,KingD,GrunhausL,CarrollBJ,

KronfolZ.Dexamethasonesuppressiontestsinantide-pressanttreatmentofmelancholia:Theprocessofnor-malizationandtest–retestreproducibility.Arch.Gen.Psychiatry1983;40:493–500.

54.ZobelAW,YassouridisA,FrieboesRM,HolsboerF.Pre-dictionofmedium-termoutcomebycortisolresponsetothecombineddexamethasone-CRHtestinpatientswithremitteddepression.Am.J.Psychiatry1999;156:949–951.

55.AppelhofBC,HuyserJ,VerweijMetal.Glucocorticoids

andrelapseofmajordepression(dexamethasone/corticotropin-releasinghormonetestinrelationtorelapse

PsychiatryandClinicalNeurosciences2015;69:597–608Biomarkersindepression607

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

ofmajordepression).Biol.Psychiatry2006;59:696–701.

AubryJM,GervasoniN,OsiekCetal.TheDEX/CRHneuroendocrinetestandthepredictionofdepressiverelapseinremitteddepressedoutpatients.J.Psychiatr.Res.2007;41:290–294.

SchatzbergAF,RothschildAJ,BondTC,ColeJO.TheDSTinpsychoticdepression:Diagnosticandpathophysi-ologicimplications.Psychopharmacol.Bull.1984;20:362–364.

KünzelHE,BinderEB,NickelTetal.Pharmacologicalandnonpharmacologicalfactorsinﬂuencinghypothalamic-pituitary-adrenocorticalaxisreactivityinacutelydepressedpsychiatricin-patients,measuredbytheDex-CRHtest.Neuropsychopharmacology2003;28:2169–2178.KaestnerF,HettichM,PetersMetal.Differentactivationpatternsofproinﬂammatorycytokinesinmelancholicandnon-melancholicmajordepressionareassociatedwithHPAaxisactivity.J.Affect.Disord.2005;87:305–311.

WatsonS,GallagherP,Del-EstalD,HearnA,FerrierIN,YoungAH.Hypothalamic-pituitary-adrenalaxisfunctioninpatientswithchronicdepression.Psychol.Med.2002;32:1021–1028.

GervasoniN,BertschyG,OsiekCetal.Cortisolresponsestocombineddexamethasone/CRHtestinout-patientswithamajordepressiveepisode.J.Psychiatr.Res.2004;38:553–557.

VanDenEedeF,VandenBosscheB,HulstijnW,SabbeBG,CosynsP,ClaesSJ.Combineddexamethasone/CRFtestinremittedoutpatientswithrecurrentmajordepres-sivedisorder.J.Affect.Disord.2006;93:259–263.

CarpenterLL,RossNS,TyrkaAR,AndersonGM,KellyM,PriceLH.Dex/CRHtestcortisolresponseinoutpatientswithmajordepressionandmatchedhealthycontrols.Psychoneuroendocrinology2009;34:1208–1213.

RydmarkI,WahlbergK,GhatanPHetal.Neuroendo-crine,cognitiveandstructuralimagingcharacteristicsofwomenonlongtermsickleavewithjobstress-induceddepression.Biol.Psychiatry2006;60:867–873.

WahlbergK,GhatanPH,ModellSetal.Suppressedneu-roendocrinestressresponseindepressedwomenonjob-stress-relatedlong-termsickleave:Astablemarkerpotentiallysuggestiveofpreexistingvulnerability.Biol.Psychiatry2009;65:742–747.

VeenG,DerijkRH,GiltayEJ,vanVlietIM,vanPeltJ,ZitmanFG.Theinﬂuenceofpsychiatriccomorbidityonthedexamethasone/CRHtestinmajordepression.Eur.Neuropsychopharmacol.2009;19:409–415.

LevitanRD,VaccarinoFJ,BrownGM,KennedySH.Low-dosedexamethasonechallengeinwomenwithatypicalmajordepression:Pilotstudy.J.PsychiatryNeurosci.2002;27:47–51.

