Efficacy and Safety of Centanafadine in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and...

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder associated with persistent functional impairment across the lifespan. Although several pharmacological treatments are available, their clinical utility is often limited by tolerability concerns, heterogeneous efficacy, and limited long-term safety data. Centanafadine, a novel triple monoamine reuptake inhibitor targeting norepinephrine, dopamine, and serotonin transporters, has emerged as a potential non-stimulant treatment for ADHD; however, its efficacy and safety have not been systematically quantified.

To systematically review and quantitatively synthesize randomized controlled trials (RCTs evaluating the efficacy and safety of centanafadine compared with placebo in individuals with ADHD.

PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to the most recent available date. Placebo-controlled RCTs enrolling participants with a formal ADHD diagnosis were included. Primary efficacy outcomes were changes in ADHD symptom severity assessed using validated rating scales and pooled as standardized mean differences (Hedges' g). Secondary efficacy outcomes included clinician-rated global severity assessed using the Clinical Global Impressions-Severity (CGI-S) scale. Safety outcomes included the incidence of any adverse event. Random-effects meta-analyses using restricted maximum-likelihood estimation with Hartung-Knapp adjustment were performed. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool.

Five RCTs (n = 1,968) showed that centanafadine significantly reduced ADHD symptom severity versus placebo (Hedges' g = -0.37, 95% CI -0.68 to -0.05; p = 0.032). Four RCTs (n = 1,683) demonstrated significant improvement in CGI-S scores (mean difference = -0.26, 95% CI -0.31 to -0.21; p = 0.0006; I² = 0%). Safety analyses of six RCTs (n = 2,287) showed a numerically higher but non-significant risk of adverse events (risk ratio = 1.29, 95% CI 0.97 to 1.71).

Centanafadine provides statistically significant and clinically meaningful improvement in ADHD symptoms with generally acceptable tolerability, supporting its role as a non-stimulant treatment option. Further long-term and comparative trials are warranted.