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TransportAccidentCommission&WorkSafeVictoria

EvidenceService

RepetitiveTranscranialMagneticStimulation
(rTMS)forDepression

Plainlanguagesummary
DepressionisacommonmentalhealthillnessinAustralia.
Medicationandpsychotherapyaretheusualtreatments,butforsomepeople,thesedontwork.For
thesepeople,ElectroconvulsiveTherapy(ECT)mayhelp.
DuringECT,apatientisputtosleepusingageneralanaesthetic.Whileasleeptheirbrainisgivenan
electricshock.ECTcanhavesideeffects.
RepetitiveTranscranialMagneticStimulation(rTMS)isanewtreatment.Amagneticpulseisusedin
rTMS.Thereisnoneedforananaesthetic.
FoursmallstudieshavebeenidentifiedwhichcomparerTMSwithECT.NostudiesfoundthatrTMS
wasbetterthanECT.EighteenstudiescomparedrTMSwithnotreatment.ItisnotclearifrTMSis
betterthannotreatment.
TherearedifferentideasonthebestamountandstrengthofrTMS,butnooneknowsthebestway
touserTMSyet.Moregoodstudiesareneeded.

Report#0513002R11.2rTMSforDepressionPlainLanguageSummary

TransportAccidentCommission&WorkSafeVictoria

EvidenceService
RepetitiveTranscranialMagneticStimulation
(rTMS)forDepression
EvidenceReview
March2013
OrnellaClavisi,EmmaDonoghue,NatashaDodge,JasonWasiak

Report#0513002R11rTMSforDepressionEvidenceReview

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

ACKNOWLEDGEMENTS
Theauthorswouldliketothankseveralcolleaguesfortheirassistanceinpreparationofthis
document.
LisaSherryfromTAC/WSVforeditingofPlainLanguageSummary.
AnneParkhillforherliteraturesearchingservices.
LorettaPiccennaforproofreading.

Report#0513002R11rTMSforDepressionEvidenceReview

EXECUTIVESUMMARY

Overview
Weupdatedthemostcomprehensive,uptodate,highqualitysystematicreview(Gaynesetal.
2011),whichinvestigatedtheeffectivenessofrTMS.Overalltwentyonestudieswerereviewedby
thisreport.Thestudieswereinconsistentintheirresults,withhalfreportingrTMSwasas
effectiveasECTandhalfreportingECTasbetter.However,smallsamplesizesandvastvariability
regardingrTMSparameterandoutcomeshasledthereviewtoconcludethatthereisinsufficient
evidencetodeterminewhetherthebenefitsandharmsofrTMSarebetter,worseorthesameas
ECT.

What is the effectiveness and safety of transcranial magnetic stimulation


(rTMS) in treating acutephase depressive symptoms (e.g., response and
remission)?
Theevidencetoanswerthisquestionisinconclusive.

What is the effectiveness and safety of transcranial magnetic stimulation


(rTMS) in maintaining response or remission (e.g., preventing relapse or
recurrence), whether as a single treatment or part of a combination
treatment?
Theevidencetoanswerthisquestionisinconclusive.

In what setting, inpatient or outpatient, is rTMS most effective in treating


acutephase depressive symptoms OR maintaining response or remission?
Theevidencetoanswerthisquestionisinconclusive.

What rTMS protocols i.e. what number of treatments over what time period,
are effective in treating acutephase depressive symptoms OR maintaining
response or remission?
Theevidencetoanswerthisquestionisinconclusive.

Report#0513002R11rTMSforDepressionEvidenceReview

BACKGROUND
Patientgroupandtreatmentpathway
Majordepressivedisorder(MDD)isacommonmentalhealthdisorderdefinedbythepresenceofa
depressedmoodeverydayformorethantwoweeks.ClinicaldiagnosisofMDDismadebasedon
thepresenceofanumberofsymptomsincluding:

Depressedmoodmostoftheday

Lossofinterestorpleasureinallormostactivities

Largeincreasesordecreasesinappetite

Significantweightlossorgain

Insomniaorexcessivesleeping

Agitationorrestlessness

Fatigueorlossofenergy

Feelingsofworthlessnessorexcessiveorinappropriateguilt

Diminishedabilitytoconcentrateorindecisiveness

Recurrentthoughtsofdeathorsuicide1

InAustralia,mentalhealthdisordersarethelargestcauseofnonfataldiseaseburden.2MDDisoften
arecurrentdisorder,thuslongtermtreatmentisnecessarytopreventnewepisodesfromoccurring.
ForpatientswithMDD,firstlinetherapyinvolvespharmacologicaltreatment(e.g.,tricyclic
antidepressants,serotoninreuptakeinhibitorsandserotoninnorepinephrinereuptakeinhibitors),
psychotherapy,oracombinationofboth.Wherethereistreatmentfailureonapharmacological
agent,aswitchtoanantidepressantdrugwithadifferentmodeofactionisthepreferredsecond
linetreatment.Ifthedepressiveillnesspersists,severaloptionsareavailable,namely,addingan
augmentingagent,suchaslithiumcarbonateortriiodothyronine,switchingtoamonoamineoxidase
inhibitorforpatientswithatypicalmajordepression,oraddingeithercognitivetherapyoranother
formofpsychotherapy.3
Forpatientswhohavenotrespondedorarerefractorytopharmacologicagentsand/or
psychotherapy,treatmentoptionscanincludeelectroconvulsivetherapy(ECT),vagusnerve
stimulation(VNS)andtranscranialmagneticstimulation(TMS).4ECTisgenerallyconsideredthenext
lineoftherapyforMDDpatients.ECTinvolvesthedeliveryofanelectricalcurrenttoinducea
seizurefortherapeuticpurposes.BeforetheadministrationofECTpatientsareanaesthetisedandan

Report#0513002R11rTMSforDepressionEvidenceReview

appropriatemusclerelaxantisadministered.ECTisusuallygiventwiceaweekandthenumberof
sessionsundertakenforpatientstorespondusuallyrangesfromsixtotwelve.5

AlthoughECThasbeenshowntobeeffective,itisassociatedwithcognitivesideeffectsandrisks
associatedwithrepeatedanaesthesia,5forthisreasonrTMShasemergedasapotentialalternative
treatment,asitdoesnotrequireanaesthesia.

Repetitivetranscranialmagneticstimulation
Transcranialmagneticstimulationinvolvesplacinganelectromagneticcoilagainsttheforeheadnear
anareaofthebraininvolvedinmoodregulation.TMSworksbycreatingmagneticpulsesinthe
loopsofthecoil.Thesemagneticfieldpulsesproducesmallelectriccurrentsthatstimulatenerve
cellsinthebrain.Whenthepulsesaredeliveredrepeatedly,itisreferredtorepetitivetranscranial
magneticstimulation(rTMS).IncontrasttoECT,rTMSdoesnotinvolvepassingelectricalcurrents
directlythroughthescalpandthereforedoesnotrequireanaesthesia.rTMSisusuallygivenina
discretecourse,mostcommonlydailyforbetween15and30consecutiveweekdayswithtreatment
sessions,lastingbetween30and45minutes.6
TherTMStechniquecanvaryinmanydifferentways,suchas:7,8

Coilplacement(usuallytheleftorrightdorsolateralprefrontalcortex(DPFC))

Stimulationintensity(determinedbytheindividualsmotorthreshold)

Stimulationfrequency(usually1to20HzovertheleftDPFC,andlowerfrequencies(<1Hz)
overtherightDPFC)

Numberofpulses/stimulationspersession(atypicaltreatmentsessionmightincorporate
10to30stimulationtrainsseveralsecondsapart(theintertraininterval).Thus,atypical
sessiondelivers1,000to1,200pulses)

Theamountoftimebetweenpulses/stimulationsduringasession(intertraininterval)

Treatmentduration(durationofeachsessionanddurationoftreatmentasawhole,
treatmentsaregenerallyconductedonweekdaysfortwotofourweeks)

CurrentlythereisnoconsensusonthemostappropriaterTMSparameterstousewhentreating
depression.8

Regulatorystatus
AlthoughrTMSisseenanalternativeforECTitisunclearforwhichindicationitwouldbemost
effective;inanupdateoftheirreviewofrTMS,theMedicalServicesAdvisoryCommittee(MSAC)
posesthequestion:shouldrTMStherapyberestrictedtopatientswhohavefailedtorespondtotwo
differentclassesofantidepressantdrugtherapy(despiteappropriatedose,durationand
compliance),orshouldtheindicationsbebroadenedtoallowtreatmentafterpatientshavefailedto

Report#0513002R11rTMSforDepressionEvidenceReview

respondtooneclassofantidepressanttherapy,andfailedtorespondtooneformofpsychological
therapy(suchCBTorinterpersonaltherapy,IPT)?9
IntheUnitedStates,theFoodandDrugAdministrationhasprovidedguidancethatrTMSisintended
tobeusedtotreatthesymptomsofMDDwithoutinducingseizureinpatientswhohavefailedat
leastoneantidepressantmedicationandarecurrentlynotonanyantidepressanttherapy.10
InAustraliathemagneticstimulatormanufacturedbyMagVenture,hasbeenapprovedforlistingon
theAustralianRegisterofTherapeuticGoods(ARTG)fortheintendedpurposeoftreatmentof
MajorDepressiveDisorderinadultpatientswhohavefailedtoachievesatisfactoryimprovement
fromtwopriorantidepressantmedications,atorabovetheminimaleffectivedoseanddurationin
thecurrentepisode.
In2008rTMSwasrefusedfundingundertheAustralianMedicareBenefitsSchedule(MBS).8The
MedicalServicesAdvisoryCommitteeiscurrentlyreconsideringfundingforthistechnology.11

Intendedpurposeofthereview
TheTransportAccidentCommission(TAC)andWorkSafeVictoria(WSV)requestedareviewofthe
evidencetodeterminewhetherrepetitivetranscranialmagneticstimulationisaneffective
treatmentformajordepressivedisorder.Thisreportsoughttoanswerthefollowingquestions:
1. WhatistheeffectivenessandsafetyofrTMSintreatingacutephasedepressivesymptoms
(e.g.,responseandremission)?
2. WhatistheeffectivenessandsafetyofrTMSinmaintainingresponseorremission(e.g.,
preventingrelapseorrecurrence),whetherasasingletreatmentorpartofacombination
treatment?
3. Inwhatsetting,inpatientoroutpatient,isrTMSmosteffectiveintreatingacutephase
depressivesymptomsORmaintainingresponseorremission?
4. WhatrTMSprotocols,i.e.,whatnumberoftreatmentsoverwhattimeperiod,areeffective
intreatingacutephasedepressivesymptomsORmaintainingresponseorremission?

Report#0513002R11rTMSforDepressionEvidenceReview

METHODS
Thereviewmethodsareoutlinedbrieflybelow.Moredetailedinformationaboutthemethodology
usedtoproducethisreportisavailableinAppendices1and2.AllAppendicesarelocatedinthe
TechnicalReportaccompanyingthisdocument.

Stage1:Identifyrelevantresearch
AcomprehensivesearchofMedline,Embase,AllEBMReviews(CochraneDatabaseofSystematic
Reviews,ACPJournalClub,DARE,CCTR,CMR,HTA,NHSEED),CINAHLandWebofKnowledgewas
undertakeninJuly2012toidentifyrelevantsynthesisedresearch(i.e.,evidencebasedguidelines
(EBGs),systematicreviews(SRs),healthtechnologyassessments(HTAs));andrelevantrandomised
controlledtrials(RCTs)andcontrolledclinicaltrials(CCTs).AcomprehensivesearchoftheInternet,
relevantwebsitesandelectronichealthdatabaseswasalsoundertaken.
Studiesidentifiedbythesearcheswerescreenedforinclusionbytworeviewers(ED&JW)using
specificselectioncriteria.Anydiscrepanciesinstudyselectiondecisionswerediscussedand
resolved.Duetothenumberofprimarystudiesidentified,studiesthatwerereportedonlyin
abstractformwereexcluded,astheyprovidelimitedinformationthusprecludingqualityappraisal
frombeingconducted.
Forfurtherinformation,seeAppendix2,TableA2.1forinclusionandexclusioncriteria,TablesA2.2
2.4forfurthersearchstrategydetails,andAppendix3forlistsofincludedstudiesbystudytype.

Stage2:Developanevidencemapofsynthesisedstudies
Duetothelargenumberofsynthesisedstudiesidentifiedonthistopicwedevelopedanevidence
maptoidentifytheircurrency,comprehensivenessandquality.Adetaileddescriptionofthe
evidencemapmethodologycanbefoundinAppendix1.
Currency
Thecurrencyofthereviewwasassessedusingtheyearofpublicationandsearchdate.
Comprehensiveness
Comprehensivenesswasassessedbythebreadthofstudiesthatthereviewsincluded.Wecross
referencedtheRCTsidentifiedbyoursearchandtheRCTsincludedinthereviewstoidentify
whetheranystudiesweremissing.
Qualityassessment
QualityassessmentwasconductedusingtheAMSTARtool(fortheAssessmentofMultiple
SysTemAticReviews)12(seeAppendix4,TablesA4.2andA4.3).TheAMSTARisanelevenitemtool
designedtogiveanoverallscoreforSRsbasedontheirmethodologicalquality.Thesescoresgivean
indicationoftheriskofbiasofeachSRwith0/11representinglowestquality(highestriskofbias),
and11/11highestquality(lowestriskofbias).Forreviewsinwhichnometaanalysishasbeen

Report#0513002R11rTMSforDepressionEvidenceReview

performed,theAMSTARscoreiscalculatedwithadenominatorofnineinsteadof11,asthetwo
AMSTARitemsthatrelatespecificallytometaanalysisarenotapplicable.

Stage3:Identifyandupdatethemostrecent,comprehensive,highqualitysynthesised
study
Based on the results of the evidence map, we identified the most recent, comprehensive, high
qualitysynthesisedstudyonwhichtobaseourreview.Thisreviewthenunderwentamoredetailed
qualityappraisalandnewstudiesnotincludedintheoriginalreportwereincorporated.
InthisreportwepresentanevidencemapofexistingstudiesontheeffectivenessofrTMSfor
depression(Table1)andanupdateofthemostrecent,highqualityreview(Gaynesetal20114).

RESULTS
Databasesearchesyielded2,757articles.Afterdeduplication,1,499werescreenedagainstour
selectioncriteria.Ofthese,248fulltextarticleswereretrievedandscreened,andofthese104
paperswereidentifiedasrelevanttothereview.Onefurtherstudywasidentifiedthroughthe
screeningofGooglesearchresults.
Intotal,105paperswereincluded,consistingof:

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

Table1.Evidencemapofidentifiedstudies
Synthesisedstudies
Primarystudies
21(20SRs/MA+1EBG)

84(81RCTs+3CCTs)

TOTAL
105

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

SUMMARYOFSYNTHESISEDSTUDIES
The21synthesisedstudieswerereviewedtoidentifytheircurrency,comprehensivenessandquality.
Overalleightofthe21reviewswerepublishedinthelastfiveyears,i.e.,between2013and2009.The
mostrecentofthesewereMinichino2012,25Gaynes2011,4andAllan2011.14Themostuptodate
searchwasconductedbyGaynes20114withasearchdateofNovember2010.
Inclusioncriteriafordepressionvariedacrossreviews.Forexample,somereviewsfocusedon
patientswithMDD,othersonpatientswithMDDordepressionalone,whileothershadmixed
populations,e.g.,MDDorbipolar;or,MDDorTreatmentResistantDepression(TRD).OnlyGaynes
20114specificallyfocusedontheindicationofTRD.

Report#0513002R11rTMSforDepressionEvidenceReview

Withregardstothecomparator,sixreviewsincludedevidenceforbothrTMSvs.ECTandrTMSvs.
shamrTMS.4,13,2628,31ThirteenreviewsexclusivelycomparedtheeffectofrTMSwithshamrTMS1424,
29,30
andtwoexclusivelycomparedrTMStoECT.8,25
UsingtheAMSTARtoolweassessedthequalityofeachofthereviews.Overallthequalityofthese
reviewswaspoorwithonlyfourofthe21reviewsscoringgreaterthan8/11.Onlyonereview,
Gaynes2011,4attainedaperfectscoreontheAMSTARtool(seeTablesA4.2A4.3).
Basedonourassessmentoftheevidencemap,themosthighquality,recent,synthesisedstudywas
theSRbyGaynes2011.4Anupdateofthisreviewispresentedinthisreport.

UPDATEOFMOSTRECENT,HIGHQUALITY,SYNTHESISEDSTUDY
TheSRbyGaynes20114isalargeanddetailedreportpreparedfortheUSAgencyforHealthCare
ResearchandQuality.ThisreviewexaminednonpharmacologicinterventionsforTRDinadults.
Interventionsassessedinthisreportincluded:rTMS,ECT,VNSandevidencebasedpsychotherapy
(i.e.,cognitivebehaviouraltherapy).Thisreportwaspublishedin2011,withevidencesearches
conductedupuntilNovember2010.Forthepurposeofthisreportweonlyfocusedonupdatingthe
sectionrelevanttorTMScomparedtoplaceboorECT.UsingtheAMSTARtoolandadetailedquality
assessmenttool,thisSRwasfoundtobeofhighquality,meetingallqualitycriteria(seeTablesA4.2
andA7.1ofTechnicalReport).
InupdatingthisreviewweidentifiedfivenewRCTs;32,51,67,70,108fourcomparingrTMSwithsham
rTMSandonecomparingrTMStoECT.Overall,includingthestudiesreviewedbyGaynes2011,4a
totalof22RCTsreportedacross25publicationswerereviewedinthisreport.Ofthese,fourstudies
comparedrTMStoECTand18studiescomparedrTMSwithshamtherapy.Thecharacteristicsofall
includedstudiesareoutlinedinTablesA5.1A5.6oftheTechnicalReport.
WeinvestigatedthepossibilityofupdatingthemetaanalysisofrTMSvs.shamprovidedinthe
Gaynesreport4withtheadditionoffournewstudies(Fitzgerald2012,51Aguirre2011,32Triggs
2010108andJakob200867).However,thiswasnotpossibleduetoalackofdataregardingremission
orresponseratesinthenewpapers,andinconsistentreportingoftheprimaryoutcomemeasure
betweenstudies(i.e.,differentpapersuseddifferentmeasurementscales,orreportedresultsin
percentage,orgraphformonly).

Report#0513002R11rTMSforDepressionEvidenceReview

StudiescomparingrTMSwithECT
Studycharacteristics
Fourstudies(reportedacrosssixpublications)wereidentifiedcomparingrTMSwithECT.
Samplesize
Allstudieshadsmallstudypopulationsrangingfrom40to73patients.
Patientpopulation
AllstudiesincludedpatientswithMDD.ThediagnosticinstrumentsusedtodefineMDDvaried
betweenstudieswithonestudyusingDSMIV(DiagnosticandStatisticalManualofMental
Disorders,fourthedition),onestudyusingHAMD(HamiltonRatingScaleforDepression).Two
studiesdidnotreportonhowMDDwasdefined.
Treatmentfailure
Priortreatmentfailuretopharmacotherapydifferedamongstudies:twostudiesRosa2006100and
Keshtkar201170recruitedpatientswithtwoormorepriortreatmentfailuresandonestudy58
recruitedpatientswithoneormorepriortreatmentfailures.Twostudies46,73didnotreportonprior
treatmentfailure.
rTMSparameters
TherTMSparametersusedtoadministertreatmentdifferedbetweenstudies.Thefrequencyat
whichthepulseswereadministeredwas10Hzinthreestudies.58,100,114Onedidnotreportthe
frequencyused.Themotorthresholdwas90%intwostudies,58,70100%inonestudy100and110%in
onestudy.114Thenumberoftrainsvariedfromtwototwentywithvariationinthelengthoftrain
fromfiveto60seconds.Theintertrainintervalvariedbetween20and160seconds.Thenumberof
pulsesvariedfrom408to2500pulsespersession.Thenumberoftreatmentsvariedbetween915
sessions.Numberofsessionsperweekvariedbetweenthreeandfivesessionsperweek.
ECTparameters
Studiesvariedbetweenbilateralorunilateralelectrodeplacement.StudiesvariedinintensityofECT
treatment,between1.5and4.5timesseizurethreshold.
Setting
Twopublicationsreportedthatstudieswereconductedinbothinpatientandoutpatientssettings,
threewereexclusivelysetwithinaninpatientsettingandonedidnotreportonsetting.
Outcomes
AllstudiesassessedtheeffectivenessofrTMSintreatingacutephasedepressivesymptoms,no
studiesassessedmaintenanceofresponseorremission.Allofthestudiesexceptoneusedaversion

Report#0513002R11rTMSforDepressionEvidenceReview

10

oftheHamiltonRatingScaleforDepression(HAMD1758,114andHAMD2470)toassess
improvementsindepression.OtherscalesusedtoassessresponseincludedClinicalGlobal
ImpressionScale100andtheBeckDepressionInventory(BDI).70Definitionofresponseandremission
differedbetweenstudies.ForexampleRosa2006100definedresponseasHAMD177while
Grunhaus200358definedresponseasadecreaseof50%ormore,orHAMD1710andafinal
GlobalAssessmentofFunctionScalerating60.IntermsofremissionRosa2006100defineditas
HAMD177,whileMcLoughlin2007114andGrunhaus200358definedremissionasHAMD178.
Themajorityofstudiesexclusivelyassessedoutcomesatendoftreatment,onlyMcLoughlin2007114
assessedoutcomesatsixmonths.

Results
WithregardstotheeffectivenessofrTMScomparedtoECT,twostudiesfoundnosignificant
difference100,58andtwostudies114,70foundrTMStobelesseffectivethanECT.
Responsetotreatment
Rosa2006andGraunhaus2003reportednosignificantdifferenceinendpointscoresbetweenrTMS
andECTmeasuredonHAMD1758andClinicalGlobalImpressionScale.100Inaddition,forthose
studiesreportingresponserates58,100nosignficantdifferencebetweenrTMSandECTwasobserved.
Keshtkar201170andMcLoughlin2007114observedsignificantlylowerendpointscoresontheHAM
D24andBDI;andtheHAMD17respectively.
Remission
Ofthethreestudiesreportingonendoftreatmentremission,two100,58foundnosignficant
differencebetweenrTMSandECT.Oneother114foundtherateofremissionwaslowerforrTMS
comparedtoECTattheendoftreatment,althoughthiseffectwasnotsustainedatsixmonthswith
bothtreatmentarmsbeingequivalent.
Severityofsymptoms
Keshtkar201170foundECTtobemoreeffectiveinreducingposttreatmentBDIandHAMDsuicide
scorescomparedtorTMS.
Neurologicalfunctioning
Twostudies100,114conductedneurologicalassesmentsbeforeandaftertreatment.Neitherstudy
foundasignificantdifferenceinneurologicalfunctioningbetweenrTMSandECTposttreatment.
Adverseeffects
NosignificantdifferenceinadverseeffectswasobservedbetweenrTMSandECTtreatmentfortwo
studies.70,100OverallthemainsideeffectsreportedforrTMSincludedlocalisedpainormild
headache.ThestudybyKeshtkar201170withdrewtwopatientsintheECTgroupduetoalossof
conciousness.Adverseeventswerenotcomparedbetweengroupsfortwostudies,asGrunhaus

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200358didnotreportadverseeventsfortheECTgroup,andMcLoughlin2007114didnotreport
adverseeventsforeithergroup.

StudiescomparingrTMSwithshamrTMS
Studycharacteristics
EighteenRCTs(reportedacross19publications)wereidentifiedcomparingrTMSwithshamrTMS.
CharacteristicsofthesestudiesareshowninTable2.
Samplesize
Thesamplesizesofthe18includedstudiesrangedbetween12and325patients.Themajorityof
studieshadsmallsamplesize,fivehadasamplesizeof20orless,65,69,82,94,96and11studieshad
between21and68patients.Amongthesestudiesthereweretwolargetrials,withsamplesizesof
199,55and32592patients.
Patientpopulations
Allstudiesrecruitedpatientswithmajordepression/MDD.Majordepressivedisorderwasdefined
differentlyacrossstudies,withninestudiesusingDSMIV;oneusingDSMIVorSCID(Structured
ClinicalInterviewforDSMdisorders);oneusingHAMD25;oneusingDSMIVorHAMD17orMADRS
(MontgomerysbergDepressionRatingScale)orBDI;oneusingDMSIVorSCIDorHAMD21.Two
studiesdidnotreporthowmajordepressionwasdefined.Otherdefinitionsincludedmajor/minor
depression(DSMIV),82medicationresistantdepressionofpsychoticsubtype(DSMIII),96moderate
tosevereTRD(HAMD17),andunipolardepression(DSMIV).52
Treatmentfailure
Fourteenstudiesreportedthatpatientsspecificallyhadtwoormorepriortreatmentfailureswith
medications.Twostudieshadoneormoretreatmentfailuresandtwodidnotspecifythenumberof
treatmentfailures,butwerejudgedtohaveahighprobabilityofhavingtwoormoretreatment
failures.
rTMSparameters
DetailedrTMSparametersfortheincludedstudiesareshowninTable3.Location,frequency,motor
thresholds,anddurationoftreatmentvariedacrossstudies.
o

Comparisons:ElevenstudiescomparedrTMStoshamstimulation.Theremainingseven
studiescomparedeitherdifferentfrequencyparameters,54,67,95differentlocations51,94,
108
ordifferentfrequenciesindifferentlocations106withsham.

Location:rTMSwasmostfrequentlyconductedoverthetheleftDPFC,thisoccurredin
12outof18studies.Insixstudies,rTMSwasconductedovertherightDPFC.Inthe

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12

remainingstudies,rTMSwasappliedanteriortotherightmotorcortex,69invarying
locations,54,96ortoanunspecifiedlocation.67
o

Frequencyandmotorthreshold:Inthe13studiesthatusedLDPFCrTMS,frequencies
rangedbetween1Hzand20Hz,with10Hzmostcommon(sixstudies)followedby20Hz
(fourstudies).MotorthresholdsinLDPFCstudiesrangedbetween80%and120%,with
110%mostcommon(fivestudies)followedby120%(threestudies).Inthesixstudies
thatusedRDPFCrTMS,frequenciesrangedbetween0.3Hzand5Hz,with1Hzthemost
common(fourstudies).MotorthresholdsinRDPFCstudiesrangedbetween90%and
120%,with110%mostcommon(threestudies).

Duration:treatmentconsistedoffivesessionsperweekforallstudies,withthenumber
ofweeksrangingbetweenoneandfourtosixweeks.Themostcommontreatment
durationwastwoweeks(eightstudies),followedbyoneweekandfourweeks(four
studieseach).Thestudiesthathadaoneweekdurationtendedtobetheoldeststudies
inthegroup(publishedbetween1996and2001),withtheexceptionofPallanti(2010).95

Setting
Sevenstudieswereconductedinanoutpatientsetting,onewasconductedinbothinpatientand
outpatientssettings,andtheremainingtendidnotspecifythetypeofsettinginwhichtheywere
conducted.
Outcomes
AllstudiesexclusivelyassessedtheeffectivenessofrTMSfortreatingacutephasedepressive
symptoms;nostudiesassessedmaintenanceofresponseorremission.Allofthestudiesexcepttwo
usedaversionoftheHamiltonRatingScaleforDepression,HAMD17,HAMD21andHAMD25
(abbreviatedasHRSD,HDRS,orHAMD)toassessimprovementsindepression.Onestudy55didnot
reporttheratingscaleused,reportingonlyremissionrates.Onestudymeasuredimprovementsin
depressivesymptomsusingtheMADRS.92

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13

Table2.CharacteristicsofrTMSvs.shamrandomisedcontrolledtrials
Year

Study

Diagnosis

Setting

Outcomes

NS

CDS(HAMD17),response,MADRS,BDI,AE

34
34
48
60

TRDdiagnosisofmoderatetosevere
depression(>15HAMD17)
Majordepression
Majordepression(DSMIV)
MDD(DSMIV,SCID)
Majordepression(DSMIV)

Rx
failure
2+

2012

Fitzgerald(51)

67

2011
2010
2010
2010

Aguirre(32)
Zheng(113)
Triggs(108)
Pallanti(95)

2010

2+*
2+
2+
2+

OP
NS
NS
NS

George(55)

199

MDD(DSMIV)

2+

OP

CDS(HAMD),response
CDS(HAMD17),BDI,response
CDS(HAMD24),BDI,STAIS,AE
CDS(<=10%,<=25%,<=50%&>50%reduction
inHAMD),numberneededtotreat,adverse
events
CDS(HAMD24),response,remission,MADRS,
BDI,adherence,AE

2008

Jakob(67)

36

2+*

NS

CDS(HAMD,MADRS,BDI),tolerability

2007

Stern(106)

45

1+

OP

2007

O'Reardon(92)

325

Majordepression(moderatetosevere
unipolarDSMIV)>18onHAMD17,
MADRSorBDI
MDDunipolarrecurrent(SCID&DSM
IV,HAMD21score>=20)
MDD(DSMIV)

1+

NS

2006
2006

GarciaToro(54)
Avery(35)

30
68

MDDunipolar
MDD(DSMIV)

2+
2+

OP
OP

2004
2004
2002

Kauffman(69)
Holtzheimer(65)
Boutros(40)

12
15
21

Majordepression(DSMIV)
MDD(DSMIV)
Majordepression(HAMD25>=20)

2+
2+
2+

2001

Manes(82)&
Moser(88)
GarciaToro(52)
Padberg(94)
PascualLeone(96)

20

Major/minordepression(DSMIV)

40
18
17

Unipolardepression(DSMIV)
Majordepression(DSMIV)
Medicationresistantdepressionof
psychoticsubtype(DSMIIIR)
resistance

2001
1999
1996

Response
definition
50%reductionin
HAMDscore
HAMD <8
notdefined
N/A
N/A

Remission
Definition
N/A

Followup
EOT(3wk)+FU(3wkPT)

N/A
N/A
N/A
N/A

EOT(4wk)+FU(4wkPT)
4wk,NSifEOTorFU
EOT(2wk)+FU(1wk,1mo&3moPT)
EOT(3wk)

>=50%decrease
inHAMD

EOT(3wk)

N/A

HAMD<=3,or2
consecutive
HAMD<10
N/A

EOT(2wk)

CDS(HAMD21)

N/A

N/A

EOT(2wk)+FU(2wkPT)

notdefined

HAMD17<8

EOT(46wk)

N/A
notdefined

N/A
HAMD21<10

NS
NS
OP

CDS(HAMD17),response,remission,MADRS,
AE
CDS(HAMD21)GCI
CDS(HAMD17),response,remission(HAM
D21),relapseat6months,BDI,AE,CF
CDS,response,relapse
CDS,AE
CDS(HAMD25),response,relapse,AE

N/A
N/A
N/A

2+

OP

CDS(HAMD),response,remission,AE,CF

HAMD21<10
N/A
30%or50%
improvementin
HAMD25
notdefined

EOT(2wk)+FU(2wkPT)
EOT(4wk)+FU(1wkPT,monthlyFU
forrespondersfor6moPT)
EOT(2weeks)+FU(3moPT?)
EOT(2wk)+FU1wkPT
EOT(2weeks)+FUforrespondersonly
(6moPT)

notdefined

EOT(1wk)+FU(1wkPT)

2+
2+
2+

NS
NS
IP&OP

CDS(HAMD17,BDI,GCI)
CDS(HAMD21)
CDS(HAMD21,BDI)

N/A
N/A
N/A

N/A
N/A
N/A

EOT(2wk)+FU(2wkPT)
EOT(1wk)
EOT(5mo,rTMSreceivedfor1st5
days,everymofor5mo)

*=notspecified,butahighprobabilityoftwoormoretreatmentfailures;1+=1ormoretreatmentfailures;2+twoormoretreatmentfailures;AE=adverseevents;BDI=BeckDepressionInventory;CDS=changeindepressive
severity;CF=cognitivefunctioning;defn=definition;DSMIIIR=Diagnostic&StatisticalManualofMentalDisorders3rdEditionRevised;DSMIV=DiagnosticandStatisticalManualofMentalDisorders,fourthedition;EOT=endof
treatment;FU=followup;GCI=GlobalClinicalImpressions;HAMD=Hamiltondepressionratingscale;IP=inpatient;MADRS=MontgomerysbergDepressionRatingScale;MDD=majordepressivedisorder;mo=month/s;n=
numberofpatients;N/A=notapplicable;NS=notspecified;OP=outpatient;PT=posttreatment;Rx=treatment;SCID=StructuredClinicalInterviewforDSMdisorders;TRD=treatmentresistantdepression;wk=week/s.

