Viloxazine extended-release capsules as an emerging treatment for attention-deficit/hyperactivity disorder in children and adolescents

ABSTRACT

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention and/or hyperactivity and impulsivity. Viloxazine extended-release (ER) capsules (Qelbree®) is a US Food and Drug Administration–approved nonstimulant treatment option for children, adolescents, and adults with ADHD.

Areas covered

This review manuscript summarizes the neurobiology of ADHD and currently available treatment options before discussing viloxazine pharmacology, efficacy, safety, and tolerability data from phase II and III trials in children and adolescents (6–17 years old). Viloxazine clinical efficacy has also been further demonstrated by post hoc analyses of pediatric clinical trial results.

Expert opinion

Current stimulant and nonstimulant treatments for ADHD may be suboptimal given low response rates and that tolerability issues are frequently experienced. Preclinical and clinical evidence has implicated both the role of catecholamine and serotonin signaling in the pathophysiology of ADHD and the pharmacologic effect of viloxazine on these critical neurotransmitter systems. With a relatively rapid onset of action, sustained symptom improvement, and clinical benefit in ADHD-associated impairments (functional and social), viloxazine ER represents a novel and emerging ADHD treatment option.

KEYWORDS:

• ADHD
• attention-deficit/hyperactivity disorder
• Qelbree
• SPN-812
• viloxazine

1. Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by behavioral symptoms such as inattention, hyperactivity, and impulsivity that can significantly interfere with an individual’s social, occupational, and academic function [1–3]. Based on recent estimates, approximately 9.4% to 10.5% of children in the US between 2 and 17 years of age have been diagnosed with ADHD at some point in their lifetime [4]. During the recent global pandemic, the diagnosis of ADHD increased in prevalence in both children and adults; the pediatric prevalence in 2022 is estimated as 10.5% (7.5% for children 4–11 years of age, and 14.2% for 12–17 years of age) [5]. Although ADHD is often diagnosed during childhood, it is a chronic condition that can persist in up to 90% of people throughout adolescence and into adulthood [6–8]. ADHD is a complex disorder, and although its pathophysiology has been associated with genetic, neurological, and environmental factors, the primary mechanism(s) is still unknown [9].

Longstanding preclinical and clinical evidence has implicated dysregulated dopamine and norepinephrine neurotransmission in ADHD pathophysiology [10], and effective ADHD treatments have been shown to modulate these systems [10,11]. Serotonergic signaling has also been associated with ADHD [12]. Extensive genetic investigations have established a link between serotonin (5-hydroxytryptamine [5-HT]) synthesis [13,14], transport [15], and receptor [16–20] genes and ADHD susceptibility. More recent studies have additionally connected alterations in gamma-aminobutyric acid and glutamate concentrations and gene expression with the pathophysiology of ADHD [21,22]. Connectivity abnormalities within neural networks of various brain regions associated with ADHD symptoms (e.g. executive and cognitive impairment, motor control, emotional regulation) that are modulated by monoamines further substantiate the monoaminergic hypothesis in ADHD pathophysiology [23].

Current treatment guidelines for children and adolescents with ADHD, per the American Academy of Pediatrics, include psychosocial/behavioral therapy and pharmacotherapies [24]. Although short-term efficacy has been robustly demonstrated in clinical trials for US Food and Drug Administration (FDA)–approved pharmacologic treatments, head-to-head comparison studies, or long-term efficacy assessments are lacking for currently available treatment options [25]. Additionally, some products may have low efficacy or tolerability issues due to the inherent heterogeneity of ADHD, comorbid psychiatric disorders, or difficulties with dose regimens/optimization [26]. Thus, there is an unmet clinical need among children and adolescents with ADHD for a novel treatment option that is predictably efficacious, generally safe, and well tolerated with a dosing regimen that aligns with a child’s daily routine.

This review focuses on the pharmacology and pediatric phase II and III clinical trial data for viloxazine extended-release (ER) capsules (Qelbree®, Supernus Pharmaceuticals, Inc.), a novel selective norepinephrine reuptake inhibitor indicated for the treatment of ADHD in children (≥6 years old) and adults.

