Simtriyo (centanafadine): FDA approval, pivotal trial and safety
Approved
Type
New molecular entity · Oral
FDA-approved use
To treat attention-deficit hyperactivity disorderWording from FDA's list of novel approvals.
FDA review
Priority review
Company
Otsuka
Application
NDA 218145
Specialty
Psychiatry
Boxed warning: Suicidal ideation and behaviors in pediatric patients aged 6 years and older; and abuse, misuse and addiction
At a glance
Simtriyo (centanafadine) is a norepinephrine-dopamine-serotonin reuptake inhibitor and CNS stimulant approved for ADHD in adults and in children 6 years and older weighing at least 20 kg. In 6-week placebo-controlled trials, the approved dose lowered ADHD-RS-5 total score more than placebo: by 5.6 points in children 6 to 12 years and 4.4 points in adolescents 13 to 17 years. It carries a boxed warning for suicidal ideation and behaviors in pediatric patients and for abuse, misuse and addiction.
What it is and how it works
Centanafadine blocks reuptake of norepinephrine, dopamine and serotonin. The label states its mechanism in ADHD is unclear, but efficacy may come from this triple reuptake inhibition. Most existing ADHD stimulants act on dopamine and norepinephrine, and nonstimulants mainly on norepinephrine, so the added serotonin activity is the distinguishing feature.
Randomized, double-blind, multicenter, placebo-controlled, 6 weeks, 1:1:1 allocation to two weight-based doses or placebo.
Patients
480 children aged 6 to 12 years with ADHD; mean age 9 years; 367 completed.
Compared with
Placebo
Primary endpoint
Change from baseline at Week 6 in ADHD-RS-5 symptoms total score.
Result
The approved dose beat placebo. Least-squares mean change was -16.3 vs -10.8, a placebo-subtracted difference of -5.6 (95% CI -8.78 to -2.33). The lower dose did not differ significantly from placebo and is not approved.
Other results
In a secondary analysis (P1), Conners 3-Parent executive functioning T-score change was -11.3 vs -6.8 (P=0.0026) and learning problems -8.2 vs -2.8 (P<0.0001), favoring centanafadine. P2 reported improvement in inattention and hyperactivity/impulsivity from Week 1, without multiplicity control.
Safety in the trial
Most common adverse reactions at 5% or more and above placebo were rash and decreased appetite. Suicidal ideation and behavior were reported more often than with placebo in this age group.
Randomized, double-blind, multicenter, placebo-controlled, 6 weeks, 1:1:1 allocation to two doses or placebo.
Patients
459 adolescents aged 13 to 17 years with ADHD; mean age 15 years; 371 completed.
Compared with
Placebo
Primary endpoint
Change from baseline at Week 6 in ADHD-RS-5 symptoms total score.
Result
The approved dose beat placebo. Least-squares mean change was -18.5 vs -14.2, a placebo-subtracted difference of -4.4 (95% CI -6.83 to -1.87). The lower dose did not differ significantly from placebo and is not approved.
Other results
In P1, Conners 3-Parent executive functioning T-score change was -13.0 vs -8.1 (P=0.0003) and learning problems -8.0 vs -3.1 (P<0.0001). Adolescent self-report of learning problems also favored centanafadine (-6.1 vs -2.5, P=0.0023).
Safety in the trial
Most common adverse reactions at 5% or more and above placebo were decreased appetite, nausea, rash, headache and abdominal pain.
How does Simtriyo (centanafadine) compare with the alternatives (Methylphenidate-based stimulants, Amphetamine-based stimulants, Atomoxetine) for attention-deficit hyperactivity disorder? Summarize head-to-head and indirect evidence, efficacy, safety and where each fits, with citations.
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Safety signals
The boxed warning covers two risks. In a 6-week study, children 6 to 12 years had higher rates of suicidal ideation and behavior than placebo, so all pediatric patients 6 and older need close monitoring, especially in the first months. As a CNS stimulant it can be abused and misused, which can lead to addiction, overdose and death, so risk should be assessed before and during treatment. Warnings also include serious cardiac disease, higher blood pressure and heart rate, new psychotic or manic symptoms, hypersensitivity including anaphylaxis, growth suppression in children, peripheral vasculopathy including Raynaud's phenomenon, serotonin syndrome, and tics. Common adverse reactions in children and adolescents were decreased appetite, rash, nausea, headache and abdominal pain. In adults they were headache, decreased appetite, insomnia, nausea, dry mouth and diarrhea. Use is not recommended under age 6 or under 20 kg because of weight loss.
What it competes with
ADHD is usually treated with stimulants, with nonstimulant medicines as alternatives, often alongside behavioral therapy, especially in children.
Methylphenidate-based stimulantsFirst-line stimulant class that inhibits dopamine and norepinephrine reuptake, available in many formulations.
Amphetamine-based stimulantsEstablished first-line stimulants that increase dopamine and norepinephrine release; also carry abuse risk.
AtomoxetineNonstimulant norepinephrine reuptake inhibitor, useful when stimulants are unsuitable.
ViloxazineNonstimulant norepinephrine-acting option without stimulant scheduling.
Alpha-2 agonists (guanfacine, clonidine)Nonstimulant options used alone or added to a stimulant.
Bottom line for clinicians
Simtriyo adds a stimulant option with a different transporter profile for adults and for children 6 and older. The pediatric evidence is from two 6-week placebo-controlled trials with moderate effect sizes, and no head-to-head data against established drugs are provided. Weigh the boxed warnings, especially suicidality monitoring in children, along with abuse risk, cardiovascular status, appetite and growth.
Dosing, contraindications and full warnings are in the prescribing information.
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Last updated October 28, 2026 by 2 Minute Medicine.
For healthcare professionals. A summary of public FDA documents and published trials, not medical advice. Check the full prescribing information before prescribing.
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