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Table3.rTMSparametersforrTMSvs.shamrandomisedcontrolledtrials
Year

Study

MT

Location

Trains

Fitzgerald(51)(Lparameters)
Fitzgerald(51)(SBarmRparameters)
Aguirre(32)
Pallanti(95)(lowfreqarm)
Pallanti(95)(highfreqarm)

Freq
(Hz)
10
1
1
0.3
10

2012
2012
2011
2010
2010

Interval
(seconds)
NS
NS
45s
NS
30s

Pulsesper
session
NS
NS
1200
75
250

Sessions

Days/Weeks

Comments

30
1
20
10
5

Train
length
5s
15min
60s
25s
5s

120%
120%
110%
90%
90%

2010
2010
2010
2010
2008
2008
2007
2007
2007
2007
2006
2006
2006
2004

Zheng(113)
George(55)
Triggs(108)(Lsidedarm)
Triggs(108)(Rsidedarm)
Jakob(67)(standardarm)
Jakob(67)(ultrahighfreqarm)
Stern(106)(lowfreqLarm)
Stern(106)(highfreqLarm)
Stern(106)(lowfreqRarm)
O'Reardon(92)
GarciaToro(54)(normalfreqarm)
GarciaToro(54)(highfreqarm)
Avery(35)
Kauffman(69)

15
10
5
5
20
50
1
10
1
10
1
20
10
1

110%
120%
100%
100%
100%
100%
110%
110%
110%
120%
110%
110%
110%
110%

2004
2002
2001
2001
1999
1999
1996

Holtzheimer(65)
Boutros(40)
GarciaToro(52)
Manes(82)&Moser(88)
Padberg(94)(SBarmLparameters)
Padberg(94)(Rparameters)
PascualLeone(96)

10
20
20
20
20
1
10

110%
80%
90%
80%
100%
110%
90%

LDLPFC
RDLPFC
RDLPFC
RDLPFC
RDLPFCthen
LDLPFC
LDLPFC
LDLPFC
LDLPFC
RDLPFC
NS
NS
LDLPFC
LDLPFC
RDLPFC
LDLPFC
various
various
LDLPFC
anteriortoR
motorcortex
LDLPFC
LDLPFC
LDLPFC
LDLPFC
LDLPFC
RDLPFC
Vertex,LorR
DLPFC

15
15
20
5
5

3weeks
3weeks
4weeks
1week
1week

Lparametersonly
LfollowedbyRparameters

50
75
50
50
NS
NS
1
20
1
75
30
30
32
2

4s
4s
8s
8s
2s
1s
1600s
8s
1600s
4s
60s
2s
5s
60s

NS
26s
22s
22s
18s
59s
N/A
52s
N/A
26s
1525s
1525s
2530s
180s

3000
3000
2000
2000
NS
NS
NS
1600
NS
3000
1800
1200
1600
120

20
15
10
10
10
10
10
10
10
5/week
10
10
15
10

4weeks
3weeks
2weeks
2weeks
2weeks
2weeks
2weeks
2weeks
2weeks
46weeks
2weeks
2weeks
4weeks
10days

28minspersession

32
20
30
20
20
3
20

5s
2s
2s
2s
5s
140s
10s

3060s
58s
2040s
60s
25s
30s
60s

1600
800
1200
800
1000
420
2000

10
10
10
5
5
5
25

2weeks
10days
10days
1week
1week
1week
1st5dayseach
mofor5mo

RfollowedbyLparameters
Rparametersonly

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

Report#0513002R11rTMSforDepressionEvidenceReview

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Resultssummary
Responsetotreatment
SixstudiesreportedasignificantdifferenceineffectivenessbetweenrTMSandsham(infavourof
rTMS)forthetreatmentofdepression.35,52,54,55,92,96Ofthesestudies,George201055andOReardon
200792hadlargesamplesizes(n=199andn=325respectively).Fouroutofthesixstudiesuseda
frequencyof10HzforrTMS.AlthoughGarciaToro52reportedasignificantdifferencebetween
changesinHAMD,theeffectsizewassmallandtherewasnosignificantdifferenceinthe
percentageofrespondersbetweengroups(thisstudyuseda20Hzfrequency).Threeofthesix
studiesmeasuredtheprimaryoutcomeattheendoftreatment.52,54,55Twostudies35,96measured
theprimaryoutcomeoneweekafteractivetreatment.Onestudymeasuredtheprimaryoutcomeat
theendoffourweeksoftreatmenttoallowcrossoverofnonrespondersandanadditionaltwo
weeksoftreatment.92
NinestudiesfoundnosignificantdifferencebetweenrTMSandshamrTMSforthetreatmentof
depression.32,40,65,67,69,82,94,108,113Allofthesestudieshadrelativelysmallsamplesizes(between12
and48patients).Effectivenessoftreatmentwasmeasuredattheendofactivetreatment;formost
studiesactivetreatmentlastedtwoweeks.Fourstudiesmadeadditionalposttreatmentfollowup
assesmentsatoneweek,65,82fourweeks,32andsixmonths.40
Threestudiesreportedmixedresults.OnestudyfoundthatunilateralbutnotbilateralrTMSwas
moreeffectivethanshamtreatment.95Onestudyfoundthathighfrequency(10Hz)rTMStotheleft
DPFC,andlowfrequency(1Hz)rTMStotherightDPFC,butnotlowfrequencytotheleftwasmore
effectivethanshamtreatment.106OnestudyreportedunilateralleftsidedrTMSwasmoreeffective
thanshamorbilateralrTMS.51Allthreeofthestudiesmeasuredtheprimaryoutcomeattheendof
activetreatment.Onestudyhadanadditionaltwoweekfollowup106andonestudyhadacrossover
ofpatients.51
Adverseevents
Noseriousadverseeventswerereported.Sideeffectsgenerallyincludedheadacheorlocalised
pain/discomfortatthesiteofapplication.Somestudiesreportedthesesideeffectsinboththesham
andtheactivetreatmentgroups.Sevenstudiesreportedthatheadachesoccuredmorefrequentlyin
theactivegroupthattheshamtreatmentgroup.52,54,55,82,92,9496Noneofthestudiesreportedany
signifcantdifferencesbetweengroups.Twostudiesreportedontestingforneurophysiological
adverseeventsandfoundthattherewasnosignificantdifferencebetweenthegroups.35,82

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FINDINGS
Table4.Keyinformationfrommostrecent,comprehensive,highqualitysystematicreview
GaynesBN,LuxLJ,LloydSW,HansenRA,GartlehnerG,KeenerP,etal.NonpharmacologicInterventionsfor
TreatmentResistantDepressioninAdults.ComparativeEffectivenessReviewNo.33.AHRQPublicationNo.
11EHC056EF.Rockville,MD:AgencyforHealthcareResearchandQuality.Availablefrom:
www.effectivehealthcare.ahrq.gov/reports/final.cfm.

Studydesign

Systematicreview

Scope

Patient/population:PatientswithTRD.
Interventionandcomparators:nonpharmacologictreatmentsincluding
rTMS,shamrTMS,ECT,VNS,andevidencebasedpsychological
treatments.
Outcomesassessed:
ECTvs.rTMS:changeindepressiveseverity,responseandremission
rate,adverseevents,withdrawalsduetoadverseevents,cognitive
functioning.
rTMSvs.sham:changeindepressiveseverity,responseandremission
rates,adverseevents,withdrawalsduetoadverseevents,cognitive
functioning,healthrelatedoutcomes.

1.Whatistheeffectivenessof
rTMSintreatingacutephase
depressivesymptoms(e.g.,
responseandremission)?

Effectivenessintreatingacutephasedepressivesymptoms
rTMSvs.ECT(n=4studies)
ThereisinsufficientevidencetodeterminewhetherrTMSismore
effectiveorevenequivalenttoECT,withhalfofthestudiesreporting
equivalenceandhalfreportingrTMSasbeinginferiortoECTwith
regardstotreatingacutephasedepressivesymptoms.
rTMSvs.shamrTMS(n=18studies)
Onlyonegoodqualitystudy92wassufficientlypoweredtodetecta
significantdifferencebetweentreatmentarms.Thisstudyreportedthat
rTMSwasmoreeffectivethansham.
ThereisinsufficientevidencetodeterminetheeffectofrTMS,asthe
resultsofthestudieswerevariablewithsixstudiesreportingrTMStobe
moreeffectivethansham,ninestudiesreportingnosignificant
differencebetweenrTMSandshamrTMS,andthreereportingmixed
results.
DespitealargenumberofRCTs,therelativelysmallsamplesizesofthe
studiesandlargevariationintreatmentparametersmakesitdifficultto
assesstheoverallresults.

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2.Whatistheeffectivenessof
rTMSinmaintainingresponseor
remission(e.g.,preventingrelapse
orrecurrence),whetherasa
singletreatmentorpartofa
combinationtreatment?

rTMSvs.ECT:Thereisnoevidencetoanswerthisquestion.
rTMSvs.shamrTMS:Thereisnoevidencetodrawconclusionsonthe
effectivenessofrTMSonmaintainingremissionorpreventingrelapse
whencomparedtoshamrTMS.

3.Inwhatsetting,inpatientor
outpatient,isrTMSmosteffective
intreatingacutephasedepressive
symptomsORmaintaining
responseorremission?

Thereisinsufficientevidencetoassessthemostappropriatetreatment
setting.Thestudiesincludedinthisreviewwereeithersetinan
inpatientenvironmentoramixedinpatientandoutpatientsetting.None
ofthestudiesindicatedatrendinresultsaccordingtosettingandno
studiescomparedtheeffectofrTMSininpatientandoutpatientsettings.

4.WhatrTMSprotocolsi.e.,what
numberoftreatmentsoverwhat
timeperiod,areeffectivein
treatingacutephasedepressive
symptomsORmaintaining
responseorremission?

ThereisinsufficientevidencetodeterminethemosteffectiverTMS
protocols.rTMSlocation,frequency,motorthresholds,anddurationof
treatmentvariedacrossstudies.

5.WhatisthesafetyofrTMSfor
depression?

Noneofthestudiesreportedanysignificantdifferencesbetweengroups.
rTMSvs.ECT
Cognitivefunctioning:InsomecasesECTcanhaveanadverseimpacton
cognitivefunctioning.
Withdrawalsduetoadverseevents:therewasnodifferencein
withdrawalsduetoadverseeffectsbetweenrTMSandECT.
rTMSvs.shamrTMS
Cognitivefunctioning:theevidenceontheeffectsofrTMSversussham
oncognitivefunctioningisinsufficienttodrawaconclusion.
Specificadverseevents:rTMSgroupsreportedsignificantlymorescalp
painatthestimulationsite(lowstrengthofevidence).
Withdrawalsduetoadverseevents:Findingsweremixedastowhether
rTMSgroupshadgreaterratesofwithdrawalsduetoadverseevents
thangroupsreceivingshamprocedures.

Qualityassessmentresults

ThisSRscored11/11usingtheAMSTARtool,thismeansitwaswell
conductedandconsideredtohavealowriskofbias.However,the
qualityoftheincludedstudiesvaried,andmanyofthemweresmall,and
notsufficientlypoweredtodetectarealeffect.

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DISCUSSION
1.WhatistheeffectivenessandsafetyofrTMSintreatingacutephasedepressivesymptoms(e.g.,
responseandremission)?
ThereisinsufficientevidencetodeterminewhetherrTMSismoreeffectiveorevenequivalentto
ECT,withhalfofthestudiesreportingequivalenceandhalfreportingrTMSasbeinginferiortoECT.
Thisuncertaintyisfurthercompoundedbythefactthatthetwostudiesreportingequivalencewere
underpowered(i.e.,thenumberofpatientsrecruitedwasinsufficienttoidentifyasignificant
differencebetweentreatmentarms).Otherissuesalsoimpactingontheoveralleffectivenessof
rTMSwasthevariationinrTMSandECTparametersacrossstudies.ThelongtermeffectsofrTMS
arealsounclearasthemajorityofstudiesonlyassessedoutcomesattheendoftreatment.
WithregardstorTMSvs.shamrTMS,theonlystudythatwassufficientlypoweredtodetecta
significantdifferencebetweentreatmentarmswasOReardon200792,whichrecruited325patients.
ThisstudyindicatedthatrTMSwasmoreeffectivethansham.Theremainingstudiesallhad
relativelysmallsamplesizesandwereeitherunderpoweredordidnotreportpowercalculations.
Notwithstandingtheissueofsamplesize,studiesofrTMSvs.shamvariedinthefrequencyof
stimulation,theareaofthebraintowhichitwasapplied,theamountoftreatmentgiveneach
session(thenumberoftrains,lengthoftrains,lengthofintervalsbetweentrains,andnumberof
pulsespersession),andthedurationoftreatment(seeTable3).
Thevariationbetweenparametersmakesitdifficulttoassesstheresultsofthesestudiesoverall
withoutmakingtheassumptionthatallrTMSparametersareequallyeffective.Sevenofthe
eighteenrTMSvs.shamtrials51,54,67,94,95,106,108includedseveralarmsthatcompareddifferentrTMS
parameterswitheachotheraswellaswithshamrTMS,thesetrialsincludesomeofthemostrecent
publicationsonthistopic,suggestingthattheoptimalrTMSparametersarestilltobedetermined.
Intermsofsafetyitwouldappearthattherewasnodifferenceinadverseeventsbetweenstudy
arms,withnostudyreportingasignificantdifferencebetweenrTMSandECTorsham.
Issuesaroundwhethertreatmentfailurewasaneffectmodifiercouldnotbeansweredinthis
review,astheresultswereinconsistentacrossthestudiesregardlessofhowmanytreatment
failurespatientsexperienced.

2.WhatistheeffectivenessandsafetyofrTMSinmaintainingresponseorremission(e.g.,
preventingrelapseorrecurrence),whetherasasingletreatmentorpartofacombination
treatment?
NotrialswereidentifiedthatspecificallyexaminedlongertermefficacyofrTMS,suchasmaintaining
remission.Thiscouldbeduetotheuncertaintyaroundtheshorttermeffectivenessofthis
treatment.OnestudydidassessremissionatsixmonthsreportingthattheeffectsofECTwerenot
sustainedaftersixmonths.

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3.Inwhatsetting,inpatientoroutpatient,isrTMSmosteffectiveintreatingacutephase
depressivesymptomsORmaintainingresponseorremission?
ThereisinsufficientevidenceidentifyingtheoptimalsettingforadministeringrTMS.Thestudies
includedinthisreviewhadeitherinpatientormixedinpatientandoutpatientsettings.Noneofthe
studiesindicatedatrendinresultsaccordingtosettingandnostudiescomparedtheeffectofrTMS
ininpatientandoutpatientsettings.

4.WhatrTMSprotocolsi.e.,whatnumberoftreatmentsoverwhattimeperiod,areeffectivein
treatingacutephasedepressivesymptomsORmaintainingresponseorremission?
ThedifferentrTMStreatmentprotocolsandparametersacrossstudiesindicatethatthereis
insufficientevidencetodeterminewhichrTMSprotocolismosteffective.

CONCLUSION
Overall,comparativeclinicalresearchonrTMSinMDDisearlyinitsinfancy,andmanyclinical
questionsaboutefficacyandeffectivenessremainunanswered.AnoptimalprotocolforrTMSneeds
tobedefinedandtestedusinghighquality,adequatelypoweredheadtoheadclinicaltrials.Overall
thereisinsufficientevidencetodeterminewhetherrTMSisaseffectiveasstandardtreatment(i.e.,
ECT),andforwhichpatients(i.e.,leveloftreatmentresistance)rTMSmaybemosteffective.

Report#0513002R11rTMSforDepressionEvidenceReview

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SUMMARYOFSYNTHESISEDSTUDIES

Table5.SynthesisedstudiesofrTMSvs.shamfordepression
STUDY
PATIENTS

Aare200313
Depressivedisorders
Notstated

Allan201114
Depression
Notstated

ShamrTMS
(orECT)
Notstated
Mixed

Coutourier200515

Gaynes20114

Gross200716

MDD
Notstated

TRD
Notstated

MDD
Notstated

ShamrTMS

Notstated

ShamrTMS

ShamrTMS

Notstated

ShamrTMS
(orECT)
Both

Mixed

Mixed

Mixed

Mixed

July2003
6RCTsofrTMSvs.sham

November2010
23RCTsofrTMSvs.sham

November2006
5RCTsofrTMSvs.sham

PRIMARYOUTCOMES

February2001
2008
8 studies of rTMS vs. sham, 31RCTsofrTMSvs.sham
unclear if they are RCTs or
CCTs
Efficacy
Efficacy

Efficacy

Efficacy,remissionmaintenance

ADVERSEEVENTS

Notreported

Notreported

Notreported

RESULTS

Modestbutclinically
insignificantresulton
efficacy.Nolasting
improvementpasttwo
weeksaftercessationof
treatment.
rTMSnotrecommendedas
astandardtreatmentfor

Moderatelysizedeffectin
favourofrTMS.
Nomeanchangein
depressionseveritybetween
theendoftreatmentand
followup.
Optimumtreatmentprotocol
yettobediscovered.

ImprovementsusingrTMS
comparedwithshamtherapy
notclinicallysignificant.

Significantlymorescalppainat
stimulationsiteinrTMSgroup.
Insufficientevidencetodraw
conclusionsondifferencesin
cognitivefunctioningand
withdrawalsduetoadverseevents
forrTMSvs.sham.
rTMSwasbeneficialrelativeto
controlsreceivingashamprocedure
forallthreeoutcomes(severityof
depressivesymptoms,response
rate,remissionrate)

Comparisonofefficacy
betweenlateandearlystudies
ofrTMS
Notreported

INPATIENTOR
OUTPATIENTSETTING
COMPARATORS
TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTS
ORDRUGFREE?
SEARCHDATE
INCLUDEDSTUDIES(n)

CONCLUSIONS

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21

Nosignificantdifference
betweenrTMSandsham

rTMSmoreeffectivethanshamfor
TRD

Notstated

Thepooleffectsizewas
significantlylargerthanthatof
earliermetaanalysis

RecentclinicaltrialsofrTMS
ondepressioninducedalarger

depression.

DIRECTIONOF
FINDINGS
AMSTARRATING

Noevidenceforlasting
treatmenteffectsbeyond12
weeks.

treatment.Mosteffective
combinationofparameters
forrTMSnotyetestablished.

effectsizewhencompared
withtheinitialstudiesfrom
Martinetal.

3/9
2/11
5/11
11/11
5/11
ECT=electroconvulsivetherapy;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation;TRD=treatmentresistant
depression;rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiortocomparator

Table5.SynthesisedstudiesofrTMSvs.shamfordepression(continued)
Herrmann200617
MDDorbipolar

Herrmann200918
MDDorbipolar

MDD

MDD

Notstated

Notstated

Notstated

Notstated

Kozel200221
depressionordepressive
disorder
Notstated

ShamTMS
Notstated

ShamTMS
Notstated

ShamTMS
Notstated

ShamTMS
Notstated

ShamrTMS
Notstated

Mixed

Mixed

Mixed

Mixed

Notstated

Notreported
31RCTsofrTMSvs.sham

2007
24RCTsofrTMSvs.sham

Dec2008
NotReported

April2002
12RCTsofrTMSvs.sham

Efficacy
Notreported

Efficacy
Smallriskofseizure

Efficacy
Headaches,scalppain

Efficacy
Notreported

RESULTS

Clinicallysignificanteffectof
rTMS

Notreported

Significantcumulativeeffect
sizeof0.53(95%CI:0.240.82).

CONCLUSIONS

rTMSismoreeffectivein

Significantlylargerproportion
ofrespondersinactiverTMS
group(35.3%)vs.shamrTMS
group(13.1%).5patients
needtobetreatedwithrTMS
toobtainaclinicalresponse.
PatientstreatedwithrTMS

Notreported
12studiesofrTMSvs.sham,
uncleariftheyareRCTsor
CCTs
Efficacy
Headaches,discomfortat
stimulationsiteduring
procedure.
Overallweightedmeaneffect
sizeof0.81wasfoundfor12
shamcontrolledstudiesof
rTMSinthetreatmentof
depression.

Somestudiestosuggestthat

DoubleblindpublishedrTMS

STUDY
PATIENTS
INPATIENTOR
OUTPATIENTSETTING
COMPARATORS
TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTS
ORDRUGFREE?
SEARCHDATE
INCLUDEDSTUDIES(n)

PRIMARYOUTCOMES
ADVERSEEVENTS

Report#0513002R11rTMSforDepressionEvidenceReview

22

Holtzheimer200119

rTMShasrealantidepressant

Kennedy200920

treatingdepressionthansham
rTMS,however,studiesare
heterogeneousandtherefore
difficulttoaccurately
determineeffectiveness.

morelikelytoshowaclinical
responsethanpatientstreated
withsham;differences
disappearatfollowup.

+initially,=atfollowup

DIRECTIONOF
FINDINGS
AMSTARRATING

effectsthatcanbelargeat
timesbutaregenerally
modest.

rTMSisbetterthansham
treatment

literaturetodatesupportsthe
useofleftprefrontalrTMSto
improvedepressivesymptoms.

1/11
3/11
3/11
1/9
CCTs=controlledclinicaltrials;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation
rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiortocomparator

4/11

Table5.SynthesisedstudiesofrTMSvs.shamfordepression(continued)
Lam200822

Martin200323
Anydiagnosisofdepression
Notstated

McNamara200124
Majordepressiveepisode
Notstated

OntarioMinistryofHealth200427
Mixed
Notstated

ShamrTMS

Notstated

ShamrTMS

ShamrTMS

Notstated

Notstated

ShamrTMS
(orECT)
Notstated

Notstated

Mixed

Mixed

Mixed

May2008
23RCTsofrTMSvs.sham
Efficacy
Notreported

January2002
14RCTsofrTMSvs.sham
Efficacy
Notreported

March2004
7SR/MAofrTMSvs.sham
Efficacyandcosteffectiveness.
Notreported

RESULTS

rTMShadsignificantlygreaterclinical
responsethansham.

CONCLUSIONS

rTMSfor14weekshasclear
antidepressanteffectsandiswell
tolerated,butresponseandremission
ratesarelowanditisunclearwhether

rTMSmoreeffectivethanshamafter
twoweeksoftreatment,butno
significantdifferenceatthetwoweek
followup
Insufficientevidencetosuggestthat
rTMSismoreeffectivethansham.Any
differencebetweenthetwogroupshas
disappearedtwoweekspost

January2000
5RCTsofrTMSvs.sham
Efficacy
Transientheadaches.Discomfortatthe
siteoftreatment.
StatisticallysignificantbenefitofrTMS.
43%differenceintherateof
improvementinthetreatedgroupand
thecontrolgroup.
rTMSisaneffectivetreatmentfor
depression.

STUDY
PATIENTS
INPATIENTOR
OUTPATIENTSETTING
COMPARATORS
TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTS
ORDRUGFREE?
SEARCHDATE
INCLUDEDSTUDIES(n)
PRIMARYOUTCOMES
ADVERSEEVENTS

TRD
Notstated

Report#0513002R11rTMSforDepressionEvidenceReview

23

Notreported

EarlymetaanalysessuggestedrTMS
maybeeffectiveforthetreatmentof
MDD

theeffectsaresustained.

DIRECTIONOF
FINDINGS
AMSTARRATING

intervention.

+initially,?longterm

8/11
7/11
4/11
6/9
ECT=electroconvulsivetherapy;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation;SR/MA=systematic
reviews/metaanalyses;TRD=treatmentresistantdepression;rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiorto
comparator

Table5.SynthesisedstudiesofrTMSvs.shamfordepression(continued)
NICE200726

RodriguezMartin200928
Depression
Notstated

Schutter201030
Majordepressiveepisode
Notstated

Schutter200929
Majordepressiveepisode
Notstated

Slotema201031
Depression
Notstated

ShamrTMS

ShamrTMS

ShamrTMS
(orECT)

Notstated

ShamrTMS
(orECTorpsychotherapyor
pharmacotherapy)
Notstated

Notstated

Notstated

Notstated

Mixed

Mixed

Notstated

Notstated

Mixed

October2006
3SR/MA&8RCTsofrTMSvs.
sham
Efficacy
Seizures,nausea,scalp
discomfort,headache,
migraine,neckstiffness,
hearingloss,mania.
Notreported

June2001
13RCTsofrTMSvs.sham

2009
9RCTsofrTMSvs.sham(slow
frequencyrTMSonly)
Efficacy
Notreported

November2007
30RCTsofrTMSvs.sham

October2008
34RCTsofrTMSvs.sham

Efficacy
Headaches,dizziness,nausea,
andpainfullocalsensation.

Efficacy
Headache,nausea,scalp
discomfort,drowsiness,facial
muscletwitching,tearfulness,
dizziness.
rTMSvs.sham;significant
meanweightedeffectsize
(0.55)infavourofrTMS.

rTMSisanoveltreatmentwith
uncertaintyarounditsefficacy

Nostrongevidencefor
possibleefficacyofrTMSfor

STUDY
PATIENTS
INPATIENTOR
OUTPATIENTSETTING
INTERVENTION&
COMPARATORS
TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTS
ORDRUGFREE?
SEARCHDATE
INCLUDEDSTUDIES(n)
PRIMARYOUTCOMES
ADVERSEEVENTS

RESULTS

CONCLUSIONS

MDD
Notstated
ShamrTMS
(orECT)

EfficacyandSafety
Nosignificantadverseeffects
intheshortterm

Benefitsshowninfavourof
rTMSversusshamattwo
weeks.

Report#0513002R11rTMSforDepressionEvidenceReview

24

Nosignificantdifference
betweenfastandslowTMS.
Cumulativeeffectsizefor
treatmentwas0.63(95%CI
0.031.24).
rTMScanimproveMDDand
additionalclinicaltrialsaimed

rTMShassignificantlymore
antidepressantefficacythan
shamtreatment.

rTMSissuperiortoshamand
maybeaseffectiveasatleast

rTMSismoreeffectivethan
shamfordepressionand

andsafety.

DIRECTIONOF
FINDINGS
AMSTARRATING

thetreatmentofdepression.
?

atoptimisingthetreatment
areworthwhile.
+

asubsetofantidepressant
medications.
+

appearstobemoreeffective
asamonotherapy.
+

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

Report#0513002R11rTMSforDepressionEvidenceReview

25

Table6.SynthesisedstudiesofrTMSvs.ECTfordepression
STUDY
PATIENTS
INPATIENTOR
OUTPATIENTSETTING
INTERVENTION&
COMPARATORS
TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTS
ORDRUGFREE?
SEARCHDATE
INCLUDEDSTUDIES(n)
PRIMARYOUTCOMES
ADVERSEEVENTS

Aare200313
Depressivedisorders
Notstated

Gaynes20114
TRD
Notstated

OntarioMinistryofHealth200427
Mixed
Notstated

MDD
Notstated

ECT
(orshamrTMS)
Notstated

ECT
(orshamrTMS)
Both

ECT
(orshamrTMS)
Notstated

ECT
(orshamrTMS)
Notstated

Mixed

Mixed

Mixed

Mixed

February2001
2Studies(1RCT)
Efficacy
Notreported

November2010
4RCTs
Efficacy,remissionmaintenance
Asmallstudyindicatednodifferencein
withdrawalsduetoadverseevents
betweentheECTandrTMSgroupsbut
didnotreportonthesignificanceof
thisresult(lowstrengthofevidence).

1fairtrialofECTvs.rTMSina
treatmentresistantMDDpopulation
showedwithlowstrengthofevidence,
nodifferencebetweentreatment
optionsfordepressiveseverity,
responserateandremissionrate.

March2004
3RCTs
Efficacyandcosteffectiveness.
Notreported

2006
7Studies(2confirmedRCTs)
Efficacy
Notreported

Notreported.

Nosignificantdifferencebetweenthe
responseratesoftherTMSgroupand
theECTgroup.OverallrTMSappeared
tobelesseffectivethanECTinthe
treatmentofmajordepression,
althoughthiswasnotstatistically
significant.

ECTappearstobeaseffectiveasrTMS
forthetreatmentofdepressionin
patientswithoutpsychosis

RESULTS

Modestbutclinicallyinsignificantresult
onefficacy.Nolastingimprovement
pasttwoweeksaftercessationof
treatment.

CONCLUSIONS

rTMS not recommended as a standard NodifferencebetweenrTMSandECT


treatmentfordepression.
(lowstrengthofevidence)

DIRECTIONOF
FINDINGS
AMSTARRATING

3/9

11/11

6/9

9/11

Report#0513002R11rTMSforDepressionEvidenceReview

26

Earlymetaanalysessuggestedthat
rTMSmaybeeffectiveforthe
treatmentofMDD

MSAC20088

Table6.SynthesisedstudiesofrTMSvs.ECTfordepression(continued)
Minichino201225

STUDY
PATIENTS
INPATIENTOR
OUTPATIENTSETTING
INTERVENTION&
COMPARATORS
TREATMENTOR
REMISSION
MAINTENANCE?
ANTIDEPRESSANT
TREATMENT?
SEARCHDATE
INCLUDEDSTUDIES(n)
PRIMARYOUTCOMES
ADVERSEEVENTS

TRD,MDD
Notstated

MDD
Notstated

ECT

ECT
(orshamrTMS)

Notstated

RodriguezMartin200928
Depression
Notstated

Slotema201031
Depression
Notstated

Notstated

ECT
(orshamrTMSorpsychotherapyor
pharmacotherapy)
Notstated

Notstated

Drugfree

Mixed

Mixed

Mixed

NR
4Studies(2RCTs)
Efficacyandtolerability
Nonereported,tolerabilitymeasured
bythenumberofdropouts

October2006
8RCTs
Efficacy
Seizures,localscalpdiscomfort,
headache,migraine,nausea,neck
stiffness,hearinglossandinductionof
mania.
Notreported

June2001
1RCTofrTMSvs.ECT
Efficacy
Notreported

October2008
6RCTs
Efficacy
Transientandmildsideeffectsinclude
headache,scalpdiscomfort,
drowsiness,facialmuscletwitching,
tearfulness,dizzinessandnausea.
ECTwassuperiortorTMSinthe
treatmentofdepression(mean
weightedeffectsize0.47,p=.004)

RESULTS

rTMSmoretolerablethanECT.ECT
moreeffectivethanrTMS.

CONCLUSIONS

rTMSprovidesbettertolerabilitythan
ECTbutitstherapeuticefficacyis
lower.

DIRECTIONOF
FINDINGS
AMSTARRATING

NICE200726

rTMSisanoveltreatmentwith
uncertaintyarounditsefficacyand
safety.

Nosignificantdifferencebetween
techniqueswhenpatientshadno
psychoticsymptoms.ECTwasmore
effectivewhenpatientshadpsychotic
symptoms.
Nostrongevidenceforpossible
efficacyofrTMSforthetreatmentof
depression.
?

ECT
(orshamrTMS)

rTMSislesseffectivethanECTinthe
treatmentofdepression.

2/11
4/9
10/11
3/11
ECT=electroconvulsivetherapy;MDD=majordepressivedisorder;RCTs=randomisedcontrolledtrials;rTMS=repetitivetranscranialmagneticstimulation;SR/MA=systematic
reviews/metaanalyses;TRD=treatmentresistantdepression;rTMSinferiortocomparator;?noconclusionsdrawn;=nodifferencebetweenrTMSandcomparator;+rTMSsuperiorto
comparator

Report#0513002R11rTMSforDepressionEvidenceReview

27

DISCLAIMER
Theinformationinthisreportisasummaryofthatavailableandisprimarilydesignedtogivereadersastarting
point to consider currently available research evidence. Whilst appreciable care has been taken in the
preparation of the materials included in this publication, the authors and the National Trauma Research
Institute do not warrant the accuracy of this document and deny any representation, implied or expressed,
concerningtheefficacy,appropriatenessorsuitabilityofanytreatmentorproduct.Inviewofthepossibilityof
human error or advances of medical knowledge the authors and the National Trauma Research Institute
cannot and do not warrant that the information contained in these pages is in every aspect accurate or
complete.Accordingly,theyarenotandwillnotbeheldresponsibleorliableforanyerrorsoromissionsthat
maybefoundinthispublication.Youarethereforeencouragedtoconsultothersourcesinordertoconfirm
the information contained in this publication and, in the event that medical treatment is required, to take
professionalexpertadvicefromalegallyqualifiedandappropriatelyexperiencedmedicalpractitioner.

CONFLICTOFINTEREST
The TAC/WSV Evidence Service is provided by the National Trauma Research Institute. The NTRI does not
acceptfundingfrompharmaceuticalorbiotechnologycompaniesorothercommercialentitieswithpotential
vestedinterestintheoutcomesofsystematicreviews.
The TAC/WSV Health Services Group has engaged the NTRI for their objectivity and independence and
recognise that any materials developed must be free of influence from parties with vested interests. The
EvidenceServicehasfulleditorialcontrol.

Report#0513002R11rTMSforDepressionEvidenceReview

28

REFERENCES
1.
AmericanPsychiatricAssociation.Diagnosticandstatisticalmanualofmentaldisorders:fourth
edition,textrevision.Revised4thed.Washington,D.C.:AmericanPsychiatricAssociation;2000.
2.
BeggS,VosT,BarkerB,StevensonC,StanleyL,LopezAD.Theburdenofdiseaseandinjuryin
Australia2003.PHE82.Canberra:AustralianInstituteofHealthandWelfare;2007.
3.
RoyalAustralianandNewZealandCollegeofPsychiatristsClinicalPracticeGuidelinesTeamfor
Depression.AustralianandNewZealandclinicalpracticeguidelinesforthetreatmentofdepression.AustNZJ
Psychiatry.2004;38:389407.
4.
GaynesBN,LuxLJ,LloydSW,HansenRA,GartlehnerG,KeenerP,etal.Nonpharmacologic
interventionsfortreatmentresistantdepressioninadults.ComparativeeffectivenesseeviewNo.33.AHRQ
PublicationNo.11EHC056EF.Rockville,MD:AgencyforHealthcareResearchandQuality;2011.Available
from:http://www.effectivehealthcare.ahrq.gov/reports/final.cfm.
5.
AmericanPsychiatricAssociationCommitteeonElectroconvulsiveTherapy.Thepracticeof
electroconvulsivetherapy:recommendationsfortreatment,trainingandprivileging.Ataskforcereportofthe
AmericanPsychiatricAssociation.Washington,DC:200108856230.
6.
FitzgeraldPB.Transcranialmagneticstimulationbasedmethodsinthetreatmentofdepression.Aus
Prescriber.2012;35(2):5961.
7.
DowdSM,JanicakPG.Therapyresistantmajordepression.Theattractionofmagnetism:How
effectiveandsafeisrTMS?TheJournalofFamilyPractice[Internet].2003;2(6).Availablefrom:
http://www.jfponline.com/pages.asp?aid=650.
8.
MedicalServicesAdvisoryCommittee,CameronA,PekarskyB.Repetitivetranscranialmagnetic
stimulationasatreatmentformajordepression.Canberra,ACT:AustralianGovernmentDepartmentofHealth
andAgeing;2008.Availablefrom:
http://www.msac.gov.au/internet/msac/publishing.nsf/Content/app11011.
9.
MedicalServicesAdvisoryCommittee.ConsultationsubmissionbytheRoyalAustralianandNew
ZealandCollegeofPsychiatristsontheconsultationDecisionAnalyticProtocol(DAP)toguidetheassessment
ofrepetitiveTranscranialMagneticStimulationasatreatmentformajordepression:MedicalServicesAdvisory
Committee(MSAC);2012.Availablefrom:
http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1196.
10.
FoodandDrugAdministration.GuidanceforindustryandFoodandDrugAdministrationstaffClassII
specialcontrolsguidancedocument:RepetitiveTranscranialMagneticStimulation(rTMS)systems:U.S.
DepartmentofHealthandHumanServices;2011.Availablefrom:

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm2652
69.htm.
11.
MedicalServicesAdvisoryCommittee.FinalDecisionAnalyticProtocol(DAP)toguidetheassessment
ofrepetitiveTranscranialMagneticStimulationasatreatmentformajordepression:MedicalServicesAdvisory
Committee(MSAC);2012.Availablefrom:
http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1196.
12.
SheaBJ,GrimshawJM,WellsGA,BoersM,AnderssonN,HamelC,etal.DevelopmentofAMSTAR:a
measurementtooltoassessthemethodologicalqualityofsystematicreviews.BMCMedResMethodol.
2007;7:10.

Report#0513002R11rTMSforDepressionEvidenceReview

29

13.
AarreTF,DahlAA,JohansenJB,KjonniksenI,NeckelmannD.Efficacyofrepetitivetranscranial
magneticstimulationindepression:areviewoftheevidence.NordJPsychiatry.2003;57(3):22732.
14.
AllanCL,HerrmannLL,EbmeierKP.TranscranialMagneticStimulationintheManagementofMood
Disorders.Neuropsychobiol.2011;64(3):1639.
15.
CouturierJL.Efficacyofrapidraterepetitivetranscranialmagneticstimulationinthetreatmentof
depression:asystematicreviewandmetaanalysis.JPsychiatryNeurosci.2005;30(2):8390.
16.
GrossM,NakamuraL,PascualLeoneA,FregniF.Hasrepetitivetranscranialmagneticstimulation
(rTMS)treatmentfordepressionimproved?Asystematicreviewandmetaanalysiscomparingtherecentvs.
theearlierrTMSstudies.ActaPsychiatrScand.2007;116(3):16573.
17.

