{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:34:36Z","timestamp":1793424876874,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pmed.1003664","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Anxiety, obsessive-compulsive, and stress-related disorders frequently co-occur, and patients often present symptoms of several domains. Treatment involves the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), but data on comparative efficacy and acceptability are lacking. We aimed to compare the efficacy of SSRIs, SNRIs, and placebo in multiple symptom domains in patients with these diagnoses over the lifespan through a 3-level network meta-analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      We searched for published and unpublished randomized controlled trials that aimed to assess the efficacy of SSRIs or SNRIs in participants (adults and children) with diagnosis of any anxiety, obsessive-compulsive, or stress-related disorder in MEDLINE, PsycINFO, Embase, and Cochrane Library from inception to 23 April 2015, with an update on 11 November 2020. We supplemented electronic database searches with manual searches for published and unpublished randomized controlled trials registered in publicly accessible clinical trial registries and pharmaceutical companies\u2019 databases. No restriction was made regarding comorbidities with any other mental disorder, participants\u2019 age and sex, blinding of participants and researchers, date of publication, or study language. The primary outcome was the aggregate measure of internalizing symptoms of these disorders. Secondary outcomes included specific symptom domains and treatment discontinuation rate. We estimated standardized mean differences (SMDs) with 3-level network meta-analysis with random slopes by study for medication and assessment instrument. Risk of bias appraisal was performed using the Cochrane Collaboration\u2019s risk of bias tool. This study was registered in PROSPERO (CRD42017069090). We analyzed 469 outcome measures from 135 studies (\n                      <jats:italic>n<\/jats:italic>\n                      = 30,245). All medications were more effective than placebo for the aggregate measure of internalizing symptoms (SMD \u22120.56, 95% CI \u22120.62 to \u22120.51,\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001), for all symptom domains, and in patients from all diagnostic categories. We also found significant results when restricting to the most used assessment instrument for each diagnosis; nevertheless, this restriction led to exclusion of 72.71% of outcome measures. Pairwise comparisons revealed only small differences between medications in efficacy and acceptability. Limitations include the moderate heterogeneity found in most outcomes and the moderate risk of bias identified in most of the trials.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this study, we observed that all SSRIs and SNRIs were effective for multiple symptom domains, and in patients from all included diagnostic categories. We found minimal differences between medications concerning efficacy and acceptability. This three-level network meta-analysis contributes to an ongoing discussion about the true benefit of antidepressants with robust evidence, considering the significantly larger quantity of data and higher statistical power when compared to previous studies. The 3-level approach allowed us to properly assess the efficacy of these medications on internalizing psychopathology, avoiding potential biases related to the exclusion of information due to distinct assessment instruments, and to explore the multilevel structure of transdiagnostic efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1003664","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T20:04:41Z","timestamp":1623355481000},"page":"e1003664","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":82,"title":["Selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors for anxiety, obsessive-compulsive, and stress disorders: A 3-level network meta-analysis"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9618-5596","authenticated-orcid":true,"given":"Natan Pereira","family":"Gosmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0303-943X","authenticated-orcid":true,"given":"Marianna de Abreu","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0090-7764","authenticated-orcid":true,"given":"Marianna de Barros","family":"Jaeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0206-1590","authenticated-orcid":true,"given":"Luis Souza","family":"Motta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"Frozi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6789-7420","authenticated-orcid":true,"given":"Lucas","family":"Spanemberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0109-7591","authenticated-orcid":true,"given":"Gisele Gus","family":"Manfro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5497-2743","authenticated-orcid":true,"given":"Pim","family":"Cuijpers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Samuel","family":"Pine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7537-7289","authenticated-orcid":true,"given":"Giovanni Abrah\u00e3o","family":"Salum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"pmed.1003664.ref001","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/S0140-6736(16)31678-6","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990\u20132015: a systematic analysis for the Global Burden of Disease Study 2015","volume":"388","author":"GBD 2015 Disease and Injury Incidence and Prevalence