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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 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
Report#0513002R11rTMSforDepressionEvidenceReview
11
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
Report#0513002R11rTMSforDepressionEvidenceReview
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.
Report#0513002R11rTMSforDepressionEvidenceReview
14
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
15
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
Report#0513002R11rTMSforDepressionEvidenceReview
16
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.
Report#0513002R11rTMSforDepressionEvidenceReview
17
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.
Report#0513002R11rTMSforDepressionEvidenceReview
18
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.
Report#0513002R11rTMSforDepressionEvidenceReview
19
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
20
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
Report#0513002R11rTMSforDepressionEvidenceReview
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
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
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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/
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
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N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
CCRNNewsApril2011rTMS:Potentialnewclinicalapplications
CentresofEvidenceBasedPracticeWebsites
WesternAustralianCentreforEvidenceInformed
HealthcarePractice
http://wacebnm.curtin.edu.au
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
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
N/A
Projectsscanned
N/A
http://www.tacsafety.com.au
www.worksafe.vic.gov.au/
www.trafficinjuryresearch.com/
Report#0513002R11.3rTMSforDepressionTechnicalReport
MotorAccidentsAuthorityNSW
http://www.maa.nsw.gov.au
WorkSafeBritishColumbia
http://www.worksafebc.com/
AccidentCompensationCorporation
www.acc.co.nz/
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
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/
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
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/
Report#0513002R11.3rTMSforDepressionTechnicalReport
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
N/A
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N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
11referencesretrieved
N/A
Termsused:RTMS,Repetitivetranscranialmagneticstimulation
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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SearchPublications
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.
15
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
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inseveredepression:amulticentrepragmaticrandomisedcontrolledtrialandeconomicanalysis.HTA.1p.
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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
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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.
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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
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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.
20
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
25
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
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
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
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
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
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.
51
Report#0513002R11.3rTMSforDepressionTechnicalReport
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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