HerrmannLL,EbmeierKP.Transcranialmagneticstimulation.Psychiatry.2006;5(6):2047.

18.

HerrmannLL,EbmeierKP.Transcranialmagneticstimulation.Psychiatry.2009;8(4):1304.

19.
Holtzheimer3rdPE,RussoJ,AveryDH.Ametaanalysisofrepetitivetranscranialmagneticstimulation
inthetreatmentofdepression.PsychopharmacolBull.2001;35(4):14969.
20.
KennedySH,MilevR,GiacobbeP,RamasubbuR,LamRW,ParikhSV,etal.CanadianNetworkfor
MoodandAnxietyTreatments(CANMAT)Clinicalguidelinesforthemanagementofmajordepressivedisorder
inadults.IV.Neurostimulationtherapies.JAffectDisord.2009;117(SUPPL.1):S44S53.
21.
KozelFA,GeorgeMS.Metaanalysisofleftprefrontalrepetitivetranscranialmagneticstimulation
(rTMS)totreatdepression.JPsychiatrPract.2002;8(5):2705.
22.
LamRW,ChanP,WilkinsHoM,YathamLN.Repetitivetranscranialmagneticstimulationfor
treatmentresistantdepression:asystematicreviewandmetaanalysis.CanJPsychiatry.2008;53(9):62131.
23.
MartinJLR,BarbanojMJ,SchlaepferTE,ThompsonE,PerezV,KulisevskyJ.Repetitivetranscranial
magneticstimulationforthetreatmentofdepression.Systematicreviewandmetaanalysis.BrJPsychiatry.
2003;182:48091.
24.
McNamaraB,RayJL,ArthursOJ,BonifaceS.Transcranialmagneticstimulationfordepressionand
otherpsychiatricdisorders.PsycholMed.2001;31(7):11416.
25.
MinichinoA,BersaniFS,CapraE,PanneseR,BonannoC,SalviatiM,etal.ECT,rTMS,anddeepTMSin
pharmacoresistantdrugfreepatientswithunipolardepression:Acomparativereview.NeuropsychiatrDis
Treat.2012;8:5564.
26.
NationalInstituteforHealthandClinicalExcellence.Transcranialmagneticstimulationforsevere
depression.London2007;Availablefrom:
http://www.nice.org.uk/nicemedia/pdf/IPG242GUIDANCE.pdf.
27.
OntarioMinistryofHealth.Repetitivetranscranialmagneticstimulationforthetreatmentofmajor
depressivedisorder:anevidencebasedanalysis.Toronto:MedicalAdvisorySecretariat,OntarioMinistryof
HealthandLongTermCare(MAS),2004.
28.
RodriguezMartinJL,BarbanojJM,SchlaepferTE,ClosSS,PrezV,KulisevskyJ,etal.Transcranial
magneticstimulationfortreatingdepression.CochraneDatabaseofSystematicReviews.2009(4).

Report#0513002R11rTMSforDepressionEvidenceReview

30

29.
SchutterDJ.Antidepressantefficacyofhighfrequencytranscranialmagneticstimulationovertheleft
dorsolateralprefrontalcortexindoubleblindshamcontrolleddesigns:ametaanalysis.PsycholMed.
2009;39(1):6575.
30.
SchutterDJ.Quantitativereviewoftheefficacyofslowfrequencymagneticbrainstimulationinmajor
depressivedisorder.PsycholMed.2010;40(11):178995.
31.
SlotemaCW,BlomJD,HoekHW,SommerIEC.Shouldweexpandthetoolboxofpsychiatrictreatment
methodstoincludeRepetitiveTranscranialMagneticStimulation(rTMS)?Ametaanalysisoftheefficacyof
rTMSinpsychiatricdisorders.JClinPsychiatry.2010;71(7):87384.
32.
AguirreI,CarreteroB,IbarraO,KuhalainenJ,MartinezJ,FerrerA,etal.Agepredictslowfrequency
transcranialmagneticstimulationefficacyinmajordepression.JAffectDisord.2011;130(3):4669.
33.
AndersonIM,DelvaiNA,AshimB,AshimS,LewinC,SinghV,etal.Adjunctivefastrepetitive
transcranialmagneticstimulationindepression.BrJPsychiatry.2007;190:5334.
34.
AveryDH,ClaypooleK,RobinsonL,NeumaierJF,DunnerDL,ScheeleL,etal.Repetitivetranscranial
magneticstimulationinthetreatmentofmedicationresistantdepression:preliminarydata.JNervMentDis.
1999;187(2):1147.
35.
AveryDH,HoltzheimerIPE,FawazW,RussoJ,NeumaierJ,DunnerDL,etal.Acontrolledstudyof
repetitivetranscranialmagneticstimulationinmedicationresistantmajordepression.BiolPsychiatry.
2006;59(2):18794.
36.
AveryDH,HoltzheimerIPE,FawazW,RussoJ,NeumaierJ,DunnerDL,etal.Transcranialmagnetic
stimulationreducespaininpatientswithmajordepression:Ashamcontrolledstudy.JNervMentDis.
2007;195(5):37881.
37.
BaresM,KopecekM,NovakT,StopkovaP,SosP,KozenyJ,etal.Lowfrequency(1Hz),right
prefrontalrepetitivetranscranialmagneticstimulation(rTMS)comparedwithvenlafaxineERinthetreatment
ofresistantdepression:adoubleblind,singlecentre,randomizedstudy.JAffectDisord.2009;118(13):94100.
BermanRM,NarasimhanM,SanacoraG,MianoAP,HoffmanRE,HuXS,etal.Arandomizedclinical
38.
trialofrepetitivetranscranialmagneticstimulationinthetreatmentofmajordepression.BiolPsychiatry.
2000;47(4):3327.
39.
BortolomasiM,MinelliA,FuggettaG,PeriniM,ComenciniS,FiaschiA,etal.Longlastingeffectsof
highfrequencyrepetitivetranscranialmagneticstimulationinmajordepressedpatients.PsychiatryRes.
2007;150(2):1816.
40.
BoutrosNN,GueorguievaR,HoffmanRE,OrenDA,FeingoldA,BermanRM.Lackofatherapeutic
effectofa2weeksubthresholdtranscranialmagneticstimulationcoursefortreatmentresistantdepression.
PsychiatryRes.2002;113(3):24554.
41.
BretlauLG,LundeM,LindbergL,UndenM,DissingS,BechP.Repetitivetranscranialmagnetic
stimulation(rTMS)incombinationwithescitalopraminpatientswithtreatmentresistantmajordepression:a
doubleblind,randomised,shamcontrolledtrial.Pharmacopsychiatry.2008;41(2):417.
42.
ChistyakovAV,KaplanB,RubichekO,KreininI,KorenD,FeinsodM,etal.Antidepressanteffectsof
differentschedulesofrepetitivetranscranialmagneticstimulationvs.clomipramineinpatientswithmajor
depression:relationshiptochangesincorticalexcitability.IntJNeuropsychopharmacol.2005;8(2):22333.

Report#0513002R11rTMSforDepressionEvidenceReview

31

43.
ChistyakovAV,KaplanB,RubichekO,KreininI,KorenD,HafnerH,etal.Effectofelectroconvulsive
therapyoncorticalexcitabilityinpatientswithmajordepression:atranscranialmagneticstimulationstudy.
ClinNeurophysiol.2005;116(2):38692.
44.
DannonPN,DolbergOT,SchreiberS,GrunhausL.Threeandsixmonthoutcomefollowingcoursesof
eitherECTorrTMSinapopulationofseverelydepressedindividualsPreliminaryreport.BiolPsychiatry.
2002;51(8):68790.
45.
EichhammerP,KharrazA,WiegandR,LangguthB,FrickU,AignerJM,etal.Sleepdeprivationin
depressionStabilizingantidepressanteffectsbyrepetitivetranscranialmagneticstimulation.LifeSci.
2002;70(15):17419.
46.
ErantiS,MoggA,PluckG,LandauS,PurvisR,BrownRG,etal.Arandomized,controlledtrialwith6
monthfollowupofrepetitivetranscranialmagneticstimulationandelectroconvulsivetherapyforsevere
depression.AmJPsychiatry.2007;164(1):7381.
47.
EschweilerGW,WegererC,SchlotterW,SpandlC,StevensA,BartelsM,etal.Leftprefrontal
activationpredictstherapeuticeffectsofrepetitivetranscranialmagneticstimulation(rTMS)inmajor
depression.PsychiatryRes.2000;99(3):16172.
48.
FitzgeraldPB,BenitezJ,deCastellaA,DaskalakisZJ,BrownTL,KulkarniJ.Arandomized,controlled
trialofsequentialbilateralrepetitivetranscranialmagneticstimulationfortreatmentresistantdepression.Am
JPsychiatry.2006;163(1):8894.
49.
FitzgeraldPB,BrownTL,MarstonNA,DaskalakisZJ,DeCastellaA,KulkarniJ.Transcranialmagnetic
stimulationinthetreatmentofdepression:adoubleblind,placebocontrolledtrial.ArchGenPsychiatry.
2003;60(10):10028.
50.
FitzgeraldPB,HoyK,McQueenS,HerringS,SegraveR,BeenG,etal.Primingstimulationenhances
theeffectivenessoflowfrequencyrightprefrontalcortextranscranialmagneticstimulationinmajor
depression.JClinPsychopharmacol.2008;28(1):528.
51.
FitzgeraldPB,HoyKE,HerringSE,McQueenS,PeacheyAVJ,SegraveRA,etal.Adoubleblind
randomizedtrialofunilateralleftandbilateralprefrontalcortextranscranialmagneticstimulationintreatment
resistantmajordepression.JAffectDisord.2012;139(2):1938.
52.
GarciaToroM,MayolA,ArnillasH,CapllonchI,IbarraO,CrespiM,etal.Modestadjunctivebenefit
withtranscranialmagneticstimulationinmedicationresistantdepression.JAffectDisord.2001;64(23):2715.
53.
GarciaToroM,PascualLeoneA,RomeraM,GonzalezA,MicoJ,IbarraO,etal.Prefrontalrepetitive
transcranialmagneticstimulationasaddontreatmentindepression.JNeurolNeurosurgPsychiatry.
2001;71(4):5468.
54.
GarciaToroM,SalvaJ,DaumalJ,AndresJ,RomeraM,LafauO,etal.High(20Hz)andlow(1Hz)
frequencytranscranialmagneticstimulationasadjuvanttreatmentinmedicationresistantdepression.
PsychiatryRes.2006;146(1):537.
55.
GeorgeMS,LisanbySH,AveryD,McDonaldWM,DurkalskiV,PavlicovaM,etal.Dailyleftprefrontal
transcranialmagneticstimulationtherapyformajordepressivedisorder:Ashamcontrolledrandomizedtrial.
ArchGenPsychiatry.2010;67(5):50716.
56.
GeorgeMS,WassermannEM,KimbrellTA,LittleJT,WilliamsWE,DanielsonAL,etal.Mood
improvementfollowingdailyleftprefrontalrepetitivetranscranialmagneticstimulationinpatientswith
depression:aplacebocontrolledcrossovertrial.AmJPsychiatry.1997;154(12):17526.

Report#0513002R11rTMSforDepressionEvidenceReview

32

57.
GrunhausL,DannonPN,SchreiberS,DolbergOH,AmiazR,ZivR,etal.Repetitivetranscranial
magneticstimulationisaseffectiveaselectroconvulsivetherapyinthetreatmentofnondelusionalmajor
depressivedisorder:anopenstudy.BiolPsychiatry.2000;47(4):31424.
58.
GrunhausL,SchreiberS,DolbergOT,PolakD,DannonPN.Arandomizedcontrolledcomparisonof
electroconvulsivetherapyandrepetitivetranscranialmagneticstimulationinsevereandresistant
nonpsychoticmajordepression.BiolPsychiatry.2003;53(4):32431.
59.
HausmannA,KemmlerG,WalpothM,MechtcheriakovS,KramerReinstadlerK,LechnerT,etal.No
benefitderivedfromrepetitivetranscranialmagneticstimulationindepression:aprospective,singlecentre,
randomised,doubleblind,shamcontrolled"addon"trial.JNeurolNeurosurgPsychiatry.2004;75(2):3202.
60.
HausmannA,PascualLeoneA,KemmlerG,RuppCI,LechnerSchonerT,KramerReinstadlerK,etal.
NodeteriorationofcognitiveperformanceinanaggressiveunilateralandbilateralantidepressantrTMSadd
ontrial.JClinPsychiatry.2004;65(6):77282.
61.
HerbsmanT,AveryD,RamseyD,HoltzheimerP,WadjikC,HardawayF,etal.Morelateraland
anteriorprefrontalcoillocationisassociatedwithbetterrepetitivetranscranialmagneticstimulation
antidepressantresponse.BiolPsychiatry.2009;66(5):50915.
62.
HerwigU,FallgatterAJ,HoppnerJ,EschweilerGW,KronM,HajakG,etal.Antidepressanteffectsof
augmentativetranscranialmagneticstimulation:randomisedmulticentretrial.BrJPsychiatry.2007;191:4418.
63.
HerwigU,LampeY,JuenglingFD,WunderlichA,WalterH,SpitzerM,etal.AddonrTMSfor
treatmentofdepression:apilotstudyusingstereotaxiccoilnavigationaccordingtoPETdata.JPsychiatrRes.
2003;37(4):26775.
64.
HoeppnerJ,PadbergF,DomesG,ZinkeA,HerpertzSC,GroheinrichN,etal.Influenceofrepetitive
transcranialmagneticstimulationonpsychomotorsymptomsinmajordepression.EurArchPsychiatryClin
Neurosci.2010;260(3):197202.
65.
HoltzheimerPE,3rd,RussoJ,ClaypooleKH,RoyByrneP,AveryDH.Shorterdurationofdepressive
episodemaypredictresponsetorepetitivetranscranialmagneticstimulation.DepressAnxiety.2004;19(1):24
30.
66.
HoppnerJ,SchulzM,IrmischG,MauR,SchlafkeD,RichterJ.Antidepressantefficacyoftwodifferent
rTMSprocedures.Highfrequencyoverleftversuslowfrequencyoverrightprefrontalcortexcomparedwith
shamstimulation.EurArchPsychiatryClinNeurosci.2003;253(2):1039.
67.
JakobF,BrakemeierEL,SchommerNC,QuanteA,MerklA,DankerHopfeH,etal.Ultrahighfrequency
repetitivetranscranialmagneticstimulationinunipolardepression.JClinPsychopharmacol.2008;28(4):4746.
68.
JanuelD,DumortierG,VerdonCM,StamatiadisL,SabaG,CabaretW,etal.Adoubleblindsham
controlledstudyofrightprefrontalrepetitivetranscranialmagneticstimulation(rTMS):Therapeuticand
cognitiveeffectinmedicationfreeunipolardepressionduring4weeks.ProgNeuropsychopharmacolBiol
Psychiatry.2006;30(1):12630.
69.
KauffmannCD,CheemaMA,MillerBE.Slowrightprefrontaltranscranialmagneticstimulationasa
treatmentformedicationresistantdepression:adoubleblind,placebocontrolledstudy.DepressAnxiety.
2004;19(1):5962.
70.
KeshtkarM,GhanizadehA,FiroozabadiA.Repetitivetranscranialmagneticstimulationversus
electroconvulsivetherapyforthetreatmentofmajordepressivedisorder,arandomizedcontrolledclinical
trial.JECT.2011;27(4):3104.

Report#0513002R11rTMSforDepressionEvidenceReview

33

71.
KimbrellTA,LittleJT,DunnRT,FryeMA,GreenbergBD,WassermannEM,etal.Frequency
dependenceofantidepressantresponsetoleftprefrontalrepetitivetranscranialmagneticstimulation(rTMS)
asafunctionofbaselinecerebralglucosemetabolism.BiolPsychiatry.1999;46(12):160313.
72.
KleinE,KreininI,ChistyakovA,KorenD,MeczL,MarmurS,etal.Therapeuticefficacyofright
prefrontalslowrepetitivetranscranialmagneticstimulationinmajordepression:adoubleblindcontrolled
study.ArchGenPsychiatry.1999;56(4):31520.
73.
KnappM,RomeoR,MoggA,ErantiS,PluckG,PurvisR,etal.Costeffectivenessoftranscranial
magneticstimulationvs.electroconvulsivetherapyforseveredepression:amulticentrerandomised
controlledtrial.JAffectDisord.2008;109(3):27385.
74.
KoerselmanF,LamanDM,vanDuijnH,vanDuijnMA,WillemsMA.A3month,followup,
randomized,placebocontrolledstudyofrepetitivetranscranialmagneticstimulationindepression.JClin
Psychiatry.2004;65(10):13238.
75.
LisanbySH,HusainMM,RosenquistPB,MaixnerD,GutierrezR,KrystalA,etal.Dailyleftprefrontal
repetitivetranscranialmagneticstimulationintheacutetreatmentofmajordepression:clinicalpredictorsof
outcomeinamultisite,randomizedcontrolledclinicaltrial.Neuropsychopharmacol.2009;34(2):52234.
76.
LittleJT,KimbrellTA,WassermannEM,GrafmanJ,FiguerasS,DunnRT,etal.Cognitiveeffectsof1
and20hertzrepetitivetranscranialmagneticstimulationindepression:preliminaryreport.Neuropsychiatry
NeuropsycholBehavNeurol.2000;13(2):11924.
77.
LooC,MitchellP,SachdevP,McDarmontB,ParkerG,GandeviaS.Doubleblindcontrolled
investigationoftranscranialmagneticstimulationforthetreatmentofresistantmajordepression.AmJ
Psychiatry.1999;156(6):9468.
78.
LooC,SachdevP,ElsayedH,McDarmontB,MitchellP,WilkinsonM,etal.Effectsofa2to4week
courseofrepetitivetranscranialmagneticstimulation(rTMS)onneuropsychologicfunctioning,
electroencephalogram,andauditorythresholdindepressedpatients.BiolPsychiatry.2001;49(7):61523.
79.
LooCK,MitchellPB,CrokerVM,MalhiGS,WenW,GandeviaSC,etal.Doubleblindcontrolled
investigationofbilateralprefrontaltranscranialmagneticstimulationforthetreatmentofresistantmajor
depression.PsychologicalMed.2003;33(1):3340.
80.
LooCK,MitchellPB,McFarquharTF,MalhiGS,SachdevPS.Ashamcontrolledtrialoftheefficacyand
safetyoftwicedailyrTMSinmajordepression.PsychologicalMed.2007;37(3):3419.
81.
LooCK,SachdevPS,HaindlW,WenW,MitchellPB,CrokerVM,etal.High(15Hz)andlow(1Hz)
frequencytranscranialmagneticstimulationhavedifferentacuteeffectsonregionalcerebralbloodflowin
depressedpatients.PsychologicalMed.2003;33(6):9971006.
82.
ManesF,JorgeR,MorcuendeM,YamadaT,ParadisoS,RobinsonRG.Acontrolledstudyofrepetitive
transcranialmagneticstimulationasatreatmentofdepressionintheelderly.IntPsychogeriatr.
2001;13(2):22531.
83.
McDonaldWM,EasleyK,ByrdEH,HoltzheimerP,TuohyS,WoodardJL,etal.Combinationrapid
transcranialmagneticstimulationintreatmentrefractorydepression.NeuropsychiatrDisTreat.2006;2(1):85
94.
84.
MingliH,ZhengtianG,XinyiW,XiaopingT.Effectsofrepetitivetranscranialmagneticstimulationon
hypothalamicpituitaryadrenalaxisofpatientswithdepression.JMedCollegesPLA.2009;24(6):33745.

Report#0513002R11rTMSforDepressionEvidenceReview

34

85.
MiniussiC,BonatoC,BignottiS,GazzoliA,GennarelliM,PasqualettiP,etal.Repetitivetranscranial
magneticstimulation(rTMS)athighandlowfrequency:anefficacioustherapyformajordrugresistant
depression?ClinNeurophysiology.2005;116(5):106271.
86.
MoggA,PluckG,ErantiSV,LandauS,PurvisR,BrownRG,etal.Arandomizedcontrolledtrialwith4
monthfollowupofadjunctiverepetitivetranscranialmagneticstimulationoftheleftprefrontalcortexfor
depression.PsychologicalMed.2008;38(3):32333.
87.
MollerAL,HjaltasonO,IvarssonO,StefanssonSB.Theeffectsofrepetitivetranscranialmagnetic
stimulationondepressivesymptomsandtheP(300)eventrelatedpotential.NordJPsychiatry.
2006;60(4):2825.
88.
MoserDJ,JorgeRE,ManesF,ParadisoS,BenjaminML,RobinsonRG.Improvedexecutivefunctioning
followingrepetitivetranscranialmagneticstimulation.Neurology.2002;58(8):128890.
89.
MosimannUP,SchmittW,GreenbergBD,KoselM,MuriRM,BerkhoffM,etal.Repetitivetranscranial
magneticstimulation:aputativeaddontreatmentformajordepressioninelderlypatients.PsychiatryRes.
2004;126(2):12333.
90.
NahasZ,DeBruxC,ChandlerV,LorberbaumJP,SpeerAM,MolloyMA,etal.Lackofsignificant
changesonmagneticresonancescansbeforeandafter2weeksofdailyleftprefrontalrepetitivetranscranial
magneticstimulationfordepression.JECT.2000;16(4):38090.
91.
O'ConnorM,BrenninkmeyerC,MorganA,BloomingdaleK,ThallM,VasileR,etal.Relativeeffectsof
repetitivetranscranialmagneticstimulationandelectroconvulsivetherapyonmoodandmemory:a
neurocognitiveriskbenefitanalysis.CognBehavNeurol.2003;16(2):11827.
92.
O'ReardonJP,CristanchoP,PilaniaP,BapatlaKB,ChuaiS,PeshekAD.Patientswithamajor
depressiveepisoderespondingtotreatmentwithrepetitivetranscranialmagneticstimulation(rTMS)are
resistanttotheeffectsofrapidtryptophandepletion.DepressAnxiety.2007;24(8):53744.
93.
PadbergF,ZwanzgerP,KeckME,KathmannN,MikhaielP,EllaR,etal.Repetitivetranscranial
magneticstimulation(rTMS)inmajordepression:relationbetweenefficacyandstimulationintensity.
Neuropsychopharmacol.2002;27(4):63845.
94.
PadbergF,ZwanzgerP,ThomaH,KathmannN,HaagC,GreenbergBD,etal.Repetitivetranscranial
magneticstimulation(rTMS)inpharmacotherapyrefractorymajordepression:comparativestudyoffast,slow
andshamrTMS.PsychiatryRes.1999;88(3):16371.
95.
PallantiS,BernardiS,DiRolloA,AntoniniS,QuercioliL.Unilaterallowfrequencyversussequential
bilateralrepetitivetranscranialmagneticstimulation:issimplerbetterfortreatmentofresistantdepression?
Neurosci.2010;167(2):3238.
96.
PascualLeoneA,RubioB,PallardoF,CatalaMD.Rapidratetranscranialmagneticstimulationofleft
dorsolateralprefrontalcortexindrugresistantdepression.Lancet.1996;348(9022):2337.
97.
PouletE,BrunelinJ,BoeuveC,LerondJ,D'AmatoT,DaleryJ,etal.Repetitivetranscranialmagnetic
stimulationdoesnotpotentiateantidepressanttreatment.EurPsychiatry.2004;19(6):3823.
98.
PridmoreS.Substitutionofrapidtranscranialmagneticstimulationtreatmentsforelectroconvulsive
therapytreatmentsinacourseofelectroconvulsivetherapy.DepressAnxiety.2000;12(3):11823.

Report#0513002R11rTMSforDepressionEvidenceReview

35

99.
PridmoreS,BrunoR,TurnierSheaY,ReidP,RybakM.Comparisonofunlimitednumbersofrapid
transcranialmagneticstimulation(rTMS)andECTtreatmentsessionsinmajordepressiveepisode.IntJ
Neuropsychopharmacol.2000;3(2):12934.
100.
RosaMA,GattazWF,PascualLeoneA,FregniF,RosaMO,RumiDO,etal.Comparisonofrepetitive
transcranialmagneticstimulationandelectroconvulsivetherapyinunipolarnonpsychoticrefractory
depression:arandomized,singleblindstudy.IntJNeuropsychopharmacol.2006;9(6):66776.
101.
RossiniD,LuccaA,ZanardiR,MagriL,SmeraldiE.Transcranialmagneticstimulationintreatment
resistantdepressedpatients:adoubleblind,placebocontrolledtrial.PsychiatryRes.2005;137(12):110.
102.
RossiniD,MagriL,LuccaA,GiordaniS,SmeraldiE,ZanardiR.DoesrTMShastentheresponseto
escitalopram,sertraline,orvenlafaxineinpatientswithmajordepressivedisorder?Adoubleblind,
randomized,shamcontrolledtrial.JClinPsychiatry.2005;66(12):156975.
103.
RumiDO,GattazWF,RigonattiSP,RosaMA,FregniF,RosaMO,etal.Transcranialmagnetic
stimulationacceleratestheantidepressanteffectofamitriptylineinseveredepression:adoubleblindplacebo
controlledstudy.BiolPsychiatry.2005;57(2):1626.
104.
SchulzeRauschenbachSC,HarmsU,SchlaepferTE,MaierW,FalkaiP,WagnerM.Distinctive
neurocognitiveeffectsofrepetitivetranscranialmagneticstimulationandelectroconvulsivetherapyinmajor
depression.BrJPsychiatry.2005;186:4106.
105.
SchutterDJLG,LamanDM,vanHonkJ,VergouwenAC,KoerselmanGF.Partialclinicalresponseto2
weeksof2Hzrepetitivetranscranialmagneticstimulationtotherightparietalcortexindepression.IntJ
Neuropsychopharmacol.2009;12(5):64350.
106.
SternWM,TormosJM,PressDZ,PearlmanC,PascualLeoneA.Antidepressanteffectsofhighandlow
frequencyrepetitivetranscranialmagneticstimulationtothedorsolateralprefrontalcortex:adoubleblind,
randomized,placebocontrolledtrial.JNeuropsychiatryClinNeurosci.2007;19(2):17986.
107.
SzubaMP,O'ReardonJP,RaiAS,SnyderKastenbergJ,AmsterdamJD,GettesDR,etal.Acutemood
andthyroidstimulatinghormoneeffectsoftranscranialmagneticstimulationinmajordepression.Biol
Psychiatry.2001;50(1):227.
108.
TriggsWJ,RicciutiN,WardHE,ChengJ,BowersD,GoodmanWK,etal.Rightandleftdorsolateralpre
frontalrTMStreatmentofrefractorydepression:arandomized,shamcontrolledtrial.PsychiatryRes.
2010;178(3):46774.
109.
UdupaK,SathyaprabhaTN,ThirthalliJ,KishoreKR,RajuTR,GangadharBN.Modulationofcardiac
autonomicfunctionsinpatientswithmajordepressiontreatedwithrepetitivetranscranialmagnetic
stimulation.JAffectDisord.2007;104(13):2316.
110.
VanderhasseltMA,deRaedtR,BaekenC,LeymanL,D'HaenenH.AsinglesessionofrTMSoverthe
leftdorsolateralprefrontalcortexinfluencesattentionalcontrolindepressedpatients.WorldJBiolPsychiatry.
2009;10(1):3442.
111.
VanderhasseltMA,DeRaedtR,LeymanL,BaekenC.Acuteeffectsofrepetitivetranscranialmagnetic
stimulationonattentionalcontrolarerelatedtoantidepressantoutcomes.JPsychiatryNeurosci.
2009;34(2):11926.
112.
WangXM,YangDB,YuYF,HuangH,ZhaoXQ.Acontrolledstudyofthetreatmentofrepetitive
transcranialmagneticstimulationinpatientswithmajordepression.ChinJClinRehab.2004;8(9):17701.

Report#0513002R11rTMSforDepressionEvidenceReview

36

113.
ZhengH,ZhangL,LiL,LiuP,GaoJ,LiuX,etal.HighfrequencyrTMStreatmentincreasesleft
prefrontalmyoinositolinyoungpatientswithtreatmentresistantdepression.ProgNeuropsychopharmacol
BiolPsychiatry.2010;34(7):118995.
114.
McLoughlinDM,MoggA,ErantiS,PluckG,PurvisR,EdwardsD.Theclinicaleffectivenessandcostof
repetitivetranscranialmagneticstimulationversuselectroconvulsivetherapyinseveredepression:a
multicentrepragmaticrandomisedcontrolledtrialandeconomicanalysis.HTA.2007(3).

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TransportAccidentCommission&WorkSafeVictoria

EvidenceService

RepetitiveTranscranialMagneticStimulation
(rTMS)forDepression
TechnicalReport:Appendices17
March2013
OrnellaClavisi,EmmaDonoghue,NatashaDodge,JasonWasiak

Report#0513002R11.3rTMSforDepressionTechnicalReport

INTRODUCTION
ThistechnicalreportisacompaniondocumenttoRepetitiveTranscranialMagneticStimulation(rTMS)for
Depression:EvidenceReview.Itcontainsdetailedinformationaboutthemethodsusedinthedevelopment
oftheEvidenceReview,summariesofthestudiesincludedinthereview,andqualityappraisalresultsforthe
mostrecentand/ormostrelevantincludedstudies.

CONTENTS
APPENDIX1:METHODS.......................................................................................................................................3
APPENDIX2:SEARCHDETAILS.............................................................................................................................4
APPENDIX3:LISTOFINCLUDEDSTUDIES..........................................................................................................13
APPENDIX4:SUMMARYOFSYNTHESISEDSTUDIES..........................................................................................21
APPENDIX5:SUMMARYOFPRIMARYSTUDIES................................................................................................28
APPENDIX6:QUALITYAPPRAISALS...................................................................................................................51
APPENDIX7:QUALITYAPPRAISALGAYNESREPORT.........................................................................................68

Report#0513002R11.3rTMSforDepressionTechnicalReport

APPENDIX1:METHODS
Atwostagedapproachwasundertaken.

STAGE1
Identifyevidenceavailableforeachintervention
Run search in health databases, websites and on the internet, limit to evidence based guidelines (EBGs), health
technology assessments (HTAs), systematic reviews (SRs,) randomised controlled trials (RCTs) and controlled clinical
trials(CCTs)
Applyinclusionandexclusioncriteria

Criticallyappraisesynthesisedresearch
Startwithmostrecentreview,applystandardappraisalcriteria
Iffoundtobeofhighquality,crosschecktoensurereferencesfromallothersynthesisedresearchareincludedand
checkforconsistencyoffindings
Ifnothighquality,appraisenextmostrecentandrepeatprocess
Ifthereareinconsistentfindingsacrosstheexistingreviews,investigatethepossibilityofsynthesisofthisinformation
orwhetheranewsystematicreviewisrequired

DecideonactionsforStage2
Mapavailableevidence(asperTableA1.1)
Identifywhethersufficienthighlevelevidenceexiststoanswerquestionsoridentifywhatfurtheractionneedstobe
taken(seealgorithminTableA1.2).

STAGE2
Addressfurtheractionsidentified.
TableA1.1.Templateformapofavailableevidence

EBGs

Synthesisedstudies
SRs&HTAs

Primarystudies

TOTAL

TableA1.2.Furtheractionrequiredtoanswerclinicalquestions
Isthereanysynthesisedresearchavailable?(e.g.,EBGs,HTAs,SRs)
Yes

No

Isthisgoodqualityresearch?
Yes

AreRCTsavailable?
No

Yes

No

UndertakenewSR

UndertakenewSR

Considerlookingfor
lowerlevelsofevidence

Isitcurrent(within2years)?
Yes

No

Nofurtheraction

UpdateexistingSR

Report#0513002R11.3rTMSforDepressionTechnicalReport

APPENDIX2:SEARCHDETAILS
TAC/WSVstaffassistedinthedevelopmentofsearchtermsandinclusionandexclusion.

Inclusionandexclusioncriteria
Inclusion and exclusion criteria were established a priori (Table A2.1). The two authors independently screened the
search results according to the inclusion and exclusion criteria. Any discrepancies in findings were discussed and
resolved.
TableA2.1InclusionandExclusioncriteria
Patient/
Inclusion:Adults,includinggeriatrics.MaleandFemale.Depression,acuteorchronic,newonset,relapsed,
population
treatmentresistantorinremission.

Exclusion:Children,bipolardepression

Intervention/
Inclusion:Repetitivetranscranialmagneticstimulation.Anydose.
indicator

Exclusion:Nonrepetitivetranscranialmagneticstimulation.

Comparison/
Inclusion:Standardcarewhichmayincludeadmission,antidepressants,psychologicalcounselling,
control
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,case
series,editorials,lettersandcommentaries.

Publication
Inclusion:AllEnglishlanguagestudiesconductedonhumans.
details

Exclusion:NonEnglishlanguagepapersorstudiesconductedonanimals.

Timeperiod
Inclusion:Anytime

Exclusion:Nil

Report#0513002R11.3rTMSforDepressionTechnicalReport

Searchesundertaken
Searchmethods
EvidenceBasedGuidelines(EBGs)aregenerallypublishedaselectronicstandalonedocumentsontheinternetrather
than papers in peer reviewed journals. We searched first in standard health databases, then in websites which are
knowntopublishhighqualityresearchandguidelinesandfinallyinageneralsearchengine,asfollows;
Searchstrategiesinelectronicdatabases
Standardsystematicreviewstrategies,asoutlinedbelowintheMedlinesearchexample,wereusedtoidentifyexisting
reviewsandtrials.AdditionalreviewingofthereferencesfromthesearchesidentifiedEBGs.
Internetsearchestoidentifyrelevantwebsites
The reviewers were aware of websites of guideline clearinghouses, guideline developers, centres of evidencebased
practice,Australiangovernmenthealthservicesandwebsitesofspecificrelevance(egg.accidentcompensationgroups)
knowntocontainevidencebasedresources.
WebsitesearchestoidentifyrelevantEBGs
The reviewers were aware of websites of guideline clearinghouses, guideline developers, centres of evidencebased
practice,Australiangovernmenthealthservicesandwebsitesofspecificrelevance(eg.accidentcompensationgroups)
knowntocontainevidencebasedresources.
The43websiteslistedbelowweresearchedforrelevantEBGs(seeTableA2.4).
Whereaninternalsearchenginewasavailable,websitesweresearchedusingthesearchstringsdetailedinthetable
below. If no search engine was available, lists of EBGs, publications or other resources identified on the site were
scannedforrelevantdocuments.
Internetsearchestoidentifyrelevantreferences
AninternetsearchstrategywasconductedusingtheGoogleAdvancedSearchfunction.Thesearchstringwaslimited
todocumentsinEnglish:
Thefirst100Googlesearchresultswerescreenedandyieldednonewstudies.AsGooglesearchresultsarepresented
inorderofrelevance,wedidnotscreenfurther.
Databasesaccessed
AhighlysensitivesearchinCochranelibrary,Medline,Embase,Compendex(Engineering),PedroandSportsdiscus
(sporting)asdetailedbelowwasundertakenforthereviewterms.
TableA2.2Databasesaccessed
Databasename

Datescovered

Datesearched

Refs

Medline(Ovid)
PreMedline(Ovid)
AllEBM(Ovid)*
CINAHL(Ovid)
EMBASE
WoK

1980toJulyWeek22012
July13,2012
CompletedatabasesJuly2012
1980date
1980to2012Week28
CompletedatabasesJuly2012

20thJuly2012
16thJuly2012
20thJuly2012
20thJuly2012
20thJuly2012
21stJuly2012

877
71
130
116
1204
97

*includingTheCochraneDatabaseofSystematicReviews,DARE,CENTRAL,NHSEED,HTAandACPJournalClub

Report#0513002R11.3rTMSforDepressionTechnicalReport

Thefollowingsearcheswereconductedandadaptedforuseinotherdatabases.

