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    Psychotherapies For Generalized Anxiety Disorder in Adults: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials - Enhanced Reader

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    Ana Borges

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    each JAMA Psychiatry | Original lvestigation Psychotherapies for Generalized Anxiety Disorder in Adults A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials ‘ave Papo MO, Ph: Clr Miguel MSc Marcin Nezzapa. MO Pamela Franco. MS: Fedktco Tesch, Pi: Sara A Romero PR: ‘ola Patel PO, Govan Cars MD, PRD, Cara Gstlen, MO. PHD Ea Kayotkt PHO: Maths Het, PA, Marna PEG PO, ‘aia Pho Voam Pate MD, HD Tost Furia, MO, PAD Pen Cues, PR, Cvrado Bab, MO Stpplementa content IMoRTANCE Generalized anset disorder (GAD) sone ofthe mast common mental ‘Ssordesin adults. Psychotherapie are among the most recommended treatments for GAD, but wich shouldbe considered frstiine treatment needs tobe arf. ‘OBJECTIVE To use a network meta-analysis to examine the short andlong term associations of ferentpsychtherapies with outcomes of effectiveness and acceptability in adults wth ao, ‘DATA SOURCES MEDLINE Embase, PsycINFO, andthe Cochrane Register of Controlled Tals ‘were searched from database inception to January 1, 2023, to identify randomized circa tals (RCTS) of psychotherapies for adults with GAD. STUDY SELECTION RCTS comparing any typeof psychotherapy against another or witha contol condition forthe treatment of adults (=18 years, both sexes) with primary diagness OF GAD were eligbieforincusion. DATA EXTRACTION ANO SYNTHESIS This study followed Cochrane standard for extracting ata and assessing data quality and used the PRISMA guideline for reporting, isk of bias of individual studies was assessed using the second version of the Cochrane risk of bias tool and the Confidence in Network Meta-Analysis was used to rete the certainty of evidence for rmetaranalytcal resus. [MAIN OUTCOMES AND MEASURES Eight psjchotherapies were compared against one another and with control conditions. Primary outcomes were severity of GAD symptoms and acceptably of the psychotherapes Random effects model pairwise and network ‘meta-analyses were conducted. For effectiveness, standardized mean differences (MDs) were pooled, and fr acceptably, relative risks with 95% Cis were calculated, [RESULTS Data from 66 RTE were ncuded, fect sin estmates on data from S597 participants (mean SD], 70.99 199] women; mean [SD] age, 42.2125] yeas sugested that thir wave cognitive behavior therapies (CBT (SMD, ~0.78 (9596 Cl, 19 to-0.371 cetanty, moderate). CBT (SMD, ~0.68 [959 Cl. 1.05 to-0.32: certainty, moderate) and relaxation therapy (SMO. ~0 54 95% C, 104 to-0.05}: certainty. low) were associated with reduced GAD symptoms treatment as usual Relative risks fr llcause ‘Sscontinuaton (indication of acceptably) signaled no dflerences compared with treatments usual forall psychotherapies (eg, relative risk, 107 [95% Cl, 073157 forCBTvs treatment as usu). When excluding studies athighrikof bas, relaxation therapy ostts supetonty overtreatment as usual GMO, 0.40; 95% C115 0034), When considering anxiety severity t 3012 months after completion ofthe intervention, cnly CBT remained sieificanty associated with greater effectiveness than treatment as usual (SMD, -O58; 9596 €.-09310-023), [CONCLUSIONS AND RELEVANCE Given the evidence inthis systematic review andnetwork ‘meta-analysis for its associations with both acute andlong teem effectiveness, CBT may represent the estine therapy of GAD. Tia-wave CBTs and relaxation therapy were ‘icorsvetaad atonal associated ith short-term eetveness and may as be oteed. are. Cameeponding utr Ose Papal WD, P80, Demet ‘eal nS tigen ene Boston MA _aua Phy doo ]0Danpsyisey20283571 tanstaeraepmoae ‘iblahed one Ober 18 2023, tener). Downloaded From: ips/jamanetwork can’ on 1101/2023 Reseach Oral iestiaton Urals (RCTS) have been conducted to examine the effects of psychotherapes for generalized anxiety disorder. These studios have shown that psychological treatments have ben ficial effects, both in terms of symptom reductions and in- creased wellbeing. So far, however, quantitative syntheses of RCTsinforming psychotherapies for generalized anxiety dis ‘order have been explored only by pairwise meta-analyses, through wich tis possbleto compare nomore than 2nter- ventions atthe same time. Due tothe intrinsic imitations of thepairwise method, previous meta-analyses have mixed dif ferent treatments with active and inactive control condi tions, generating useful but not specific results regarding the eMcacy and acceptability profiles of individual types of psychotherapy Which types of paychotherapy should be pi ortized for generalized anxiety disorder is yet tobe substan tiated by a thorough and consistent investigation using a ‘method suited for this purpose. In network meta-analysis it 's possible to rank treatment options by comparing multiple treatments using both direct comparisons of interventions within RCTsand indirect comparisons across trals.