What is the comparison of the mechanisms of action of Viloxazine (Viloxazine) and Atomoxetine (Atomoxetine)?

From the Guidelines

Viloxazine and atomoxetine are both medications used to treat attention-deficit/hyperactivity disorder (ADHD), but they work through slightly different mechanisms. Both drugs primarily function as norepinephrine reuptake inhibitors (NRIs), which means they increase the concentration of norepinephrine in the synaptic cleft by preventing its reuptake into the presynaptic neuron. However, viloxazine has additional effects on serotonin receptors, acting as a serotonin 2C receptor antagonist, which may contribute to its therapeutic profile 1. Atomoxetine, on the other hand, is a more selective norepinephrine reuptake inhibitor with minimal effect on other neurotransmitters, as stated in a study published in the journal Pharmacology and Therapeutics 1. This selectivity for norepinephrine explains why atomoxetine has less impact on dopamine levels in most brain regions, except in the prefrontal cortex where norepinephrine transporters also regulate dopamine. The increased norepinephrine and dopamine in the prefrontal cortex is believed to improve executive functions and attention. Neither medication directly affects dopamine in the reward pathways of the brain, which explains why they have lower abuse potential compared to stimulant ADHD medications like methylphenidate or amphetamines. Some key points to consider when comparing viloxazine and atomoxetine include:

• Mechanism of action: Both are norepinephrine reuptake inhibitors, but viloxazine has additional effects on serotonin receptors.
• Selectivity: Atomoxetine is more selective for norepinephrine, while viloxazine has a broader mechanism of action.
• Effects on dopamine: Both medications increase dopamine in the prefrontal cortex, but do not directly affect dopamine in the reward pathways of the brain.
• Abuse potential: Both medications have lower abuse potential compared to stimulant ADHD medications. It's worth noting that the evidence for viloxazine is based on a study published in 2022, which found that viloxazine increases serotonin levels in the prefrontal cortex and exhibits moderate inhibitory effects on the norepinephrine transporter 1. In contrast, the evidence for atomoxetine is based on a study published in 2022, which found that atomoxetine increases synaptic noradrenaline by binding to the norepinephrine transporter and is therefore classified as a norepinephrine reuptake inhibitor 1. Overall, the choice between viloxazine and atomoxetine will depend on individual patient needs and circumstances, and should be made in consultation with a healthcare professional.

From the FDA Drug Label

The mechanism of action of viloxazine in the treatment of ADHD is unclear; however, it is thought to be through inhibiting the reuptake of norepinephrine. The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies.

The mechanisms of action of viloxazine and atomoxetine are similar in that they both involve the inhibition of norepinephrine reuptake. However, the exact mechanisms are not fully understood and may involve other pathways as well. Viloxazine is thought to inhibit the reuptake of norepinephrine, while atomoxetine is believed to selectively inhibit the pre-synaptic norepinephrine transporter. Key points to note are:

• Both drugs are norepinephrine reuptake inhibitors
• The exact mechanisms of action are not fully understood
• Viloxazine may have additional effects on other neurotransmitters, such as serotonin 2
• Atomoxetine has been shown to have a high affinity for the norepinephrine transporter 3

From the Research

Mechanism of Action Comparison

The mechanisms of action of viloxazine and atomoxetine can be compared based on their effects on neurotransmitter systems.

• Viloxazine is a serotonin norepinephrine modulating agent (SNMA) that increases extracellular serotonin (5-HT) levels in the prefrontal cortex (PFC) and exhibits moderate inhibitory effects on the norepinephrine transporter (NET) 4.
• Atomoxetine, on the other hand, is a selective norepinephrine reuptake inhibitor (NRI) that primarily works by increasing norepinephrine levels in the brain 5, 6.

Key Differences

The key differences between viloxazine and atomoxetine lie in their effects on the serotonergic system.

• Viloxazine has been shown to have antagonistic activity at 5-HT2B and agonistic activity at 5-HT2C receptors, which contributes to its mechanism of action 4.
• In contrast, atomoxetine's mechanism of action is primarily attributed to its inhibition of norepinephrine reuptake, with less emphasis on its effects on the serotonergic system.

Clinical Implications

The differences in mechanism of action between viloxazine and atomoxetine may have clinical implications.

• A study comparing the two medications found that viloxazine was associated with greater improvements in ADHD symptoms, including inattention and hyperactivity/impulsivity, compared to atomoxetine 7.
• Additionally, viloxazine was found to be better tolerated than atomoxetine, with fewer patients discontinuing treatment due to side effects 7.