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ExpectationandDopamineReleaseMechanismofthePlaceboEffectinParkinsonsld


NeurodegenerativeDisordersCentreTRIUMFUni-versityofBritishColumbiaVancouverBCCanadaV6T2B5TowhomcorrespondenceshouldbeaddressedE-mailjstoesslinterchangeubccaTable1StriatalRACbindingpotentialmeanSDofPDp

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ExpectationandDopamineReleaseMechanismofthePlaceboEffectinParkinsonsld
ExpectationandDopamineReleaseMechanismofthePlaceboEffectinParkinsonsld

NeurodegenerativeDisordersCentreTRIUMFUni-versityofBritishColumbiaVancouverBCCanadaV6T2B5TowhomcorrespondenceshouldbeaddressedE-mailjstoesslinterchangeubccaTable1StriatalRACbindingpotentialmeanSDofPDp

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Document on Subject : "ExpectationandDopamineReleaseMechanismofthePlaceboEffectinParkinsonsld"— Transcript:

1 ExpectationandDopamineRelease:Mechanismo
ExpectationandDopamineRelease:MechanismofthePlaceboEffectinParkinsonÕs«ldelaFuente-Ferna«ndez,ThomasJ.Ruth,VesnaSossi,MichaelSchulzer,DonaldB.Calne,A.JonStoesslThepowerofplaceboshaslongbeenrecognizedforimprovingnumerousmedicalconditionssuchasParkinsonÕsdisease(PD).Littleisknown,however,aboutthemechanismunderlyingtheplaceboeffect.Usingtheabilityofen-dogenousdopaminetocompetefor[C]raclopridebindingasmeasuredbypositronemissiontomography,weprovideinvivoevidenceforsubstantialreleaseofendogenousdopamineinthestriatumofPDpatientsinresponsetoplacebo.OurÞndingsindicatethattheplaceboeffectinPDispowerfulandismediatedthroughactivationofthedamagednigrostriataldopaminesystem.Thesimpleactofreceivinganytreatment(activeornot)may,initself,beefficaciousbecauseofexpectationofbenefit().ThisistheplaceboeffectÐapotentialconfounderinassessingtheefficacyofanytherapeuticin-tervention(2,3).Placebo-controlledstudiesweredesignedpreciselytocontrolforsuchaneffect().Ithasbeenassumedthatthepla-ceboresponseisnotmediateddirectlythroughanyphysicalorchemicaleffectoftreatment().InParkinson'sdisease(PD),theplaceboeffectcanbeprominent(6,7WeaskedwhethertheplaceboeffectinPDisproducedbyactivationofthepathwayprimarilydamagedbydegeneration[i.e.,thenigrostriataldopaminergicsystem(8,9)].Toanswerthisquestion,wetookadvantageoftheabilityofpositronemissiontomography(PET)toestimatepharmacologicallyorbe-haviorallyinduceddopaminereleasebasedonthecompetitionbetweenendogenousdo-pamineand[C]raclopride(RAC)forbind-ingtodopamineDreceptors(Wehypothesizedthatiftheplaceboeffectismediatedthroughtheactivationofthepath-wayrelevanttothedisorderunderstudy,weshouldbeabletodetectplacebo-inducedre-leaseofendogenousdopamineinPD.WeexaminedthestriatalRACbindingpotentialofsixpatientswithPD(group1,placebogroup)undertwoconditions(Condition1,aplacebo-controlled,blindedstudyinwhichthepatientsdidnotknowwhentheywerereceivingplacebooractivedrug(apomorphine)()Ðallpatientsre-ceivedbothplaceboandactivedrug;andcondition2,anopenstudyinthesamepa-tientswithoutplacebo.WefoundasignificantdecreaseinstriatalRACbindingpotential[17%forthecaudatenucleus(range,8to25%);19%fortheputa-men(range,8to28%);0.005forboth,two-tailedpairedtest]whenthepatientsreceivedplacebocomparedwithopenbase-lineobservations(Table1).Thisplacebo-inducedchangeinRACbindingpotentialwaspresentineachpatientandineachstri-atalsubregion,althoughitwasgreatestintheposterolateralpartoftheputamen(Table1).Themagnitudeoftheplaceboresponsewascomparabletothatoftherapeuticdosesoflevodopa(),orapomorphine(seebelow)).TherewerenodifferencesinthestriatalRACbindingpotentialbetweenthisgroupofpatientswhenstudiedwithoutplaceboandasecondgroupofpatientsmatchedbyageandseverityofparkinsonismstudiedexclusivelyinanopenfashion(group2,opengroup)((Fig.1).Theseobservationsindicatethatthereisplacebo-inducedreleaseofendogenousdopa-mineinthestriatum().Theestimatedre-leaseofdopaminewasgreaterinpatientswhoperceivedplacebobenefitthaninthosewhodidnot().Thissuggestsaªdose-dependentºrelationbetweenthereleaseofendogenousdopamineandthemagnitudeoftheplaceboeffect.Wenextaskedwhethertheremightbeaninteractionbetweentheeffectsoftheplaceboandtheactivedrug().Theplacebore-sponsecouldsynergisticallyenhancetheben-efitofanactivedrug,inwhichcasedouble-blind,placebo-controlledstudieswouldover-estimatetheactivedrugeffect.Alternatively,theplaceboeffectcouldmask(ordecrease)thespecificeffectofanactivedrug,whichwouldleadtotheoppositeconclusionintheinterpretationofaplacebo-controlledstudy.Afteradjustingfordifferencesinªbase-lineºRACbindingpotential,wefoundnosignificantdifferencesintheresponsetoapo-morphinebetweentheopengroupandtheplacebogroup(combiningpatientswhoper-ceivedaplaceboeffectandthosewhodidnot)().However,thedegreeofapomor-phine-inducedchangeinRACbindingpoten-tialtendedtobelowerinpatientswhoper-ceivedaplaceboeffectcomparedwiththosewhodidnotandwithpatientsstudiedinanopenfashion(Fig.2).Weexploredwhetherthisobservationcouldreflectaflooreffectintheplacebogroup(i.e.,whetherthetechniquewasinsensitiveforfurtherreductionsinRACbinding),butthisdidnotappeartobethecase(Fig.3)().Weconcludethattheplaceboresponsedoesnotpotentiatetheeffectofanactivedrug.Indeed,ourresultssuggestthatinsomepatients,mostofthebenefitobtainedfromanactivedrugmightderivefromaplaceboeffect.Thedopaminergicsystemisinvolvedintheregulationofseveralcognitive,behavior-al,andsensorimotorfunctions,andparticu-larlyinrewardmechanisms().Howev-er,ourexperimentsdidnotinvolveadirectreward.Weconcludethatdopaminereleaseinthenigrostriatalsystemislinkedtoexpec-tationofarewardÐinthiscase,theanticipa-tionoftherapeuticbenefit(29,30).Allpa-tientswerefamiliarwiththeeffectofanactivedrug(levodopa),andsuchpreviousexperiencemayhaveenhancedtheirexpec-tation.Wefoundthatthelevelofexpectationmaydetermineexperience()Ðpatientswhoperceivedaplaceboeffecthadhigherreleaseofdopaminethanthosewhodidnot.OurobservationsindicatethattheplaceboeffectinPDismediatedbyanincreaseinthe NeurodegenerativeDisordersCentre,TRIUMF,Uni-versityofBritishColumbia,Vancouver,BC,CanadaV6T2B5.*Towhomcorrespondenceshouldbeaddressed.E-mail:jstoessl@interchange.ubc.caTable1.StriatalRACbindingpotential(meanSD)ofPDpatients(group1)scannedatopenbaseli

2 neandafterreceivingplacebo( SiteOpenbase
