E-COMPARED - Final Report - publishable summary

FinalReport

SeventhFrameworkProgramme-Health

EuropeanComparativeEffectivenessResearchon

Internet-basedDepressionTreatment

GrantAgreementno. 603098-2

Projectacronym E-COMPARED

Projecttitle EuropeanComparativeEffectivenessResearchonInternet-basedDepressionTreatment

Fundingscheme Collaborativeproject

DateofAnnex1 25-04-2017

Representativeofproject’scoordinator

HeleenRiper,Ph.D.

ProfessoreMental-Health/clinicalpsychology

VUUniversityAmsterdam

Tel. +31205988759

E-mail [email protected]

Project’swebsite http://www.e-compared.eu

GrantAgreementNo:603098-2 E-COMPARED

FinalReport Page3of27

E-COMPARED:AIMTheE-COMPAREDprojectevaluatedthecomparativeeffectivenessofblendedCognitiveBehaviourTherapy(bCBT)foradultdepressionincomparisontotreatmentasusual(TAU)ineightEuropeancountriesandonesatellitecountry(Denmark).BlendedCBTentailsoneintegratedstandardizedCBT-treatmentprotocolthatcombines face-to-face sessions anddigitalmodules to thebest clinical and cost-benefits forpatients andtherapists (Riper, 2017). The hypothesis was that bCBT for unipolar major depression (MDD) would beclinicallynon-inferiorcomparedtoTAUbutcost-effectiveinroutinecarease.g.lesstherapisttimewouldbeneeded.

The three-yearproject started in January2014. E-COMPAREDhasbeen conductedby amulti-disciplinarygroupofscientists,mentalhealthserviceprovidersandrelevantstakeholdersofwhicharepresentativeEUpatientorganisation (GAMIAN)playedapivotal role inallphasesof theproject. Informationabout theE-COMPAREDprojectcanbefoundattheproject’swebsitewww.e-compared.eu(seefigure1).Thiswebsiteprovidesinsightintothework-processoftheprojectincludingthework-packages,organisationsinvolvedandtheongoingresultsofit.

figure1www.e-compared.eu

HereweprovidetheresultsoftheprojectandanumberofEUandnationalrecommendations.Someoftheseresults have been published already in international peer reviewed journals and the remainder of theseresultswillbesubmittedforpublicationin2018.Theresultsaspublishedwillaccountasourfinalresults,theresultspresentedherearethereforereferredtoas‘first’results.Werefertoprogressreport2foradetailedaccountoftheactivitiesundertakentoobtaintheseresults.

E-COMPARED:StakeholdersperspectivesondigitaltreatmentfordepressioninEuropeTheintegrationofdigitaltreatmentsintonationalmentalhealthservicesisontheagendaintheEuropeanUnion(seee.g.ROAMERandtheJointActionforMentalHealthandWellbeing).AtthestartoftheprojecttheE-COMPAREDconsortiumconductedanonlinesurveyamongthe8countries(France,Germany,Netherlands,Poland,Spain,Sweden,SwitzerlandandTheUnited

Kingdom)thatwouldconductthecomparativeeffectivenessstudies.Theaimwastoexplorestakeholders’knowledge,acceptanceandexpectationsofdigital treatments fordepression,and to identify factors thatmightinfluencetheiropinionswhenconsideringtheimplementationoftheseapproaches.

175 out of the 768 organizations that we approached responded to our survey. These respondentsrepresented a variety of government bodies, care providers, service-users, funding/insurance bodies,technicaldevelopersandresearcherswereinvitedtopartakeinthesurvey.Theparticipatingcountriesandorganizationsreflectthediversityinhealthcareinfrastructuresande-healthimplementationacrossEurope.



MentalhealthstakeholdersinEuropeappeartobeawareofthepotentialbenefitsofdigitalinterventions.However,therearevariationsbetweencountriesandstakeholdersintermsoflevelofknowledgeaboutsuchinterventions and their feasibility within routine care services. The participating stakeholders reportedmoderateknowledgeofdigitaltreatmentswithhigherlevelsofknowledgeandacceptancein‘frontrunning’countries like NL, SWE and the UK. Many stakeholders considered cost-effectiveness to be the primaryincentiveforintegrationintoroutinecareservices.Lowfeasibilityofdeliverywithinexistingcareserviceswasconsidered to be a primary barrier. Digital treatments were regardedmore suitable formilder forms ofdepression. An important finding was that across all stakeholders showed greater acceptability towardsblendedtreatment(theintegrationofface-to-faceandinternetsessionswithinthesametreatmentprotocol)comparedtostandaloneinternettreatmentsprovidedcompleteonlinethuswithoutface-to-facecontacts.Thisindicatesanopennessforagradualintegrationoftechnologyintoroutineclinicalpracticewhichmayfitbest the attitudes and needs of stakeholders. For more information see Topooco et al. 2017, InternetInterventions.

ClinicalEffectivenessofbCBTin9Europeancountries–pooleddataanalysisOurmainhypothesiswas thatbCBT forunipolarmajordepression (MDD)wouldbe clinicallynon-inferiorcomparedtoTAUbutcost-effectiveinroutinecareasforexamplelesstherapisttimewouldbeneededtoprovidebCBT.Inordertotestthishypothesis,weconducted8randomisedcontrolledtrials in8Europeancountriesandoneinasatellitecountry(Denmark).Asstatedbefore,theresultsfromthepooledanalysisareinfluencedby thecountrieswith larger sample sizes thatwereavailable in the30thof June2017dataset,However,thepooledanalysisincludeddatafromallcountries.

figure2

figure3



MethodsIn total 841 patients were included, providing sufficient power to assess our non-inferiority hypothesisregardingtheclinicaleffectivenessat3,6and12months(seefigure2and3).Missingdatawashandledusingmultiple imputationtechniques.Theclinicaleffectivenessresultsarebasedonthe Intention-to-Treat (ITT)principlemeaningthatallrandomisedparticipantswereincludedintheanalyses.Regardinginterpretationoftheresults,bCBTwasconsiderednon-inferiorascomparedwithTAUwhenthetwo-sided95%confidenceinterval (the rangeofplausibledifferencesbetween the two treatments) liesentirelyabove the standardmean difference of Cohen's d -0.20, i.e. the non-inferioritymargin and the smallest clinically acceptabledifference(seefigure4forthepooledresults).Ifthetwo-sided95%confidenceintervalliesentirelyabove0,bCBTisconsideredsuperiortoTAU,iftheintervalliesentirelybelow0TAUissuperiortobCBT.Therefore,we calculated Cohen’s d effect sizes and 95% confidence intervals to determine the magnitude of thetreatmenteffectsbetweenbCBTandTAU.EffectsizesofCohen’sd<0.2aredeemedtobesmall,between0.2and0.5aremoderate,and>0.8areconsideredtobelarge.

ResultspooleddataanalysesTable1showsanumberofbaselinecharacteristicsoftheoverallsample.

Table1OverallSampleCharacteristics

Overall BlendedCBT

(n=423)

TAU

(n=418)

Overall

(n=841)

Age(mean,SD) 39.45(13.24) 38.72(13.10) 39.09(13.17)

Female(n,%) 282(66.7) 285(68.2) 567(67.4)

Relationshipstatus(n,%)

Single 199(47.0) 178(42.6) 377(44.8)

Partner 224(53.0) 240(57.4) 464(55.2)

Education(n,%)

Low 56(13.2) 58(13.9) 114(13.6)

Middle 157(37.1) 145(34.7) 302(35.9)

High 210(49.6) 215(51.4) 425(50.5)

Comorbiddisorder(n,%)

Anxiety1 228(53.9) 212(50.7) 440(52.3)

Medicationuse2 190(449) 190(45.5) 380(45.2)

1Currentpanicdisorderwithorwithoutagoraphobia,agoraphobiawithoutpanicdisorder,socialphobia,GAD;2Medicationuseatbaselineforlowmood.

The PHQwas the primary outcome and at baseline it was around 15 for both the bCBT and TAU groupindicatingamajordepressiveepisodewithmoderateseverity(seefigure2).Bothgroupsshowedlargewithingroupchangesforallthreefollowups(seetable2).Next,threeand6monthsfollowupsshowedthatbCBTwas significantly clinically effective (superior) over TAU regarding reduction of depressive symptoms asassessedwiththePHQ(smalleffectsofCohen’sd0.16(CI0.02;0.29andd0.17(CI0.04;0.31)respectively).At12monthsbCBTwascomparedtoTAUwithinthenon-inferioritymargin(meaningaboveCohen’sd-0.20withaCohen’sdof0.07,CI-0.07;0.21,allbasedonimputeddata,seetable2andfigure3).



Table2

TheresultsoftheQIDSwereinlinewiththeresultsforthePHQ-9withsuperiorityofbCBTfordecreaseindepressivesymptomsat3monthsandnon-inferiorityat6monthsand12months(seetable3).

Table3ResultsoftheQIDSat3,6and12months(imputed).

