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ComprehensivePsychiatry106(2021)152223 Contents lists available at ScienceDirect ComprehensivePsychiatry journalhomepage:www.elsevier.com/locate/comppsych Cognitive behavioural therapy with exposure and response prevention in the treatment of obsessive-compulsive disorder: A systematic reviewandmeta-analysisofrandomisedcontrolledtrials a,b, a c d d ⁎ JemmaE.Reid , Keith R. Laws , Lynne Drummond , Matteo Vismara , Benedetta Grancini , a,b a,b,e Davis Mpavaenda , Naomi A. Fineberg a University of Hertfordshire, Hatfield, Hertfordshire, UK b Hertfordshire Partnership University NHS Foundation Trust, Hertfordshire, UK c South West London and St George's NHS Trust, UK d University of Milan, Department of Biomedical and Clinical Sciences Luigi Sacco, Milano, Italy e University of Cambridge School of Clinical Medicine, Cambridge, UK article info abstract Available online xxxx Background: Cognitive behavioural therapy (CBT), incorporating exposure and response prevention (ERP) is widely recognised as the psychological treatment of choice for obsessive-compulsive disorder (OCD). Uncer- Keywords: tainty remainshoweveraboutthemagnitudeoftheeffectofCBTwithERPandtheimpactofmoderatingfactors Cognitive behavioural therapy in patients with OCD. Exposureandresponseprevention Method:Thissystematicreviewandmeta-analysisassessedrandomised-controlledtrialsofCBTwithERPinpa- researcher allegiance tientsofallageswithOCD.ThestudywaspreregisteredinPROSPERO(CRD42019122311).Theprimaryoutcome Meta-analysis wasend-of-trial OCD symptomscores. The moderating effects of patient-related and study-related factors in- Obsessive-compulsive disorder cluding type of control intervention and risk of bias were examined. Additional exploratory analyses assessed theeffects of treatment fidelity and impact of researcher allegiance. Results: Thirty-six studies were included, involving 2020 patients (537 children/adolescents and 1483 adults) with1005assignedtoCBTwithERPand1015tocontrolconditions.Whencomparedagainstallcontrolcondi- tions, a large pooled effect size (ES) emerged in favour of CBT with ERP (g=0.74: 95% CI = 0.51 to 0.97 k = 36),whichappearedtodiminishwithincreasingage.WhileCBTwithERPwasmoreeffectivethanpsychological placebo(g=1.1395%CI0.71to1.55,k=10),itwasnomoreeffectivethanotheractiveformsofpsychological therapy(g =−0.05:95%CI−0.27to0.16,k=8).Similarly,whereasCBTwithERPwassignificantlysuperior whencomparedtoallformsofpharmacologicaltreatment(g=0.36:95%CI0.7to0.64,k=7),theeffectbecame marginalwhencomparedwithadequatedosagesofpharmacotherapyforOCD(g=0.32:95%CI−0.00to0.64, k=6).Aminorityofstudies(k=8)weredeemedtobeatlowriskofbias.Moreover,threequartersofstudies (k=28)demonstratedsuspectedresearcherallegianceandthesestudiesreportedalargeES(g=0.95:95%CI 0.69 to 1.2), while those without suspected researcher allegiance (k = 8) indicated that CBT with ERP was not efficacious (g = 0.02: 95% CI −0.29 to 0.33). Conclusions: AlargeeffectsizewasfoundforCBTwithERPinreducingthesymptomsofOCD,butdependsupon thechoiceofcomparatorcontrol.Thismeta-analysisalsohighlightsconcernsaboutthemethodologicalrigorand reporting of published studies of CBT with ERP in OCD. In particular, efficacy was strongly linked to researcher allegiance and this requires further future investigation. ©2021PublishedbyElsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction................................................................2 2. Aims...................................................................3 3. Method..................................................................3 ⁎ Corresponding author at: Hertfordshire Partnership University NHS Foundation Trust, Rosanne House, Parkway, Welwyn Garden City, Hertfordshire AL8 6HG, UK. E-mail address: jemma.reid1@nhs.net (J.E. Reid). https://doi.org/10.1016/j.comppsych.2021.152223 0010-440X/©2021PublishedbyElsevierInc.