LamersF,VogelzangsN,MerikangasKR,deJongeP,BeekmanAT,PenninxBW.Evidenceforadifferential

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

roleofHPA-axisfunction,inﬂammationandmetabolicsyndromeinmelancholicversusatypicaldepression.Mol.Psychiatry2013;18:692–699.

YehudaR,SouthwickSM,KrystalJH,BremnerD,CharneyDS,MasonJW.Enhancedsuppressionofcorti-solfollowingdexamethasoneadministrationinposttrau-maticstressdisorder.Am.J.Psychiatry1993;150:83–86.GaabJ,HüsterD,PeisenRetal.Low-dosedexametha-sonesuppressiontestinchronicfatiguesyndromeandhealth.Psychosom.Med.2002;64:311–318.

WingenfeldK,WagnerD,SchmidtI,MeinlschmidtG,HellhammerDH,HeimC.Thelow-dosedexamethasonesuppressiontestinﬁbromyalgia.J.Psychosom.Res.2007;62:85–91.

DerogatisLR,LipmanRS,RickelsK,UhlenhuthEH,CoviL.TheHopkinsSymptomChecklist(HSCL):Aself-reportsymptominventory.Behav.Sci.1974;19:1–15.

FolkmanS,LazarusRS.Ifitchangesitmustbeaprocess:Studyofemotionandcopingduringthreestagesofacollegeexamination.J.Pers.Soc.Psychol.1985;48:150–170.

HoriH,OzekiY,TeraishiTetal.Relationshipsbetweenpsychologicaldistress,copingstyles,andHPAaxisreac-tivityinhealthyadults.J.Psychiatr.Res.2010;44:865–873.

CloningerCR,SvrakicDM,PrzybeckTR.Apsychobio-logicalmodeloftemperamentandcharacter.Arch.Gen.Psychiatry1993;50:975–990.

HoriH,TeraishiT,SasayamaDetal.Relationshipoftemperamentandcharacterwithcortisolreactivitytothecombineddexamethasone/CRHtestindepressedoutpa-tients.J.Affect.Disord.2013;147:128–136.

HoriH,TeraishiT,OtaMetal.Psychologicalcopingindepressedoutpatients:Associationwithcortisolresponsetothecombineddexamethasone/CRHtest.J.Affect.Disord.2014;152:441–447.

YehudaR,HalliganSL,GolierJA,GrossmanR,BiererLM.EffectsoftraumaexposureonthecortisolresponsetodexamethasoneadministrationinPTSDandmajordepressivedisorder.Psychoneuroendocrinology2004;29:389–404.

CarpenterLL,CarvalhoJP,TyrkaAR.Decreasedadreno-corticotropichormoneandcortisolresponsestostressinhealthyadultsreportingsigniﬁcantchildhoodmaltreat-ment.Biol.Psychiatry2007;62:1080–1087.

KunugiH,HoriH,AdachiN,NumakawaT.Interfacebetweenhypothalamic-pituitary-adrenalaxisandbrain-derivedneurotrophicfactorindepression.PsychiatryClin.Neurosci.2010;64:447–459.

MillerAH,MaleticV,RaisonCL.Inﬂammationanditsdiscontents:Theroleofcytokinesinthepathophysiologyofmajordepression.Biol.Psychiatry2009;65:732–741.DantzerR,O’ConnorJC,LawsonMA,KelleyKW.Inﬂammation-associateddepression:Fromserotonintokynurenine.Psychoneuroendocrinology2011;36:426–436.

608H.Kunugietal.PsychiatryandClinicalNeurosciences2015;69:597–608

83.HowrenMB,LamkinDM,SulsJ.Associationofdepres-sionwithC-reactiveprotein,IL-1andIL-6:Ameta-analysis.Psychosom.Med.2009;71:171–186.

