{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:46:33Z","timestamp":1791413193022,"version":"4.3.3"},"reference-count":29,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"\n Importance<\/jats:title>\n This study represents a first successful use of a genetic biomarker to select potential responders in a prospective study in psychiatry. Liafensine, a triple reuptake inhibitor, may become a new precision medicine for treatment-resistant depression (TRD), a major unmet medical need.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine whether ANK3-positive patients with TRD benefit from a 1-mg and\/or 2-mg daily oral dose of liafensine, compared with placebo, in a clinical trial.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n A novel pharmacogenomic biomarker, ANK3, was discovered as a predictor of liafensine\u2019s efficacy retrospectively. In this biomarker-guided, randomized, double-blind, placebo-controlled, phase 2b clinical trial conducted at 58 sites from July 2022 through March 2024, 1967 patients were assessed for eligibility and 189 ANK3-positive patients with TRD were randomized. Key exclusion criteria included specified disorders, concomitant medications, or organ dysfunction. Investigators, patients, raters, and sponsors were blinded to ANK3 status and treatment. Data analysis was performed from March 26 to April 23, 2024.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Patients were randomized 1:1:1 to once-daily oral liafensine, 1 mg; once-daily oral liafensine, 2 mg; or oral placebo once daily.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was the Montgomery-\u00c5sberg Depression Rating Scale (MADRS) total score change from baseline to day 42.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of the 189 ANK3-positive patients with TRD who were randomized, 188 received study drug (mean [SD] age, 43.2 [14.8] years; 119 [63.3%] female), and 186 had at least 1 dose of study drug and 1 postrandomization efficacy evaluation. The mean (SE) MADRS score change in these patients was \u221215.4 (0.9) for liafensine (including both 1- and 2-mg doses) vs \u221211.0 (1.3) for placebo (mean treatment difference, \u22124.4; 95% CI, \u22127.6 to \u22121.3;\n P<\/jats:italic>\n \u2009=\u2009.006). Statistically significant improvements were also seen in all secondary end points. Adverse events were tolerable, with low rates of meaningful events. Adverse events leading to discontinuation of treatment occurred in 5 patients (4.0%) receiving liafensine and 9 (14.1%) receiving placebo.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Liafensine was efficacious and well tolerated in ANK3-positive patients with TRD, with clinically meaningful and statistically significant improvements over placebo suggesting ANK3 as a predictive genetic biomarker for liafensine. This represents a first successful prospective genetic biomarker-guided trial in psychiatry.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT05113771<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2025.2416","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T15:00:28Z","timestamp":1757516428000},"page":"1186","source":"Crossref","is-referenced-by-count":10,"title":["ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression"],"prefix":"10.1001","volume":"82","author":[{"given":"Gang","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Anding Hospital, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Aguado","sequence":"additional","affiliation":[{"name":"SG Research, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew 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