neandafterreceivingplacebo( SiteOpenbaselinePlaceboMeanpercentchangeHeadofcaudate1.9640.2211.6380.23016.6(8.4Ð25.1)Rostral2.3980.3421.9760.32117.6(5.3Ð26.3)Intermediate2.6210.4382.1420.38918.2(7.4Ð27.0)Caudal2.0950.2691.6460.26121.2(8.8Ð32.6)10AUGUST2001VOL293SCIENCEwww.sciencemag.org synapticlevelsofdopamineinthestriatum.Expectation-relateddopaminereleasemightbeacommonphenomenoninanymedicalconditionsusceptibletotheplaceboeffect.PDpatientsreceivinganactivedruginthecontextofaplacebo-controlledstudybenefitfromtheactivedrugbeingtestedaswellasfromtheplaceboeffect.Bycontrast,intheusualclinicalpracticesetting,activedrugsmaybedevoidofplaceboeffect.Wefoundnoevidencetosuggestthattheplaceboeffectsynergisticallyaugmentstheactionofactivedrugs(infact,atrendfortheoppositewasobserved),sopositiveconclusionsderivedfromplacebo-controlledstudiesarenotim-pugnedbyourfindings.ReferencesandNotes1.D.G.Altman,PracticalStatisticsforMedicalResearch(Chapman&Hall,London,1991),pp.450Ð451.2.H.K.Beecher,JAMA(J.Am.Med.Assoc,16023.E.Ernst,K.L.Resch,Br.Med.J.,551(1995).4.T.J.Kaptchuk,,1722(1998).5.L.D.Fisher,G.vanBelle,Biostatistics:AMethodologyfortheHealthSciences(Wiley,NewYork,1993),p.6.N.ShettyetalClin.Neuropharmacol.,2077.C.G.Goetz,S.Leurgans,R.Raman,G.T.Stebbins,,710(2000).8.J.M.Fearnley,A.J.Lees,,2283(1991).9.S.J.Kish,K.S.Shannak,O.Hornykiewicz,N.Engl.J.Med.,876(1988).10.P.Seeman,H.C.Guan,H.B.Niznik,,9611.N.D.Volkowetal,255(1994).12.M.J.Koeppetal.,266(1998).13.A.J.Stoessl,T.J.Ruth,NeuroScienceNews,5314.M.Laruelle,J.Cereb.BloodFlowMetab.,42315.AllPETscanswereperformedinthree-dimensional(3D)modeusinganECAT953B/31tomograph.Weobtained16sequentialframesover60minutes,startingatthetimeofinjectionof5mCiof[clopride(meanSEMspeciÞcactivity349Ci/mmolatligandinjection).Atime-integratedimagewith31planes,each3.37mmthick,wasmadefromtheemissiondata(from30to60minutes)foreachsubject.TheÞveaxialplanesinwhichthestriatumwasbestvisualizedweresummed.Onthistime-andspatiallysummedimage,onecircularre-gionofinterest(ROI)of61.2mmwaspositionedontheheadofeachcaudatenucleus(Caud),andthreecircularROIsofthesamesizewereplacedwithoutoverlapalongtheaxisofeachputamen(fromrostraltocaudalputamen:P1,P2,andP3);ROIpositionwasadjustedtomaximizetheaverageradioactivity.TheROIswerereplicatedonthespatiallysummedimageofeachtimeframe.ThebackgroundactivitywasaveragedfromasingleellipticalROI(2107mmdrawnoverthecerebellumonthesummedimageoftwocontiguousaxialplanes.Thebindingpotential,whereNSisthefreefractionoftracer)wasdeterminedusingatissueinputgraphicalapproach[J.LoganetalJ.Cereb.BloodFlowMetab.,834(1996)].FurtherdetailsofthePETscanprotocolarereportedelsewhere().WestudiedtwogroupsofPDpatients,ofsixpatientseach,undertwodifferentprotocolsasdescribedbelow.BothgroupswerematchedbyageandseverityofparkinsonismasmeasuredbytheModiÞedColumbiaScale(MCS)[R.C.Duvoisin,inMonoaminesnoyauxgriscentrauxetsyndromedeParkinson,J.deAjuriaguerra,G.Gau-thier,Eds.(GeorgandCieSA,Geneva,1971),pp.313Ð325].ClinicaldetailscanbefoundonOnlineatwww.sciencemag.org/cgi/content/full/293/5532/1164/DC1.Afterbeingpretreatedwithdomp-eridonefor48hourstopreventsideeffects,allpatientsunderwentthreeconsecutiveRACPETscansonthesamedayaccordingtothefollowingprotocol:(i)eitherbaselineorplaceboscan12to18hoursafterwithdrawalofmedications;(ii)aftersubcutane-ousinjectionof0.03mgofapomorphineperkilo-gramofbodyweight;and(iii)aftersubcutaneousinjectionof0.06mg/kgofapomorphine.Thetreat-mentorderwasmaintainedconstantforallpatients.Group1(theplacebogroup)wasstudiedinablindfashionÑpatientsdidnotknowwhentheywerereceivingplacebo(subcutaneousinjectionofsaline)orapomorphine(allpatientsreceivedallthreetreat-ments).Thisgroupalsoreceivedafourthinjection,consistingof0.12mg/kgofapomorphineonthesameday,toexplorethepossibilityofaßooreffect