At12months (N=371,non-imputeddata) thepercentageofbCBTpatients (82%)withacurrentM.I.N.I.diagnosisofadepressiveepisodewassignificantlylower(p<.05)comparedtoTAUparticipants(71%).InmostcountriespatientswereassatisfiedwithbCBTasTAUatpost-treatmentbutbCBTwassignificantlyfavouredover TAU in Germany and Spain (CSQ 8, range 8 to 32, high scores indicating greater satisfaction withtreatment;N=519(completersonly);bCBT25.6SD4.9,TAU21.4,SD6.2).Overallpatientsandtherapistsvaluedthetechnicaltreatmentplatformsas(very)good.

bCBTmean(SD) TAUmean(SD) Cohen’sd CI(95%)Pooled9trialsites 423 418 Baseline 14.6(4.5) 14.7(4.2) 3months 10.1(6.2) 10.9(5.3) 0.15 0.02;0.29*6months 9.0(6.5) 9.8(6.2) 0.12 -0.02;0.2512months 8.1(7.0) 8.8(8.5) 0.09 -0.05;0.22



ClinicaleffectivenessofbCBTversusTAUindifferentHealthcareSettingsThe bCBT treatments were provided following the most feasible routine care practices in the partakingcountries.Asaresult,thebCBTtreatmentsweredeliveredineitherprimarycareorspecialisedmentalhealthcare.Accordingly, theTAUconditionsdifferedacross thetrial sites.Wethereforeconductedanumberofsensitivityanalysestotestinfluenceofthesedifferencesinsettingsontheclinicalandcost-effectivenessofbCBTversusTAU.

Theresultsfromtheseanalysesforprimarycareandspecializedcareparticipantsareinlinewiththeresultsinthemainanalyses.MostMDDpatients(573)weretreatedinprimarycaresettings inGermany,Poland,Spain,Sweden,UK,while268patientsweretreatedinspecialisedmentalhealthcaresettingsinDenmark,France,Netherlands,Switzerland.bCBTinprimarycareshowedtobeclinicallysignificantlymoreeffective(superior)thanTAUfordecreaseindepressivesymptomsatmonths3and6,andnon-inferioratmonth12(seetable4).However,whenwemadeadistinctionbetweenactiveprimarycareasTAUcondition(face-to-faceCBTprovidedbypsychologists)andpassiveprimarycare(TAUbyGP’s)resultsshowedaslightlydifferentpicture.bCBTcomparedtopassiveTAUwassignificantlymoreeffectiveatall timepoints,howeverwhencomparedtoactiveTAU,bCBTwasinferior(theconfidenceintervalliedbelowthemarginof-0.20at3,6and12 months). A similar pattern was observed when comparing bCBT versus TAU (face-to-face CBT bypsychotherapists).TheseresultsshowedthatbCBTwasnon-inferiorat6follow-upandontheedgeofbeingsoat12monthsfollowup,meaningbCBTandTAUperformequally.partlythelittledifferencesbetweenthesetwo conditions. Pleasenote that for the group that received treatment in specializedmental health carefinishedtreatmentbetween3and6months.

Table4SubgroupanalysesPHQ-9outcomespersetting

bCBT mean(SD)

TAU mean(SD)

Cohen’sd CI(95%)

Primarycare

285 288 Baseline 15.1(4.4) 14.8(4.4)

3months 8.6(5.6) 9.9(5.6) 0.23 0.06-0.39*6months 7.8(6.0) 9.0(6.0) 0.20 0.04-0.37*12months 7.3(7.1) 8.2(9.2) 0.11 -0.05-0.27Passiveprimarycare

207 211 Baseline 15.0(4.7) 14.9(4.4)

3months 8.8(5.6) 10.7(5.4) 0.36 0.16;0.55*6months 7.9(6.0) 9.8(6.3) 0.29 0.10;0.49*12months 7.4(7.1) 8.6(8.5) 0.15 -0.05;0.34Activeprimarycare

78 77 Baseline 15.3(4.6) 14.7(4.4) 3months 8.0(6.8) 7.9(6.0) -0.02 -0.34;0.296months 7.0(6.0) 6.8(6.2) -0.03 -0.35;0.2812months 6.9(6.5) 7.1(7.5) 0.03 -0.29;0.35Specializedcare

138 130 Baseline 15.9(5.1) 15.9(4.8) 3months 10.7(6.4) 10.7(6.1) 0.01 -0.23;0.256months 8.5(6.6) 9.2(6.6) 0.11 -0.13;0.3512months 7.6(7.0) 7.5(7.1) -0.02 -0.25;0.23

CI:Confidenceinterval;SD:Standarddeviation



Clinicalresultsonanindividualcountry-triallevelWepresenthereinbrieftheresultsoftheindividualparticipatingcountriesaswell.Itshouldbenotedthattheseresultsareexplorativeasthesamplesizeofourstudywasbasedonthepooledsampleofthe9trialsitesa-priori.Trialsitesweretherefornotpoweredonanindividualstudylevel,meaningmoststudieswillhavebeenunderpoweredonan individual level.However,theseexplorativeresultshighlightanumberofimportantissuesregardingthefeasibility,acceptabilityofbCBTandmayshedlightonthepotentialclinicalandcost-effectivenessofbCBTversusTAUindifferentEUcountries.Resultsneedtobethereforeinterpretedwithcautionaswell.The resultsof the individual trial sitesarepresented in figure5.Pleaseseealso theevidencebriefsforboththepooledandindividualcountrytrials.

figure5

FranceIn France bCBTwas compared to TAU (face-to-face CBT) in specialisedmental health care. The technicalplatformappliedwasMoodbuster(developedintheFP7ICT4DepressionprojectandtranslatedfromDutchtoFrenchinthecurrentproject,seefigure6aand6b).Thetreatmentconsistedof16modules.InthebCBTcondition8sessionswereprovidedf-t-fbyapsychotherapistand8indigitalformat.TAUconsistedof16f-t-fsessionsbyapsychotherapist.Treatmentdurationforbothgroupswas18weeks.

TheFrenchsampleincluded105patientswithanaverageageof45years(SD13.51)andofwhichtwo-thirdsconsistedoffemales(65%).Mostwereeitherhighlyeducated(66%)ormiddleeducated(32%),loweducatedpatients were under-represented (2%). All had a MDD diagnosis, half of them had a co-morbid anxietydisorderandthreequarterswereonmoodmedicationatthestartofthetrial.

BothconditionsshowedlargedecreaseindepressionseverityonallthreefollowupperiodsandtherewasasmalldifferencebetweenthegroupsinfavourofTAU.ThebCBTconditionhadaconfidenceintervalbelowd=-0.20indicatingthatnon-inferioritycouldnotbeconfirmedonthebasisofthecurrentdataset.Halfofthepatientsdidnothaveadiagnosisofdepressionat12months(MINI,non-imputeddata,n=50)andtherewasno significant difference between the bCBT and TAU conditions. bCBT patients were satisfied with thetreatmentandhalfofthesevaluedthedigitalcomponentsofthetreatmentaboveaverageandsodidmosttherapists.



figure6aand6b

GermanyInGermanybCBTwascomparedtoTAU(treatmentasusualbyaGP)inprimarycare.ThetechnicalplatformappliedwasMoodbuster(developedintheFP7ICT4DepressionprojectandtranslatedfromDutchtoGermanlanguage in the current project). The bCBT treatment consisted of 5 face-to-facemodules and 10 digitalmodules,TAUconsistedofdepressiontreatmentasusualdeliveredbyaGP.

TheGermansampleincluded173patientswithanaverageageof43years(SD12.6),aroundtwo-thirdswerefemales(61%).Halfwerehighlyeducated(50%),athirdhadamiddleeducationalbackground(30%),andapproximately20%hadalowerone.AllhadaMDDdiagnosis,4outof10hadaco-morbidanxietydisorderandhalfofthesample(45%)wasonmoodmedicationatthestartofthetrial.

Bothconditionsshowedalargedecreaseindepressionseverity(PHQ9)onallthreefollowupperiodsandtherewasasignificantsmalltomoderatedifferencebetweenthegroupsinfavourofbCBToverTAU,thusbCBTwassuperioroverTAU.Morethantwothirdsofthepatientsdidnothaveadiagnosisofdepressionat12months(MINI,non-imputeddata,n=115)andtherewasnosignificantdifferencebetweenthebCBTandTAUconditions.bCBTpatientsweresignificantlymoresatisfiedwiththetreatmentthanthosethatreceivedTAU(p<.001)andmostthesevaluedthedigitalcomponentsofthetreatmentaboveaverageandsodidmosttherapists.

NetherlandsIn theNetherlands bCBTwas compared to TAU (face-to-face CBT) in specialisedmental health care. ThetechnicalplatformappliedwasMoodbuster(developedintheFP7ICT4Depressionproject,leadedbytheVrijeUniversiteit,Amsterdam).Thetreatmentconsistedof19modules.InthebCBTcondition9f-t-fsessionswereincludedand10indigitalformat,allguidedbyapsychotherapist.TAUconsistedof19f-t-fCBTsessionsbyapsychotherapist.Treatmentdurationforbothgroupswas20weeks.

TheDutchsampleincluded84patientswithanaverageageof40years(SD11.30)ofwhichtwo-thirdswerefemale(65%).IncontrasttomostotherE-COMPAREDtrialsites(aswellasefficacytrials),theDutchsampleincludedahighpercentageofmiddle(50%)andloweducated(20%)patientsandarelativelylownumberofhighlyeducatedpatients(30%).AllhadaMDDdiagnosis,twothirdshadaco-morbidanxietydisorderandaratherhighpercentage(80%)wasonmoodmedicationatthestartofthetrial.