“Because psychotherapy for mental health problems is dynamic and controversial” shedding light on the most appropriate psy chotherapies in terms of risk to benefit ratioisaprioity that amstoincrease recourse topsychologcalinterventionsbacked by trustworthy evidence-based science.* Given this back- ground, the present systematic review and network meta analysis assessed the comparative effectiveness and aocept- abt ofthe diferent types of psychotherapy forthetreatment ‘of adults experiencing generalized anxiety disorder. | 1 recent decades, a lage number of randomized clinical Methods ‘This systematic review and network meta-analysis was re ported acording othe Preferred Reporting tems for System atic Reviews and Meta-Analyss (PRISMA) guideline specific fornetworkmeta-analyses9(eAppendixinSupplement). ‘The study protocol was published in advance in FROSPERO. Identification and Selection of Studies ‘Twoindependentinvestigators(D.P, PF) searched MEDLINE, 'Embase, PsycINFO, and the Cochrane Register of Controlled “rials fom database inception to January 1,2023,todentily [CTs examining the effects of psychotherapy forany anxiety Aisorder compared with any other psychotherapy or control conditions, an enterprise that we termed the anxiety meta analytical researchdomain." From this pool of RCTs, thesame investigators further selected only RCTs comparingany kind of psychotherapy against another, or witha contra condi tion, forthe treatment ofadults 18 years or older, both sexes) hhavinga primary diagnosis of generalized anxiety disorder ac- cordingtoany standard operationalized criteria, includingthe esearch Diagnostic Criteria, DSM, DSM-IIE-R, DSM-IV, DSM-IV-TR, DSM5, International Statistica Classification of ‘Diseases and Related Health Problems, Tenth Revision, ot “International Classification of Diseases, Ith Revision or that selected patients with anxiety according to a cutoff ona JAMA Poyetary Pubsdesonine Cetcber 8 2023 Downloaded From: ips/jamanetwork con’ on 1101/2023 Phuc fr Gena Arty Orrin As Key Points ‘Question Whehpsychaherapes are assed with the mest effective and scatable outcomes for dus wah gereraaed arity order? lings Inthssystemaieie and network eta abso ‘sues comping 5597 partians, coger therapy (CBN. tre-vave CTs anreaxaton thoy ‘upertomed vente ati for rere feectenes after removing tte wintigh ist cfs, ony CBT nd thrtwave CBs remainedsuperir wo westmentasusua aden CaTwasasiocited withing temeffecteness Treatments ‘sual snot outperformed by ny pychterapy ners t treatment acceptably, Meaning Consderngthe ade twee eectivenes and accept efectveessin he ngterandcartanyinthe level evidence, CT shouldbe consered fat ie chce or resent of gnaaled aneety dard selEreport scale of anslety Psychotherapies could be deliv cred in any type of treatment delivery format." Twoindepen: entraters (DP, MM. extracted relevant data on study char acteristics and outcome measures. For both screening and ataextraction, disagreements were resolved by discussionand arbitration by senior review authors (PC, C.B.). For the full search strategy, see eAppendix Bin Supplement We grouped therapies in 8 nodes (behavior therapy, cognitive behavior ‘therapy (CHT), cognitiverestructuring,psychoeducation, psy chodynamic therapy, relaxation therapy, supportive psycho: therapy, and thitd-wave CBTS) and controls in 2 nodes. Two independent researchers (DP.,C.M.) classified the psycho therapies, and conflicts were resolved through discussion with senior authors (C.8.,.AF, and PC) Definitions of interven tions and controlsare given in Table Riskof Bias ‘We assessed the risk ofbias ofthe included studies using er son 2 of the Cochrane risk of bias tool for randomized tials (ROB 2.” investigators (DP, CG. and M.P. independently used the ROB 2 signaling questions toform judgments onthe '5 ROB 2 domains. Disagreements were resolved by discus son and arbitration by senior review authors (PC, C.B). Outcomes We considered 2 primary outcomes: generalized anxiety disorder symptoms