First Triple Reuptake Inhibitor Enters ADHD Treatment as Simtriyo Wins FDA Approval

Responses and tolerability to medication vary widely among patients with attention-deficit/hyperactivity disorder (ADHD), so adding a mechanism of action is often more meaningful than simply adding another brand. On July 24, the U.S. Food and Drug Administration (FDA) approved Otsuka Pharmaceutical’s once-daily extended-release capsule Simtriyo (centanafadine) for adults and for children and adolescents aged six or older who weigh at least 20 kilograms.

Centanafadine simultaneously inhibits the reuptake of norepinephrine, dopamine, and serotonin, increasing the availability of these three neurotransmitters in relevant neural pathways. This makes it the first triple reuptake inhibitor approved in the United States to treat ADHD; however, it is still classified as a central nervous system stimulant, and having a newer mechanism does not mean it has been shown to be more effective than existing medications.

The approval was based on four randomized, double-blind, placebo-controlled Phase 3 trials, including two studies in adults and one study each in adolescents and children. After six weeks of treatment, the effective-dose groups in the adult trials and the high-dose groups in the child and adolescent trials all achieved greater reductions in symptom scale scores than placebo; the low-dose groups in the child and adolescent studies did not show a statistical advantage. Otsuka said some improvements were visible during the first week, but trials directly comparing centanafadine with other ADHD medications are currently lacking, and the short-term results are insufficient to determine whether efficacy can be maintained over the long term.

Prescribed doses are adjusted by age and weight: children aged six to twelve receive weight-tiered dosing, while the recommended dose for adolescents is 280 mg once daily. Adults start at 210 mg once daily, which may be increased to 280 mg if necessary. Use is not recommended in children younger than six because weight loss occurred more frequently in this group during trials, while patients weighing less than 20 kilograms should not use the drug because of insufficient data and the risk of weight loss.

Safety is another aspect of this approval that cannot be overlooked. Decreased appetite was a common adverse reaction across all age groups. Rash was also more common in children; nausea, headache, and abdominal pain were observed in adolescents; and adverse reactions in adults included insomnia, dry mouth, and diarrhea. Two children receiving centanafadine experienced suicidal ideation during the trials, while no cases occurred in the placebo group. The label therefore includes a boxed warning requiring close monitoring of all pediatric patients for suicidal ideation and behavior.

Another boxed warning concerns abuse, misuse, and addiction. The prescribing information also requires physicians to assess the risks of cardiovascular and psychiatric disorders, monitor blood pressure, heart rate, and growth in children, and watch for severe allergic reactions, serotonin syndrome, and the worsening of tics or Tourette syndrome. The drug must not be used concurrently with monoamine oxidase inhibitors or within 14 days after their discontinuation.

The FDA designated Simtriyo as the 29th new molecular entity approved in 2026. The product must still await controlled-substance scheduling by the U.S. Drug Enforcement Administration and is expected to launch later in 2026. This approval expands the ADHD treatment toolkit, but its actual place in clinical practice will still depend on long-term safety, real-world discontinuation rates, and future direct comparisons with existing stimulant and non-stimulant medications.