Centanafadine in ADHD: Clinical Significance of the First Triple Reuptake Inhibitor for ADHD

Raman Baweja, MD, MS, discussed the clinical significance of centanafadine's approval by the US Food and Drug Administration (FDA) for attention-deficit hyperactivity disorder (ADHD), its novel mechanism of action, and its potential role in the treatment landscape across pediatric and adult populations.

Centanafadine received FDA approval on July 24, 2026, under the brand name Simtriyo, becoming the first norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) approved for ADHD—a mechanism that distinguishes it from all existing treatments. Central nervous system (CNS) stimulants act primarily on dopamine and norepinephrine, while currently available nonstimulants such as atomoxetine and viloxazine target primarily norepinephrine. Centanafadine's addition of serotonergic reuptake inhibition is the key pharmacological novelty, given emerging evidence linking the serotonin system to neuropsychological processes relevant to ADHD including attention, impulsivity, emotional regulation, and executive function.

Baweja highlighted that ADHD is a heterogeneous condition extending well beyond its core triad of inattention, hyperactivity, and impulsivity to encompass executive dysfunction, emotional dysregulation, learning difficulties, daily functioning impairment, and sleep disturbances. Phase 3 data across adult and adolescent populations demonstrated that centanafadine improved not only core ADHD symptoms but also executive functioning, learning, and—in post hoc analyses of adult data presented at the 2026 American Society of Clinical Psychopharmacology annual meeting—emotional dysregulation.¹ The adolescent phase 3 randomized, double-blind, placebo-controlled trial, published in the Journal of the American Academy of Child and Adolescent Psychiatry in July 2025, evaluated centanafadine 164.4 mg and 328.8 mg once daily versus placebo over 6 weeks in patients aged 13 to 17, with the higher dose demonstrating significant improvement in the Attention-Deficit/Hyperactivity Disorder Rating Scale total score at week 6.²

Baweja identified several patient populations for whom centanafadine may be particularly well suited: children and adults with prominent executive dysfunction, patients with ADHD and significant emotional dysregulation, and individuals for whom CNS stimulant use is problematic due to abuse or misuse potential or comorbid substance use disorder.

Dr Baweja is professor of psychiatry and public health sciences at Penn State College of Medicine.

References

1. Otsuka presents new phase 3 post hoc analyses of centanafadine highlighting improvement in executive function and emotional dysregulation in adults with ADHD at the 2026 American Society of Clinical Psychopharmacology Annual Meeting. Press release. May 28, 2026. Accessed July 31, 2026. https://www.otsuka-us.com/news/otsuka-presents-new-phase-3-post-hoc-analyses-centanafadine-highlighting-improvement-executive

2. Ward CL, Childress AC, Jin N, et al. Centanafadine for attention-deficit/hyperactivity disorder in adolescents: a randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2025;64(10):1023–1034.