Bothconditionsshowedlargeeffectsizes(withingroup,PHQ-9)fordecreaseindepressionseverityon6and12monthsfollowupperiodswithasmalldifferenceinfavourofbCBT,confirmingnon-inferiority.Thiswasnotthecaseatthreemonthswhichcouldbeexplainedbythefactthatthetreatmentwasstillrunningatthattime.TherewasnodifferencebetweenthetwogroupsconcerningthepercentageofpatientsthatwasMDDdiagnosefreeat12months,thiswasthecaseformorethantwothirdsofthepatients(atthattimehoweverassessedforasmallnumberofpatients=29outofN=84,thustheseresultsneedtobeinterpretedwithcaution).bCBTpatientswereonaveragesatisfiedwiththeirtreatmentaswereTAUparticipantsand40%ofthesevaluedthedigitalcomponentsofthetreatmentaboveaverageandsodidmosttherapists.



PolandInPolandbCBTwascomparedtoTAU(treatmentasusualprovidedbyapsychotherapist(trainee))inprimarycare. The technical platform appliedwasMoodbuster (developed in the FP7 ICT4Depression project andtranslated fromDutch intoPolish in the currentproject). ThebCBT treatment consistedof7 face-to-facemodulesand6digitalmodules,TAUconsistedof face-to-faceCBTdepressiontreatmentasdeliveredbyapsychotherapist.

The Polish sample included 65 patientswith an average age of 35 years (SD 13.66), three quarterswerefemales (75%). Over half of the sample was highly educated (60%), a third had a middle educationalbackground(34%),andapproximately6%hadalowereducationalbackground.AllhadaMDDdiagnosis,halfofthesamplehadaco-morbidanxietydisorderandmorethanhalf(58%)wasonmoodmedicationatthestartofthetrial.

Bothconditionsshowedalarge(withingroup)decreaseindepressionseverity(PHQ9)onallthreefollowupperiodsandtherenodifferencebetweenthegroupsinclinicaloutcomebutTAUwasinfavourasthebCBTconfidence intervals were not above d= -0.20.More than three quarters of the patients did not have adiagnosisofdepressionat12monthsandtherewasnosignificantdifferencebetweenthetwoconditions(MINI,non-imputeddata,smalln=36outofthen=65atthatmomentintime).bCBTpatientswerehighlysatisfied with both treatment-conditions and most these valued the digital components of bCBT aboveaverageandsodidmosttherapists.

SpainInSpainbCBTwascomparedtoTAU(treatmentasusualbyaGP) inprimarycare.ThetechnicalplatformappliedwasSmilingisFun(developedintheFP7Optimiproject).ThebCBTtreatmentconsistedof3face-to-facemodulesand8digitalmodules,TAUconsistedofdepressiontreatmentasusualdeliveredbyaGP inprimarycare.

TheSpanishsample included98patientswithanaverageageof42years(SD10.36),threequarterswerefemales(75%).Halfhadamiddleeducationalbackground(49%),aquarterhadalowandrespectivelyhigheducationalbackgroundtherebyincludingarelativelyhigherpercentageoflowandmiddleleveleducatedpatientscomparedtomostotherparticipatingsamplesandcomparedtomostefficacytrialsaswell,whichareallpopulatedmostlybyhighlyeducatedsamples.AllhadaMDDdiagnosis,halfhadaco-morbidanxietydisorderandtwothirdsofthesample(66%)wasonmoodmedicationatthestartofthetrial.

Bothconditionsshowedalargewithingroupdecreaseindepressionseverity(PHQ9)onallthreefollowups.bCBTwasslightlyfavouredoverTAUandontheedgeofbeingnon-inferior.Overhalfofthepatientsdidnothaveadiagnosisofdepressionat12months(MINI,non-imputeddata,smalln=32atthatmomentintimeoutofthetotalN=98sample),therewasnosignificantdifferencebetweenthebCBTandTAUconditions.bCBTpatientsweresignificantlymoresatisfiedwiththetreatmentthanthosethatreceivedTAU(p<.001)andmostthesevaluedthedigitalcomponentsofbCBTaboveaverageandsodidmosttherapists.

SwedenInSwedenbCBTwascomparedtoTAU(treatmentasusualbyaGP)inprimarycare.Thetechnicalplatformapplied was Interapi (a longstanding platform, developed by the Swedish team). The bCBT treatmentconsistedof4face-to-facemodulesand8digitalmodules,TAUconsistedofdepressiontreatmentasdeliveredbyGP’sinprimarycare.

TheSwedishsampleincluded147patientswithanaverageageof34years(SD12.96),threequarterswerefemales(73%).Threequarterhadahighereducationalbackground(49%),aquarterhadamiddleandonly1%hadaloweducationalbackgroundtherebyrelativelysimilartosamplecharacteristicsofefficacytrials.AllhadaMDDdiagnosis,twothirdhadaco-morbidanxietydisorderandcomparedtoothertrialsitesarelativelylowpercentageofpatients(15%)wereonmoodmedicationatthestartofthetrial.

Bothconditionsshowedalargewithingroupdecreaseindepressionseverity(PHQ9)onallthreefollowups.bCBTwasfavouredoverTAUwithsmalltomoderateeffectsizeandaCIabovethenon-inferioritymargin.



Almostallpatientsdidnothaveadiagnosisofdepressionat12months(MINI,non-imputeddata,butsmalln=53atthatmomentintimeoutofthetotalN=147sample),therewasnosignificantdifferencebetweenthebCBTandTAUconditions.bCBTpatientsweresatisfiedwiththeirtreatmentandwiththedigitalcomponents,mostvaluedtheseaboveaverage,therapistsappearedtobelesssatisfiedwiththetechnicalplatform.

SwitzerlandInSwitzerlandbCBTwascomparedtoTAU(face-to-faceCBT)inspecialisedmentalhealthcare.ThetreatmentplatformappliedwasDeprexis (developedbyGAIAAG,Germany).bCBTconsistedof9 face-to-faceand9digitalmodules,allguidedbyapsychotherapist.TAUconsistedof18ftfCBTsessionswithapsychotherapist.Treatmentdurationforbothgroupswas18weeks.

TheSwisssampleincluded50patientswithanaverageageof39years(SD14.87)ofwhichtwo-thirdswerefemale (64%). Two thirdsof thepatients (64%)hadamiddle educational background,one third ahigherbackgroundandfewaloweducationalbackground(4%).AllhadaMDDdiagnosis,onethirdhadaco-morbidanxietydisorderandhalf(50%)wasonmoodmedicationatthestartofthetrial.

Bothconditionsshowedlargeeffectsizes(withingroup)fordecreaseindepressionseverity(PHQ-9)withasmalldifferenceineffectsizesinfavourofbCBT,ontheedgeofconfirmingnon-inferiorityat3and6monthsbutnotat12months.TherewasnodifferencebetweenthetwogroupsconcerningthepercentageofpatientsthatwasMDDdiagnosefreeat12months,whichwasthecaseforalmostthecompletesample(atthattimehoweverassessedforasmallnumberofpatients=13outofN=50,thustheseresultsneedtobeinterpretedwithcaution).bCBTpatientswereonaveragesatisfiedwiththeirtreatmentaswereTAUparticipantsandmostofthebCBTpatientsvaluedthedigitalcomponentsofthetreatmentaboveaverageandsodidmosttherapists.

UnitedKingdomIntheUKbCBTwascomparedtoTAU(face-to-faceCBT)inprimarycare(IAPTsetting).ThetechnicalplatformappliedwasMoodbuster(developedintheFP7ICT4Depressionproject,leadedbytheVrijeUniversiteit).ThebCBTtreatmentconsistedof11modulesofwhich6wereftfsessionsand5digitalmodules.TAUconsistedof6face-to-faceCBTsessions,bothconditionswereleadedbypsychotherapists.Treatmentdurationforbothgroupswas11weeks.

TheUKsampleincluded90patientswithanaverageageof34years(SD11.37)ofwhichapproximatelyhalfwerefemale(56%)thisincontrasttotheotherparticipatingtrialsitesandefficacystudiesingeneralwerefemalespopulatearoundthreequartersofthesamplesconcerned.Halfofthesamplewashighlyeducatedfollowedbyaquarterofbothmiddleandloweducatedparticipantsrespectively.AllhadaMDDdiagnosis,twothirdshadaco-morbidanxietydisorder(67%)and4outof10patientswereonmoodmedicationatthestartofthetrial.

Bothconditionsshowedlargeeffectsizes(withingroup)fordecreaseindepressionseverity(PHQ-9)forall3follow up periods but favouring TAU over bCBT, as non-inferiority could not be assumed. Therewas nodifferencebetweenthetwogroupsconcerningthepercentageofpatientsthatwasMDDdiagnosefreeat12months,thiswasthecasefortwothirdsofthepatients(atthattimehoweverassessedforasmallnumberofpatient’sn=29outofN=90,thustheseresultsneedtobeinterpretedwithcaution).bCBTpatientswereonaveragesatisfiedwiththeirtreatmentandmostofthesevaluedthedigitalcomponentsaboveaverageandsodidmosttherapists.

DenmarkAsexplainedintheaforementionedtext,Denmarkwasaddedontoourstudyandstartedthetrialatalaterpointintime.Denmarkhasbecomeaformalbutnon-fundedpartnerintheE-COMPAREDproject.GiventhesmallsamplesizeofDenmarkatthefrozendatasetof30June2017(n=29),wewillnotreporthereontheindividualDanishoutcomesyet,wewilldosohoweveronthe31Decemberdataset.



Cost-effectivenessofbCBTversusTAUupto1year–combinedanalysisThecost-effectivenessresultsthatarepresentedherearebasedonthe6and12-monthfollow-updataof841participants(i.e.similardata-setusedfortheclinicaleffectivenessanalyses,seeprevioussection). These first results are potentially subject to fine-tuning on the basis of the final 31December2017datasetwhichshouldbetakenintoaccountwheninterpretingthefindings.