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/). J.E. Reid, K.R. Laws, L. Drummond et al. Comprehensive Psychiatry 106 (2021) 152223 3.1. Primaryoutcome..........................................................4 3.2. Secondaryoutcomes.........................................................4 3.2.1. Sub-groups.........................................................4 3.2.2. Moderators.........................................................4 3.3. Bias................................................................4 3.4. Exploratoryoutcomes........................................................4 3.4.1. Treatment fidelity......................................................4 3.4.2. Researcherallegiance....................................................4 3.5. Analysis..............................................................4 4. Results..................................................................4 4.1. Publicationbias...........................................................5 4.2. Moderatorandexploratoryanalyses.................................................5 4.3. Controltype............................................................5 4.4. Researcherallegiancebias......................................................6 4.5. Adultsvschildren..........................................................6 4.6. Groupvsindividualtherapy.....................................................7 4.7. Othermoderatoranalyses......................................................7 4.8. Riskofbias.............................................................7 5. Discussion.................................................................8 6. Conclusions............................................................... 11 References.................................................................. 11 1. Introduction practice guidelines [7] which also concluded that CBT primarily based on behavioural techniques such as ERP has the strongest evidence Obsessive Compulsive Disorder (OCD) is a highly debilitating and baseforefficacy.Incontrast,themorerecentlyupdatedBritishAssocia- disabling illness, associated with significant impairment both of the tionofPsychopharmacologyguidancecitesevidenceforERPmonother- quality of life of the affected individual and on a wider societal scale in apy, cognitive therapy as a monotherapy and a combination of the two terms of loss of productivity and functioning (Hollander et al. [1]). as being effective [10]. Indeed, both documents acknowledge that, OCD is relatively common with a 12-month prevalence of approxi- based on the available evidence, we cannot yet determine which ele- mately 1.2% (DSM-5) [2]. The illness usually emerges in childhood or ments of CBT are most responsible for its success. What is, however, early adulthood and runs a chronic, relapsing course (Fineberg et al. clear is that determiningtheprecisetypeofCBTdeliveredfromreading [3]). Detection of OCD frequentlyoccurs late and manypatients experi- thedescriptionsgiveninmanyofthepublishedtreatmenttrialscanbe ence untreated illness for a significant length of time before receiving difficult. It is also evident from the variability within published studies treatment (Dell'Osso et al. [4]). Increasingly, evidence suggests that a andsubsequentmeta-analyses(seebelow)thatmodelsandstandards longerdurationofuntreatedillnessleadstopooreroutcomesandprog- vary. Of note, a recent small study in adults (Fineberg et al. [11]) that nosis (Fineberg etal.) [5]. Therefore, it is of paramount importancethat comparedSertraline monotherapy, CBT with ERP monotherapy deliv- patientswithOCDreceiveappropriatetreatmentinatimelymannerto eredstrictly accordingtoamanualisedprotocol,andcombination(Ser- reduce suffering and improve functioning. traline and CBT with ERP) therapy, found disappointing results for CBT Recommendedtreatmentsfor OCD include psychological therapy withERP.Whereascombinationtherapywasthemostefficacioustreat- with cognitive behavioural therapy (CBT) involving exposure and re- mentoptionat16weeks,theadvantagewasnotsustainedandsertra- sponseprevention(ERP)(ERPisatherapyinwhichpatientsaretaught line monotherapy was both the most efficacious and cost effective to confront and tolerate conditions that provoke obsessions and com- optionatthe52weekendpoint. pulsionsandresistactingonthem)orpharmacotherapywithaselective Previous meta-analytic evidence has largely focused on CBT rather serotoninreuptakeinhibitor(SSRI)ortheserotonergictricyclicclomip- than specifically on CBT with the ERP. For example, a recent meta- ramine.AsSSRIinOCDshowsapositivedose-responserelationship[6] analysis of pediatric OCD by Uhre et al. [12], analysed 12 randomised thehighestavailabledosagesarerecommended[7].Theinfluential2005 controlled trials comparing CBT to wait-list, psychological placebo or NICE guidelines (CG31) [8], which were based on a meta-analysis of pill