{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T13:49:09Z","timestamp":1791985749191,"version":"4.4.0"},"reference-count":20,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["PCN Reports"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Centanafadine is a multimodal norepinephrine\u2013dopamine\u2013serotonin reuptake inhibitor (NDSRI) that has been evaluated for the treatment of attention\u2010deficit\/hyperactivity disorder (ADHD) across pediatric, adolescent, and adult populations. This systematic review aimed to evaluate the efficacy, safety, and tolerability of centanafadine compared with placebo, with particular emphasis on dose\u2013response patterns across different age groups. PubMed\/MEDLINE, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from database inception to July 2026. Randomized, double\u2010blind, placebo\u2010controlled trials evaluating centanafadine in patients with ADHD were eligible for inclusion. The Cochrane Risk of Bias 2 (RoB 2) tool was used to assess the risk of bias. Because of differences in populations, formulations, dosing regimens, outcome measures, and reported effect estimates, findings were synthesized narratively rather than quantitatively. Four randomized trials reported in three publications, including 1845 randomized participants, were included. In children, high\u2010dose centanafadine significantly improved attention\u2010deficit\/hyperactivity disorder rating scale, version 5 (ADHD\u2010RS\u20105) scores compared with placebo (\u221216.3 vs. \u221210.8;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), whereas the low\u2010dose group did not demonstrate a statistically significant difference (mean difference [MD] \u22122.7; 95% confidence interval [CI], \u22126.0 to 0.5;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.10). In adolescents, 328.8\u2009mg significantly improved ADHD\u2010RS\u20105 scores compared with placebo (\u221218.5 vs. \u221214.2;\n                    <jats:italic>p<\/jats:italic>\n                    = 0.0006; Cohen's\n                    <jats:italic>d<\/jats:italic>\n                    = \u22120.40), whereas 164.4\u2009mg did not (\n                    <jats:italic>p<\/jats:italic>\n                    = 0.3016). In adults, both 200 and 400\u2009mg\/day significantly improved Adult ADHD Investigator Symptom Rating Scale (AISRS) scores, with LSMDs ranging from \u22122.74 to \u22124.42 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2264 0.039). Treatment\u2010emergent adverse events occurred in 25%\u201339% of children, 23.8%\u201350.3% of adolescents, and 17.6%\u201331.8% of adults, with higher rates generally observed at higher doses in some populations. Centanafadine demonstrated improvement in core ADHD symptoms across pediatric, adolescent, and adult populations, with a more apparent dose\u2013response pattern in children and adolescents and significant efficacy across the adult doses evaluated. Higher doses were associated with increased treatment\u2010emergent adverse events in some populations. However, the evidence base remains limited to four randomized trials from three publications, with predominantly short\u2010term follow\u2010up, no active\u2010comparator trials, and limited independently sponsored evidence. Therefore, the efficacy, safety, and dose\u2013response findings should be interpreted cautiously. Longer term, independently sponsored, and head\u2010to\u2010head comparative trials are needed to further establish the optimal dosing, comparative effectiveness, and long\u2010term safety of centanafadine.\n                  <\/jats:p>","DOI":"10.1002\/pcn5.70428","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T13:14:02Z","timestamp":1791983642000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dose\u2010dependent efficacy and safety of centanafadine in patients with attention\u2010deficit\/hyperactivity disorder: A systematic review of the latest evidence"],"prefix":"10.1002","volume":"5","author":[{"given":"Daud","family":"Gul","sequence":"first","affiliation":[{"name":"Department of Medicine Bridgeport Medical Clinic Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Medicine Ibn\u2010e\u2010Sina University Mirpurkhas Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushal","family":"Baral","sequence":"additional","affiliation":[{"name":"Department of Medicine Beni Provincial Hospital Dhaulagiri Nepal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziad","family":"Saber","sequence":"additional","affiliation":[{"name":"Department of Medicine Xavier University School of Medicine Oranjestad Aruba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arindam","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Medicine Dr. B.C. Roy Multi\u2010Speciality Medical Research Centre, IIT Kharagpur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eemaz","family":"Nathaniel","sequence":"additional","affiliation":[{"name":"Department of General Medicine\/Cardiology University Hospital Wishaw  Scotland UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onuwabhagbe Daniel","family":"Omomhenle","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Tees, Esk and Wear Valleys NHS Foundation Trust Middlesbrough UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel Oluwakayode","family":"Oyedeji","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Tees, Esk and Wear Valleys NHS Foundation Trust Middlesbrough UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana Omar Saed","family":"Alkhatib","sequence":"additional","affiliation":[{"name":"Department of Medicine Yarmouk University Irbid 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