Wepresenttheresultsfrompooledat6and12monthsandcountry-specificcost-effectivenessanalysesat6months.Ascanbeseenfromtheanalysessomecountrieshaveprovidedalmostcompleteddatasetstrials(e.g.GermanyandSweden)andotherswilldoforforthefinaldatasetof31December2017.Therefore,theresultsfromthepooledanalysisareinfluencedfromthecountrieswithlargersamplesize,likewasthecasefortheclinicaldataset.However,thepooledanalysisincludeddatafromallcountries.

MethodsIntheanalysisN=841participantswereincluded.Cost-outcomesweremeasuredatbaseline,and3-month,6and12monthsafterbaseline. Theprimaryoutcomewas improvement indepressive symptomseveritymeasuredbythePatientHealthQuestionnaire-9(PHQ-9).WealsousedPHQ-9tocalculatepositiveresponsetotreatment.Responsewasdefinedasanatleast50%reductioninPHQ-9scorefrombaselineto6-monthfollow-up.Weincludedthisresponseasanoutcomebecauseiteasytobeinterpretedandunderstood.

Qualityof lifewasmeasuredby theEuroQolquestionnaire (EQ-5D-5L).UtilityweightswerecalculatedbyusingtheDutchtariffs.Utilityscoresareapreference-basedmeasureofqualityoflifeanchoredat0(worstperceivablehealth)and1(perfecthealth).QALYswerecalculatedbymultiplyingtheutilityweightswiththeamountoftimeaparticipantspentinaparticularhealthstate.Transitionsbetweenthehealthstateswerelinearlyinterpolated.

Costsweremeasuredfromthesocietalperspective(includinghealthcareutilizationandproductivitylosses)basedontheadaptedversionoftheTrimbosandiMTAQuestionnairesonCostsAssociatedwithPsychiatricIllness(TiC-P).Forthepresentreport,Dutchunitcosts(€,2016)wereusedtovaluehealthcareutilizationandproductivitylosses.Also,DutchutilityweightswereusedtocalculateQuality-AdjustedLife-Years(QALYs).TheDutchunitcostsandtheDutchutilityweightswerechosenbecauseoftheirhighqualityandduetothefactthat they have been used extensively in the literature in previous studies. The aforementionedmethodologicalchoicesareexpectedtohaveacertainimpactonourfindings.Itispossiblethattheycanleadtosomediscrepancieswhencomparedtoanalysisconductedfrompartnersontheircountry-specificdataandforexamplewithotherutilityweightsandunitcosts.Weplantousecountry-specificunitcostsonthecompletedatasetof31December2017.Costs for theonlinepartof thebCBT includedmaintenanceandhostingofthetreatmentandthecostoftherapists’timespenttoprovidefeedbacktoparticipants.

StatisticalanalysisTheanalysiswasconductedassumingasuperioritydesign.Theanalyseswereperformedoncountry-specificandpooleddata.Multipleimputationwasusedtoimputethemissingcostandeffectdata.Twentyimputeddatasetswereconstructedinorderforthelossofefficiencytobelessthan5%.MultilevelregressionanalyseswereusedinthepooledanalysistoestimatethedifferencesincostsandclinicaleffectsbetweenthebCBTandtheTAUwhileaccountingforthehierarchicalstructureofthedata.Atwo-levelstructurewasusedwhereparticipantswerenestedwithincountries.Weincludedbaselinedepressionseverity,gender,andageinthemodeltoadjustforpossibleconfounding.

We calculated the incremental cost-effectiveness ratios (ICERs) by dividing the difference in total costsbetween the bCBT and TAU by the difference in effects (ΔC/ΔE). The ICER should be interpreted afterconsidering whether the numerator (ΔC) and the denominator (ΔE) are positive or negative. The 95%confidenceintervalsaroundthecostdifferencesandtheuncertaintysurroundingtheICERswereestimatedusing bias-corrected bootstrapping with 5000 replications. In addition, we estimated cost-effectivenessacceptabilitycurves(CEAcurves).TheCEAcurvesdemonstratetheprobabilitythatthebCBTiscost-effectivein comparison with TAU for a range of different values of willingness to pay, which was defined as the



maximumamountofmoneysocietyiswillingtopayextratogainonemoreunitoftreatmenteffect.Thereisnoconsensusonwhatprobabilityisacceptableforcost-effectiveness,buta0.95isthepreferredconservativeestimatehere.

SensitivityanalysisWeconductedtheanalysesseparatelyforparticipantsthatwererecruitedinprimarycareandparticipantsrecruitedinspecializedcare,becausewehypothesizedthatpatientsfromdifferentsettingsmaybenefiteddifferentlyfrombCBTwhencomparedtoTAUinthesesettings(seealsotheclinicaleffectivenesssection).Secondly,wecarriedoutsensitivityanalysisseparatelyforcountrieswithanactiveprimarycaretreatment(i.e.UnitedKingdomandPoland)andpassiveprimarycaretreatment(Germany,Sweden,Spain).Thirdly,weperformed the analyses from the healthcare provider perspective, in which only healthcare costs wereincludedandnotproductivitylosses,becausethisistherecommendedperspectiveinsomecountries,suchas the United Kingdom. Finally, we carried out the analysis using participants without missing data (i.e.completedataonly),toexamineiftheimputationinfluencestheresults.

Pooledoveralldataanalysescost-effectivenessofbCBTversusTAUWeincluded841participantsinthepooledanalysis,423inthebCBTgroupand418intheTAUgroup.Table6 shows themeanunadjusted costs for various categoriesat6-month follow-up. In table5, theadjusteddepressivesymptomseverityscoresofparticipantsinthebCBTimprovedonaverage1.16pointsmorethanthescoresofparticipantsintheTAUgroupandthisdifferencewasstatisticallysignificant(95%CI=0.35to2.00).Similarly,responseratewashigherfortheblendedgroupascomparedtoTAUandthemeandifferencewasstatisticallysignificant(meandifference=0.11,95%CI=0.04to0.18).QALYsgainedwereonlyslightlyhigherfortheinterventiongroup(meandifference=0.01,95%CI-0.01to0.02).

Total societal costs were higher for the bCBT as compared to TAU and the difference was statisticallysignificant(meandifference=1,505,95%CI=482to2,558).Productivitylosseswerethelargestcontributortototalcosts.Thisisnotasurprisingfindingsinceithasbeenshownbeforethatproductivelossesaccountforalargepartofthetotalcostofdepression.

The results of the cost-effectiveness analyses are presented in Table 5. The ICER for improvement indepressivesymptomswas1,304,meaningthatonepointimprovementextrainPHQ-9scoreinthebCBTwason average associated with €1,304 higher costs as compared to TAU. As shown in the CEA curve, theprobability of the bCBT being cost-effective compared to TAUwas 0.01 at a ceiling ratio of 0 €/point ofimprovementextrainPHQ-9score,and0.98ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score(figure7).

The ICER for treatment responsewas 13,449,meaning that for one additional participant responding totreatmentinthebCBTincomparisontoTAUaninvestmentofonaverage€13,449isneeded.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.01ataceilingratioof0€/responderextra,and0.30ataceilingratioof10,000€/responderextra(.

For QALYs gained, the ICER was 275,317, meaning that for one additional QALY gained in the bCBT incomparisontoTAUanadditionalcostof€275,317isneeded.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.01ataceilingratioof0€/QALY,0.02ataceilingratioof24,000€/QALYand0.02ataceilingratioof35,000€/QALY.



Table5.Adjusteddifferencesinmeancosts(€,2016)andeffects(95%confidenceintervals)at6-monthsfollow-up,andincrementalcost-effectivenessratios

Analysis Samplesize ΔC(95%CI) ΔE(95%CI) ICER

Outcome bCBT;TAU € Units €/Unit

Pooledanalysis 423;418

ImprovementinPHQ-9 1,505(482;2,558) 1.16(0.35;2.00) 1,304

Response 1,505(482;2,558) 0.11(0.04;0.18) 13,449

QALYs 1,505(482;2,558) 0.01(-0.01;0.02) 257,317

Sensitivityanalysis

Primarycare 285;288


Response 1,454(341;2,626) 0.14(0.06;0.22) 10,439

QALYs 1,454(341;2,626) 0.01(-0.01;0.02) 251,412

Specializedcare 138;130

ImprovementinPHQ-9 1,217(-761;3,214) 0.71(-0.79;2.21) 1,721

Response 1,217(-761;3,214) 0.06(-0.08;0.19) 21,777

QALYs 1,217(-761;3,214) 0.00(-0.02;0.03) 298,012

Primarycare-passive 207;211

ImprovementinPHQ-9 1,517(180;2,389) 1.82(0.73;2.90) 835

Response 1,517(180;2,389) 0.20(0.11;0.30) 7,473

QALYs 1,517(180;2,389) 0.01(-0.01;0.02) 269,176

Primarycare-active 78;77


Response 1,386(-558;3,503) -0.04(-0.21;0.14) -35,652

QALYs 1,386(-558;3,503) 0.01(-0.03;0.04) 254,585

Healthcareperspective 423;418

ImprovementinPHQ-9 419(-134;917) 1.16(0.35;2.00) 363

Response 419(-134;917) 0.11(0.04;0.18) 3,740

QALYs 419(-134;917) 0.01(-0.01;0.02) 76,560

Patientswithcompletedata 177;185


Response 2,126(544;3,708) 0.14(0.04;0.24) 15,123

QALYs 2,126(544;3,708) 0.01(-0.01;0.03) 298,418



Table6:Mean(SE)multiplyimputedunadjustedcostsandeffectsat6monthsfor841participants(pooledanalysis)(Dutchunitcosts,€2016)