at study end point (continuous outcome, indicated as effectiveness) and all-cause til discontinua- tion (dichotomous outcome, indicated as acceptability). For the effectiveness outcome, we selected scale foreach study using a preplanned hierarchical algorithm (eAppendix¢ in. Supplement D, giving priority to scales specifically devel- ‘oped for generalized anxiety disorder, All-causediscontin ation was measured as the proportion of participants who <éropped out from the end-of treatment assessment for any ree son, AS secondary outcome, we analyzed severity of an ty symptoms at 3to L2 months of follow-up aftercompletion ofthe intervention. prapsenayeem Pcotralefx Ganralzd Anety Orden Aas ‘Oferalinestanton Research aon ean nen marae efor therapy Iarveton, witht witout oleic eames. na ater att hatin or ere is tig nti rea oe ron Imereti, ith or itoat scoedcaonstcanoorenscraongcopitve ‘scttn ps bev ortesntn trp mers oth Imereti hat nso em ansasnte come tarts teal ee ‘abate vas tsa Sates sh Scat gsr, owt eg, one ‘nied rose. Foyemeeation Iason ih esr el oie infra but th rd imac ced onresig étaient Tet ag piel aig, ete ror ‘Sole cain woreda anteaters Sunpertve Inarertion thor thst syed congas, need as ssnsn which Daycmtoroy gas re sinatra stugh moran pega ese. TWrewaveCBT ——_Iarveton ining acentans ad compstnen erp. nnn ae ea, ‘denen esd ae rape samme uth ute te ‘Sree cy Sega ae cot Tiesment asus Parca rec assent ny to without sil ovr af formation ‘tocar minal eran cna ar bot noua ey wok ere este eaten sere a Pras nscontion we ypeay Samed ‘Setar cone vestments atl hecammuny when sh eae ese ‘Sewshsante om ncvnewentraron tre wate botnets J eoraee Watingte arp eeive asesnet, with win sie ain ferment ‘mimi heaps ob seunutatowtby alco acne ret eave torres Statistical Analysis Weconducteda series of pairwise meta-analyses foralldirect comparisons usinga random-effecs pooling model. For each ‘outcome, we performed a frequentist network meta-analysis, witha random-effects model. For the continuous outcome of effectiveness, we pooled the standardized mean differences (SMD) using intention-to-reat datawhen availble and com- pleters data otherwise, A 2sided P< .05 ora 959 CLexclud> ing was considered statistically significant. For thedichoto ‘mous outcome of acceptability, we calculated relative risks (Re) with 295% CL. A2-sided P< 05 or 95% Cexcluding was considered statistically significant. Dichotomous data, were calculated on a strict intention to-teat bass, consider ing the total number ofrandomlyallocatedpartcipantsasthe denominator. Corresponding to intervention definitions (rable), whena study included different groupswithasightly diferent version ofthe same intervention, we pooled these ‘roups intoa single one.!* ‘To assess the transitivity assumption, we compared thedis tribution ofthe percentage of women, mean age, number of psychotherapy sessions, and baseline symptoms severity across comparisons. Furthermore, we performed meta- regression analyses on the same variables, to identify pos- sible tretment effect moderators. We considered that disti- bution differences in specific study charactristis across the diferent comparisons were only relevant in case of signif cant imbalances according to visual inspection of box plots ‘generated forthe purpose, the Kruskal Wallis test, and meta regression analyses showing an association with treatment effect. The variance inthe random-effects dst amapsyinyccr Downloaded From: ips/jamanetwork con’ on 1101/2023 was assessed by means of in comparison with empirically erived evidence. For each comparison, we evaluated the presence ofincoherenceby comparing direct and indirect ev {dence within each closed loop and through the sie-spliting approach by using the Stata commands mvmeta, plot, and network sdespli alin the Stata network suite.” For the effectiveness outcome, we conducted a series of preplanned sensitivity analyses otest the consistency of ur preplanned outcome hierarchy and to examine whether the results forthe primary outcome of effectiveness changed when we excluded studies that included participants without fr. ‘mal diagnosis of generalized anxiety disorder andstudes that used DSM-II criteria to diagnose generalized anxiety disor der. A further sot of sensitivity analyses was carried out ex luding tials judged tobe at high rsk of bas to explore the putative associations of study quality with effectiveness and to test whether the results could be influenced by consider. ng behavior experiments either asa cognitive orabehavioral, component. If10 or more studies wereincludedin adirect pai. \wise comparison, weassessed publication bias by visually in specting the funnel plot and testing for asymmetry with the Egger regression test.