{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:11:37Z","timestamp":1775542297908,"version":"3.50.1"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Major depressive disorder (MDD) constitutes a significant global mental health concern. Although selective serotonin reuptake inhibitors (SSRIs) are first-line treatment, their effectiveness may be limited by adverse effects including anhedonia, emotional blunting, sleep disturbances, and sexual dysfunction. Trazodone, a serotonin antagonist and reuptake inhibitor, offers a more favorable tolerability profile, particularly in its extended-release (XR) formulation. Previous studies within the trazodone effectiveness in depression (TED) project demonstrated more pronounced improvements with trazodone XR compared to SSRIs in reducing depressive, anxiety, and insomnia symptoms. The present analysis extends these findings by comparing trazodone XR with SSRIs and quantifying the extent and clinical importance of treatment outcomes through effect size estimates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-center, non-randomized, open-label, 12-week naturalistic study\u2014conducted as part of the TED project\u2014included adults aged 18\u201365 diagnosed with MDD. Symptom severity and outcomes were assessed at baseline and weeks 2, 4, 8, and 12 using validated clinician- and self-rated scales. Cohen\u2019s d quantified the magnitude and clinical relevance of differences between trazodone XR and SSRIs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Effect-size analyses demonstrated consistently greater and earlier improvements with trazodone XR versus SSRIs across all measures. In both self-rated (QIDS-SR) and clinician-rated (QIDS-CR; MADRS) scales assessing depressive symptoms, trazodone XR showed larger effect sizes from week 4, with further increases through week 12. Similar patterns were observed for anhedonia (SHAPS), anxiety (HAM-A) and insomnia (AIS), where trazodone XR produced greater and progressively increasing effect sizes, while SSRIs reached a plateau. These findings indicate a more robust and sustained therapeutic impact of trazodone XR, reflected by consistently higher effect-size magnitudes across domains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Trazodone XR demonstrated greater and progressively increasing effect sizes compared with SSRIs, indicating a more sustained antidepressant response over 12\u00a0weeks. This trajectory, marked by continued symptom reduction without a linear response pattern, suggests a cumulative therapeutic effect potentially attributable to trazodone\u2019s multimodal serotonergic mechanism and favorable pharmacokinetics. By concurrently addressing mood, anxiety, and sleep-related domains, trazodone XR appears to facilitate both symptomatic improvement and broader functional stabilization. These findings highlight the need for randomized, controlled investigations to further elucidate its comparative efficacy and real-world relevance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1739359","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:29:42Z","timestamp":1775539782000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Trazodone effectiveness in depression (TED): a comparative evaluation of effect sizes trazodone extended release and SSRIs in the treatment of major depressive disorder"],"prefix":"10.3389","volume":"17","author":[{"given":"Dominika","family":"Dudek","sequence":"first","affiliation":[{"name":"Department of Adult Psychiatry, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian Andrzej","family":"Chrobak","sequence":"additional","affiliation":[{"name":"Department of Adult Psychiatry, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolina","family":"Podkowa","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Julia","family":"Krupa","sequence":"additional","affiliation":[{"name":"Department of Biological and Community Psychiatry, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Gorostowicz","sequence":"additional","affiliation":[{"name":"Department of Adult Psychiatry, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafa\u0142","family":"Jaeschke","sequence":"additional","affiliation":[{"name":"Department of Biological and Community Psychiatry, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrzej","family":"Juryk","sequence":"additional","affiliation":[{"name":"Department of Adult Psychiatry, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcin","family":"Siwek","sequence":"additional","affiliation":[{"name":"Department of Biological and Community Psychiatry, Jagiellonian University Medical College","place":["Cracow, Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1017\/S1092852921000304","article-title":"Early response to trazodone once-a-day in major depressive disorder: review of the clinical data and putative mechanism for faster onset of action","volume":"26","author":"Albert","year":"2021","journal-title":"CNS Spectr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s00213-004-2095-0","article-title":"Effects of the antidepressant trazodone, a 5-HT 2A\/2C receptor antagonist, on dopamine-dependent behaviors in rats","volume":"179","author":"Balsara","year":"2005","journal-title":"Psychopharmacol. 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