placebo. Although symptoms (as measured by change in CY-BOCS) existingtrialdata,advocatetheuseoflowintensitypsychologicaltreat- were significantly reduced by CBT (MD: -8.51, 95% CI: −10.82 to ments(including ERP) for adult patients with mild symptoms of OCD. −6.18), all trials included in the analyses were deemed to be at high Monotherapy with either more intensive CBT (including ERP) or an risk of bias and the certainty of evidence was graded as ‘low’ or ‘very SSRIisrecommendedforpatientswithmoderatesymptomsorpatients low’. It is important to note that some authors challenged the findings withmildillnesswhocannottoleratelow-intensitypsychologicaltreat- on methodological grounds [13], generating a debate in the journal's ment,whereascombinationtherapy(SSRIandCBTwithERP)isrecom- pages [14,15]. A network meta-analysis of CBT and pharmacotherapy mendedforpatientswithmoresevereorresistantillness.Inthecaseof for adults with OCD by Skapinakis et al. [16,17] was unable to find a childrenandyoungpeoplewithOCD,CBTisprioritisedoverpharmaco- clearadvantageofoneformoftreatmentovertheother.Thestudyiden- therapy, to avoid potential adverse effects of medication in this age tifiedthatmostofthepatientswithinthestudieswhowereallocatedto groupandERPiscitedastherecommendedtypeofCBT[8].However, CBTwerealsotakingpharmacologicaltreatment,suggestingthatthese as the original analyses upon which this guidance is based is now wereinfact trials of combination treatment, and further highlighting more than 15 years old and as more data has since accrued (NICE difficulties in interpreting the results from studies of CBT in OCD have stated support for a review of the OCD treatment guidelines) (Skapinakis et al. [18]). [8,9], it is timely to review the evidence supporting the effectiveness Existingmeta-analyseshaverarelyexclusivelyfocusedonERPstud- of CBT involving ERP across the age range in OCD. ies, withmostanalysingERPinsub-groupanalysesofmultipleinterven- Alarge number of individual studies, varying in quality and size, tions. The earliest ERP for OCD meta-analytic finding often cited is that have demonstrated that ERP can be an effective treatment for OCD. by Christensen et al. [19] who reported a large effect size (2.34), but ThesewerereviewedindetailintheAmericanPsychiatricAssociation this was derived from a pre-post analysis of just one trial. Almost a 2 J.E. Reid, K.R. Laws, L. Drummond et al. Comprehensive Psychiatry 106 (2021) 152223 decade later Abramowitz (1996) [20] meta-analysed a substantial cor- data. In particular, the limitations of previous meta-analyses relate to pus of 24 trials (29 samples) assessing the impact of ERP on OCD in the assessment of pre-post effect sizes (Abramowitz [20]; Eddy et al. adults and reported a large effect size of 1.16 for pre-post changes. [24]; Christensen et al. [19]) or mixing pre-post and end of trial effect Pre-post effect sizes however are likely to provide unreliable and in- sizes (Kobak et al. [23]); the inclusion of small RCTs (e.g. studies by flatedeffect size estimations because of their lack of a control compari- Abramowitzetal.[22]weremostly<10perarm);theexclusionofac- son (see Cuijpers et al. [21]). It is also notable that most studies in this tive controls and a focus largely on comparisons with wait-list controls meta-analysis(17/29)hadverysmallsamples,withfewerthan10par- (Olatjunji et al. [29]; McGuire et al. [26]); a reliance on self-report mea- ticipants, which is also likely to produce less reliable findings. A second sures (Abramowitz et al. [22]); meta-analysing small numbers of ERP meta-analysis by Abramowitz [22] one year later did examine studies (McGuire et al. [26], k = 8; Eddy et al. [24] k = 2; Abramowitz randomised controlled trials in adult patient samples for whom OCD etal. [22]k=8;Ӧstetal.[28]k=7;Ӧstetal.[27],k=8;Christensen wastheprimarydiagnosis.Theanalysisincludedeightcomparisonsbe- et al. [19] k = 1), which limits the possibility of examining moderator tweenversionsofERPandotherpsychologicalinterventions.Thestudy variables (see Borenstein et al. [31]); the inclusion of non- reportedalargeeffect(usingCohen'sd)favouringERPwhenrelaxation experimental designs (e.g. Jónsson, H., & Hougaard, 2008; Rosa- wasusedasapsychological control treatment (d = 1.18; 2 studies), Alcázar et al. [25]). Some have examined only children (McGuire et al. whereaswhenERPwascomparedtocognitivetherapy(d=−0.19;4 [26]; Ӧst et al. [27]), while others only adults (Abramowitz 1996 [20]; studies) or individual components of ERP (i.e. response prevention or Ӧst et al. [28]). Most have failed to address publication bias and earlier exposureonly)nosignificanteffectofERPwasfound(d=0.59;2stud- meta-analyses produced effect size estimates based on fixed effects ies). All 8 studies exceptoneusedself-reportoutcomemeasuresandin- models. Few existing meta-analyses have assessed study quality (e.g. volvedintotalonly137participantswhoreceivedERPand105controls. Ӧstetal.