Centanafadine: A Novel Triple Reuptake Inhibitor for the Treatment of ADHD in Adolescents

September 17, 2025

Ruta Nonacs, MD PhD

A randomized controlled trial looks at centanafadine, a novel norepinephrine, dopamine, serotonin reuptake inhibitor, for the treatment of ADHD in adolescents.

Neurobiological and pharmacologic research into attention-deficit/hyperactivity disorder (ADHD) has long focused on dopamine and norepinephrine as primary targets for intervention. Most traditional treatments, including stimulants, are designed to improve attention and reduce hyperactivity by modulating these two neurotransmitter systems. Yet, ADHD is a heterogeneous and complex disorder, commonly accompanied by emotional dysregulation, impulsivity, anxiety, and depression, symptoms that may not be adequately treated with traditional ADHD medications.

In a recent clinical trial, researchers, including Timothy Wilens, MD, Chief of the Division of Child and Adolescent Psychiatry and the Co-Director of the Center for Addiction Medicine at Mass General Hospital, evaluate the efficacy, safety, and tolerability of centanafadine, a novel norepinephrine, dopamine, serotonin reuptake inhibitor, for the treatment of ADHD in adolescents.

Emerging Science: The Role of Serotonin in ADHD

Increasingly, evidence suggests that serotonin may also contribute to the complex array of symptoms seen in patients with ADHD. Serotonin influences mood, impulsivity, executive functioning, sleep, and memory — domains that are commonly affected in ADHD and its psychiatric comorbidities. This has prompted interest in medications that have a broader range of actions, influencing serotonin, as well as dopamine and norepinephrine, neurotransmitter systems.

Centanafadine: Mechanism of Action and Clinical Data

Centanafadine is an investigational non-stimulant medication (Otsuka Pharmaceuticals) that acts as a norepinephrine, dopamine, and serotonin reuptake inhibitor. Its strongest affinity is for norepinephrine transporters, followed by dopamine and, to a lesser extent, serotonin. Unlike conventional stimulants, which exert minimal serotonergic effects, centanafadine has a more pronounced effect on serotonin.

In a recent phase 3 randomized, double-blind, placebo-controlled trial in adolescents (ages 13-17), centanafadine (328.8 mg once daily) demonstrated statistically significant and clinically meaningful reductions in ADHD Rating Scale-5 (ADHD-RS-5) scores compared to placebo at week 6 (−18.50 vs −14.15; p = .0006), with separation from placebo as early as week 1. The lower dose (164.4 mg) did not perform better than placebo.

The high-dose group experienced higher rates of treatment-emergent adverse events (primarily decreased appetite, nausea, headache, and rash), but most adverse events were mild or moderate. Importantly, centanafadine was generally well tolerated; severe adverse events were rare, and there were no indications of abuse or diversion.

How Does Centanafadine Compare—and What About Mood?

Comparative effectiveness studies in adults indicate that centanafadine’s efficacy for core ADHD symptoms is similar to that of other non-stimulants like atomoxetine and viloxazine, and slightly less robust than stimulant medications, but with a more favorable side effect profile with respect to appetite, sleep, and abuse risk.

Regarding mood, secondary outcomes and post hoc analyses from adult trials and mechanistic data suggest that centanafadine’s activity at serotonin transporters could theoretically benefit mood symptoms, emotional dysregulation, and anxiety, symptoms commonly seen in patients with ADHD. A recent phase 2 study posited that serotoninergic activity may help address comorbid symptoms but may also mitigate stimulant-induced side effects (e.g., insomnia, appetite disturbance). However, current published clinical trials have not specifically focused on mood, and data on Centanafadine’s direct efficacy for mood symptoms are still emerging.

Notably, studies comparing centanafadine to methylphenidate and atomoxetine in adults reported lower risks of anxiety, initial insomnia, and other adverse events, which may indirectly support its use in patients with comorbid mood or anxiety symptoms. Ongoing and planned trials, including those examining centanafadine as adjunct therapy to SSRIs, could provide additional insight into its utility for patients with prominent comorbid mood disorders.

Clinical Implications

Centanafadine represents a new pharmacological option for ADHD, particularly in individuals who have comorbid emotional or mood symptoms or are at risk for stimulant misuse.
While its triple reuptake activity holds promise for broader symptom relief, robust data demonstrating direct improvements in mood remain limited and await further study.
For now, centanafadine is best positioned as an effective, well-tolerated non-stimulant ADHD option with theoretical but not yet proven advantage for comorbid mood symptoms.