*22 ‘Weassessed the certainty inthebody ofevidence forthe pr rary outcomes through the Confidence in Network Meta Analysis application.” Weals produceda treatment hierarchy bbymeansofsusface under thecumulativerankingcurve(SUCRA) and mean ranks, having treatment as usual asthe reference. ‘Statistical evaluations and production of network graphs and figures were performed using the network and network ‘raph packages in StataSE, version 16.1 (StataCorp LLO.”* InMAPayiony Aatsdednine drab 8 2023 Reseach Oral iestiaton Figo Network Plt of Eidencafor Econo Results Characteristics of Included Studies ‘The searches identified 19487 records. After removing dupi- cates and examining tiles and abstracts we selected 125 rec- fords for full-text assessment. Eventually, we selected 66 studies®*" for inelusion in the network analysis eAppen: dives DF, F, and Gin Supplement 1). Overall, 5597 partci- pants were randomly assigned to the 8 different psycho: therapies (behavior therapy, CBT, cognitive restructuring, psychoeducation psychodynamic therapy, relaxation therapy, supportive psychotherapy, and third-wave CBTS)and2lifer- ent control conditions (treatment as usual and waiting list) (Figure As shown in the Table, the mean (SD) age ofthe participants was 42.2 (12.5) years, The mean (SD) percentage of included women was 70.9% (1.9%) and of men was29.1% (4.9%). The included studies were published across 42 years (0980 02022, following progressive trend in terms of num- ber of publications per decade. Studies were generally short (0-12 weeks), with follow-up observations up to I year after treatment completion (mean (SD), 24.5 [14.2] weeks). The ‘mean (SD) numberof therapy sessions was Il (5) per RCT. ‘Twenty-seven stadles (ny! 27 2h 96 2598,40. 50553505 £00570.72.7679,889 yoed scales specifically designed to cap ture generalized anxiety disorder symptoms. Risk of Bias Evaluation ‘Twenty-three studies (2534)"9-# 28.7 40. 4.0871.75.88.0.95 89 were a high risk of bias, 32 studies (4995) 26. 28.20.3620 448 4440515565258 6005627079. 86.09 were evaluated ashaving “some concerns” and 11 studies (1794139994.556308092779 20 were considered at low risk ofbia Table2, eappendix HinSupplement tn the domain of “selection ofthe reported result" the majority of the RCTs failed to provide information onthe study protocol and the preplanned analysis plan leading to "some con: coms” judgment in 42 studies (649). 2628 9.529.952 JAMA PsyetaryPubsdesonine Cetcber 8 2023 Downloaded From: ips/jamanetwork con’ on 1101/2023 Phuc fr Gena Arty Orrin As etree Lemire epranao the Sreesaes proportion ‘tener Gayest scutes erg ses fol Cat natn nate 40,4, 445,475,568 62,6497, 70,7275, 8085978, 4 tudes (6ay24262820.22 2495.97.90, 4045 4.5853, 56.0,64 00" 26% "7.8.4.9. fled to adequately report onthe randomiza tion proces inthe “randomization process" domain, with de tails on allocation concealment being almost never reported. ‘That RCT statistical analyses were carried out mainly follow Inga per-protocol approach (44 (67%) had a backlash on the “deviations from the intended interventions” domain, with ‘more than half the studies being classified as either having Someconcerns (22 [33%e)>#3# 280.9898 0-9-1058 70.0. ora highs (19 [2996 729-22 25.97.0-0 5 seh e4 06, 7475.82.84.85 88 Qn the other hand, 60 RCTS (o1n?4213)-748-0,6:0-707-4980 bad low iskofbiasin the measurement ofthe outcome, Study Outcomes Figure shows the network plot forthe primary effectiveness ‘outcome. We foundno evidence of violations ofthe transi ity assumption when assessing the distribution of effect, ‘modifersacross comparisons (eAppendix in Supplement Result for both primary outcomes (effectiveness and acept ability) are shown in Figure 2in the form ofanet league table and in Figure3as forest plots. Forthe? primary outcomes, all standard pairwise meta-analyses, network meta-analyses, assessments of heterogeneity and incoherence, smal study effect and quality of evidencearereported in eAppendic and eappendix Kin Supplement ‘Third-wave CBTs (SMD, -0.78 [959% Cl -1.19 to -0.37} SUCRA, 89756; moderate certainty), CBT (SMD,-0.68[959%CI, 1.05 to ~0.32); SUGRA, 82.2%; moderate certainty), and re laxation therapy SMD, -0.54[95%6 Cl, ~LO4to-0.05},SUCRA, 68.4%:low certainty) were superiorbothto treatment asusual (eference) and watinglist SMD, 0.37(95%4Cl, -0.04 100.78}; SSUCRA, 4.2%; low