[28]usedabespokemeasureandthenexaminedthisinalim- AroundthesametimeKobaketal.[23] also reported a large effect size ited way rather than as a moderator) and none appear to have used a for ERP (0.99 [0.89 to 1.08]) across 36 studies; however this analysis standardised measure risk of bias. It is also notable that, where moder- pooled data from within (pre-post) changes and end-point between atorshavebeenanalysed,previousmeta-analyseshavealsofounditdif- group changes. Later, another pre-post meta-analysis by Eddy et al. ficult to confidently identify treatment or patient factors that predict a [24] also reported a large effect size of 1.53 for ERP in 16 studies. As better outcome with ERP (Hezel and Simpson, 2019 [32]). Moreover, noted, such analyses inflate effect sizes and a further analysis was con- as the focus of previous meta-analyses has been primarily on CBT of ductedcomparingERPwithcontrols,butthisincludedjust2trials and anyform,ratherthanonethatspecificallyincorporatesERP,littleclarity indicated an effect size of 1.16. exists about thesuperiorityofCBTwithERPoverotherformsofCBTfor In a meta-analysis involving both experimental and quasi- OCDacross the full age range affected. Thus, while CBT with ERP re- experimental designs, Rosa-Alcázar et al. [25] reported a large pooled mainsthesuggestedpsychologicaltreatmentofchoiceforOCD[6],un- effect size for ERP in 13 samples (1.127, 0.80 to 1.45) and this was not certainty exists regarding its relative efficacy, the methodological significantly larger than for cognitive restructuring (CR) alone (1.09) quality and coverage of previous meta-analyses as well as the extent or ERP plus CR (0.998). to which patient or treatment-related factors might render CBT with Turningtomorerecentmeta-analyseswithsomecomponentofERP ERPthemostsuitableoptionforaparticularindividual. assessed in children, McGuire et al. [26] meta-analysed 8 randomised controlled trials of individually-delivered ERP tested in children only. 2. Aims In comparisons with non-active controls conditions (mostly waiting- list and relaxation therapy), they reported a large effect size (g = This meta-analysis aims to comprehensively evaluate the available 1.52), althoughthiswasnolargerthanfortrialsusingcognitivetherapy evidence from randomised controlled trials addressing the efficacy of (1.41). Öst et al. [27] assessed CY-BOCS changes in pediatric OCD both CBTwithERPasatreatmentforadultsandchildrenwithOCD.There- for individual and for group formats of ERP. The effect size for ERP fore, the analysis only includes studies of CBT that incorporate ERP. (g =0.68(95%CI0.18–1.18,k=8)wassomewhatsmallerthanthat Wealsoaimtoidentify whether treatment-related or patient-related of McGuire et al. [26] and smaller than that for Cognitive Therapy factors impact on the treatment-response, in order to aid clinical (g =1.04(95%CI0.45–1.63, k = 4)withtheeffect size for ERP + CT decision-making. As concerns about the methodological quality of CBT being even smaller and non-significant (g = 0.35 (95% CI −0.04 to studies have been raised in previous reviews (Olantunji et al. [29], 0.73,k=18).Ӧstetal.[28]alsopublishedameta-analysisofadulttrials Skapinakis et al. [16]), we aim to conduct a ‘risk of bias’ quality assess- andshowedthatERPdidnotdifferinefficacyfromCBTatreducingY- ment. As it is evident that the CBT delivered in previous studies has BOCS scores at end-of-trial (0.07 [95%CI -0.15 to 0.30], k = 7) or at shown considerable variability in quality, we also incorporate an follow-up (0.07 [95%CI -0.27 to 0.41; k = 4). assessment of the fidelity of the CBT with ERP delivered within this Olatunji et al. [29] combined trials of CBT and ERP in both adults meta-analysis. In addition, we assess studies for the presence of re- (k=13)andchildren(k=3),andinanassessmentof12ERPtrials,re- searcherallegiance(RA),definedastheresearchers'“beliefinthesupe- portedalargeeffectsizeof1.35(CI:0.96–1.74).However,likeMcGuire riorityofatreatmentandinthesuperiorvalidityofthetheoryofchange et al. [26], their analysis excluded trials using an active psychological that is associated with the treatment” (Leykin & DeRubeis, 2009) [33]. control and the majority (10/12) of control arms comprised wait-list controls.Theuseofwait-listgroupsinpsychotherapytrialsisalsoasso- 3. Method ciated withexaggeratedeffectsizes(Furukawaetal.