Viloxazine
Viloxazine, sold under the brand name Qelbree among others, is a medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and depression. It was marketed for more than two decades as an antidepressant in Europe before being repurposed as a treatment for ADHD and launched in the United States in April 2021. Viloxazine is taken by mouth. Viloxazine acts as a selective norepinephrine reuptake inhibitor (NRI). However, it may also act as an antagonist of the serotonin 5-HT receptor and as an agonist of the serotonin 5-HT receptors, actions which may  be involved in its therapeutic effects. Medical uses. Viloxazine is indicated to treat attention deficit hyperactivity disorder (ADHD) in people aged six through seventeen. It was previously marketed as an antidepressant for the treatment of major depressive disorder; and is proven to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms. Available forms. Viloxazine is available for ADHD in the form of 100, 150, and 200 mg extended-release capsules. These capsules can be opened and sprinkled into food for easier administration. Side effects. Side effects included nausea, vomiting, insomnia, loss of  appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies [and clinical trials that included epilepsy patients] indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy) and increased libido. Interactions. Viloxazine increased plasma levels of phenytoin by an average of 37%. It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body, sometimes resulting in accidental  overdose of theophylline. Pharmacology. Mechanism of action. Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake. Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects. More recent research has found that the mechanism of  action of viloxazine may be more complex than previously assumed. It appears to act as a potent antagonist of 5-HT receptors and as a potent agonist of 5-HT receptors. These actions may be involved in its effectiveness for ADHD. It has also been found to up-regulate GABA receptors in the frontal cortex of rats. Pharmacodynamics. The affinities (K) of viloxazine at the human monoamine transporters are 155–630 nM for the norepinephrine transporter (NET), 17,300 nM for the serotonin transporter (SERT), and >100,000 nM for the dopamine transporter (DAT). As such, viloxazine is a highly selective norepinephrine  reuptake inhibitor (NRI). Viloxazine has negligible affinity for a variety of assessed receptors, including the serotonin 5-HT and 5-HT receptors, the dopamine D receptor, the α- and α-adrenergic receptors, the histamine H receptor, and the muscarinic acetylcholine receptors (all >10,000 nM). The binding of viloxazine to other receptors has also been assessed. In 2020, viloxazine was reported to have significant affinity for the serotonin 5-HT and 5-HT receptors (K = 3,900 nM and 6,400 nM) and to act as an antagonist and agonist of these receptors, respectively. It also showed weak antagonistic activity at  the serotonin 5-HT receptor and the α- and β-adrenergic receptors. Pharmacokinetics. The bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%. Peak and levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily. The time to peak levels is 5 hours with a range of 3 to 9 hours after a single 200 mg dose. A high-fat meal modestly decreases levels of viloxazine and delays the time to peak by about 2 hours. Steady-state levels of viloxazine are released after 2 days of  once-daily administration and no accumulation occurs. Levels of viloxazine are approximately 40 to 50% higher in children age 6 to 11 years compared to children age 12 to 17 years. The plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL. The metabolism of viloxazine is primarily via the cytochrome P450 enzyme CYP2D6 and the UDP-glucuronosyltransferases UGT1A9 and UGT2B15. The major metabolite of viloxazine is 5-hydroxyviloxazine glucuronide. Viloxazine levels are slightly higher in CYP2D6 poor metabolizers relative to CYP2D6 extensive metabolizers. The elimination of viloxazine is mainly renal . Approximately 90% of the dose is excreted in urine within 24 hours and less than 1% of the dose is recovered in feces. The elimination half-life of instant-release viloxazine is 2 to 5 hours (2–3 hours in the most reliable studies) and the half-life of extended-release viloxazine is 7.02 ± 4.74 hours. Chemistry. Viloxazine is a racemic compound with two stereoisomers, the ("S")-(–)-isomer being five times as pharmacologically active as the ("R")-(+)-isomer. History. Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the  brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine. The drug was first marketed in 1976. It was never approved by the FDA, but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984. It was withdrawn from markets worldwide in 2002 for business reasons. As of 2015, Supernus Pharmaceuticals was developing extended release formulations of viloxazine as a treatment for ADHD and major depressive disorder under  the names SPN-809 and SPN-812. Research. Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine. By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers. In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM without really improving daytime somnolence. In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy. Viloxazine has also been studied for the treatment of alcoholism, with some success. While viloxazine may have been  effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.