FDA Approves First-in-Class Centanafadine for Treatment of ADHD

The FDA approved centanafadine (Simtriyo), a once-daily extended-release capsule for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults and pediatric patients 6 years and older weighing at least 20 kg. Centanafadine is the first and only approved norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI), working by inhibiting the reuptake of the hormones to increase the availability of these neurotransmitters in pathways involved in attention and behavioral regulation.¹

As an NDSRI and central nervous system (CNS) stimulant, the drug is expected to be commercially available later this year following Drug Enforcement Administration scheduling.¹

“ADHD can significantly affect many aspects of daily life across school, work, and relationships,” Lenard A. Adler, MD, director of the adult ADHD program at NYU Langone Health, said in a news release.¹ “The approval of Simtriyo introduces a novel mechanism of action and expands the range of options available to healthcare professionals and patients.”

Trial Data Supporting the Approval

The approval draws on 4 randomized, double-blind, placebo-controlled phase 3 trials spanning children, adolescents, and adults.¹

In 2 pivotal adult trials (NCT03605680 and NCT03605836), both centanafadine dose groups (200 mg/d and 400 mg/d) showed statistically significant improvements in Adult ADHD Investigator Symptom Rating Scale (AISRS) total scores compared with placebo, with effects observed as early as week 1 and maintained through the 6-week treatment period.^1,2

In study 1, the least-squares (LS) mean difference versus placebo was −3.15 for the 200 mg/d dose (P = .019) and −2.74 for the 400 mg/d dose (P = .039); in study 2, the LS mean differences were −4.01 (200 mg/d; P = .002) and −4.42 (400 mg/d; P < .001).²

In the pediatric trial (NCT05428033), children aged 6 to 12 years receiving high-dose centanafadine showed significantly greater improvement on the ADHD Rating Scale, version 5 (ADHD-RS-5) total raw score than those on placebo at week 6 (−16.3 vs −10.8; P < .001), with separation from placebo as early as week 1. The low dose did not reach statistical significance (mean difference, −2.7; 95% CI, −6.0 to 0.5; P = .10).³

In the adolescent trial (NCT05257265), the 328.8-mg dose produced significantly greater improvement in ADHD-RS-5 total raw score than placebo at week 6 (−18.50 vs −14.15; P = .0006), with separation from placebo at week 1 maintained throughout the study; the 164.4-mg dose did not meet the primary endpoint.⁴

Safety Profile and Boxed Warnings

Across the phase 3 program, centanafadine was generally well tolerated, though treatment-emergent adverse events (TEAEs) increased with dose. The most common adverse reactions were rash and decreased appetite in children aged 6 to 12 years; decreased appetite, nausea, rash, headache, and abdominal pain in adolescents aged 13 to 17 years; and headache, decreased appetite, insomnia, nausea, dry mouth, and diarrhea in adults.¹

Centanafadine carries 2 boxed warnings. The first warns that higher rates of suicidal ideation and behaviors occurred in centanafadine-treated patients aged 6 to 12 years than in placebo-treated patients and instructs clinicians to closely monitor all pediatric patients and to consider stopping treatment if emergent suicidal ideation or behavior occurs.¹

The second warns of abuse, misuse, and addiction potential associated with CNS stimulants, including centanafadine, and directs prescribers to assess each patient's risk before prescribing, educate patients and families on storage and disposal, and reassess risk throughout treatment.¹

Additional warnings and precautions include risks in patients with serious cardiac disease, increased blood pressure and heart rate, psychiatric adverse reactions, hypersensitivity reactions including anaphylaxis and angioedema, long-term suppression of growth in pediatric patients, peripheral vasculopathy including Raynaud phenomenon, serotonin syndrome, and motor and verbal tics or worsening of Tourette syndrome.¹

Centanafadine is contraindicated in patients with known hypersensitivity to centanafadine or its excipients, those taking or within 14 days of stopping a monoamine oxidase inhibitor, and those with pheochromocytoma or a history of pheochromocytoma. Use is not recommended in pediatric patients younger than 6 years or weighing less than 20 kg because of a higher incidence of weight loss in younger children and a lack of data in lower-weight patients.¹

What This Means for Pharmacists

The dual boxed warnings on suicidal ideation and abuse potential make patient and caregiver counseling central to centanafadine’s rollout. Pharmacists should be prepared to reinforce monitoring expectations for pediatric patients and to counsel on safe storage and disposal given the drug's stimulant classification and pending DEA scheduling. Weight-based dosing in pediatric patients, cardiac risk assessment, and screening for concomitant serotonergic medications before dispensing are additional counseling points that align with the label's warnings.

Ongoing Research

Otsuka noted that a recently completed phase 3b study in adults with ADHD and comorbid anxiety showed statistically significant improvements in ADHD symptoms compared with placebo, with full results to be presented at an upcoming scientific meeting.¹

“The approval of Simtriyo marks an important milestone for people living with ADHD, as it introduces a novel treatment approach for this condition,” John Kraus, MD, PhD, executive vice president and chief medical officer at Otsuka, said in a news release.¹ “ADHD is a complex and highly individualized disorder that can affect people throughout childhood, adolescence, and adulthood.”

References

1. Otsuka receives FDA approval for first-in-class SIMTRIYO® (centanafadine) for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients aged 6 years and older. News release. Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceutical Co., Ltd. July 24, 2026. Accessed July 27, 2026. https://www.otsuka-us.com/otsuka-shares-fda-review-update-for-centanafadine

2. Adler LA, Adams J, Madera-McDonough J, et al. Efficacy, safety, and tolerability of centanafadine sustained-release tablets in adults with attention-deficit/hyperactivity disorder: results of 2 phase 3, randomized, double-blind, multicenter, placebo-controlled trials. J Clin Psychopharmacol. 2022;42(5):429-439. doi:10.1097/JCP.0000000000001575

3. Ward CL, Wilens TE, Jin N, Turkoglu O, Skubiak T, Childress AC. Efficacy and safety of centanafadine for ADHD treatment in children: a randomized clinical trial. Pediatrics Open Science. 2025;1(3). doi:10.1542/pedsos.2024-000349

4. Ward CL, Childress AC, Jin N, Turkoglu O, Skubiak T, Wilens TE. Centanafadine for attention-deficit/hyperactivity disorder in adolescents: a randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2026;65(6):805-817. doi:10.1016/j.jaac.2025.06.023