<p>New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties</p>

Abstract

Background: Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other ADHD medications targeting norepinephrine reuptake. Considering the complexity of neuropsychiatric disorders, understanding the mechanism of action (MoA) is an important differentiating point between viloxazine and other ADHD medications and provides pharmacology-based rationale for physicians prescribing appropriate therapy. Methods: Viloxazine was evaluated in a series of in vitro binding and functional assays. Its effect on neurotransmitter levels in the brain was evaluated using microdialysis in freely moving rats. Results: We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT 2B and agonistic activity at 5-HT 2C receptors, along with predicted high receptor occupancy at clinical doses. In vivo, viloxazine increased extracellular 5-HT levels in the prefrontal cortex (PFC), a brain area implicated in ADHD. Viloxazine also exhibited moderate inhibitory effects on the norepinephrine transporter (NET) in vitro and in vivo, and elicited moderate activity at noradrenergic and dopaminergic systems. Conclusion: Viloxazine's ability to increase 5-HT levels in the PFC and its agonistic and antagonistic effects on certain 5-HT receptor subtypes, which were previously shown to suppress hyperlocomotion in animals, indicate that 5-HT modulating activity of viloxazine is an important (if not the predominant) component of its MoA, complemented by moderate NET inhibition. Supported by clinical data, these findings suggest the updated psychopharmacological profile of viloxazine can be best explained by its action as a serotonin norepinephrine modulating agent (SNMA).

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

“…Viloxazine has demonstrated activity at serotonin (5-HT) receptors and the norepinephrine transporter (NET) [ 23 ]. Via in vivo microdialysis in a rodent model, therapeutic concentrations of viloxazine were shown to potentiate five- to sixfold increases in 5-HT, norepinephrine, and dopamine levels in the prefrontal cortex (PFC) [ 23 ], a region strongly implicated in ADHD pathophysiology [ 24 ]. In vitro, viloxazine also exhibits antagonistic activity at 5-HT 2B receptors and agonistic activity at 5-HT 2C receptors [ 23 ], although the downstream effect of this activity remains to be fully elucidated.…”

“…Via in vivo microdialysis in a rodent model, therapeutic concentrations of viloxazine were shown to potentiate five- to sixfold increases in 5-HT, norepinephrine, and dopamine levels in the prefrontal cortex (PFC) [ 23 ], a region strongly implicated in ADHD pathophysiology [ 24 ]. In vitro, viloxazine also exhibits antagonistic activity at 5-HT 2B receptors and agonistic activity at 5-HT 2C receptors [ 23 ], although the downstream effect of this activity remains to be fully elucidated. Viloxazine increases norepinephrine and dopamine in the PFC via NET inhibition, with no apparent activity at the dopamine transporter [ 23 ].…”

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Lisdexamfetamine in Healthy Adults

“…SPN-812 (viloxazine extended-release) has a novel, multimodal mechanism of action, with demonstrated activity at serotonin receptors and the norepinephrine transporter. 20 The original, immediate-release viloxazine formulation was approved in Europe as an antidepressant in 1974 and marketed for 28 years, before being discontinued in the early 2000s for business reasons unrelated to safety or efficacy, 21 , 22 resulting in a long history of clinical safety and tolerability. 23 – 25 Viloxazine extended-release is currently under development as an extended release nonstimulant treatment for ADHD.…”

Evaluation of the Effect of SPN-812 (Viloxazine Extended-Release) on QTc Interval in Healthy Adults

“…It is a multimodal serotonergic and noradrenergic modulating agent with demonstrated activity at serotonin receptors and the norepinephrine transporter. In vivo, viloxazine has been shown to increase serotonin (5-HT), norepinephrine, and dopamine levels in the prefrontal cortex, 8 a region strongly implicated in ADHD pathophysiology. In vitro, viloxazine exhibits antagonistic activity at 5-HT 2B receptors and agonistic activity at 5-HT 2C receptors, 8 although the downstream effects of this activity remain to be fully elucidated.…”

“…In vivo, viloxazine has been shown to increase serotonin (5-HT), norepinephrine, and dopamine levels in the prefrontal cortex, 8 a region strongly implicated in ADHD pathophysiology. In vitro, viloxazine exhibits antagonistic activity at 5-HT 2B receptors and agonistic activity at 5-HT 2C receptors, 8 although the downstream effects of this activity remain to be fully elucidated. The objective of this phase 1 study was to assess the potential effects of a supratherapeutic dose of SPN-812 (1,800 mg once daily) on cardiac repolarization relative to positive and negative controls in healthy adult subjects.…”