certainty) inelievng the symptoms of gen cralized anxiety disorder. No significant differences in terms of effectiveness between psychotherapies were found (Figure and Figure 3). The global twas 0.29, and there was no ev {dence of global inconsistency according to the design-by prapsenayeem Pcotralefx Ganralzd Anety Orden Aas ‘Tibia? Character of Randomized Gia raked ithe Network etary ‘arc Su a0) ‘ex me 5) ef pra Men rs249) ores roscins) ae mean sO). y 22025) 190.1990 se 150-2000 sa) 2001-2010 cc) 20112022 35055) a 260) 16 265) 2736 26) ry Bee nas 368) 2756 820) moe of ens “4 2468) on B09) nao 1909) tot bas lows nap Sone cones 249) Highs B00 ‘peek mi neon totes 269) Per rte an ‘pect come cet Focsedon gna ese nan Focsedon ety 3768 fomadeneiny 26) *otewp data wer proved 35585, or thierry ofeanes ee append CSupionet treatment interaction test (¢,17.78;P = 81).None of 23 loops (@2triangular, quadratic showed signs ofincoherence when tested through the loop-specfic approach. There was no in- consistency between direct and indirect estimates, as inves tigated through the sidesplit all Stata command. Regardingthe certainty in the evidence asessed through the Confidence in Network Meta-Analysis tool, we didnot rate any ofthe com: parisonsashigh certainty, mainly because of within-study bias and heterogeneity. Certainty in the estimate was mainly low, with selected comparisons scoring moderate or very low (onostly indirect comparisons). We identified 2 comparisons featuring more than 10 studies (waiting list vs CBT?-92.5 uaeatnshsnsesbo. cher 6077276998085. and thd wave CBTS vs CBT?25260154037%018.0426; both the visual Inspection ofthe funnel plotand the Eggertest were negative for small study effects. amapsyinyccr Downloaded From: ips/jamanetwork con’ on 1101/2023 ‘Oferalinestanton Research ‘Apart from psychoeducation, which was slightly Tess fceepted than thid-wave CBTS and waiting list, no differ- fences for the primary acceptability outcome were found between different psychotherapies, between psychothera- pies and comparators, and between comparators (eg, RR, 107 (95% Cl, 0.73 1.57] for CBT vs treatment as usual) (igure 2). The acceptability network showed low heteroge neity (€? = 0.04; P= 24), no incoherence was found at the Joop level, and the design-by-treatment interaction model {indicated no incoherence in the network (= 174; P =.) There was no evidence of inconsistency between all direct and indirect estimates. No comparison gained the rating of high certainty in the estimate. Most comparisons were rated at moderate or low certainty. We identified just 1 comparison featuring more than 10 studies (waiting list vs CBT!” Bo, e556 58 59,6163, 677 5,76 79.8.5-8), but we detected no small study effect, ‘At 3to 12 months aftr the completion ofthe study sec ‘ondary outcome: effectiveness at follow-up) (eAppendix Lin Supplement 1), only CBT performed better than treatment as ‘usual (SMD, -0.58;95%6CI -0.93 0-0.23),andtheeffectsizes for third-wave CRTs and relaxation therapy became demon: strably smaller than for the acute phase. eAppendix lin Supplement I shows that decreased to 0.19, and the other tests provided no evidence of inconsistency at both the net work (= 5.33; = S1)and loop levels Sensitivity Analysis Preplanned sensitivity analyses (eappendix M in Supple ‘ment I) indicated the intemal consistency of our outcome Inerarchy, with results ofthe effectiveness analysis remain ing overall unaltered when considering each of the 3 types ‘of outcome scales at the top of the hierarchy and when. each of these types of outcome scales was considered as ‘unique contributors of data forthe primary effectiveness ‘outcome. Also results remained unaltered after excluding studies***°562 that enrolled participants scoring above threshold on anxiety questionnaires but who had not, received a formal diagnosis of generalized anxiety disorder and studies™#4855. that used DSM-II criteria to establish the diagnosis of generalized anxiety disorder. Tree add tional post hoc sensitivity analyses conducted (eAppendix N in Supplement) showed that excluding 23 studies with high tisk of bias (ssn)? 