[30]),anditisrea- sonable to interpret the efficacy of CBT in such studies with caution. This meta-analysis was pre-registered with the International Pro- Intriguingly, Olatunji et al. [29]werealsounabletodemonstrateanyef- spective Register of Systematic Reviews (PROSPERO: registration num- fectonoutcomesofcandidatemoderatorssuchasageatonsetofsymp- ber CRD42019122311) as a systematic review and meta-analysis of toms, duration of illness, gender, number of CBT sessions or the cognitive behavioural therapy for OCD. We subsequently refined our presence of co-morbidities. However, they did find that the control search criteria to focus exclusively on those published studies that in- groupmoderatedtheeffectsize,withwait-listcontrolcomparisonsre- cluded an ERP component within the CBT arm, as this is the form of vealing larger effect sizes than comparison to placebo controls. CBTusually recommended for OCD [7,8]. We conducted a systematic In summary, data from individual randomised controlled trials and search of the literature in accordance with PRISMA guidelines (Moher existing meta-analyses suggest that CBT with ERP is an effective treat- et al.) [34]. The electronic databases PubMed, PsychINFO and EMBASE mentmodalityforOCD.Concernsaboutmethodologicalrigorarehow- weresearchedforeligible studies. We also checked the reference lists everrepeatedlyhighlightedasalimitationoninterpretingtheavailable of relevant studies and previous systematic reviews for unidentified 3 J.E. Reid, K.R. Laws, L. Drummond et al. Comprehensive Psychiatry 106 (2021) 152223 studiesandsearchedforregisteredtrialsonwww.ClinicalTrials.govand deviations from intended interventions, missing outcome data, out- Google Scholar (http://scholar.google.dk). There was no lower limit comemeasurementandbiasinselectionofthereportedresults. with regards to publication date and searches continued until April 2020. 3.4. Exploratory outcomes Aninclusivesearchstrategywasperformedusingtheterms:‘Cogni- tive behavioural therapy’ OR ‘CBT’ OR ‘exposure response prevention’ Exploratory outcomes, which emergedduringthe stage of data col- OR ‘ERP’ AND ‘obsessive compulsive disorder’ OR ‘OCD’ generated lection and were therefore not preregistered at PROSPERO, included 2265articles.Thearticleswerethenscreenedusingthefollowinginclu- analysis of the moderating effect of treatment fidelity and the presence sion criteria: of researcher allegiance on effect size. 1. Randomised controlled trials in patients with OCD involving CBT with ERP in at least one treatment arm and a control group (which 3.4.1. Treatment fidelity couldbeanalternative(non-ERP)psychologicaltreatment,psycholog- Basedonthedescriptionsgivenwithineachstudy,anassessmentof ical placebo, pharmacological treatment or wait-list). treatment fidelity was made by an independent CBT expert (LD). This 2. The study employed the Yale-Brown Obsessive Compulsive Scale involvedassessing eachofthecomponentsofERPdeemedtobeessen- (Y-BOCS)(orsimilarsymptomseverityscale)asanoutcomemeasure. tial e.g. the presence of response prevention, the exposure being 3. Full text article published in English. prolonged, graded and regular, the therapy being collaborative and Abstracts wereinitiallyscreenedforrelevancebytwostudyauthors the level of experience of the therapist. Each component was given a (JR and NF). Papers not meeting these criteria were excluded from the score of between zero (insufficient information was available to make analysis. Accepted studies were then independently assessed by two a decision) and five (awarded where the component appeared was at membersoftheteam(JRandMV)toevaluatewhethertheyincorpo- a level consistent with recognised ‘best practice’) with a maximum rated ERP into their treatment. Protocol- disagreements were resolved available score of 35 (Individual scores are included in Table 1). bydiscussionandtheinvolvementofathirdassessor(NF).Aconsensus wasreached in all cases. 