R11_rTMS for depression evidence review FINAL REPORT.pdf

Report#0513002R11.2rTMSforDepressionPlainLanguageSummary

TransportAccidentCommission&WorkSafeVictoria

EvidenceService

RepetitiveTranscranialMagneticStimulation(rTMS)forDepression

Plainlanguagesummary

DepressionisacommonmentalhealthillnessinAustralia.

Medicationandpsychotherapyaretheusualtreatments,butforsomepeople,thesedontwork.Forthesepeople,ElectroconvulsiveTherapy(ECT)mayhelp.

DuringECT,apatientisputtosleepusingageneralanaesthetic.Whileasleeptheirbrainisgivenanelectricshock.ECTcanhavesideeffects.

RepetitiveTranscranialMagneticStimulation(rTMS)isanewtreatment.AmagneticpulseisusedinrTMS.Thereisnoneedforananaesthetic.

FoursmallstudieshavebeenidentifiedwhichcomparerTMSwithECT.NostudiesfoundthatrTMSwasbetterthanECT.EighteenstudiescomparedrTMSwithnotreatment.ItisnotclearifrTMSisbetterthannotreatment.

TherearedifferentideasonthebestamountandstrengthofrTMS,butnooneknowsthebestwaytouserTMSyet.Moregoodstudiesareneeded.

1

Report#0513002R11rTMSforDepressionEvidenceReview


EvidenceService

RepetitiveTranscranialMagneticStimulation(rTMS)forDepressionEvidenceReview

March2013OrnellaClavisi,EmmaDonoghue,NatashaDodge,JasonWasiak

2Report#0513002R11rTMSforDepressionEvidenceReview

CONTENTS

CONTENTS.............................................................................................................................................2ACKNOWLEDGEMENTS..........................................................................................................................2EXECUTIVESUMMARY...........................................................................................................................3BACKGROUND.......................................................................................................................................4METHODS.............................................................................................................................................7RESULTS................................................................................................................................................8FINDINGS............................................................................................................................................17DISCUSSION........................................................................................................................................19CONCLUSION.......................................................................................................................................20SUMMARYOFSYNTHESISEDSTUDIES..................................................................................................21REFERENCES........................................................................................................................................29

ACKNOWLEDGEMENTS

Theauthorswouldliketothankseveralcolleaguesfortheirassistanceinpreparationofthisdocument.

LisaSherryfromTAC/WSVforeditingofPlainLanguageSummary.

AnneParkhillforherliteraturesearchingservices.

LorettaPiccennaforproofreading.


EXECUTIVESUMMARY

Overview

Weupdatedthemostcomprehensive,uptodate,highqualitysystematicreview(Gaynesetal.2011),whichinvestigatedtheeffectivenessofrTMS.Overalltwentyonestudieswerereviewedbythisreport.Thestudieswereinconsistentintheirresults,withhalfreportingrTMSwasaseffectiveasECTandhalfreportingECTasbetter.However,smallsamplesizesandvastvariabilityregardingrTMSparameterandoutcomeshasledthereviewtoconcludethatthereisinsufficientevidencetodeterminewhetherthebenefitsandharmsofrTMSarebetter,worseorthesameasECT.Whatistheeffectivenessandsafetyoftranscranialmagneticstimulation(rTMS)intreatingacutephasedepressivesymptoms(e.g.,responseandremission)?

Theevidencetoanswerthisquestionisinconclusive.

Whatistheeffectivenessandsafetyoftranscranialmagneticstimulation(rTMS)inmaintainingresponseorremission(e.g.,preventingrelapseorrecurrence),whetherasasingletreatmentorpartofacombinationtreatment?


Inwhatsetting,inpatientoroutpatient,isrTMSmosteffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?


WhatrTMSprotocolsi.e.whatnumberoftreatmentsoverwhattimeperiod,areeffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?



BACKGROUND

Patientgroupandtreatmentpathway

Majordepressivedisorder(MDD)isacommonmentalhealthdisorderdefinedbythepresenceofadepressedmoodeverydayformorethantwoweeks.ClinicaldiagnosisofMDDismadebasedonthepresenceofanumberofsymptomsincluding:

Depressedmoodmostoftheday

Lossofinterestorpleasureinallormostactivities

Largeincreasesordecreasesinappetite

Significantweightlossorgain

Insomniaorexcessivesleeping

Agitationorrestlessness

Fatigueorlossofenergy

Feelingsofworthlessnessorexcessiveorinappropriateguilt

Diminishedabilitytoconcentrateorindecisiveness

Recurrentthoughtsofdeathorsuicide1

InAustralia,mentalhealthdisordersarethelargestcauseofnonfataldiseaseburden.2MDDisoftenarecurrentdisorder,thuslongtermtreatmentisnecessarytopreventnewepisodesfromoccurring.ForpatientswithMDD,firstlinetherapyinvolvespharmacologicaltreatment(e.g.,tricyclicantidepressants,serotoninreuptakeinhibitorsandserotoninnorepinephrinereuptakeinhibitors),psychotherapy,oracombinationofboth.Wherethereistreatmentfailureonapharmacologicalagent,aswitchtoanantidepressantdrugwithadifferentmodeofactionisthepreferredsecondlinetreatment.Ifthedepressiveillnesspersists,severaloptionsareavailable,namely,addinganaugmentingagent,suchaslithiumcarbonateortriiodothyronine,switchingtoamonoamineoxidaseinhibitorforpatientswithatypicalmajordepression,oraddingeithercognitivetherapyoranotherformofpsychotherapy.3

Forpatientswhohavenotrespondedorarerefractorytopharmacologicagentsand/orpsychotherapy,treatmentoptionscanincludeelectroconvulsivetherapy(ECT),vagusnervestimulation(VNS)andtranscranialmagneticstimulation(TMS).4ECTisgenerallyconsideredthenextlineoftherapyforMDDpatients.ECTinvolvesthedeliveryofanelectricalcurrenttoinduceaseizurefortherapeuticpurposes.BeforetheadministrationofECTpatientsareanaesthetisedandan


appropriatemusclerelaxantisadministered.ECTisusuallygiventwiceaweekandthenumberofsessionsundertakenforpatientstorespondusuallyrangesfromsixtotwelve.5

AlthoughECThasbeenshowntobeeffective,itisassociatedwithcognitivesideeffectsandrisksassociatedwithrepeatedanaesthesia,5forthisreasonrTMShasemergedasapotentialalternativetreatment,asitdoesnotrequireanaesthesia.

Repetitivetranscranialmagneticstimulation

Transcranialmagneticstimulationinvolvesplacinganelectromagneticcoilagainsttheforeheadnearanareaofthebraininvolvedinmoodregulation.TMSworksbycreatingmagneticpulsesintheloopsofthecoil.Thesemagneticfieldpulsesproducesmallelectriccurrentsthatstimulatenervecellsinthebrain.Whenthepulsesaredeliveredrepeatedly,itisreferredtorepetitivetranscranialmagneticstimulation(rTMS).IncontrasttoECT,rTMSdoesnotinvolvepassingelectricalcurrentsdirectlythroughthescalpandthereforedoesnotrequireanaesthesia.rTMSisusuallygiveninadiscretecourse,mostcommonlydailyforbetween15and30consecutiveweekdayswithtreatmentsessions,lastingbetween30and45minutes.6

TherTMStechniquecanvaryinmanydifferentways,suchas:7,8

Coilplacement(usuallytheleftorrightdorsolateralprefrontalcortex(DPFC))

Stimulationintensity(determinedbytheindividualsmotorthreshold)

Stimulationfrequency(usually1to20HzovertheleftDPFC,andlowerfrequencies(


respondtooneclassofantidepressanttherapy,andfailedtorespondtooneformofpsychologicaltherapy(suchCBTorinterpersonaltherapy,IPT)?9

IntheUnitedStates,theFoodandDrugAdministrationhasprovidedguidancethatrTMSisintendedtobeusedtotreatthesymptomsofMDDwithoutinducingseizureinpatientswhohavefailedatleastoneantidepressantmedicationandarecurrentlynotonanyantidepressanttherapy.10

InAustraliathemagneticstimulatormanufacturedbyMagVenture,hasbeenapprovedforlistingontheAustralianRegisterofTherapeuticGoods(ARTG)fortheintendedpurposeoftreatmentofMajorDepressiveDisorderinadultpatientswhohavefailedtoachievesatisfactoryimprovementfromtwopriorantidepressantmedications,atorabovetheminimaleffectivedoseanddurationinthecurrentepisode.