250 4040750 asco c663055, from the network caused a decrease inthe effec: tiveness of relaxation therapy (SMD, ~0.40; 95% Cl, ~115 to 0.34), which los its superiority over treatment as usual. The effectiveness ranking of psychotherapies did not change when CBT trial groups delivering cognitive restructuring and behavior experiments to test belief were counted as cogni- tive restructuring instead of CBT. Finally, the exclusion of CTs that performed statistical analyses following a per- protocol approach led to the exclusion of two-thirds ofthe tudieg 2422025 2430, 403,005023,9,sn59 even et 74% 29,82 85.5729 and the network analysis became underpow- xed to detect differences between intervention and control conditions. eAppendix O in Supplement 1 gives the differ. ences between the prespecified protocol and this report InMAPayiony Aatsdednine drab 8 2023 Reseach Oral iestiaton ‘PcethepefoGenaland Arie Dorin Fipwe2 Net League Table of Hed to Head Comparisons caitaion costisban)| (ities) cu0t129)| casSio1s0)| (4509) C12z 179 (2.164155) cossisagn| costiea2 astie139 Castie10n| (1106139) cosseo7s| (16ht09 coskte1sy casros9| 1596109 coutisi an) coxbe0a0) astern cassier2n| corer costatan cxifadan| costaosn| cudwoan| azieooa)| (rasio04s)| (1.26%008)| -1.58%004)| Stand res arene and 95% Clee apo fr pray sutcone af efectnenes iit) with stnaremamen eres Ibwernan 0 scrngth cn dfn esr fae i 95% Cre rpeedtr the pm aceare of cepa ited, wth ‘ate over han aor tec fiir eset. Groen repeats nevertons wnt (reser sl Wang) cote “Sristeysieaerenite e dare retainer agnivetchver they Fire 3 Forest Ps or fectveness and Accoplabliy, Corpaing Each Payhotherapy Wi Tear as Usa AL) eanssco__ neta TA ane oe aeciee-o notation ica s3t608) : eoverthenpy 240886046) . reamamceaey —-022¢097605), a — Score poehthenny 021 08646) x Cemiereecing 01321186080) - watatit ta7coatiea7e) : ‘won 5c) 5) Aap marta sae s¥cn_mrein TH Capers O88 O11) nstngit 07802910129 Sppriepehotercy 095(05210 167) ar osn(outs137) Tiree 033 (08010145) eoatonnenpy 115 (083102.2) Pyertrametrey 1880888048) 2isiosive755), ana souiaare se) — Mean o5809 elec vena orb pos isTAL CBT eres cope bao hey Discussion “Thiseystematicreview and networkmeta-analysisfound mod: erate to lange effect sizes favoring third-wave CBT, CBT, and. relaxation therapy overtreatment as usual fortreatmentofthe acute phase of generalized anxiety disorder. We noted no ef- fectiveness differences between different types of psycho therapies and did nt detect critical diferencesin temsofac- ceptabilty The latter finding suggests that any psychotherapy {sas accepted streatments usual. Results from oursecond: ary outcome analysis, suggesting thatafteramean($D)of24.5 (04.2) weeks from the end ofthe psychotherapy only CBT re ‘mained more effective than treatment as usta, are consis tent with previous findings.* JAMA Paytiany Pubsredenine ber 8 2023 Downloaded From: ips/jamanetwork con’ on 1101/2023 Although network meta-analyses are more specific than pairwisemeta-analysesin disentanglingand systematizingthe Afferent psychotherapy protocols, theboundariesbetween dit ferent kindsof psychotherapis are often blurred and stand lone intervention can also bea component ofa more struc tured psychotherapy. For example, astandard package of CBT for generalized anxiety disorder typically includes both cog nitive restructuring and applied relaxation along with educa tion sbout the nature of anxiety, traininginthe recognition and ‘monitoring of situational, physiological, cognitive, and be- havior cues astociated with anxious responding, and imagi nal exposure to anxiety cues coupled with coping skill, rehearsal # Welimited the overlapbetween therapiesby iso lating the 2 most important CBT components in 2 separate nodes: cognitive restructuring and relaxation therapy. While prapsenayeem Pcotralefx Ganralzd Anety Orden Aas pure cognitive restructuring was not adecisively active igre dient when consideredalone, relaxation therapy continues to occupyan ambiguousroleinthe treatment of generalized an ety disorder.*** Relaxation therapy outperformed treatment 8s usual in the main analysis but couké not stand its ranking position when high-risk of bas studies were removed ina sen sitivity analysis o at fellow-up assessment. Also, the level of certainty in the evidence for relaxation therapy in the main. analysis was judged as low, mainly for concerns telated to statistical heterogeneity. While our findings supportotheresearch showing that tra ditional CBT itself isthe leading psychotherapy for general ‘nedanniety dsorder,'as wellasfor other anxiety disorders," third-wave CBT have recently emergedassoidalternatives.”” Inrecent times, there hasbeen growing intrest in testing third wave CBTsacross mood and anxiety disorders. Theburstinthe production of randomized evidence on third-wave CBT was captured by oursystematicreview,asonly ofthe 20 RCTsae sessing them was published before 2010." The third wave of (CBT hitthe shore