TableA2.3MedlineSearchStrategy
1
Depression/
2

expdepressivedisorder/

(depressionordepressiveormelanchol*).ti,ab.

or/13

TranscranialMagneticStimulation/

(transcranialadj2stimulat*).ti,ab.

or/56

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

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

Antidepressantefficacyofhighfrequencytranscranialmagneticstimulationovertheleftdorsolateralprefrontalcortex
in.m_titl.

18

(Repetitivetranscranialmagneticstimulationfortreatmentresistantdepressionasystematicreviewand
metaanalysis).m_titl.

Report#0513002R11.3rTMSforDepressionTechnicalReport

TableA2.4WebsitesearchestoidentifyrelevantEBGs
Search1:IdentificationofrelevantguidelinesforRepetitiveTranscranialMagneticStimulation(rTMS)forDepressionusingspecificguidelinerelatedwebsites
GuidelineServices

Results

Search

NationalHealthandMedicalResearchCouncil(NHMRC)

http://www.nhmrc.gov.au

Termsused:RTMS,Repetitivetranscranialmagneticstimulation
AustralianGuidelinesfortheTreatmentofAdultswithAcuteStressDisorderand
PosttraumaticStressDisorder
http://www.nhmrc.gov.au/guidelines/publications/mh13mh14mh15mh16

NationalInstituteforHealthandClinicalExcellenceUK
(NICE)

http://www.nice.org.uk

NewZealandGuidelineGroup(NZGG)

ScottishIntercollegiateGuidelinesNetwork(SIGN)

JoannaBriggsInstitute

http://www.nzgg.org.nz/search

GuidelinesInternationalNetwork

http://www.gin.net

GuidelinesAdvisoryCommittee

http://www.gacguidelines.ca/

NationalGuidelineClearinghouseUS(NGC)

guideline.gov/

IPG242Transcranialmagneticstimulationforseveredepression
http://publications.nice.org.uk/transcranialmagneticstimulationforsevere
depressionipg242

http://www.sign.ac.uk/search.html
http://www.joannabriggs.edu.au/
Subscriptionservice
LogintoCOnNECT+|SubscribetoCOnNECT+

Termsused:RTMS,Repetitivetranscranialmagneticstimulation
1referencefromscannedsearchresults

Report#0513002R11.3rTMSforDepressionTechnicalReport

Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
1of3referencesscanned
Depression:AssessmentandTreatmentDate:03/02/2012Version:1.2
LisaKundeBA,BPsych(Hons)
Muchcheaper,almostasgood:decrementallycosteffectivemedicalinnovation
http://www.ncbi.nlm.nih.gov/pubmed/19884627
ScannedtheirlistofEndorsedguidelines.2references
Depression:ManagementofMildDepression

Depression:ManagementofModeratetoSevereDepression
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
5referenceschosen
Practiceguidelineforthetreatmentofpatientswithmajordepressivedisorder,third
edition.1993(revised2010Oct).NGC:008093
AmericanPsychiatricAssociation

Depression.Thetreatmentandmanagementofdepressioninadults.2004(revised
2009Oct).NGC:007598
NationalCollaboratingCentreforMentalHealthNationalGovernmentAgency[Non
U.S.].
Majordepressioninadultsinprimarycare.1996Jan(revised2011May).[NGC
UpdatePending]NGC:008573
InstituteforClinicalSystemsImprovement
ExpertCommentary:PrimaryCareDepressionGuidelinesandTreatmentResistant
Depression:VariationsonanImportantbutUnderstudiedTheme
Practiceparametersfortheassessmentandtreatmentofchildrenandadolescents
withdepressivedisorders.1998(revised2007).NGC:005924
AmericanAcademyofChildandAdolescentPsychiatry

TRIPDatabase

www.tripdatabase.com/

AustralianGovernmentWebsitescontainingGuidelines
AustralianInstituteofHealthandWelfare
www.aihw.gov.au

HealthInsite

www.healthinsite.gov.au/

ACTHealth

www.health.act.gov.au/

NSWHealth

www.health.nsw.gov.au/

Report#0513002R11.3rTMSforDepressionTechnicalReport

Termsused:RTMS,Repetitivetranscranialmagneticstimulation
141referencesdownloadedtotheEndnotedatabase
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
4referencesscanned
Preventionandmanagementofdepression(NHPAreporton...
evaluationofTranscranialMagneticStimulation(TMS)asapossiblealternativeto
electroconvulsivetherapy(ECT).Australianresearchershavealsoplayeda...
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
SystematicReviewsofTreatmentsforDepressionLinkstosummariesofsystematic
reviewsoftheevidencefortheeffectivenessoftreatmentsfordepression.
Transcranialmagneticstimulation(TMS)fordepressionJohnWileyandSons~Ltd.for
TheCochraneCollaborationJul2001Transcranialmagneticstimulationcaneither
exciteorinhibitcorticalareasofthebrain,dependingonwhether
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation

N/A
NTDepartmentofHealthandCommunityServices

www.health.nt.gov.au/

QueenslandHealth

www.health.qld.gov.au/

SADepartmentofHealthandHumanServices

www.health.sa.gov.au/

TasmanianDepartmentofHealthandHumanServices

www.dhhs.tas.gov.au/

VictorianDepartmentofHumanServices

www.dhs.vic.gov.au/

WADepartmentofHealth

www.jobs.health.wa.gov.au/

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CCRNNewsApril2011rTMS:Potentialnewclinicalapplications

CentresofEvidenceBasedPracticeWebsites
WesternAustralianCentreforEvidenceInformed
HealthcarePractice

http://wacebnm.curtin.edu.au

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N/A

TAC/WSVrelevantsites
TransportAccidentCommission

AustralianTransportSafetyBureau

RoadSafetyVictoria(TAC)

WorkSafeVictoria

TrafficInjuryResearchFoundation

www.tac.vic.gov.au/

Termsused:RTMS,Repetitivetranscranialmagneticstimulation:1reference
TraumaticBrainInjuryProjects:TranscranialMagneticStimulation(TMS)Treatment
inDepression...

http://www.atsb.gov.au/

Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
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Projectsscanned
N/A

http://www.tacsafety.com.au
www.worksafe.vic.gov.au/
www.trafficinjuryresearch.com/

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MotorAccidentsAuthorityNSW

http://www.maa.nsw.gov.au

WorkSafeBritishColumbia

http://www.worksafebc.com/

AccidentCompensationCorporation

www.acc.co.nz/

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N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
ChronicPainTreatments:WhatistheEvidence?
WorkSafeBCEvidenceBasedPracticeGroup
http://www.worksafebc.com/health_care_providers/Assets/PDF/poster
presentations/ChronicPainTreatmentsEvidence.pdf
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A

PainTreatmentTopics

TheGeorgeInstitute

http://paintopics.org/

InjuryResearchandPreventionUnit

www.injuryresearch.bc.ca/

www.georgeinstitute.org.au/

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N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A

TheBrainTraumaFoundation

SaferRoads

RailAccidentInvestigationBranch

OsloSportsTraumaResearchCentre

OregonEvidenceBasedPracticeCentre

www.braintrauma.org/

InjuryPreventionNetworkofAotearoaNewZealand

ipnanz.org.nz/

10

http://www.rta.nsw.gov.au/
www.raib.gov.uk/
www.klokavskade.no/en/
www.ohsu.edu/epc/

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11referencesretrieved
N/A

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N/A

TraumaCentreatJusticeResourceCentre

www.traumacenter.org/

TheDANAFoundation

www.dana.org/

Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
11referencesretrieved.2toreview
StudySupportsTranscranialMagneticStimulationtoTreatDepression
http://www.dana.org/news/features/detail.aspx?id=28882

BiomarkersandtheFutureofTreatmentforDepression
http://www.dana.org/news/cerebrum/detail.aspx?id=38554

EuropeanAssociationforInjuryPreventionandSafety
Promotion

NewZealandInjuryPreventionstrategy

NHSHealthatWork

TheCanadianAssociationofRoadSafetyProfessionals

http://www.eurosafe.eu.com/

www.nzips.govt.nz/
www.nhshealthatwork.co.uk/
www.carsp.ca/

Search2:IdentificationofrelevantstudiesforrTMSforDepressionusingGoogle
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Appraisal
Appraisalwasundertakeninsteps:
1.Themostrecentreview(evidencebasedguideline,systematicrevieworHTA)wasassessedforqualityusing
standardappraisalcriteria.
2.Iffoundtobeofhighquality,itwascrosscheckedagainsttheotheravailablereviewstocomparescopeand
consistencyoffindings.
3.Iffoundnottobeofhighquality,thenextmostrecentwasappraisedandtheaboveprocessrepeated.
Quality
Evidencebasedguidelinesandsystematicreviewswereappraisedusingstandardcriteriabyasinglereviewer
in consultation with colleagues as required. RCTs were also appraised using standard criteria by a single
reviewerinconsultationwithcolleaguesasrequired.DetailsofqualityappraisalsareincludedinAppendix5.
DataExtraction
Dataoncharacteristicsofthestudieswereextractedandsummarised.

12

Report#0513002R11.3rTMSforDepressionTechnicalReport

APPENDIX3:LISTOFINCLUDEDSTUDIES
PrimaryStudies
RandomisedControlledTrials
1.
AguirreI,CarreteroB,IbarraO,KuhalainenJ,MartinezJ,FerrerA,etal.Agepredictslowfrequency
transcranialmagneticstimulationefficacyinmajordepression.JAffectDisord.2011;130(3):4669.
2.
AndersonIM,DelvaiNA,AshimB,AshimS,LewinC,SinghV,etal.Adjunctivefastrepetitive
transcranialmagneticstimulationindepression.BrJPsychiatry.2007;190:5334.
3.
AveryDH,ClaypooleK,RobinsonL,NeumaierJF,DunnerDL,ScheeleL,etal.Repetitivetranscranial
magneticstimulationinthetreatmentofmedicationresistantdepression:preliminarydata.JNervMentDis.
1999;187(2):1147.
4.
AveryDH,HoltzheimerIPE,FawazW,RussoJ,NeumaierJ,DunnerDL,etal.Acontrolledstudyof
repetitivetranscranialmagneticstimulationinmedicationresistantmajordepression.BiolPsychiatry.
2006;59(2):18794.
5.
AveryDH,HoltzheimerIPE,FawazW,RussoJ,NeumaierJ,DunnerDL,etal.Transcranialmagnetic
stimulationreducespaininpatientswithmajordepression:Ashamcontrolledstudy.JNervMenDis.
2007;195(5):37881.
6.
BaresM,KopecekM,NovakT,StopkovaP,SosP,KozenyJ,etal.Lowfrequency(1Hz),right
prefrontalrepetitivetranscranialmagneticstimulation(rTMS)comparedwithvenlafaxineERinthetreatment
ofresistantdepression:adoubleblind,singlecentre,randomizedstudy.JAffectDisord.2009;118(13):94100.
7.
BermanRM,NarasimhanM,SanacoraG,MianoAP,HoffmanRE,HuXS,etal.Arandomizedclinical
trialofrepetitivetranscranialmagneticstimulationinthetreatmentofmajordepression.BiolPsychiatry.
2000;47(4):3327.
8.
BortolomasiM,MinelliA,FuggettaG,PeriniM,ComenciniS,FiaschiA,etal.Longlastingeffectsof
highfrequencyrepetitivetranscranialmagneticstimulationinmajordepressedpatients.PsychiatryRes.
2007;150(2):1816.
9.
BoutrosNN,GueorguievaR,HoffmanRE,OrenDA,FeingoldA,BermanRM.Lackofatherapeutic
effectofa2weeksubthresholdtranscranialmagneticstimulationcoursefortreatmentresistantdepression.
PsychiatryRes.2002;113(3):24554.
10.
BretlauLG,LundeM,LindbergL,UndenM,DissingS,BechP.Repetitivetranscranialmagnetic
stimulation(rTMS)incombinationwithescitalopraminpatientswithtreatmentresistantmajordepression:a
doubleblind,randomised,shamcontrolledtrial.Pharmacopsychiatry.2008;41(2):417.
11.
ChistyakovAV,KaplanB,RubichekO,KreininI,KorenD,FeinsodM,etal.Antidepressanteffectsof
differentschedulesofrepetitivetranscranialmagneticstimulationvs.clomipramineinpatientswithmajor
depression:relationshiptochangesincorticalexcitability.IntJNeuropsychopharmacol.2005;8(2):22333.
12.
ChistyakovAV,KaplanB,RubichekO,KreininI,KorenD,HafnerH,etal.Effectofelectroconvulsive
therapyoncorticalexcitabilityinpatientswithmajordepression:atranscranialmagneticstimulationstudy.
ClinNeurophysiol.2005;116(2):38692.
13.
DannonPN,DolbergOT,SchreiberS,GrunhausL.Threeandsixmonthoutcomefollowingcoursesof
eitherECTorrTMSinapopulationofseverelydepressedindividualsPreliminaryreport.BiolPsychiatry.
2002;51(8):68790.

13

Report#0513002R11.3rTMSforDepressionTechnicalReport

14.
EichhammerP,KharrazA,WiegandR,LangguthB,FrickU,AignerJM,etal.Sleepdeprivationin
depressionStabilizingantidepressanteffectsbyrepetitivetranscranialmagneticstimulation.LifeSci.
2002;70(15):17419.
15.
ErantiS,MoggA,PluckG,LandauS,PurvisR,BrownRG,etal.Arandomized,controlledtrialwith6
monthfollowupofrepetitivetranscranialmagneticstimulationandelectroconvulsivetherapyforsevere
depression.AmJPsychiatry.2007;164(1):7381.
16.
EschweilerGW,WegererC,SchlotterW,SpandlC,StevensA,BartelsM,etal.Leftprefrontal
activationpredictstherapeuticeffectsofrepetitivetranscranialmagneticstimulation(rTMS)inmajor
depression.PsychiatryRes.2000;99(3):16172.
17.
FitzgeraldPB,BenitezJ,deCastellaA,DaskalakisZJ,BrownTL,KulkarniJ.Arandomized,controlled
trialofsequentialbilateralrepetitivetranscranialmagneticstimulationfortreatmentresistantdepression.Am
JPsychiatry.2006;163(1):8894.
18.
FitzgeraldPB,BrownTL,MarstonNA,DaskalakisZJ,DeCastellaA,KulkarniJ.Transcranialmagnetic
stimulationinthetreatmentofdepression:adoubleblind,placebocontrolledtrial.ArcGenPsychiatry.
2003;60(10):10028.
19.
FitzgeraldPB,HoyK,McQueenS,HerringS,SegraveR,BeenG,etal.Primingstimulationenhances
theeffectivenessoflowfrequencyrightprefrontalcortextranscranialmagneticstimulationinmajor
depression.JClinPsychopharmacol.2008;28(1):528.
20.
FitzgeraldPB,HoyKE,HerringSE,McQueenS,PeacheyAVJ,SegraveRA,etal.Adoubleblind
randomizedtrialofunilateralleftandbilateralprefrontalcortextranscranialmagneticstimulationintreatment
resistantmajordepression.JAffectDisord.2012;139(2):1938.
21.
GarciaToroM,MayolA,ArnillasH,CapllonchI,IbarraO,CrespiM,etal.Modestadjunctivebenefit
withtranscranialmagneticstimulationinmedicationresistantdepression.JAffectDisord.2001;64(23):2715.
22.
GarciaToroM,PascualLeoneA,RomeraM,GonzalezA,MicoJ,IbarraO,etal.Prefrontalrepetitive
transcranialmagneticstimulationasaddontreatmentindepression.JNeurolNeurosurgPsychiatry.
2001;71(4):5468.
23.
GarciaToroM,SalvaJ,DaumalJ,AndresJ,RomeraM,LafauO,etal.High(20Hz)andlow(1Hz)
frequencytranscranialmagneticstimulationasadjuvanttreatmentinmedicationresistantdepression.
PsychiatryRes.2006;146(1):537.
24.
GeorgeMS,LisanbySH,AveryD,McDonaldWM,DurkalskiV,PavlicovaM,etal.Dailyleftprefrontal
transcranialmagneticstimulationtherapyformajordepressivedisorder:Ashamcontrolledrandomizedtrial.
ArchGenPsychiatry.2010;67(5):50716.
25.
GeorgeMS,WassermannEM,KimbrellTA,LittleJT,WilliamsWE,DanielsonAL,etal.Mood
improvementfollowingdailyleftprefrontalrepetitivetranscranialmagneticstimulationinpatientswith
depression:aplacebocontrolledcrossovertrial.AmJPsychiatry.1997;154(12):17526.
26.
GrunhausL,DannonPN,SchreiberS,DolbergOH,AmiazR,ZivR,etal.Repetitivetranscranial
magneticstimulationisaseffectiveaselectroconvulsivetherapyinthetreatmentofnondelusionalmajor
depressivedisorder:anopenstudy.BiolPsychiatry.2000;47(4):31424.
27.
GrunhausL,SchreiberS,DolbergOT,PolakD,DannonPN.Arandomizedcontrolledcomparisonof
electroconvulsivetherapyandrepetitivetranscranialmagneticstimulationinsevereandresistant
nonpsychoticmajordepression.BiolPsychiatry.2003;53(4):32431.
28.
HausmannA,KemmlerG,WalpothM,MechtcheriakovS,KramerReinstadlerK,LechnerT,etal.No
benefitderivedfromrepetitivetranscranialmagneticstimulationindepression:aprospective,singlecentre,
randomised,doubleblind,shamcontrolled"addon"trial.JNeurolNeurosurgPsychiatry.2004;75(2):3202.
14

Report#0513002R11.3rTMSforDepressionTechnicalReport

29.
HausmannA,PascualLeoneA,KemmlerG,RuppCI,LechnerSchonerT,KramerReinstadlerK,etal.
NodeteriorationofcognitiveperformanceinanaggressiveunilateralandbilateralantidepressantrTMSadd
ontrial.JClinPsychiatry.2004;65(6):77282.
30.
HerbsmanT,AveryD,RamseyD,HoltzheimerP,WadjikC,HardawayF,etal.Morelateraland
anteriorprefrontalcoillocationisassociatedwithbetterrepetitivetranscranialmagneticstimulation
antidepressantresponse.BiolPsychiatry.2009;66(5):50915.
31.
HerwigU,FallgatterAJ,HoppnerJ,EschweilerGW,KronM,HajakG,etal.Antidepressanteffectsof
augmentativetranscranialmagneticstimulation:randomisedmulticentretrial.BrJPsychiatry.2007;191:4418.
32.
HerwigU,LampeY,JuenglingFD,WunderlichA,WalterH,SpitzerM,etal.AddonrTMSfor
treatmentofdepression:apilotstudyusingstereotaxiccoilnavigationaccordingtoPETdata.JPsychiatrRes.
2003;37(4):26775.
33.
HoeppnerJ,PadbergF,DomesG,ZinkeA,HerpertzSC,GroheinrichN,etal.Influenceofrepetitive
transcranialmagneticstimulationonpsychomotorsymptomsinmajordepression.EurArchPsychiatryClin
Neurosci.2010;260(3):197202.
34.
HoltzheimerPE,3rd,RussoJ,ClaypooleKH,RoyByrneP,AveryDH.Shorterdurationofdepressive
episodemaypredictresponsetorepetitivetranscranialmagneticstimulation.DepressAnxiety.2004;19(1):24
30.
35.
HoppnerJ,SchulzM,IrmischG,MauR,SchlafkeD,RichterJ.Antidepressantefficacyoftwodifferent
rTMSprocedures.Highfrequencyoverleftversuslowfrequencyoverrightprefrontalcortexcomparedwith
shamstimulation.EurArchPsychiatryClinNeurosci.2003;253(2):1039.
36.
JakobF,BrakemeierEL,SchommerNC,QuanteA,MerklA,DankerHopfeH,etal.Ultrahighfrequency
repetitivetranscranialmagneticstimulationinunipolardepression.JClinPsychopharmacol.2008;28(4):4746.
37.
JanuelD,DumortierG,VerdonCM,StamatiadisL,SabaG,CabaretW,etal.Adoubleblindsham
controlledstudyofrightprefrontalrepetitivetranscranialmagneticstimulation(rTMS):Therapeuticand
cognitiveeffectinmedicationfreeunipolardepressionduring4weeks.ProgNeuroPsychopharmacolBiol
Psychiatry.2006;30(1):12630.
38.
KauffmannCD,CheemaMA,MillerBE.Slowrightprefrontaltranscranialmagneticstimulationasa
treatmentformedicationresistantdepression:adoubleblind,placebocontrolledstudy.DepressAnxiety.
2004;19(1):5962.
39.
KeshtkarM,GhanizadehA,FiroozabadiA.Repetitivetranscranialmagneticstimulationversus
electroconvulsivetherapyforthetreatmentofmajordepressivedisorder,arandomizedcontrolledclinical
trial.JECT.2011;27(4):3104.
40.
KimbrellTA,LittleJT,DunnRT,FryeMA,GreenbergBD,WassermannEM,etal.Frequency
dependenceofantidepressantresponsetoleftprefrontalrepetitivetranscranialmagneticstimulation(rTMS)
asafunctionofbaselinecerebralglucosemetabolism.BiolPsychiatry.1999;46(12):160313.
41.
KleinE,KreininI,ChistyakovA,KorenD,MeczL,MarmurS,etal.Therapeuticefficacyofright
prefrontalslowrepetitivetranscranialmagneticstimulationinmajordepression:adoubleblindcontrolled
study.ArchGenPsychiatry.1999;56(4):31520.
42.
KnappM,RomeoR,MoggA,ErantiS,PluckG,PurvisR,etal.Costeffectivenessoftranscranial
magneticstimulationvs.electroconvulsivetherapyforseveredepression:amulticentrerandomised
controlledtrial.JAffectiveDisord.2008;109(3):27385.
43.
KoerselmanF,LamanDM,vanDuijnH,vanDuijnMA,WillemsMA.A3month,followup,
randomized,placebocontrolledstudyofrepetitivetranscranialmagneticstimulationindepression.JClin
Psychiatry.2004;65(10):13238.
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Report#0513002R11.3rTMSforDepressionTechnicalReport

44.
LisanbySH,HusainMM,RosenquistPB,MaixnerD,GutierrezR,KrystalA,etal.Dailyleftprefrontal
repetitivetranscranialmagneticstimulationintheacutetreatmentofmajordepression:clinicalpredictorsof
outcomeinamultisite,randomizedcontrolledclinicaltrial.Neuropsychopharmacol.2009;34(2):52234.
45.
LittleJT,KimbrellTA,WassermannEM,GrafmanJ,FiguerasS,DunnRT,etal.Cognitiveeffectsof1
and20hertzrepetitivetranscranialmagneticstimulationindepression:preliminaryreport.Neuropsychiatry
NeuropsycholBehavNeurol.2000;13(2):11924.
46.
LooC,MitchellP,SachdevP,McDarmontB,ParkerG,GandeviaS.Doubleblindcontrolled
investigationoftranscranialmagneticstimulationforthetreatmentofresistantmajordepression.AmJ
Psychiatry.1999;156(6):9468.
47.
LooC,SachdevP,ElsayedH,McDarmontB,MitchellP,WilkinsonM,etal.Effectsofa2to4week
courseofrepetitivetranscranialmagneticstimulation(rTMS)onneuropsychologicfunctioning,
electroencephalogram,andauditorythresholdindepressedpatients.BiolPsychiatry.2001;49(7):61523.
48.
LooCK,MitchellPB,CrokerVM,MalhiGS,WenW,GandeviaSC,etal.Doubleblindcontrolled
investigationofbilateralprefrontaltranscranialmagneticstimulationforthetreatmentofresistantmajor
depression.PsychologicalMed.2003;33(1):3340.
49.
LooCK,MitchellPB,McFarquharTF,MalhiGS,SachdevPS.Ashamcontrolledtrialoftheefficacyand
safetyoftwicedailyrTMSinmajordepression.PsychologicalMed.2007;37(3):3419.
50.
LooCK,SachdevPS,HaindlW,WenW,MitchellPB,CrokerVM,etal.High(15Hz)andlow(1Hz)
frequencytranscranialmagneticstimulationhavedifferentacuteeffectsonregionalcerebralbloodflowin
depressedpatients.PsychologicalMed.2003;33(6):9971006.
51.
ManesF,JorgeR,MorcuendeM,YamadaT,ParadisoS,RobinsonRG.Acontrolledstudyofrepetitive
transcranialmagneticstimulationasatreatmentofdepressionintheelderly.IntPsychogeriatr.
2001;13(2):22531.
52.
McDonaldWM,EasleyK,ByrdEH,HoltzheimerP,TuohyS,WoodardJL,etal.Combinationrapid
transcranialmagneticstimulationintreatmentrefractorydepression.NeuropsychiatricDisTreat.
2006;2(1):8594.
53.
McLoughlin,Dm,Mogg,Eranti,Pluck,Purvis,etal.Theclinicaleffectivenessandcostofrepetitive
transcranialmagneticstimulationversuselectroconvulsivetherapyinseveredepression:amulticentre
pragmaticrandomisedcontrolledtrialandeconomicanalysis(Briefrecord).HealthTechnologyAssessment
Database.2012(3).Originalarticle:McLoughlin,DM,Mogg,A,Eranti,S,Pluck,G,Purvis,R,Edwards,D.The
clinicaleffectivenessandcostofrepetitivetranscranialmagneticstimulationversuselectroconvulsivetherapy
inseveredepression:amulticentrepragmaticrandomisedcontrolledtrialandeconomicanalysis.HTA.1p.
2007.
54.
MingliH,ZhengtianG,XinyiW,XiaopingT.Effectsofrepetitivetranscranialmagneticstimulationon
hypothalamicpituitaryadrenalaxisofpatientswithdepression.JMedCollofPLA.2009;24(6):33745.
55.
MiniussiC,BonatoC,BignottiS,GazzoliA,GennarelliM,PasqualettiP,etal.Repetitivetranscranial
magneticstimulation(rTMS)athighandlowfrequency:anefficacioustherapyformajordrugresistant
depression?ClinNeurophysiol.2005;116(5):106271.
56.
MoggA,PluckG,ErantiSV,LandauS,PurvisR,BrownRG,etal.Arandomizedcontrolledtrialwith4
monthfollowupofadjunctiverepetitivetranscranialmagneticstimulationoftheleftprefrontalcortexfor
depression.PsychologicalMed.2008;38(3):32333.
57.
MollerAL,HjaltasonO,IvarssonO,StefanssonSB.Theeffectsofrepetitivetranscranialmagnetic
stimulationondepressivesymptomsandtheP(300)eventrelatedpotential.NordJPsychiatry.
2006;60(4):2825.

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Report#0513002R11.3rTMSforDepressionTechnicalReport

58.
MoserDJ,JorgeRE,ManesF,ParadisoS,BenjaminML,RobinsonRG.Improvedexecutivefunctioning
followingrepetitivetranscranialmagneticstimulation.Neurol.2002;58(8):128890.Epub2002/04/24.
59.
MosimannUP,SchmittW,GreenbergBD,KoselM,MuriRM,BerkhoffM,etal.Repetitivetranscranial
magneticstimulation:aputativeaddontreatmentformajordepressioninelderlypatients.PsychiatryRes.
2004;126(2):12333.
60.
NahasZ,DeBruxC,ChandlerV,LorberbaumJP,SpeerAM,MolloyMA,etal.Lackofsignificant
changesonmagneticresonancescansbeforeandafter2weeksofdailyleftprefrontalrepetitivetranscranial
magneticstimulationfordepression.JournalofECT.2000;16(4):38090.
61.
O'ConnorM,BrenninkmeyerC,MorganA,BloomingdaleK,ThallM,VasileR,etal.Relativeeffectsof
repetitivetranscranialmagneticstimulationandelectroconvulsivetherapyonmoodandmemory:a
neurocognitiveriskbenefitanalysis.CognBehavNeurol.2003;16(2):11827.
62.
O'ReardonJP,CristanchoP,PilaniaP,BapatlaKB,ChuaiS,PeshekAD.Patientswithamajor
depressiveepisoderespondingtotreatmentwithrepetitivetranscranialmagneticstimulation(rTMS)are
resistanttotheeffectsofrapidtryptophandepletion.DepressAnxiety.2007;24(8):53744.
63.
PadbergF,ZwanzgerP,KeckME,KathmannN,MikhaielP,EllaR,etal.Repetitivetranscranial
magneticstimulation(rTMS)inmajordepression:relationbetweenefficacyandstimulationintensity.
Neuropsychopharmacol.2002;27(4):63845.
64.
PadbergF,ZwanzgerP,ThomaH,KathmannN,HaagC,GreenbergBD,etal.Repetitivetranscranial
magneticstimulation(rTMS)inpharmacotherapyrefractorymajordepression:comparativestudyoffast,slow
andshamrTMS.PsychiatryRes.1999;88(3):16371.
PallantiS,BernardiS,DiRolloA,AntoniniS,QuercioliL.Unilaterallowfrequencyversussequential
65.
bilateralrepetitivetranscranialmagneticstimulation:issimplerbetterfortreatmentofresistantdepression?
Neurosci.2010;167(2):3238.
66.
PascualLeoneA,RubioB,PallardoF,CatalaMD.Rapidratetranscranialmagneticstimulationofleft
dorsolateralprefrontalcortexindrugresistantdepression.Lancet.1996;348(9022):2337.
67.
PouletE,BrunelinJ,BoeuveC,LerondJ,D'AmatoT,DaleryJ,etal.Repetitivetranscranialmagnetic
stimulationdoesnotpotentiateantidepressanttreatment.EurPsychiatry.2004;19(6):3823.
68.
PridmoreS.Substitutionofrapidtranscranialmagneticstimulationtreatmentsforelectroconvulsive
therapytreatmentsinacourseofelectroconvulsivetherapy.DepressAnxiety.2000;12(3):11823.
69.
PridmoreS,BrunoR,TurnierSheaY,ReidP,RybakM.Comparisonofunlimitednumbersofrapid
transcranialmagneticstimulation(rTMS)andECTtreatmentsessionsinmajordepressiveepisode.IntJ
Neuropsychopharmacol.2000;3(2):12934.
70.
RosaMA,GattazWF,PascualLeoneA,FregniF,RosaMO,RumiDO,etal.Comparisonofrepetitive
transcranialmagneticstimulationandelectroconvulsivetherapyinunipolarnonpsychoticrefractory
depression:arandomized,singleblindstudy.IntJNeuropsychopharmacol.2006;9(6):66776.
71.
RossiniD,LuccaA,ZanardiR,MagriL,SmeraldiE.Transcranialmagneticstimulationintreatment
resistantdepressedpatients:adoubleblind,placebocontrolledtrial.PsychiatryRes.2005;137(12):110.
72.
RossiniD,MagriL,LuccaA,GiordaniS,SmeraldiE,ZanardiR.DoesrTMShastentheresponseto
escitalopram,sertraline,orvenlafaxineinpatientswithmajordepressivedisorder?Adoubleblind,
randomized,shamcontrolledtrial.JClinPsychiatry.2005;66(12):156975.
73.
RumiDO,GattazWF,RigonattiSP,RosaMA,FregniF,RosaMO,etal.Transcranialmagnetic
stimulationacceleratestheantidepressanteffectofamitriptylineinseveredepression:adoubleblindplacebo
controlledstudy.BiolPsychiatry.2005;57(2):1626.
17

Report#0513002R11.3rTMSforDepressionTechnicalReport

74.
SchutterDJLG,LamanDM,vanHonkJ,VergouwenAC,KoerselmanGF.Partialclinicalresponseto2
weeksof2Hzrepetitivetranscranialmagneticstimulationtotherightparietalcortexindepression.IntJ
Neuropsychopharmacol.2009;12(5):64350.
75.
SternWM,TormosJM,PressDZ,PearlmanC,PascualLeoneA.Antidepressanteffectsofhighandlow
frequencyrepetitivetranscranialmagneticstimulationtothedorsolateralprefrontalcortex:adoubleblind,
randomized,placebocontrolledtrial.JNeuropsychiatryClinNeurosci.2007;19(2):17986.Epub2007/04/14.
76.
SzubaMP,O'ReardonJP,RaiAS,SnyderKastenbergJ,AmsterdamJD,GettesDR,etal.Acutemood
andthyroidstimulatinghormoneeffectsoftranscranialmagneticstimulationinmajordepression.Biological
Psychiatry.2001;50(1):227.
77.
TriggsWJ,RicciutiN,WardHE,ChengJ,BowersD,GoodmanWK,etal.Rightandleftdorsolateralpre
frontalrTMStreatmentofrefractorydepression:arandomized,shamcontrolledtrial.PsychiatryRes.
2010;178(3):46774.
78.
VanderhasseltMA,deRaedtR,BaekenC,LeymanL,D'HaenenH.AsinglesessionofrTMSoverthe
leftdorsolateralprefrontalcortexinfluencesattentionalcontrolindepressedpatients.WorldJBiological
Psychiatry.2009;10(1):3442.
79.
WangXM,YangDB,YuYF,HuangH,ZhaoXQ.Acontrolledstudyofthetreatmentofrepetitive
transcranialmagneticstimulationinpatientswithmajordepression.ChineseJClinRehab.2004;8(9):17701.
80.
ZhengH,ZhangL,LiL,LiuP,GaoJ,LiuX,etal.HighfrequencyrTMStreatmentincreasesleft
prefrontalmyoinositolinyoungpatientswithtreatmentresistantdepression.ProgNeuropsychopharmacol
BiolPsychiatry.2010;34(7):118995.

