Efficacy and clinical predictors of response to rTMS treatment ...

In the SMA-rTMS protocol, TMS was delivered at 120% of AMT. Stimulation frequency was 1 Hz, which was applied for 30 min, resulting in a total ... Skiptomaincontent Advertisement SearchallBMCarticles Search EfficacyandclinicalpredictorsofresponsetorTMStreatmentinpharmacoresistantobsessive-compulsivedisorder(OCD):aretrospectivestudy DownloadPDF DownloadPDF Researcharticle OpenAccess Published:16July2020 EfficacyandclinicalpredictorsofresponsetorTMStreatmentinpharmacoresistantobsessive-compulsivedisorder(OCD):aretrospectivestudy RezaRostami  ORCID:orcid.org/0000-0001-9318-108X1,2,RezaKazemi1,2,ArezooJabbari1,2,AzamSadatMadani2,3,HosseinrezaRostami2,MohammadAminTaherpour1,ParvizMolavi4,NematollahJaafari5,6,Min-FangKuo7,CarmeloM.Vicario8,MichaelA.Nitsche7,9&MohammadAliSalehinejad7,10  BMCPsychiatry volume 20,Article number: 372(2020) Citethisarticle 6778Accesses 6Citations 1Altmetric Metricsdetails AbstractBackgroundApplicationofrepetitivetranscranialmagneticstimulation(rTMS)fortreatingobsessive-compulsivedisorder(OCD)hasbeenpromisingandapprovedbytheFoodandDrugAdministrationin2018,buteffectsdifferbetweenpatients.KnowledgeaboutclinicalpredictorsofrTMSresponsemayhelptoincreaseclinicalefficacybutisnotavailablesofar.MethodsInaretrospectivestudy,weinvestigatedtheefficacyofrTMSoverthedorsolateralprefrontalcortex(DLPFC)orsupplementarymotorarea(SMA)in65pharmaco-resistantOCDoutpatientsrecruitedforrTMStreatmentfromJuly2015toMay2017.PatientsreceivedeitherSMArTMS(n = 38)orbilateralDLPFCrTMS(n = 27)incaseofreportinghigheraffectiveanddepressivesymptomsinadditiontotheprimaryOCDsymptoms.OCDsymptomsanddepression/anxietystatesweremeasuredatbaseline(beforethe1stsession)andafterthe20thsessionofrTMS.Additionally,weperformedabinarylogisticregressionanalysisonthedemographicandclinicalvariablesbasedontheYale-BrownObsessive-CompulsiveScale(Y-BOCS)3-factorand2-factormodelsandindividualitemstoinvestigatepotentialpredictorsofrTMSresponse.ResultsPatients’scoresinY-BOCSandBeckanxiety/depressioninventoriesweresignificantlydecreasedfollowingrTMStreatment.46.2%ofallpatientsrespondedtorTMS,basedonthecriterionofatleasta30%reductioninY-BOCSscores.TherewasnosignificantdifferencebetweenresponseratesofpatientsinDLPFCandSMAgroups.NosignificantdemographicpredictorsofrTMSefficacywereidentified.Thefactors“obsessionseverity”,“resistance”and“disturbance”andthe“interferenceduetoobsessions”and“resistanceagainstcompulsions”itemsoftheY-BOCSsignificantlypredictedresponsetorTMS.ConclusionsInpatientswithlessintrusive/interferingthoughts,andlowscoresinthe“obsessionseverity”,“disturbance”,and“resistance”factors,rTMSmighthavesuperioreffects.Identifyingclinicalandnon-clinicalpredictorsofresponseisrelevanttopersonalizeandadaptrTMSprotocolsinpharmaco-resistantOCDpatients.InterpretationofrTMSefficacyshouldbedonewithcautionduetothelackofashaminterventioncondition. PeerReviewreports