[PDF] Immuno-inflammation et résistance aux traitements.

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Immuno-inflammation et résistance aux traitements. Nora HAMDANI MD-PhD Cabinet Cédiapsy nora.hamdani@cediapsy.com

FACTEURS DE RESISTANCE AUX TRAITEMENTS DANS LA DEPRESSION ET LA SCHIZOPHRÉNIEisderivedfrom non-specificeffects,which maybe largerearlierin

thecourseof illness[27]. Thedistinctionbetween primaryand secondarytreatment resistanceisonly referredtoin oneofthe consensusstatements orguidelinesrecorded inTable 1[22].Inthis context,itwould be helpfulforfuture studiesto investigateifthere aredifferences betweenpatientswith primaryversus secondarytreatment resistanceintreatment outcomesor neurobiology.Wherethis is notpossibleor warranted,clear reportingofthe relative proportionofpatients withprimary versussecondarytreatment resistancewouldhelp enablecomparisons withotherstudies. Pseudo-resistance:diagnostic andtreatment-relatedfactors Pseudo-resistancedescribesthe circumstancewherea patientÕs conditiondoesnot respondto treatment,butthe criteriafor treatmentresistancehave notbeen fulfilled;forexample, becausethediagnosis wasincorrector theexposureto treatment wasnotadequate. Diagnosticinstability,especially earlyin thecourseof amentalillness, iswelldescribed [28].For example,bipolaraffective disordermayinitially presentwitha majordepressiveepisode andbetreated asunipolardepression. If suchapatient hasapoor outcomebecauseof atreatment emergentmixedstate orworseningof selectedsymptoms(e.g., insomniaoragitation), thepatientmay bedeemedto have treatmentresistantdepression, wheninactuality thewrong treatmenthadbeen selected[29].Thisscenario highlightsthe needtoensure carefulhistoryand assessmentofpatients and cautionsagainstconcluding treatmentresistanceafter onlyashort presentation. Anothercommoncause ofpseudo-resistance isaninadequate therapeutictrialof treatment.Psychiatric drugsneedto crossthe blood-brainbarrierand bindto theirtargetin thebrain.Several factorscanlead toinsuf ficientdrugreaching thetarget inthe brain.Theseare summarisedinTable 2andFig.3(seeeTable1 for additionalevidence).They includenon-concordancewith treat- ment,poorabsorption oforal medicationatthe levelofthe gut endothelia,fastmetabolism ofmedicationby theliver,and poor blood-brain-barrierpenetranceof medication.Some treatments mayalsobe associatedwitha bell-shapeddose-responsecurve, whereincreasingdose leadstoincreasing efficacyonlyup toa point,whereuponfurther doseincreases leadtodecreasing efficacy[30];inthis scenario,high dosesoftreatment maybe responsibleforpseudo-resistance.

Theclinicalassessment oftreatment resistance

Theclinicalassessment ofpotentialtreatment resistanceis summarisedinFig. 4.Akey stepisto ruleoutpseudo-resistance asfaras possible(Table 2andFig.3).Assuch, clinicalassessment shouldruleout alternatepsychiatricdiagnoses, e.g.,featuresof autismspectrumdisorder orOCDwhich maybemistaken for schizophrenia[31,32]orbipolar-type depressionwhichmay be mistakenforunipolar depression[ 33,34].Wherepossible, durationandseverity ofsymptoms, associateddistress,and level offunctioningshould bequanti fiedusingvalidated clinicalrating scales,whichfacilitates objectiveand accuratelongitudinal assessmentoftreatment response.A comprehensivemedication historyshouldbe takento ensurethatprevious psychiatric medicationtrialswere adequate,documenting doseandduration, Table2.Potentialcontributorstopseudo-re sistanceinschizophreniaanddepressi on.

SchizophreniaDepression

Drugplasmalev elsand

adherence resistantÕshowevidenceof pooradherence [23]

Across-sectionalstudy observe dthat15% ofpatients

withMDDpresentin gwith poorclinicalresponseto tricyclicantidepressanttherapy hadÔunusuallylow plasmaconcentrationsrelative todoseÕ[119].Poor adherenceisrepor tedin10 Ð60%ofpatients with depression[24]

Geneticvariantsaffecting

trans-membrane transporters

P-glycoproteintransporterpolymor phismsinfluence

antipsychoticresponseinschizophre nia[120]

P-glycoproteintransporterpolymor phismspredict

treatmentresponsein depression[121]

Geneticvariantsaffecting

liverdrugmetabolis m

Bothfirst-generationandsecond-generation

antipsychoticsplasmalevels and/orefficacyreducedby someCYP1A2,2D6 and3A4 polymorphisms[ 122]