ControlledClinicalTrials
1.
SchulzeRauschenbachSC,HarmsU,SchlaepferTE,MaierW,FalkaiP,WagnerM.Distinctive
neurocognitiveeffectsofrepetitivetranscranialmagneticstimulationandelectroconvulsivetherapyinmajor
depression.BrJPsychiatry.2005;186:4106.
2.
UdupaK,SathyaprabhaTN,ThirthalliJ,KishoreKR,RajuTR,GangadharBN.Modulationofcardiac
autonomicfunctionsinpatientswithmajordepressiontreatedwithrepetitivetranscranialmagnetic
stimulation.JAffectDisord.2007;104(13):2316.
3.
VanderhasseltMA,DeRaedtR,LeymanL,BaekenC.Acuteeffectsofrepetitivetranscranialmagnetic
stimulationonattentionalcontrolarerelatedtoantidepressantoutcomes.Journalofpsychiatry&
neuroscience:JPN.2009;34(2):11926.

18

Report#0513002R11.3rTMSforDepressionTechnicalReport

SynthesisedStudies
SystematicReviewsandMetaAnalyses
1.
AarreTF,DahlAA,JohansenJB,KjonniksenI,NeckelmannD.Efficacyofrepetitivetranscranial
magneticstimulationindepression:areviewoftheevidence.NordJPsychiatry.2003;57(3):22732.
2.
AllanCL,HerrmannLL,EbmeierKP.TranscranialMagneticStimulationintheManagementofMood
Disorders.Neuropsychobiol.2011;64(3):1639.
3.
CouturierJL.Efficacyofrapidraterepetitivetranscranialmagneticstimulationinthetreatmentof
depression:asystematicreviewandmetaanalysis.JPsychiatryNeurosci.2005;30(2):8390.
4.
GaynesBN,LuxLJ,LloydSW,HansenRA,GartlehnerG,KeenerP,etal.Nonpharmacologic
InterventionsforTreatmentResistantDepressioninAdults.ComparativeEffectivenessReviewNo.33.
(PreparedbyRTIInternationalUniversityofNorthCarolina(RTIUNC)EvidencebasedPracticeCenterunder
ContractNo.290020016I.)AHRQPublicationNo.11EHC056EF.Rockville,MD:AgencyforHealthcare
ResearchandQuality;2011includeSR].Availablefrom:www.effectivehealthcare.ahrq.gov/reports/final.cfm.
5.
GrossM,NakamuraL,PascualLeoneA,FregniF.Hasrepetitivetranscranialmagneticstimulation
(rTMS)treatmentfordepressionimproved?Asystematicreviewandmetaanalysiscomparingtherecentvs.
theearlierrTMSstudies.ActaPsychiatrScand.2007;116(3):16573.
6.

HerrmannLL,EbmeierKP.Transcranialmagneticstimulation.Psychiatry.2006;5(6):2047.

7.

HerrmannLL,EbmeierKP.Transcranialmagneticstimulation.Psychiatry.2009;8(4):1304.

8.
Holtzheimer3rdPE,RussoJ,AveryDH.Ametaanalysisofrepetitivetranscranialmagneticstimulation
inthetreatmentofdepression.PsychopharmacologyBull.2001;35(4):14969.
9.
KozelFA,GeorgeMS.Metaanalysisofleftprefrontalrepetitivetranscranialmagneticstimulation
(rTMS)totreatdepression.JPsychiatrPract.2002;8(5):2705.
LamRW,ChanP,WilkinsHoM,YathamLN.Repetitivetranscranialmagneticstimulationfor
10.
treatmentresistantdepression:asystematicreviewandmetaanalysis.CanJPsychiatry.2008;53(9):62131.
11.
MartinJLR,BarbanojMJ,SchlaepferTE,ThompsonE,PerezV,KulisevskyJ.Repetitivetranscranial
magneticstimulationforthetreatmentofdepression.Systematicreviewandmetaanalysis.BrJPsychiatry.
2003;182:48091.
12.
McNamaraB,RayJL,ArthursOJ,BonifaceS.Transcranialmagneticstimulationfordepressionand
otherpsychiatricdisorders.PsychologicalMed.2001;31(7):11416.
13.
MedicalAdvisoryS,OntarioMinistryofH,LongTermC.Repetitivetranscranialmagneticstimulation
forthetreatmentofmajordepressivedisorder:anevidencebasedanalysis(Structuredabstract).Health
TechnologyAssessmentDatabase.2004(3).Originalarticle:Repetitivetranscranialmagneticstimulationfor
thetreatmentofmajordepressivedisorder:anevidencebasedanalysis.Toronto:MedicalAdvisory
Secretariat,OntarioMinistryofHealthandLongTermCare(MAS).96p.2004.
14.
MedicalServicesAdvisoryCommittee,CameronA,PekarskyB.Repetitivetranscranialmagnetic
stimulationasatreatmentformajordepression.Canberra,ACT:AustralianGovernmentDepartmentofHealth
andAgeing;2008includeSR].Availablefrom:
http://www.health.gov.au/internet/msac/publishing.nsf/Content/115CC907F00447B3CA2575AD0082FD6C/.
15.
MinichinoA,BersaniFS,CapraE,PanneseR,BonannoC,SalviatiM,etal.ECT,rTMS,anddeepTMSin
pharmacoresistantdrugfreepatientswithunipolardepression:Acomparativereview.NeuropsychiatricDis
Treat.2012;8:5564.

19

Report#0513002R11.3rTMSforDepressionTechnicalReport

16.
NationalInstituteforHealthandClinicalExcellence.Transcranialmagneticstimulationforsevere
depression.London2007;Availablefrom:http://www.nice.org.uk/nicemedia/pdf/IPG242GUIDANCE.pdf.
17.
RodriguezMartinJL,BarbanojJM,SchlaepferTE,ClosSS,PrezV,KulisevskyJ,etal.Transcranial
magneticstimulationfortreatingdepression.CochraneDatabaseofSystematicReviews.2009(4).
18.
SchutterDJ.Antidepressantefficacyofhighfrequencytranscranialmagneticstimulationovertheleft
dorsolateralprefrontalcortexindoubleblindshamcontrolleddesigns:ametaanalysis.PsychologicalMed.
2009;39(1):6575.
19.
SchutterDJ.Quantitativereviewoftheefficacyofslowfrequencymagneticbrainstimulationinmajor
depressivedisorder.PsychologicalMed.2010;40(11):178995.
20.
SlotemaCW,BlomJD,HoekHW,SommerIEC.Shouldweexpandthetoolboxofpsychiatrictreatment
methodstoincludeRepetitiveTranscranialMagneticStimulation(rTMS)?Ametaanalysisoftheefficacyof
rTMSinpsychiatricdisorders.JClinPsychiatry.2010;71(7):87384.

EvidenceBasedGuidelines
1.
KennedySH,MilevR,GiacobbeP,RamasubbuR,LamRW,ParikhSV,etal.CanadianNetworkfor
MoodandAnxietyTreatments(CANMAT)Clinicalguidelinesforthemanagementofmajordepressivedisorder
inadults.IV.Neurostimulationtherapies.JAffectDisord.2009;117(SUPPL.1):S44S53.

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Report#0513002R11.3rTMSforDepressionTechnicalReport

APPENDIX4:SUMMARYOFSYNTHESISEDSTUDIES

TableA4.1summaryofincludedstudies
1stauthor,year,title
Inclusion,Exclusioncriteria(forP.I.C.O)
Aare2003

Efficacyofrepetitive
transcranialmagnetic
stimulationindepression:
areviewoftheevidence

POPULATION/CLINICALINDICATION

Patientswithdepressivedisorders

Study
design

Conclusion/Recommendation

Recommendationcategory

SR

rTMSnotrecommendedasastandardtreatmentfordepression.

Negative,rTMSlesseffective
thanECT.

SR

Optimumtreatmentprotocolyettobediscovered.
Noevidenceforlastingtreatmenteffectsbeyond12weeks.

Inconclusive

SR

NosignificantdifferencebetweenrTMSandshamtreatment.
Maybeduetodifferencesinstudyprotocol.Mosteffective
combinationofparametersforrTMSnotyetestablished.

Neutralnodifferencebetween
rTMSandShamrTMS

SR

rTMSmoreeffectivethanshamfortreatmentresistant
depression

PositiveforrTMSvsSham
Inconclusiveevidenceforthe
efficacyofrTMScomparedwith
ECT.

SR

RecentclinicaltrialsofrTMSondepressioninducedalarger

Positive

INTERVENTIONandCOMPARATORS

ShamTMSorECT

OUTCOMES:

Efficacy
Allan2011
TranscranialMagnetic
Stimulationinthe
ManagementofMood
Disorders.
Coutourier2005
Efficacyofrapidrate
repetitivetranscranial
magneticstimulationin
thetreatmentof
depression:asystematic
reviewandmetaanalysis
Gaynes2011
Nonpharmacologic
Interventionsfor
TreatmentResistant
DepressioninAdults.
Comparative
EffectivenessReviewNo.
33
Gross2007

POPULATION/CLINICALINDICATION
MoodDisorders
INTERVENTIONandCOMPARATORS

ShamTMSorECT

OUTCOMES:
Efficacy
POPULATION/CLINICALINDICATION

MDD

INTERVENTIONandCOMPARATORS

ShamTMS

OUTCOMES:

Efficacy

POPULATION/CLINICALINDICATION
TRD
INTERVENTIONandCOMPARATORS
ShamrTMSorECT
OUTCOMES:

POPULATION/CLINICALINDICATION

MDD

21

Report#0513002R11.3rTMSforDepressionTechnicalReport

Hasrepetitive
transcranialmagnetic
stimulation(rTMS)
treatmentfordepression
improved?Asystematic
reviewandmetaanalysis
comparingtherecentvs.
theearlierrTMSstudies.
Herrmann2006
Transcranialmagnetic
stimulation.

effectsizewhencomparedwiththeinitialstudiesfromMartin
etal.

INTERVENTIONandCOMPARATORS

VariousfrequencyofTMSorSham
OUTCOMES:

ComparisonofefficacybetweenlateandearlystudiesofrTMS

POPULATION/CLINICALINDICATION

SR

rTMSismoreeffectiveinthetreatmentofdepressionthan
shamrTMS,withamediumsizedeffectsize.Studiesare
heterogeneousandthereforedifficulttodetermineaccurately
theeffectofrTMScomparedtoshamrTMS.Nocompelling
evidenceofthemosteffectiveparameters.

Positive rTMSmoreeffective
thanShamrTMS

SR

PatientstreatedwithrTMSmorelikelytoshowaclinical
responsethanpatientstreatedwithshamtreatment.
DifferencesbetweenrTMSandShamdisappearatfollowup.

Positive rTMSmoreeffective
thanShamrTMS
Neutralforlongtermefficacy

SR

ResultsofmetaanalysissupporttheconclusionthatrTMShas
realantidepressanteffectsthatcanbelargeattimesbutare
generallymodest.Thereisvariabilityinthestudyoutcomesthat
cannotbeexplainedbysamplingerroralone.

Positive rTMSmoreeffective
thanShamrTMS

EBG

TherearesomestudiestosuggestthatrTMSisbetterthansham
treatmentbutthereislittleevidencetosuggestthatrTMSis
moreeffectivethanECT.

Positive rTMScomparedto
Sham.
Insufficientevidencetosuggest
rTMSismoreeffectivethanECT.

MDDorbipolar
INTERVENTIONandCOMPARATORS
ShamTMS
OUTCOMES:

Efficacy
Herrmann2009
Transcranialmagnetic
stimulation.

POPULATION/CLINICALINDICATION

MDDorBipolar

INTERVENTIONandCOMPARATORS

ShamTMS

OUTCOMES:

EfficacyandNNTS

Holtzheimer2001
Ametaanalysisof
repetitivetranscranial
magneticstimulationin
thetreatmentof
depression.
Psychopharmacology
bulletin.
Kennedy2009
CanadianNetworkfor
MoodandAnxiety
Treatments(CANMAT)
Clinicalguidelinesforthe
managementofmajor

22

POPULATION/CLINICALINDICATION
MDD
INTERVENTIONandCOMPARATORS

SHAMTMS

OUTCOMES:

Efficacy

POPULATION/CLINICALINDICATION

MDD

INTERVENTIONandCOMPARATORS
ShamTMS

OUTCOMES:

Report#0513002R11.3rTMSforDepressionTechnicalReport

depressivedisorderin
adults.
Kozel2002
Metaanalysisofleft
prefrontalrepetitive
transcranialmagnetic
stimulation(rTMS)to
treatdepression.
Lam2008
Repetitivetranscranial
magneticstimulationfor
treatmentresistant
depression:asystematic
reviewandmetaanalysis.

Efficacy

POPULATION/CLINICALINDICATION

SR

DoubleblindpublishedrTMsliteraturetodatesupportstheuse
ofleftprefrontalrTMStoimprovedepressivesymptoms.

Positive LeftprefrontalrTMS
moreeffectivethansham

SR

rTMSwithshorttreatmentduration(14)weekshasclearAD
effectsandiswelltolerated,buttheoverallresponseand
remissionratesarelowanditisunclearwhethertheeffectsare
sustained.

Insufficientevidencetoshow
rTMSismoireffectivethan
shamlongterm.

SR

InsufficientevidencetosuggestthatrTMSiseffectiveinthe
treatmentofdepression.Studiesthattestedpatientstwoweeks
postinterventionshowedthatanydifferencebetweenthetwo
groupshasdisappeared.

Insufficientevidencetodraw
conclusions

SR

rTMseffectivetreatmentfordepressionbutfurtherstudiesare
neededtodetermineifrTMSisaseffectiveasECT.

Neutral/InsufficientrTMSis
effectivefordepressionbutmore
evidenceisneededtodetermine
itseffectivenesscomparedwith
ECT.

SR

SomeearlymetaanalysessuggestedthatrTMSmaybeeffective
forthetreatmentofMDD(fortreatmentresistantMDDorasan
addontopharmacotherapyforpatientswhoarenotspecifically

Positive

Depressionordepressivedisorder
INTERVENTIONandCOMPARATORS

rTMSofleftprefrontalcortexvssham

OUTCOMES:
Efficacy
POPULATION/CLINICALINDICATION

TRD

INTERVENTIONandCOMPARATORS

rTMSvsSham

Positiveforshorttermefficacy

OUTCOMES:

EfficacyandNNT

Martin2003
Repetitivetranscranial
magneticstimulationfor
thetreatmentof
depression.Systematic
reviewandmetaanalysis.

POPULATION/CLINICALINDICATION

Anydiagnosisofdepression

INTERVENTIONandCOMPARATORS

rTMSvsSham

OUTCOMES:

Efficacy
McNamara2001
Transcranialmagnetic
stimulationfor
depressionandother
psychiatricdisorders

POPULATION/CLINICALINDICATION

MDD

INTERVENTIONandCOMPARATORS

rTMSvariousmethodsvsPlacebo

OUTCOMES:

EfficacyandNNT
MedicalAdvisory2004
Repetitivetranscranial
magneticstimulationfor

23

POPULATION/CLINICALINDICATION

MDD

INTERVENTIONandCOMPARATORS

Report#0513002R11.3rTMSforDepressionTechnicalReport

thetreatmentofmajor
depressivedisorder:an
evidencebasedanalysis

rTMSvssham,rTMSvsECT,rTMSvsdrugs,rTMSvs
psychotherapy

definedastreatmentresistant).Therearehoweverseveral
crucialmethodologicalconsiderationsandlimitationsinthe
includedstudiesthatwerenotcriticallyassessed.

OUTCOMES:

Efficacyandcosteffectiveness
MSAC2008
Repetitivetranscranial
magneticstimulationasa
treatmentformajor
depression.

POPULATION/CLINICALINDICATION

ECTvsrTMS;Nosignificantdifferencebetweentheresponse
ratesoftherTMSgroupandtheECTgroup.OverallrTMS
appearedtobelesseffectivethanECTinthetreatmentofmajor
depression,althoughthiswasnotstatisticallysignificant.
rTMSvsSham;Inthestudiesthathadafollowupperiod,the
responseratewasnotmaintainedbymostpatients(>75%)after
3months.

Inconclusiveevidenceto
determinelongtermeffect

SR

DeepTMSistheonlytherapythatprovidessubstantial
improvementinbothdepressivesymptomsandcognitive
performancesbutithaspoortolerability.rTMSprovidesbetter
tolerabilitythanECTbutitstherapeuticefficacyislower.

NegativeTherapeuticefficacyof
rTMSlowerthanECT.

SR

rTMSisanoveltreatmentwithuncertaintyarounditsefficacy
andsafety.

Inconclusive

SR

Overalltheanalysisshowedthattherewasnostrongevidence
forpossibleefficacyofrTMSforthetreatmentofdepression.

Inconclusive nostrongevidence
fortheuseofrTMSforthe
treatmentofdepression.

MDD

INTERVENTIONandCOMPARATORS

rTMSvsECT,rTMSvsSham.

OUTCOMES:

Efficacy
Minichino2012
ECT,rTMS,anddeepTMS
inpharmacoresistant
drugfreepatientswith
unipolardepression:A
comparativereview

POPULATION/CLINICALINDICATION
TRDandMDD

INTERVENTIONandCOMPARATORS
rTMSvsdeepTMSvsECT

OUTCOMES:

Efficacyandtolerability

NICE2007
Transcranialmagnetic
stimulationforsevere
depression.

POPULATION/CLINICALINDICATION

MDD

INTERVENTIONandCOMPARATORS

ShamTMSandECT

OUTCOMES:

Efficacy
RodriguezMartin2009
Transcranialmagnetic
stimulationfortreating
depression.

24

POPULATION/CLINICALINDICATION

depressiondiagnosedbyrecognisedcriteria

INTERVENTIONandCOMPARATORS

rTMSvsnothingrTMSvshamrTMSvspsychotherapyrTMSvs
psychotropicdrugsrTMSvsanyothertreatment

Report#0513002R11.3rTMSforDepressionTechnicalReport

OUTCOMES:

Efficacyandsafety
Schutter2010
Quantitativereviewof
theefficacyofslow
frequencymagneticbrain
stimulationinmajor
depressivedisorder
Schutter2009
Antidepressantefficacyof
highfrequency
transcranialmagnetic
stimulationovertheleft
dorsolateralprefrontal
cortexindoubleblind
shamcontrolleddesigns:
ametaanalysis
Slotema2010
Shouldweexpandthe
toolboxofpsychiatric
treatmentmethodsto
includeRepetitive
TranscranialMagnetic
Stimulation(rTMS)?A
metaanalysisofthe
efficacyofrTMSin
psychiatricdisorders.

POPULATION/CLINICALINDICATION
MDD
INTERVENTIONandCOMPARATORS

PositiveforrTMScomparedto
shamrTMSforthetreatmentof
depression.

SR

FastfrequencyrTMSovertheleftDPLPFCissuperiortosham
andmaybeaseffectiveasatleastasubsetofantidepressant
medications.Itiswelltoleratedbypatientswithfewside
effects.Limitationstotrialsduetoinsufficientblinding.

Positive rTMS(leftDPLPFC)
moreeffectivethansham
treatment.

SR

RepetitiveTMSismoreeffectivethanshamtreatmentinthe
treatmentofdepressionbutlesseffectivethanECT.
rTMSappearstobemoreeffectivewhengivenasa
monotherapy.

Positive rTMSmoreeffective
thanSham.

OUTCOMES:

Effiacy

POPULATION/CLINICALINDICATION

MDDwithoutpsychoticfeatures
INTERVENTIONandCOMPARATORS

HighFrequencyrTMSvsSham

OUTCOMES:

Efficacy

POPULATION/CLINICALINDICATION

mixedpsychdisorderswithsubgroupof'depression'
INTERVENTIONandCOMPARATORS

rTMSvsshamrTMSvsECT

OUTCOMES:
Efficacy

FindingssuggestthatslowfrequencyrTMScanimproveMDD
andadditionalclinicaltrialsaimedatoptimisingthetreatment
areworthwhile.

slowfrequencyrTMSvssham

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Report#0513002R11.3rTMSforDepressionTechnicalReport

NegativerTMScomparedto
ECT.

TableA4.2AMSTARRatingofIncludedSynthesizedStudies
AMSTARchecklistitems
Aare2003 Allan2011

Coutourier
2005

Gaynes
2011

Gross2007

Herrmann
2006

Herrmann
2009

Holtzheimer
2001

Kennedy
2009

Kozel2002

Lam2008

1.Wasan'apriori'designprovided?

2.Wasthereduplicatestudyselectionand
dataextraction?

3.Wasacomprehensiveliteraturesearch
performed?

4.Wasthestatusofpublication(i.e.,grey
literature)usedasaninclusioncriterion?

5.Wasalistofstudies(includedand
excluded)provided?

6.Werethecharacteristicsoftheincluded
studiesprovided?

7.Wasthescientificqualityoftheincluded
studiesassessedanddocumented?

8.Wasthescientificqualityoftheincluded
studiesusedappropriatelyinformulating
conclusions?

9.Werethemethodsusedtocombinethe
findingsofstudiesappropriate?

NA

NA

10.Wasthelikelihoodofpublicationbias
assessed?

NA

NA

11.Wastheconflictofinterestincluded?
AMSTARscore

26

3/9

2/11

5/11

11/11

5/11

1/11

3/11

3/11

1/9

4/11

8/11

Report#0513002R11.3rTMSforDepressionTechnicalReport

TableA4.3AMSTARratingofincludedsystematicReviewsContinued.
AMSTARchecklistitems
Martin2003 McNamara
2001

Medical
Advisory
2004

MSAC2008

Minichino
2012

NICE2007

Rodriguez
Martin2009

Schutter
2009

Schutter
2010

Slotema
2010

1.Wasan'apriori'designprovided?

2.Wasthereduplicatestudyselectionanddata
extraction?

3.Wasacomprehensiveliteraturesearch
performed?

4.Wasthestatusofpublication(i.e.,grey
literature)usedasaninclusioncriterion?

5.Wasalistofstudies(includedandexcluded)
provided?

6.Werethecharacteristicsoftheincludedstudies
provided?

7.Wasthescientificqualityoftheincluded
studiesassessedanddocumented?

8.Wasthescientificqualityoftheincluded
studiesusedappropriatelyinformulating
conclusions?

9.Werethemethodsusedtocombinethe
findingsofstudiesappropriate?

NA

NA

10.Wasthelikelihoodofpublicationbias
assessed?

NA

NA

11.Wastheconflictofinterestincluded?
AMSTARscore

27

7/11

4/11

6/9

9/11

2/11

4/9

10/11

6/11

4/11

3/11

Report#0513002R11.3rTMSforDepressionTechnicalReport

APPENDIX5:SUMMARYOFPRIMARYSTUDIES
TableA5.1PrimarystudiesofECTvsrTMSfordepression(studiesincludedinGaynes)
STUDY
PATIENTS
TREATMENTFAILURE

INPATIENTOR
OUTPATIENTSETTING
INTERVENTION&
COMPARATORS

TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTSOR
DRUGFREE?

28

Rosa2006
N=42AdultpopulationwithTRD.Unipolardepressive
disorder(HamD>=22)w/opsychoticsymptoms
Patientsspecificallyhadtwoormorepriortreatment
failureswithmedications

Grunhaus2003
N=40Adultpopulation.Unipolarmajordepression
(DSMIV).HAMD>=18
Patientshadoneormoretreatmentfailureswith
medications

Inpatientandoutpatient

Inpatientandoutpatient

rTMsvs.ECT

Duration
Activetxt24wks(rTMSptsnotrespondingafter2wks
switchedovertoECT).

rTMS:
Parameters:Frequency(Hz):10
Motorthreshold(%):100
Duration:Numberoftrains:25
Lengthoftrain(seconds):10
Intertraininterval:20
Pulsespersession:2500
Totalnumberofsessions:20over4wks

ECT:
%receivingbilateral:NR
Intensity:4.5timesthreshold
Numberofsessions(range,mean,SD):10(1.5)

rTMsvs.ECT

Duration
4weeksoftreatment

rTMS:
Parameters:Frequency(Hz):10
Motorthreshold(%):90
Duration:Numberoftrains:20
Lengthoftrain(seconds):6
Intertraininterval:60
Pulsespersession:1200
Totalnumberofsessions:5/wkover4wks

ECT:
%receivingbilateral:35
Intensity:2.5timesseizurethreshold
Numberofsessions(range,mean,SD):10.25(3.1)

Treatment

Treatment

rTMSvs.ECT

rTMS
Parameters:Frequency(Hz):10
Motorthreshold(%):110
Numberoftrains:20
Duration:Lengthoftrain(seconds):5
Intertraininterval:55
Pulsespersession:1000
Totalnumberofsessions:15
ECT:
%receivingbilateral:82
Intensity:1.5STforbilateralfrontotemporalECTand
2.5STforrightunilateralECT
Numberofsessions(range,mean,SD):range=210,
mean=6.3,SD=2.5

Duration
Primaryendpointat3weeksforrTMSandat
cliniciansdiscretionforECT,additionalfollowupat6
months
Treatment

ADs,antipsychotics,moodstabilizerswerediscontinued
whileantianxietymedswereallowed/initiatedas

Patientsinbothgroupsrequiredtotaperpsychotropic
medications.Onlylorazepramallowedregularly,

Patientscontinuedtheirusualmedicalcareandstable
psychotropicmedicationswereallowed.

Report#0513002R11.3rTMSforDepressionTechnicalReport

McLoughlin2007,Eranti2007,andKnapp2008
N=46AdultsreferredforECTduetomajordepressive
episode.
Priortreatmentfailurenotspecifiedbutclinical
situationsuggestshighprobabilityofpatientshaving
twoormorepriortreatmentfailureswith
antidepressants
Inpatient

PRIMARYOUTCOMES

ADVERSEEVENTS

RESULTS

29

needed
DepressionImprovement.HAMD17endpointscore,
mean(SD)atfourweeks.
ClinicalGlobalImpression
Suicidality,%
ECT:10.0
rTMS:9.1
rTMS:2ptsdevelopednewpsychologicalsymptoms
(i.e.,1=dissociativestate,1=hypomanicsymptoms)
andwereremovedfromstudy.
Withdrawalsduetoadverseevents,%
ECT:NR
rTMS:9.1
Responders,n(%)
ECT:6(20)
rTMS:10(45)
P=0.35
Remitters,n(%)
HamD17<=7
ECT:3(15)
rTMS:2(9)
P=0.65
InstrumentCGIEndpointscore,mean(SD)
2wk
ECT:4.0(1.0)
rTMS:3.7(1.1)
4wk
ECT:3.2(1.5)
rTMS:3.1(1.3)

benzodiazepineallowedonlyforsleepinduction
Improvementindepression.HAMD17endpointscore,
mean(SD).
Overall,%
ECT:NR"theECTgroupwashandledclinicallyandno
specialrecordingofsideeffectswasdone
rTMS:NR
Headache,%
ECT:NR
rTMS:15.0
Sleepdisturbance:
ECT:NR
rTMS:10%
HAMD17
Endpointscore,mean(SD):
Atweek2
ECT:15.9(6.6)
rTMS:14.7(8.8)
Atweek4
ECT:13.2(6.6)
rTMS:13.3(9.2)

Change,mean(SD)
Atweek2
ECT:9.6
rTMS:9.7
Atweek4
ECT:12.3
rTMS:11.1
Responders,n
Responsedefinedasadecrease50%or
HAMD17score10andaGAFrating60
ECT:12(60%)
rTMS:11(55%)
P=NS
Remitters,n
HAMD178
ECT:6(30%)

Report#0513002R11.3rTMSforDepressionTechnicalReport

ImprovementindepressionmeasuredbyHAMD.

Noadverseeventswerereported.

HAMD17
Analyzedn
ECT:22
rTMS:23
Endpointscore,mean(SD)
Endoftreatment
ECT:10.7
rTMS:18.5
P=0.002,effectsizeof1.44

Followupat6months
ECT:NR
rTMS:NR
P=0.93

Change,mean(SD)
Endoftreatment
ECT:14.1
rTMS:5.4
P=0.017

Responders,n
Endoftreatment
ECT:13(59.1%)
rTMS:4(17.4%)

rTMS:6(30%)
P=NS

CONCLUSIONS

EfficacyforrTMSissimilartothatofECT.Nostatistical
differencebetweenrTMSandECT.

COMMENTS

Country=Brazil

Theoverallresponseratewas58%(23outof40
patientsrespondedtotreatment).IntheECTgroup,12
respondedandeightdidnot;intherTMSgroup,11
respondedandninedidnot.Thus,patientsresponded
aswelltoeitherECTorrTMS.
Country=Israel

30

Report#0513002R11.3rTMSforDepressionTechnicalReport

P=0.005

Remitters,n
HAMD8
Endoftreatment
ECT:13(59.1%)
rTMS:4(17.4%)
P=0.005

Followupat6months*
ECT:6(27.4%)
rTMS:2(8.7%)

*only12ECTremitters
followedafterEndoftxt

rTMSislesseffectivethanECTforthetreatmentof
depression.

Country=UnitedKingdom

TableA5.2PrimarystudiesofECTvsrTMSfordepression(studiesNOTincludedinGaynes)
STUDY
Keshtkar2011
PATIENTS
n=73patientswithrefractorymajordepressivedisorder(DSMIV)
Patientshadalreadyreceived2fullcoursesofdrugtherapyduringthecurrentepisode.Theywereall
diagnosedasrefractorycases.
TREATMENTFAILURE
Patientsspecificallyhadtwoormorepriortreatmentfailureswithmedications
INPATIENTOR
Inpatient/outpatientstatusnotclearlyreported
OUTPATIENTSETTING
INTERVENTION&
rTMSvsECT
COMPARATORS

Parameters:90%MT
Location:LDPC
Duration:10days,10minsessions,408stimulationspersession.

ECTbilateralfor10sessions(3perweek),seizuredurationatleast20seconds
TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTSOR
DRUGFREE?
PRIMARYOUTCOMES
ADVERSEEVENTS

RESULTS

Treatment

Allpatientsonmedication
BDI&HDRS
Nosignificantadverseeffects(i.e.,seizure,mania)observed.
Headache(n=1rTMSgroup)
decreasedlevelsofconsciousnessandwithdrawalfromstudy(n=2ECTgroup)
BothECTandrTMSsignificantlyimproveddepressionandsuicidalbehaviorscores.However,ECTreduced
depressionandsuicidalbehaviorscoresmorethanrTMS.

BDI
HDRS

CONCLUSIONS

COMMENTS

31

pre

ECT
Mean(SD)
34.8(9.9)

rTMS
Mean(SD)

post

17.9(8.3)

pre

25.8(6.1)

21.0(7.5)

post

8.4(6.1)

15.1(5.6)

34.0(9.6)
26.5(9.2)

BDI
suicide

pre

1.4(1.0)

1.5(0.8)

post

0.5(0.7)

1.2(0.9)

HDRS
suicide

pre

2.3(1.1)

1.9(1.3)

Post

0.3(0.5)

1.4(1.2)

BothtreatmentsimprovedMDDintheshortterm,buttheantidepressantefficacyofECTwasgreaterthan
rTMS.Moreover,ECTledtogreaterreductionsinsuicidalbehaviorthanrTMS.Untilstrongevidenceforthe
safetyandefficacyofrTMSisavailable,furtherstudiesareneededtocompareECTandrTMSintermsof
thelongtermrelapserateandqualityoflife.
Country=Iran

Report#0513002R11.3rTMSforDepressionTechnicalReport

TableA5.3PrimarystudiesofrTMSvsShamrTMSfordepression(StudiesincludedinGaynes)
STUDY
PATIENTS
TREAMENTFAILURE

Boutros2002
N=21MajorDepression(HAMD25>=20)
Patientsspecificallyhadtwoormoreprior
treatmentfailureswithmedications
Outpatient

GarciaToro2001
N=40Unipolardepression(DSMIV)
Patientsspecificallyhadtwoormorepriortreatment
failureswithmedications
Inpatient/outpatientstatusnotclearlyreported

GarciaToro2006
N=30MDD,unipolar
Patientsspecificallyhadtwoormorepriortreatmentfailureswith
medications
Outpatient

rTMS:
Frequency(Hz):20
Motorthreshold(%):80
Numberoftrains:20
Lengthoftrain(seconds):2
Intertraininterval:58
Pulsespersession:800
Totalnumberofsessions:10over10days

Sham:
Coilangled90degreestoscalp
1wingoffigure8touchingscalp

rTMS:
Frequency(Hz):20
Motorthreshold(%):90
Numberoftrains:30
Lengthoftrain(seconds):2
Intertraininterval:2040
Pulsespersession:1200
Totalnumberofsessions:10in10days

Sham:
Edgewasplacedat90degrees

TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTSOR
DRUGFREE?

Treatment(augmentcurrenttherapies)

Treatment(augmentcurrenttherapies)

rTMS:
Frequency(Hz):1
Motorthreshold(%):110
Numberoftrains:30
Lengthoftrain(seconds):60
Intertraininterval:
Pulsespersession:1800
Totalnumberofsessions:10in2wks

High
Frequency(Hz):20
Motorthreshold(%):110
Numberoftrains:30
Lengthoftrain(seconds):2
Intertraininterval:20+5
Pulsespersession:1200
Totalnumberofsessions:10in2wks

Sham
Samebutwithcoilangling45degreesawayfromscalp
Treatment(augmentcurrenttherapies)

PRIMARYOUTCOMES

HAMD25

ADVERSEEVENTS

AdverseEvents
Overall,%

INPATIENTOR
OUTPATIENTSETTING
INTERVENTION&
COMPARATORS

32

Pts allowed to
psychotropicmeds

continue

all

current Medicationsallowed
stabletreatmentwithantidepressants
mostptstakingbenzodiazepines
HAMD17
BDI
CGIS
AdditionalComments:

Report#0513002R11.3rTMSforDepressionTechnicalReport

All pts continued (failed) AD medication and other psychotropic


meds
HAMD21
CGIS
Notreported

RESULTS

33

G1:(%ofptsreportingAEs)66.7
G2:55.6
Cognitiveimpairment,%
Difficultyconcentrating
(phase1only)
G1:25
G2:NR
Headache,%
"mostfrequentcomplaint"
%NR
Other:
scalptendernessatsiteofstimulation:
25%,11.1%
hearingproblem:
8.3%,NR;
diarrhoea:8.3%,NR
HAMD25
Endpointscore,mean
(SD)
At2weeks
G1:29.0
G2:28.11
Change,mean(SD)
G1:11.75
G2:6.22
P=NS
Responders,n
Definedas30%improvementonHamD
25
G1:7
G2:2
Responders,n(%)
Definedas50%
improvementonHamD
25
G1:3
G2:2
Relapse
Definedasbaseline

"most frequency side effects were scalp discomfort


andslightandtransitoryheadachesinapproximately
athirdofcases,nearlyallfromstimulationgroup"

HAMD17
Nanalyzed
G1:17
G2:18

Change,mean(SD)
Atweek1
G1:4.52(4.66)
G2:2.87(4.27)
P=0.297

Atweek2
G1:7.05(5.66)
G2:1.77(3.78)
P=0.003

2weekfollowup
G1:8.17(7.69)
G2:2.05(6.07)
P=0.013

Responders,n(%)
G1:5(25)

Report#0513002R11.3rTMSforDepressionTechnicalReport

HAMD21
Endpointscore,mean(SD)

Atweek1
G1:23.6(7.04)
G2:24.1(7.91)
G3:21.6(3.10)

Atweek2
G1:23.6(7.79)
G2:20.10(8.18)
G3:18.10(6.15)

Followup2weeksposttreatment
G1:23.67(5.55)
G2:20.88(7.26)
G3:16.9(7.0)

Change,mean(%change)
At1week
G1:1.5(5.9%)
G2:3.2(13.27%)
G3:3.4(13.6%)

CONCLUSIONS

COMMENTS

score10%
Of 6 active treatment responders included in
20week
followup
(no
continuing
intervention),4relapsed.Of1shamresponder
includedinthe20weekfollowup,1relapsed.