2. Overview of the market

Pharmacologic treatment methods for ADHD are traditionally divided into central nervous system (CNS) stimulants and nonstimulants [9,25,27,28]. Stimulants, which can be further classified into methylphenidate- or amphetamine-based agents, are often considered a first-line pharmacologic approach given their effectiveness [25,29,30]. Although both agents increase norepinephrine and dopamine levels via blocking their reuptake, methylphenidate-based agents also stimulate noradrenergic and 5-HT1_A receptors [27,29,31–35]. Amphetamine-based agents additionally disrupt catecholamine storage in presynaptic vesicles and increase their concentration in the cytosol, eventually reversing transporter function and leading to extrusion of neurotransmitters into the synaptic cleft [36]. Furthermore, amphetamines interact with trace amine-associated receptor 1 (TAAR1), indirectly influencing dopamine and excitatory amino acid transporter trafficking to the cell membrane [37]. Despite stimulants being highly efficacious in treating core symptoms of ADHD, a significant number of individuals do not tolerate them or have contraindications to their use (i.e. allergic reaction or comorbid condition) [27,38,39]. Additionally, stimulant treatments are Schedule II controlled substances designated by the US Drug Enforcement Administration as having high abuse potential and risk of psychological or physical dependencies [40]. In response to the recent increase in stimulant utilization and the rising US population health indicators of misuse, addiction, and mixed overdose deaths, in 2023 the FDA instituted labeling requirements that address safety- and misuse-related aspects as well as updated the black-box warning for all stimulant medications [41,42].

Among nonstimulant ADHD treatments are atomoxetine, a norepinephrine reuptake inhibitor, and α₂ agonists (e.g. guanfacine and clonidine) that directly modulate pre- and postsynaptic α₂ adrenergic receptors [43–45]. However, even nonstimulant treatments are associated with significant clinical limitations such as delayed/gradual onset to symptom improvement (2–12 weeks depending on the nonstimulant), marginal improvement of core ADHD symptoms, and mild effects on ADHD-associated cognitive impairments [25,46,47]. The largest unmet need for individuals with ADHD among currently available treatments is a treatment option that circumvents the tolerability and abuse potential limitations of stimulants, while improving upon the limited efficacy of nonstimulants.

Viloxazine ER is the most recent offering in the treatment of ADHD, having been approved in the US for children (≥6 years old) in 2021 and more recently in 2022 for adults [48]. In addition to viloxazine ER, several other pharmacologic agents are being developed (or repurposed) and assessed in clinical trials as viable treatment options for individuals with ADHD. Dasotraline, a potent inhibitor of dopamine (half-maximal inhibitory concentration [IC₅₀] = 3 nM), norepinephrine (IC₅₀ = 4 nM), and 5-HT (IC₅₀ = 15 nM) reuptake transporters, has a favorable pharmacokinetic profile [49–54]. Despite demonstrating clinical improvement in ADHD symptoms in both children and adults, dasotraline did not receive FDA approval due to significant safety concerns (i.e. insomnia, anxiety, and emotional lability) and development was therefore halted [55]. Centanafadine sustained-release (SR), which is also a potent inhibitor of dopamine (IC₅₀ = 38 nM), norepinephrine (IC₅₀ = 6 nM), and 5-HT (IC₅₀ = 83 nM) reuptake transporters, was recently assessed in phase II and III clinical trials for the treatment of ADHD in adults [56–58]. Results from the phase III studies demonstrated significant symptom improvements in participants who received centanafadine SR and that both doses evaluated (200 and 400 mg/day) were generally safe and well tolerated [57]. Most treatment-emergent adverse events reported were considered mild or moderate, with the most common being headache and decreased appetite [57]. The long-term safety and tolerability of centanafadine in children and adolescents with ADHD was recently assessed in a phase III clinical trial (NCT05257265) and open-label extension (NCT05279313) [59].

Mazindol, originally indicated for the treatment of obesity in adults in the 1970s and 1980s, demonstrated the potential for improving ADHD symptoms in children in an open-label, pilot, phase II study [60]. Following the completion of this clinical trial, a controlled-release formulation was developed, and in vitro studies revealed its inhibitory potential on norepinephrine (IC₅₀ = 4.9 nM), dopamine (IC₅₀ = 43 nM), and 5-HT (IC₅₀ = 94 nM) reuptake transporters and its modulatory activity related to 5-HT (5-HT_1A and 5-HT₇), muscarinic, histamine, and µ-opioid receptors [61,62]. Furthermore, results from a subsequent phase II study in adults with ADHD showed that mazindol significantly improved ADHD symptoms and was generally well tolerated, warranting progression to phase III trials [62]. Solriamfetol is approved by the FDA in adults for the treatment of excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea [63]. Given that solriamfetol inhibits norepinephrine (IC₅₀ = 4.4 µM) and dopamine (IC₅₀ = 2.9 µM) reuptake, albeit with low potency, investigations into its potential use as an ADHD treatment are currently underway [63–65]. Preliminary results from a double-blind, randomized, placebo-controlled clinical trial of solriamfetol in adults demonstrate its capacity to alleviate ADHD symptoms [66].