decades ago,” leaning ona set of new be hhavior and cognitive approaches based on contextual con cepts focused more on the persons relationship to thought, and emotion than ontheir content.» Ourfindingson the equal effectiveness associated with traditional CRT and third wave (CBTS ate consistent with those from RCTs comparing such psychotherapies head-to-head and are also aligned with the results of previous meta-analyses." ‘Our findings have implications for policy and practice. Clinica guidelines unanimously recommend CBT for the reat- ment of adults with generalized anxiety dizorer.” Na tional institute for Health and Care Excellence guidelines also recommend applied relaxations the first-linechoice While ‘ourresults largely confirm these indications cautions needed when recommending relaxation techniques as stand-alone interventions. Relaxation techniques may bebest valued when considered embeded in CBT protocols. Cognitive behavior therapy isequally more effective than treatment asusual when 4elivered in the individual, group, or guided self-help deliv ery format.°" 4 recent trial showed thatthe same CBT pro: tocol equally effective for generalized anxiety disorder when delivered in person or by videoconference.“ Policymakers, should inform service organization according toa stepped care approach, in which people are first offered flexible and low- cost options (eg, guided self-help programs, videoconferenc- in) followed by more intensive and structured therapies (2, ‘in-person psychotherapy, drug therapy) in case of need. Fu ture guidelines should alo consider the mounting and slid evidence on third-wave CBTS. ‘Tothebest ofour knowledge, the present study is thelr cst systematicreview summarizing quantitaiveeffectsabout theeffectivenessand acceptabilt of psychotherapes for gen eralized anxiety disorder. Through the use of network meta- analysis methods, we compared all availabe psychothera- pies, administered in any delivery format. We selected 1 ‘outcome measure foreach study using @ preplanned out- comebierarchy We tested such hierarchy ina st of prespec: fied sensitivity analyses, which demonstrated that findings do not change when scales on “worry symptoms” or “anxiety amapsyinyccr Downloaded From: ips/jamanetwork con’ on 1101/2023 ‘Oferalinestanton Research symptoms" wete prioritized over scales on “generalized an ety symptoms.” lso, our results demonstrated that behavior experiments to test beliefs do not tip the effectiveness bal- nce when considered part of either cognitiverestructuring or (Br protocols Limitations This study has limitations. First, the included RCTs were published over a relatively long period. This has inevitably Introduced heterogeneity in terms of study design, diagnos Uc itera, and follow-up periods. The overall interpretation ofthe findings should thus be cautious. Second, our analysis was based on aggregate-level data, and results ofthe present, Investigation are informative for prototypical patients only. Further analyses based on individual participant data are warranted to explore the influence of paticipant-level prog nostic factors and effect modifiers an intervention autcomes.. ‘Third, one-third ofthe studies were judged tobe at high risk of bias. The most frequent methodological shortcomings were the failure to report details of allocation concealment, Jack of earty on how trial authors handled missing partic. pant data, andthe low rates of studies that were accompa nied by their prespecified analytical plans. Furthermore, two-thirds ofthe studies didnot analyze data according to Intention-to-treat principles, and this could have introduced. a source of bias in favor ofthe experimental conditions. Fourth, since psychotherapy protocol of different therapies frequently share similar theoretical background and active components, on selected occasions it was dificult to draw straight lines between different types of psychothorapies. To ‘maximize the reliability of our findings, 2 independent. researchers classified the psychotherapies, and help was sought directly from the trial authors when needed. Compo- nent analyses are warranted to disentangle efficacy of com ponents separately or in various combinations. Filth, only a selection of possible outcomes was considered. While potentially interesting to investigate, information on out- ‘comes such as functioning, quality of life, or psychotherapy adverse effects was seldom reported in the trial reports. We reasoned that pooling data on such secondary outcomes, would have led to findings potentially