Centanafadine (SIMTRIYO): A Ritalin-SRI Hybrid With No Upside
- Jason Cafer MD
- Aug 2
- 2 min read
Centanafadine (Simtriyo)
Simtriyo is the first FDA-approved norepinephrine–dopamine–serotonin reuptake inhibitor (NDSRI).
We had SSRIs, SNRIs, NRIs, NDRIs, DRIs...and now all three in one.
Also, now there are three classes of ADHD stimulants: methylphenidates, amphetamines, and the new NDSRI.
Think of centanafadine as a weak serotonin reuptake inhibitor (SRI) bolted onto methylphenidate (Ritalin) – providing all downside, no upside.
Indication: ADHD
Centanafadine is similar to Ritalin in most ways, including the expected stimulant-class effects and potential for abuse...but effect size versus placebo suggests centanafadine is less effective.
Although not declared, expect it to be a Schedule II controlled substance, like methylphenidate and amphetamine (Adderall).
The SRI component looks like nothing but baggage. Amphetamine and methylphenidate products do not carry a boxed warning for suicidality in youth like SRI antidepressants. But there were suicide attempts in the child/adolescent treatment groups (not entirely surprising for an SRI). Therefore, centanafadine has the boxed suicide warning – not based on theory but on clinical trial events.
Also consider the Simtriyo rash: ~9% incidence in children (4% in adults), with risk of angioedema, anaphylaxis, and other serious hypersensitivity reactions. This is not a problem with amphetamine/methylphenidate products.
And it inhibits CYP1A2.
Bottom line: I see no scenario in which I'd recommend this medication, but here's the monograph:
Available strengths
Structure
Warnings
BOXED WARNING – Suicidal Ideation and Behavior in Pediatric Patients
❖ 6-wk study, ages 6–12, suicide attempts:
➤ centanafadine: 2/304 patients (0.7%) ➤ placebo: 0/153
❖ Long-term pediatric study:
❖ 4/620 (0.6%) discontinued for suicidal ideation
BOXED WARNING – Abuse, Misuse, and Addiction
❖ Positive drug-liking
❖ Amphetamine-like drug-liking scores at high dose
❖ No withdrawal effects noted
Other Adverse Effects (ages 6–12)
❖ Rash ~9% in children (4% in adults)
❖ Decreased appetite ~8%
(children under 6 had disproportionate weight suppression)
❖ Nausea 3–10%
❖ Height reduction by z-score: estimated in ~16% of participants (ages 6–12); minimal in adolescents
❖ All other side effects of methylphenidate
Rash
❖ The most consistent adverse effect leading to discontinuation
❖ Angioedema, anaphylaxis, and other serious hypersensitivity reactions occurred
❖ The 210 mg capsule contains tartrazine, which may provoke allergic-type reactions, particularly in aspirin-sensitive patients
Alcohol—Dose Dumping
Avoid alcohol for at least 2 hours after taking centanafadine to avoid dose dumping (immediate release of what is intended for extended release)
Adult dosing:
❖ Start 210 mg q AM with or without food
❖ Max 280 mg but no additional benefit seen
Ages 13–17:
❖ Target 280 mg q AM with or without food
➤ higher than the recommended adult dose
➤ 140 mg was ineffective
Ages 6–12:
❖ 20 to <35 kg → 140 mg q AM
❖ 35–50 kg → 210 mg q AM
❖ >50 kg → 280 mg q AM
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