In2008rTMSwasrefusedfundingundertheAustralianMedicareBenefitsSchedule(MBS).8TheMedicalServicesAdvisoryCommitteeiscurrentlyreconsideringfundingforthistechnology.11

Intendedpurposeofthereview

TheTransportAccidentCommission(TAC)andWorkSafeVictoria(WSV)requestedareviewoftheevidencetodeterminewhetherrepetitivetranscranialmagneticstimulationisaneffectivetreatmentformajordepressivedisorder.Thisreportsoughttoanswerthefollowingquestions:

1. WhatistheeffectivenessandsafetyofrTMSintreatingacutephasedepressivesymptoms(e.g.,responseandremission)?

2. WhatistheeffectivenessandsafetyofrTMSinmaintainingresponseorremission(e.g.,preventingrelapseorrecurrence),whetherasasingletreatmentorpartofacombinationtreatment?

3. Inwhatsetting,inpatientoroutpatient,isrTMSmosteffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?

4. WhatrTMSprotocols,i.e.,whatnumberoftreatmentsoverwhattimeperiod,areeffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?


METHODS

Thereviewmethodsareoutlinedbrieflybelow.MoredetailedinformationaboutthemethodologyusedtoproducethisreportisavailableinAppendices1and2.AllAppendicesarelocatedintheTechnicalReportaccompanyingthisdocument.

Stage1:Identifyrelevantresearch

AcomprehensivesearchofMedline,Embase,AllEBMReviews(CochraneDatabaseofSystematicReviews,ACPJournalClub,DARE,CCTR,CMR,HTA,NHSEED),CINAHLandWebofKnowledgewasundertakeninJuly2012toidentifyrelevantsynthesisedresearch(i.e.,evidencebasedguidelines(EBGs),systematicreviews(SRs),healthtechnologyassessments(HTAs));andrelevantrandomisedcontrolledtrials(RCTs)andcontrolledclinicaltrials(CCTs).AcomprehensivesearchoftheInternet,relevantwebsitesandelectronichealthdatabaseswasalsoundertaken.

Studiesidentifiedbythesearcheswerescreenedforinclusionbytworeviewers(ED&JW)usingspecificselectioncriteria.Anydiscrepanciesinstudyselectiondecisionswerediscussedandresolved.Duetothenumberofprimarystudiesidentified,studiesthatwerereportedonlyinabstractformwereexcluded,astheyprovidelimitedinformationthusprecludingqualityappraisalfrombeingconducted.

Forfurtherinformation,seeAppendix2,TableA2.1forinclusionandexclusioncriteria,TablesA2.22.4forfurthersearchstrategydetails,andAppendix3forlistsofincludedstudiesbystudytype.

Stage2:Developanevidencemapofsynthesisedstudies

Duetothelargenumberofsynthesisedstudiesidentifiedonthistopicwedevelopedanevidencemaptoidentifytheircurrency,comprehensivenessandquality.AdetaileddescriptionoftheevidencemapmethodologycanbefoundinAppendix1.

Currency

Thecurrencyofthereviewwasassessedusingtheyearofpublicationandsearchdate.

Comprehensiveness

Comprehensivenesswasassessedbythebreadthofstudiesthatthereviewsincluded.WecrossreferencedtheRCTsidentifiedbyoursearchandtheRCTsincludedinthereviewstoidentifywhetheranystudiesweremissing.

Qualityassessment

QualityassessmentwasconductedusingtheAMSTARtool(fortheAssessmentofMultipleSysTemAticReviews)12(seeAppendix4,TablesA4.2andA4.3).TheAMSTARisanelevenitemtooldesignedtogiveanoverallscoreforSRsbasedontheirmethodologicalquality.ThesescoresgiveanindicationoftheriskofbiasofeachSRwith0/11representinglowestquality(highestriskofbias),and11/11highestquality(lowestriskofbias).Forreviewsinwhichnometaanalysishasbeen


performed,theAMSTARscoreiscalculatedwithadenominatorofnineinsteadof11,asthetwoAMSTARitemsthatrelatespecificallytometaanalysisarenotapplicable.

Stage3:Identifyandupdatethemostrecent,comprehensive,highqualitysynthesisedstudy

Based on the results of the evidencemap,we identified themost recent, comprehensive, highqualitysynthesisedstudyonwhichtobaseourreview.Thisreviewthenunderwentamoredetailedqualityappraisalandnewstudiesnotincludedintheoriginalreportwereincorporated.

InthisreportwepresentanevidencemapofexistingstudiesontheeffectivenessofrTMSfordepression(Table1)andanupdateofthemostrecent,highqualityreview(Gaynesetal20114).

RESULTS

Databasesearchesyielded2,757articles.Afterdeduplication,1,499werescreenedagainstourselectioncriteria.Ofthese,248fulltextarticleswereretrievedandscreened,andofthese104paperswereidentifiedasrelevanttothereview.OnefurtherstudywasidentifiedthroughthescreeningofGooglesearchresults.

Intotal,105paperswereincluded,consistingof:

214,8,1331synthesisedstudies(SRs,MA,orEBGs) 8432113primarystudyreferences(RCTsorCCTs)

Table1.Evidencemapofidentifiedstudies

Synthesisedstudies Primarystudies TOTAL

21(20SRs/MA+1EBG) 84(81RCTs+3CCTs) 105

Key:SR=systematicreview;MA=metaanalysis;EBG=evidencebasedguideline;RCT=randomisedcontrolledtrial;CCT=controlledclinicaltrial

SUMMARYOFSYNTHESISEDSTUDIES

The21synthesisedstudieswerereviewedtoidentifytheircurrency,comprehensivenessandquality.

Overalleightofthe21reviewswerepublishedinthelastfiveyears,i.e.,between2013and2009.ThemostrecentofthesewereMinichino2012,25Gaynes2011,4andAllan2011.14ThemostuptodatesearchwasconductedbyGaynes20114withasearchdateofNovember2010.

Inclusioncriteriafordepressionvariedacrossreviews.Forexample,somereviewsfocusedonpatientswithMDD,othersonpatientswithMDDordepressionalone,whileothershadmixedpopulations,e.g.,MDDorbipolar;or,MDDorTreatmentResistantDepression(TRD).OnlyGaynes20114specificallyfocusedontheindicationofTRD.


Withregardstothecomparator,sixreviewsincludedevidenceforbothrTMSvs.ECTandrTMSvs.shamrTMS.4,13,2628,31ThirteenreviewsexclusivelycomparedtheeffectofrTMSwithshamrTMS1424,29,30andtwoexclusivelycomparedrTMStoECT.8,25

UsingtheAMSTARtoolweassessedthequalityofeachofthereviews.Overallthequalityofthesereviewswaspoorwithonlyfourofthe21reviewsscoringgreaterthan8/11.Onlyonereview,Gaynes2011,4attainedaperfectscoreontheAMSTARtool(seeTablesA4.2A4.3).

Basedonourassessmentoftheevidencemap,themosthighquality,recent,synthesisedstudywastheSRbyGaynes2011.4Anupdateofthisreviewispresentedinthisreport.

UPDATEOFMOSTRECENT,HIGHQUALITY,SYNTHESISEDSTUDY

TheSRbyGaynes20114isalargeanddetailedreportpreparedfortheUSAgencyforHealthCareResearchandQuality.ThisreviewexaminednonpharmacologicinterventionsforTRDinadults.Interventionsassessedinthisreportincluded:rTMS,ECT,VNSandevidencebasedpsychotherapy(i.e.,cognitivebehaviouraltherapy).Thisreportwaspublishedin2011,withevidencesearchesconductedupuntilNovember2010.ForthepurposeofthisreportweonlyfocusedonupdatingthesectionrelevanttorTMScomparedtoplaceboorECT.UsingtheAMSTARtoolandadetailedqualityassessmenttool,thisSRwasfoundtobeofhighquality,meetingallqualitycriteria(seeTablesA4.2andA7.1ofTechnicalReport).

InupdatingthisreviewweidentifiedfivenewRCTs;32,51,67,70,108fourcomparingrTMSwithshamrTMSandonecomparingrTMStoECT.Overall,includingthestudiesreviewedbyGaynes2011,4atotalof22RCTsreportedacross25publicationswerereviewedinthisreport.Ofthese,fourstudiescomparedrTMStoECTand18studiescomparedrTMSwithshamtherapy.ThecharacteristicsofallincludedstudiesareoutlinedinTablesA5.1A5.6oftheTechnicalReport.

WeinvestigatedthepossibilityofupdatingthemetaanalysisofrTMSvs.shamprovidedintheGaynesreport4withtheadditionoffournewstudies(Fitzgerald2012,51Aguirre2011,32Triggs2010108andJakob200867).However,thiswasnotpossibleduetoalackofdataregardingremissionorresponseratesinthenewpapers,andinconsistentreportingoftheprimaryoutcomemeasurebetweenstudies(i.e.,differentpapersuseddifferentmeasurementscales,orreportedresultsinpercentage,orgraphformonly).


StudiescomparingrTMSwithECT

Studycharacteristics

Fourstudies(reportedacrosssixpublications)wereidentifiedcomparingrTMSwithECT.

Samplesize

Allstudieshadsmallstudypopulationsrangingfrom40to73patients.

