{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T22:30:36Z","timestamp":1788474636527,"version":"build-2803163510"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T00:00:00Z","timestamp":1655337600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Anxiety disorders, including panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), agoraphobia, and specific phobia, are among the most common psychiatric disorders. Although the traditional pharmacologic treatments for anxiety included barbiturates and then benzodiazepines, the introduction of tricyclic antidepressants, followed by the selective serotonin reuptake inhibitors (SSRIs), marked a tidal shift in the treatment of anxiety. Although not approved for treatment of anxiety disorders (with the exception of trifluoperazine) there is ongoing off-label, unapproved use of both first-generation \u201ctypical\u201d antipsychotics (FGAs) and second-generation or \u201catypical\u201d antipsychotics (SGAs) for anxiety. Although there have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of these reviews focused on SGAs, primarily the use of quetiapine in GAD. Given that there is little known about the potential benefits and short-and long-term risks of using antipsychotics in anxiety, there is a need for an umbrella review of systematic reviews and meta-analyses of the use of both FGAs and SGAs in anxiety disorders. The specific aims of this study are as follows: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs) and other non-antipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects; and (3) Evaluate the short- and long-term risks and side effects of prescribing antipsychotics in anxiety disorders. The review is registered on PROSPERO (CRD42021237436). Since data extraction has not begun, there is not preliminary data to share.<\/jats:p>","DOI":"10.1371\/journal.pone.0269772","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T17:40:34Z","timestamp":1655401234000},"page":"e0269772","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["An umbrella review on the use of antipsychotics in anxiety disorders: A registered report protocol"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-8372","authenticated-orcid":true,"given":"Amir","family":"Garakani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3875-4601","authenticated-orcid":true,"given":"Rafael C.","family":"Freire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank D.","family":"Buono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn P.","family":"Thom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn","family":"Larkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-4846","authenticated-orcid":true,"given":"Melissa C.","family":"Funaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Salehi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes M.","family":"Perez-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"issue":"6","key":"pone.0269772.ref001","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1001\/archpsyc.62.6.617","article-title":"Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication","volume":"62","author":"RC Kessler","year":"2005","journal-title":"Arch Gen Psychiatry"},{"key":"pone.0269772.ref002","doi-asserted-by":"crossref","DOI":"10.1176\/appi.books.9780890425596","volume-title":"Diagnostic and Statistical Manual of Mental Disorders","author":"American Psychiatric Association","year":"2013","edition":"5"},{"key":"pone.0269772.ref003","author":"National Institute for Health and Care Excellence (NICE)","journal-title":"Social Anxiety Disorder: Recognition, Assessment and Treatment"},{"issue":"Suppl 1","key":"pone.0269772.ref004","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1186\/1471-244X-14-S1-S1","article-title":"Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders","volume":"14","author":"MA Katzman","year":"2014","journal-title":"BMC Psychiatry"},{"issue":"6","key":"pone.0269772.ref005","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1176\/appi.ajp.2019.19030315","article-title":"Associations of Benzodiazepines, Z-Drugs, and Other Anxiolytics With Subsequent Dementia in Patients With Affective Disorders: A Nationwide Cohort and Nested Case-Control Study","volume":"177","author":"M Osler","year":"2020","journal-title":"Am J Psychiatry"},{"key":"pone.0269772.ref006","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/978-981-32-9705-0_20","article-title":"Role of Benzodiazepines in Anxiety Disorders","volume":"1191","author":"R Balon","year":"2020","journal-title":"Adv Exp Med