Outcome bCBT(n=325) TAU(n=318) Meandifference(95%CI)

Clinicaleffects

ImprovementPHQ-9 -7.42 -6.12 -1.31(-2.26;-0.37)

Response 0.56 0.44 0.12(0.04;0.20)

QALYs 0.34 0.34 0.00(-0.01;0.02)

Costcategories

OnlineIntervention* 322 n/a n/a

Mentalhealth 971 953 18(-360;350)

Primarycare 255 278 -23(-84;37)

Specializedsomaticcare 572 271 301(-39;597)

Complementarytherapy 35 33 2(-20;25)

Domesticcare 435 607 -172(-420;75)

Medication 22 22 0(-5;6)

Totalhealthcarecosts 2,611 2,164 447(-144;1,038)

Lostproductivitycosts 5,522 4,317 1,205(-7;2,416)

Totalsocietalcosts 8,133 6,481 1,652(-212;3,092)

*Costsformaintenanceanddevelopmentoftheonlineplatforms,andcostforonlinefeedbackfromtherapists

12-monthsfollow-upTheresultsofthecost-effectivenessanalysesat12-monthsfollow-uparepresentedinTable7.TheICERforimprovementindepressivesymptomswas3,571,meaningthatonepointimprovementextrainPHQ-9scoreinthebCBTwasonaverageassociatedwith€3,571highercostsascomparedtoTAU.AsshownintheCEAcurve,theprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.04ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.62ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.

The ICER for treatment responsewas 27,823,meaning that for one additional participant responding totreatmentinthebCBTincomparisontoTAUaninvestmentofonaverage€27,823isneeded(Table7).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.04ataceilingratioof0€/responderextra,and0.15ataceilingratioof10,000€/responderextra.

For QALYs gained, the ICER was 128,226, meaning that for one additional QALY gained in the bCBT incomparisontoTAUanadditionalcostof€128,226isneeded(Table7).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.04ataceilingratioof0€/QALY,0.09ataceilingratioof24,000€/QALYand0.13ataceilingratioof35,000€/QALY.



Table7.Adjusteddifferencesinmeancosts(€,2016)andeffects(95%confidenceintervals)at12-monthsfollow-up,andincrementalcost-effectivenessratios


Outcome bCBT;TAU € Units €/Units

Pooledanalysis 423;418

ImprovementinPHQ-9 2,398(546;4,259) 0.67(-0.42;1.76) 3,571

Response 2,398(546;4,259) 0.09(-0.02;0.19) 27,823

QALYs 2,398(546;4,259) 0.02(-0.01;0.05) 128,226

M.I.N.I.* 2,398(546;4,259) 0.09(-0.02;0.19) 27,822

*Percentageofparticipantswithoutacurrentdepressiveepisode

TheICERfortreatmentM.I.N.I.was27,822,meaningthatforoneadditionalparticipantwithoutadepressiveepisode diagnosis in the bCBT compared to TAU an investment of on average €27,822 is needed. TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.04ataceilingratioof0€/participantextrawithoutadiagnosis,and0.15ataceilingratioof10,000€/participantextrawithoutadiagnosis.

Weexpectthattheseestimationscanslightlychangeintermsofamplitudewhenusingthefinaldatasetof31December2017(i.e.smallerconfidenceintervals),butnotforthedirectionoftheresults;i.e.overallbCBTwillremainsmoreeffectivebutnotlessexpensivethanTAU.Itis,however,possiblethatthemeandifferenceintotalsocietalcostswillnotremainstatisticallysignificant.Insum,wecouldnotconfirmourhypothesisthatbCBTwouldbelessexpensivethanTAU.

PrimaryandspecialisedsensitivityanalysesTheresultsfromthesensitivityanalysesforprimarycareandspecializedcareparticipantswereinlinewiththe results in themainanalyses,demonstrating that thebCBTwasmoreexpensiveandmoreeffective incomparisonwithTAU(Table4).Moreover,themeandifferenceincostsbetweenthebCBTandTAUintheanalysisfromthehealthcareperspectiveissmaller,ascomparedtotherespectivemeandifferenceincostsfromthesocietalperspective.ThisisalsoreflectedintheCEAcurvesinfigure8.Finally,theanalysesincludingonly patientswith complete data (i.e. no imputationwas used) showed similar as themain analysis (i.e.analysiswithimputeddata).



a) b)

c)

Figure7a-c.Cost-effectivenessacceptabilitycurvesfromthesocietalperspective(a)improvementinPHQ-9score(b)responsetotreatmentand(c)QALYsforpooleddataat6-monthfollow-up.

a) b)

c)

Figure8a-c.Cost-effectivenessacceptabilitycurvesfromthehealthcareproviderperspective(a) improvementinPHQ-9score(b)responsetotreatmentand(c)QALYsforpooleddataat6-monthfollow-up.



IndividualcountrylevelanalysesWepresent here in brief the results of the individual participating countries aswell. Trial siteswere notpoweredonanindividualstudylevel,meaningstudieshavebeenunderpoweredonanindividuallevel(liketheclinicaleffectivenessanalyses).However,theseexplorativeresultshighlightanumberofimportantissuesregardingthecostsofbCBTversusTAUindifferentEUcountries.Resultsneedtobethereforeinterpretedwith caution aswell. The results of the individual trial sites arepresented in table 8. Please see also theevidencebriefsforboththepooledandindividualcountrytrials.

Theresultsfromtheindividualcountry-specificanalysisvariedbetweenthecountries.ThedirectionoftheresultswassimilarinmostcountriesforimprovementinPHQ-9scoresandresponsetotreatment,withbCBTbeingmoreeffectivethanTAUbutnotlessexpensive.ResultsindicatedthatthedifferencesincostsbetweenbCBT and TAU (from a societal perspective) were for all countries, except France and Switzerland, non-significantlydifferentwhichisnotsurprisinglygiventhesmallsamplesizes.TheFrancedatashowedthatbCBTwassignificantlymoreexpensiveandlessclinicallyeffectivewhencomparedtoTAU.Switzerlandindicatedtheopposite,bCBTwasmoreeffectiveandnotmoreexpensive.



Table8.


Outcome bCBT;TAU € Units €/Unit

Country-specificanalysis

Germany 86;87

ImprovementinPHQ-9 1,607(-954;3.977) 2.73(1.23;4.23) 589

Response 1,607(-954;3.977) 0.29(0.15;0.44) 5,499

QALYs 1,607(-954;3.977) -0.00(-0.03;0.03) -39,225,363

Sweden 73;74

ImprovementinPHQ-9 1,147(-922;3,228) 1.44(-0.51;3.41) 791

Response 1,147(-922;3,228) 0.17(-0.01;0.35) 6,666

QALYs 1,147(-922;3,228) 0.01(-0.02;0.05) 88,745

France 51;54

ImprovementinPHQ-9 2,853(245;5,715) -0.80(3.35;1.74) -3,565

Response 2,853(245;5,715) -0.11(-0,34;0.12) -26,438

QALYs 2,853(245;5,715) -0.01(-0.05;0.03) -214,610

Spain 48;50


Response 1,784(-369;4,259) 0.08(-0.14;0.31) 21,632

QALYs 1,784(-369;4,259) 0.01(-0.03;0.04) 362,101

UnitedKingdom 45;45

ImprovementinPHQ-9 827(-1,098;3,100) 0.23(-2.21;2.68) 3,587

Response 827(-1,098;3,100) -0.06(-0.28;0.16) -14,378

QALYs 827(-1,098;3,100) 0.01(-0.03;0.05) 82,530

Netherlands 45;39

ImprovementinPHQ-9 2,285(-1,553;6,397) 2.79(-0.15;5.73) 821

Response 2,285(-1,553;6,397) 0.27(0.03;0.52) 8,426

QALYs 2,285(-1,553;6,397) 0.01(-0.04;0.07) 187,782

Poland 33;32

ImprovementinPHQ-9 2,543(-951;6,826) -0.02(-3.18;2.78) -12,574

Response 2,543(-951;6,826) -0.02(-0.31;0.26) -107,406

QALYs 2,543(-951;6,826) -0.00(-0.05;0.05) -2,030,831

Switzerland 26;24

ImprovementinPHQ-9 -1,014(-6,815;5,148) 2.04(-1.19;5.27) -497

Response -1,014(-6,815;5,148) 0.16(-0.17;0.48) -6,470

QALYs -1,014(-6,815;5,148) 0.03(-0.02;0.07) -40,375



DenmarkAsexplainedintheaforementionedtext,Denmarkwasaddedontoourstudyandstartedthetrialatalaterpointintime.Denmarkhasbecomeaformalbutnon-fundedpartnerintheE-COMPAREDproject.GiventhesmallsamplesizeofDenmarkatthefrozendatasetof30June2017(n=29),wewillnotreporthereontheindividualDanishoutcomesyet,wewilldosohoweveronthe31Decemberdataset.

FranceTheanalysisforFranceincluded105participants.TheICERforimprovementindepressivesymptomswas-3,565,meaningthatonelesspointimprovementmoreinPHQ-9scoreinthebCBTwasonaverageassociatedwith€3,565highercostsascomparedtoTAU.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.04ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.15ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.

TheICERforresponsewas-26,438,meaningthatoneparticipantlessrespondingtotreatmentinthebCBTincomparisontoTAUwasrelatedonaveragewith€26,438highercost.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.04ataceilingratioof0€/responderextra,and0.03ataceilingratioof10,000€/responderextra.