BackgroundWithalifetimeprevalenceof1–3%[1],obsessive-compulsivedisorder(OCD)isafrequentanddisablingpsychiatricdisorder.Itischaracterizedbyintrusive,anxiety-provoking,interferingthoughts(obsessions),andassociatedrepetitivebehaviors(compulsions)[2].OCD,whichisfrequentlyundertreated[3],isremarkablyheterogeneousinetiology,symptoms,subtypeandtreatmentresponse[4,5].Asaresult,approximately40–60%ofOCDpatientsremaintreatment-refractorytocurrentfirst-linetherapies[6,7,8],possiblyduetothesub-optimalandnon-adaptedtreatmentinnon-responders.Accordingly,thedevelopmentofnoveltherapeuticstrategiesbasedonanimprovedunderstandingofOCDpathophysiologyisrelevant[3,9].Previousstudiesinhumansandanimalmodelssuggestthatfunctionalabnormalitiesofthecortico-striato-thalamo-corticalcircuitsandsupplementarymotorarea(SMA)mightbecentralpathophysiologicalcomponentsofOCD[10,11,12,13].Thedorsolateralanddorsomedialprefrontalcortex(DLPFC,DMPFC),orbitofrontalcortex(OFC)andanteriorcingulatecortex arealsoproposedtobeinvolved.InvolvementofsuchadiverseregionssuggeststhatthepathophysiologyofOCDisheterogeneouswhichmightbeanimportantsourceofvariabilityintheefficacyofconventionalOCDtreatments.NeuromodulatorytreatmentsinvolvingbrainstimulationcanmodulaterespectivetargetregionsinOCDandotherdisorderswithabnormalitiesrelatedtotheseregionssuchasdrugaddiction,depression,schizophrenia,borderlinepersonalitydisorder,andADHD[14,15,16,17,18,19].Theyhavealsopotentialforindividualizationviatheinformedchoiceofrespectivetargets.Repetitivetranscranialmagneticstimulation(rTMS)isanon-invasivebrainstimulationtechniqueproposedasapromisingmethodfortreatingOCDviaalteringexcitabilityofDLPFCandSMA[20,21,22].TMSaltersneuralactivityandexcitabilityoftargetedbrainregions[23,24].Repetitive applicationofTMS (i.e.,rTMS)caninduceneuroplasticafter-effectsintargetareas,anddependingonthespecificstimulationprotocol,theeffectscanbeinhibitoryorexcitatory[25,26].TheseneuroplasticeffectsarethemainrationalebehindtheclinicaltherapeuticeffectsofrTMS[26,27].PreviousrTMSstudiesreportedanaverageresponserateof35%inOCDpatients,definedasaminimumof25–40%reductioninpost-treatmentsymptoms[20].Higherresponseratesandaugmentedefficacywererecentlyreportedinpatientswithamorehomogenouspathologicalprofile,includingcommonpathophysiologicaldeficits[9,28,29].ThisimpliesthepotentialrelevanceofpredictorsofeffectiverTMStreatmentinOCD,andaccordinglytheneedforpersonalizingrTMStreatmentbasedonthepathophysiologicalandclinicalprofilesofthepatients[28].Inthisline,recentreviewsofrTMSstudiesshowthatbrainstate-dependentmodulatoryeffectsofrTMSareanadditionalparameterthatmaypotentiallyaffectrTMSeffects[30],andtakingthisfactorintoaccountmightimprovetreatmentoutcomesinpatientswhousuallydeveloptreatment-resistantillnesssubtypes.Moreover,differentcorticalregionshavebeentargetedinpreviousstudieswithmixedresults[31,32,33,34,35],leavingthequestionofwhichcorticalregionstostimulateunanswered.WhilespecificstimulationparametersandneurobiologicalpredictorsofresponsetorTMStreatmenthavebeeninvestigatedinOCD[9,36],theimportanceofclinicalanddemographicfactorshasnotbeensystematicallyexploredyet.Thesefactors,especiallyclinicalpredictors,playapotentiallykeyroleinaccuratelyselectingpatientsforrTMStreatment.FindingsfromrTMSstudiesinotherneuropsychiatricdisorderssuggestthatspecificsymptoms,subtypesorpsychologicalstatescandistinguishbetweenrespondersandnon-responderstorTMS.WerecentlyinvestigatedclinicalanddemographicpredictorsofrTMSresponseindepressivedisordersandfoundthatcognitive-