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This systematic review and meta\u2010analysis examined the efficacy and safety of combination therapy with antidepressants and sleep medication for treating MDD with insomnia compared to antidepressant monotherapy by sleep medication class (benzodiazepine, Z\u2010drug, melatonin receptor agonist, and orexin receptor antagonist). This study was preregistered with PROSPERO (CRD42025636571). PubMed, CENTRAL, and Embase were searched for double\u2010blind randomized controlled trials published until June 2024, resulting in eight eligible studies (1945 participants; eszopiclone\u2009=\u20094, zolpidem\u2009=\u20092, triazolam\u2009=\u20091, ramelteon\u2009=\u20091). Meta\u2010analyses were performed based on six trials of Z\u2010drugs. Compared with antidepressant monotherapy, combination therapy with antidepressants and Z\u2010drugs resulted in higher remission rates from depressive symptoms (risk ratio: 1.25, 95% confidence interval [CI]: 1.08\u20131.45, <jats:italic>P<\/jats:italic>\u2009=\u20090.003), greater improvement in depressive symptoms (standardized mean difference [SMD]: 0.17, 95% CI: 0.01\u20130.33, <jats:italic>P<\/jats:italic>\u2009=\u20090.04) and insomnia symptoms (SMD: 0.43, 95% CI: 0.28\u20130.59, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) in the short\u2010term (within 12\u2009weeks), with no difference in safety outcomes except for dizziness. Combination therapy with antidepressants and Z\u2010drugs may be more useful for MDD with insomnia symptoms than antidepressant monotherapy in the short term. However, this study did not evaluate the benefits and harms of long\u2010term adjunctive Z\u2010drug therapy. Further long\u2010term studies are needed to draw definitive conclusions regarding the efficacy and safety of combination therapy with antidepressants and Z\u2010drugs. Moreover, further research is warranted to assess whether the findings of this study are applicable to other sleep medication classes.<\/jats:p>","DOI":"10.1111\/pcn.13811","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T13:53:24Z","timestamp":1742478804000},"page":"306-318","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Efficacy and safety of each class of sleep medication for major depressive disorder with insomnia symptoms: A systematic review and meta\u2010analysis of double\u2010blind randomized controlled trials"],"prefix":"10.1111","volume":"79","author":[{"given":"Taku","family":"Maruki","sequence":"first","affiliation":[{"name":"Department of Neuropsychiatry Kyorin University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0614-7524","authenticated-orcid":false,"given":"Masahiro","family":"Takeshima","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Yoshizawa","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuna","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Kyorin University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoaki","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Graduate School of Medicine, University of the Ryukyus  Okinawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2674-0707","authenticated-orcid":false,"given":"Yumi","family":"Aoki","sequence":"additional","affiliation":[{"name":"Psychiatric and Mental Health Nursing, Graduate School of Nursing Science St. Luke's International University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Utsumi","sequence":"additional","affiliation":[{"name":"Department of Sleep\u2010Wake Disorders, National Institute of Mental Health National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4538-5381","authenticated-orcid":false,"given":"Kentaro","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, National Center Hospital National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3926-8867","authenticated-orcid":false,"given":"Aran","family":"Tajika","sequence":"additional","affiliation":[{"name":"Department of Health Promotion and Human Behavior Kyoto University Graduate School of Medicine\/School of Public Health  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9169-3249","authenticated-orcid":false,"given":"Yoshikazu","family":"Takaesu","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Kyorin University School of Medicine  Tokyo Japan"},{"name":"Department of Neuropsychiatry Graduate School of Medicine, University of the Ryukyus  Okinawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-publhealth-031912-114409"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-9-90"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0327(03)00168-X"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1001\/jama.2017.3826","article-title":"Depression is the leading cause of disability around the world","volume":"317","author":"Friedrich MJ","year":"2017","journal-title":"JAMA"},{"key":"e_1_2_9_6_1","unstructured":"World Health Organization.The global burden of disease: 2004 update. 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