Collaborators","year":"2016","journal-title":"Lancet"},{"key":"pmed.1003664.ref002","doi-asserted-by":"crossref","DOI":"10.1001\/jamapediatrics.2019.0337","article-title":"Diseases, injuries, and risk factors in child and adolescent health, 1990 to 2017: findings from the Global Burden of Diseases, Injuries, and Risk Factors 2017","author":"GBD 2017 Child and Adolescent Health Collaborators","year":"2019","journal-title":"Study. JAMA Pediatr"},{"key":"pmed.1003664.ref003","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/da.22711","article-title":"Treatment gap for anxiety disorders is global: results of the World Mental Health Surveys in 21 countries","volume":"35","author":"J Alonso","year":"2018","journal-title":"Depress Anxiety"},{"key":"pmed.1003664.ref004","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jad.2008.07.014","article-title":"Cost-of-illness studies and cost-effectiveness analyses in anxiety disorders: a systematic review","volume":"114","author":"A Konnopka","year":"2009","journal-title":"J Affect Disord"},{"key":"pmed.1003664.ref005","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1192\/bjp.2018.98","article-title":"The benefits of antidepressants: news or fake news?","volume":"213","author":"G Parker","year":"2018","journal-title":"Br J Psychiatry"},{"key":"pmed.1003664.ref006","article-title":"Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis","author":"K Munkholm","year":"2019","journal-title":"BMJ Open"},{"key":"pmed.1003664.ref007","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3399\/bjgp12X616481","article-title":"Common mental health disorders\u2014identification and pathways to care: NICE clinical guideline","volume":"62","author":"T Kendrick","year":"2012","journal-title":"Br J Gen Pract"},{"key":"pmed.1003664.ref008","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1136\/eb-2017-102718","article-title":"A systematic review of network meta-analyses for pharmacological treatment of common mental disorders","volume":"21","author":"T Williams","year":"2018","journal-title":"Evid Based Ment Health"},{"key":"pmed.1003664.ref009","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1001\/jamapsychiatry.2015.15","article-title":"Reporting bias in clinical trials investigating the efficacy of second-generation antidepressants in the treatment of anxiety disorders: a report of 2 meta-analyses","volume":"72","author":"AM Roest","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"pmed.1003664.ref010","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0193-953X(05)70205-7","article-title":"Comorbidity in generalized anxiety disorder","volume":"24","author":"R Noyes","year":"2001","journal-title":"Psychiatr Clin North Am"},{"key":"pmed.1003664.ref011","article-title":"The heterogeneity of mental health assessment","author":"JJ Newson","year":"2020","journal-title":"Front Psychiatry"},{"key":"pmed.1003664.ref012","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jad.2016.10.019","article-title":"The 52 symptoms of major depression: lack of content overlap among seven common depression scales","volume":"208","author":"EI Fried","year":"2017","journal-title":"J Affect Disord"},{"key":"pmed.1003664.ref013","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0140-6736(16)30385-3","article-title":"Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis","volume":"388","author":"A Cipriani","year":"2016","journal-title":"Lancet"},{"key":"pmed.1003664.ref014","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/S0140-6736(18)31793-8","article-title":"Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis","volume":"393","author":"A Slee","year":"2019","journal-title":"Lancet"},{"key":"pmed.1003664.ref015","doi-asserted-by":"crossref","first-page":"777","DOI":"10.7326\/M14-2385","article-title":"The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations","volume":"162","author":"B Hutton","year":"2015","journal-title":"Ann Intern Med"},{"key":"pmed.1003664.ref016","article-title":"Estimating effect sizes from pretest-posttest-control group designs","author":"SB Morris","year":"2007","journal-title":"Organ Res Methods"},{"key":"pmed.1003664.ref017","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1017\/S2045796016000809","article-title":"Pre-post effect sizes should be avoided in meta-analyses","volume":"26","author":"P Cuijpers","year":"2017","journal-title":"Epidemiol Psychiatr Sci"},{"key":"pmed.1003664.ref018","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jclinepi.2005.06.006","article-title":"Imputing missing standard deviations in meta-analyses can provide accurate results","volume":"59","author":"TA Furukawa","year":"2006","journal-title":"J Clin Epidemiol"},{"key":"pmed.1003664.ref019","volume-title":"Statistical power analysis for the behavioral sciences","author":"J Cohen","year":"1988","edition":"2"},{"key":"pmed.1003664.ref020","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jclinepi.2020.01.017","article-title":"Forrest plots or caterpillar plots?","volume":"121","author":"JC Hurley","year":"2020","journal-title":"J Clin Epidemiol"},{"key":"pmed.1003664.ref021","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/jrsm.35","article-title":"Fixed effects and variance components estimation in three-level meta-analysis","volume":"2","author":"S Konstantopoulos","year":"2011","journal-title":"Res Synth Methods"},{"key":"pmed.1003664.ref022","doi-asserted-by":"crossref","DOI":"10.1002\/9781119536604","volume-title":"Cochrane handbook for systematic reviews of interventions. Version 6.0","author":"JPT