affectivesymptoms,ascomparedtosomaticsymptoms,significantlypredictresponsetorTMS[37].AnotherstudyfoundthatnonresponderstorTMStreatmentfordepressionhadmarkedlyhigherbaselineanhedoniasymptoms[38].AlthoughrecentstudiestriedtopredictresponsetorTMStreatmentinOCDbasedonelectrophysiologicalmeasures[33],clinicalpredictorsofresponsesofarhavenotbeenexplored.Inthepresentstudy,weaimedtoinvestigatetheefficacyofrTMSovertwopotentiallyinvolvedcorticalregions(i.e.,SMAandDLPFC)forreducingOCDsymptoms.Moreimportantly,weaimedtoidentifypotentialclinicalanddemographicpredictors,thatcoulddistinguishbetweenrTMSrespondersandnonrespondersinOCD.BasedonpreviousfindingsabouttheefficacyofrTMSinOCDpatients[20],weexpectedtoobservearesponserateof35–55%,basedona30%reductionoftheYale-BrownObsessive-CompulsiveScale(Y-BOCS)baselinescore(respondercriterion).WithregardtoclinicalpredictorsofrTMSresponse,weaimedtoidentifypredictabilityoftherTMSeffects inOCDbyclinicalvariables(basedonY-BOCSfactorsanditems)anddemographiccharacteristics.MethodsStudydesignWeretrospectivelyanalyzedadatasetofpharmaco-resistantOCDoutpatientswhoreceivedanrTMStreatmentbetweenJuly2015andMay2017.PatientswerereferredtotheAtiehClinicalNeuroscienceCenterinTehran,Iran,toreceiverTMS.Thecenteradmitspatientswithpsychiatricdisorders(e.g.depression,OCD),neurologicaldisorders(e.g.stroke,dementia),andpediatricneurodevelopmentaldisorders(e.g.attention-deficithyperactivitydisorder,autism,learningdisabilities).ParticipantsSixty-fivepharmaco-resistantOCDoutpatients(Meanage = 32.25,SD = 10.23,35females)wereincludedinthisreport.69patientswereinitiallyincluded,butfourpatientsdidnoteitherfinishthetreatmentcoursewithoutanyreportedreasonormeettheminimumsymptomseveritytobeincluded.Of65patients38patientsunderwentSMArTMSprotocoland27patientsreceivedDLPFCrTMSprotocol(seeTable 2formoredetails).Apriorisamplesizecalculationshowedthatbasedonamediumeffectsize(f = 0.5)whichissuggestedforNIBSstudies[39],acriticalp-valueof0.05,andacriticalpowerlevelof0.95,therequiredsamplesizeis42.TheOCDdiagnosiswasbasedontheStructuralClinicalInterviewbyalicensedpsychiatristaccordingtotheDSM5diagnosticcriteria,confirmedbypatientscoresontheY-BOCS[40].Theinclusioncriteriawere:(1)18–65 yearsold,(2)currentOCDdiagnosisbasedonDSM-5(3)moderatetosevereOCDscoreontheY-BOCS(scores16andhigher)(4)responsefailuretopreviousorcurrentuseofmedication/psychotherapy(responsefailurewasdefinedasscores> 16atY-BOCSdespiteatleasttwoSSRItrialsofadequatedosageandduration)and(5)stablemedicationregimen8-10 weeksbeforetheinterventionandunchangedduringthetreatment(4–6 weeks)[9].Exclusioncriteriaincludedprevioustreatmentwithelectroconvulsivetherapy,andpresenceorhistoryofpsychosis,substanceabuse,suicideattemptand/oractivesuicideideation,neurologicaldisorder,epilepsy,seizures,andheadinjuryorlossofconsciousness.AccordingtothesafetycriteriaforrTMS[41],patientswithimplanteddevices,metalbodies,cardiacarrhythmia,unstablemedicalconditions,orpregnancy,werealsoexcluded.51patientsweretakingselectiveserotoninreuptakeinhibitors(SSRIs)duringrTMStreatment,andtheremainingpatientshadahistoryofSSRImedicationuse.Mostofthepatientshadnohistoryofpsychotherapy.Allpatientsprovidedwritteninformedconsenttotreatment.DemographicandclinicalcharacteristicsofpatientsaresummarizedinTables 