{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T08:17:31Z","timestamp":1783325851279,"version":"3.54.6"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016350","name":"Sichuan Provincial Administration of Traditional Chinese Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100016350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014895","name":"Southwest Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background and Objective<\/jats:title>\n                    <jats:p>To address the high mortality, slow onset, and suboptimal efficacy of current treatments for comorbid anxiety and depression (CAD), this study developed and systematically evaluated a novel combination formulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The anxiolytic tandospirone (TDS) was combined with fluoxetine (FLU), escitalopram, or milnacipran for cell-based screening. The optimal combination was selected for pharmacokinetic studies in rats, followed by a 49-day pharmacodynamic evaluation and mechanistic investigation in a CAD mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Two optimal TDS-FLU combinations, TF-1 (TDS:FLU = 1.2:1,w\/w) and TF-2 (TDS:FLU = 2.4:1,w\/w), were obtained, both exhibiting good neuroprotective effects. Pharmacokinetic results showed that TF-1 and TF-2 significantly increased drug exposure and prolonged half-life compared with monotherapies of TDS and FLU. Pharmacodynamically, TF-1 and TF-2 exhibited superior anxiolytic-antidepressant efficacy compared with monotherapies after 28-day and 49-day interventions. At day 28, both formulations significantly increased open-field central-zone activity and sucrose preference, and reduced immobility time (all P &amp;lt; 0.05). Their therapeutic benefits were further augmented at day 49, with sustained and improved behavioral improvements upon long-term treatment. Mechanistic studies showed that both combinations elevated plasma and hippocampal 5-HT and BDNF levels, upregulated hippocampal 5-HT1AR and TrKB expression, and enhanced neuronal plasticity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TF-1 and TF-2 were superior to single agents in pharmacokinetics and long-term CAD efficacy, acting via 5-HT modulation and BDNF-TrKB activation, supporting their development as CAD combination therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1866088","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T07:44:46Z","timestamp":1783323886000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel anxiolytic-antidepressant combinations TF-1 and TF-2 and their intervention mechanisms in a mouse model of comorbid 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