Patientpopulation

AllstudiesincludedpatientswithMDD.ThediagnosticinstrumentsusedtodefineMDDvariedbetweenstudieswithonestudyusingDSMIV(DiagnosticandStatisticalManualofMentalDisorders,fourthedition),onestudyusingHAMD(HamiltonRatingScaleforDepression).TwostudiesdidnotreportonhowMDDwasdefined.

Treatmentfailure

Priortreatmentfailuretopharmacotherapydifferedamongstudies:twostudiesRosa2006100andKeshtkar201170recruitedpatientswithtwoormorepriortreatmentfailuresandonestudy58recruitedpatientswithoneormorepriortreatmentfailures.Twostudies46,73didnotreportonpriortreatmentfailure.

rTMSparameters

TherTMSparametersusedtoadministertreatmentdifferedbetweenstudies.Thefrequencyatwhichthepulseswereadministeredwas10Hzinthreestudies.58,100,114Onedidnotreportthefrequencyused.Themotorthresholdwas90%intwostudies,58,70100%inonestudy100and110%inonestudy.114Thenumberoftrainsvariedfromtwototwentywithvariationinthelengthoftrainfromfiveto60seconds.Theintertrainintervalvariedbetween20and160seconds.Thenumberofpulsesvariedfrom408to2500pulsespersession.Thenumberoftreatmentsvariedbetween915sessions.Numberofsessionsperweekvariedbetweenthreeandfivesessionsperweek.

ECTparameters

Studiesvariedbetweenbilateralorunilateralelectrodeplacement.StudiesvariedinintensityofECTtreatment,between1.5and4.5timesseizurethreshold.

Setting

Twopublicationsreportedthatstudieswereconductedinbothinpatientandoutpatientssettings,threewereexclusivelysetwithinaninpatientsettingandonedidnotreportonsetting.

Outcomes

AllstudiesassessedtheeffectivenessofrTMSintreatingacutephasedepressivesymptoms,nostudiesassessedmaintenanceofresponseorremission.Allofthestudiesexceptoneusedaversion


oftheHamiltonRatingScaleforDepression(HAMD1758,114andHAMD2470)toassessimprovementsindepression.OtherscalesusedtoassessresponseincludedClinicalGlobalImpressionScale100andtheBeckDepressionInventory(BDI).70Definitionofresponseandremissiondifferedbetweenstudies.ForexampleRosa2006100definedresponseasHAMD177whileGrunhaus200358definedresponseasadecreaseof50%ormore,orHAMD1710andafinalGlobalAssessmentofFunctionScalerating60.IntermsofremissionRosa2006100defineditasHAMD177,whileMcLoughlin2007114andGrunhaus200358definedremissionasHAMD178.Themajorityofstudiesexclusivelyassessedoutcomesatendoftreatment,onlyMcLoughlin2007114assessedoutcomesatsixmonths.

Results

WithregardstotheeffectivenessofrTMScomparedtoECT,twostudiesfoundnosignificantdifference100,58andtwostudies114,70foundrTMStobelesseffectivethanECT.

Responsetotreatment

Rosa2006andGraunhaus2003reportednosignificantdifferenceinendpointscoresbetweenrTMSandECTmeasuredonHAMD1758andClinicalGlobalImpressionScale.100Inaddition,forthosestudiesreportingresponserates58,100nosignficantdifferencebetweenrTMSandECTwasobserved.Keshtkar201170andMcLoughlin2007114observedsignificantlylowerendpointscoresontheHAMD24andBDI;andtheHAMD17respectively.

Remission

Ofthethreestudiesreportingonendoftreatmentremission,two100,58foundnosignficantdifferencebetweenrTMSandECT.Oneother114foundtherateofremissionwaslowerforrTMScomparedtoECTattheendoftreatment,althoughthiseffectwasnotsustainedatsixmonthswithbothtreatmentarmsbeingequivalent.

Severityofsymptoms

Keshtkar201170foundECTtobemoreeffectiveinreducingposttreatmentBDIandHAMDsuicidescorescomparedtorTMS.

Neurologicalfunctioning

Twostudies100,114conductedneurologicalassesmentsbeforeandaftertreatment.NeitherstudyfoundasignificantdifferenceinneurologicalfunctioningbetweenrTMSandECTposttreatment.

Adverseeffects

NosignificantdifferenceinadverseeffectswasobservedbetweenrTMSandECTtreatmentfortwostudies.70,100OverallthemainsideeffectsreportedforrTMSincludedlocalisedpainormildheadache.ThestudybyKeshtkar201170withdrewtwopatientsintheECTgroupduetoalossofconciousness.Adverseeventswerenotcomparedbetweengroupsfortwostudies,asGrunhaus


200358didnotreportadverseeventsfortheECTgroup,andMcLoughlin2007114didnotreportadverseeventsforeithergroup.

StudiescomparingrTMSwithshamrTMS

Studycharacteristics

EighteenRCTs(reportedacross19publications)wereidentifiedcomparingrTMSwithshamrTMS.CharacteristicsofthesestudiesareshowninTable2.

Samplesize

Thesamplesizesofthe18includedstudiesrangedbetween12and325patients.Themajorityofstudieshadsmallsamplesize,fivehadasamplesizeof20orless,65,69,82,94,96and11studieshadbetween21and68patients.Amongthesestudiesthereweretwolargetrials,withsamplesizesof199,55and32592patients.

Patientpopulations

Allstudiesrecruitedpatientswithmajordepression/MDD.Majordepressivedisorderwasdefineddifferentlyacrossstudies,withninestudiesusingDSMIV;oneusingDSMIVorSCID(StructuredClinicalInterviewforDSMdisorders);oneusingHAMD25;oneusingDSMIVorHAMD17orMADRS(MontgomerysbergDepressionRatingScale)orBDI;oneusingDMSIVorSCIDorHAMD21.Twostudiesdidnotreporthowmajordepressionwasdefined.Otherdefinitionsincludedmajor/minordepression(DSMIV),82medicationresistantdepressionofpsychoticsubtype(DSMIII),96moderatetosevereTRD(HAMD17),andunipolardepression(DSMIV).52

Treatmentfailure

Fourteenstudiesreportedthatpatientsspecificallyhadtwoormorepriortreatmentfailureswithmedications.Twostudieshadoneormoretreatmentfailuresandtwodidnotspecifythenumberoftreatmentfailures,butwerejudgedtohaveahighprobabilityofhavingtwoormoretreatmentfailures.

rTMSparameters

DetailedrTMSparametersfortheincludedstudiesareshowninTable3.Location,frequency,motorthresholds,anddurationoftreatmentvariedacrossstudies.

o Comparisons:ElevenstudiescomparedrTMStoshamstimulation.Theremainingsevenstudiescomparedeitherdifferentfrequencyparameters,54,67,95differentlocations51,94,108ordifferentfrequenciesindifferentlocations106withsham.

o Location:rTMSwasmostfrequentlyconductedoverthetheleftDPFC,thisoccurredin12outof18studies.Insixstudies,rTMSwasconductedovertherightDPFC.Inthe


remainingstudies,rTMSwasappliedanteriortotherightmotorcortex,69invaryinglocations,54,96ortoanunspecifiedlocation.67

o Frequencyandmotorthreshold:Inthe13studiesthatusedLDPFCrTMS,frequenciesrangedbetween1Hzand20Hz,with10Hzmostcommon(sixstudies)followedby20Hz(fourstudies).MotorthresholdsinLDPFCstudiesrangedbetween80%and120%,with110%mostcommon(fivestudies)followedby120%(threestudies).InthesixstudiesthatusedRDPFCrTMS,frequenciesrangedbetween0.3Hzand5Hz,with1Hzthemostcommon(fourstudies).MotorthresholdsinRDPFCstudiesrangedbetween90%and120%,with110%mostcommon(threestudies).

o Duration:treatmentconsistedoffivesessionsperweekforallstudies,withthenumberofweeksrangingbetweenoneandfourtosixweeks.Themostcommontreatmentdurationwastwoweeks(eightstudies),followedbyoneweekandfourweeks(fourstudieseach).Thestudiesthathadaoneweekdurationtendedtobetheoldeststudiesinthegroup(publishedbetween1996and2001),withtheexceptionofPallanti(2010).95

Setting

Sevenstudieswereconductedinanoutpatientsetting,onewasconductedinbothinpatientandoutpatientssettings,andtheremainingtendidnotspecifythetypeofsettinginwhichtheywereconducted.

