Centanafadine May Offer Second-Line Option for Patients With ADHD If Stimulants Fail

In this episode of Psychiatric Pharmacy Pulse, host Megan Maroney, PharmD, BCPP, FAAPP, speaks with Danielle Stutzman, PharmD, BCPP, clinical assistant professor at the University of Colorado Skaggs School of Pharmacy and assistant adjunct professor at the Child and Adolescent Mental Health Division of the Department of Psychiatry at the University of Colorado School of Medicine, and member of the American Association of Psychiatric Pharmacists Board of Directors, about where centanafadine (Simtriyo; Otsuka Pharmaceutical) fits into attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy.

Centanafadine received FDA approval in July 2026 as a norepinephrine-dopamine-serotonin reuptake inhibitor (NDSRI) for ADHD in both pediatric and adult patients, with DEA scheduling still pending. Maroney and Stutzman note its mechanism is not entirely novel, drawing comparisons to tricyclic antidepressants, atomoxetine (Eli Lilly), and viloxazine (Qelbree; Supernus Pharmaceuticals, Inc).

A pooled meta-analysis of 4 phase 3 trials plus a phase 2b crossover study found a Hedges’ g effect size of about 0.37 for overall symptom severity versus placebo, a modest result that falls short of typical stimulant effect sizes of 0.8 to 1.0, though executive functioning outcomes on caregiver-rated scales appeared more promising.

Safety data showed a nonsignificant increase in adverse effects (AEs) overall (pooled risk ratio, 1.29), with appetite suppression, nausea, and rash among the most common issues. Rash was the leading cause of study discontinuation in the youngest age group. Indirect comparisons suggested centanafadine may carry a lower risk of insomnia than methylphenidate and fewer AEs than atomoxetine and viloxazine, though lisdexamfetamine (Vyvanse; Takeda Pharmaceuticals) remained more effective. A boxed warning for suicidal ideation applies, which is consistent with other ADHD medications.

Practical advantages discussed include a lack of reliance on cytochrome P450 metabolism, lower drug interaction risk than atomoxetine or viloxazine, and capsules that can be opened and sprinkled on applesauce, yogurt, or orange juice. Centanafadine did increase caffeine exposure roughly 2-fold, warranting patient counseling. Both Maroney and Stutzman positioned the drug as a potential second-line option for patients who are not candidates for stimulants or who have not tolerated or responded to first-line therapies.

To provide feedback or suggest topics of discussion for Psychiatric Pharmacy Pulse, please reach out to Gillian McGovern, Editor ([email protected]).

REFERENCES

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2. Otsuka Pharmaceutical Development & Commercialization, Inc; Otsuka Pharmaceutical Co, Ltd. Otsuka receives FDA approval for first-in-class SIMTRIYO (centanafadine) for the treatment of attention-deficit/hyperactivity disorder. Otsuka US. July 24, 2026. Accessed September 16, 2026. https://www.otsuka-us.com/otsuka-shares-fda-review-update-for-centanafadine

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