3. Introduction to the drug

Viloxazine was discovered during attempts to synthesize molecules chemically related to propranolol with CNS-modulating properties [67]. Shortly thereafter, viloxazine's immediate-release was approved in 1974 and marketed for over 25 years in the United Kingdom and in several other countries in the European Union for the treatment of adult major depressive disorder [68]. In 1984, viloxazine received an orphan drug designation for the treatment of cataplexy and narcolepsy, but was never approved for either indication for unknown reasons [69]. In addition to significantly improving depressive symptoms, preclinical and clinical studies have reported that viloxazine may ameliorate symptoms of comorbid CNS conditions, such as anxiety [70], alcoholism [71], and epilepsy [67,72]. Due to the short (~2.5 h) elimination half-life of viloxazine, the immediate-release formulation necessitated multiple daily doses and was discontinued in the early 2000s, for business reasons unrelated to the efficacy or safety of the product [68].

3.1. Chemistry and mechanism of action

The conventional International Union of Pure and Applied Chemistry name for viloxazine is (±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride (molecular formula: C₁₃H₂₀NO₃Cl), with a molecular weight of 273.8 g/mol that is notably soluble in aqueous solutions of pH ≤ 9.5 [48]. Viloxazine was initially characterized as a selective norepinephrine reuptake inhibitor, with reportedly no effect on norepinephrine release [73,74]. Although the exact mechanism of action for viloxazine in the treatment of ADHD is not fully understood, it is presumed to be via inhibition of NET and consequent modulation of norepinephrine and dopamine in brain regions such as the prefrontal cortex [75] and activities on specific serotonin receptors [76]. The mechanisms behind increases in serotonin levels in different brain regions as observed in rat microdialysis studies (PFC, nucleus accumbens, and amygdala) are still not fully understood, as viloxazine does not have activity on the serotonin transporter [75]. Notably, viloxazine showed negligible activity on the dopamine transporter and minimal effect on dopamine in the nucleus accumbens, suggesting low abuse liability [76].

3.2. Pharmacokinetics

Viloxazine ER is formulated such that the pharmacokinetic profile is not altered, whether it is consumed as an intact capsule or if the contents are sprinkled onto applesauce or pudding [48]. In addition to determining the pharmacokinetic profiles for each recommended method of administration in children, adolescents, and adults, results from population pharmacokinetic (popPK) modeling are reported below [77–79]. A summary of viloxazine ER pharmacokinetic parameters is presented in Table 1.

Table 1. Pharmacokinetics of viloxazine extended-release capsules.

PK parameter	Children and adolescents (6–17 years old)
Absorption
Cmax, µg/mL*	1.2–8.9
Tmax, hours*	4–5
Distribution
Plasma protein binding, %^†	76–82
Vd/F, L, range*	61.8–94.7
Metabolism
Metabolizing enzymes	CYP2D6, UGT1A9, and UGT2B15
Primary metabolite	5-hydroxyviloxazine glucuronide
Tss, days	2
Elimination
T1/2, hours, range*	7.9–10.1
CL/F, %, urine vs feces	90 vs ≤1

*Reported parameters represent the range of estimated average values at steady state, modeled separately for children and adolescents receiving viloxazine ER doses of 100, 200, 400, or 600 mg/day, based on population PK modeling.

^†Plasma protein binding is over the blood concentration range of 0.5 µg/mL to 10 µg/mL.

CL = clearance, C_max = maximum observed concentration, CYP = cytochrome P450, ER = extended-release, F = bioavailability, PK = pharmacokinetic, T_1/2 = elimination half-life, T_max = median time-to-maximum concentration, T_ss = time until steady-state, UGT = UDP-glucuronosyltransferase, V_d = volume of distribution.