Outcomes

AllstudiesexclusivelyassessedtheeffectivenessofrTMSfortreatingacutephasedepressivesymptoms;nostudiesassessedmaintenanceofresponseorremission.AllofthestudiesexcepttwousedaversionoftheHamiltonRatingScaleforDepression,HAMD17,HAMD21andHAMD25(abbreviatedasHRSD,HDRS,orHAMD)toassessimprovementsindepression.Onestudy55didnotreporttheratingscaleused,reportingonlyremissionrates.OnestudymeasuredimprovementsindepressivesymptomsusingtheMADRS.92


Table2.CharacteristicsofrTMSvs.shamrandomisedcontrolledtrialsYear Study n Diagnosis Rx

failureSetting Outcomes Response

definitionRemissionDefinition

Followup

2012 Fitzgerald(51) 67 TRDdiagnosisofmoderatetoseveredepression(>15HAMD17)

2+ NS CDS(HAMD17),response,MADRS,BDI,AE 50%reductioninHAMDscore

N/A EOT(3wk)+FU(3wkPT)

2011 Aguirre(32) 34 Majordepression 2+* OP CDS(HAMD),response HAMD


Table3.rTMSparametersforrTMSvs.shamrandomisedcontrolledtrialsYear Study Freq

(Hz)MT Location Trains Train

lengthInterval(seconds)

Pulsespersession

Sessions Days/Weeks Comments

2012 Fitzgerald(51)(Lparameters) 10 120% LDLPFC 30 5s NS NS 15 3weeks Lparametersonly2012 Fitzgerald(51)(SBarmRparameters) 1 120% RDLPFC 1 15min NS NS 15 3weeks LfollowedbyRparameters2011 Aguirre(32) 1 110% RDLPFC 20 60s 45s 1200 20 4weeks 2010 Pallanti(95)(lowfreqarm) 0.3 90% RDLPFC 10 25s NS 75 5 1week 2010 Pallanti(95)(highfreqarm) 10 90% RDLPFCthen

LDLPFC5 5s 30s 250 5 1week

2010 Zheng(113) 15 110% LDLPFC 50 4s NS 3000 20 4weeks 28minspersession2010 George(55) 10 120% LDLPFC 75 4s 26s 3000 15 3weeks 2010 Triggs(108)(Lsidedarm) 5 100% LDLPFC 50 8s 22s 2000 10 2weeks 2010 Triggs(108)(Rsidedarm) 5 100% RDLPFC 50 8s 22s 2000 10 2weeks 2008 Jakob(67)(standardarm) 20 100% NS NS 2s 18s NS 10 2weeks 2008 Jakob(67)(ultrahighfreqarm) 50 100% NS NS 1s 59s NS 10 2weeks 2007 Stern(106)(lowfreqLarm) 1 110% LDLPFC 1 1600s N/A NS 10 2weeks 2007 Stern(106)(highfreqLarm) 10 110% LDLPFC 20 8s 52s 1600 10 2weeks 2007 Stern(106)(lowfreqRarm) 1 110% RDLPFC 1 1600s N/A NS 10 2weeks 2007 O'Reardon(92) 10 120% LDLPFC 75 4s 26s 3000 5/week 46weeks 2006 GarciaToro(54)(normalfreqarm) 1 110% various 30 60s 1525s 1800 10 2weeks 2006 GarciaToro(54)(highfreqarm) 20 110% various 30 2s 1525s 1200 10 2weeks 2006 Avery(35) 10 110% LDLPFC 32 5s 2530s 1600 15 4weeks 2004 Kauffman(69) 1 110% anteriortoR

motorcortex2 60s 180s 120 10 10days

2004 Holtzheimer(65) 10 110% LDLPFC 32 5s 3060s 1600 10 2weeks 2002 Boutros(40) 20 80% LDLPFC 20 2s 58s 800 10 10days 2001 GarciaToro(52) 20 90% LDLPFC 30 2s 2040s 1200 10 10days 2001 Manes(82)&Moser(88) 20 80% LDLPFC 20 2s 60s 800 5 1week 1999 Padberg(94)(SBarmLparameters) 20 100% LDLPFC 20 5s 25s 1000 5 1week RfollowedbyLparameters1999 Padberg(94)(Rparameters) 1 110% RDLPFC 3 140s 30s 420 5 1week Rparametersonly1996 PascualLeone(96) 10 90% Vertex,LorR

DLPFC20 10s 60s 2000 25 1st5dayseach

mofor5mo

DLPFC=dorsolateralprefrontalcortex;freq=frequency;L=left;mo=month;MT=motorthreshold;N/A=notapplicable;NS=notspecified;R=right;SB=sequentialbilateral.


Resultssummary

Responsetotreatment

SixstudiesreportedasignificantdifferenceineffectivenessbetweenrTMSandsham(infavourofrTMS)forthetreatmentofdepression.35,52,54,55,92,96Ofthesestudies,George201055andOReardon200792hadlargesamplesizes(n=199andn=325respectively).Fouroutofthesixstudiesusedafrequencyof10HzforrTMS.AlthoughGarciaToro52reportedasignificantdifferencebetweenchangesinHAMD,theeffectsizewassmallandtherewasnosignificantdifferenceinthepercentageofrespondersbetweengroups(thisstudyuseda20Hzfrequency).Threeofthesixstudiesmeasuredtheprimaryoutcomeattheendoftreatment.52,54,55Twostudies35,96measuredtheprimaryoutcomeoneweekafteractivetreatment.Onestudymeasuredtheprimaryoutcomeattheendoffourweeksoftreatmenttoallowcrossoverofnonrespondersandanadditionaltwoweeksoftreatment.92

NinestudiesfoundnosignificantdifferencebetweenrTMSandshamrTMSforthetreatmentofdepression.32,40,65,67,69,82,94,108,113Allofthesestudieshadrelativelysmallsamplesizes(between12and48patients).Effectivenessoftreatmentwasmeasuredattheendofactivetreatment;formoststudiesactivetreatmentlastedtwoweeks.Fourstudiesmadeadditionalposttreatmentfollowupassesmentsatoneweek,65,82fourweeks,32andsixmonths.40

Threestudiesreportedmixedresults.OnestudyfoundthatunilateralbutnotbilateralrTMSwasmoreeffectivethanshamtreatment.95Onestudyfoundthathighfrequency(10Hz)rTMStotheleftDPFC,andlowfrequency(1Hz)rTMStotherightDPFC,butnotlowfrequencytotheleftwasmoreeffectivethanshamtreatment.106OnestudyreportedunilateralleftsidedrTMSwasmoreeffectivethanshamorbilateralrTMS.51Allthreeofthestudiesmeasuredtheprimaryoutcomeattheendofactivetreatment.Onestudyhadanadditionaltwoweekfollowup106andonestudyhadacrossoverofpatients.51

Adverseevents

Noseriousadverseeventswerereported.Sideeffectsgenerallyincludedheadacheorlocalisedpain/discomfortatthesiteofapplication.Somestudiesreportedthesesideeffectsinboththeshamandtheactivetreatmentgroups.Sevenstudiesreportedthatheadachesoccuredmorefrequentlyintheactivegroupthattheshamtreatmentgroup.52,54,55,82,92,9496Noneofthestudiesreportedanysignifcantdifferencesbetweengroups.Twostudiesreportedontestingforneurophysiologicaladverseeventsandfoundthattherewasnosignificantdifferencebetweenthegroups.35,82


FINDINGSTable4.Keyinformationfrommostrecent,comprehensive,highqualitysystematicreviewGaynesBN,LuxLJ,LloydSW,HansenRA,GartlehnerG,KeenerP,etal.NonpharmacologicInterventionsforTreatmentResistantDepressioninAdults.ComparativeEffectivenessReviewNo.33.AHRQPublicationNo.11EHC056EF.Rockville,MD:AgencyforHealthcareResearchandQuality.Availablefrom:www.effectivehealthcare.ahrq.gov/reports/final.cfm.

Studydesign Systematicreview

Scope Patient/population:PatientswithTRD.

Interventionandcomparators:nonpharmacologictreatmentsincludingrTMS,shamrTMS,ECT,VNS,andevidencebasedpsychologicaltreatments.

Outcomesassessed:

ECTvs.rTMS:changeindepressiveseverity,responseandremissionrate,adverseevents,withdrawalsduetoadverseevents,cognitivefunctioning.

rTMSvs.sham:changeindepressiveseverity,responseandremissionrates,adverseevents,withdrawalsduetoadverseevents,cognitivefunctioning,healthrelatedoutcomes.

1.WhatistheeffectivenessofrTMSintreatingacutephasedepressivesymptoms(e.g.,responseandremission)?

Effectivenessintreatingacutephasedepressivesymptoms

rTMSvs.ECT(n=4studies)

ThereisinsufficientevidencetodeterminewhetherrTMSismoreeffectiveorevenequivalenttoECT,withhalfofthestudiesreportingequivalenceandhalfreportingrTMSasbeinginferiortoECTwithregardstotreatingacutephasedepressivesymptoms.

rTMSvs.shamrTMS(n=18studies)

Onlyonegoodqualitystudy92wassufficientlypoweredtodetectasignificantdifferencebetweentreatmentarms.ThisstudyreportedthatrTMSwasmoreeffectivethansham.

ThereisinsufficientevidencetodeterminetheeffectofrTMS,astheresultsofthestudieswerevariablewithsixstudiesreportingrTMStobemoreeffectivethansham,ninestudiesreportingnosignificantdifferencebetweenrTMSandshamrTMS,andthreereportingmixedresults.