G2:1(5)
P=NR

BDI
Endpointscore,mean(SD)
NR

Change,mean(SD)
At2weeks
G1:1.35(4.44)
G2:2.75(4.28)
P=0.299

CGIS
Change,mean(SD)

Atweek2
G1:0.82(0.80)
G2:0.27(0.66)
P=0.04

2weekfollowup
G1:1.00(1.17)
G2:+0.27(0.95)
P=0.037

rTMS administered utilizing subthreshold


stimulation,a2weekcourseoftreatment,or
atotalsmallnumberofstimuli(800ysessionas
in the current study) may not be a clinically
effective approach and support the recent
reports suggesting that stronger stimulation
parameters or longer periods of stimulation
arenecessary.

Real, but not sham HFrTMS, was associated with a


significant decrease in the Hamilton Depression
Rating Scale, but only twelve patients decreased
more than 50%. Left prefrontal HFrTMS was
effectively
associated
with
antidepressant
treatment,althoughthesizeeffectwassmall

34

Report#0513002R11.3rTMSforDepressionTechnicalReport

At2weeks
G1:1.5(5.9%)
G2:7.2(26.37%)
G3:6.9(27.6%)
G1:vs.G2+G3(mean=7.05),P=0.048

Followupatweek4
G1:1.43(5.6%)
G2:6.42(23.51%)
G3:8.1(32.4%)
G1:vs.G2+G3,P=0.121

Responders,n(%)
G1:0(0)
G2:2(20)
G3:2(20)
P=NR
CGIS
Endpointscore,mean(SD)
At2weeks
G1:4.6(0.97
G2:3.8(1.48)
G3:3.9(0.99)

2weekfollowup
G1:4.75(1.16)
G2:4.00(1.15)
G3:3.7(1.57)
Comparison of the sham rTMS group with the overall group that
receivedactiverTMSrevealedstatisticallysignificantchangesonthe
Hamilton Rating Scale for Depression after 10 sessions. This study
demonstrated that combined 20+1Hz rTMS was effective, but no
additional advantages were obtained by focusing rTMS on areas
identified by single photon emission tomography as showing high
versuslowlevelsoffunctionalactivity.

TableA5.3PrimarystudiesofrTMSvsShamrTMSfordepression(StudiesincludedinGaynes)Continued.
STUDY
PATIENTS
TREAMENTFAILURE
INPATIENTOROUTPATIENT
SETTING
INTERVENTION&
COMPARATORS

TREATMENTORREMISSION
MAINTENANCE?
ONANTIDEPRESSANTSOR

35

Kauffmann2004
N=12MajorDepression(DSMIV)
Patientsspecificallyhadtwoormoreprior
treatmentfailureswithmedications
Inpatient/outpatient status not clearly
reported
rTMS
Frequency(Hz):1
Motorthreshold(%):110
Numberoftrains:2
Lengthoftrain(seconds):60
Intertraininterval:180
Pulsespersession:120
Totalnumberofsessions:10in10days

Sham
Sameasabovebutcoilwasheldata45
degreeanglefromskull

Treatment(augmentcurrenttherapies)

Padberg1999
N=18MajorDepression(DSMIV)
Patientsspecificallyhadtwoormorepriortreatment
failureswithmedications
Inpatient/outpatientstatusnotclearlyreported

Pallanti2010
N=60MajorDepression(DSMIV)
Patientsspecificallyhadtwoormorepriortreatmentfailureswith
medications
Inpatient/outpatientstatusnotclearlyreported

G1:Bilateral:
LocationofStimuli:1stappliedofrightDLPFC
thenleftDLPFC

RightDLPFC
Frequency:3140s
trainsat1Hz
Intensity:110%RMT
Interval:30sintertraininterval
Total420stimulipersession

LeftDLPFC
Frequency:205s
trainsat10Hz
Intensity:100%RMT
Interval:25sintertraininterval
Total1000stimulipersession

G2:Unilateral:
LocationofStimuli:RightDLPFC
Frequency:3140s
trainsat1Hz
Intensity:110%RMT
Interval:30sintertraininterval
Total420stimulipersession

Sham:LeftDLPFC
Samelengthoftimeasthe420stimulipersession.
Treatment(augmentcurrenttherapies)

rTMSHigh
Frequency(Hz):10
Motorthreshold(%):90
Numberoftrains:5
Lengthoftrain(seconds):5
Intertraininterval:30
Pulsespersession:250
Totalnumberofsessions:5/wk

rTMSLow
Frequency(Hz):0.3
Motorthreshold(%):90
Numberoftrains:10
Lengthoftrain(seconds):25
Intertraininterval:NR
Pulsespersession:75
Totalnumberofsessions:5/wk

Sham:
Same as high rTMS except coil angled at 90 degrees with 1 wing
restingonskull

Allowed to continue antidepressants but 83.3% of pts continued on their current [failed] AD Current[failed]antidepressantregimecontinued

Report#0513002R11.3rTMSforDepressionTechnicalReport

DRUGFREE?
PRIMARYOUTCOMES

advisedtodiscontinuebenzodiazepines&
moodstabilizers

HAMD21

ADVERSEEVENTS

Notreported

36

medication, others were not on a med and did not


startonepriortotrial
HAMD21
MADRS
Headache,%
G1:16.7
G2:16.7
G3:NR
FocalPainatrTMSsite
duringstimulations:50%,
33.3%,&0%.TherewerenoseriousAE.

Neuropsychologicalorexecutivefunctioning
VerbalMemoryTests
(included3learningtrialsand
aconsecutive,delayedrecall
taskafterdistraction):

Verbalmemoryperformance
improvedsignificantlyafter
fastrTMS

Learning
1.P=0.006
2.NA
3.FastrTMSimprovementP
=0.032,SlowrTMSP=NS,
Shamdecreasein
performanceP=0.09

Report#0513002R11.3rTMSforDepressionTechnicalReport

HAMD17
Cognitiveimpairment,%
Week0
G1:25
G2:20
G3:35
Week3
G1:15
G2:10
G3:30

Headache,%
Week0
G1:40
G2:30
G3:20
Week3
G1:5
G2:5
G3:5

Pain/burninginthescalp:
Week0
G1:50
G2:40
G3:15
Week3
G1:5
G2:0
G3:10
Anxiety
Week0
G1:20
G2:15
G3:15
Week3

RESULTS

HAMD21
Endpointscore,mean(SEM)
G1:11.29(3.17)
G2:11.80(1.93)
Change,mean(SD)
G1:10.57
G2:6.31
P=NR(ns)

Responders,n
G1:4(57%)
G2:2(40%)

Response2,n
HAMD21<10
G1:4(57%)
G2:1(20%)

HAMD21
Endpointscore,mean(SD)
G1:28.5(9.4)
G2:21.5(21.5)
G3:23.5(10.4)

Change,mean(SD)
G1:1.7
G2:5.2
G3:1.3
P>0.05

MADRS
Endpointscore,mean(SD)
graphonly
Groupxtime,P<0.1

CONCLUSIONS

Thisstudysupportsthetherapeuticpotential
of rTMS in the lowfrequency range of 1 Hz
on right prefrontal cortex for the treatment
ofrefractorymajordepression.

ThisstudyfurthersupportedthesafetyofrTMSbut
does not show any clinically meaningful
antidepressant efficacy of rTMS at 250 daily stimuli
over 5 days in pharmacotherapyrefractory major
depression.

37

Report#0513002R11.3rTMSforDepressionTechnicalReport

G1:0
G2:0
G3:5
HAMDreductionupto10%
G1:5
G2:4
G3:15
219.17,df6,Sig.=
0.04
HAMDreductionupto25%
G1:5
G2:6
G3:3
HAMDreductionupto50%
G1:6
G2:3
G3:0
HAMDreductionover50%
G1:4
G2:7
G3:2

NNT(Response)
rTMS1vs.sham10.00
(95%CI:3.13to8.39)

rTMS2vs.sham4.00
(95%CI:2.01to328.11)
Low frequency rightsided and sequential bilateral stimulation
showeddifferentantidepressantefficacyat3weeksandacrossthe
full duration of the study, only the unilateral method appearing
significantly more effective than sham at the end of the trial, and
correlatedtothehigherpercentofremitters(30%ofthegroupvs.
10% bilateral and 5% sham). Unilateral stimulation, but not
bilateral,showedhigherantidepressantefficacycomparedtosham
stimulation. The data suggest that right sided low frequency
stimulation may be a first line treatment alternative in resistant
depression.

TableA5.3PrimarystudiesofrTMSvsShamrTMSfordepression(StudiesincludedinGaynes)Continued.
STUDY
PATIENTS

Zheng2010
N=34MajorDepression(DSMIV)

TREAMENTFAILURE

Patientsspecificallyhadtwoormoreprior
treatmentfailureswithmedications
Inpatient/outpatientstatusnotclearlyreported

INPATIENTOROUTPATIENT
SETTING
INTERVENTION&COMPARATORS

TREATMENTORREMISSION
MAINTENANCE?
ONANTIDEPRESSANTSORDRUG
FREE?

38

Holtzheimer2004
N=15Patientswithtreatmentresistant
depression(musthavefailedatleasttwo
previousantidepressanttrialsduetolackof
responsetoanadequatetrial(definedbyATHF)
ormedicationintolerance)

MeetDSMIVcriteriaforamajordepressive
episodeduetoMDD(HAMD1718)
Patientsspecificallyhadtwoormoreprior
treatmentfailureswithmedications
Inpatient/outpatientstatusnotclearlyreported

Avery2006
N=68patientswithtreatmentresistantdepression(Failedto
respondtoorunabletotolerateatleast2+adequateADtrials
(definedbyscore3onATHF)

MeetDSMIVcriteriaforcurrentmajordepressivedisorder
(MDD)
HAMD1717andadecreaseofnomorethan20%between
screeningand1sttxtday
Patientsspecificallyhadtwoormorepriortreatmentfailures
withmedications
Outpatient
rTMSvsshamrTMS

4weeks(15sessions)oftxt,primaryassessment1weekafter
completionoftxts.
Responderswereevaluatedforrelapse2wksafterprimary
endpoint

Parameters
rTMS
Frequency(Hz):10
Motorthreshold(%):110
Numberoftrains:32
Lengthoftrain(seconds):5
Intertraininterval:2530
Pulsespersession:1600
Totalnumberofsessions:15in4wks

TRD

rTMSvsshamrTMS

Primaryendpointfollowing2weeksoftreatment
andfollowup

Parameters
rTMS
Frequency(Hz):10
Motorthreshold(%):110
Numberoftrains:32
Lengthoftrain(seconds):5
Intertraininterval:3060
Pulsespersession:1600
Totalnumberofsessions:10over2wks

ShamrTMS
Deliveredinsameanatomicallocationwith
identicalstimulationparameters,butwithlateral
edgeofcoilrotated45degreesawayfromscalp
Treatment

Augmentallpatientstakingescitalopram
from2+weeksbeforetrial

Allpatientsdiscontinued(failed)ADmedication
switchstudy*

rTMS
20 sessions of over the left DLPFC within four
weeks, at 110% stimulation intensity related to
restingmotorthreshold

15Hz,50trainsof4sduration3000stimuli/day,
28minpersession,20sessionsofstimulation
overa4weekperiod

Report#0513002R11.3rTMSforDepressionTechnicalReport

Treatment
Ptsencouraged,althoughnotrequired,todiscontinuecurrent
antidepressantmedication,sedatives,orbenzodiazepines;
(continuingADmedicationG1:31%vs.G2:27%;continuing

PRIMARYOUTCOMES

HAMD(17)
BDI

ADVERSEEVENTS

39

Effectiveness(antidepressanteffects)HDRS,
BDI
Safety
Tolerability
Nomajoradverseeventsatanypointinstudy.
Somesubjectsexperiencedmildpainwithactive
rTMS,buttreatmentsweregenerallywell
tolerated.

Neuropsychologicalorexecutivefunctioning
Bothgroupsperformedequallywellwith
exceptionofonemeasureofverbalmemory,
Trial7ofReyAuditoryVerbalLearningTest,in
whichsubjectsthatreceivedrTMSperformed
slightlybetter(rTMS:meanscore=12.7(2.1)vs.:
shammeanscore=12.0(2.3);P<0.05).
Noacutechangesinlevelofconsciousness,
orientation,orshorttermmemoryassociated
withanyrTMSorshamtreatmentssessions.

Therewerenomajoradverseeventsatanypoint
instudy.Somesubjectsexperiencedmildpain
withactiverTMS,buttreatmentsweregenerally
welltolerated.

Report#0513002R11.3rTMSforDepressionTechnicalReport

benzodiazapinesG1:26%vs.G2:24%)
Thosestoppingmedicationshadtobemedicationfreeforat
least2weeks
AllrespondersgivenADpostrTMStreatment(activeor
sham)
Response,remission(HAMD17,BDI)
cognitivefunctioning,adverseeffects(discomfortpainscale,
SAFTEE,GOAT,RAVLT,WAISR.COWAT)
Sitepainfirstsessionshamnone(0/33)vs.TMSgroup,41%
(14/35)15thsessionsham3%(1/30)vs.TMS33%(11/33).
Thediscomfortpainscaleratings(04)decreasedinTMS
groupinsubsequenttreatmentsessions,decreasingfroma
meanof1.89(1.02)atsession1to1.11(1.03)atsession15(t
=4.24,P<0.001).
Changesfrombaselinein128individualSAFTEEscores
emergingsymptomswereanalyzedbychisquareanalysesat
visits5,10,15,and16withaBonferronicorrection,there
werenosignificantdifferencesbetweenTMSandshaminany
ofemergingsymptoms.

Neuropsychologicalorexecutivefunctioning
NosigdifferencesinGOAT,RAVLT,WAISR,COWAT,and
th
SAFTEE;SUBGROUPANALYSIS11:At15 sessionpainTMS
33%vs,sham3%(P<0.05)nostatisticallysignificant(P>0.05)
timebytreatmentgroupinteractionsforanyof
neuropsychologicaltestmeasures.modelswererefitwithout
interactionterm,therewasnosignificanttreatmentgroup
maineffect(P>0.05)evidentforanyofneuropsychological
tests,indicatinggroupshadsimilarlevelsof
neuropsychologicalperformancecollapsedovertime.
Severalmeasuresshowedsignificantmaineffectsoftime,that
is,collapsedovergroups,therewassignificantimprovement
inindividualneuropsychologicaltestperformancesforboth
groups.
NoconfusionwasassociatedwithTMStreatments.GOAT
assessmentswerewellwithinnormalrangeandrangedfrom
98to100.Nosignificant(P>0.05)differencesbetweengroups
foranysession.

RESULTS

40

HAMD(17)
Endpointscore,mean
(SD)
G1:13.5(5.1)
G2:22.9(3.4)
Change,mean(SD)
G1:11.1
G2:1.7
P=NR
Responders,n
G1:12
G2:1

BDI
Yes
G1:rTMS
G2:Sham

Endpointscore,mean
(SD)
G1:13.5(5.1)
G2:19.8(5.1)

Change,mean(SD)
G1:7.6
G2:1.2

Treatment(rTMSvs.sham)didnotsignificantly
predictchangesindepressionseverity.Shorter
durationofepisodeandmorelifetimetreatment
trialssignificantlypredictedimprovementsinBDI
butnotHDRSscores.Datafromallsubjectswho
receivedactiverTMS(n14)showedthatthose
withadepressiveepisodedurationofshorter
than4yearshadameanHDRSdecreaseof52%
comparedto6%inthosewithanepisode
durationlongerthan10years.ActiverTMSwas
welltoleratedandwasnotassociatedwith
neuropsychologicaldecrementswhencompared
tosham.

HAMD17
Endpointscore,mean
(SD)
Atweek1
G1:18.0(1.2)
G2:18.0(2.7)
Atweek2
G1:14.6(3.2)
G2:15.3(3.0)
1weekfollowup
G1:18.8(2.5)
G2:17.6(2.1)
Change,mean(SD)
Atweek1
G1:4.7
G2:2.8
Atweek2
G1:8.1
G2:5.5
1weekfollowup
G1:3.9
G2:3.2
Allendpoints,P=NS
Responders,n(%)
Atweek1

Report#0513002R11.3rTMSforDepressionTechnicalReport

TheresponseratefortheTMSgroupwas30.6%(11/35),
significantly(p=.008)greaterthanthe6.1%(2/33)rateinthe
sham
group.TheremissionratefortheTMSgroupwas20%(7/35),
significantly(p=.033)greaterthanthe3%(1/33)rateinthe
sham
group.TheHDRSscoresshowedasignificantly(p<.002)
greaterdecreaseovertimeintheTMSgroupcomparedwith
theshamgroup.

HAMD17
Endpointscore,mean
(SD)
G1:15.7
G2:19.8
Change,mean(SD)
G1:7.8(7.8)
G2:3.7(6.3)
GroupxtimeP=0.002
Responders,n
G1:11(31.4%)
G2:2(6.1%)
P=0.008
Remitters,n
HAMD21<10
G1:7(20.0%)
G2:1(3.0%)
P=0.033
NoRelapse(at6mos),
N
G1:5
G2:Unknown(1
relapsed,1lossto
followafter3mosof
withoutrelapse)
BDI
Change,mean(SD)
G1:11.3(12.8)
G2:4.8(8.5)

CONCLUSIONS

Ourresultssupportthenotionthatmajor
depressivedisorderisaccompaniedbystate
dependentmetabolicalterations,especiallyin
myoinositolmetabolism,whichcanbepartly
reversedbysuccessfulrTMS.

COMMENTS

G1:0
G2:0
Atweek2
G1:2(28.6)
G2:1(12.5)
1weekfollowup
G1:0
G2:0
BDI
Endpointscore,mean
(SD)
Atweek1
G1:27.5(3.2)
G2:24.9(2.7)
Nosignificantantidepressanteffectswere
foundfor2weeksofrTMScomparedtosham.
AmongallsubjectsreceivingrTMSthosewitha
shorterdurationofthecurrentepisodeshowed
agreaterresponse.Patientsmayneedmore
than10treatmentstoobtainfullbenefitfrom
rTMS.
QualityRating:Fair

41

Report#0513002R11.3rTMSforDepressionTechnicalReport

Transcranialmagneticstimulationcanproducestatisticallyand
clinicallysignificantantidepressanteffectsinpatients
withmedicationresistantmajordepression.

QualityRating:Good
FairforKQ2andsubgroups11(smallnumberofpeople
followedforrelapse;usedasinglemeasureanddidnot
accountforadditionalmedicalconditions)

TableA5.3PrimarystudiesofrTMSvsShamrTMSfordepression(StudiesincludedinGaynes)Continued.

STUDY
PATIENTS

TREATMENTFAILURE

INPATIENTOR
OUTPATIENTSETTING
INTERVENTION&
COMPARATORS

42

PascualLeone1996
17patientswithmedicationresistant
depressionofpsychoticsubtype(DSMIIIR)
TRDdefinition:Atleastthreeepisodesof
depressionthathadbeenresistanttomultiple
medicationsdespitecombinationsandhigh
doses
Patientsspecificallyhadtwoormoreprior
treatmentfailureswithmedications

George2010
199patientswithtreatmentresistantdepression.
"Allpatientshadeitheronefailedantidepressant
failure,ormultipleintolerancetoantidepressant
medications."
DSMIVMDD,singleorrecurrent;HAMD2420;
Stableduring2wkmedicationfreeleadin
Patientsspecificallyhadtwoormorepriortreatment
failureswithmedications

Manes2001 andMoser2002
20patientswithMajor/MinorDepression(DSMIV)

Inpatientsandoutpatients

Outpatient

Outpatient

G1:HighFrequencyrTMS
G2:HighfrequencyrightrTMS(control)
G3:ShamleftrTMS
G4:ShamrightrTMS
G5:Realvertexstimulation(control)

Thestudywasdesignedasamultiplecorss
over,randomisedplacebocontrolledtrial.
ShamrTMSandstimulationofdifferent
corticalareaswereusedascontrols

Primaryendpointafter1weekoftreatment.
Totalstudyduration5months(3week
washoutbetweentreatments)

Strategy
Mixedwithingroupdifferences

Parameters
Frequency(Hz):10
Motorthreshold(%):90
Numberoftrains:20
Lengthoftrain(seconds):10

rTMSvsshamrTMS

rTMSParameters
Location:Leftprefrontalcortex
Frequency:10Hz
Intensity120%MT
Pulses:10pulsespersecondfor4seconds;3000per
session
Intertraininterval:26seconds
LengthofSession:37.5minutes(75trains)
FixedActiveTreatment
2 Numberofsessions:dailyweekday
sessions(15sessions)

Duration
2weeks(1weekoftreatment,1wkfollowupfollowinglast
treatment)
Interventions
G1:rTMS(N=10)
G2:ShamrTMS(N=10)

Parameters
rTMS
Frequency(Hz):20
Motorthreshold(%):80
Numberoftrains:20
Lengthoftrain(seconds):2
Intertraininterval:60
Pulsespersession:800
Totalnumberofsessions:5/wk

Report#0513002R11.3rTMSforDepressionTechnicalReport

Patientsspecificallyhadtwoormorepriortreatmentfailureswith
medications

TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTSOR
DRUGFREE?

PRIMARYOUTCOMES
ADVERSEEVENTS

RESULTS

43

Intertraininterval:60
Pulsespersession:2000
Totalnumberofsessions:5in5days
LeftShamCoilangeledat45degreeswith
edgeofcoilrestingonscalp
RightShamCoilangeledat45degreeswith
edgeofcoilrestingonscalp
Treatment

Attempts were made to taper medications.


Nine patients continued AD medication and
only4patientswereADfreeattheendofthe
study. All pts given nimodipine at a constant
doseof30mg/3xdaily

Reductionindepressivesymptoms(HAMD21,
BDI)
Nopatientsexperiencedanysignificant
undesirablesideeffects
AllpatientstoleratedrTMSwithout
complicationscomplicationswerenotrelated
tostimulationconditionanddidnotprompt
ptstorequestdiscontinuationofstudy.

LeftdorsolateralprefrontalcortexrTMS
resultedinasignificantdecreaseinscoreson

treatment

treatment

Antidepressantmedicationfree(2weekwashout)

Noantidepressantmedication

Remissionrates

PrimaryoutcomesHAMDatendoftreatmentandat1weekfollow
up
AdverseEvents
Headache,%
G1:40%
G2:0%
Other:
Localpain/localdiscomfort:10%/40%vs.0%/40%;anxiety:0vs10%
Neuropsychologicalorexecutivefunctioning
**somevariationinptsincludedintwosamplesbutreportedas
samestudybyauthors.#1564includesatleast1participant<50
yearsold,n=19
Otherneuropsychologicaltestsshowingnostatisticalsignificancein
eithergroup:TrailMakingTestA,StroopTest,WAISRdigitsymbol,
ControlledOralWordAssociation,Bostonnamingtest,sentence
repetition,ReyAuditoryVerbalLearningtest,&JudgementofLine
Orientation

Minimaladverseeffectsdidnotdifferbytreatment
arm
ManypatientsreceivingshamrTMSalsoreported
headache,sitediscomfort,andfacialtwitching,
commonadverseeffectsassociatedwithactiverTMS
thathaveraisedconcernsinFivepatients
discontinuedstudyparticipationbecauseofadverse
events,allofwhomwerereceivingactiveTMS(5.4%
dropoutrateowingtoadverseeventsintheactive
group).Fourofthe5patientsdroppedoutbecause
ofpainorheadacheandreceivedonlyasingleTMS
treatment.Onepatientreceived14treatmentsand
thendroppedoutbecauseofsyncope.Noseizures
orsuicidesoccurredTherewere2seriousadverse
eventswithoutlongtermsequelae:1patienthad
syncope(activerTMS)thattheinvestigatordeemed
unlikelyrelatedtothestudyand1patienthad
paranoidideation(shamTMS),possiblyrelatedto
thestudy.
Primaryefficacyanalysisrevealedasignificant
effectoftreatmentontheproportionofremitters

Report#0513002R11.3rTMSforDepressionTechnicalReport

TherewerenosignificantdifferencesinHDRSscoreseitherbefore
oraftertreatmentat7daysfollowup.Therewere3respondersto

CONCLUSIONS

COMMENTS

44

theHamiltondepressionratingscaleHDRS
(from25.2to13.8)andtheBeckQuestionnaire
BQ(from47.9to25.7).11ofthe17patients
showedpronouncedimprovementthatlasted
forabout2weeksafter5daysofdailyrTMS
sessions.

(14.1%activerTMSand5.1%sham)(P=.02).The
oddsofattainingremissionwere4.2timesgreater
withactiverTMSthanwithsham(95%confidence
interval,1.3213.24).Thenumberneededtotreat
was12.Mostremittershadlowantidepressant
treatmentresistance.Almost30%ofpatients
remittedintheopenlabelfollowup(30.2%
originallyactiveand29.6%sham).

G1:rTMS
G2:shamstimulation
Change,mean(SD)
At2weeks
G1:5.25
G2:+3.33
P<0.03

Ourfindingsemphasisetherowloftheleft
dorsolateralprefrontalcortexindepression,
andsuggestthatrTMSoftheleftdorsolateral
prefrontalcortexmightbecomeasafe,non
convulsivealternativetoelectrconvulsive
alternativetoelectroconvulsivetreatmentin
depression
QualityRating
Fair

DailyleftprefrontalrTMSasmonotherapy
producedstatisticallysignificantandclinically
meaningfulantidepressanttherapeuticeffects
greaterthansham.

QualityRating
Good

Report#0513002R11.3rTMSforDepressionTechnicalReport

activetreatmentandthreetoshamtreatmentandrespondershad
significantlygreaterfrontallobevolumethannonresponders
(p=.03)
HAMD
Endpointscore,mean
(SD)
At1week
G1:13.7(5.4)
G2:16.2(8.5)
1weekFollowup
G1:14.4(6.4)
G2:15.5(9.1)
Change,mean(SD)
Atweek1
G1:9
G2:6.5
1weekfollowup
G1:8.3
G2:7.2
Alltimepoints
P>0.66;ptswithMDD
onlyP=0.3919
Responders,n(%)
G1:3(30)
G2:3(30)
P=NS
Remitters,n
G1:2
G2:2
P=NR
Thesefindingssuggestthatthestimulationparametersusedinthis
studywereprobablyinsufficienttoproducetreatmentresponse
andthatfrontalatrophymayinterferewiththeeffectivenessof
rTMS

QualityRating
Fair

TableA5.3PrimarystudiesofrTMSvsShamrTMSfordepression(StudiesincludedinGaynes)Continued.
STUDY
PATIENTS

TREATMENTFAILURE
INPATIENTOROUTPATIENTSETTING
INTERVENTION&COMPARATORS

45

Stern2007
N=45patientswunipolarrecurrentmajordepressivedisorder(SCID&
DSMIV)HAMD21score20
AllpatientswerereferredforECThavingfailedanadequatecourseof
antidepressantmed
Patientsspecificallyhadoneormorepriortreatmentfailureswith
medications
Outpatient
HighfrequencyleftrTMSvslowfrequencyleftrTMSvslowfrequency
rightrTMSvsshamrTMS

Duration
10days(2wk)stimulationand2wkf/uforall4gps
Anadditional2wkofunblindedf/uwithgp1&3toassessfor
relapse.

rTMSparameters
HighFrequency:
Frequency(Hz):10
Motorthreshold(%):110
Numberoftrains:20
Lengthoftrain(seconds):8
Intertraininterval:52
Pulsespersession:1600
Totalnumberofsessions:10days

LowFrequencyLDLPFC:
Frequency(Hz):1
Motorthreshold(%):110
Numberoftrains:1
Lengthoftrain(seconds):1600
Intertraininterval:1
Pulsespersession:1600
Totalnumberofsessions:10days

LowFrequencyRDLPFC:
Frequency(Hz):1
Motorthreshold(%):110

Report#0513002R11.3rTMSforDepressionTechnicalReport

OReardon2007
N=325patientswithDSMIVdiagnosisofMDD
Singleepisodeorrecurrent,withacurrentepisodeduration3
CGISscore4,HAMD1720
Patientsspecificallyhadoneormorepriortreatmentfailureswithmedications
Outpatient/inpatientstatusnotclearlyreported
rTMS(n=165)vsshamrTMS(n=160)
Duration:6weeks;Shampatientscouldcrossoveraftr4weeksifnotresponding.

ParametersrTMS
Frequency(Hz):10
Motorthreshold(%):120
Numberoftrains:75
Lengthoftrain(seconds):4
Intertraininterval:26
Pulsespersession:3000
Totalnumberofsessions:5/weekfor46wks

TREATMENTORREMISSION
MAINTENANCE?
ONANTIDEPRESSANTSORDRUG
FREE?

PRIMARYOUTCOMES
ADVERSEEVENTS

RESULTS

46

Numberoftrains:1
Lengthoftrain(seconds):1600
Intertraininterval:1
Pulsespersession:1600
Totalnumberofsessions:10days
Treatment
Nopsychotropicmedicationswereallowed

HAMD21
AdverseEvents
9/45ptsreportedsevereheadaches(ptsbygroupNR);noseizures

Though8ptswithdrewduetoAE,only3ofthosewerelistedasw/d
duringactiveperiod.
Reportedintextasdroppedoutfollowingweek2.
NoneofthepatientsinGroup2(leftsided,lowfrequencyrTMS)or
Group4(shamrTMS)metthecriteriaforaclinicalresponse.However,
attheendofthe10daysofstimulation,60%ofthepatientsinGroup1
(leftsided,highfrequencyrTMS)and60%inGroup3(rightsided,low
frequencyrTMS)showedaclinicalresponse.
Similarly,whilenoneofthepatientsinGroup2orGroup4metthe
criteriaforremission,33.3%ofthepatientsinGroup1and10%ofthe
patientsinGroup3showedthislevelofimprovement

HAMD21
Endpointscore,mean
(SD)
Atweek1
G1:22.2(5.6)
G2:27.6(5.9)
G3:20.9(4.1)
G4:25.6(4.5)
Atweek2
G1:15.1(6)
G2:27.6(5.9)
G3:15.8(4.8)

Report#0513002R11.3rTMSforDepressionTechnicalReport

treatment
AllpatientswerefreeofADsandotherpsychotropicmedicationsdirectedattreating
depression.Ptsallowedonlylimiteduseofhypnotics,anxiolyticsfortxtemergent
insomniaoranxiety

ChangeinMADRSscore
Therewerenodeathsinthisstudy,andnoseizureswerereported.Duringtheacute
treatmentphase,16seriousadverseeventswerereported,9intheactiveTMSgroup
and7intheshamTMSgroup.Eventsreflectingdiseaserelatedexacerbationwerethe
mostcommonseriousadverseevents.Theseincludedsuicidality(1.9%withshamvs..6%
withactiveTMS),exacerbationofdepression(1.9%withshamvs..6%withactive),anda
singlesuspectedsuicidegesture(intheshamgroup).
ActiveTMSwassignificantlysuperiortoshamTMSontheMADRSatweek4(withapost
hoccorrectionforinequalityinsymptomseveritybetweengroupsatbaseline),aswellas
ontheHAMD17andHAMD24scalesatweeks4and6.Responseratesweresignificantly
higherwithactiveTMSonallthreescalesatweeks4and6.Remissionrateswere
approximatelytwofoldhigherwithactiveTMSatweek6andsignificantontheMADRS
andHAMD24scales(butnottheHAMD17scale).ActiveTMSwaswelltoleratedwitha
lowdropoutrateforadverseevents(4.5%)thatweregenerallymildandlimitedto
transientscalpdiscomfortorpain.