Ultra-rapidmetabolizer capacityrecognisedwith

polymorphismsofcertainCYP450 enzymes(e .g.,CYP2D6 andCYP2C19)result inreduced plasmalevels forsev eral antidepressants,includingTCAs ,SSRIsand SNRIs,and influenceclinicalresponse [123]

Liverdrugmetabolis m:

influenceofco-prescribe d psychiatricmedication Co-prescriptionofpsychiatricmedications thatact as CYP450inducers(e .g., lamotrigineandcarbamazepine) canreduceplasma levels ofsomeantipsych otics[124] Co-prescriptionofpsychiatricmedications thatact as CYP450inducers(e .g., lamotrigine,carbamazepine)can reduceplasmalevel sof someantidepressants,including

TCAs,SSRIsandbupropion[ 125]

Liverdrugmetabolis m:

influenceofco-prescribe d physicalhealthmedication

Co-prescriptionofmedicationsthat actas CYP450

inducers(e.g., omeprazole,phenytoin,St JohnÕswort, rifampicin)canreduce plasmalevels ofsome antipsychotics[122]

Co-prescriptionofmedicationsthat actas CYP450

inducers(e.g., StJohnÕswort, phenytoin)mayreduce plasmalevels ofsomeantidepressants[126] TobaccosmokingSmokingreduces plasmaleve lsofthoseantipsychotics metabolisedviaCYP1A2 (e.g.,olanzapine ,clozapine) [127]

Smokingreducesplasmaconcentrations ofv arious

antidepressants[128]

SexMalegender predictslowerplasma levels ofsome

antipsychotics[129]

Malegenderpredicts lowerplasmaleve lsof some

antidepressants[130] AlternativeDiagnosisSymptomsof otherdisorders, suchasbipolar affective disorder,obsessivecompulsive disorderorautism spectrumdisorder, maybemistakenforschizophre nia [31,32] Aminorityof apparentlyresistant unipolardepression mayinfac tbe depressionassociatedwithbipolar disorder[33,34]

Furtherevidenceisp rovidedineTable1.

TCAtricyclicanti-depressant,SSRIselectiveserotoninreuptak einhibitor,SNRIserotoninandnorepinephrine reuptakeinhibitor.

O.D.Howeset al.

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andassociatedresponse. Finally,currenttreatment shouldbe defined,andplasma levelsmeasured wherepossible.This process shouldallowthe assessmentof keyfactorsrequisite for determiningtreatmentresistance summarisedin Fig.4.

Epidemiologyandimpact oftreatment resistance

Prevalenceestimatesof TRS,TRDand treatmentresistantOCD varyfrom20 to60%of thepopulationwith thecondition[ 26,35Ð

40].Wewere unabletoidentify prevalencedatafor treatment

resistantbipolaraffective disorder(whetherdepression ormania) orPTSD.Differences inthede finitionsofresistance between studies,asdiscussed above,are certaintosubstantially determine thisvariation.Another importantfactor isthepopulation from whichprevalenceestimates arecalculated, whichcanlead to ascertainmentbiases.For example,studies examininghospital populationswithchronic illnessare likelytorecord higherratesof treatmentresistancecompared withstudiesexamining outpatient samplesmadeof patientsat theonsetof illness. IntheUSA, annualdirect medicalcostsassociated withTRSare conservativelyestimated atover$34 billion[41].Ithas been estimatedthathospitalisation costsand totalhealthresource utilisationsforTRS are10-fold higherthanthose fornon-TRS,and thatupto 80%of thetotalyearly healthcostsassociated with schizophreniainthe USAareattributed toTRS[ 41].Directmedical costsassociatedwith TRDare estimatedtobe 2Ð6timeshigher comparedwithother patientswithMDD [42,43],withcosts increasingwithchronicity andseverity ofTRD[ 44].Patientswith TRDaretwice aslikely tobehospitalised comparedwithnon-TRD patients,andrequire increasednumbers ofpsychiatricoutpatient visits[43].Patientswith TRShavemore functionalimpairmentin thecommunitycompared withotherserious mentalillnesses[ 45], andthemean qualityof lifeisestimated tobe20% lowerinTRS comparedwithnon-TRS [41].Meanquality oflife isapproximately

25Ð40%lowerin patientswith TRDcomparedwith patientswho

respondtotreatment orwho areinremission [46],and30% of

TRDpatientsattempt suicidein theirlifetime[ 47].