3.4.2. Researcher allegiance Our inclusive search strategy located a large number of studies, Researcher allegiance was assessed for all trials utilising the ‘re- whichoncloserexaminationweredeemedunsuitableastheydidnot searcher allegiance assessmenttool’ used by Turner et al. [36]; adapted have a non-ERP comparator treatment arm within their study design. fromCuijpers et al. [37]) in a recent meta-analysis that examined psy- Thesestudiesweresubsequentlyextractedandexcludedfromtheanal- chological interventions in psychosis. Following Turner et al. (2014) ysis. Our aim was to include studieswhereERPwasfundamentaltothe [36], we posed the following questions to evaluate the presence of re- CBTbeingapplied.Onanalysingthestudies,itwasapparentthatsignif- searcher allegiance: Is only one of the interventions mentioned in the icant variability emerged in the level of description of the included ERP title? In the introduction is one of the interventions explicitly described components.Therefore, where a published report stated that ERP was as being the main experimental intervention? Was one intervention anintegralcomponentoftheCBTbeingdelivered,weincludeditwithin specificallydescribedasacontrolcondition?Isthereanexplicithypoth- our analysis. esis that onetreatmentisexpectedtobemoreeffectivethantheother? If the answer to any of these questions was yes, the study was deemed 3.1. Primary outcome at risk of researcher allegiance. Our primary outcome measure was end-of-trial OCD symptom 3.5. Analysis scores in the CBT with ERP group versus the control group. Data were initially extracted independently by two of the authors 3.2. Secondary outcomes (JR and NF), and were then independently re-extracted by another au- thor (KL), with differences being resolved. 3.2.1. Sub-groups Pooled effect sizes were calculated using Comprehensive Meta- Sub-groupanalyseswereperformedonthestudiesstratifiedonthe analysis, version 3. The effect size employed was Hedges g, which is basisoftypeofcontrol:Threeoftheauthors(JR,NFandMV)collabora- thestandardiseddifferencebetweenmeans,correctedforthetendency tivelycategorisedallstudiesaccordingtothetypeofcontrol:activepsy- towards overestimation in small studies (Hedges, 1981). Effect sizes chological treatment (e.g. cognitive therapy, EMDR), psychological were calculated comparing end-of trial total Y-BOCS (or alternative placebo (e.g. stress management training), pharmacological treatment scale) scores for the intervention and control groups. Random-effects (e.g. SSRI), wait-list or treatment as usual (TAU). There were nostudies modelswereusedinallanalyses. 2 2 that relied on a pill placebo control. Studies were also grouped and HeterogeneitywasexaminedbyuseofQandI statistics.AnI value analysed according to whether the study population comprised adults of 0–40% suggests that heterogeneity may not be important, 30–60% or children. mayrepresent moderate heterogeneity, 50–90% may represent sub- stantial heterogeneity, and 75–100% may represent considerable het- 3.2.2. Moderators erogeneity (see Higgins & Green, Cochrane Handbook, 2011 [38]). Potential treatment moderators were examined including Publication bias was examined using the statistical techniques of patient-relatedfactors(age,durationofillness,OCDseverityatbaseline, DuvalandTweedie's (2000)[39]trimandfill, which aims to estimate depression scores at baseline and end-point) and study-related factors the number of missing studies within an analysis and the effect that (duration of treatment, control group type, details of control treatment those studies might have on outcomes. within each arm, experience level of therapists delivering CBT, and in- formation about concurrent medication), 4. Results 3.3. Bias Followingoursearchstrategyasoutlinedabove,thirty-sixtrials[11], [40-74 were included in the final analysis Fig. 1. EachstudywasassessedforriskofbiasusingtheCochraneriskof The trials involved 2020 participants (1005 receiving CBT with a bias tool version 2.0 (RoB2: Higgina Higgins et al. [35]) by two authors substantive ERP component,and1015assignedtoacontrolcondition). (JRandMV)andanydiscrepanciesresolvedbydiscussion.TheRoB2as- Thecomparatorcontrolconditionswereactivepsychologicaltreatment sessesbiasthatmayariseacrossfivedomains:biasfromrandomisation, (k =8),psychological placebo (k = 10), a pharmacological treatment 4
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