3.2.1. Absorption

Absorption of viloxazine ER is relatively consistent across age groups and methods of administration, with a median time-to-maximum concentration (T_max) of approximately 4 h in children, and 4 to 5 h in adolescents and adults [77–79]. Notably, in children and adolescents, the maximum observed concentration (C_max) and area under the concentration–time curve between 0 and 24 h post dose (AUC_0–t) increase proportionally across the daily recommended dose range (100–600 mg) [79]. The average overall bioavailability of a single dose is approximately 85% [80]. Following a high-fat meal (800 to 1000 calories), T_max increases by approximately 2 h [77]. The effect of food is evident by an 8% and 9% decrease in C_max and area under the concentration–time curve from time 0 to the last measurable concentration time (AUC_last), respectively [48,77]. Additionally, sprinkling viloxazine ER atop applesauce decreases C_max and AUC_last by approximately 10% and 5%, respectively, but has no reported effect on bioavailability [48,77]. The relative bioavailability of viloxazine ER relative to an immediate-release formulation is approximately 88% [48].

3.2.2. Distribution

Viloxazine ER in a blood concentration range of 0.5 to 10 µg/mL is highly bound (76–82%) to human plasma proteins [48,81]. PopPK modeling estimated the volume of distribution for the daily maximum dose (400 mg) in children and adolescents to be 74.7 and 94.7 L, respectively [79].

3.2.3. Metabolism

Metabolism of viloxazine occurs through oxidation, primarily by the cytochrome P450 (CYP) enzyme, CYP2D6, with minor contribution from CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, followed by glucuronidation via UDP-glucuronosyltransferase (UGT) enzymes, UGT1A9 and UGT2B15 [48,81,82]. Viloxazine concentrations are not meaningfully affected by CYP2D6 metabolizer status, likely due to the potential for metabolism via alternative pathways [48,82]. Steady-state blood concentration is generally achieved within 2 days of once-daily viloxazine ER administration [48]. Glucuronidation of viloxazine yields 5-hydroxy-viloxazine glucuronide, the predominant inactive metabolite detected in plasma [48,81,82]. Preclinical in vitro data revealed that viloxazine ER also functions as a reversible inhibitor of various CYP isoforms (CYP2B6, CYP2D6, and CYP3A4/5), most notably exhibiting potent inhibition of CYP1A2 [82]. US labeling includes a contraindication for concurrent use of viloxazine ER with drugs that are metabolized by CYP1A2 and have a narrow therapeutic range.

3.2.4. Elimination

Elimination of viloxazine occurs primarily via renal clearance, with an average elimination half-life (T_1/2) of approximately 7 h [48]. Metabolism studies, which used radiolabeled viloxazine, revealed 90% of the dose was recovered in the urine within 24 h following ingestion and ≤1% of the dose is excreted in the feces [48,83]. popPK estimated clearance rate for viloxazine ER (100–600 mg) in children and adolescents ranged from 6.06 to 8.11 L/h [79]. Although no dose adjustment is recommended in individuals with mild-to-moderate renal impairment (estimated glomerular filtration rate [eGFR], 30–89 mL/min/1.73 m²), the recommended starting dose for individuals with severe renal impairment (eGFR <30 mL/min/1.73 m²) is 100 mg/day [48].

3.3. Pharmacodynamics

The initial pharmacodynamic studies conducted during the mid-1980s designed to elucidate viloxazine’s mechanism of action primarily focused on catecholamine inhibition. Although these studies did not consider therapeutic potential beyond catecholamine modulation, one pivotal study revealed viloxazine to be a reversible, albeit weak, competitive inhibitor of monoamine oxidase (MAO) A and B [84]. Mitochondrial fractions and tissue homogenates prepared from rats that were administered increasing subcutaneous doses of viloxazine (35, 70, and 105 mg/kg), revealed a time- and dose-dependent inhibitory effect on MAO (maximum inhibition within 3 h) that led to increased norepinephrine, dopamine, and 5-HT concentrations [84]. However, since these effects were only achieved using relatively high doses of viloxazine, the authors concluded MAO inhibition was unlikely to substantially contribute to the overall antidepressant effect of viloxazine.

Results from initial pharmacologic studies, preclinical data in animals, and the development of the ER formulation, rekindled interest in viloxazine’s mechanism of action, and prompted additional studies to characterize its effects more fully [76]. A radioligand binding competition assay was used to assess the affinity of viloxazine for various receptors, neurotransmitter transporters, ion channels, and MAOs. Among the molecular targets confirmed was the norepinephrine transporter (NET) for which viloxazine has a moderate inhibitory effect (IC₅₀ = 0.26 µM). This study also revealed affinity for 5-HT (5-HT_2B, 5-HT_2c, 5-HT_1B, and 5-HT₇) and adrenergic (α_1A and α_1B) receptors. To predict the potential clinical relevance of these binding affinities, it was also necessary to calculate relevant receptor occupancy based on viloxazine plasma concentrations equating to 100-, 200-, 400-, and 600-mg/day doses. These calculations showed an estimated receptor occupancy ≥80% for 5-HT_2B and 5-HT_2C at all tested doses except 100 mg/day for 5-HT_2C, suggesting serotonergic effects likely contribute to the mechanism of action of viloxazine [76].