DespitealargenumberofRCTs,therelativelysmallsamplesizesofthestudiesandlargevariationintreatmentparametersmakesitdifficulttoassesstheoverallresults.


2.WhatistheeffectivenessofrTMSinmaintainingresponseorremission(e.g.,preventingrelapseorrecurrence),whetherasasingletreatmentorpartofacombinationtreatment?

rTMSvs.ECT:Thereisnoevidencetoanswerthisquestion.

rTMSvs.shamrTMS:ThereisnoevidencetodrawconclusionsontheeffectivenessofrTMSonmaintainingremissionorpreventingrelapsewhencomparedtoshamrTMS.

3.Inwhatsetting,inpatientoroutpatient,isrTMSmosteffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?

Thereisinsufficientevidencetoassessthemostappropriatetreatmentsetting.Thestudiesincludedinthisreviewwereeithersetinaninpatientenvironmentoramixedinpatientandoutpatientsetting.NoneofthestudiesindicatedatrendinresultsaccordingtosettingandnostudiescomparedtheeffectofrTMSininpatientandoutpatientsettings.

4.WhatrTMSprotocolsi.e.,whatnumberoftreatmentsoverwhattimeperiod,areeffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?

ThereisinsufficientevidencetodeterminethemosteffectiverTMSprotocols.rTMSlocation,frequency,motorthresholds,anddurationoftreatmentvariedacrossstudies.

5.WhatisthesafetyofrTMSfordepression?

Noneofthestudiesreportedanysignificantdifferencesbetweengroups.

rTMSvs.ECT

Cognitivefunctioning:InsomecasesECTcanhaveanadverseimpactoncognitivefunctioning.

Withdrawalsduetoadverseevents:therewasnodifferenceinwithdrawalsduetoadverseeffectsbetweenrTMSandECT.

rTMSvs.shamrTMS

Cognitivefunctioning:theevidenceontheeffectsofrTMSversusshamoncognitivefunctioningisinsufficienttodrawaconclusion.

Specificadverseevents:rTMSgroupsreportedsignificantlymorescalppainatthestimulationsite(lowstrengthofevidence).

Withdrawalsduetoadverseevents:FindingsweremixedastowhetherrTMSgroupshadgreaterratesofwithdrawalsduetoadverseeventsthangroupsreceivingshamprocedures.

Qualityassessmentresults ThisSRscored11/11usingtheAMSTARtool,thismeansitwaswellconductedandconsideredtohavealowriskofbias.However,thequalityoftheincludedstudiesvaried,andmanyofthemweresmall,andnotsufficientlypoweredtodetectarealeffect.


DISCUSSION

1.WhatistheeffectivenessandsafetyofrTMSintreatingacutephasedepressivesymptoms(e.g.,responseandremission)?

ThereisinsufficientevidencetodeterminewhetherrTMSismoreeffectiveorevenequivalenttoECT,withhalfofthestudiesreportingequivalenceandhalfreportingrTMSasbeinginferiortoECT.Thisuncertaintyisfurthercompoundedbythefactthatthetwostudiesreportingequivalencewereunderpowered(i.e.,thenumberofpatientsrecruitedwasinsufficienttoidentifyasignificantdifferencebetweentreatmentarms).OtherissuesalsoimpactingontheoveralleffectivenessofrTMSwasthevariationinrTMSandECTparametersacrossstudies.ThelongtermeffectsofrTMSarealsounclearasthemajorityofstudiesonlyassessedoutcomesattheendoftreatment.

WithregardstorTMSvs.shamrTMS,theonlystudythatwassufficientlypoweredtodetectasignificantdifferencebetweentreatmentarmswasOReardon200792,whichrecruited325patients.ThisstudyindicatedthatrTMSwasmoreeffectivethansham.Theremainingstudiesallhadrelativelysmallsamplesizesandwereeitherunderpoweredordidnotreportpowercalculations.

Notwithstandingtheissueofsamplesize,studiesofrTMSvs.shamvariedinthefrequencyofstimulation,theareaofthebraintowhichitwasapplied,theamountoftreatmentgiveneachsession(thenumberoftrains,lengthoftrains,lengthofintervalsbetweentrains,andnumberofpulsespersession),andthedurationoftreatment(seeTable3).

ThevariationbetweenparametersmakesitdifficulttoassesstheresultsofthesestudiesoverallwithoutmakingtheassumptionthatallrTMSparametersareequallyeffective.SevenoftheeighteenrTMSvs.shamtrials51,54,67,94,95,106,108includedseveralarmsthatcompareddifferentrTMSparameterswitheachotheraswellaswithshamrTMS,thesetrialsincludesomeofthemostrecentpublicationsonthistopic,suggestingthattheoptimalrTMSparametersarestilltobedetermined.

Intermsofsafetyitwouldappearthattherewasnodifferenceinadverseeventsbetweenstudyarms,withnostudyreportingasignificantdifferencebetweenrTMSandECTorsham.

Issuesaroundwhethertreatmentfailurewasaneffectmodifiercouldnotbeansweredinthisreview,astheresultswereinconsistentacrossthestudiesregardlessofhowmanytreatmentfailurespatientsexperienced.

2.WhatistheeffectivenessandsafetyofrTMSinmaintainingresponseorremission(e.g.,preventingrelapseorrecurrence),whetherasasingletreatmentorpartofacombinationtreatment?

NotrialswereidentifiedthatspecificallyexaminedlongertermefficacyofrTMS,suchasmaintainingremission.Thiscouldbeduetotheuncertaintyaroundtheshorttermeffectivenessofthistreatment.OnestudydidassessremissionatsixmonthsreportingthattheeffectsofECTwerenotsustainedaftersixmonths.


3.Inwhatsetting,inpatientoroutpatient,isrTMSmosteffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?

ThereisinsufficientevidenceidentifyingtheoptimalsettingforadministeringrTMS.Thestudiesincludedinthisreviewhadeitherinpatientormixedinpatientandoutpatientsettings.NoneofthestudiesindicatedatrendinresultsaccordingtosettingandnostudiescomparedtheeffectofrTMSininpatientandoutpatientsettings.

4.WhatrTMSprotocolsi.e.,whatnumberoftreatmentsoverwhattimeperiod,areeffectiveintreatingacutephasedepressivesymptomsORmaintainingresponseorremission?

ThedifferentrTMStreatmentprotocolsandparametersacrossstudiesindicatethatthereisinsufficientevidencetodeterminewhichrTMSprotocolismosteffective.

CONCLUSION

Overall,comparativeclinicalresearchonrTMSinMDDisearlyinitsinfancy,andmanyclinicalquestionsaboutefficacyandeffectivenessremainunanswered.AnoptimalprotocolforrTMSneedstobedefinedandtestedusinghighquality,adequatelypoweredheadtoheadclinicaltrials.OverallthereisinsufficientevidencetodeterminewhetherrTMSisaseffectiveasstandardtreatment(i.e.,ECT),andforwhichpatients(i.e.,leveloftreatmentresistance)rTMSmaybemosteffective.


SUMMARYOFSYNTHESISEDSTUDIES

Table5.SynthesisedstudiesofrTMSvs.shamfordepressionSTUDY Aare200313 Allan201114 Coutourier200515 Gaynes20114 Gross200716PATIENTS Depressivedisorders Depression MDD TRD MDDINPATIENTOROUTPATIENTSETTING

Notstated Notstated Notstated Notstated Notstated

COMPARATORS ShamrTMS(orECT)

ShamrTMS

ShamrTMS ShamrTMS(orECT)

ShamrTMS

TREATMENTORREMISSIONMAINTENANCE?

Notstated Notstated Notstated Both Notstated

ONANTIDEPRESSANTSORDRUGFREE?

Mixed Mixed Mixed Mixed Mixed

SEARCHDATE February2001 2008 July2003 November2010 November2006INCLUDEDSTUDIES(n) 8studiesofrTMSvs.sham,

unclear if they are RCTs orCCTs

31RCTsofrTMSvs.sham 6RCTsofrTMSvs.sham 23RCTsofrTMSvs.sham 5RCTsofrTMSvs.sham

PRIMARYOUTCOMES Efficacy Efficacy Efficacy Efficacy,remissionmaintenance ComparisonofefficacybetweenlateandearlystudiesofrTMS

ADVERSEEVENTS Notreported Notreported Notreported SignificantlymorescalppainatstimulationsiteinrTMSgroup.InsufficientevidencetodrawconclusionsondifferencesincognitivefunctioningandwithdrawalsduetoadverseeventsforrTMSvs.sham.

Notreported

RESULTS Modestbutclinicallyinsignificantresultonefficacy.Nolastingimprovementpasttwoweeksaftercessationoftreatment.

ModeratelysizedeffectinfavourofrTMS.Nomeanchangeindepressionseveritybetweentheendoftreatmentandfollowup.

