Viloxazine in the Treatment of Attention Deficit Hyperactivity Disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children. Over the past twenty years, research on the disease and its characteristics and treatment options has grown exponentially. The first-line pharmacologic treatment of ADHD is stimulants, which have a response rate of ~70%. With the support of four phase 3 studies involving more than 1,000 pediatric patients 6–17 years old, the FDA has approved the non-stimulant, serotonin-norepinephrine modulating agent (SNMA) viloxazine in an extended-release capsule (viloxazine ER) for treatment of ADHD in children aged 6–17. Viloxazine modulates serotonergic activity as a selective 5-HT22B receptor antagonist and 5-HT2C receptor agonist and moderately inhibits norepinephrine transporter (NET), thus blocking the reuptake of norepinephrine. A phase 2 study by Johnson et al. found that once-daily dosing of viloxazine ER in 200, 300, or 400 mg dosages in children with ADHD for eight weeks resulted in a statistically significant reduction of ADHD-RS-IV total score. A post hoc analysis of data from four phase 3, randomized, placebo-controlled, double-blind, three-arm, clinical trials by Faraone et al. found that early response to viloxazine treatment, defined as a change in ADHD-RS-5 total score at week 2, best predicted the treatment response at week 6 [75% positive predictive power (PPP), 75% sensitivity]. Proper treatment of the symptoms and comorbidities associated with ADHD is crucial in improving a patient's quality of life, cognitive function, and overall therapeutic outcomes. Viloxazine's mechanism of action, clinical effects, and limited side effect profile point toward the drug's relevance in the treatment of ADHD.

Extended-Release Viloxazine for the Treatment of Attention-Deficit Hyperactivity Disorder in School-Age Children and Adolescents

“…In one of the phase III studies (NCT03247543), 4 patients reported suicidal ideation as per C-SSRS (n = 3 [2.8%], 200 mg/d; n = 1 [1%], 400 mg/d). In contrast, no suicidal ideation as per C-SSRS was reported in the 2 viloxazine ER Studies in Adolescents (12)(13)(14)(15)(16)(17) Efficacy assessment. Two phase III studies (NCT03247517 and NCT03247556) evaluated the efficacy of viloxazine ER in adolescents diagnosed with ADHD.…”

“…Also, viloxazine has been used as an antidepressant and anxiolytic medication in adults in Europe for at least 2 decades. 12 It is thus hypothesized that viloxazine ER may be beneficial in patients with ADHD with comorbid conditions such as anxiety disorders and/or depression. Studies directly assessing the efficacy and safety of viloxazine ER in patients with ADHD with specific comorbid conditions (eg, substance abuse disorder, mood disorder, anxiety) are required to make firm recommendations.…”

“…11 The immediate-release formulation of viloxazine was first marketed in the 1970s in the United Kingdom and many European countries as an antidepressant for adult patients. 12 Even though viloxazine ER has also been approved for use in adult patients with ADHD, this article will specifically discuss the efficacy and safety of viloxazine ER for the treatment of ADHD in school-age children and adolescents.…”

Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges

“…Viloxazine is a selective norepinephrine reuptake inhibitor with activity in the noradrenergic and serotonergic pathways [ 233 ], is approved to be used in the treatment of ADHD children and adolescents and is administered orally in once-daily oral doses [ 234 ]. One possible action mechanism for viloxazine against ADHD is through increased efflux of norepinephrine and dopamine in the prefrontal cortex [ 235 ].…”

“…One possible action mechanism for viloxazine against ADHD is through increased efflux of norepinephrine and dopamine in the prefrontal cortex [ 235 ]. Viloxazine has no drug interactions with LDX or MPH [ 233 , 236 ]. Adverse effects include somnolence, sedation, headache, fatigue, decreased appetite, abdominal pain, upper respiratory infection, nausea and vomiting, cardiovascular effects and suicidal ideation.…”