Theneurobiologyof treatmentresistance

Therearethree broaddisease modelsproposedby theliterature toexplaintreatment resistance,summarised inFig.5(see eAppendix3for searchdetails) [48Ð51].Thefirstpossibility (Fig.5A)isthat thetreatmentresistant formofa givenpsychiatric illnesshasthe sameunderlyingneurobiology asthetreatment responsiveillness,but thepathophysiologicalalterations aremore severesuchthat standardtreatmentis inadequate.Thisis partly supportedbyevidence thatresistantsymptoms ofdepressionand schizophreniamayimprove withhigherdoses oftreatmentin somepatients[ 52Ð54].Furthermore,as discussedabove, second- arytreatmentresistance maybea consequenceofeither progressiveneurobiologicalchanges (pathoplasty)oriatrogenic effects.Forexample, inschizophrenia, anupregulationin dopamineD2/3receptor levelswith treatmentcouldmean that agivenantipsychotic doseis nolongerenough toblock dopaminergicneurotransmissionadequately, leadingto break- throughresistantsymptoms andnecessitatinghigher doses[48]. Alternatively,treatment resistancecouldbe neurobiologically distinctfromtreatment responsiveillness(Fig. 5B).Supporting this,insome individuals,their illnessshowslittle ornobene fit fromadequatetreatment fromillness onsetdespiteevidence of hightargetengagement [55,56],andthere issomeevidence of neurobiologicaldifferences betweenpatientswith TRSorTRD [57Ð59].Forexample, studiesusing protonmagneticresonance spectroscopyhaveobserved thatlevels ofglutamatergicmeta- bolitesareparticularly elevatedin theanteriorcingulate cortexin TRScomparedto levelsin patients,whorespond toantipsychotic treatmentandhealthy controlsand geneticandpost-mortem studiesalsoimplicate glutamatergicpathways inTRS[ 60Ð62].It shouldalsobe recognisedthat secondarytreatmentresistance maytheoreticallybe aconsequence ofiatrogenic-changein neurotransmittersystemsother thanthoseprimarily targetedby drugs,owingto off-targetreceptoractions. Thethirdpossibility (Fig.5C)isa hybridmodelwhere patients showacombination ofboth thesamepathophysiology as responsiveillnessand additionalneurobiological alterations meaningthatstandard treatmentisinadequate. Oneexampleis thatofimmune dysregulation.Converginglines ofgenetic,post- mortem,andpre-clinical evidencesuggestimmune dysregulation mayplaya rolein thepathogenesisof bothschizophrenia[ 63Ð67] anddepression[ 68,69],andit ishypothesisedthat immune alterationsareseen onlyin aproportionof thesepatients (immune/inflammatorysubgroups)and arelinked topoor treatmentresponse[ 67,70Ð72].Forexample, indepression, levels ofC-reactiveprotein (CRP)arehigher inTRDcompared withthose whorespondto antidepressanttreatment [73].Furthermore,some [74],butnot all[75],clinicaltrials examiningimmunotherapy in depressionhaveobserved efficacyonlyin patientswithperipheral inflammation.Immunedysregulation hasbeen implicatedin dysregulationofmultiple neurotransmittersystems[ 76Ð78]that someantipsychoticand antidepressantagents maynottherapeu- ticallytarget.Thus, withoutspeci ficallytargetingimmune dysregulationalongsideconventional therapy,symptoms will persist.Thishighlights theneedto betterunderstandthe neurobiologyoftreatment resistancetohelp guidetreatment design.Furthermore,it introducesthe possibilitythatdrugs previouslydeemedineffective ona group-levelmayyet provide benefittosubgroups ofpatients.

Therapeuticapproachesto treatmentresistance

Foradrug tobeconsidered inthemanagement oftreatment resistantpsychiatricillness, itsefficacyandspeci ficityforuse in treatmentresistancemust bedemonstrated. Althoughstudies thattestdrugs againstplacebo(or withno treatment)controlfor Fig.3Pseudo-resistanceto treatmentinpsychiatry: treatment relatedfactors.A Poorconcordancewithmedicationor forgetful- nessmayresult ininsufficientdrugbeing takentoachieve a gutendotheliamay resultinpoor absorptionofdrugs and insufficientdrugexposure. CSmokingtobaccoinducesexpression ofCYP450enz ymes,par ticularlyCYP1A2,intheliver( D)resultingin enhancedbreakdown ofpsychiatricmedication metabolisedby theseenzymes. PolymorphismsinCYP450enz ymesthatenhance theiractivity orco-administrationofotherpsychiatric/non-psychia- tricmedicationsthat act asenzyme inducerswillhaveasimilar effect.EPoorbrainaccumulationofdrug owingto poorbloodbrain barrierpermeabilityand/or polymorphismsin P-glycoproteinmay resultininsuf ficientcentralner voussystem druglevelstoachievea therapeuticresponse.