ForQALYsgained,theICERwas-214,610,meaningthatoneQALYlessinthebCBTincomparisontoTAUisassociatedwith€214,610highercosts(Table8).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.04ataceilingratioof0€/QALY,0.04ataceilingratioof24,000€/QALYandagain0.04ataceilingratioof35,000€/QALY.

GermanyTheanalysisforGermanyincluded173participants.TheICERforimprovementindepressivesymptomswas589,meaningthatonepointimprovementextrainPHQ-9scoreinthebCBTwasonaverageassociatedwith€589highercostsascomparedtoTAU.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.11ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.99ataceilingratioof3,000€/pointofimprovementextrainPHQ-9score.

TheICERforresponsewas5,499,meaningthatforoneadditionalparticipantrespondingtotreatmentinthebCBTincomparisontoTAUaninvestmentofonaverage€5,499isneeded.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.11ataceilingratioof0€/responderextra,and0.79ataceilingratioof10,000€/responderextra.

ForQALYsgained,theICERwas-39,225,363,meaningthatforonelessQALYinthebCBTincomparisontoTAUanadditionalcostof€39,225,363isneeded(Table8).TheICERissolargebecausethedifferenceinQALYsbetweenthetwogroupsisminimal.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.11ataceilingratioof0€/QALY,0.13ataceilingratioof24,000€/QALYand0.14ataceilingratioof35,000€/QALY.

NetherlandsTheanalysisforNetherlandsincluded84participants.TheICERforimprovementindepressivesymptomswas821,meaningthatonepointimprovementextrainPHQ-9scoreinthebCBTwasonaverageassociatedwith€821highercostascomparedtoTAU.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.15ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.94ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.

TheICERforresponsewas8,426,meaningthatanadditionalparticipantrespondingtotreatmentinthebCBTincomparisontoTAUwasassociatedonaveragewith€8,426highercost.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.15ataceilingratioof0€/responderextra,and0.57ataceilingratioof10,000€/responderextra.

ForQALYsgained,theICERwas187,782,meaningthatanadditionalQALYgainedinthebCBTincomparisontoTAUwasassociatedonaveragewith€187,782highercost.(Table8).TheprobabilityofthebCBTbeingcost-



effectivecomparedtoTAUwas0.15ataceilingratioof0€/QALY,0.21ataceilingratioof24,000€/QALYand0.24ataceilingratioof35,000€/QALY.

PolandTheanalysisforPolandincluded65participants.TheICERfor improvementindepressivesymptomswas-12,574,meaningthatonepointimprovementlessinPHQ-9scoreinthebCBTwasonaverageassociatedwith€12,574highercostsascomparedtoTAU.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.13ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.32ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.


ForQALYsgained,theICERwas-2,030,831,meaningthatoneQALYlessinthebCBTincomparisontoTAUisassociatedwith€2,030,831highercosts(Table8).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.13ataceilingratioof0€/QALY,0.14ataceilingratioof24,000€/QALYandagain0.15ataceilingratioof35,000€/QALY.

SpainTheanalysisforSpainincluded98participants.TheICERforimprovementindepressivesymptomswas2,362,meaningthatonepointimprovementextrainPHQ-9scoreinthebCBTwasonaverageassociatedwith€2,362highercostascomparedtoTAU.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.09ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.62ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.

The ICER for responsewas21,632,meaningthatanadditionalparticipant respondingto treatment in thebCBTincomparisontoTAUwasassociatedonaveragewith€21,632highercost.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.09ataceilingratioof0€/responderextra,and0.30ataceilingratioof10,000€/responderextra.

ForQALYsgained,theICERwas362,101,meaningthatanadditionalQALYgainedinthebCBTincomparisontoTAUwasassociatedonaveragewith€362,101highercost.(Table8).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.09ataceilingratioof0€/QALY,0.10ataceilingratioof24,000€/QALYandagain0.13ataceilingratioof35,000€/QALY.

SwedenTheanalysisforSwedenincluded147participants.TheICERforimprovementindepressivesymptomswas791,meaningthatonepointimprovementextrainPHQ-9scoreinthebCBTwasonaverageassociatedwith€791highercostascomparedtoTAU.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.19ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.89ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.

TheICERforresponsewas6,666,meaningthatanadditionalparticipantrespondingtotreatmentinthebCBTincomparisontoTAUwasassociatedonaveragewith€6,666highercost.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.19ataceilingratioof0€/responderextra,and0.64ataceilingratioof10,000€/responderextra.

ForQALYsgained,theICERwas88,745,meaningthatanadditionalQALYgainedinthebCBTincomparisontoTAUwasassociatedonaveragewith€88,745highercost.(Table8).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.19ataceilingratioof0€/QALY,0.27ataceilingratioof24,000€/QALYand0.32ataceilingratioof35,000€/QALY.



UnitedKingdomThe analysis for the United Kingdom included 90 participants. he ICER for improvement in depressivesymptomswas3,587,meaningthatonepointimprovementmoreinPHQ-9scoreinthebCBTwasonaverageassociatedwith€3,587highercostsascomparedtoTAU.Theprobabilityof thebCBTbeingcost-effectivecomparedtoTAUwas0.27ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.52ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.


ForQALYsgained,theICERwas82,530,meaningthatoneQALYmoreinthebCBTincomparisontoTAUisassociatedwith€82,530highercosts(Table8).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.27ataceilingratioof0€/QALY,0.35ataceilingratioof24,000€/QALYand0.39ataceilingratioof35,000€/QALY.

SwitzerlandTheanalysisforSwitzerlandincluded50participants.TheICERforimprovementindepressivesymptomswas-497,meaningthatonepointimprovementextrainPHQ-9scoreinthebCBTwasonaverageassociatedwith€497lowercostascomparedtoTAU.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.63ataceilingratioof0€/pointofimprovementextrainPHQ-9score,and0.88ataceilingratioof5,000€/pointofimprovementextrainPHQ-9score.

TheICERforresponsewas-6,470,meaningthatanadditionalparticipantrespondingtotreatmentinthebCBTincomparisontoTAUwasassociatedonaveragewith€6,470lowercost.TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.63ataceilingratioof0€/responderextra,and0.78ataceilingratioof10,000€/responderextra.

ForQALYsgained,theICERwas-40,375,meaningthatanadditionalQALYgainedinthebCBTincomparisontoTAUwasassociatedonaveragewith€40,375lowercost.(Table8).TheprobabilityofthebCBTbeingcost-effectivecomparedtoTAUwas0.63ataceilingratioof0€/QALY,0.70ataceilingratioof24,000€/QALYand0.73ataceilingratioof35,000€/QALY.

ConclusionsTheresultsofthepooledanalysisshowedthatthebCBTwasmoreeffectiveinreducingdepressivesymptomsascomparedtoTAU.ThedifferenceinQALYsgainedbetweenthetwogroupswasnotsignificant.Previousstudies indicated thatEQ-5D,whichweused tocalculateQALYs, isnot sensitiveenough to identifysmallchanges inqualityof life [9].Therefore, thismaybeanexplanationofour finding.ThebCBTwasnot lessexpensiveincomparisontoTAU,andthemeandifferencetotalsocietalcostwasstatisticallysignificant.Weexpectthatourestimationswillchangeafter includingmoredatafromdifferentcountriesand12-monthsfollow-updata(i.e.smallerconfidenceintervals)butwedonotexpectthatthedirectionoftheresultswillchange(i.e.overallbCBTwillpossiblyremainmoreexpensiveandmoreeffective). It is,however,possiblethatthemeandifferenceintotalsocietalcostswillnotremainstatisticallysignificant.

Theresultsfromthecountry-specificanalysisvariedconsiderablybetweenthecountries.Thedirectionoftheresults was however, similar in most countries, with bCBT being more effective than TAU but not lessexpensive.However,therearedifferencesinthedirectionoftheresultsforsomecountries,mainlyinthosewithsmallersamplesize.Forinstance,inSwitzerland,bCBTwaslessexpensiveandmoreeffectivethanTAU.



Economicmodelling–cost-effectivenessofbCBTonthelong-termThe aimof the economicmodelling (WP3)was to develop a generic set ofmodels to estimate the cost-effectivenessofinternet-based‘blended’cognitivebehaviouraltreatment(bCBT)comparedtotreatmentasusual(TAU)foradultdepressionovera5-yeartimehorizon.TwomodelsweredevelopedwithinthisWP(aMarkovmodel(MM)andaDiscreteEventSimulationmodel(DES))whichwillbepublishedinopen-accessjournals (andavailable through thee-comparedwebsite)and freelyavailable in2018 for researchersandexpertswhoare interestedtoperformcost-effectivenessanalysis indifferentcountriesorsettingsonthelongerterm.Bothmodelsexaminedthesameresearchquestion(i.e.‘IsbCBTcost-effectivecomparedtoTAUfordepressionatfiveyears?’).ThebasicdifferenceisthatMMsimulatesacohortofpatientsusingfixedtimecycles,whereastheDESsimulateseachpatientindividuallyandacontinuoustime-scale.

Thecost-effectivenessestimatesthatarepresentedherearebasedonthedata-setofDecember31st2016forboththeMMandtheDESmodel.712participantswereincludedintheMManalysesusingallbaselinedata, and 412 participants in theDES analyses using only those patients that should have finished the 6monthsfollow-updataonDecember31,2017.FortheDESmodelling,missingdatawereimputed.ForMMnodataimputationtechniqueswereapplied.Wereferaswelltothepublishedpapers(seee.g.Kolovosetal.2017)foradetaileddescriptionofthemethodsapplied.

