Mechanism of Action of Qelbree (Viloxazine)
Primary Mechanism
Qelbree (viloxazine) functions primarily through inhibition of the norepinephrine transporter (NET), with significant serotonergic modulation via 5-HT2C receptor partial agonism, making it best classified as a serotonin-norepinephrine modulating agent (SNMA) rather than a pure norepinephrine reuptake inhibitor. 1, 2
Receptor-Level Actions
Noradrenergic System
- Norepinephrine transporter (NET) inhibition occurs with a binding affinity (Ki) of 0.13 μM, representing moderate inhibitory effects 1
- This NET inhibition increases extracellular norepinephrine levels in the prefrontal cortex, a brain region critically implicated in ADHD pathophysiology 2
Serotonergic System
- 5-HT2C receptor partial agonist activity with a binding affinity (Ki) of 0.66 μM, which is considered an important—if not predominant—component of viloxazine's therapeutic mechanism 1, 2
- 5-HT2B receptor antagonism has been demonstrated in vitro, contributing to its serotonergic profile 2
- Viloxazine significantly increases serotonin levels in the prefrontal cortex, as demonstrated in microdialysis studies in freely moving rats 3, 2
- The predicted receptor occupancy at clinical doses is high for these serotonergic targets 2
Dopaminergic System
- Viloxazine elicits moderate activity at dopaminergic systems, though this is not its primary mechanism 3, 2
- Importantly, dopamine elevation in the nucleus accumbens is considerably less than with traditional stimulant ADHD medications, contributing to its lower abuse potential 4
Neurotransmitters Involved
The three key neurotransmitters modulated by viloxazine are:
- Norepinephrine (primary target via NET inhibition) 1, 4
- Serotonin (via 5-HT2C agonism, 5-HT2B antagonism, and increased prefrontal cortex levels) 3, 2
- Dopamine (moderate indirect effects) 3, 2
Clinical Distinction from Other ADHD Medications
- Unlike atomoxetine, which is a pure norepinephrine reuptake inhibitor, viloxazine's dual serotonin-norepinephrine modulation represents a mechanistically distinct profile 5
- The serotonergic activity differentiates viloxazine from other NET inhibitors and may explain its unique clinical and safety profile compared to other ADHD medications targeting norepinephrine reuptake 2, 6
Important Clinical Caveat
- Due to its serotonergic properties, the American Academy of Child and Adolescent Psychiatry recommends caution when combining viloxazine with other serotonergic agents due to potential serotonin syndrome risk, particularly in the first 24-48 hours after initiation or dose adjustments 5