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MolecularPsychiatry

thescenariowhere symptomsimprovewith time,theydo not controlforthe factthatlonger treatmentdurationwith anexisting medicationmaylead toresponse. Thus,todemonstrate efficacy, theagentshould demonstratesuperiorityover activecompara- tors.Pharmacotherapystrategies fortreatmentresistance canbe dividedintotwo groups:monotherapiesand adjunctivestrategies. Todate,the onlydrugthat hasbeenlicensed asmonotherapy foratreatment resistantconditionin psychiatryisclozapine for TRS,whichgained regulatoryapprovalon thebasisof twostudies [12,79].Althoughclozapine isa dopamineantagonist,relative to otherantipsychoticsit exhibitslow D2dopaminereceptor occupancy[80],suggestingthat diseasemodel1 isunlikelyand modulationofother neurotransmittersystems mayplaya therapeuticrole[ 81].Thisis mostinkeeping withdiseasemodel

2oftreatment resistancedescribedabove (Fig.5B),althoughit

shouldberecognised thatthisneeds testingandthe modeof actionofclozapine forTRSremains unclear. Twoadjuncti vestrategiesfortreatmentre sistancehavebeen approved,bothforTRD.Esketa mineincombin ationwithan ti- depressanttherapyhasrec entlyreceivedapprovalinbothth eUS andEurope[ 82].Eske tamineblockstheNMDAreceptorch annel, andtherei sevidencethatitin ducesplas ticchangesatglutamate synapsestoimproveconnec tivity[83],and mayalsoaffe ctother neurotransmitters[84].The novelmechan ismofactionande fficacy ofeske tamineasanadjuncttoconventiona lanti depre ssants diseasemodel3(Fig. 5C).IntheUS ,olan zapinecombin edwith fluoxetineisalicensedthe rapyforTR D.FDA approvalwasbasedon datafromstudies thatexamin edtheolanzapine/fluoxetine combinationcomparedwitholanzapine orfluoxetinemonotherapy [85Ð87].Thes estudieswere8- weeksinduration,and definedTRD asdepr essionmeetingDSM-IVcriteriawith persistenceof symptomsdespiteatleas ttwodifferentantide press anttrials, includingaprospectivecourse offluoxetinemonotherapy. Inall trials,depressivesymp tomsofpatientswhometcrit eriafor treatmentresistanceimprovedsign ificantlymorewhen treated withtheolan zapine/fluoxetinecombinationve rsusolanzapineor fluoxetinemonotherapy.Ther eisalsoevidencethatadjunctive aripiprazolealongsideantidepressant therapyiseffectiveinpeople withMDDand inadequate responsetoan tidepressantmonother- apy[88];fur thermore,themagnitudeofsymptomaticim provement withadjuncti vetherapywasobservedto begreaterinthosewith onlyminimal responsetoantidepress antmonotherapycompare d tothosewi thpartialrespon se[88].The superiore fficacyof combinationtherapypointstowards patientswithTRDpresentin g withacombin atio nofthesameneurochemicalabnormalit yse enin first-linetreatmentresponde rswithanadditionalneuroch emical dysfunction,whichismostinkeepingwi thdiseasemode l3of treatmentresistancedetailedab ove(Fig.5C). Asmentionedabove, thereisalso someevidencethat high dosesofcertain antidepressants(e.g.,venlafaxine) [53,89]or antipsychotics(e.g.,olanzapine) [52]canbe effectivestrategiesin themanagementof treatmentresistantdepression andschizo- phreniarespectively.In thecase ofvenlafaxine,there isevidence thatincreasingthe dosebeyond 150mg/dayresults inagreater effectonnoradrenergic neurotransmission[ 90].Thisapproach is mostinkeeping withdisease model1of treatmentresistance detailedabove(Fig. 5A),althoughit shouldberecognised that,at higherdoses,drug actionsat otherreceptorsmay becomemore important. Intermsof neuro-stimulatorytreatments,the FDAhasapproved useoftranscranial magneticstimulationin thetreatmentof MDD inpatientswho havefailedto achieveÔsatisfactoryimprovement fromoneprior antidepressantmedicationÕ[91].However,it is unclearifsuch ade finitionreliablydescribes truetreatment resistance(seeÔCurrentdefinitionsoftreatment resistanceacross disordersÕsectionabove),and theFDA warnsthatef ficacyof transcranialmagneticstimulation hasnotbeen establishedin patientswithÔvaryingdegreesof medicationresistance Õ.Electro- convulsivetherapy(ECT) haswidespreadregulatory approvalfor treatmentresistantdepression andmania.The mechanismby whichECTeffects responsewhere medicationhasbeen unsuc- cessfulremainspoorly defined,butmay stemfrom alterationsin cerebralbloodflowandregional metabolism[ 92].Thisnovel mechanismofaction isinkeeping withdiseasemodel 2of treatmentresistancedetailed above(Fig.5B).

Newtreatmentdirections

Toidentifynew treatmentsin thepipeline,we searchedquotesdbs_dbs50.pdfusesText_50

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