To further elucidate the pharmacologic profile of viloxazine, functional activity assays were conducted. Viloxazine has antagonistic activity at 5-HT_2B (IC₅₀ = 27 µM) and 5-HT₇ receptors, agonistic activity at 5-HT_2C receptors (half-maximal effective concentration [EC₅₀] = 1.6 µM, Ca²⁺ assay), and no significant agonistic or antagonistic activity toward 5-HT_1B receptors [75]. Follow-up binding studies further supported the serotonergic effect of viloxazine and demonstrated an antagonistic effect at 5-HT₇ receptors (inhibitory constant [K_i] = 1.9 µM; IC₅₀ = 6.7 µM) [85]. Changes in neurotransmitter levels across different parts of the brain were characterized using microdialysis in freely moving rats [76]. Peak levels of norepinephrine, dopamine, and 5-HT were observed in the prefrontal cortex within 60 min of viloxazine administration, all of which gradually declined over 4 h [76].

In summary, the pharmacodynamic properties of viloxazine appear to be the primary antagonism of NET, 5-HT_2B, and 5-HT₇ receptors and predominantly agonistic action at the 5-HT_2C receptor. Viloxazine has shown 80–90% NET, 5-HT_2B, and 5-HT_2C occupancy at plasma concentrations that reflect the dose range utilized in human ADHD studies [82]. Lastly, based on historical studies that evaluated monoamine concentrations in the brain homogenate, and contemporary, sophisticated microdialysis studies, viloxazine consistently elevates prefrontal cortex catecholamine and 5-HT levels in response to clinically relevant doses/concentrations.

4. Clinical efficacy

The efficacy, safety, and tolerability of the original immediate-release formulation of viloxazine were established during its investigation and over a 25-year period of use for adult depression and anxiety disorders, and is extensively summarized elsewhere [68]. This body of knowledge, combined with an early proof-of-concept study using the immediate-release product in adult ADHD, provided impetus for the viloxazine ER clinical development program as an ADHD therapy [86]. The clinical development program consisted of six double-blind placebo-controlled trials, including five pediatric trials (one phase II and four phase III) [86–90] and one adult trial (phase III) [91] as well as two long-term, open-label extension safety trials (one pediatric and one adult) that additionally served to provide double-blind trial participants a pathway to receive the medication until it was commercially available [92,93].

4.1. Phase II clinical trial

The phase II, double-blind, placebo-controlled, fixed-dose, proof-of-concept study (NCT02633527) assessed ascending doses of viloxazine ER (100, 200, 300, and 400 mg/day) in children (6–12 years old) with ADHD over an 8-week period [86]. The primary efficacy endpoint was the change from baseline in the ADHD Rating Scale-IV (ADHD-RS-IV). Efficacy outcomes are summarized in Table 2. Of the 217 participants that were randomized and received treatment, 160 (73.7%) completed the study. The mean ADHD-RS-IV total score and subscale scores decreased from baseline at all timepoints. The primary outcome was statistically different from placebo for all viloxazine ER dosages except 100 mg/day. Likewise, decreases (improvement) in the Clinical Global Impression-Severity (CGI-S) score were significantly different from placebo (p < 0.05) for all dosages except 100 mg/day. The results of this phase II trial demonstrated the potential for viloxazine ER to significantly improve ADHD-related symptoms in children 6–12 years old.

Table 2. Results from the phase II trial in children (aged 6–12 years old) [86].

	NCT02633527 (Children 6–12 years old)
		Viloxazine ER
	Placebo(n = 24)	100 mg(n = 45)	200 mg(n = 46)	300 mg(n = 47)	400 mg(n = 44)
ADHD-RS-IV total score
CFB, LS mean*	−10.5	−16.7	−18.4	−18.6	−19.0
P-value^†		0.0899	0.0310	0.0268	0.0209
Hyperactivity/Impulsivity subscale
CFB, LS mean^‡	−4.7	−7.9	−9.0	−9.5	−9.8
P-value^†		0.1007	0.0254	0.0121	0.0086
Inattentional subscale
CFB, LS mean*	−5.7	−8.9	−9.0	−9.4	−9.5
P-value^†		0.1014	0.0909	0.0552	0.0533
CGI-I
LS mean*	3.0	2.6	2.6	2.2	2.4
P-value^†		0.1305	0.1376	0.0090	0.0546
CGI-S
CFB, LS mean*	−0.8	−1.4	−1.5	−1.6	−1.7
P-value^†		0.0708	0.0309	0.0148	0.0136

*Estimated from ANOVA including fixed effect for treatment.