1and2. Table1DemographicinformationofparticipantsFullsizetableTable2Group(SMAvsDLPFCrTMS)charactristicsFullsizetablerTMStreatmentparametersRTMSwasadministratedwithaNeuroMSrTMSdevice(Neurosoft,Russia)usinga70-mmfigure-of-8-shapedcoil(airfilmcoil).Activemotorthreshold(AMT)wasdefinedastheminimumstimulusintensitythatproducedaliminalmotorevokedresponseduringactivecontractionoftheabductorpoliciesbrevismuscle(APB)(atabout20%maximumcontraction)[42].Motorthresholddeterminationwasbasedonvisualinspectionoftherespectivefingermovement.PatientsreceivedeitherSMArTMS,orbilateralDLPFCrTMS.ForSMArTMS,thecoilwaspositionedovertheSMA,whichwaslocalizedviathe10–20EEGsystem,anddefinedas15%ofthedistancebetweennasionandinionanteriortothevertexinthesagittalplane[43].IntheSMA-rTMSprotocol,TMSwasdeliveredat120%ofAMT.Stimulationfrequencywas1 Hz,whichwasappliedfor30 min,resultinginatotalof1800pulsespersession.Stimulationwasperformedonceaday,3 daysperweekfor7 weeks,resultingin20sessions(36,000pulsesover20sessions).ForDLPFCrTMS,allpatientsreceivedbilateralstimulation,basedonresultsofpreviousstudiesthatshowedmixedeffectsofunilateralrTMS[35].ForDLPFCrTMS,thepositionofthecoilwas5 cmanterioralongaparasagittallinefromthesiteofoptimumAPBstimulation[44].StimulationwasdeliveredovertherightandleftDLPFCrespectively.First,15 minof1 Hzstimulation(inhibitory) at120%AMT,resultinginatotalof900pulsespersession,wasappliedovertherightDLPFC,resultinginatotalof18,000pulsesover20sessions.TheleftDLPFCwasstimulatedimmediatelyafterwardsbyapplying10 Hzstimulation(excitatory) at120%AMTvia60stimulationtrainsofadurationof5 seach,with10 sinter-trainintervals,resultinginatotalof3000pulsespersessionin15 min(60,000pulsesover20sessions).ClinicalprocedureAllpatientsunderwentabaselineclinicalassessmentwiththeY-BOCS,BeckAnxietyInventory(BAI)[45]andBeckDepressionInventory(BDI-II)[46]1weekbeforerTMStreatment(pre-treatment)andafterthe20thsessionofrTMS(post-treatment)(Fig. 1).ParticipantsreceivedSMAorDLPFCrTMSbasedontheclinicalimpressionofapsychiatristaccordingtothereportedsymptoms.Althoughnosignificantdifferencewasfoundinparticipants’depressivesymptomsbasedonthequestionnaires,thosewhoreportedmoredepressivesymptomswereallocatedtoDLPFCrTMS.Baselinesymptomseverityforinclusionwasdefinedasascoreof16orhigherontheY-BOCS(Mean = 22.20,SD = 7.01),whichisthecut-offcriterionformoderateOCD(8–15mild,16–23moderate,24–31severe,32–40extreme).Treatmentresponsewasdefinedasareductionofatleast30%intheY-BOCStotalscore,basedonseveralpreviousstudies[33,47]andissuggestedtorepresentarelevantclinicalimprovement(i.e.,improvementofClinicalGlobalImpression).Although35%ofsymptomreductionistakenas“response”criterioninotherstudies[48],wechoseamoreliberalcriteriontoachieveamorebalancedresponsedistributionforthebinaryregressionanalysis.TheprotocolwasconductedinaccordancewiththelatestversionoftheDeclarationofHelsinkiandwasapprovedbytheInstitutionalReviewBoardandethicalcommitteeatthelocaluniversityandAtiehClinicalNeuroscienceCenter. Fig.1TheprocedureofrTMStreatment.Note:Y-BOCS=Yale-BrownObsessive-CompulsiveScale;BAI = BeckAnxietyInventory;BDI-II = BeckDepressionInventory;SMA = supplementarymotorarea;DLPFC = dorsolateralprefrontalcortexFullsizeimageMeasuresY-BOCSTheY-BOCSisthemostwidelyusedclinician-ratedinterviewforassessingOCDsymptomseveritywithadequatepsychometriccharacteristics(i.e.,inter-raterreliabilityandpredictivevalidity)[49].Itcontains10items,andeachitemisratedfrom0(nosymptoms)to4(extremesymptoms).TheY-BOCSissensitivetochange,andduring-treatmentscorereductionsarevalidoutcomeindicators[49].Therefore,resultsofthisquestionnairearesuitedasclinicalpredictorsoftreatmentresponse,asshownbypreviousrTMSstudies[37].TheY-BOCSitemsweighobsessionsandcompulsionsequally.Obsessionitemsassessspenttimeonobsessions(item1),interference(item2)anddistress(item3)duetoobsessivethoughts,resistanceagainstobsessions(item4)anddegreeofcontroloverobsessivethoughts(item5).Items6–10assessrespectivevariables(i.e.,spenttime,interference,distress,resistance,anddegreeofcontrol)forcompulsionsrespectively.BAI&BDI-IIBothBAIandBDI-IIconsistof21items,whichareratedonaLikertscalerangingfrom0to3,resultinginrawscoresrangingfrom0to63,andareindicativeforthepresenceofanxietyordepression.TheBAIiswellsuitedtomonitoranxietytreatmentoutcomes[50],andtheobtainedanxietystateiscorrelatedwithOCDsymptoms[51,52].Similarly,theBDI-IIscoresareassociatedwithOCDsymptoms[52]inlinewiththefactthataroundone-thirdofOCDpatientssufferfromcomorbiddepression[53].Bothmeasureshaveadequatepsychometricproperties[54,55].StatisticalanalysisDataanalyseswereconductedusingIBM,SPSS(version24).InordertoexaminerTMSefficacy,mixedmodelanalysisofvariance(ANOVA)wasconductedwith“protocol”(DLPFCrTMSvs.SMArTMS)asthebetween-subjectandtime(pre-interventionvs.post-intervention)asthewithin-subjectfactors.Mauchly’stestwasusedtoevaluatesphericityofthedataandincaseofviolationofsphericity,degreesoffreedomwerecorrectedusingtheGreenhouse–Geisserestimatesofsphericity.ThenormalityandhomogeneityofthedatawereconfirmedbyShapiro-WilkandLevintests,respectively.ForidentifyingdemographicandclinicalpredictorsofresponsetorTMStreatment,participantsweresplitinto“responders”and“non-responders”andabinarylogisticregression wasconducted.Tocontrolforpotentialconfoundingvariables,weaddedthesevariables intothemodel,asthemodeladjustsitselfforpotentialconfoundersusingadjustedodds-ratio[56].ThegoodnessoffitwasevaluatedbytheHosmer-Lemeshawstatistic,whichalsoadjustsforpotentialcovariates,andthevariableselectionwasbasedonthe“stepwiseforward”strategyduetoalargesetofpotentialindependentvariables.Themodelwasrunin2stepsinallanalyses.Independentvariableswereage,gender,education,maritalstatus(asdemographicvariables),andclinicalfactorswereselected basedonthe3-factorand2-factormodelofY-BOCS,aswellasall10itemsoftheY-BOCSthatareassumedtomeasuredifferentOCDsymptoms.GiventhattheY-BOCSitemsarenotindependentofeachother,wefirstdefined3and2factors-basedonrespectivemodelsderivedfromsingleitems[57,58]-asclinicalpredictorsinseparateanalyses.Afterwardandinaseparateanalysis,eachindividualitemwastreatedasapotentialclinicalpredictorofresponsetorTMStreatment.Werantheregressionanalysisseparatelyforthedemographicvariables,Y-BOCSfactors,andtheY-BOCSitemsinordernottoincreasethenumberofpredictorsassuggested[59].Todiagnosemulticollinearity,weusedthelinearregressionprocedureandenteredallcovariatesinthemodel.Asignificancelevelofp