{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:46:15Z","timestamp":1780361175682,"version":"3.54.1"},"reference-count":45,"publisher":"Royal College of Psychiatrists","issue":"2","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Br J Psychiatry"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:sec id=\"S0007125021001653_sec_a1\"><jats:title>Background<\/jats:title><jats:p>Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear.<\/jats:p><\/jats:sec><jats:sec id=\"S0007125021001653_sec_a2\"><jats:title>Aims<\/jats:title><jats:p>To find the optimal dosage of aripiprazole augmentation.<\/jats:p><\/jats:sec><jats:sec id=\"S0007125021001653_sec_a3\" sec-type=\"methods\"><jats:title>Method<\/jats:title><jats:p>Multiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (\u226518 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose\u2013effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: \u226550% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4\u201312 weeks).<\/jats:p><\/jats:sec><jats:sec id=\"S0007125021001653_sec_a4\" sec-type=\"results\"><jats:title>Results<\/jats:title><jats:p>Ten studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose\u2013efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15\u20131.85) and 5 mg (OR = 1.93, 95% CI 1.33\u20132.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52\u20132.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate.<\/jats:p><\/jats:sec><jats:sec id=\"S0007125021001653_sec_a5\" sec-type=\"conclusions\"><jats:title>Conclusions<\/jats:title><jats:p>Low-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.<\/jats:p><\/jats:sec>","DOI":"10.1192\/bjp.2021.165","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T08:59:35Z","timestamp":1636966775000},"page":"440-447","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":20,"title":["Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose\u2013effect meta-analysis"],"prefix":"10.1192","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1317-0220","authenticated-orcid":false,"given":"Yuki","family":"Furukawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4700-6990","authenticated-orcid":false,"given":"Tasnim","family":"Hamza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5179-8321","authenticated-orcid":false,"given":"Andrea","family":"Cipriani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2159-3776","authenticated-orcid":false,"given":"Toshi A.","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3830-8508","authenticated-orcid":false,"given":"Georgia","family":"Salanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8717-0832","authenticated-orcid":false,"given":"Edoardo G.","family":"Ostinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"170","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"S0007125021001653_ref31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2013.07.035"},{"key":"S0007125021001653_ref12","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2007.08.010"},{"key":"S0007125021001653_ref10","doi-asserted-by":"publisher","DOI":"10.1177\/0706743715620411"},{"key":"S0007125021001653_ref24","article-title":"Questionable utility of the relative risk in clinical research: a call for change to practice","author":"Doi","year":"2020","journal-title":"J Clin Epidemiol"},{"key":"S0007125021001653_ref7","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.17r11693"},{"key":"S0007125021001653_ref44","doi-asserted-by":"publisher","DOI":"10.1136\/ebmental-2019-300118"},{"key":"S0007125021001653_ref43","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyv060"},{"key":"S0007125021001653_ref42","unstructured":"42 Otsuka Pharmaceutical Development & Commercialization. Study to Evaluate the Efficacy, Safety and Tolerability of an Oral Aripiprazole\/Escitalopram Combination Therapy in Patients With Major Depressive Disorder (MDD) (ACES 255) (NCT01111539). US National Library of Medicine (https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01111539)."},{"key":"S0007125021001653_ref2","doi-asserted-by":"publisher","DOI":"10.1002\/wps.20701"},{"key":"S0007125021001653_ref19","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"S0007125021001653_ref3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32802-7"},{"key":"S0007125021001653_ref22","doi-asserted-by":"publisher","DOI":"10.1097\/00004850-200501000-00010"},{"key":"S0007125021001653_ref13","doi-asserted-by":"publisher","DOI":"10.1080\/09540261.2020.1765748"},{"key":"S0007125021001653_ref36","doi-asserted-by":"publisher","DOI":"10.1017\/S1092852900020216"},{"key":"S0007125021001653_ref21","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l4898"},{"key":"S0007125021001653_ref29","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-19425-7_2"},{"key":"S0007125021001653_ref30","doi-asserted-by":"publisher","DOI":"10.1177\/0962280220982643"},{"key":"S0007125021001653_ref27","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v072.c01"},{"key":"S0007125021001653_ref38","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00308-6"},{"key":"S0007125021001653_ref37","doi-asserted-by":"publisher","DOI":"10.1159\/000332050"},{"key":"S0007125021001653_ref35","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e31816774f9"},{"key":"S0007125021001653_ref15","volume-title":"Depression