^†Comparison between each viloxazine ER dose group and placebo; raw (unadjusted for multiplicity) P-values.

^‡Estimated using ANCOVA model with fixed effects for treatment and baseline.

ADHD = attention-deficit/hyperactivity disorder, ADHD-RS-IV = ADHD Rating Scale-IV, ANCOVA = analysis of covariance, ANOVA = analysis of variance, CFB, change from baseline, CGI = Clinical Global Impression, CGI-I = CGI-Improvement score, CGI-S = CGI-Severity score, ER = extended-release, LS = least squares.

4.2. Phase III clinical trials

Three of the four placebo-controlled phase III trials assessing viloxazine ER as a monotherapy for ADHD were confirmatory, two in children (6–11 years old, NCT03247530, NCT03247543) and one in adolescents (12–17 years old, NCT03247517) [87–89]. The results from these studies are summarized in Table 3 (the fourth trial is summarized later in this section). In these three trials, 784 children and 308 adolescents were treated with placebo or viloxazine ER 100 (children only), 200, or 400 mg/day. Treatment was initiated at 100 mg/day for children and 200 mg/day for adolescents and titrated weekly (by 100 mg/day [children] or 200 mg/day [adolescents]) in blinded fashion to the assigned dose. The 6–8-week duration of each trial ensured at least 5 weeks of maintenance treatment at the highest assigned dose in each trial. The ratio of enrolled males to females was approximately 2:1 across these three trials [87–89], which is representative of the general diagnosed pediatric population with ADHD [94]. Mean baseline ADHD Rating Scale-5 (ADHD-RS-5) total scores ranged from 39.9 to 45.0, indicating a moderate-to-severe level of ADHD symptoms, and mean baseline CGI-S scores ranged from 4.6 to 4.7 [87–89], indicating a moderately to markedly ill severity of ADHD symptoms [95].

Table 3. Results from the pivotal phase III trials in children (6–11 years old) and adolescents (12–17 years old) [87–89].

	NCT03247530			NCT03247543			NCT03247517
	(Children 6–11 years old)			(Children 6–11 years old)			(Adolescents 12–17 years old)
		Viloxazine ER			Viloxazine ER			Viloxazine ER
	Placebo(n = 155)	100 mg(n = 147)	200 mg(n = 158)	Placebo(n = 97)	200 mg(n = 107)	400 mg(n = 97)	Placebo(n = 104)	200 mg(n = 94)	400 mg(n = 103)
ADHD-RS-5 total score
CFB, LS mean ± SE	−10.9 ± 1.14	−16.6 ± 1.16	−17.7 ± 1.12	−11.7 ± 1.5	−17.6 ± 1.4	−17.5 ± 1.5	−11.4 ± 1.37	−16.0 ± 1.45	−16.5 ± 1.38
P-value		0.0004	<0.0001		0.0038	0.0063		0.0232	0.0091
Hyperactivity/ Impulsivity subscale
CFB, LS mean ± SE	−5.5 ± 0.59	−8.0 ± 0.60	−8.7 ± 0.58	−5.1 ± 0.8	−8.4 ± 0.8	−8.3 ± 0.8	−5.1 ± 0.69	−7.7 ± 0.73	−8.4 ± 0.69
P-value		0.0026	<0.0001		0.0020	0.0039		0.0069	0.0005
Inattentional subscale
CFB, LS mean ± SE	−5.7 ± 0.60	−8.6 ± 0.62	−9.2 ± 0.60	−6.2 ± 0.8	−8.9 ± 0.7	−8.6 ± 0.8	−6.6 ± 0.74	−8.7 ± 0.78	−8.7 ± 0.74
P-value		0.0006	<0.0001		0.0087	0.0248		0.0424	0.0390
CGI-I
LS mean ± SE	3.1 ± 0.10	2.7 ± 0.10	2.6 ± 0.09	3.1 ± 0.12	2.6 ± 0.12	2.6 ± 0.12	3.0 ± 0.11	2.5 ± 0.12	2.4 ± 0.12
P-value		0.0020	<0.0001		0.0028	0.0099		0.0042	0.0003

CFB LS means and P-values were obtained using a mixed model for repeated measures model with fixed effect terms for baseline ADHD-RS-5 total score, age group, treatment, visit, and treatment-by-visit interaction as independent variables; subscales and CGI were analyzed using ANCOVA with treatment as fixed effect and baseline as covariate, except for CGI-I were CGI-S score at baseline was used as a covariate.

