More dopamine, but does it make a difference?
STUDY: Muneer MA et al; Psychopharm Bulletin June 2026; 56(3):47-65
STUDY TYPE: Meta-analysis
FUNDING: All trials were industry-funded
Background
On July 24, 2026, the FDA approved the first triple-reuptake inhibitor for ADHD. Centanafadine (Simtriyo) is approved across the lifespan, ages 6 and up (the trials went up to age 55).
The approval follows a growing list of medications with antidepressant-like activity that treat ADHD, each of which affects a broader range of neurotransmitters:
- Atomoxetine (Strattera, 2002): Norepinephrine
- Viloxazine (Qelbree, 2021): Norepinephrine and serotonin
- Centanafadine (Simtriyo, 2026): Norepinephrine, serotonin, and dopamine
The Clinical Data
Whether this broader profile translates into bigger effects is not clear. When the five centanafadine trials are pooled together, the effect size is small (0.37) and similar to that for atomoxetine and viloxazine (total n = 1,968).
However, it has a more rapid onset of action, with meaningful effects within 1-2 weeks. That places it faster than atomoxetine (4-6 weeks for meaningful effect, but early response by 2 weeks) but on par with viloxazine (1-2 weeks).
The medication improved inattention, hyperactivity/impulsivity, executive function, and emotional dysregulation. “Executive function” is a broad domain covering time management, planning and prioritization, task initiation and completion, and working memory.
In contrast with stimulants, “defiance/aggression” did not change in these trials, possibly because behavioral problems were low to begin with in the populations studied.
The benefits are dose-dependent, with higher doses (400 mg in adults; 328.8 mg in teens) outperforming lower doses significantly (200 mg in adults; 164.4 mg in teens). The studies used fixed-dosing, and it’s possible more flexible dosing might bring greater effects.
Two doses of Centanafadine vs placebo in adolescents
Two doses (200 mg vs 400 mg, divided bid) of Centanafadine vs placebo in adults
Side Effects
Most common: Decreased appetite, nausea, headache, and rash.
Centanafadine may have a tolerability advantage over atomoxetine and viloxazine. In an indirect comparison study, it had:
- Less fatigue and nausea compared to atomoxetine and viloxazine
- Compared to atomoxetine: Less dry mouth, erectile dysfunction, low appetite, and urinary hesitation
- Compared to viloxazine: Less insomnia and constipation
Practice Implications
- Unfortunately, our faster non-stimulants in this class (centanafadine and viloxazine) are brand-only, while the slower one is atomoxetine.
- Centanafadine may have a tolerability advantage over viloxazine and atomoxetine.
- Still, atomoxetine has a new role in sleep apnea, which is very common in children and adults with ADHD.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