84.DowlatiY,HerrmannN,SwardfagerWetal.Ameta-analysisofcytokinesinmajordepression.Biol.Psychiatry2010;67:446–457.

85.MillerAH.Mechanismsofcytokine-inducedbehavioral

changes:Psychoneuroimmunologyatthetranslationalinterface.BrainBehav.Immun.2009;23:149–158.

86.BonaccorsoS,MarinoV,PuzellaAetal.Increaseddepres-siveratingsinpatientswithhepatitisCreceivinginterferon-alpha-basedimmunotherapyarerelatedtointerferon-alpha-inducedchangesintheserotonergicsystem.J.Clin.Psychopharmacol.2002;22:86–90.

87.CapuronL,NeurauterG,MusselmanDLetal.Interferon-alpha-inducedchangesintryptophanmetabolism.Rela-tionshiptodepressionandparoxetinetreatment.Biol.Psychiatry2003;54:906–914.

88.CowenPJ,Parry-BillingsM,NewsholmeEA.Decreased

plasmatryptophanlevelsinmajordepression.J.Affect.Disord.1989;16:27–31.

89.MaesM,RiefW.Diagnosticclassiﬁcationsindepression

andsomatizationshouldincludebiomarkers,suchasdisordersinthetryptophancatabolite(TRYCAT)pathway.PsychiatryRes.2012;196:243–249.

90.XuHB,FangL,HuZCetal.Potentialclinicalutilityof

plasmaaminoacidproﬁlinginthedetectionofmajordepressivedisorder.PsychiatryRes.2012;200:1054–1057.

91.MyintAM,KimYK,VerkerkR,ScharpeS,SteinbuschH,

LeonardB.Kynureninepathwayinmajordepression:Evidenceofimpairedneuroprotection.J.Affect.Disord.2007;98:143–151.

92.SubletteME,GalfalvyHC,FuchsDetal.Plasmakynuren-inelevelsareelevatedinsuicideattempterswithmajor

93.

94.

95.

96.

97.

98.

99.

100.

depressivedisorder.BrainBehav.Immun.2011;25:1272–1278.

OgawaS,FujiiT,KogaNetal.PlasmaL-tryptophancon-centrationinmajordepressivedisorder:Newdataandmeta-analysis.J.Clin.Psychiatry2014;75:e906–e915.

HannestadJ,DellaGioiaN,BlochM.Theeffectofantide-pressantmedicationtreatmentonserumlevelsofinﬂammatorycytokines:Ameta-analysis.Neuropsycho-pharmacology2011;36:2452–2459.

HilesSA,BakerAL,deMalmancheT,AttiaJ.Interleukin-6,C-reactiveproteinandinterleukin-10afterantidepressanttreatmentinpeoplewithdepression:Ameta-analysis.Psychol.Med.2012;42:2015–2026.

AraI,BanoS.Citalopramdecreasestryptophan2,3-dioxygenaseactivityandbrain5-HTturnoverinswimstressedrats.Pharmacol.Rep.2012;64:558–566.

SalterM,PogsonCI.Theroleoftryptophan2,3-dioxygenaseinthehormonalcontroloftryptophanmetabolisminisolatedratlivercells.Effectsofglucocor-ticoidsandexperimentaldiabetes.Biochem.J.1985;229:499–504.

MaesM,JacobsMP,SuyEetal.SuppressanteffectsofdexamethasoneontheavailabilityofplasmaL-tryptophanandtyrosineinhealthycontrolsandindepressedpatients.ActaPsychiatr.Scand.1990;81:19–23.

SchwarczR,PellicciariR.Manipulationofbrainkynurenines:Glialtargets,neuronaleffects,andclinicalopportunities.J.Pharmacol.Exp.Ther.2002;303:1–10.

SasayamaD,HattoriK,WakabayashiCetal.Increasedcerebrospinalﬂuidinterleukin-6levelsinpatientswithschizophreniaandthosewithmajordepressivedisorder.J.Psychiatr.Res.2013;47:401–406.

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