{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:52:11Z","timestamp":1791118331710,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIA p\u201030 Alzheimer's STAC grant"],"award-info":[{"award-number":["NIA p\u201030 Alzheimer's STAC grant"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Addict"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Objectives<\/jats:title>\n                    <jats:p>Major depressive disorder (MDD) and alcohol use disorder (AUD) frequently co\u2010occur and are associated with greater symptom severity and elevated suicide risk relative to either disorder alone, yet no pharmacological regimen is approved for the combined indication. This review systematically catalogs trials of combined and multimodal pharmacotherapy for comorbid AUD and MDD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We searched PubMed\/MEDLINE, Web of Science, and Google Scholar from inception through May 2024 for randomized or prospective open\u2010label trials of combined pharmacotherapy, or single agents with dual\u2010target activity, in adults with comorbid AUD and MDD. Seven trials (total\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009758) met inclusion criteria.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Five trials tested combination regimens (naltrexone+acamprosate; naltrexone+disulfiram; naltrexone+sertraline; acamprosate+escitalopram; aripiprazole+escitalopram) and two tested single agents (vortioxetine; memantine vs. escitalopram). Naltrexone plus sertraline showed the strongest signal of dual benefit on drinking and depressive outcomes; acamprosate plus escitalopram was also promising, although based on a small pilot trial. Neither finding has been independently replicated, and the remaining regimens yielded mixed or modest results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion and Conclusions<\/jats:title>\n                    <jats:p>Converging dopaminergic, serotonergic, glutamatergic, opioidergic, and neuroimmune mechanisms support combined pharmacotherapy, but the evidence base remains thin, underpowered, and unreplicated. Available evidence and current integrated\u2010care approaches favor concurrent rather than sequential treatment of AUD and MDD, although the evidence supporting specific pharmacological combinations remains limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Scientific Significance<\/jats:title>\n                    <jats:p>This is among the first reviews to integrate combination\u2010pharmacotherapy trials with emerging multimodal single agents for comorbid AUD\/MDD, and to map proposed mechanisms onto specific drug pairings, providing a framework for prioritizing future biologically stratified trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ajad.70205","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:01:05Z","timestamp":1791115265000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Treating co\u2010occurring alcohol use disorder and major depressive disorder: A systematic review of combination and multimodal pharmacotherapy"],"prefix":"10.1111","author":[{"given":"Aisha F.","family":"Sharif","sequence":"first","affiliation":[{"name":"University of Texas Rio Grande Valley School of Medicine Edinburg\/Harlingen Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aava Bushra","family":"Jahan","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihsan M.","family":"Salloum","sequence":"additional","affiliation":[{"name":"University of Texas Rio Grande Valley School of Medicine Edinburg\/Harlingen Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8851-0758","authenticated-orcid":false,"given":"Alan N.","family":"Francis","sequence":"additional","affiliation":[{"name":"University of Texas Rio Grande Valley School of Medicine Edinburg\/Harlingen Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"issue":"1","key":"e_1_2_10_2_1","article-title":"Alcohol use disorder and depressive disorders","volume":"40","author":"McHugh RK","year":"2019","journal-title":"Alcohol Research: Current Reviews"},{"issue":"8","key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1001\/jamapsychiatry.2015.0584","article-title":"Epidemiology of DSM\u20105 alcohol use disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions III","volume":"72","author":"Grant BF","year":"2015","journal-title":"JAMA Psychiatry"},{"issue":"4","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1001\/jamapsychiatry.2017.4602","article-title":"Epidemiology of adult DSM\u20105 major depressive disorder and its specifiers in the United 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