ImprovementsusingrTMScomparedwithshamtherapynotclinicallysignificant.

rTMSwasbeneficialrelativetocontrolsreceivingashamprocedureforallthreeoutcomes(severityofdepressivesymptoms,responserate,remissionrate)

Thepooleffectsizewassignificantlylargerthanthatofearliermetaanalysis

CONCLUSIONS rTMSnotrecommendedasastandardtreatmentfor

Optimumtreatmentprotocolyettobediscovered.

NosignificantdifferencebetweenrTMSandsham

rTMSmoreeffectivethanshamforTRD

RecentclinicaltrialsofrTMSondepressioninducedalarger


depression. Noevidenceforlastingtreatmenteffectsbeyond12weeks.

treatment.MosteffectivecombinationofparametersforrTMSnotyetestablished.

effectsizewhencomparedwiththeinitialstudiesfromMartinetal.

DIRECTIONOFFINDINGS ? = + +AMSTARRATING 3/9 2/11 5/11 11/11 5/11ECT=electroconvulsivetherapy;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation;TRD=treatmentresistantdepression;rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiortocomparatorTable5.SynthesisedstudiesofrTMSvs.shamfordepression(continued)STUDY Herrmann200617 Herrmann200918 Holtzheimer200119 Kennedy200920 Kozel200221PATIENTS MDDorbipolar MDDorbipolar MDD MDD depressionordepressive

disorderINPATIENTOROUTPATIENTSETTING


COMPARATORS ShamTMS ShamTMS ShamTMS ShamTMS ShamrTMSTREATMENTORREMISSIONMAINTENANCE?



Mixed Mixed Mixed Mixed Notstated

SEARCHDATE Notreported 2007 Notreported Dec2008 April2002INCLUDEDSTUDIES(n) 31RCTsofrTMSvs.sham 24RCTsofrTMSvs.sham 12studiesofrTMSvs.sham,

uncleariftheyareRCTsorCCTs

NotReported 12RCTsofrTMSvs.sham

PRIMARYOUTCOMES Efficacy Efficacy Efficacy Efficacy EfficacyADVERSEEVENTS Notreported Smallriskofseizure Headaches,discomfortat

stimulationsiteduringprocedure.

Headaches,scalppain

Notreported

RESULTS ClinicallysignificanteffectofrTMS

SignificantlylargerproportionofrespondersinactiverTMSgroup(35.3%)vs.shamrTMSgroup(13.1%).5patientsneedtobetreatedwithrTMStoobtainaclinicalresponse.

Overallweightedmeaneffectsizeof0.81wasfoundfor12shamcontrolledstudiesofrTMSinthetreatmentofdepression.

Notreported Significantcumulativeeffectsizeof0.53(95%CI:0.240.82).

CONCLUSIONS rTMSismoreeffectivein PatientstreatedwithrTMS rTMShasrealantidepressant Somestudiestosuggestthat DoubleblindpublishedrTMS


treatingdepressionthanshamrTMS,however,studiesareheterogeneousandthereforedifficulttoaccuratelydetermineeffectiveness.

morelikelytoshowaclinicalresponsethanpatientstreatedwithsham;differencesdisappearatfollowup.

effectsthatcanbelargeattimesbutaregenerallymodest.

rTMSisbetterthanshamtreatment

literaturetodatesupportstheuseofleftprefrontalrTMStoimprovedepressivesymptoms.

DIRECTIONOFFINDINGS + +initially,=atfollowup + + +AMSTARRATING 1/11 3/11 3/11 1/9 4/11CCTs=controlledclinicaltrials;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulationrTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiortocomparatorTable5.SynthesisedstudiesofrTMSvs.shamfordepression(continued)STUDY Lam200822 Martin200323 McNamara200124 OntarioMinistryofHealth200427PATIENTS TRD Anydiagnosisofdepression Majordepressiveepisode MixedINPATIENTOROUTPATIENTSETTING

Notstated Notstated Notstated Notstated

COMPARATORS ShamrTMS

ShamrTMS ShamrTMS ShamrTMS(orECT)




Notstated Mixed Mixed Mixed

SEARCHDATE May2008 January2002 January2000 March2004INCLUDEDSTUDIES(n) 23RCTsofrTMSvs.sham 14RCTsofrTMSvs.sham 5RCTsofrTMSvs.sham 7SR/MAofrTMSvs.shamPRIMARYOUTCOMES Efficacy Efficacy Efficacy Efficacyandcosteffectiveness.ADVERSEEVENTS Notreported Notreported Transientheadaches.Discomfortatthe

siteoftreatment.Notreported

RESULTS rTMShadsignificantlygreaterclinicalresponsethansham.

rTMSmoreeffectivethanshamaftertwoweeksoftreatment,butnosignificantdifferenceatthetwoweekfollowup

StatisticallysignificantbenefitofrTMS.43%differenceintherateofimprovementinthetreatedgroupandthecontrolgroup.

Notreported

CONCLUSIONS rTMSfor14weekshasclearantidepressanteffectsandiswelltolerated,butresponseandremissionratesarelowanditisunclearwhether

InsufficientevidencetosuggestthatrTMSismoreeffectivethansham.Anydifferencebetweenthetwogroupshasdisappearedtwoweekspost

rTMSisaneffectivetreatmentfordepression.

EarlymetaanalysessuggestedrTMSmaybeeffectiveforthetreatmentofMDD


theeffectsaresustained. intervention.DIRECTIONOFFINDINGS +initially,?longterm ? + +AMSTARRATING 8/11 7/11 4/11 6/9ECT=electroconvulsivetherapy;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation;SR/MA=systematicreviews/metaanalyses;TRD=treatmentresistantdepression;rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiortocomparatorTable5.SynthesisedstudiesofrTMSvs.shamfordepression(continued)STUDY NICE200726 RodriguezMartin200928 Schutter201030 Schutter200929 Slotema201031PATIENTS MDD Depression Majordepressiveepisode Majordepressiveepisode DepressionINPATIENTOROUTPATIENTSETTING


INTERVENTION&COMPARATORS

ShamrTMS(orECT)

ShamrTMS(orECTorpsychotherapyorpharmacotherapy)

ShamrTMS

ShamrTMS

ShamrTMS(orECT)




Mixed Mixed Notstated Notstated Mixed

SEARCHDATE October2006 June2001 2009 November2007 October2008INCLUDEDSTUDIES(n) 3SR/MA&8RCTsofrTMSvs.

sham13RCTsofrTMSvs.sham 9RCTsofrTMSvs.sham(slow

frequencyrTMSonly)30RCTsofrTMSvs.sham 34RCTsofrTMSvs.sham

PRIMARYOUTCOMES Efficacy EfficacyandSafety Efficacy Efficacy EfficacyADVERSEEVENTS Seizures,nausea,scalp

discomfort,headache,migraine,neckstiffness,hearingloss,mania.

Nosignificantadverseeffectsintheshortterm

Notreported Headaches,dizziness,nausea,andpainfullocalsensation.

Headache,nausea,scalpdiscomfort,drowsiness,facialmuscletwitching,tearfulness,dizziness.

RESULTS Notreported BenefitsshowninfavourofrTMSversusshamattwoweeks.

NosignificantdifferencebetweenfastandslowTMS.Cumulativeeffectsizefortreatmentwas0.63(95%CI0.031.24).

rTMShassignificantlymoreantidepressantefficacythanshamtreatment.

rTMSvs.sham;significantmeanweightedeffectsize(0.55)infavourofrTMS.

CONCLUSIONS rTMSisanoveltreatmentwithuncertaintyarounditsefficacy

NostrongevidenceforpossibleefficacyofrTMSfor

rTMScanimproveMDDandadditionalclinicaltrialsaimed

rTMSissuperiortoshamandmaybeaseffectiveasatleast

rTMSismoreeffectivethanshamfordepressionand


andsafety. thetreatmentofdepression. atoptimisingthetreatmentareworthwhile.

asubsetofantidepressantmedications.

appearstobemoreeffectiveasamonotherapy.

DIRECTIONOFFINDINGS ? ? + +

+

AMSTARRATING 4/9 10/11 6/11 4/11 3/11ECT=electroconvulsivetherapy;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation;SR/MA=systematicreviews/metaanalyses;rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiortocomparator


Table6.SynthesisedstudiesofrTMSvs.ECTfordepressionSTUDY Aare200313 Gaynes20114 OntarioMinistryofHealth200427 MSAC20088PATIENTS Depressivedisorders TRD Mixed MDDINPATIENTOROUTPATIENTSETTING



ECT(orshamrTMS)

ECT(orshamrTMS)

ECT(orshamrTMS)

ECT(orshamrTMS)


Notstated Both Notstated Notstated


Mixed Mixed Mixed Mixed

SEARCHDATE February2001 November2010 March2004 2006INCLUDEDSTUDIES(n) 2Studies(1RCT) 4RCTs 3RCTs 7Studies(2confirmedRCTs)PRIMARYOUTCOMES Efficacy Efficacy,remissionmaintenance Efficacyandcosteffectiveness. EfficacyADVERSEEVENTS Notreported Asmallstudyindicatednodifferencein

withdrawalsduetoadverseeventsbetweentheECTandrTMSgroupsbutdidnotreportonthesignificanceofthisresult(lowstrengthofevidence).