FortheMarkovModelling,twoclinicaleffectivenessoutcomes(i.e.depression-freedaysandQALYS)wereanalysed, includingvarioussensitivityanalyses (e.g. stratificationbetweenprimaryandspecializedmentalhealthcare),andanalysesfromdifferentperspectives(e.g.societalandhealthcare).TheDESperformedananalysisfromthesocietalperspectiveusingQALYsasanoutcomeofclinicaleffectiveness.Allanalyseswillberepeated for bothmodels on the 31December 2017 dataset. Therefore, current conclusions need to betreatedwithcaution.

MarkovModelling-overallresultsFromthesocietalperspective,with treatmentavailable inbothprimaryandspecializedcaresettings, thescenariowithtreatedpatientsonly(scenario1)estimatedthatbCBTtobelesseffective(-0.2QALYand-201DFD)butalsolesscostlythanTAU(€-3,412)at5years.TheICERswere€16,941perQALYand€17perDFD(depressionfreedays).Inscenario2thatincludedapreviouslyuntreatedpopulation,bCBTwasfoundtobeslightlylesseffective(-0.05QALYand-32DFD)butalsolesscostlythanTAUat5years(€-2,450).TheICERswere€45,528perQALYand€77perDFD.Incomparisonwiththemodelsinscenario1,bCBTwasassociatedwithfewerlostQALYs(closetozero)onaverageandwaslesscostlythanTAU(vs.moreinscenario1).

Cost-effectivenessacceptabilitycurves(CEAC)estimatedtheprobabilitythatbCBTwouldbeconsideredcost-effectiveincomparisonwithTAUdependingonthedecisionmakers’willingnesstopayforaQALYandaDFDgained,respectively.Inscenario1,includingpatientstreatedinaprimaryorspecializedcaresetting,theCEACforQALYsshowedthattheprobabilitythatbCBTiscost-effectivewasneverabove2%regardlessofthecostperspective,evenwhenthewillingness topay foranextraQALYwasveryhigh. Inscenario2, includingapreviouslyuntreatedpopulation,theCEACfoundthattheprobabilitythatbCBTiscost-effectiveascomparedtoTAUwasbetween30%and40%whenDFDwereconsideredandbetween8%and18%whenQALYswereconsidered,dependingonthepayerperspective.

DiscreteEventsSimulations(DES)-overallresultsTheresults fromDESmodelestimated that thedifference inQALYs (bCBT -TAU) is0.07 (95%confidenceinterval-2.23,2.59)andthedifferenceincostsis€7,678(95%confidenceinterval-€192,290,€212,482).bCBTwasthus0.07QALYsmoreeffectiveonaverageintermsofQALYsgained(95%confidenceinterval-2.23,2.59)and€7,678moreexpensiveonaverage(95%confidenceinterval-€192,290,€212,482).However,thesemeandifferenceswerenotstatisticallysignificant.Alsonotethe95%confidenceintervalincludeupperandlowervaluesforQALYswherebCBTwasashighas2.59QALYsmoreeffectiveandaslowas2.23QALYslesseffectivethanTAU.Also,the95%confidenceintervalincludeupperandlowervaluesforcostswherebCBTwasashighas€212,482morecostlyandaslowas-€192,290lesscostlythanTAU.Theseareverylarge95%confidenceintervals. The cost-effectiveness acceptability curve shows a 50% probability that bCBT is cost-effective



comparedtoTAUforwillingnesstopayvaluesbetween0to50,000€/QALY.Theinterpretationofthecost-effectiveness acceptability curve value of 50% suggests that there is an equally likely chance that eitherinterventioniscost-effectiveateachvalueforthewillingnesstopay.Thus,therearenosignificantdifferencesinQALYsorsocietalcostsbetweenbCBTandTAU,andbCBTcannotbeconsideredcost-effectiveascomparedtoTAU.However,resultsshouldbeinterpretedwithcautiongiventhehighuncertaintyshownbythewideconfidenceintervalsandthefactthatonlyinterimresultsareincludedinthemodelnow.

ResultsfromtheMMandDESmodelsintermsofcost-effectivenessshowthusnottobeconcordant,howevertheobserveddifferencesappearrathersmall.Theresultsofthetwomodelshaveincommonthatthecost-effectivenessofbCBToverTAUfromasocietalperspectiveonthelongertermcouldnotbeconfirmed.TheydifferintermsofestimatingtheclinicaleffectivenessofbCBToverTAU.IntheMMmodelbCBTappearedtobe slightly less effectivewhile in theDESmodel bCBT appeared tobemoreeffective. Currently, it is notpossibletomakedefiniteconclusionsabouttheappropriatenessofeithermodelsfor long-termeconomicmodellingforbCBTversusTAUasdifferentsubsetsoftheavailabledatawereusedbythetwoapproaches.ThefinalanalysisonthesetofDecember2017willenableinterpretationoftheresultswithmorecertaintyandtocomparetheresultsofthetwomodelsinamorerobustmanner.

BudgetimpactanalysisusingMarkovmodellingAdynamicbudgetimpactanalysismodelwasbuiltwithintheMarkovmodeltoevaluatethepotentialbudgetimpactofincludingbCBTinthetreatmentmix(i.e.inadditiontoTAU)ofmajordepressivedisordersinagivencountry.Twoscenariosarethereforeevaluatedandcompared:

- onewhereonlyTAUisavailabletothedepressedpopulation,andtheyeitheruseitornot(therearebothtreatedanduntreatedpatients),

- onewherebothTAUandbCBTareavailabletothedepressedpopulation,andtheyeitheruseitornot(therearebothtreatedanduntreatedpatients).

Costs and health benefits (DFDs and QALYs) over a five-year period were reported annually based on ahypotheticalmixofTAUandbCBT.

Inthefirstscenario(scenario1),treatmentmixwas100%TAUand0%bCBTfromYear1to5.InthesecondscenarioinwhichbothTAUandbCBTwereavailable,a10%uptakeofbCBTatYear1wasassumed,followedbya5%increaseeachyear.

Thebudget impactwaspresentedusingtheNHIperspectivesincetheyarethemost likelypayerofbCBT.Thus,NHIwilldecidewhethertoreimbursebCBT;thisdecisionwillbeinpartbasedontheimpactofprovidingbCBTonitsbudget.Inaddition,inthemajorityofparticipatingcountriesthereareveryfewout-of-pocketexpensesforpatients,makingtheimpactontheNHIbudgetthelargest.Thebudgetimpactanalysiswasalsocarriedoutfromtheothertwoperspectives(allpayersandsocietalperspective),butresultsnotpresentedhere.Asforthecost-effectivenessanalysis,thebasecasescenario(scenario1)includedthreesituations:oneinwhichbCBTisavailableonlyinprimarycare,oneinwhichbCBTisavailableonlyinspecializedmentalhealthcare,andoneinwhichthebCBTisavailableinbothprimaryandspecializedmentalhealthcare.

ThebudgetimpactfortheNetherlandswaspresentedsothatresultsfromthecost-effectivenessanalysisandthebudgetimpactanalysiscanbeinterpretedtogether.Thesamedeterministicsensitivityanalysesasinthecost-effectivenessanalysis(seeTask3.3to3.6)werecarriedoutforthebudgetimpactanalysis.

Preliminary findings:When bCBTwas introduced in primary care only or in specialized care only, it wasassociatedwithlowercostsfortheNHIthefirstyear(€4,093,885and€28,308,102,respectively),butwithhighercostsinthefollowingyears.Inaddition,itwasassociatedwithfewerQALYsgainedinthepopulationeachyearandfewerDFDsgained.

WhenbCBTwasintroducedinbothprimaryandspecializedcare,itwasassociatedwithcostsavingsfortheNHIofover€20millionthefirstyear.However,thefollowingyearsitwasassociatedwithahighercostofbetween€48millionand€121millioneachyearasmoreandmorepatientsweretreatedwithbCBT,including



peoplethathadpreviouslybeenuntreated.Inaddition,itwasassociatedwithfewerQALYsgainedeachyear,althoughitwasbarelyvisiblewhenlookingattheper-person-per-monthlosses(closeto0).ThesamewasobservedwithDFD(betweenhalfandthree-quarterofaDFDlosteachmonthperpersonafterthefirstyear).

DeterministicsensitivityanalysesfoundthatthenumberofuntreatedpatientsinthedepressedpopulationofthecountryhadahugeimpactontheoverallbudgetimpactofbCBT.

ConclusionsTheMarkovandDESmodelsdevelopedintheE-COMPAREDprojectareuniversallyapplicable(i.e.generic)models for assessing the cost-effectiveness of bCBT in comparison with TAU including for countries notparticipatinginE-COMPARED.Adecision-makerfromanon-participatingcountrymayusethegenericmodelstoassessthecost-effectivenessofbCBTinhisorherowncountrybyadjustingawiderangeofparameterstoreflecttheirsituationascloselyaspossible(e.g.repartitionofpatientsbyseveritylevels,typeofcaresettinginwhichbCBTwillbeintroduced,costperspectiverequiredtomakethedecision,unitcosts,etc.).Toachievestableassessments,themodelswillbepopulatedwiththeDecember2017trialdata-setinstep3ofthethree-steppedanalysis.