ADHD = attention-deficit/hyperactivity disorder, ADHD-RS-5 = ADHD Rating Scale-5, ANCOVA = analysis of covariance, ANOVA = analysis of variance, CFB = change from baseline, CGI = Clinical Global Impression, CGI-I = CGI-Improvement score, CGI-S = CGI-Severity score, ER = extended-release, LS = least squares, SE = standard error.

The primary endpoint for all three phase III trials, the change from baseline in ADHD-RS-5 total score at the end of study (EOS), showed significant improvement for each viloxazine ER treatment arm relative to placebo (Table 3), with a rapid onset of effect observed as early as week 1 (while subjects were still undergoing dose titration) [87–89]. The magnitude of the change in ADHD-RS-5 total score across studies and doses ranged between −16.0 and −17.7, representing a clinically meaningful change in ADHD symptoms. Significant improvements in the secondary endpoints, ADHD-RS-5 Hyperactivity/Impulsivity and Inattention subscales (p < 0.05 for both subscales), further substantiated the therapeutic effect of viloxazine ER.

Additional secondary endpoints for the three studies were CGI-Improvement (CGI-I) score, the Conners 3 – Parent Composite T-score (Conners 3-PS), the Weiss Functional Impairment Rating Scale – Parent Form (WFIRS-P), and ADHD-RS-5 responder rates (defined as the percentage of participants who exhibit a ≥ 50% reduction [improvement] in ADHD-RS-5 total score). Overall, CGI-I scores at EOS uniformly showed significant improvement with viloxazine ER relative to placebo (p < 0.01) at all tested doses in both children and adolescents, demonstrating clinically meaningful improvements across the dose range assessed. Improvements in WFIRS-P and Conners 3-PS scores, though numerically favoring viloxazine ER, were not consistently significantly different relative to placebo.

In addition to the aforementioned trials, a fourth phase III clinical trial was conducted in adolescents (NCT03247556) [90]. In this 7-week, randomized, double-blind, parallel-group trial, 296 participants received treatment with viloxazine ER (400 or 600 mg/day) or placebo. Nominally significant improvement in primary and secondary endpoints were observed for the 400 mg/day treatment arm; however, due to unexpectedly high placebo response, the treatment difference in ADHD-RS-5 score (primary outcome) for the 600 mg/day treatment arm did not reach statistical significance [90]. Therefore, this trial contributed only safety information for the US regulatory filing. A post hoc band-pass analysis of site-specific data across all four phase III trials supports the premise of high placebo response as a confound in the fourth study, and yields an adjusted p-value of 0.028 for the 600 mg/day dose group after applying the band-pass filter [96]. Viloxazine ER 600 mg/day has since demonstrated efficacy in adult ADHD.

4.3. Post hoc analyses

4.3.1. Executive function

Executive function is often impaired in conjunction with, and independent of, ADHD symptoms in children. To evaluate the impact of viloxazine on executive function deficits (EFD), a post hoc analysis of data from 1154 children and adolescents in the four phase III clinical trials was conducted [97]. The Conners 3^rd Edition Parent Short Form – Executive Function (C3PS-EF) content scale was used to measure executive function, with EFD presence defined as a C3PS-EF content scale T-score >70 (2 standard deviations above the population mean). Those with EFD at baseline who subsequently had a C3PS-EF content scale T-score <65 (<1.5 standard deviations above population mean) at endpoint were considered to be EFD responders for purposes of the analysis [97]. Overall, participants treated with viloxazine ER demonstrated a statistically significant improvement in executive function compared to placebo (p = 0.0002). Additionally, responder rates were significantly larger for viloxazine ER (38.6%) compared to placebo (27.4%; p = 0.001). The correlation between change in EFD (C3PS-EF score change) and ADHD symptoms (ADHD-RS-5 score change) was 0.47 (p < 0.0001), demonstrating that while improvement in ADHD symptoms with viloxazine ER is often associated with an improvement in executive function deficits, these constructs are not identical and changes in ADHD behaviors and EFD are not always concordant.

