{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T11:00:55Z","timestamp":1784890855370,"version":"3.55.0"},"reference-count":39,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Major depressive disorder (MDD) is among the most prevalent mental health disorders, causing substantial disability and economic burden. Although several first-line treatments exist with mild adverse effects, up to 50% to 60% of patients do not tolerate or respond to them. Ammoxetine, a novel selective serotonin and norepinephrine reuptake inhibitor, has been found to reduce adverse effects and hepatotoxicity and more potent inhibition of serotonin and norepinephrine transporters, making it more tolerable and effective.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the efficacy and safety of ammoxetine in treating adults with MDD.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This phase 2 randomized clinical trial was a multicenter, double-masked, placebo-controlled, parallel-group, fixed-dose study of ammoxetine treatment in patients with MDD in China. Patients aged 18 to 65 years from 15 study centers were randomized into daily ammoxetine or placebo groups between March 27, 2023, and June 13, 2024, and followed up for 10 weeks.<\/jats:p><\/jats:sec>Interventions<\/jats:title>Participants were randomized 1:1:1 to 3 treatment groups: ammoxetine 40 mg\/d, ammoxetine 60 mg\/d, and placebo.<\/jats:p><\/jats:sec>Main Outcome and Measures<\/jats:title>The primary outcome was change in Montgomery-\u00c5sberg Depression Rating Scale (MADRS) total score from baseline to 8 weeks. Efficacy analyses were performed on both the full-analysis and per-protocol sets using least-squares (LS) mean differences. The safety set analysis was performed using descriptive statistics.<\/jats:p><\/jats:sec>Results<\/jats:title>Among 239 enrolled patients (mean [SD] age, 30.4 [10.0] years, 158 female [66.1%]), 80 were randomized to the ammoxetine 60 mg\/d group, 80 to the ammoxetine 40 mg\/d group, and 79 to the placebo group. In the full-analysis set, both ammoxetine doses led to statistically significant improvements in MADRS total scores at week 8 compared with placebo. The LS mean changes (SE) from baseline were \u221216.7 (1.3) for ammoxetine 40 mg\/d, \u221216.6 (1.3) for ammoxetine 60 mg\/d, and \u221213.5 (1.3) for placebo. The differences vs placebo were \u22123.3 (97.3 CI, \u22126.3 to \u22120.3) for ammoxetine 40 mg\/d and \u22123.1 (97.3% CI, \u22126.2 to 0.0) for ammoxetine 60 mg\/d. Consistent results were observed in the per-protocol set analysis at week 8 for ammoxetine 40 mg\/d (LS mean change, \u22123.2; 97.3% CI, \u22126.2 to \u22120.2) and ammoxetine 60 mg\/d (LS mean change, \u22123.18; 97.3% CI, \u22126.2 to \u22120.2), both superior to placebo. Treatment-emergent adverse events were reported in 68 participants (85.0%) receiving ammoxetine 60 mg\/d, 63 (78.8%) receiving ammoxetine 40 mg\/d, and 48 (60.8%) receiving placebo; most were mild to moderate in severity.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>This randomized clinical trial demonstrated superiority over placebo of ammoxetine treatment at both 40 mg\/d and 60 mg\/d in patients with MDD. In addition, all doses of ammoxetine were generally well tolerated.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT05762458<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.32650","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T15:30:45Z","timestamp":1758555045000},"page":"e2532650","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy and Safety of Ammoxetine in Major Depressive Disorder"],"prefix":"10.1001","volume":"8","author":[{"given":"Shen","family":"He","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Xu","family":"Chen","sequence":"additional","affiliation":[{"name":"Sleep Medicine Center, Beijing Huilongguan Hospital, Beijing, 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