in Adults: Recognition and Management (Clinical Guideline CG90)","year":"2009"},{"key":"S0007125021001653_ref39","doi-asserted-by":"publisher","DOI":"10.1111\/pcn.12663"},{"key":"S0007125021001653_ref4","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.2006.163.11.1905"},{"key":"S0007125021001653_ref14","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyaa033"},{"key":"S0007125021001653_ref18","first-page":"CD008121","article-title":"Second-generation antipsychotics for major depressive disorder and dysthymia","volume":"12","author":"Komossa","year":"2010","journal-title":"Cochrane Database Syst Rev"},{"key":"S0007125021001653_ref1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30925-9"},{"key":"S0007125021001653_ref23","doi-asserted-by":"publisher","DOI":"10.1002\/jrsm.1347"},{"key":"S0007125021001653_ref45","doi-asserted-by":"publisher","DOI":"10.1136\/ebmental-2020-300149"},{"key":"S0007125021001653_ref25","volume-title":"R: A Language and Environment for Statistical Computing","year":"2020"},{"key":"S0007125021001653_ref33","first-page":"23","article-title":"When at first you don't succeed: sequential strategies for antidepressant nonresponders","volume":"58","author":"Thase","year":"1997","journal-title":"J Clin Psychiatry"},{"key":"S0007125021001653_ref20","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2020.00035"},{"key":"S0007125021001653_ref5","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-018-1096-5"},{"key":"S0007125021001653_ref17","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.14r09204"},{"key":"S0007125021001653_ref41","unstructured":"41 Otsuka Pharmaceutical Development & Commercialization. Study to Evaluate the Efficacy, Safety and Tolerability of an Oral Aripiprazole\/Escitalopram Combination Therapy in Patients with Major Depressive Disorder (MDD) (ACES 263) (NCT01111565). US National Library of Medicine (https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01111565)."},{"key":"S0007125021001653_ref34","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.v68n0604"},{"key":"S0007125021001653_ref8","doi-asserted-by":"publisher","DOI":"10.1111\/acps.13145"},{"key":"S0007125021001653_ref32","doi-asserted-by":"publisher","DOI":"10.1097\/YIC.0b013e32835ce232"},{"key":"S0007125021001653_ref6","doi-asserted-by":"publisher","DOI":"10.1177\/0706743716664885"},{"key":"S0007125021001653_ref11","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.16r10749"},{"key":"S0007125021001653_ref40","unstructured":"40 Otsuka Pharmaceutical Development & Commercialization. Study to Evaluate the Efficacy, Safety and Tolerability of an Oral Aripiprazole\/Escitalopram Combination Therapy in Patients with Major Depressive Disorder (MDD) (ACES 256) (NCT01111552). US National Library of Medicine (https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01111552)."},{"key":"S0007125021001653_ref26","doi-asserted-by":"publisher","DOI":"10.1136\/ebmental-2019-300117"},{"key":"S0007125021001653_ref16","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S156619"},{"key":"S0007125021001653_ref9","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(19)30217-2"},{"key":"S0007125021001653_ref28","doi-asserted-by":"publisher","DOI":"10.1177\/0962280218773122"}],"container-title":["The British Journal of Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S0007125021001653","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T11:24:00Z","timestamp":1666956240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S0007125021001653\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":45,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["S0007125021001653"],"URL":"https:\/\/doi.org\/10.1192\/bjp.2021.165","relation":{},"ISSN":["0007-1250","1472-1465"],"issn-type":[{"value":"0007-1250","type":"print"},{"value":"1472-1465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]},"assertion":[{"value":"Copyright \u00a9 The Author(s), 2021. Published by Cambridge University Press on behalf of the Royal College of Psychiatrists","name":"copyright","label":"Copyright","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (https:\/\/creativecommons.org\/licenses\/by\/4.0\/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.","name":"license","label":"License","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}]}}