Fig.1.Placebo-inducedchangesinRACbindingpotentialinthestriatumipsilateral()andcontralateral()tothemoreaffectedbodysideofpatientswithPD.TheROIsareontheheadofthecaudatenucleus(Caud)andontheputamen,fromrostraltocaudal,P1,P2,P3(Comparisonsweremadebetweenthegroupofpatientsstudiedinanopenfashion(group2,opengroup;openbars)andthegroupofpatientsstudiedbothwith(solidbars)andwithout(hatchedbars)placebointervention(group1,placebogroup).Within-subjectplacebo-inducedchangesinRACbindingpotentialtendedtobegreaterinthestriatumcontralateraltothemoreaffectedbodyside(20%)thanintheipsilateralstriatum(17%).Theplacebogroupandtheopengroupdidnotdifferintheirbaselineplacebo-freeRACbindingpotentialvalues[forthecaudatenucleus,1.960.22(SD)versus2.070.40,respectively;two-tailedÐ0.55(df0.59;fortheputamen,2.370.34versus2.42Ð0.20(df0.84].Errorbars,SEM. Fig.2.Apomorphine-inducedchangesinRACbindingpotentialinthecaudatenucleus()andputamen()before(APO_0)andafter(APO_10.03mg/kg,andAPO_20.06mg/kg)subcutaneousinjectionofapomorphine.Patientsstudiedinanopenfashion(openbars)hadhigherRACbindingpotentialvaluesthanthoseincludedintheplacebogroup[independentlyofwhethertheydidnot(hatchedbars)ordid(solidbars)perceiveaplaceboeffect].ThedeclineinRACbindingpotentialinducedbyanincrementaldoseofapomorphinetendedtobelesspronouncedinpatientswhoperceivedaplaceboeffectascomparedwiththosewhodidnot,andwithpatientsstudiedinanopenfashion:

3 interactionterm(groupapomorphinedose)eva
interactionterm(groupapomorphinedose)evaluatedbyrepeatedmeasures4.66(df2,9),0.041forthecaudatenucleus;3.40(df2,9),fortheputamen.Errorbars,SEM. Fig.3.Linearregressionplotsforpatientswithout(3;opensymbols,thinlines)andwith(3;solidsymbols,thicklines)perceivedplaceboeffect:()caudateand()putamenRACbindingpotentialvaluesagainstapomorphinedose(APO_dose).ThefourslopesweresigniÞcantlydifferentfromzero(0.01),buttheydidnotdiffersigniÞcantlybetweenpatientswithandwithoutperceivedplaceboeffect(forthecaudatenucleus,Ð3.2versusÐ5.1,respectively,0.28;fortheputamen,Ð3.8versusÐ6.5,www.sciencemag.orgSCIENCEVOL29310AUGUST2001 (seebelow).Group2(opengroup)wasstudiedinanopenfashionforcomparisonpurposes(e.g.,toinvesti-gatetheeffectofnoveltyondopaminerelease).Here,recipientswerescannedunderallthreeconditionsbutknewexplicitlyiftheywerereceivingnomedicationorwhichdoseofapomorphinetheywerereceivingatanygiventime.Theadvantagesofthisdesignarethreefold:(i)Itminimizespotentialcarry-overeffectsfromtheactivedrug(apomorphine)().(ii)Ithelpsmaintainthelevelofexpectationthroughoutthestudy,whichiscrucialtothisexperiment.Forexample,theoccurrenceofapomorphine-inducedsideeffectscouldÒunblindÓthestudy.(iii)Itmaximizesthetolerabilityofthepro-cedure.Intotal,therewasa2.5-hourintervalbetweenscans(1-hourscanplus1.5-hourbreak),sufÞcienttoallowfordecayofradioactivity,aswellasfordopaminereceptorrecoveryafterapomorphineinjection(16,17Anadditionalopenbaselinescanwasperformedongroup1patientsonadifferentdaytoobtainplacebo-freebaselinevalues(intervalbetweenbothsetsofscans,1to4months).Allpatientshadbeencontacted1monthbeforethescans,anddetailsoftheprotocolinwhichtheywereincludedwereexplained;theywereremindedofthesedetails3daysbeforethescans.Weavoidedanticipationbias(e.g.,patientsÕknowledgeofthefactthattheplaceboeffectcandeterminemeasur-ablechangesindopaminereleasemightalterthere-sults