ADHD Non-Stimulant Triple Reuptake Inhibitor Seeks FDA Approval

December 16, 2025

Last month, Otsuka Pharmaceutical filed a New Drug Application (NDA) for centanafadine, a first-in-class non-stimulant medication that is a norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI). The U.S. Food and Drug Administration (FDA) is now considering centanafadine for the treatment of ADHD in children, adolescents, and adults.¹

Centanafadine is a once-daily, extended-release capsule that increases the availability of three neurotransmitters involved in ADHD (norepinephrine, dopamine, and serotonin) by blocking their reabsorption. While prior research links ADHD with dopamine and norepinephrine dysregulation, rising evidence indicates that serotonin, which influences mood, impulsivity, sleep, and digestion, also contributes to ADHD symptoms and comorbidities.² An August report in Neuroscience & Biobehavioral Reviews concluded that serotonin dysregulation “is likely to generate a broad spectrum of clinical manifestations, which may account for the unique presentation of neuropsychiatric behaviors and comorbidities found in patients with ADHD.”

“Centanafadine represents a new mechanism of action among available ADHD therapies,” says John Kraus, M.D., Ph.D., executive vice president and chief medical officer at Otsuka. “By inhibiting the reuptake of these three key neurotransmitters, the mechanism is designed to address the core symptoms of ADHD and may also help with executive dysfunction and emotional dysregulation.”

Non-stimulant medications are generally considered second- or third-line treatments behind stimulant medications, which are often prescribed to patients who do not respond to or cannot tolerate stimulants. Compared to quick-acting stimulants, non-stimulant ADHD medications may take weeks or longer become fully effective. However, centanafadine demonstrated an earlier onset of action more characteristic of stimulant medications, with clinical benefits emerging by week 1 and maintained through week 6, according to clinical trials.^{3, 4, 5}

“Patients who may be particularly well-suited for centanafadine are those seeking a balanced approach to ADHD management and who may not fully benefit from or tolerate current standard therapies,” Kraus says.

Four Phase 3 clinical trials using extended-release (children and adolescents) and sustained-release (adults) formulations support the NDA submission. Across studies, centanafadine produced statistically significant and clinically meaningful improvements in ADHD symptoms compared with placebo, measured by the ADHD Rating Scale–5 (ADHD-RS-5) in youth and the Adult ADHD Investigator Symptom Rating Scale (AISRS) in adults.^{2, 3, 4}

Adolescent & Pediatric Phase 3 Trial Results

Tim Wilens, M.D., Chief of Child and Adolescent Psychiatry at Massachusetts General Hospital, and a researcher on the centanafadine pediatric and adolescent trials, presented findings from the studies at the American Professional Society of ADHD and Related Disorders (APSARD) conference in January 2025. “Centanafadine had a significant impact on ADHD symptoms,” he said. “It also improves executive functioning — time management, hierarchical thinking, organization, and start/stop/shift transitions.”

A randomized, 6-week, double-blind, placebo-controlled Phase 3 trial involving 480 children (ages 6–12) with ADHD found that high-dose centanafadine significantly improved ADHD symptoms versus placebo. (Footnote 3) Children in the study were assigned to a high-dose, low-dose, or placebo group based on weight. Among those within the high-dose group, 34% achieved an 18-point or greater reduction on the ADHD-RS-5 compared with 23% in the placebo group.

Mean ADHD-RS-5 score reductions (ages 6–12)