Biol"},{"issue":"9","key":"pone.0269772.ref007","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/sj.mp.4001852","article-title":"Treatment-resistant anxiety disorders","volume":"11","author":"A. Bystritsky","year":"2006","journal-title":"Mol Psychiatry"},{"issue":"3","key":"pone.0269772.ref008","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/da.23113","article-title":"Co-morbidity between mood and anxiety disorders: A systematic review and meta-analysis","volume":"38","author":"S Saha","year":"2021","journal-title":"Depress Anxiety"},{"key":"pone.0269772.ref009","first-page":"22","article-title":"Comorbid anxiety and depression","volume":"66","author":"MH Pollack","year":"2005","journal-title":"J Clin Psychiatry"},{"issue":"6","key":"pone.0269772.ref010","first-page":"29","article-title":"Should psychiatrists use atypical antipsychotics to treat nonpsychotic anxiety?","volume":"6","author":"R. Pies","year":"2009","journal-title":"Psychiatry (Edgmont)"},{"issue":"4","key":"pone.0269772.ref011","first-page":"170","article-title":"Effective short-term treatment of generalized anxiety disorder with trifluoperazine","volume":"47","author":"J Mendels","year":"1986","journal-title":"J Clin Psychiatry"},{"issue":"12","key":"pone.0269772.ref012","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1016\/j.clinthera.2013.09.006","article-title":"Diagnoses associated with use of atypical antipsychotics in a commercial health plan: a claims database analysis","volume":"35","author":"L Citrome","year":"2013","journal-title":"Clin Ther"},{"issue":"12","key":"pone.0269772.ref013","doi-asserted-by":"crossref","first-page":"e006135","DOI":"10.1136\/bmjopen-2014-006135","article-title":"Prescribing of antipsychotics in UK primary care: a cohort study","volume":"4","author":"L Marston","year":"2014","journal-title":"BMJ Open"},{"key":"pone.0269772.ref014","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jad.2015.11.031","article-title":"Prevalence of antipsychotic prescriptions among patients with anxiety disorders treated in inpatient and outpatient psychiatric settings","volume":"191","author":"SR Weber","year":"2016","journal-title":"J Affect Disord"},{"issue":"12","key":"pone.0269772.ref015","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1001\/jama.2011.1360","article-title":"Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis","volume":"306","author":"AR Maher","year":"2011","journal-title":"JAMA"},{"issue":"3","key":"pone.0269772.ref016","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s11920-016-0668-3","article-title":"Long-Term Pharmacological Treatments of Anxiety Disorders: An Updated Systematic Review","volume":"18","author":"G Perna","year":"2016","journal-title":"Curr Psychiatry Rep."},{"issue":"4","key":"pone.0269772.ref017","doi-asserted-by":"crossref","first-page":"551","DOI":"10.3390\/ijms17040551","article-title":"Is There Room for Second-Generation Antipsychotics in the Pharmacotherapy of Panic Disorder? A Systematic Review Based on PRISMA Guidelines","volume":"17","author":"G Perna","year":"2016","journal-title":"Int J Mol Sci."},{"issue":"12","key":"pone.0269772.ref018","first-page":"CD008120","article-title":"Second-generation antipsychotics for anxiety disorders","author":"AM Depping","year":"2010","journal-title":"Cochrane Database Syst Rev."},{"issue":"3","key":"pone.0269772.ref019","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1097\/JCP.0b013e31821b2b3f","article-title":"Treating generalized anxiety disorder with second generation antipsychotics: a systematic review and meta-analysis","volume":"31","author":"CD LaLonde","year":"2011","journal-title":"J Clin Psychopharmacol"},{"key":"pone.0269772.ref020","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2147\/DDDT.S89485","article-title":"Quetiapine monotherapy in acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials","volume":"10","author":"N Maneeton","year":"2016","journal-title":"Drug Des Devel Ther"},{"issue":"9","key":"pone.0269772.ref021","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1177\/0706743716659417","article-title":"Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments","volume":"61","author":"SH Kennedy","year":"2016","journal-title":"Can J Psychiatry"},{"issue":"2","key":"pone.0269772.ref022","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/bdi.12609","article-title":"Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder","volume":"20","author":"LN Yatham","year":"2018","journal-title":"Bipolar Disord."