a systematic review and meta-analysis | Schizophrenia - Nature

Several trials have shown preliminary evidence for the efficacy of transcranial magnetic stimulation (TMS) as a treatment for negative ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature schizophrenia reviewarticles article Theefficacyoftranscranialmagneticstimulation(TMS)fornegativesymptomsinschizophrenia:asystematicreviewandmeta-analysis DownloadPDF DownloadPDF Subjects NeuralcircuitsSchizophrenia AbstractSeveraltrialshaveshownpreliminaryevidencefortheefficacyoftranscranialmagneticstimulation(TMS)asatreatmentfornegativesymptomsinschizophrenia.Here,wesynthesizethisliteratureinasystematicreviewandquantitativemeta-analysisofdouble-blindrandomizedcontrolledtrialsofTMSinpatientswithschizophrenia.Specifically,MEDLINE,EMBASE,WebofScience,andPsycINFOweresearchedforsham-controlled,randomizedtrialsofTMSamongpatientswithschizophrenia.TheeffectofTMSvs.shamonnegativesymptomsineachstudywasquantifiedbythestandardizedmeandifference(SMD,Cohen’sd)with95%confidenceintervals(95%CI)andpooledacrossstudiesusinganinversevariancerandomeffectsmodel.Weidentified57studieswithatotalof2633participantsthatwereincludedinthemeta-analysis.ThepooledanalysisshowedstatisticallysignificantsuperiorityofTMS(SMD = 0.41,95%CI:0.26;0.56,p-value 1 Hzwasmostefficacious.Therewas,however,substantialheterogeneityandhighriskofbiasamongtheincludedstudies.Inconclusion,TMSappearstobeanefficacioustreatmentoptionforpatientswithschizophreniasufferingfromnegativesymptoms,buttheoptimalTMSparametersareyettobeestablished. IntroductionPharmacologicaltreatmentisthecornerstoneofcareinschizophreniaandotherpsychoticdisorders1.Thoughpositivesymptoms(e.g.,delusionsandhallucinations)respondrelativelywelltopharmacologicaltreatment,negativesymptomsoftendonotrespondtothesamedegree2,3,4.Thenegativesymptomsofschizophreniaarethoserepresentingabsence/lesseningofnormalfunctionsandincludeaffectiveflattening,alogia,apathyandsocialwithdrawal5.Patientswithpredominantlynegativesymptomsaremoreresistanttotreatmentthanpatientswithprimarilypositivesymptoms,andnegativesymptomsarestronglyassociatedwithlowdailyfunctioningandpoorlong-termprognosis6,7,8.Therefore,identificationanddevelopmentofefficacioustreatmentsofnegativesymptomsisapriority3,9.Transcranialmagneticstimulation(TMS)isanon-invasiveneuromodulationtechniqueinwhichalocalizedelectricalfieldiselicitedinunderlyingbrainparenchymathroughelectromagneticinduction,generallylimitedtosuperficialcorticalregions10,11.WhetherTMSincreasesordecreasestheactivityofthetargetedneuronsdependsonthefrequencyofthemagneticpulseswith1 Hzandbelow(lowfrequency)beinginhibitoryand>1 Hzbeingexcitatory(highfrequency)12.RepetitiveTMS(rTMS)isthemostwidelyusedmodalitywithasinglesessionlasting20–40 min,typicallydeliveringbetween1200-3000magneticpulses13.OthertypesincludedeepTMSinwhichthemagneticfieldreachesdeepersubcorticalregionsofthebrainaswellasthetaburststimulation(TBS)inwhichthefrequencyofstimulationis50 