HAMD17
Analyzedn
G1:155
G2:146
Endpointscore,mean
(SD)
Atweek4
G1:17.4(6.5)
G2:19.4(6.5
Atweek6
G1:17.1(7.7)
G2:19.6(7.0)

G4:26.7(3.6)
Week1Followup
G1:12.8(5.7)
G2:26.4(2.3)
G3:15.3(6.4)
G4:26.5(2.3)
Week2Followup
G1:13.4(5.6)
G2:26.6(3.0)
G3:14.9(5.9)
G4:26.8(2.3)
Change,mean(SD)
Atweek2
G1:12.7
G2:0.0
G3:12.1
G4:0.7
%change,P=0.001
2weekfollowup
G1:0
G2:1.0
G3:13.0
G4:0.6
%change,P=0.00001
Responders,n
Atweek1
G1:0
G2:0
G3:0
G4:0
Atweek2
G1:2(50%)
G2:0(0%)
G3:5(50%)
G4:0(0%)
G1/G3vs.G2/G4
(P<0.0005)
1weekfollowup
G1:6(60%)

47

Report#0513002R11.3rTMSforDepressionTechnicalReport

Change,mean(SD)
Atweek2
G1:5.2
G2:3.5
Atweek6
G1:5.5
G2:3.3
P=0.005
Responders,n(%)
Atweek2
G1:18(11.6)
G2:13(8.9)
P>0.10
Atweek4
G1:32(20.6)
G2:17(11.5)
P<0.05

Atweek6
G1:38(24.5)
G2:20(13.7)
P<0.05
Remissionraten(%)
HAMD17<8
Atweek2
G1:5(3.2)
G2:3(2.1)
P>0.10
Atweek4
G1:110(7.1)
G2:9(6.2)
P>0.10
Atweek6
G1:24(15.5)
G2:13(8.9)
P=0.065
MADRS
Endpointscore,mean
(SD)

CONCLUSIONS

COMMENTS

G2:0(0%)
G3:6(60%)
G4:0(0%)
G1/G3vs.G2/G4
(P<0.0005)
2weekfollowup
G1:4(40%)
G2:0(0%)
G3:6(6%)
G4:0
G1/G3vs.G2/G4
(P<0.0005)
ThisstudydemonstratesthathighfrequencyrTMStotheleftDLPFC
andlowfrequencyrTMStotherightDLPFCarebotheffectiveinthe
treatmentofdepression,whileshamTMSandlowfrequencyrTMSto
theleftDLPFCareineffective.
QualityRating:Fair

48

Report#0513002R11.3rTMSforDepressionTechnicalReport

At4weeks
G1:27(11.1)
G2:29.8(10.1)
At6weeks
G1:26.8(12.8)
G2:30(10.8)
Change,mean(SD)
At4weeks
G1:5.8
G2:4.1

Transcranialmagneticstimulationwaseffectiveintreatingmajordepressionwith
minimalsideeffectsreported.Itofferscliniciansanovelalternativeforthetreatmentof
thisdisorder.
QualityRating:Good

TableA5.4PrimarystudiesofrTMSvsShamrTMSfordepression(studiesNOTincludedinGaynes)
STUDY
PATIENTS

Aguirre2011
n=34MajorDepressionpatients

TREATMENTFAILURE

Priortreatmentfailurenotspecifiedbutclinical
situationsuggestshighprobabilityofpatients
havingtwoormorepriortreatmentfailureswith
antidepressants
Outpatient

LFTMSvsshamLFTMS

Parameters:1Hz,110%MT
Location:RDPC
Duration:20sessionsof20x60strains,4wks
treatment+4wksfollowup

INPATIENTOR
OUTPATIENTSETTING
INTERVENTION&
COMPARATORS

TREATMENTOR
REMISSION
MAINTENANCE?
ONANTIDEPRESSANTSOR
DRUGFREE?
PRIMARYOUTCOMES
ADVERSEEVENTS

RESULTS

CONCLUSIONS

COMMENTS

Fitzgerald2012
n=67patientswithTRDdiagnosisofmoderateto
severedepression(>1517itemHAMD)+failureto
respondtoatlest2coursesofantidepressantmeds
foratleast6weeks
Patientsspecificallyhadtwoormoreprior
treatmentfailureswithmedications

Inpatient/outpatientstatusnotclearlyreported

Notstated

SBrTMS
vsstandardhighfrequencyleftsidedrTMSvssham
rTMS
Parameters:RS:15mintrainat1Hz(120%RMT)
LS:30trainsat10Hzfor5s(120%RMT)
Location:Bilateral
Duration:treatmentovera3weekperiod(5
Sessionsperweek)withafurther3week
comparisonofthetwoactivetreatments
Treatment

Asadjuvanttreatmenttopharmacotherapy

Mixed

DecreaseinscoresontheHamiltonDepression
RatingScale.
Mildheadachepaindiscomfort
increaseinanxiety
onepatienthadamildandshorthypomanic
episodeafterthesessions(hadnothadonebefore)
Bothgroupssignificantlyimproved,butno
statisticaldifferencesbetweenthem.
IntherealTMSgrouppatientsageinversely
correlatedwithimprovementofdepressive
symptomsattheendofthestudy(r=0683
p=0.002).PercentageofdecreaseinHamilton
scoreswasgreaterinsubjectsyoungerthan45
yearsoldvs.others(41.3+/22.6vs.15.1+/15.8;
t=2.8df=16,p=0.011).
OnlyyoungerpatientsbenefitedfromLFrTMSas
adjuvanttreatmenttoantidepressantsinthisstudy.

Scoresonthe17itemHamiltonDepressionRating
Scale(HAMD).
Noseriousadverseevents.
NoevidenceofcognitivedeteriorationinrTMS
groupsfrombaselinetoweek3.

Country=Spain

Inthethreeweekdoubleblindphaseofthetrial
therewasagreaterantidepressantresponseto
unilateralleftsidedrTMScomparedwithshamor
bilateralrTMS.Acrossthefullsixweeksofactive
rTMS,therewasalsoaconsistentpatternof
improvedresponseinunilateralleftcomparedto
bilateraltreatment.Responserateswerelowin
bothactivegroups.
Thisstudydoesnotsupportthehypothesisthat
sequentialbilateralrTMSismoreeffectivethan
unilateralhighfrequencyleftsidedrTMS
Country=Australia

49

Report#0513002R11.3rTMSforDepressionTechnicalReport

TableA5.4PrimarystudiesofrTMSvsShamrTMSfordepression(studiesNOTincludedinGaynes)Continued.
STUDY
PATIENTS

TREATMENT
FAILURE

INPATIENTOR
OUTPATIENT
SETTING
INTERVENTION&
COMPARATORS

TREATMENTOR
REMISSION
MAINTENANCE?
ON
ANTIDEPRESSANTS
ORDRUGFREE?
PRIMARY
OUTCOMES
ADVERSEEVENTS

RESULTS

CONCLUSIONS

COMMENTS

Jakob2008
n=36patientsdiagnosedwithmajordepression
moderatetosevereunipolardepression(DSMIV)>18
HAMD17,MADRSorBDI
Priortreatmentfailurenotspecifiedbutclinical
situationsuggestshighprobabilityofpatientshaving
twoormorepriortreatmentfailureswith
antidepressants
Inpatient/outpatientstatusnotclearlyreported

Triggs2010
n=48patientswithmajordepressivedisorder(DSMIV,
SCID)medicationresistantdepression

Patientsspecificallyhadtwoormorepriortreatment
failureswithmedications

Inpatient/outpatientstatusnotclearlyreported

UHFrTMS(50Hz)vsstandardrTMS(20Hz)vssham
2weektrial

Parameters:20Hz,100%MT
Location:notspecified
Duration:10sessions.2sduration,18sintervalover2
weeks

Parameters:50Hz,100%MT
Location:notspecified
Duration:10sessions.1sduration,59sintervalover2
weeks
Treatment

Treatment

Mixed

Onantidepressants

Tolerabilityandefficacy
HDRS,MADRS,BDIscorereduction
Treatmentsinthistrialwerefoundtobesafe

MoodHAMD,BDI,STAI

leftfrontalrTMSvsrightfrontalrTMSvsshamrTMS

Parameters:5Hz,100%MT
Location:RorLDPFC
Duration:10sessionsover2weeks.
50trainsof40stimul(2000persession),8sduration,
22sinterval

Nosubjectsexperiencedanyseriousadverseevents.
Adverseeventsconsistedmainlyofheadacheand
localizedscalpdiscomfort.Theseadverseeventswere
reportedinbothTMSandshamtreatmentgroups
Althoughwewereabletofindthat50HzrTMSissafe, no significant group differences in HAMD scores
we were not able to find clinical effects with the between subjects receiving left rTMS, right rTMS and
shamstimulation(F2,169=2.02;P=0.14).
chosenparametersafter2weeksoftreatment.
Although a clinical improvement after real rTMS
treatment at 20Hz and 50Hz was observed, this was
clinically indistinguishable from that seen in the
placebo arm. Furthermore after 2 weeks, high
frequency rTMS with 50Hz did not seem to be
superiortotheconventional20HzrTMS
Becausesafetydatafora50HzrTMStreatmentwere We found no statistically significant effect of 5 Hz
not available, we decided to restrict the treatment dorsolateral prefrontal rTMS, left or right, on
periodtodurationof2weeks.Becausewewereable depression. Our study suggests that the effects of the
todemonstratethatthisissafe,furtherRCTscanbe rTMS treatment paradigm on depression likely reflect a
conductedandareneededtoclarifywhetherfinding complexmixofplacebo,social,andsomaticstimulation
optimal stimulation parameters can help to create a effects in which laterality of simulation may be
substantialtreatmentefficacyinpatientswithmajor important.AlthoughwedidnotfindanrTMSeffect,we
depression
cannot rule it out, particularly when it is applied to the
lefthemisphere,andfuturestudiesneedtoconsiderthe
possiblevalueofrTMSappliedatothersites,possiblyat
differentfrequencies,andultimately,tailoredtospecific
patients.
Country=Germany
Country=USA

50

Report#0513002R11.3rTMSforDepressionTechnicalReport

APPENDIX6:QUALITYAPPRAISALS
TableA6.1Qualityappraisaltable(Aquirre,2011)
Study:Aguirre,I.,B.Carretero,etal.(2011)."Agepredictslowfrequencytranscranialmagneticstimulationefficacyinmajordepression."JAffectDisord130(3):466469
Descriptionofstudy:RandomizedControlTrial
Patient/population

Patientsolderthan18yearsfulfillingDSMIVcriteriaforunipolarmajordepression.

Ntotal=34.rTMS=19sham=15

Setting

Outpatients,nonpsychotic

Intervention/indicator

LFrTMS
Parameters:1Hz,110%MT
Location:RDPC
Duration:20sessionsof20x60strains,4wkstreatment+4wksfollowup.

Comparison/control

shamLFrTMS

Outcomes

DecreaseofscoresintheHamiltonDepressionratingscale.

InclusionCriteria

Patientsolderthan18fulfillingDSMIVcriteriaforunipolarmajordepression.Musthavefollowedatleastoneadequatetrialofantidepressantmedication(maximum
dosestoleratedwithinthetherapeuticrange,foratleastonemonth).Patientswererequiredtotakethesamemedicationforatleastonemonthpriortoinclusion
andtoandtoagreetocontinuedoingsoduringtheentirestudy.

ExclusionCriteria

ContradictionstorTMS,personalorfamilyhistoryofseizures,pastneurosurgicalprocedures,Implantedpacemakers,innerearprosthesis,medicationpumps,and
unstablemedicalconditions.Pregnantwomenorthoseofchildbearingpotentiallackinganeffectivecontraceptivemethod.Patientswithhighsuicidalrisk.

StudyValidity.
Isitclearthattherewerenoconflictsofinterestin
thewritingorfundingofthisstudy?

Yes

FundingforthisstudywasprovidedbytheIUNICSResearchInstituteandtheMateuOrfilaFoundation.Bothinstituteshadnofurther
roleinthestudydesign;inthecollection,analysisandinterpretationofdata;inthewritingofthereport;andinthedecisionto
submitthepaperforpublication.
Allauthorsdeclaredthattheyhadnoconflictsofinterest.

Doesthestudyhaveaclearlyfocusedquestion?

Yes

ThestudyaimstoanalyzetheefficacyofLFrTMSasacoadjuvanttopharmacologicaltreatmentinpatientswithmajordepression.

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IsaRCTtheappropriatemethodtoanswerthe
question?

Yes

Doesthestudyhavespecifiedinclusion/exclusion
criteria?

Yes

ContradictionstorTMS,personalorfamilyhistoryofseizures,pastneurosurgicalprocedures,Implantedpacemakers,innerear
prosthesis,medicationpumps,andunstablemedicalconditions.Pregnantwomenorthoseofchildbearingpotentiallackingan
effectivecontraceptivemethod.Patientswithhighsuicidalrisk.

Iftherewerespecifiedinclusion/exclusioncriteria,
weretheseappropriate?

Yes

Didthestudyhaveanadequatemethodof
randomization?

Notreported

Wasallocationtointerventiongroupconcealed?

Notreported

Werepatientsblindtotheinterventiongroup?

Yes

Authorsstatethatpatientswereblindtotheprocedure.Shamtreatmentwasperformedinawaythatmeantnomagneticfieldwas
producedbutsothattheapparatusstillmadesound.

Wereinvestigatorsandcareprovidersblindto
interventiongroup?

No

Thephsycianswhoadministeredtheprocedurewerenotblindtotheprocedure.Duetothenatureoftheinterventionisdifficultto
blindthecareproviders.

Methodofrandomisationnotreported.

Wereoutcomeassessorsblindtointerventiongroup? Yes

Anexternalassessorwasusedtoevaluatetheoutcomes.

Alloutcomesweremeasuredinastandard,validand Yes
reliableway?

Theoutcomewasmeasuredusingthe17itemHamiltonDepressionRatingScaleforeachofthepatientsintheinterventionand
controlgroup.

Wereoutcomesassessedobjectively?

Yes

Theoutcomewasmeasuredusingthe17itemHamiltonDepressionRatingScalebyanexternalassessorblindedtotheintervention.

Wereoutcomesassessedindependently?

Yes

Werethegroupssimilaratbaselinewithregardsto
keyprognosticvariables?

Yes

Thegroupreceivingactiveandshamtreatmentdidnotdiffersignificantlyingender,agebaseline,scoresorotherclinicalparameters.
Patientscomparableinsociodemographicparameters.Mostofthepatientsweretakingselectiveserotoninreuptakeinhibitorsand
mostweretakingthemincombinationwithbenzodiazepines.

Asidefromtheexperimentalintervention,werethe
groupstreatedthesame?

Yes

Therewasnoreporteddifferenceinthewaythepatientsweretreatedasidefromtheexperimentalintervention.Allsubjectswere

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outpatientsandnonpsychotic.
Weretheoutcomesmeasuredappropriate?

Yes

OutcomemeasurewasascorefromtheHamiltonDepressionRatingScale.

Wasthereasufficientdurationoffollowup?

Notreported

Wasthere20%dropout?

Yes

34Patientscommencedthestudy.Thereweretwodropouts.Oneintheactivetreatmentleftinthesecondweekduetotheonset
ofalcoholabusewithirregularattendanceatTMSsessions.Theother,inthecontrolgroupleftinthefourthweekduetothe
emergenceofmyeloma.Datafromthesepatientswasincludedinthestatisticalanalysis.

Wasthestudysufficientlypoweredtodetectany
differencebetweenthegroups?

No

Lackofstatisticalpowerduetoarelativelysmallsamplesize.

Ifstatisticalanalysiswasundertaken,wasthis
appropriate?

Yes

AtwotailedStudentsttestwasusedtocompareindependentandmatchedsamplesafterconfirmingthatthedistributionwas
normal.Whentheapplicationofparametrictestswasnotpossible,theMannWhitneytestwasused.Qualitativevariableswere
comparedusingthechisquareandfishersexacttest.

Wereallthesubjectsanalysedingroupstowhich
theywererandomlyallocated(intentiontotreat
analysis)?

Yes

Thereweretwodropoutsinthestudywhowerebothanalysedintheiroriginalgroupallocation.

Isthepaperfreeofselectiveoutcomereporting?

Yes

Plannedoutcomesweremeasured,HamiltondepressionscoresinLFrTMScomparedtoshamtreatment.

Other

Whatistheoverallriskofbias?

Low

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Results.
Bothgroupssignificantlyimproved,butnostatisticaldifferencesbetweenthem.
IntherealTMSgrouppatientsageinverselycorrelatedwithimprovementofdepressivesymptomsattheendofthestudy(r=0683p=0.002).PercentageofdecreaseinHamiltonscoreswasgreaterinsubjects
youngerthan45yearsoldvs.others(41.3+/22.6vs.15.1+/15.8;t=2.8df=16,p=0.011).

Seearticleforrelevanttablesandfigures
AuthorsConclusions.
OnlyyoungerpatientsbenefitedfromLFrTMSasadjuvanttotreatmenttoantidepressantsinthisstudy.
OurComments/Summary.
LowriskofBias.
Lackofstatisticalpowerduetosmallstudypopulation.
ItispossiblefromthestudythatthereisaninverserelationshipbetweenageandeffectivenessofLFrTMS,duetothesmallstudypopulationandlackofstatisticalpowertheseresultscannotbegeneralisedto
awiderpopulation.

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TableA6.2Qualityappraisaltable(Fitzgerald,2012)
Study:Fitzgerald,P.B.,K.E.Hoy,etal.(2012)."Adoubleblindrandomizedtrialofunilateralleftandbilateralprefrontalcortextranscranialmagneticstimulationintreatmentresistantmajordepression."
JAffectDisord139(2):193198.
Descriptionofstudy:RandomizedControlTrial
Patient/population

Patientswithtreatmentresistantdepressionwithascore(>1517itemHAMD)+failuretorespondtoatleast2coursesofantidepressantmedsforatleast6weeks

Ntotal=67

Setting

Notstated

Intervention/indicator

SBrTMSvsstandardhighfrequencyleftsidedrTMS

Comparison/control

ShamrTMStreatment

Outcomes

scoresonthe17itemHamiltonDepressionRatingScale(HAMD).

InclusionCriteria

Adiagnosisofmoderatetoseveredepression(scoringgreaterthan15onthe17itemversionoftheHamiltonDepressionratingscale(HAMD).

ExclusionCriteria

Bipolardisorder,asignificantactivemedical/neurologicalillness,oracontradictiontorTMS.Thosewithschizophreniaspectrumdisorders.

StudyValidity.
Isitclearthattherewerenoconflictsofinterestin
thewritingorfundingofthisstudy?

No

Theauthorsreportedthattherewerenoactualorpotentialconflictsofinterest

Doesthestudyhaveaclearlyfocusedquestion?

Yes

IsaRCTtheappropriatemethodtoanswerthe
question?

Yes

Doesthestudyhavespecifiedinclusion/exclusion
criteria?

Yes

Iftherewerespecifiedinclusion/exclusioncriteria,
weretheseappropriate?

Yes

Didthestudyhaveanadequatemethodof
randomization?

Notreported

Wasallocationtointerventiongroupconcealed?

Notreported

Werepatientsblindtotheinterventiongroup?

Yes

Wereinvestigatorsandcareprovidersblindto
interventiongroup?

No

Careproviderswerenotblindedtotheinterventionduetothenatureofthetreatment.

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Wereoutcomeassessorsblindtointerventiongroup? Yes

Raterswereblindtothetreatment.

Alloutcomesweremeasuredinastandard,validand Yes
reliableway?

Wereoutcomesassessedobjectively?

Yes

Wereoutcomesassessedindependently?

Notreported

Werethegroupssimilaratbaselinewithregardsto
keyprognosticvariables?

Yes

Asidefromtheexperimentalintervention,werethe
groupstreatedthesame?

Yes

Weretheoutcomesmeasuredappropriate?

Yes

Wasthereasufficientdurationoffollowup?

Notreported

Wasthere20%dropout?

No

Therewasa22%dropoutrate.

Wasthestudysufficientlypoweredtodetectany
differencebetweenthegroups?

No

Ifstatisticalanalysiswasundertaken,wasthis
appropriate?

Yes

Wereallthesubjectsanalysedingroupstowhich
theywererandomlyallocated(intentiontotreat
analysis)?

Yes

Isthepaperfreeofselectiveoutcomereporting?

Yes

Other

Whatistheoverallriskofbias?

Low

Results.
InthethreeweekdoubleblindphaseofthetrialtherewasagreaterantidepressantresponsetounilateralleftsidedrTMScomparedwithshamorbilateralrTMS.AcrossthefullsixweeksofactiverTMS,there
wasalsoaconsistentpatternofimprovedresponseinunilateralleftcomparedtobilateraltreatment.Responserateswerelowinbothactivegroups.
Seearticleforrelevanttablesandfigures

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AuthorsConclusions.
ThisstudydoesnotsupportthehypothesisthatsequentialbilateralrTMSismoreeffectivethanunilateralhighfrequencyleftsidedrTMS
OurComments/Summary.
Lowriskofbias,resultgeneralisabletopatientswithtreatmentresistantdepression.

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TableA6.3Qualityappraisaltable(Jakob,2008)
Study:JakobF,BrakemeierEL,SchommerNC,QuanteA,MerklA,DankerHopfeH,etal.Ultrahighfrequencyrepetitivetranscranialmagneticstimulationinunipolardepression.JournalofClinical
Psychopharmacol.2008;28(4):4746.
Descriptionofstudy:RandomizedControlTrial
Patient/population

Inpatientswithmoderatetosevereunipolardepression(DSMIVcriteria)

N=36

Setting

Unknown

Intervention/indicator

Parameters:20Hz,2000stimuli;trainduration,2seconds;interstimulusinterval,18seconds,100%MTor50Hz,2000stimuli;trainduration,1second;interstimulus
interval,59seconds;100%MT
Location:DLPFC
Duration:dailyrunsofrTMSfor5consecutiveworkingdayswithin1week

Comparison/control

ShamrTMS

Outcomes

HDRS,MADRSandBDI

InclusionCriteria

Inpatientswithmoderatetosevereunipolardepression(DSMIVcriteria)

ExclusionCriteria

Refertoapreviousstudy(seecitation9,pg.476)

StudyValidity.
Isitclearthattherewerenoconflictsofinterestin
thewritingorfundingofthisstudy?

Yes

ThisstudywassupportedbyagrantfromtheGermanMinistryofEducationandResearchandtheChariteResearchProgram.

Doesthestudyhaveaclearlyfocusedquestion?

Yes

TodeterminethetolerabilityandtheantidepressiveefficacyofanultrahighfrequencyrTMSwith50Hzascomparedwithastandard
intervention(20Hz)andaplacebo.

IsaRCTtheappropriatemethodtoanswerthe
question?

Yes

Doesthestudyhavespecifiedinclusion/exclusion
criteria?

Yes

Iftherewerespecifiedinclusion/exclusioncriteria,
weretheseappropriate?

Yes

Referenceismadetoapreviousstudy(seecitation9,pg.476)

Didthestudyhaveanadequatemethodof
randomization?

Notreported

Methodofrandomisationnotreported

Wasallocationtointerventiongroupconcealed?

Notreported

Methodofallocationwasnotreported

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Werepatientsblindtotheinterventiongroup?

Yes

patientswereblindedtotreatmenttype.

Wereinvestigatorsandcareprovidersblindto
interventiongroup?

Notreported

Wereoutcomeassessorsblindtointerventiongroup? Yes

clinicalraterswereblindedtotreatmenttype.

Alloutcomesweremeasuredinastandard,validand Yes
reliableway?

Seeoutcomesabove

Wereoutcomesassessedobjectively?

Notreported

Outcomesobjectivelyassessednotreported

Wereoutcomesassessedindependently?

Notreported

Outcomesindependentlyassessednotreported

Werethegroupssimilaratbaselinewithregardsto
keyprognosticvariables?

Yes

Atbaseline,thethreegroupsreceivingrealtreatmentdidnotdiffersignificantlyinsexdistributionorantidepressantmediation.

Asidefromtheexperimentalintervention,werethe
groupstreatedthesame?

Notapplicable

Thiswasarandomised,crossover,singleblindstudy.

Weretheoutcomesmeasuredappropriate?

Yes

Standardobjectivetoolsandmeasures

Wasthereasufficientdurationoffollowup?

NotReported

Wasthere20%dropout?

No

Wasthestudysufficientlypoweredtodetectany
differencebetweenthegroups?

Notapplicable

Ifstatisticalanalysiswasundertaken,wasthis
appropriate?

Yes

Wereallthesubjectsanalysedingroupstowhich
theywererandomlyallocated(intentiontotreat
analysis)?

Notapplicable

Thiswasarandomised,crossover,singleblindstudy

Isthepaperfreeofselectiveoutcomereporting?

Yes

Other

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Whatistheoverallriskofbias?

Moderate

Results.

AuthorsConclusions.
Althoughwewereabletofindthat50HzrTMSissafe,wewerenotabletofindclinicaleffectswiththechosenparametersaftertwoweeksoftreatment
OurComments/Summary.
Moderateriskofbias.

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TableA6.4Qualityappraisaltable(Keshtkar,2011)
Study:KeshtkarM,GhanizadehA,FiroozabadiA.Repetitivetranscranialmagneticstimulationversuselectroconvulsivetherapyforthetreatmentofmajordepressivedisorder,arandomized
controlledclinicaltrial.JECT.2011;27(4):3104.
Descriptionofstudy:RandomizedControlTrial
Patient/population

Patientswithmajordepressivedisorder(DSMIVcriteria)

N=73

Setting

Unknown

Intervention/indicator

rTMS;Parameters:90%MT
Location:leftDLPFC
Duration:10minutesessionfor10days

Comparison/control

BilateralECT(10sessions,3weekly)

Outcomes

BDIandHDRS

InclusionCriteria

Inpatientswithdysthymiaormajordepressivedisorderwithoutpsychoactivemedicationfor7days

ExclusionCriteria

Exclusion criteria were previous experience with transcranial magnetic stimulation, implanted devices such as a cochlear implant or pacemaker, history of
seizures,bipolardisorder,adiagnosisofsubstanceoralcoholabuse,ahistoryofsignificantheadtrauma,severemedicalconditionssuchashypothyroidism,a
historyofnonresponsetoearlierECT,andpregnancyorplanningtobecomepregnantduringthestudyperiod.Patientswhodidnotprovidewritteninformed
consentwereexcludedinthestudy.

StudyValidity.
Isitclearthattherewerenoconflictsofinterestin
thewritingorfundingofthisstudy?

Notreported

Doesthestudyhaveaclearlyfocusedquestion?

Yes

InthepresentstudyofpatientswithMDD,wehypothesizedthattheantidepressanteffectofbilateraltemporalECTandrTMS
would be similar. In addition, we compared the effects of rTMS and ECT on suicidal behavior. To the best of the authors
knowledge,thisisthefirststudythatexaminestheeffectsofthese2treatmentsonsuicidalbehaviorinpatientswithMDD

IsaRCTtheappropriatemethodtoanswerthe
question?

Yes

Doesthestudyhavespecifiedinclusion/exclusion
criteria?

Yes

Thestudylistsaninclusionandexclusioncriteria

Iftherewerespecifiedinclusion/exclusioncriteria,
weretheseappropriate?

Yes

Seeabove

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Didthestudyhaveanadequatemethodof
randomization?

No

Simplerandomizationbytossingacoinwasusedforeachtrialparticipant.

Wasallocationtointerventiongroupconcealed?

Notreported

Methodofallocationnotstated

Werepatientsblindtotheinterventiongroup?

No

Theparticipantswerenotblindtothetreatmenttheyreceived

Wereinvestigatorsandcareprovidersblindto
interventiongroup?

Notreported

Methodofblindingnotstated

Wereoutcomeassessorsblindtointerventiongroup? Notreported

Methodofblindingnotstated

Alloutcomesweremeasuredinastandard,validand Yes
reliableway?

Seeoutcomesabove

Wereoutcomesassessedobjectively?

Partial

TheBDIisaselfreportingquestionnaire,whereastheHDRSisadministeredinastructured,facetoface
Interview.

Wereoutcomesassessedindependently?

Partial

DatafortheHDRSwereprovidedbythepatientsthemselvesandalso,inmanycases,bytheirrelatives

Werethegroupssimilaratbaselinewithregardsto
keyprognosticvariables?

Yes

Asidefromtheexperimentalintervention,werethe
groupstreatedthesame?

Yes

Weretheoutcomesmeasuredappropriate?

Yes

Standardobjectivetoolsandmeasureswereused

Wasthereasufficientdurationoffollowup?

Unsure

Wasthere20%dropout?

Yes

.60patientscompletedthestudy

Wasthestudysufficientlypoweredtodetectany
differencebetweenthegroups?

Yes

ThepowerofthisstudyintheECTgroupfortheBDIscoreandHDRSwas0.999and0.999,respectively.ThepowerintherTMS
groupfortheBDIscoreandHDRSwas0.993and0.999,respectively

Ifstatisticalanalysiswasundertaken,wasthis
appropriate?

Yes

Generallinearmodel,repeatedmeasuresanalysis,wasconductedtoexaminethetrendforreductionofthescoresbetween
the2groups.ThepreinterventionBDIscore,HDRSscore,andsexwereconsideredasindependentfactors.

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Wereallthesubjectsanalysedingroupstowhich
theywererandomlyallocated(intentiontotreat
analysis)?

Yes

Isthepaperfreeofselectiveoutcomereporting?

Yes

Other

Whatistheoverallriskofbias?

Moderate

Results.
BothinterventionssignificantlydecreasedBDIscore.However,ECTdecreasedBDIscoremorethanrTMS.ElectroconvulsivetherapyandrTMSdecreaseddepressionmeasuredbyHDRS.Again,ECT
decreasedHDRSscoremorethanrTMS.BothECTandrTMSsignificantlydecreasedthesuicidalsubscalescoreofBDI.ElectroconvulsivetherapysignificantlydecreasedthescoremorethanrTMS
AuthorsConclusions.
Inconclusion,inasampleofadultpatientswithrefractoryMDD,ECTwasmoreeffectivethanrTMSinreducingsymptomsofdepression.Moreover,ECTwasmoreeffectivethanrTMSinreducingsuicidal
behaviorintheshortterm.UntilstrongevidenceforthesafetyandefficacyofrTMSisavailable,furtherstudiesshouldbedesignedtocompareECTandrTMSintermsofthelongtermrelapserateand
qualityoflife.
OurComments/Summary.
Moderateriskofbias

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TableA6.5Qualityappraisaltable(Triggs,2010)
Study:TriggsWJ,RicciutiN,WardHE,ChengJ,BowersD,GoodmanWK,etal.RightandleftdorsolateralprefrontalrTMStreatmentofrefractorydepression:arandomized,sham
controlledtrial.PsychiatryRes.2010;178(3):46774.
Descriptionofstudy:RandomizedControlTrial
Patient/population

Patientsbetween18and75yearsofagewithmedicallyresistantmajordepressivedisorder(DSMIV,SCID)over6years

n=48:rightrTMS(n=16);leftrTMS(n=18);rightshamrTMS(n=7);leftshamrTMS(n=7)

Setting

Notstated,conductedinUSA

Intervention/indicator

leftvsrightfrontalrTMS(5Hz,100%MT;10sessionsover2weeks;50trainsof40stimul(2000persession),8sduration,22sinterval)
Allpatientscontinuedtheirantidepressantmedicationthroughoutthestudyperiod

Comparison/control

RightshamrTMSvsleftshamrTMS

Outcomes

MoodHAMD,BDI,STAI

InclusionCriteria

Patientsbetween18and75yrsofagewithmedicallyresistantmajordepressionover6yearsMajorDepressiveDisorderaccordingtoDSMIVcriteriaandverifiedby
StructuredClinicalInterviewforDSMDisorders(SCID).Allpatientshadatotalscoreof18orhigherandascoreofatleast3onitemnumber1ofthe24item
HamiltonRatingScaleforDepression(HAMD)intwoseparatescreeningsessions.Allpatientshadfailedhistoricallytorespondtoatleasttwoseparatetrials
(minimumduration4weeks)oftherapeuticdosagesofantidepressantmedication(includingatleastoneSSRI)orwereintolerantofatleastthreedifferent
antidepressantmedications(includingatleastoneSSRI).Allpatientscontinuedtheirantidepressantmedicationthroughoutthestudyperiod.

ExclusionCriteria

Exclusionarycriteriaforparticipationincludedalifetimehistoryofschizophrenia,schizoaffectivedisorder,otherfunctionalpsychosis,rapidcyclingbipolarillness,
alcoholordrugabusewithinthepastyear;apositiveurinedrugtest;axisIIdiagnosisofClusterA(paranoid,schizoid,orschizotypal)orClusterB(antisocial,
borderline,histrionic,ornarcissistic)personalitydisorderormentalretardation.Additionalexclusionarycriteriaincluded:
I.Useofmedicationsthatmaylowerseizurethreshold(e.g.,metronidazole)iftheparticularmedicationcouldnotbestoppedoralteredwithoutaffectingthe
patient'smedicalcare.
II.Historyofneurologicalillness,epilepsyorseizuredisorder,intracranialtumor,ormajorheadtraumaleadingtolossofconsciousnessofanyduration.
III.Evidenceofcentralnervoussystemdiseasebasedonbaselinecompleteneurologicalexamination,EEGandcontrastenhancedcomputerizedtomographyor
magneticresonanceimagingofthebrain.
IV.Historyofimplantedpacemakerormedicationpump,metalplateinskull,ormetalobjectsintheeyeorskull.
VIII.Needforrapidclinicalresponseduetoconditionssuchasinanition,psychosis,orsuicidality(definedassuicideattemptduringthecurrentmajordepressive
episodeorhavingaspecificplanforcommittingsuicide).
IX.Amedicalconditionthatwasnotwellcontrolled,suchasdiabetesorhypertension,orconcomitantmedicalornutritionalproblemsnecessitatinghospitalization.
X.Useofanticonvulsantmoodstabilizers(e.g.,carbamazepine,valproicacid).
XI.Inabilitytopersonallygrantinformedconsent.

StudyValidity.
Isitclearthattherewerenoconflictsofinterestin
thewritingorfundingofthisstudy?

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Doesthestudyhaveaclearlyfocusedquestion?

Yes

IsaRCTtheappropriatemethodtoanswerthe
question?

Yes

Doesthestudyhavespecifiedinclusion/exclusion
criteria?

Yes

Iftherewerespecifiedinclusion/exclusioncriteria,
weretheseappropriate?

Yes

Didthestudyhaveanadequatemethodof
randomization?

Notreported

Subjectswererandomized1:1:1toreceiveleftfrontalrTMS,rightfrontalrTMS,orshamrTMS.Subjectsrandomizedtoreceivesham
rTMSwerefurtherrandomized1:1toeitherleftorrightfrontalshamrTMS.

Wasallocationtointerventiongroupconcealed?

Notreported

Werepatientsblindtotheinterventiongroup?

Yes

Wereinvestigatorsandcareprovidersblindto
interventiongroup?

Partial

OneofthelimitationsinherenttocontrolledstudiesofrTMSisthatitisimpracticaltoblindtheinvestigatoradministeringrealor
shamstimulation.Itisthereforepossiblethatsomeaspectoftheproposedtreatmentotherthanactualelectromagneticbrain
stimulation(e.g.,psychologicalinteractionwithanunblindedtreatinginvestigator)mightcontributetothetherapeuticeffectof
rTMS.InreviewingcontrolledtrialsofECT,CrowandJohnstone(1986)suggestedthatthepsychologicaleffectsofparticipationin
anelaboratephysicalprocedureareunderestimated.Weattemptedtocontrolforthisbydeliberatelylimitinginteractionbetween
unblindedtreatinginvestigatorsandpatients.Instead,ablindedpsychiatricresearchnurseaccompaniedallpatientstoalltreatment
sessions.Duringeachtreatmentsession,theresearchnurseengagedeachpatientinconversationabouttheirlivesandaddressed
patientexpectationsandexperienceregardingtheirparticipationinthisclinicaltrial(i.e.,possiblediscomfortsassociatedwitheither
realorsimulatedrTMS).

Wereoutcomeassessorsblindtointerventiongroup? Yes

Themoodassessmentswereadministeredbytrainedpsychiatryresearchnursesunawareofthepatient'streatmentgroup(realor
shamrTMS).

Alloutcomesweremeasuredinastandard,validand Yes
reliableway?

Wereoutcomesassessedobjectively?

Yes

Weratedmoodusingthe24itemHamiltonRatingScaleforDepression(HAMD)andthelongformoftheBeckDepressionInventory
(BDI).WeusedtheStateTraitAnxietyInventory(STAI)asasecondarymeasure...Themoodassessmentswereadministeredby
trainedpsychiatryresearchnursesunawareofthepatient'streatmentgroup(realorshamrTMS).

Wereoutcomesassessedindependently?

Notreported

Werethegroupssimilaratbaselinewithregardsto
keyprognosticvariables?