},{"issue":"4","key":"pone.0269772.ref023","doi-asserted-by":"crossref","first-page":"19m12828","DOI":"10.4088\/JCP.19m12828","article-title":"Association of Benzodiazepines and Antidepressants With 180-Day Mortality Among Patients With Dementia Receiving Antipsychotic Pharmacotherapy: A Nationwide Registry-Based Study","volume":"81","author":"A Norgaard","year":"2020","journal-title":"J Clin Psychiatry."},{"issue":"5","key":"pone.0269772.ref024","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1001\/archgenpsychiatry.2011.1532","article-title":"Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia","volume":"69","author":"J Tiihonen","year":"2012","journal-title":"Arch Gen Psychiatry"},{"issue":"9","key":"pone.0269772.ref025","doi-asserted-by":"crossref","first-page":"e0239206","DOI":"10.1371\/journal.pone.0239206","article-title":"Mortality risk of antipsychotic augmentation for adult depression","volume":"15","author":"T Gerhard","year":"2020","journal-title":"PLoS One"},{"issue":"3","key":"pone.0269772.ref026","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/YCO.0000000000000491","article-title":"Antipsychotic-induced tardive dyskinesia: update on epidemiology and management","volume":"32","author":"CG Widschwendter","year":"2019","journal-title":"Curr Opin Psychiatry"},{"issue":"3","key":"pone.0269772.ref027","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/XEB.0000000000000055","article-title":"Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach","volume":"13","author":"E Aromataris","year":"2015","journal-title":"Int J Evid Based Healthc."},{"key":"pone.0269772.ref028","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"MJ Page","year":"2021","journal-title":"BMJ"},{"key":"pone.0269772.ref029","doi-asserted-by":"crossref","first-page":"g7647","DOI":"10.1136\/bmj.g7647","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation","volume":"350","author":"L Shamseer","year":"2015","journal-title":"BMJ"},{"key":"pone.0269772.ref030","author":"SIGN","year":"2015","journal-title":"Scottish Intercollegiate Guidelines Network Search Filters"},{"key":"pone.0269772.ref031","doi-asserted-by":"crossref","first-page":"j4008","DOI":"10.1136\/bmj.j4008","article-title":"AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both","volume":"358","author":"BJ Shea","year":"2017","journal-title":"BMJ"},{"key":"pone.0269772.ref032","doi-asserted-by":"crossref","first-page":"g2035","DOI":"10.1136\/bmj.g2035","article-title":"Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials","volume":"348","author":"E Theodoratou","year":"2014","journal-title":"BMJ"},{"issue":"7109","key":"pone.0269772.ref033","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"M Egger","year":"1997","journal-title":"BMJ"},{"issue":"6","key":"pone.0269772.ref034","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/j.1751-9004.2011.00355.x","article-title":"Mediation Analysis in Social Psychology: Current Practices and New Recommendations","volume":"5","author":"DD Rucker","year":"2011","journal-title":"Social and Personality Psychology"},{"issue":"4","key":"pone.0269772.ref035","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.jclinepi.2013.11.007","article-title":"Systematic review finds overlapping reviews were not mentioned in every other overview","volume":"67","author":"D Pieper","year":"2014","journal-title":"J Clin Epidemiol"},{"issue":"3","key":"pone.0269772.ref036","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1177\/1740774507079441","article-title":"An exploratory test for an excess of significant findings","volume":"4","author":"JP Ioannidis","year":"2007","journal-title":"Clin Trials"},{"issue":"3","key":"pone.0269772.ref037","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1136\/bmjebm-2018-110891","article-title":"The effect of publication bias magnitude and direction on the certainty in evidence","volume":"23","author":"MH Murad","year":"2018","journal-title":"BMJ Evid-Based Med"},{"issue":"12","key":"pone.0269772.ref038","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1002\/sim.6475","article-title":"A Bayesian framework to account for uncertainty due to missing binary outcome data in pairwise meta-analysis","volume":"34","author":"NL Turner","year":"2015","journal-title":"Stat Med."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0269772","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T17:41:05Z","timestamp":1655401265000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0269772"}},"subtitle":[],"editor":[{"given":"Tina","family":"Hinton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,6,16]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0269772","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,16]]}}}