Hzadministeredfivetimespersecondtomimicendogenousthetawaveseithercontinuouslyorintermittently14.TMSisapprovedforthetreatmentofmajordepression(https://www.accessdata.fda.gov/cdrh_docs/pdf6/K061053.pdf)andsincethenegativesymptomsofschizophreniaandthesymptomsofmajordepressionbothrepresentdeficitsofnormalfunctions,TMShasalsobeenexploredasapotentialtreatmentofnegativesymptomsamongpatientswithschizophrenia15,16,17,18.SincethemostrecentreviewsoftheliteratureonTMSfortreatmentofnegativesymptoms15,16,17,18,severaltrialshavebeenconducted—someusingnovelstimulationparametersaswellasneuronavigationtoimprovetargeting19,20,21,22,23,24,25,26,27.Duetothesedevelopmentsinthefield,anupdatedsynthesiswouldbeofrelevance.Therefore,weconductedasystematicreviewandquantitativemeta-analysisofrandomizedcontrolledtrialsreportingontheefficacyofrTMSinthetreatmentofnegativesymptomsamongpatientswithschizophrenia.MethodsProtocolandregistrationThestudyprotocolwasregisteredattheInternationalProspectiveRegisterofSystematicReviews(PROSPERO,ID:CRD42021238828)(https://www.crd.york.ac.uk/PROSPERO)andcarriedoutinaccordancewiththePreferredReportingItemsforSystematicReviewsandMeta-Analyses(PRISMA)guidelines28.InformationsourcesandscreeningMEDLINE(PubMed),PsycINFO,WebofScienceandEMBASEweresearchedforrelevantstudies.Earlierreviewsonthesubject,clinicaltrials.gov,aswellascitationsofincludedstudieswerereviewedinordertofindfurthereligiblestudies.ThesearchwascarriedoutonMay1st2021usingthefollowingsearchstringinMEDLINE:(“schizophreni*”OR“schizoaffectivedisorder”OR“schizophreniformdisorder”OR“schizophrenia”[MeSHTerms]OR“negativesymptom*”OR“CHR”OR“ClinicalHighRisk”OR“UltraHighRisk”OR“UHR”OR“PsychoticDisorders”[MeSHTerms]OR“PsychoticDisorder*“)AND(“transcranialmagneticstimulation”OR“TMS”OR“rTMS”OR“thetaburst”OR“iTBS”OR“cTBS”ORTranscranialMagneticStimulation*[MeSHTerms]).TheanaloguesearchstringsusedfortheotherdatabasesareavailableintheSupplementaryMaterial.Titlesandabstractsofstudiesidentifiedviathesearchstrategydescribedabovewerescreenedindependentlybytwoauthors(RLandTDN)assistedbyCovidence29.Fulltextversionsofthestudiesdeemedrelevantafterinitialscreeningweresubsequentlyassessedforeligibility.EligibilitycriteriaInlinewithearlierreviewsinthefield,thefollowinginclusioncriteriawereemployed15,17,18.Notably,nolanguagerestrictionswereemployed: Randomized,sham-controlledtrialsoftranscranialmagneticstimulation(e.g.,rTMSorthetaburststimulation) Participantswithaprimarydiagnosisofschizophrenia,schizoaffectivedisorderoranotherpsychoticdisorder(e.g.,acute/transient/briefpsychoticdisorderorpersistentdelusionaldisorder),accordingtotheDSM-IV,DSM-5,orICD-10. Adultparticipants(≥18years) Outcomemeasuredusinganestablishedpsychometricscalefornegativesymptomsinschizophrenia(e.g.,thenegativesubscaleofthePositiveandNegativeSyndromesScale(PANSS-N)30ortheScaleforAssessmentofNegativeSymptoms(SANS)31). Thefollowingexclusioncriterionwasemployed: Co-initiationofothertreatments,e.g.,pharmacologicaltreatment,astheresultsofsuchstudiescouldbeaffectedbyaninteractioneffectbetweenTMSandtheco-initiatedtreatment. DataextractionThefollowingitemswereextractedfromeachincludedstudy:Authorname,publicationyear,country,studytype(cross-overorparallel),analysis-type(perprotocolorintention-to-treat(ITT)),numberofparticipants,drop-outrates,meanageofparticipants,sexdistributionofparticipants,diagnosticdistribution,whethersampleswereselectedforpredominantlynegativesymptoms,frequencyandintensityofTMSincludingthetotalnumberofstimuliandnumberoftreatments,TMStarget,natureoftheshamintervention,outcomemeasure(ratingscale),posttreatmentscores,follow-upscoresandposttreatmentdepressionscores(ifavailable).Ifthesedatawerenotreported,theauthorswerecontactedbye-mailwitharequesttoprovidethedata.Ifauthorsdidnotreply,datafromgraphs(ifavailable)wereextractedusingtheGetDataGraphDigitizer(http://getdata-graph-digitizer.com/).Previousmeta-analyseswerescreenedforpost-treatmentoutcomedatarequiredtocomputeeffectsizes.Studieswheredatawasnotavailableuponrequest,viagraphsorthroughpreviousmeta-analyses,wereexcludedfromtheanalyses.EvaluationofriskofbiasTheincludedstudieswereevaluatedaccordingtofivedomainsofbias(articlesinnon-Englishlanguageswerenotevaluated)usingtheCochraneRiskofBiasTool2.0:(https://methods.cochrane.org/risk-bias-2)(A)Randomizationprocess(allocationsequencegenerationandconcealment),(B)Deviationsfromintendedinterventions(biasarisingfromnon-protocolinterventions),(C)Missingoutcomedata(dropouts),(D)Measurementoftheoutcome(usingavalidatedtool),and(E)Selectionofthereportedresult(alignmentwithprotocolandmethodsection).InaccordancewiththeinstructionsfortheCochraneRiskofBiasTool2.0,thehighestriskscoreassignedinoneofthesedomainsdefinedtheoverallriskofbiasscoreforeachstudy(https://methods.cochrane.org/risk-bias-2).Furthermore,potentialpublicationbiaswasexploredviaafunnelplotandEgger’sregressiontest.StatisticalanalysisTheeffectofTMSvs.shamonnegativesymptomsineachincludedstudywasquantifiedbythestandardizedmeandifference(SMD,Cohen’sd)with95%confidenceintervals(95%CI)basedonendpointscoresorchangescores(withendpointscoresbeingpreferred).Ifmultipleoutcomemeasureswereused,PANSS-Nwaspreferredtoimprovemethodologicalhomogeneitybecauseitwasusedin89%(51/57)oftheincludedstudies.Ifastudydidnotprovidestandarddeviations(SD)ordatathatcouldbeusedtocalculateSD(e.g.,standarderror),themeanstandarddeviationacrossallstudiesofthesameoutcomemeasurewasused.Forcross-overstudies,datawasextractedafterthefirsttreatmentphase(beforecross-over)toexcludepossiblecarry-overeffectsoftreatmentandthusregardedasaparalleldesignstudy.SMDswerepooledusingtheinversevariancerandomeffectsmodelinReviewManager5.332.Thismodeltakesintoaccountbothin-studyandbetween-studyvariability.Fortheprimaryanalysis,numberneededtotreat(NNT)wasestimatedusingthemethodproposedbyKraemerandKupfer33.HeterogeneitywasassessedusingtheI²-testwithI²-values≥50%suggestingconsiderableheterogeneity.Formulti-armstudies,datafromdifferentactiveTMStreatmentarmswerepooledinthecalculationofoverallefficacyastonotduplicatedatafromtheshamgroup,usingtheformulasprovidedintable6.5aintheCochraneHandbook(https://training.cochrane.org/handbook/current/chapter-06#section-6-5-2-10).Followingthemainanalysis,thefollowingsecondary/subgroupanalyses(yieldingeffectsizes)werecarriedout:(i)focusingonlongtermeffectusingdatafromatleastfourweeksafterthelasttreatment(thelastfollowupineachstudywasused),(ii)focusingonpatientswithpredominantlynegativesymptoms,(iii)focusingontheeffectsizeofTMSfordepressivesymptoms(alldepressionmeasuresallowedwithapreferencefortheCalgaryDepressionScaleinSchizophrenia34),(iv)afterstratifyingbytargetsite(v)afterstratifyingbytypeofTMS,(vi)afterstratifyingbystimulationfrequency,(vii)afterstratifyingbystimulationintensity,and(viii)afterstratifyingbyage.Finally,thefollowingsensitivityanalyses(yieldingeffectsizes)wereconducted:(I)afterexcludingstudieswithdataextractedfromgraphs,(II)afterexcludingstudieswithhighriskofbias,(III)afterexcludingstudiesreportingchange-from-baselinescores,(IV)afterexcludingstudieswithdataextractedfromotherreviews,and(V)afterstepwiseexclusionofthe10mostoutlyingstudiescomparedtotheoverallefficacyestimate.ResultsStudyselectionThesearchyielded3287articlesofwhich1573wereduplicates,resultingin1714studiesthatunderwenttitle-andabstractscreening(Fig.1).Followingthisscreening,1565wereexcluded.Thisleft149articlestobeassessedinfulltext,ofwhich80studiesdidnotmeettheeligibilitycriteria.Themostcommonreasonforexclusioninthisfinalstepwas“notrandomizedsham-controlledtrials”(31studies),whichincludednon-blindedstudies,studieswithnosham-treatedgroupandstudies,whichwerenotclinicaltrials.Thesecondmostcommonreasonforexclusionwas“didnotincludeeligibleoutcomemeasure”(14studies),whichincludedstudiesthatdidnotmeasurenegativesymptoms,buthadotherprimaryendpointssuchasbiomarkers/neuroimagingorcognitivefunction.Ofthe69eligiblestudies,35reportedinsufficientdataandthustheauthorswerecontactedbye-mailrequestingadditionaldata.ThemeansandstandarddeviationsofPANSS-Nwasthemostcommonmissingpieceofinformation(i.e.,fromstudieswhereonlythetotalPANSSscoreswerereported).Fromthese35studies,threeauthorgroupsprovideddata21,26,35,anddatawereextractedfromgraphsinanadditionaleightstudies27,36,37,38,39,40,41,42.Hence,24articleswereexcludedduetonon-availabledata43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66.Intotal,thesearchyielded45includablestudies,with51comparisonsasaresultofstudiesincludingmultipleinterventions19,20,21,22,23,24,25,26,27,35,36,37,38,39,40,41,42,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94.Noadditionalstudieswerefoundincitationsorinthedatabaseofclinicaltrials.gov.Summarydatawasavailablefrom15studiesreviewedbyWangandcolleagues18fromnon-Englishreports90,91,92,95,96,97,98,99,100,101,102,103,104,105,106,ofwhich3werealsoidentifiedbythedatabasesearch,leavingatotalof57studiesand63comparisons19,20,21,22,23,24,25,26,27,35,36,37,38,39,40,41,42,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106.Fig.1:PRISMAflowchartillustratingtheliteraturescreening.*Authorswerecontactedbye-mail.Ifdatawasnotprovidedanddatacouldnotbetakenfromgraphs,thestudywasexcluded.FullsizeimageStudycharacteristicsTable1showsthecharacteristicsofthe57includedstudies.Table1Characteristicsoftheincludedstudies.FullsizetableThe57studiesincluded2633participants,ofwhom1481receivedactivetreatmentand1152shamtreatment.Inthe55studies(n = 2525)thatreportedthespecificdiagnosesoftheparticipants,98.9%hadschizophreniaand1.1%hadschizoaffectivedisorder.Thetworemainingstudiesreportedthattheparticipantshadeitherschizophreniaorschizoaffectivedisorder,withoutprovidingthedistributionbetweenthetwo.Thestudieswereconductedin15differentcountries,ofwhichChinawasthemostcommon(n = 25).AlmostallincludedstudiesreportedtheoutcomeusingPANSS-NorSANSwithonlyonestudyusingtheBriefPsychiatricRatingScale–Negative/Disorganizedfactor(BPRS-N/D)69.SeveraldifferentactiveTMSmodalitieswereusedintheincludedtrials,withsometestingmorethanoneactivemodalityagainstshamtreatment:rTMS(48studies,10used≤1 