Yes

WefoundnosignificantdifferencesinbaselinecharacteristicsamongthesubjectsrandomizedtoreceiveleftrTMS,rightrTMSor
shamstimulation,orbetweenthesubjectsinthetwoshamgroups

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Asidefromtheexperimentalintervention,werethe
groupstreatedthesame?

Yes

Itisthereforepossiblethatsomeaspectoftheproposedtreatmentotherthanactualelectromagneticbrainstimulation(e.g.,
psychologicalinteractionwithanunblindedtreatinginvestigator)mightcontributetothetherapeuticeffectofrTMS.Inreviewing
controlledtrialsofECT,CrowandJohnstone,(1986)suggestedthatthepsychologicaleffectsofparticipationinanelaboratephysical
procedureareunderestimated.Weattemptedtocontrolforthisbydeliberatelylimitinginteractionbetweenunblindedtreating
investigatorsandpatients.Instead,ablindedpsychiatricresearchnurseaccompaniedallpatientstoalltreatmentsessions.During
eachtreatmentsession,theresearchnurseengagedeachpatientinconversationabouttheirlivesandaddressedpatient
expectationsandexperienceregardingtheirparticipationinthisclinicaltrial(i.e.,possiblediscomfortsassociatedwitheitherrealor
simulatedrTMS).

Weretheoutcomesmeasuredappropriate?

Yes

Wasthereasufficientdurationoffollowup?

Yes

Patientsfollowedupat1and3months

Wasthere20%dropout?

Yes

All48enrolledpatientscompletedtreatmentandposttreatmentevaluation
3werelosttofollowupat3months(thetreatmentgroupthatthesepatientsbelongedtowasnotspecified)

Wasthestudysufficientlypoweredtodetectany
differencebetweenthegroups?

No

notstatisticallysignificantbecauseofthelowerstatisticalpowerofoursmallerstudy
Itcanbeseenthatbecausetherewasalargertreatmenteffectinourstudy,wewouldlikelyhavehadstatisticalpowerto
demonstratesignificanceatoneoftwoendpointsatanalphalevelof0.025with80%probabilitywith2230subjectsintheleftrTMS
groupand2230subjectsintheleftshamgroup.therewere18patientsintheleftrTMSgroups,and7intheleftshamrTMS
group

Ifstatisticalanalysiswasundertaken,wasthis
appropriate?

Yes

MeansandS.D.swerecomputedforcontinuousbaselinevariablesandoutcomesandpercentageswerecomputedforbinary
variablesforthesham,rightrTMSandleftrTMSgroups.Thebalanceofbaselinecharacteristicsacrossthreegroupswascompared
usingANOVAforcontinuousvariablesandchisquaredandFisher'sexacttestsforcategoricalvariables.Alinearmixedeffectmodel
wasusedtoevaluatetheeffectsofstudyintervention(leftrTMS,rightrTMS,orsham)onHAMDscoresbycontrollingthebaseline
HAMDscoresandtakingintoaccountthecorrelationbetweenrepeatedmeasurementswithinsubject.Themodeladequacywas
assessedwithstandardmodeldiagnostics.AnalyseswereconductedinSAS(SASInstitute,Cary,NorthCarolina).Posthocanalyses
werecarriedoutsimilarly.

Wereallthesubjectsanalysedingroupstowhich
theywererandomlyallocated(intentiontotreat
analysis)?

Yes

Thereshouldnotbeanycrossoversinablindedshamcontrolledstudy

Isthepaperfreeofselectiveoutcomereporting?

Yes

Other

Whatistheoverallriskofbias?

Low

LowMostofthecriteriahavebeenfulfilledandthosecriteriathathavenotbeenfulfilledareunlikelytoaffecttheconclusionsof
thestudy.

Results.

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Mean(S.D.)reductionsintheHAMD24frombaselineto3monthswerenotsignificantlydifferentbetweenrTMSandshamtreatmentgroups.However,rightcranialstimulation(shamorrTMS)was
significantlymoreeffectivethanleftcranialstimulation(shamorrTMS)(P=0.012).Mean(S.D.)reductionsintheHAMDfrombaselineto3monthswere:left:28.1(5.36)to19.2(11.2);andright27.2(4.2)
to11.5(9.4).
3.ResultsWefoundnosignificantdifferencesinbaselinecharacteristicsamongthesubjectsrandomizedtoreceiveleftrTMS,rightrTMSorshamstimulation,orbetweenthesubjectsinthetwoshamgroups
(Table1).Noneofoursubjectsexperiencedanyseriousadverseevents.All48subjectscompletedthe2weekcourseofrTMStreatment(Fig.1).Adverseeventsconsistedmainlyofheadacheandlocalizedscalp
discomfort.TheseadverseeventswerereportedinbothTMSandshamtreatmentgroupsaspresentedinTable2.Wedidnotasksubjectsiftheythoughttheywerereceivingeitherrealorshamstimulation
becausewedidnotwantsubjectstofocustheirattentiononthisissue.However,previousstudies(Rossietal.,2007;Mennemeieretal.,2009)involunteersnavetoTMSsuggestthatthistechniqueprovides
effectivesubjectblinding.
MeanresultsfortheHAMD,BDIandSTAIarepresentedinTable3.ThelinearmixedmodelfortheHAMDasthedependentmeasurerevealednosignificantgroupdifferencesinHAMDscoresbetweensubjects
receivingleftrTMS,rightrTMSandshamstimulation(Fig.2;F2,169=2.02;P=0.14).
Fig.2andTable3suggestthatpatientsreceivingrightrTMStendedtoimprovemorethanpatientsreceivingleftrTMSorshamstimulation,butalsothatpatientsreceivingrightsidedshamstimulation
improvedmorethanpatientsreceivingleftsidedshamstimulation.Thedifferencebetweentheshamgroupswasstatisticallysignificantat1month(P=0.022)and3months(P=0.0053)aftercompletionof
treatment.Thesetwogroupswerecomparableatbaseline(Tables1and3).AposthoclinearmixedmodelcomparingrightsidedandleftsidedstimulationcollapsedacrossbothrTMSandshamstimulation
typesalsoshowedasignificantdifference(F1,169=6.45,P=0.012),suchthatonaveragepatientsreceivingrightsidedstimulation(rTMSorsham)achievedHAMDscoresabout8pointslowerthanpatients
receivingleftsidedstimulation(rTMSorsham).ThisdifferenceisillustratedinFig.3.WefoundthatMEPthresholdsdecreasedslightlyafterrTMS(0.971.30;Pb0.0001)butnotaftershamstimulation(0.14
0.55;Pb0.37).ThechangeinthresholdswassignificantlydifferentbetweenrTMSandsham(P=0.0036).
Seearticleforrelevanttablesandfigures
AuthorsConclusions.
LeftrTMSachievedareductioninHAMD9.5pointsgreaterthanthatachievedbyleftsham,abenefitgreaterthanthatreportedinarecentmulticenterPhaseIIItrialofrTMS(O'Reardonetal.,2007),albeit
notstatisticallysignificant.Theseresultssuggestthatsomatosensorystimulithatrepeatedlyengagethelefthemispheremaybeimportanttotheachievementoftherapeuticeffect.
OurstudysuggeststhattheeffectsoftherTMStreatmentparadigmondepressionlikelyreflectacomplexmixofplacebo,social,andsomaticstimulationeffectsinwhichlateralityofsimulationmaybe
important.AlthoughwedidnotfindanrTMSeffect,wecannotruleitout,particularlywhenitisappliedtothelefthemisphere,andfuturestudiesneedtoconsiderthepossiblevalueofrTMSappliedatother
sites,possiblyatdifferentfrequencies,andultimately,tailoredtospecificpatients
OurComments/Summary.
Thisstudyhasalowriskofbias.
Overallthisstudywasconductedwell.Thelackofinformationaboutthemethodofrandomisationusedmakesitdifficulttodetermineifrandomisationwasdoneeffectively,however,thesimilarityofthe
groupsatbaselineshowthatanadequatemethodmayhavebeenused.
Despitethelowriskofbias,thesmallsamplesizemakesthisstudyunderpoweredtoconfidentlydetectadifferenceinoutcomesbetweengroups,thereforetheresultsshouldnotbegeneralised.

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APPENDIX 7: QUALITYAPPRAISALGAYNESREPORT
TableA7.1Criticalappraisaltable(Gaynes,2011)
Study:Gaynes,B.N.,L.J.Lux,etal.(2011).NonpharmacologicInterventionsforTreatmentResistantDepressioninAdults.ComparativeEffectivenessReviewNo.33.AHRQPublicationNo.11EHC056EF.
Rockville,MD,AgencyforHealthcareResearchandQuality.
Descriptionofstudy:SystematicReview
Patient/population

PatientswithMajordepressiveDisorder.

64studies
Pleasenoteallthesestudiesmaynothaveassessedouroutcomesofinterest.

Setting

Inpatientandoutpatient

Intervention/indicator
Comparison/control

Reference

Intervention

Comparison

Rosaetal.,2006

rTMS

ECT

rTMS

ShamTreatment

Grunhausetal.,2003
Hansenetal.,2010
McLoughlinetal.,2007,Erantiet
al.,2007,andKnappetal.,2008
Boutrosetal.,2002
GarciaToroetal.,2001
GarciaToroetal.,2006
Kauffmannetal.,2004
Padbergetal.,1999
Pallantietal.,2010
Zhengetal.,2010
Holtzheimeretal.,2004
Averyetal.,2006
PascualLeoneetal.,1996
Georgeetal.,2010
Manesetal.,2001andMoseret
al.,2002
Sternetal.,2007
O'Reardon,2007

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Pleasenotesomeofthesestudiesmayhaveusedcomparatorsnotrelevanttoourquestion.

Outcomes

Responseandremission,Maintenanceofremssion,safetyadverseeventsandadherence,healthrelatedoutcomes

InclusionCriteria

RCTscomparingnonpharmacologicaltreatments,RCTscomparingnonpharmacologicaltreatmentstopharmacologicaltreatment.Observationalstudies.

ExclusionCriteria

Nomajorexclusioncriteriareported.

StudyValidity.
Isitclearthattherewerenoconflictsofinterestinthe Yes
writingorfundingofthisreview?

Noneoftheinvestigatorshasanyaffiliationsorfinancialinvolvementthatconflictswiththematerialpresentedinthisreport

Doesthereviewhaveaclearlyfocusedquestion?

Thereporthasasetofkeyquestionsitwishestoanswer.

Yes

Isasystematicreviewtheappropriatemethodto
answerthequestion?

Yes

Doesthereviewhavespecifiedinclusion/exclusion
criteria?

Yes

Iftherewerespecifiedinclusion/exclusioncriteria,
weretheseappropriate?

Yes

Doesthereviewdocumentacomprehensivesearch
strategy?

Yes

Werereviewersblindtoauthors,institutionsand
affiliations?

Not
reported

Were2ormoreindependentreviewersusedfor:
Yes
1. applicationofinclusioncriteriatoassesseligibility

ofstudies?

2.

extractionofdatafromstudyreports?

Yes

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3.

appraisalofstudyquality?

Yes

Werethestrengthsandlimitationsofincludedstudies
andpotentialimpactontheresultsdiscussed?

Yes

Wasthevalidityofincludedtrialsappraisedusing
appropriatecriteria?

Yes

Isthereasummaryoftheresultsofindividualstudies? Yes

Ifmetaanalyseswereconducted,wasitreasonableto Yes
doso?

Ifmetaanalyseswereconducted,wasitdone
appropriately?

Yes

Other

Whatistheoverallriskofbias?

Low

Results.
From a total of 2,754 citations retrieved, we ultimately identified 79 good, fair, or poorquality articles in this review; they represent 64 studies. Of these studies, there were 17 headtohead RCTs (19
articles):7studies(9articles)wereheadtoheadRCTsofanonpharmacologicinterventionversusanonpharmacologicintervention;3wereheadtoheadRCTSofanonpharmacologicinterventionversusa
pharmacologicone;and7wereheadtoheadstudiesofapharmacologicversuspharmacologicintervention.Further,therewere38additionalRCTs(50articles)thatwereshamorplacebocontrolled,and2
observationalstudies(2articles).Weexcluded8studies(8articles)becauseofpoorquality.Wepresentevidencethatallowscomparisonofthefournonpharmacologictreatmentsofinterest(ECT,rTMS,
VNS, and psychotherapy) stratified by tiers of evidence. Comparative clinical research on nonpharmacologic interventions in a TRD population is in its infancy. Many clinical questions about efficacy and
effectivenessremainunanswered.Thetextbelowpresentsourprincipalresults;summarytables(AJ)documentTier1TRDfindingsformajorcomparisonsandoutcomesforeachkeyquestion,givethe
overallstrengthofevidenceforthatcomparison,andoutlinekeyfindings.Wereportfirstondirectevidence(headtoheadcomparisons)andthenonindirectevidence(e.g.,trialsusingcontrols).Ifaspecific
comparisondidnotinvolveaTier1populationbutdidhavetrialsconductedinaTier2and/orTier3population,wehavelisteditinthistable,notedNoeligiblestudiesidentified,andaddedafootnote
indicatingthepresenceofatleastonesuchstudy.ThegreatestvolumeofevidenceisforECTandrTMS;however,thedirectcomparativeevidenceabouteventhesetreatmentsisquitelimited.Available
indirectevidenceprimarilyinvolvesrTMS;alittleinformationisavailableonVNSandpsychotherapy(chieflyforefficacyandadverseevents),andnoavailableindirectevidenceinvolvesECT.Giventhelimited
numberofTier1studiesincompletereportingonthenumberoffailedtreatmentattempts,wewereunabletostratifyouroutcomesbythenumberoftreatmentfailureswithinTier1.

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Seearticleforrelevanttablesandfigures
EfficacyofNonpharmacologicInterventionsAgainstOtherNonpharmacologicInterventions(KQ1a)

DirectEvidence
TheavailableheadtoheadliteratureconcerningtheefficacyofthenonpharmacologicinterventionsforTier1TRDislimitedtotwofairtrials(bothinMDDonlypopulations).OnecomparedECTand
rTMS,andtheothercomparedECTandECTplusrTMS.Theyshowed,withlowstrengthofevidence,nodifferencesbetweentreatmentoptionsfordepressiveseverity,responserates,andremission
rates.Notrialinvolvedadirectcomparisonofpsychotherapywithanothernonpharmacologicintervention.

IndirectEvidence
Weidentifiedtrialsthatcomparedanonpharmacologicintervention,generallyrTMS,VNS,orpsychotherapy,withacontrolorshamprocedureinTier1populations.WeidentifiednoeligibleECT
versuscontrolstudies.Thenumberofthesetrialswiththesameorsimilarcontrolgroupwasverysmall,sowecouldnotpoolthemquantitatively.Wecould,however,assessthepotentialbenefitsof
nonpharmacologicinterventionsversuscontrolsbycalculatingmeanchangesindepressiveseverity,relativerisksofresponse,andrelativerisksofremission.rTMSwasbeneficialrelativetocontrols
receiving a sham procedure for all three outcomes(severity of depressive symptoms, response rate, remission rate). rTMS produced a greater decrease in depressive severity (high strength of
evidence). Specifically, rTMS averaged a decrease in depressive severity measured by the Hamilton Rating Scale for Depression (HAMD) of more than 5 points relative to sham control, and this
changemeetstheminimumthresholdofthe3pointHAMDdifferencethatisconsideredclinicallymeaningful.ResponseratesweregreaterwithrTMSthansham(alsohighstrengthofevidence);
thosereceivingrTMSweremore
thanthreetimesaslikelytoachieveadepressiveresponseaspatientsreceivingashamprocedure.Finally,rTMSwasalsomorelikelytoproduceremissionthanthecontrolprocedure(moderate
strengthofevidence);patientsreceivingrTMSweremorethansixtimesaslikelytoachieveremissionasthosereceivingthesham.IntheonlyotherTier1comparison,onegoodqualityVNSversus
shamcontroltrial(amixedMDD/bipolarpopulation)reportednodifferencesbetweenthegroupsasmeasuredbyachangeindepressiveseverityorresponserates(lowstrengthofevidence).

EfficacyofNonpharmacologicInterventionsComparedWithAntidepressantPharmacotherapies(KQ1b)
DirectEvidence
Theavailableheadtoheadliteratureconcerningtheefficacyofthenonpharmacologicinterventionscomparedwithpharmacologictreatment(inthiscase,paroxetine)forTier1trialsislimitedto
onefairtrial(amixedMDD/bipolarpopulation).ECTproducedasignificantlygreaterdecreaseindepressiveseverity(9pointsbyHAMD)andsignificantlybetterresponserates(71percentvs.28
percent)thanmedications(lowstrengthofevidence).

IndirectEvidence
Indirectevidenceaboutproceduresorpsychotherapy(vs.shamornonpharmacologic
controls)waspresentedaboveaspartofKQ1.Weattemptedtodeterminemeanchangesindepressiveseverity,relativerisksofresponse,andrelativerisksofremissionforpharmacologicversus
controlstudiestoallowacomparison
with similar outcomes in the nonpharmacologic versus control trials (KQ 1a, indirect). However, we found no comparable, common control groups (i.e., patients not receiving a moodrelated
medication)toallowsuchcomparisons.Instead,wedeterminedmeanaverageoutcomesforpharmacologictreatments. Forswitchingstrategies,meanpharmacologicresponseratesaveraged39.8
percent(95%CI,30.7%to48.9%)andmeanremissionratesaveraged22.3percent(95%CI,16.2%to28.4%).Foraugmentation,meanresponseratesaveraged38.1percent(31.0%to45.3%)and

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meanremissionratesaveraged27.2percent(20.4%to34.0%).Formaintenancestrategies,meanresponseratesaveraged27.3percent(19.8%to34.8%)andmeanremissionratesaveraged16.8
percent(13.5%to20.2%).AlthoughtheseresultsprovideanideaofthegeneraldegreeofresponseseenwithnextsteppharmacologictreatmentinTRD,theyserveasanuncontrolledcaseseries
andshouldbecomparedtononpharmacologicoutcomesonlywithcaution.

MaintenanceofRemissionorPreventionofRelapse(KQ2)
DirectEvidence
Withrespecttomaintainingremission(orpreventingrelapse),wehadnodirectcomparisonsinvolvingECT,rTMS,VNS,orCBT.

IndirectEvidence
Three fair trials compared rTMS with a sham procedure and found no significant differences.However, too few patients were followed during the relapseprevention phases in two of the three
studies,andpatientsinthethirdreceivedacointerventionprovidinginsufficientevidenceforaconclusion.WehadnoeligiblestudiesforECT,VNS,orpsychotherapy.

EfficacyofNonpharmacologicInterventionsforPatientsWithDifferentSymptomatology(KQ3)
DirectEvidence
WeidentifiednoTier1trialsthataddressedwhetherprocedurebasedtreatmentsdifferedasafunctionofsymptomsubtypes.Also,nocomparativeevidencewasavailableaboutpsychotherapyin
subgroupsdefinedbysymptomclusters.

IndirectEvidence
Weidentifiednostudiestestingeitherprocedurebasedorpsychotherapeuticinterventionsagainstshamproceduresorothercontrols.

Safety,AdverseEvents,andAdherence(KQ4)
DirectEvidence
Inexaminingsafety,adverseevents,andadherence,wefoundsomedifferencesacrosstheinterventionsintheharmsandnegativesideeffectstopatients.However,thedatawereinsufficientto
reach a conclusive result. For just this set of analyses, we examined both clinical trials and cohort studies, and we focus on cognitive functioning, occurrence of specific adverse events, and
withdrawals.

CognitiveFunctioning
ForTier1studiesoncognitivefunctioning,someevidencesuggestsnodifferencesinchangesincognitivefunctioningbetweengroups,whilesomeevidencesuggestsECTmayhaveadeleterious
impact on cognitive functioning compared to rTMS (insufficient strength of evidence). No differences between groups on a singleitem measure of cognitive functioning were found in a study
comparingECTwithECTandrTMS(insufficientstrengthofevidence).

SpecificAdverseEvents
OneTier1studycomparingECTwithacombinationofECTandrTMSfoundnodifferencesinspecificadverseevents(lowstrengthofevidence).

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Withdrawals
We looked at both withdrawals that investigators attributed to adverse events and overall numbers or rates of withdrawals. A single study with a small sample size indicated no difference in
withdrawalsduetoadverseeventsfortheECTgroupwhencomparedtorTMSbutdidnotreportonthesignificanceofthisresult(lowstrengthofevidence).EvidenceforECTcomparedwithrTMS
indicatedhigherratesofoverallwithdrawalsintheECTcomparedtotherTMSgroup(P=NR;lowstrengthofevidence).

IndirectEvidence
Weattemptedtoincludedatafromthesametypesofstudiesandforthesameoutcomesasfordirectevidence.WeidentifiednostudiescomparingECTversuscontrol.

CognitiveFunctioning
MixedevidenceoncognitivefunctioninginrTMSversusshamwasinsufficientevidencetodrawaconclusion(insufficientstrengthofevidence).

SpecificAdverseEvents
rTMSgroupsreportedsignificantlymorescalppainatthestimulationsite(lowstrengthofevidence).SomedifferencesinthefrequencyofspecificadverseeventswereseenwhencomparingVNS
andshamgroups,butthesignificanceofthefindingswasnotreported(P=NR)(lowstrengthofevidence).

Withdrawals
FindingsweremixedinTier1studiesastowhetherrTMSgroupshadgreaterratesofwithdrawals(overallandduetoadverseevents)thangroupsreceivingshamprocedures(insufficientevidencefor
both).WithdrawalsattributabletoadverseeventswerehigherintheVNSgroupcomparedwithsham(lowstrengthofevidence).NoTier1studiesreportedonwithdrawalsforCBTgroupsversus
thosereceivingsomeformofusualcare.
EfficacyorHarmsofNonpharmacologicTreatmentsforSelectedPatientSubgroups(KQ5)
DirectEvidence
Wefoundnostudies(inanytier)directlycomparingnonpharmacologicinterventionsinselectedpopulations,suchastheelderly,thosewithstroke,orthosewithothermedicalcomorbidities.

IndirectEvidence
Two Tier 1 trials compared rTMS with sham. All findings provided low strength of evidence. For young adults (ages 1837), one trial found that rTMS produced a greater decrease in depressive
severityandagreaterresponseratethansham.Asecondtrial,conductedinolderadultswithpoststrokedepression,foundthatrTMSproducedagreaterdecreaseindepressiveseverityanda
greaterresponseratebutnodifferenceinremissionratescomparedwithashamcontrol.

HealthRelatedOutcomesofNonpharmacologicTreatments(KQ6)
DirectEvidence
Withrespecttopatientreportedhealthrelatedoutcomes,wefocusedonqualityoflife(variousmeasures)andabilitytofunctionindailylife.OneTier1studycomparedECTwithacombinationof
ECTandrTMSandfoundnodifferencesbetweengroupsinimprovementontheGlobalAssessmentofFunctioningscale(lowstrengthofevidence).

IndirectEvidence

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Twotrials(bothinmixedMDD/bipolarpopulations)assessedgeneralhealthstatusandmentalandphysicalfunctioning(allhealthdomainsrelatedtoqualityoflife).Inonefairtrial,lowrTMShad
significantlygreaterimprovementinhealthstatusanddailyfunctioningthansham,whilethisrelationshipapproachedstatisticalsignificancewhencomparinghighrTMStosham(asmeasuredbythe
GlobalAssessmentofFunctioningscale;lowstrengthofevidence).Intheotherfairtrial,VNSandshamgroupsdidnotdiffersignificantlyindailyfunctioning(asmeasuredbythe36itemMedical
OutcomesStudyShortForm[MOSSF36];lowstrengthofevidence).Nostudiesofpsychotherapywereidentified.

Applicability
Forthelimitedamountandlowstrengthofevidenceavailable,thedataforTier1(TRD)isgenerallyapplicabletoTRDpopulations.Populationsenrolledinthesetrialsappearedrepresentativeofour
targetpopulation.Studiedinterventionswerecomparabletothoseinroutineuse,thoughdoseanddurationofnonpharmacalogictreatmentoftenvariedbetweenstudies.Measuredoutcomeson
thewholereflectedthemostimportantclinicaloutcomesfordepressionmeasures,althoughreportingwasinconsistent;outcomesfortheotherkeyquestionsweremuchmorerestricted.Followup
periodsweregenerallyshorterthandesirable,butmostweresufficienttomeasureaninitialacutephasetreatmentresponse.Studysettingswereamixtureofinpatientandoutpatient,becauseECT
isgenerallyaninpatientprocedureandthe
othersaregenerallyoutpatient.Someevidencehighlightstheimportanceofpatientacceptabilityoftreatmentassomepatientsrefuseparticularinterventions.Anindividualizedbalancebetweena
patientsneedsandconcernsmustbetakenintoaccountduringselectionfromarangeofnonpharmacologicandpharmacologicantidepressanttreatmentoptions.
TheuseofinconsistentdefinitionsofTRDinthetrialsandtheabsenceofanalysesconsideringtheeffectofthenumberofcurrenttreatmentfailuresonoutcomeshinderedinterpretationofdata,
leading to our use of a tiered system for analyses. The evidence base combining data for Tiers 13 on the whole produced findings that were consistent with Tier 1 TRD data and also appear
applicabletoTRDpopulations

RemainingIssues
This area of comparative clinical research is in its infancy. Key areas for future research need primarily to lay more robust foundations for an evidence base that can better inform decisions for
cliniciansandpatients.

TheFieldNeedsaStandardDefinitionofTRDThatInvestigatorsShoulduseinTheirClinicalTrialsResearch
Comparisonofanyofthepotentialinterventionsinthefield,nonpharmacologicorotherwise,ishamperedbythevariabilityinTRDdefinitions.Althoughthesedefinitionsappeartobeconvergingon
asinglemeaningtwoormoretreatmentfailuresinthecurrentepisodeveryfewstudiesofTRDhaveappliedit.Progressinthisareaofresearchrequiresbetterstandardizationofthisconcept,so
thatfuturereviewsoftheevidencedonotneedtoresorttodifferentiating,aswedid,betweenTier1studies(i.e.,TRDbythisdefinitionbasedontwoormoretreatmentfailures)andTier2or3
typesofstudies.ThelatterdoprovideinformationthathelpsilluminatelikelyimpactsoftheseinterventionsonpatientswithTRD,butthatisnotthesamethingashavingrobuststudiesfocused
clearly on the patient population of greatest interest. The challenge will be to provide a definition that operationalizes TRD to make it feasible for clinicians while at the same time successfully
capturingthecomplexityoftreatmentresistance.

More Clinical Trials, as Well as Other Possible Study Designs, That Compare Nonpharmacologic Interventions With Other Nonpharmacologic Options and With Pharmacologic Treatments are
NecessarytoInformDecisionmakinginTRDClinicians,patients,andpolicymakersneedadditionalrelevantdatatoguidedifficulttreatmentdecisionsaboutwhattodonext:tryanothermedication
(and should it be an augmentation, switch, or combination strategy?) or add (or switch to) rTMS, ECT, VNS, or psychotherapy?Also, given that treatment options for many TRD patients include
medications,trialsshoulddirectlycomparenonpharmacologicinterventionswitheachotherandwithpharmacologic
treatments.

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TheNumberofTreatmentFailuresintheCurrentEpisodeShouldbeDelineatedCarefully
Thisinformation,morelikelytobeaccuratethanlifetimehistoriesoffailures,canhelpinvestigatorsdeterminewhethertheparticularnumberoffailures,orreachingaparticularnumberoffailuresin
a current episode, can help differentiate betweennonpharmacologic treatment choices. For example, for patients with two treatment failures in a current episode, the outcomes may not differ
betweencognitivetherapyandrTMS;however,forpatientswithadifferent(higherorlower)numberoftreatmentfailuresinthecurrentepisode,onenonpharmacologictreatmentmayindeedbe
better than the other. Currently, we do not know what the proper threshold is for selection of treatment. Clarification of the scientific basis for such a decision would substantially improve
decisionmaking

ClarifyingWhetherResponsesDifferforTRDPatientsWithMDDComparedWithThoseWithBipolarDisorderWillHelpGuide
FutureClinicalTrialDesign
Ourdecisiontoincludetrialswithpatientpopulationsincludingupto20percentwithbipolardisorder(i.e.,themixedpopulationsnotedearlier)wasguidedbyclinicalexperienceandcommon
sensebutnotbydata.Testingtoseewhetheroutcomesdifferbetweenthetwogroupscanyieldinformationaboutinclusioncriteria(shouldthemixbe0percent,10percent,20percent,etc.?)that
maybeusefultoinvestigatorsindesigningTRDtrialsandmaybeimportanttoconsiderasapotentialcovariateinanalysesinvolvingsuchmixes.

GreaterConsiderationShouldbeGiventotheRoleThattheSpectrumofDepressiveSeverityPlays
Usingafinergradationofdepressiveseveritythaninvestigatorsnowtypicallyemploymightidentifywhetherparticularlyseveredegreesofdepression,mostcommonlyunderstoodcurrentlyasa
HAMD17 20,mayresponddifferentlytotheavailablenonpharmacologicinterventionsthandolessseverelevelsofdepression.Thesegradationsmayleadclinicianstoabetterunderstandingof
severedepressionanditsroleinguidingtreatmentselectioninTRD.

DirectComparisonsofTreatmentStrategies,HoldingConsistentanyCoexistingorConcomitantTherapies,areImperative
Decisionmakersneedtoknowwhetheroutcomeswithnonpharmacologictreatmentsarebetterwhensuchatreatmentaugmentsthecurrenttreatment,replacesthecurrenttreatment,orreplaces
the current treatment in combination with another treatment. When ongoing treatment is uncontrolled and reflects a variety of treatmentse.g., some patients continue with atypical
antipsychotics,somewithmoodstabilizers,somewithnopsychotropicmedicationsresultsof
suchstudiesaredifficult,ifnotimpossible,tointerpret.

ConsistentReportingofChangesinDepressiveSeverity,ResponseRates,andRemissionRatesisCrucial
To allow for better comparisons of clinical outcomes in this difficulttotreat population, all three measures offer useful information for clinicians. Thus, for either clinical trials or observational
studies,investigatorsshouldattempttocollectdataonallthreeroutinely.
ApplicationofConsistent,AcceptedProtocolsinTrialsisNecessary
Makingsurethatpatientsreceiveequivalentdosesofdifferentnonpharmacologicinterventionsismoredifficultthanmakingsureofthisforpharmacologicinterventions.Nevertheless,investigators
designingtrialsofnonpharmacologictherapiescanattempttodosobyimplementingstandardacceptedprotocolsfortheirtrials.Suchdosinghadbeendifficulttocontrolwhenthatprotocolwas
intheprocessofbeingdeveloped,aswithrTMS,butgivencurrenttreatmentparameters,thisstandardizationisagoalwellworthtryingtoreach.

MoreCarefulandConsistentAssessmentofAdverseEventsisRequired

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Adverseeventreportingisquitelimitedandtendstocoveronlyashorttimespan;whatreportingdoesexistisvariableandinconsistent.Systematiccollectionandmoreconsistentreportingofdata
onharmsthatis,adverseeventsandnegativesideeffectsandinformationaboutattritionandwithdrawalwouldprovideusefulinformationtohelpbalanceinformationnowfocusedonclinical
benefits.UseoftheCONSORTstatement(availableat:http://www.consortstatement.org/home/),whichguidesproperreportingofstudyinformation(includingthepresentationofadverseevents),
wouldstrengthenreportingofbothharmsandotherclinicaltrialfindings;itwouldalsoaidinthecriticalappraisalandinterpretationofallstudyresults.Further,amoreinformativeassessmentof
adverseeventswouldrequirestudiesto
beabletoassesslongtermandcumulativeoutcomes.

IncludingKeyRelevantMeasuresandSubgroupsinSubsequentResearchisDesirable
As indicated by the review, nearly no evidence exists on how the effectiveness of nonpharmacologic treatments differs (or not) as a function of symptom subtypes or for subgroups defined by
sociodemographiccharacteristic(suchasage)orcoexistingmedicalconditions(e.g.,poststrokeorpostmyocardialinfarctiondepression;perinataldepression).Also
essentiallymissingisinformationabouthealthrelatedoutcomes,especiallythosereportedbypatients,thatconcerntheirqualityoflifeorlevelsoffunctionalimpairment.Subsequentstudiesshould
focusonemployingknown,reliable,andvalidmeasuresofpatientreportedoutcomes,suchastheMOSSF36,theQualityofLifeEnjoymentandSatisfactionQuestionnaire(QLESQ),andtheEQ5D.

IncludingComparisonsofNewerNonpharmacologicInterventionsWillbeImportantinFutureResearch
Asnewnonpharmacologictreatmentsaredevelopedandtested,investigatorsshouldtrytoincludethemaspotentialcomparators.Atthetimewestartedthiscomparativeeffectivenessreview,
clinicaltrialdataonsomeofthedevelopingnonpharmacologicinterventions,suchasmagneticseizuretherapyordeepbrainstimulation,wereinsufficient(fromthepublishedliterature)forustotry
toincludethem.Astheevidencebasesgrowtosupporttheefficacyofsuchadditionalnonpharmacologicinterventions,thenewerstrategiesshouldbeincludedincomparativeeffectivenessstudy
designs.

AuthorsConclusions.
Conclusion
Our review suggests that comparative clinical research on nonpharmacologic interventions in a TRD population is early in its infancy, and many clinical questions about efficacy and effectiveness remain
unanswered.InterpretationofthedataissubstantiallyhinderedbyvaryingdefinitionsofTRDandthepaucityofrelevantstudies.ThegreatestvolumeofevidenceisforECTandrTMS.However,evenforthe
fewcomparisonsoftreatmentsthataresupportedbysomeevidence,thestrengthofevidenceislowforbenefits,reflectinglowconfidencethattheevidencereflectsthetrueeffectandindicatingthatfurther
researchislikelytochangeourconfidenceinthesefindings.Thisfindingoflowstrengthismostnotableintwocases:ECTandrTMSdidnotproducedifferentclinicaloutcomesinTRD,andECTproducedbetter
outcomesthanpharmacotherapy.Notrialsdirectlycomparedthelikelihoodofmaintainingremissionfornonpharmacologicinterventions.Thefewtrialsaddressingadverseevents,subpopulations,subtypes,
andhealthrelatedoutcomesprovidedloworinsufficientevidenceofdifferencesbetweennonpharmacologicinterventions.ThemosturgentnextstepsforresearcharetoapplyaconsistentdefinitionofTRD,
to conduct more headtohead clinical trials comparing nonpharmacologic interventions with themselves and with pharmacologic treatments, and to delineate carefully the number of treatment failures
followingatreatmentattemptofadequatedoseanddurationinthecurrentepisode.
OurComments/Summary.
Thisisawellconductedstudywithalowriskofbias.

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