{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T18:09:58Z","timestamp":1785607798608,"version":"3.56.0"},"reference-count":24,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T00:00:00Z","timestamp":1621900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Psychiatr Scand"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium\u00a0+\u00a0valproic acid which showed a significant effect on time to mood relapses (HR\u00a0=\u00a00.57) compared to valproic acid monotherapy, especially for manic episodes (HR\u00a0=\u00a00.51). The effect was significant in terms of time to new drug treatment (HR\u00a0=\u00a00.51) and time to hospitalization (HR\u00a0=\u00a00.57). A significant reduction in the frequency of mood relapses was also reported for lithium\u00a0+\u00a0valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine\u00a0+\u00a0valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium\u00a0+\u00a0valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/acps.13312","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T20:31:51Z","timestamp":1620505911000},"page":"259-276","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Polypharmacy as maintenance treatment in bipolar illness: A systematic review"],"prefix":"10.1111","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3439-340X","authenticated-orcid":false,"given":"Andrea","family":"Amerio","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) Section of Psychiatry University of Genoa Genoa Italy"},{"name":"IRCCS Ospedale Policlinico San Martino Genoa Italy"},{"name":"Department of Psychiatry Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) Section of Psychiatry University of Genoa Genoa Italy"},{"name":"IRCCS Ospedale Policlinico San Martino Genoa Italy"},{"name":"Department of Mental Health A.S.L. CN1 Cuneo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norberto","family":"Miletto","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) Section of Psychiatry University of Genoa Genoa Italy"},{"name":"IRCCS Ospedale Policlinico San Martino Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Aguglia","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) Section of Psychiatry University of Genoa Genoa Italy"},{"name":"IRCCS Ospedale Policlinico San Martino Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Costanza","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Faculty of Medicine University of Geneva (UNIGE) Geneva Switzerland"},{"name":"Department of Psychiatry ASO Santi Antonio e Biagio e Cesare Arrigo Hospital Alessandria Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Benatti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Luigi Sacco Luigi Sacco Hospital University of Milan Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Odone","sequence":"additional","affiliation":[{"name":"Department of Public Health, Experimental and Forensic Medicine University of Pavia Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-3662","authenticated-orcid":false,"given":"Sergio A.","family":"Barroilhet","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Tufts University Boston MA USA"},{"name":"Center for Quantitative Health Massachusetts General Hospital Boston MA USA"},{"name":"Department of Psychiatry Harvard Medical School Boston MA USA"},{"name":"Department of Psychiatry Clinical Hospital University of Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlasios","family":"Brakoulias","sequence":"additional","affiliation":[{"name":"Western Sydney Local Health District Mental Health Service and School of Medicine Western Sydney University Blacktown Hospital Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo","family":"Dell\u2019Osso","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Luigi Sacco Luigi Sacco Hospital University of Milan Milan Italy"},{"name":"\u201cAldo Ravelli\u201d Center for Nanotechnology and Neurostimulation University of Milan Milan Italy"},{"name":"Department of Psychiatry and Behavioral Sciences Stanford University Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-856X","authenticated-orcid":false,"given":"Gianluca","family":"Serafini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) Section of Psychiatry University of Genoa Genoa Italy"},{"name":"IRCCS Ospedale Policlinico San Martino Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Amore","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) Section of Psychiatry University of Genoa Genoa Italy"},{"name":"IRCCS Ospedale Policlinico San Martino Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9259-0885","authenticated-orcid":false,"given":"S. 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