Hz,39used>1 Hz,42usedunilateraltreatment,andeightbilateralormidlinetreatment),thetaburststimulation(TBS)(9studies,5usedintermittentTBS(iTBS),1usedcontinuousTBS(cTBS),and3usedunspecifiedTBS),anddeep-TMS(2studies).ThemeantotalnumberofTMSpulsespertrialwas25,684varyingfrom1200to80,000withanaverageof1455pulsespertreatment.Themajorityofthestudies(n = 39)hadtheleftdorsolateralprefrontalcortex(L-DLPFC)astheprimarystimulationtarget.RiskofbiasofindividualstudiesEightstudieswereregardedashavinglowriskofbias,10studieswith“someconcerns”,and23studieswithhighriskofbias(SupplementaryTable1).Themostcommonreasonfor“someconcerns”wasinsufficientreportingwhethertherandomizationsequencewasconcealedadequately(domainA).Improperanalysis(e.g.“perprotocol”analysis,domainB)andmissingoutcomedata(domainC)werethemostcommonreasons(n = 12andn = 21,respectively,withn = 11havingboth)forastudybeingregardedashavinghighriskofbias.ResultsofindividualstudiesStandardizedmeandifferencesfortheincludedstudiesareshowninFig.2.EighteenstudiesshowedastatisticallysignificantsuperioreffectofTMScomparedtoshamtreatment21,22,38,78,79,81,82,88,89,90,95,96,100,101,102,103,105,106andonestudyfoundastatisticallysignificantsuperioreffectofshamtreatment36.Theremainingstudiesdidnotshowastatisticallysignificantdifferencebetweenthetreatmentgroups.Therewasconsiderableheterogeneitybetweentheincludedstudies(I2 = 67%).Fig.2Forestplotofstandardizedmeandifferences(effectsize)ofTMSonnegativesymptoms.FullsizeimageSynthesisofresultsAsevidentfromtheforestplotinFig.2,theoverallSMDwas0.41(95%CI:0.26;0.56,p 1 HzisshowninFig.3.Table2EffectsizesofTMSonnegativesymptoms.FullsizetableFig.3Forestplotofstandardizedmeandifferences(effectsizes)ofTMStargetingnegativesymptomsviastimulationoftheleftdorsolateralprefrontalcortex(L-DLPFC)at > 1Hz.FullsizeimageRiskofbiasacrossstudiesBasedonthefunnelplotexaminingstudyprecisionversuseffectsize(Fig.4),wesawnoqualitativeevidenceofasymmetryandthiswasconfirmedwithEgger’sregression(p = 0.9498).Therewere,however,outlyingstudiesonbothsidesoftheconfidenceinterval.Notablyinthisregard,thesensitivityanalysis(no.V)involvingstepwiseexclusionofthe10mostoutlyingstudiesyieldednosubstantialchangeintheefficacyestimate(seeSupplementaryTable4).Fig.4:Funnelplotexaminingstudyprecisionversuseffectsize.SEStandarderror,SMDStandardizedmeandifference.FullsizeimageDiscussionBasedonmeta-analysisof57studieswithatotalof2633participantswithschizophrenia(thevastmajority)orschizoaffectivedisorder,wefoundasuperioreffectofactiveTMSonnegativesymptomscomparedtoshamtreatment.TheSMDwas0.41(95%CI:0.26;0.56)infavourofactiveTMS,translatingtoaNNTof5.Thisresultalignswiththosefrompriormeta-analysesonthesubject,asAlemanetal.15foundanSMDof0.64(95%CI:0.32;0.96),Heetal.16anSMDof0.41(95%CI:−0.35;1.16),Wangetal.18anSMDof0.40(95%CI:0.18;0.62),andOsoegawaetal.17anSMDof0.19(95%CI:0.07;0.32).ThesuperiorityofactiveTMSonnegativesymptomsremainedstatisticallysignificantinsensitivityanalysesfollowing(a)exclusionofdataextractedfromgraphs,(b)exclusionofstudiesdeemedtobeathighriskofbias,and(c)exclusionofstudiesreportingchange-from-baselinescores,respectively.Subgroupanalysessuggestedthatusing>1 Hzstimulation(SMD = 0.51vs.SMD = 0.05,p = 