)bykeepingthepatientsandtheclinicalstaffunawareofthepurposeofthestudy.Inallcases,carewastakentooptimizepatientpositioninginthescan-ner.Motionwithinandbetweenscanswasminimizedbytheuseofamoldedthermoplasticmask.Allsubjectsgavewritteninformedconsent.ThestudywasapprovedbytheU.B.C.ethicscommittee.16.S.T.Gancher,W.R.Woodward,B.Boucher,J.G.Nutt,Ann.Neurol.,232(1989).17.R.delaFuente-Ferna«ndezetalAnn.Neurol.,29818.Theplacebo-inducedchangeinstriatalRACbindingpotentialismuchhigherthanthereportedwithinsubjectscan-rescanvariationexpectedtooccurwith-insubjectforscanandrescan(mean,5%)[N.D.etalJ.Nucl.Med.,609(1993)].Theadministrationof0.03and0.06mg/kgofapomor-phineledtoa14%and26%decrease,respectively,inputamenRACbindingpotentialintheopengroup(seeFig.2).19.Theincreasingrostrocaudalgradientoftheplaceboeffect(Table1)eliminatesthepossibilitythattheresultscouldbeduetodown-regulationofpresyn-apticDreceptors.PartialvolumeeffectscannotexplainthegradientinBPopenbaselineÐBPportedhere.Otherconsiderationssupportingourin-terpretationoftheresultscanbefoundelsewhere20.BecausetheclinicalbeneÞtfromapomorphinelaststypicallyabout1hour(whichisthedurationofRACPETscans,noobjectivemeasurementsonchangesintheclinicalstatusafterplaceboorapo-morphineinjectionweremade(motoractivitymightconfoundtheassessmentofchangesinstriatalRACbindingpotential).However,onlyhalfofthepatientsreportedplacebo-inducedclinicalimprovement(comparableinmagnitudetotheclinicalbeneÞtob-tainedwhentheywereontheirregulartreatmentwithlevodopa).Althoughthenumberofsubjectsissmall,thosepatientswhoperceivedtheplaceboef-fect(3)hadhigherchangesinRACbindingpotentialthanthosewhodidnot(3)[forthecaudatenucleus,22%versus12%;fortheputamen,24%versus14%;0.05and0.01,respective-ly,byanalysisofcovariance(ANCOVA)](Fig.2).21.J.Kleijnen,A.J.M.deCraen,J.vanEverdingen,L.Krol,,1347(1994).22.RepeatedmeasuresANCOVAgavethefollowingre-sults:Forthecaudatenucleus,between-groupdiffer-0.03(df1,9),0.87;interactionterm(groupapomorphinedose),0.09(df0.77.Fortheputamen,between-group0.71(df1,9),0.42;interaction1.81(df1,10),0.21.ThepowerfortheinteractiontermsmaynothavebeensufÞcient.23.Anapomorphinedoseof0.12mg/kgledtoafurtherdecreaseinRACbindingpotentialintheplacebogroup(Fig.3).ThetotalreductioninRACbindingpotential(comparedwithplacebo-freebaselineval-ues)was42%inthecaudatenucleus(range,19to59%)and46%intheputamen(range,24to60%).24.R.A.Wise,TrendsNeurosci.,91(1980).25.H.C.Fibiger,A.G.Phillips,inHandbookofPhysiology:TheNervousSystem,vol.4,IntrinsicSystemsofthe,V.B.Mountcastle,F.E.Bloom,S.R.Geiger,Eds.(AmericanPhysiologicalSociety,Bethesda,MD,1986),pp.647Ð675.26.T.W.Robbins,B.J.Everitt,Semin.Neurosci.,11927.W.Schultz,J.Neurophysiol.,1(1998).28.S.Ikemoto,J.Panksepp,BrainRes.BrainRes.Rev.6(1999).29.I.Kirsch,Ed.,HowExpectanciesShapeExperience(AmericanPsychologicalAssociation,Washington,DC,1999).30.J.M.Fish,,914(1999).31.WethankJ.McKenzie,S.Jivan,J.Leighton,T.Dobko,andmembersoftheUBC-TRIUMFPETteamforassistancewiththescans.ThisstudywasfundedbytheCanadianInstitutesofHealthResearch,theBrit-ishColumbiaHealthResearchFoundation(R.F.-F.andV.S.),thePaciÞcParkinsonÕsResearchInstitute(Van-couver,B.C.,Canada)(R.F.-F.),andaTRIUMFLifeSciencegrant.A.J.S.issupportedbytheCanadaRe-searchChairsprogram.22March2001;accepted5June2001 10AUGUST2001VOL293SCIENCEwww.sciencemag.or