Dose‐dependent efficacy and safety of centanafadine in patients with attention‐deficit/hyperactivity disorder: A systematic review of the latest evidence

Abstract Centanafadine is a multimodal norepinephrine–dopamine–serotonin reuptake inhibitor (NDSRI) that has been evaluated for the treatment of attention‐deficit/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–response 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‐blind, placebo‐controlled 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‐dose centanafadine significantly improved attention‐deficit/hyperactivity disorder rating scale, version 5 (ADHD‐RS‐5) scores compared with placebo (−16.3 vs. −10.8; p < 0.001), whereas the low‐dose group did not demonstrate a statistically significant difference (mean difference [MD] −2.7; 95% confidence interval [CI], −6.0 to 0.5; p = 0.10). In adolescents, 328.8 mg significantly improved ADHD‐RS‐5 scores compared with placebo (−18.5 vs. −14.2; p = 0.0006; Cohen's d = −0.40), whereas 164.4 mg did not ( p = 0.3016). In adults, both 200 and 400 mg/day significantly improved Adult ADHD Investigator Symptom Rating Scale (AISRS) scores, with LSMDs ranging from −2.74 to −4.42 ( p ≤ 0.039). Treatment‐emergent adverse events occurred in 25%–39% of children, 23.8%–50.3% of adolescents, and 17.6%–31.8% 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–response pattern in children and adolescents and significant efficacy across the adult doses evaluated. Higher doses were associated with increased treatment‐emergent adverse events in some populations. However, the evidence base remains limited to four randomized trials from three publications, with predominantly short‐term follow‐up, no active‐comparator trials, and limited independently sponsored evidence. Therefore, the efficacy, safety, and dose–response findings should be interpreted cautiously. Longer term, independently sponsored, and head‐to‐head comparative trials are needed to further establish the optimal dosing, comparative effectiveness, and long‐term safety of centanafadine.