Notreported Notreported

RESULTS Modestbutclinicallyinsignificantresultonefficacy.Nolastingimprovementpasttwoweeksaftercessationoftreatment.

1fairtrialofECTvs.rTMSinatreatmentresistantMDDpopulationshowedwithlowstrengthofevidence,nodifferencebetweentreatmentoptionsfordepressiveseverity,responserateandremissionrate.

Notreported. NosignificantdifferencebetweentheresponseratesoftherTMSgroupandtheECTgroup.OverallrTMSappearedtobelesseffectivethanECTinthetreatmentofmajordepression,althoughthiswasnotstatisticallysignificant.

CONCLUSIONS rTMSnot recommendedasastandardtreatmentfordepression.

NodifferencebetweenrTMSandECT(lowstrengthofevidence)

EarlymetaanalysessuggestedthatrTMSmaybeeffectiveforthetreatmentofMDD

ECTappearstobeaseffectiveasrTMSforthetreatmentofdepressioninpatientswithoutpsychosis

DIRECTIONOFFINDINGS = + =AMSTARRATING 3/9 11/11 6/9 9/11


Table6.SynthesisedstudiesofrTMSvs.ECTfordepression(continued)STUDY Minichino201225 NICE200726 RodriguezMartin200928 Slotema201031PATIENTS TRD,MDD MDD Depression DepressionINPATIENTOROUTPATIENTSETTING



ECT ECT(orshamrTMS)

ECT(orshamrTMSorpsychotherapyorpharmacotherapy)

ECT(orshamrTMS)



ANTIDEPRESSANTTREATMENT?

Drugfree Mixed Mixed Mixed

SEARCHDATE NR October2006 June2001 October2008INCLUDEDSTUDIES(n) 4Studies(2RCTs) 8RCTs 1RCTofrTMSvs.ECT 6RCTsPRIMARYOUTCOMES Efficacyandtolerability Efficacy Efficacy EfficacyADVERSEEVENTS Nonereported,tolerabilitymeasured

bythenumberofdropoutsSeizures,localscalpdiscomfort,headache,migraine,nausea,neckstiffness,hearinglossandinductionofmania.

Notreported Transientandmildsideeffectsincludeheadache,scalpdiscomfort,drowsiness,facialmuscletwitching,tearfulness,dizzinessandnausea.

RESULTS rTMSmoretolerablethanECT.ECTmoreeffectivethanrTMS.

Notreported Nosignificantdifferencebetweentechniqueswhenpatientshadnopsychoticsymptoms.ECTwasmoreeffectivewhenpatientshadpsychoticsymptoms.

ECTwassuperiortorTMSinthetreatmentofdepression(meanweightedeffectsize0.47,p=.004)

CONCLUSIONS rTMSprovidesbettertolerabilitythanECTbutitstherapeuticefficacyislower.

rTMSisanoveltreatmentwithuncertaintyarounditsefficacyandsafety.

NostrongevidenceforpossibleefficacyofrTMSforthetreatmentofdepression.

rTMSislesseffectivethanECTinthetreatmentofdepression.

DIRECTIONOFFINDINGS ? ?

AMSTARRATING 2/11 4/9 10/11 3/11ECT=electroconvulsivetherapy;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation;SR/MA=systematicreviews/metaanalyses;TRD=treatmentresistantdepression;rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiortocomparator


DISCLAIMER

Theinformationinthisreportisasummaryofthatavailableandisprimarilydesignedtogivereadersastartingpoint to consider currently available research evidence. Whilst appreciable care has been taken in thepreparation of thematerials included in this publication, the authors and the National Trauma ResearchInstitutedonotwarrant theaccuracyof thisdocumentanddenyany representation, impliedorexpressed,concerningtheefficacy,appropriatenessorsuitabilityofanytreatmentorproduct.Inviewofthepossibilityofhuman error or advances ofmedical knowledge the authors and the National Trauma Research Institutecannot and do notwarrant that the information contained in these pages is in every aspect accurate orcomplete.Accordingly,theyarenotandwillnotbeheldresponsibleorliableforanyerrorsoromissionsthatmaybefound inthispublication.Youarethereforeencouragedtoconsultothersources inordertoconfirmthe information contained in thispublication and, in theevent thatmedical treatment is required, to takeprofessionalexpertadvicefromalegallyqualifiedandappropriatelyexperiencedmedicalpractitioner.

CONFLICTOFINTEREST

The TAC/WSV Evidence Service is provided by theNational Trauma Research Institute. TheNTRI does notacceptfundingfrompharmaceuticalorbiotechnologycompaniesorothercommercialentitieswithpotentialvestedinterestintheoutcomesofsystematicreviews.

The TAC/WSV Health Services Group has engaged the NTRI for their objectivity and independence andrecognise that anymaterials developedmust be free of influence from partieswith vested interests. TheEvidenceServicehasfulleditorialcontrol.


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1 Report#0513002R11.3rTMSforDepressionTechnicalReport


EvidenceService

RepetitiveTranscranialMagneticStimulation(rTMS)forDepressionTechnicalReport:Appendices17

March2013OrnellaClavisi,EmmaDonoghue,NatashaDodge,JasonWasiak


INTRODUCTION

ThistechnicalreportisacompaniondocumenttoRepetitiveTranscranialMagneticStimulation(rTMS)forDepression:EvidenceReview.ItcontainsdetailedinformationaboutthemethodsusedinthedevelopmentoftheEvidenceReview,summariesofthestudiesincludedinthereview,andqualityappraisalresultsforthemostrecentand/ormostrelevantincludedstudies.

CONTENTS

APPENDIX1:METHODS.......................................................................................................................................3

APPENDIX2:SEARCHDETAILS.............................................................................................................................4

APPENDIX3:LISTOFINCLUDEDSTUDIES..........................................................................................................13

APPENDIX4:SUMMARYOFSYNTHESISEDSTUDIES..........................................................................................21

APPENDIX5:SUMMARYOFPRIMARYSTUDIES................................................................................................28

APPENDIX6:QUALITYAPPRAISALS...................................................................................................................51

APPENDIX7:QUALITYAPPRAISALGAYNESREPORT.........................................................................................68


APPENDIX1:METHODSAtwostagedapproachwasundertaken.

STAGE1

Identifyevidenceavailableforeachintervention

Run search in health databases,websites and on the internet, limit to evidence based guidelines (EBGs), healthtechnology assessments (HTAs), systematic reviews (SRs,) randomised controlled trials (RCTs) and controlled clinicaltrials(CCTs)Applyinclusionandexclusioncriteria

Criticallyappraisesynthesisedresearch

Startwithmostrecentreview,applystandardappraisalcriteriaIffoundtobeofhighquality,crosschecktoensurereferencesfromallothersynthesisedresearchareincludedandcheckforconsistencyoffindingsIfnothighquality,appraisenextmostrecentandrepeatprocessIfthereareinconsistentfindingsacrosstheexistingreviews,investigatethepossibilityofsynthesisofthisinformationorwhetheranewsystematicreviewisrequired

DecideonactionsforStage2

Mapavailableevidence(asperTableA1.1)Identifywhethersufficienthighlevelevidenceexiststoanswerquestionsoridentifywhatfurtheractionneedstobetaken(seealgorithminTableA1.2).

STAGE2Addressfurtheractionsidentified.

TableA1.1.TemplateformapofavailableevidenceSynthesisedstudies Primarystudies TOTAL

EBGs SRs&HTAs

TableA1.2.Furtheractionrequiredtoanswerclinicalquestions

Isthereanysynthesisedresearchavailable?(e.g.,EBGs,HTAs,SRs)Yes No

Isthisgoodqualityresearch? AreRCTsavailable?Yes No Yes No

Isitcurrent(within2years)?

UndertakenewSR UndertakenewSRConsiderlookingfor

lowerlevelsofevidenceYes No

Nofurtheraction UpdateexistingSR


APPENDIX2:SEARCHDETAILSTAC/WSVstaffassistedinthedevelopmentofsearchtermsandinclusionandexclusion.

InclusionandexclusioncriteriaInclusionandexclusion criteriawereestablishedapriori (TableA2.1).The twoauthors independently screened thesearch results according to the inclusion and exclusion criteria. Any discrepancies in findings were discussed andresolved.

TableA2.1InclusionandExclusioncriteriaPatient/population

Inclusion:Adults,includinggeriatrics.MaleandFemale.Depression,acuteorchronic,newonset,relapsed,treatmentresistantorinremission.Exclusion:Children,bipolardepression

Intervention/indicator

Inclusion:Repetitivetranscranialmagneticstimulation.Anydose.Exclusion:Nonrepetitivetranscranialmagneticstimulation.