PredictiveModelling–whobenefitsmost?InWP4machinelearningtechniqueswereappliedtopredictonanindividualpatientlevelwhetherbCBTorTAUwould lead to the best treatment outcome. For these analyses,WP2 trial data including EcologicalMomentary Assessments were used from the various data sets. The modelling showed that baselinemeasuresandearlytreatmentresponsecanbeusedtopredictthemoodofindividualpatientsandtreatmentoutcomewithafairlevelofcertainty(areaundertheROCcurve(AUC)CIof0.7016–0.7769).Predictionofshort-termchangesofdepressivesymptomsprovedhowever,tobestilldifficultandaddingtheEMAdataintothemodeldid,unexpectedly,notimprovepredictionaccuracy.Theseexplorativeresultsjustifyfurtherresearch into the application of machine learning techniques for predictive modelling activities, therebycontributing to a personalizedmental health service strategy.We assume to achieve a higher predictionaccuracywhenweareabletoincludemoredataintoourmodels.Wereferforamoredetailedaccountoftheinnovativepredictivemodellingstrategiesandresultstothetothepapersthathaveyetbeenpublishedininternationalpeerreviewedjournals(seesectiononscientificoutput).

BusinesscasemodellingABusinessCaseModelling tool (BCMT)wasdevelopedenabling servicedeliveryorganisationsandhealthsystemplannerstobuildpersonalizedandcontextualizedbusinesscasesforbCBTandTAUinterventionsondifferent levels of service delivery. The tool enables evaluation of service cost delivery,margins,market-shares,andreturn-on-investments.ThisBCMTisopensourceandaccessibleforallthosewhoareinterestedthroughtheE-COMAPREDConsortiumandreportedoninDeliverableD5.7.

InsumThefirstoverallresultsoftheE-COMPAREDprojectshowthat:

- bCBTforadultdepressioninroutinementalcareisfeasible,acceptableandimplementableamongawidevariety of EU countries with different levels of digital mental health experience, ranging from‘frontrunners’ (NL, SWE, UK), to ‘runners’ (Germany, Denmark), ‘joggers’ (Switzerland) and ‘strollers’(Spain,PolandandFrance).SharingeMHknowledgeanddigital interventionsamongEUcountriescanspeeduptheknowledgeanddigitalservicesrequiredforimprovingdepressiontreatmentinroutinecare.

- BlendedCBThasahighchangeofbeingsignificantlysuperiortoTreatment-as-Usualatmonth3and6,and non-inferior atmonth 12 based on pooled data analyses. bCBTmay lead to a significant higherdecreaseinMDDdiagnosescomparedtoTAU12monthsafterbaseline.

- Specifichealthcarecontextsshowvarianceinclinicalandcost-effectivenessoutcomes.



- Froma societalperspectiveandat the short term (12months),blendedCBT seems to lead tobetterclinical outcomes compared to TAU but at higher costs. From a healthcare providers’ perspectivedifferencesincostsarenon-significant.

- Theestimationsforthe5-yeartimehorizonareyetinconclusive.TheMarkovmodelsestimateahigherchanceofbCBTtobemoreexpensiveandinsomecaselesseffective,dependingonthescenariotakenintoaccount.TheDEShaveamoreconsistentestimationinlinewiththe12monthsCEAresults(betterclinicaloutcomesforbCBTbutathighercosts).

- Itseemspromising(fairly/feasible)topredicttreatmentoutcomesforindividualpatientsbyexplorativemodellingonbaselineassessmentsandmakinguseofmachinelearningtechniques.Itshouldbenotedthatthistypeofpersonalizedmodellingapproachisstillinit’sinfancy.

- Europeanandnational/regionalstakeholdersoptforincreasingtheuseofeMHinroutinementalhealthcarepracticeforallmentaldisorders.

- PatientsareassatisfiedwithblendedCBTaswithTreatment-as-Usualand3outof4ratetheusabilityofthedigitaltreatmentplatformsappliedintheE-COMPAREDprojectas(very)good.

- CollaborationandsharingbCBTtreatmentandtechnicalsolutionsacrossEuropeansettingsandcountriesispossibleandcanacceleratedevelopmentanduptakeofeMHinroutinepractice.

RecommendationsBasedonapooledanalysisof9EUcountriesbCBThasbeenestimatedatbeingsuperiortoTAUat3and6monthsfollowupandatleastnon-inferiorat12monthsfollowup.ItisestimatedhoweverthatbCBTwasnotlessexpensivethanTAUat6and12monthswhenassessedfromasocietalperspective(notsurprisinglywithproduction lossesasthehighestcost-driverasdepressionhasaknownsubstantial impactonproductivitylosses).Fromahealthcareprovidersperspective(oneyearperspective) thedifferences incostswerenotsignificantdifferentbetweenbCBTandTAU.bCBTdidthusperformclinicallybetterthanwehypothesizedbutagainsthighercostsfromasocietalperspectiveandnon-significantdifferenceincostfromahealthcareprovidersperspective.Basedontheseresultsandthefeedbackofstakeholdersthatwereconsultedduringthe total duration of the E-COMPARED project, the consortium (that included a patient representativeorganisationasprojectpartner(GAMIAN)formulatedthefollowingmainrecommendations:

- Increasetheactive involvementof ‘patients’ inall stagesofeMental-health innovationfordepressiontreatment,includingdevelopmental,researchandimplementationactivities.Patientsstresstheirneedsfor access to evidence-based digital mental health but also emphasize the need for an increase ofawarenessandaccesstodigitalinterventionsfordepressioninroutinecareforbothpatientsandhealthprofessionals.

- TreatmentprotocolsfordepressionusingbCBTcouldbefurtheroptimisedinrelationtothesettinginwhichtheyareused,e.g.primaryversusspecialisedmentalhealthcareservicesandinrelationtothedoseoftreatmentandthehealthservicecontextinwhichtheyaremostsuccessfullyapplied.Thesedifferbetween EU countries based on the characteristics of their health care system including the healthreimbursementsettingandtheneedsofpatientsandserviceproviders.

- Trans-diagnosticbCBTtreatmentprotocolsfore.g.depressionandanxietycouldbeexploredandtestedgiven the high comorbidity between depression and anxiety in routine care populations. In addition,translatethebCBTfordepressionComparativeEffectivenessResearchresultstoothermentaldisorders.

- TheE-COMPAREDtrialsindicatedthatbCBTisacceptableandvaluedasgoodasTAU(andinsomecasesevenbetter),bCBTcouldthereforefunctionasanadditionaltreatmentoptioninroutinecare.Comparedtoefficacytrials,thesampleofE-COMPAREDtrialsreflectedahigherdegreeoflowereducatedpersons,however persons with a lower educational background, male patients and migrant patients are stillunderrepresented.Futuretrialsshouldspecificallyfocusonthesetargetgroups.

- IncreaseawarenessaboutdepressionandpotentialuseofeMHingeneralandbCBTspecificallyamongstemployersandemployeesforbothtreatmentandpreventionpurposesasthehighestcost-driverfromasocietalperspectivearecostsduetoproductivitylosses.

- FosternationalandEUpolicydevelopmentandcollaborationregardingtheintegrationofeMHingeneralandbCBTspecificallyinprofessionalguidelines,professionaltrainingandeducationcurricula.



- Fosteraprogrammaticapproachtotheimprovementofthepreventionandtreatmentofdepressionbymeansofdigitalmentalhealth(eMH)byroadmappingindividualH2020projecttostrengtheningthewin-winofindividualprojectsandtheimplementationoftheirresultsaftertheprojectshavebeenfinished.EmbedtheseprojectsinactionplansofEUinitiativessuchasROAMERandtheJointActionforMentalHealthandWellbeing.

- Supportfutureresearchwithinthedomainofpersonalizedpsychotherapyfordepressionbymeansofmodelingstudiesusingsophisticatedmachinelearningtechniques.

DisseminationandscientificoutputsAlready in the course of the project the E-COMPARED consortium published 14 scientific articles ininternationalpeer-reviewedscientificjournalsincludingJAMA;TRIALS;JMIR,QualLifeRes.;JAffectDisord.andInternetInterventions.Fourpapersaresubmittedandunderpeer-review.E-COMPAREDwaspresentedinmore than 14 high profile oral presentations, 8 posters, a round table discussion, and a workshop atinternationalhigh-impactconferencesincludingISRII(2016,2017),theEuropeanHealthForumGastein,theEuropeanPsychiatryAssociationConferenceandtheWPAWorldCongressofPsychiatry.TheprojectobtainedsubstantialattentionasitisgoballythefirstbCBTtrialfordepressioninroutinecare(includingthelargestsample). Furthermore, partners in the E-COMPARED project engaged in over 60 regional and nationaldissemination activities for different target groups ranging from patient organisations to professionaltherapist associations and relevant networks (e.g. foundation FondaMental, France) and health insurersrepresentatives (e.g. theNetherlands InovationFoundationofHealth Insurers.Theworkalready receivedrecognitionofthefieldasitwontheprestigiousErlangerMedizinpreis2017inGermany.Furthermore,closecollaborationandstrengtheningofcombinedactivitieshasbeenestablishedwithotherrelatedprojectssuchastheMasterMindproject(CIP-ICT-PSP),iCARE(H2020-SC1),eMEN(EUINTEREGG-NW),andImpleMentAll(H2020-SC1),bywhichtheE-COMPAREDresultsdirectlyareappliedandimplementedinroutinecare.Withthese projects, a portfolio of research and innovation has been established in advancing science andimprovingmentalhealthcare.AllthisinformationandmoreisaccessibleandfrequentlyupdatedthroughtheE-COMPAREDwebsite(www.e-compared.eu)andothersocialmediachannels.

E-COMPARED - Final Report - publishable summary

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