Higgins","year":"2019"},{"key":"pmed.1003664.ref023","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0895-4356(97)00049-8","article-title":"The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials","volume":"50","author":"HC Bucher","year":"1997","journal-title":"J Clin Epidemiol"},{"key":"pmed.1003664.ref024","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor Package","volume":"36","author":"W Viechtbauer","year":"2010","journal-title":"J Stat Softw"},{"key":"pmed.1003664.ref025","article-title":"The Cochrane Collaboration\u2019s tool for assessing risk of bias in randomised trials","author":"JPT Higgins","year":"2011","journal-title":"BMJ"},{"key":"pmed.1003664.ref026","article-title":"Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis","author":"TA Furukawa","year":"2016","journal-title":"BMJ Open"},{"key":"pmed.1003664.ref027","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jad.2015.03.021","article-title":"Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials","volume":"180","author":"Y Hayasaka","year":"2015","journal-title":"J Affect Disord"},{"key":"pmed.1003664.ref028","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1001\/jama.2017.2200","article-title":"Obsessive-compulsive disorder: advances in diagnosis and treatment","volume":"317","author":"ME Hirschtritt","year":"2017","journal-title":"JAMA"},{"key":"pmed.1003664.ref029","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1192\/bjp.bp.111.096594","article-title":"Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses","volume":"200","author":"S Leucht","year":"2012","journal-title":"Br J Psychiatry"},{"key":"pmed.1003664.ref030","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/S0140-6736(17)32802-7","article-title":"Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis","volume":"391","author":"A Cipriani","year":"2018","journal-title":"Lancet"},{"key":"pmed.1003664.ref031","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.comppsych.2017.06.009","article-title":"Understanding eating disorders within internalizing psychopathology: a novel transdiagnostic, hierarchical-dimensional model","volume":"79","author":"KT Forbush","year":"2017","journal-title":"Compr Psychiatry"},{"key":"pmed.1003664.ref032","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1017\/S0033291798008162","article-title":"A comparison of the utility of dimensional and categorical representations of psychosis","volume":"29","author":"J Van Os","year":"1999","journal-title":"Psychol Med"},{"key":"pmed.1003664.ref033","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s00406-016-0715-4","article-title":"Network meta-analyses should be the highest level of evidence in treatment guidelines","volume":"266","author":"S Leucht","year":"2016","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"pmed.1003664.ref034","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1002\/jrsm.1037","article-title":"Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool","volume":"3","author":"G Salanti","year":"2012","journal-title":"Res Synth Methods"},{"key":"pmed.1003664.ref035","article-title":"Multivariate and network meta-analysis of multiple outcomes and multiple treatments: rationale, concepts, and examples","author":"RD Riley","year":"2017","journal-title":"BMJ"},{"key":"pmed.1003664.ref036","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cct.2015.03.005","article-title":"A multilevel approach to network meta-analysis within a frequentist framework","volume":"42","author":"T Greco","year":"2015","journal-title":"Contemp Clin Trials"},{"key":"pmed.1003664.ref037","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1080\/13651501.2017.1306082","article-title":"Pharmacological treatment of unipolar depressive disorders: summary of WFSBP guidelines","volume":"21","author":"WFSBP Task Force on Unipolar Depressive Disorders","year":"2017","journal-title":"Int J Psychiatry Clin Pract"},{"key":"pmed.1003664.ref038","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/YIC.0000000000000078","article-title":"Efficacy of treatments for anxiety disorders: a meta-analysis","volume":"30","author":"B Bandelow","year":"2015","journal-title":"Int Clin Psychopharmacol"},{"key":"pmed.1003664.ref039","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.jad.2017.04.068","article-title":"Obsessive-compulsive disorder has a reduced placebo (and antidepressant) response compared to other anxiety disorders: a meta-analysis","volume":"218","author":"MA Sugarman","year":"2017","journal-title":"J Affect Disord"},{"key":"pmed.1003664.ref040","article-title":"Psychotherapy for depression across different age groups: a systematic review and meta-analysis","author":"P Cuijpers","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"pmed.1003664.ref041","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jclinepi.2018.11.023","article-title":"Getting more out of meta-analyses: a new approach to meta-analysis in light of unexplained heterogeneity","volume":"107","author":"A Saad","year":"2019","journal-title":"J Clin Epidemiol"}],"updated-by":[{"DOI":"10.1371\/journal.pmed.1003664","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000}}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003664","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T13:45:48Z","timestamp":1624542348000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003664"}},"subtitle":[],"editor":[{"given":"Vikram","family":"Patel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,10]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1003664","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,10]]}}}