Comparison/control

Inclusion:Standardcarewhichmayincludeadmission,antidepressants,psychologicalcounselling,electroconvulsivetherapy(ECT)orcomparisontoplacebo.Exclusion:Nil

Outcomes Inclusion:Remissionofdepression,preventionofdepressionrelapse,medicationuse,healthcareuse,functionindailyactivities,qualityoflife,socialfunctioning,returntowork,adverseevents.Exclusion:Nil

Setting Inclusion:inoroutpatient.Exclusion:Patientsinalongtermcarefacility.

StudyDesign Inclusion:Evidencebasedguidelines(EBGs),systematicreviews(SR),healthtechnologyassessments(HTA)andcontrolledtrials.Exclusion:Nonevidencebasedguidelines,nonsystematicreviews,cohortstudies,casecontrolstudies,caseseries,editorials,lettersandcommentaries.

Publicationdetails

Inclusion:AllEnglishlanguagestudiesconductedonhumans.Exclusion:NonEnglishlanguagepapersorstudiesconductedonanimals.

Timeperiod Inclusion:AnytimeExclusion:Nil


Searchesundertaken

Searchmethods

EvidenceBasedGuidelines(EBGs)aregenerallypublishedaselectronicstandalonedocumentsontheinternetratherthanpapers inpeer reviewed journals.We searched first in standardhealthdatabases, then inwebsiteswhichareknowntopublishhighqualityresearchandguidelinesandfinallyinageneralsearchengine,asfollows;

Searchstrategiesinelectronicdatabases

Standardsystematicreviewstrategies,asoutlinedbelowintheMedlinesearchexample,wereusedtoidentifyexistingreviewsandtrials.AdditionalreviewingofthereferencesfromthesearchesidentifiedEBGs.

Internetsearchestoidentifyrelevantwebsites

The reviewerswereawareofwebsitesofguideline clearinghouses,guidelinedevelopers, centresofevidencebasedpractice,Australiangovernmenthealthservicesandwebsitesofspecificrelevance(egg.accidentcompensationgroups)knowntocontainevidencebasedresources.

WebsitesearchestoidentifyrelevantEBGs

The reviewerswereawareofwebsitesofguideline clearinghouses,guidelinedevelopers, centresofevidencebasedpractice,Australiangovernmenthealthservicesandwebsitesofspecificrelevance(eg.accidentcompensationgroups)knowntocontainevidencebasedresources.

The43websiteslistedbelowweresearchedforrelevantEBGs(seeTableA2.4).

Wherean internalsearchenginewasavailable,websitesweresearchedusingthesearchstringsdetailed inthetablebelow. Ifno searchenginewas available, listsofEBGs,publicationsorother resources identifiedon the sitewerescannedforrelevantdocuments.

Internetsearchestoidentifyrelevantreferences

AninternetsearchstrategywasconductedusingtheGoogleAdvancedSearchfunction.ThesearchstringwaslimitedtodocumentsinEnglish:

Thefirst100Googlesearchresultswerescreenedandyieldednonewstudies.AsGooglesearchresultsarepresentedinorderofrelevance,wedidnotscreenfurther.

Databasesaccessed

AhighlysensitivesearchinCochranelibrary,Medline,Embase,Compendex(Engineering),PedroandSportsdiscus(sporting)asdetailedbelowwasundertakenforthereviewterms.TableA2.2DatabasesaccessedDatabasename Datescovered Datesearched RefsMedline(Ovid) 1980toJulyWeek22012 20thJuly2012 877PreMedline(Ovid) July13,2012 16thJuly2012 71AllEBM(Ovid)* CompletedatabasesJuly2012 20thJuly2012 130CINAHL(Ovid) 1980date 20thJuly2012 116EMBASE 1980to2012Week28 20thJuly2012 1204WoK CompletedatabasesJuly2012 21stJuly2012 97*includingTheCochraneDatabaseofSystematicReviews,DARE,CENTRAL,NHSEED,HTAandACPJournalClub


Thefollowingsearcheswereconductedandadaptedforuseinotherdatabases.TableA2.3MedlineSearchStrategy1 Depression/

2 expdepressivedisorder/

3 (depressionordepressiveormelanchol*).ti,ab.

4 or/13

5 TranscranialMagneticStimulation/

6 (transcranialadj2stimulat*).ti,ab.

7 or/56

8 (repeat*orrepetitiveorrepetitionor(highadjfrequency)orhighfrequency).ti,ab.

9 and/78

10 RTMS.ti,ab.

11 or/910

12 and/4,11

13 (aeorco).fs.

14 and/11,13

15 14not12

16 transcranialmagneticstimulationfortreatingdepression.m_titl.

17 Antidepressantefficacyofhighfrequencytranscranialmagneticstimulationovertheleftdorsolateralprefrontalcortexin.m_titl.

18 (Repetitivetranscranialmagneticstimulationfortreatmentresistantdepressionasystematicreviewandmetaanalysis).m_titl.


TableA2.4WebsitesearchestoidentifyrelevantEBGsSearch1:IdentificationofrelevantguidelinesforRepetitiveTranscranialMagneticStimulation(rTMS)forDepressionusingspecificguidelinerelatedwebsitesGuidelineServices Results SearchNationalHealthandMedicalResearchCouncil(NHMRC)

http://www.nhmrc.gov.au Termsused:RTMS,Repetitivetranscranialmagneticstimulation

AustralianGuidelinesfortheTreatmentofAdultswithAcuteStressDisorderandPosttraumaticStressDisorder

http://www.nhmrc.gov.au/guidelines/publications/mh13mh14mh15mh16

NationalInstituteforHealthandClinicalExcellenceUK(NICE)

http://www.nice.org.uk Termsused:RTMS,Repetitivetranscranialmagneticstimulation1referencefromscannedsearchresults

IPG242Transcranialmagneticstimulationforseveredepressionhttp://publications.nice.org.uk/transcranialmagneticstimulationforseveredepressionipg242

NewZealandGuidelineGroup(NZGG)

http://www.nzgg.org.nz/search Termsused:RTMS,RepetitivetranscranialmagneticstimulationN/A

ScottishIntercollegiateGuidelinesNetwork(SIGN)

http://www.sign.ac.uk/search.html Termsused:RTMS,RepetitivetranscranialmagneticstimulationN/A

JoannaBriggsInstitute http://www.joannabriggs.edu.au/SubscriptionserviceLogintoCOnNECT+|SubscribetoCOnNECT+

Termsused:RTMS,Repetitivetranscranialmagneticstimulation1of3referencesscannedDepression:AssessmentandTreatmentDate:03/02/2012Version:1.2LisaKundeBA,BPsych(Hons)

GuidelinesInternationalNetwork

http://www.gin.net Muchcheaper,almostasgood:decrementallycosteffectivemedicalinnovationhttp://www.ncbi.nlm.nih.gov/pubmed/19884627

GuidelinesAdvisoryCommittee

http://www.gacguidelines.ca/ ScannedtheirlistofEndorsedguidelines.2referencesDepression:ManagementofMildDepressionDepression:ManagementofModeratetoSevereDepression

NationalGuidelineClearinghouseUS(NGC)

guideline.gov/

Termsused:RTMS,Repetitivetranscranialmagneticstimulation

5referenceschosenPracticeguidelineforthetreatmentofpatientswithmajordepressivedisorder,thirdedition.1993(revised2010Oct).NGC:008093AmericanPsychiatricAssociation


Depression.Thetreatmentandmanagementofdepressioninadults.2004(revised2009Oct).NGC:007598NationalCollaboratingCentreforMentalHealthNationalGovernmentAgency[NonU.S.].

Majordepressioninadultsinprimarycare.1996Jan(revised2011May).[NGCUpdatePending]NGC:008573InstituteforClinicalSystemsImprovement

ExpertCommentary:PrimaryCareDepressionGuidelinesandTreatmentResistantDepression:VariationsonanImportantbutUnderstudiedTheme

Practiceparametersfortheassessmentandtreatmentofchildrenandadolescentswithdepressivedisorders.1998(revised2007).NGC:005924AmericanAcademyofChildandAdolescentPsychiatry

TRIPDatabase

www.tripdatabase.com/ Termsused:RTMS,Repetitivetranscranialmagneticstimulation141referencesdownloadedtotheEndnotedatabase

AustralianGovernmentWebsitescontainingGuidelinesAustralianInstituteofHealthandWelfare www.aihw.gov.au Termsused:RTMS,Repetitivetranscranialmagneticstimulation

4referencesscannedPreventionandmanagementofdepression(NHPAreporton...evaluationofTranscranialMagneticStimulation(TMS)asapossiblealternativetoelectroconvulsivetherapy(ECT).Australianresearchershavealsoplayeda...

HealthInsite www.healthinsite.gov.au/ Termsused:RTMS,Repetitivetranscranialmagneticstimulation