biased by random error and of uncertain clinieal meaning. Sixth, although comorbidity between generalized anxiety disorder and other ‘mental health disorders is common, due to scant and incon sistent information nthe trial reports, we were unable to test whether the presence of comorbidities at baseline was asso ciated with the treatment outcome, Finally, the network ‘meta-analysis approach isnot free from technical and theo: retical shortcomings, including rsks of multiple statistical assumptions andthe challenges in addressing the problems of intransitvty and inconsistency." Conclusions ‘Moderate certainty in the evidence assessed in this system: aticreview and network meta-analysis suggests that CBT and thied-wave CBTSsareassocated with effectivenessintheacute InMAPayiony Aatsdednine drab 8 2023 Reseach Oral iestiaton phase of generalized anxiety disorder. Although formally superior to treatment as usual the main analysis, the low level of certainty in the evidence together with insights from secondary analyses call for further evidence toclarfytherole of relaxation therapy when considered asa standalone inter vention. In the longer term, only traditional CBT remained Accepted Peto Apt? 202. Pulsed Onine tbe 2023 sevici00ierapehan) 20233871 (ovat ude the tame ofthe Coby Lee napa Dat A Pena Atha Afton: Depart of abl eath {ndsealMedene Hanardieacs So Boson Masha Pod, Acer Vat ‘WO clare catefer scars 2 Tranngintiealiesthand series ation Unies of ero vacna tay eel srg Td rn ato, aga Seu secton of Paya, Deane Scenes, verity of ena Verona, ly (Papi zal, edt, Gtr estan Pg. Sab) Seton of ina Peo Depurmert Cina New ander Poco Vleet ansterdr he eters gt Kayak Sitar pes: WHO Colibortg Cree Reseach {ndDasemnaton of Paha ees Srwterd Publ Heath erin ‘Rete than gue aya Sif cupers: epanet of Pare entices tes Che Satag, Gilera ilerniminste fo Rese in Depress Poy MDA Santos, iletFaca Hava TH Chan Scot fPIC Heath ard Ue, ost sachets (4A aes Poel & Da Metal Heath (Ge Deputies, Teh ‘sty aneh, Munch Geary are Deparment Meat Proton an ana Beavor Wore Unersy rede efor Nedine!cnodol aie Hest Ky pan (ran. ‘Author Contratons Ppl hatllacest9 let he dat thst repertty Torte gry ofthe ota nt aca ofthe ceasayss Wiest oreo eremences ‘Siperson osu pupa V Pat Cpe, Bro ‘confctof ret Diclnures Or Het ‘puted puttin empiyeceCETON inate fe One est ranger 28 etobets rsprangjpertedrecavig gets fromthe urpeanUnen ute raed ero Fuanarepoteecawrgperraees ‘Fomomigergsnem.O eo. ‘Urersty Oren shop roy owe the mited war ree are rm se (nadethesubntedwark sponges {orto spp kare Mis Tanabe Nooterdatesues nee epoed Funding Support Ths nas func te reach progam ude pagent oleof he Fuerponsor: Te fonder ofl nthe csgnand cont ofthe Stu lecton manageren rs nd ‘raretaiono ne dat preparation review ‘Sprolottnemsnserp ard dcsiontsutnit ‘emarscit raion ata surg tatomert Soper 1. Cupar ce 8 ana ele {ide How flectverecognve behave ‘ene frm depen adarmty (Ger amet te eve, Wer Pet 201653)245 258. coo 1002! 2 carded Saget A 24. leans vesindO energies Dachogea sme ant deed ‘neta anaysso flow p suds B Pyenory. 2016201535358 ao Op 203889. Botingt anders, oyogcal eaten clgmealadancey due amen sae. GPa 2043403010 SOD ‘PcethepefoGenaland Arie Dorin associated with greater effectiveness than treatment asustal; hhence, CHT should be considered th fs-line psychological treatment of generalized aniety disorder. Data analysesusing ‘the component method arenceded to shed light on which com Ponents ae the most effective across the different psycho- therapy protocols. Bebe Ther 2008469129632 d10106) sbae200712005 8. Ler 50. whats" Paretheape? Wed yey 2018). 55.246 ao oda 20054 9 fan9 Sant cael OM a he Pataikenenionsateren or rparngst ‘remat resesinepastng wc Imeteorasesof eaters (hector expansions ered 215, taun.77- 784 076-2305 10, Paget Mek Ses PA eta The PRs 2020 tere an ote gael er ‘eprtngsyenate eves. 202137200. ‘auianbotrear 1 Gps ges. Papa Hane anole. Fm ung systenairevewsto Inebaraalesere oma 6 Bes Mt Heath. 202225145 47 ds 1Ta6 ements 12 Pepa On Tec atl CBT {Teaent lery oma for pan dsr {opomterevewandnetwcrkmet ara of ‘ardomed contol Us Peel ed. 202353 (Ghee ert 10750033251722009608 1 sure AC Soe age eta R62 rend ole seinen ‘anders Bw. 20938514658, fessor 858 14. His, Thomas. 3 Chander ete advan Haak teat ees evento ded. We 209. 15. Onn, Seto Toei et alana longucigartpayenti la resse penton 2 ‘csoprena sperm ears aa Ine arayasofo7 none wb LaeAsporerars Word Pyehiony 2022212) 235307 cuz. 20972 16. 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