0.003)andtargetingtheL-DLPFC(SMD = 0.55vs.SMD = 0.04,p = 0.0002)maybemoreeffective.However,therewasconsiderableheterogeneityacrosstheincludedstudiesandtheseresultsshouldthereforebeconsideredtentative.Incontrasttothemeta-analysisbyAlemanetal.15,wefoundnosupportforthesuggestionthatTMSshouldhaveaparticularlybeneficialeffectuponnegativesymptomsamongyoungerpatients(SMD = 0.34vs.SMD = 0.46,p = 0.43).Themeta-analysisbyAlemanetal.was,however,basedondatafromamuchsmallernumberofstudies/participatingpatientscomparedtothepresentwork.Indeed,whiletherearepriormeta-analysisontheeffectofTMSonnegativesymptoms,ourupdatedversioncoverssubstantiallymorestudiesandparticipants(138%morestudiesand219%moreparticipantsthanAlemanetal.15,714%morestudiesand539%moreparticipantsthanHeetal.16,97%morestudiesand83%moreparticipantsthanWangetal.18,and138%morestudiesand142%moreparticipantsthanOsoegawaetal.17)andshouldthereforebemorerepresentativeofthestate-of-the-art.SeveraldifferentbrainareasweretargetedbyTMSinthestudiesincludedinthissynthesis,inwhichsubgroupanalysessuggestedthatstimulationoftheL-DLPFCmaybeparticularlybeneficial(SMD = 0.55).Theseresultsalignwithearlierstudiesthathavefoundaninversecorrelationbetweenfrontallobesizeandglucosemetabolism,andnegativesymptomseverity107,108.Togetherwithsmallsamplesize,thisvariabilityintargetcouldinpartexplainwhyonlyeighteenstudiesfoundstatisticallysignificanteffectsofTMSsince17ofthesetargetedL-DLPFC.Hence,increasedactivityintheL-DLPFCduetomagneticstimulationcouldbethemechanismofactionunderlyingtheeffectonnegativesymptomsofTMSasproposedinseveralofthelargestincludedstudies25,87,88.Moreover,thereisanincreasingbodyofdatasuggestingthattheDLPFChasaprivilegedrelationshipwithotherstructuresimplicatedinnegativesymptoms,includingthemidlinecerebellum109.Forthesereasons,circuitriesinvolvingtheDLPFCwilllikelyreceivesubstantialattentioninfutureeffortstorelievenegativesymptomsofschizophreniaandrelatedpsychoticdisorders.Conversely,TMSof“othertargets”thantheL-DLPFCyieldednopositiveeffectcomparedtoshamtreatment(SMD = 0.06).Whilethereisconsiderablemethodologicalheterogeneityamongthesestudies,thequantitativesynthesisconvergedonanulleffectwithlowstatisticalheterogeneity.Furthermore,severalofthestudiestargetingothersitesthantheL-DLPFChadotherprimaryendpointssuchastheseverityofauditoryhallucinations(thetemporo-parietalcortexastarget)withnegativesymptomseverityasasecondaryoutcome36,40,67,71,77,84,whichlikelycontributestothelackofeffectcomparedtoshamtreatment.Therearelimitationstothisstudy,whichshouldbeacknowledgedbythereaders.First,astherearephenomenologicaloverlapsbetweennegativeanddepressivesymptomsandsincedepressionrespondswelltoTMS110,111,thereliefofdepressivesymptomsduringtreatmentcouldpotentiallyconfoundtheestimationoftheeffectonnegativesymptoms.However,theresultsfromouranalysisofdatafromstudiesmeasuringdepressivesymptomsinthecontextofschizophrenia(noeffectofTMS)donotsupportthisexplanation.Second,56%oftheevaluatedstudieswereregardedashaving“highriskofbias”,whichisasubstantiallylargerproportioncomparedtothe13%reportedinthereviewbyWangetal.18.Thisdifference,however,ispredominantlyaconsequenceofclassificationasweusedtheCochraneRiskofBiasTool2.0,whileWangetal.usedtheCochraneRiskofBiasTool1.0.Themostcommonreasonforstudiesbeingconsideredas“highrisk”inthecontextofthepresentreviewwasmissingdata.Weemployedarelativelyconservative10%cut-offformissingdata,butthereisnoagreeduponthreshold(https://training.cochrane.org/handbook/current/chapter-08#section-8-5)andtheproportionofstudiesclassifiedas“highriskofbias”canthusvaryconsiderablybetweenreviews.Also,publicationbiasseemsunlikelyasEgger’sregressiontestshowednon-significantresults(p = 0.9498),butcannotberuledout.Thetwomostoutlyingstudies88,103didnotdiffersubstantiallyintheirtreatmentparametersasbothtargetedtheL-DLPFCwith>1 Hzover20daysoftreatment,however,thestimulationintensity(percentofMT)wasnotdescribedforZhang2015.Third,weusedabroadsearchstrategy,butrelevantstudiesmayhavebeenmissednevertheless.However,assumingthatsuchpotentialmissesoccuratrandom,itshouldnothaveaffectedthereportedefficacyestimates.Fourth,theinclusionofdatadrawnfromreviewsandgraphsissuboptimal.However,theanalysesexcludingthesedatayieldedresultsequivalenttothosefromtheprimaryanalysis.Fifth,therewassignificantheterogeneityinoutcomeacrosstheincludedstudies,withI2-assessmentsat50%oraboveinallbutsevencases(66%intheprimaryanalysis;Fig.2).WhilethisislikelypartlyduetotheconsiderableheterogeneityoftheTMStreatmentprovidedacrosstheincludedstudies,othersourcesofheterogeneity,suchasdifferencesinshamconditions,patientpopulations,outcomemeasures,orrandomchance,arealsolikelycontributors.Relatedly,inthereviewbyHeetal.16,aunivariatemeta-regressionofstimulationfrequency,totalsimulation,motorthreshold,stimulationsite,studydesign,andtypeofcoilwasconducted.Noneofthesefactorswereshowntobethemainsourceofheterogeneity.Seventh,24studiescouldnotbeincludedduetounavailabledata.Thesestudieswere,however,generallysmaller,whichreducestheimpactofthislimitation.Inconclusion,thissystematicreviewandmeta-analysisofdatafromsham-controlledstudiessuggeststhatTMSisefficaciousinthetreatmentofnegativesymptomsofschizophrenia.AlthoughitappearsthattargetingtheL-DLPFCandusingastimulationfrequency>1 Hzarethemostefficacioussettings,theoptimaltreatmentparametersareyettobeestablished. Dataavailability Alldataareavailableinthemanuscript,figures,tables,andsupplementaryfiles. 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ReprintsandPermissionsAboutthisarticleCitethisarticleLorentzen,R.,Nguyen,T.D.,McGirr,A.etal.Theefficacyoftranscranialmagneticstimulation(TMS)fornegativesymptomsinschizophrenia:asystematicreviewandmeta-analysis. Schizophr8,35(2022).https://doi.org/10.1038/s41537-022-00248-6DownloadcitationReceived:19November2021Accepted:21March2022Published:09April2022DOI:https://doi.org/10.1038/s41537-022-00248-6SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative DownloadPDF Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Collections FollowusonTwitter Signupforalerts RSSfeed Aboutthejournal Aims&Scope JournalInformation Contenttypes Contact AbouttheEditors OpenAccess MeetingAbstracts&Reports ArticleProcessingCharges Editorialpolicies JournalMetrics AboutthePartner Publishwithus ForAuthors&Referees Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies Closebanner Close SignupfortheNatureBriefingnewsletter—whatmattersinscience,freetoyourinboxdaily. 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