4.3.2. Functional impairment

The 5^th edition of ADHD-RS scale (i.e. ADHD-RS-5) added a functional impairment assessment for each of the two symptom subscales, measuring the degree to which hyperactivity/impulsivity and inattention symptoms impact the following six functional domains: family relationships, peer relationships, completing/returning homework, academic performance at school, controlling behavior at school, and self-esteem [95]. The functional rating is separate from the ADHD-RS total and subscale scores. Impairment for each domain is rated on a 4-point scale from 0 (no problem) to 4 (severe problem). Post hoc analysis of the four phase III trials (N = 1354) demonstrated that viloxazine ER improved functional impairment on all six domains (p < 0.05 relative to placebo) [98]. Improvements in ADHD-related functional impairment were correlated with reductions in hyperactive/impulsive and inattentive ADHD symptoms. Supplemental post hoc analyses evaluating secondary trial measures similarly showed that viloxazine ER improved the quality of peer relationships, social activities, learning, and controlling behavior at school [99,100]. In addition, symptom improvement per ADHD-RS-5 and WFIRS-P score changes from viloxazine ER trials can be translated into CGI levels to provide clinically meaningful benchmarks [101]. Consistently, the results of short-term trials showed that viloxazine ER improved both symptoms and associated functional impairments commonly observed in patients with ADHD.

4.3.3. Early response as a prediction of response

The primary endpoint in viloxazine ER phase III clinical trials was assessed following at least 5 weeks of maintenance treatment at the assigned dose (approximately 6 to 8 weeks after starting treatment). A post hoc analysis of all four pediatric trials determined that a change in ADHD-RS-5 total score at week 2 could predict treatment response (defined as ≥50% reduction from baseline in ADHD-RS-5 total score) at week 6, with a 75% positive predictive power, 75% sensitivity, and 74% specificity [102]. In clinical practice, this finding suggests that if no response is seen in 2 weeks, consideration of dose optimization may be warranted.

4.4. Treatment effect size: likelihood to be helped or harmed

While many stimulant ADHD medications report their effect size in terms of improvement in ADHD symptoms relative to placebo, effect size comparisons generally have utility only when comparing agents with similar risk profiles. In contrast, the Likelihood to be Helped or Harmed (LHH) is a succinct measure of the balance between potential treatment benefit and potential harm. LHH is comprised of the Number Needed to Treat (NNT), which describes the beneficial effect of treatment, and the Number Needed to Harm (NNH), which describes the risk associated with treatment, and is calculated as the NNH/NNT ratio. Smaller values for NNT indicate fewer participants need to be treated before one participant responds to the intervention, whereas larger values for NNH indicate more participants need to be treated before a participant experiences an adverse outcome. Larger LHH values indicate more favorable treatment outcomes.

The benefit–risk ratio of viloxazine ER was evaluated by a post hoc analysis that applied the LHH measurement based on pooled efficacy and safety results from the four phase III pediatric trials [103]. The NNT was calculated utilizing the 50% responder rates for ADHD-RS-5, and the NNH was based on discontinuation rates due to adverse events.

At the 50% response level, the NNT (95% CI) value for viloxazine ER for both age groups was 7 (5, 10). By convention, a therapeutic agent with an NNT value of <10 is generally accepted as a potentially useful intervention [104,105]. Discontinuations due to adverse events occurred in 3.5% of children and adolescents treated with viloxazine ER compared to 1.3% with placebo. This equated to an NNH (95% CI) value of 46 (26, 167). By convention, an NNH in the range of 10–100 is considered to be indicative of a potentially well-tolerated agent [105]. Taken together, the individual NNT and NNH values yield a favorable LHH of 8, meaning that pediatric patients are 8 times more likely to experience meaningful response, rather than discontinue, to viloxazine ER for ADHD.

5. Safety and post-marketing surveillance

5.1. Clinical trial safety and tolerability

Table 4 lists the combined incidence of adverse events across five dosages of viloxazine ER (100, 200, 300, 400, and 600 mg/day) assessed in the phase II and III clinical trials [86–90]. Adverse events were similar across viloxazine ER treatment arms and did not appear to be dose related, with most being mild or moderate in severity and <2% being serious across all dosages. Incidence of suicidal thoughts and behaviors in clinical trials, assessed using the Columbia Suicide Severity Rating Scale, were low and did not appear to be dose related. There were no completed suicides or deaths reported in the five pediatric studies nor in the (over 5-year) open-label extension (NCT02736656). Analysis of data from the double-blind trials and the first year of the open-label extension trial indicated no clinically meaningful impact on growth, with height and weight z-scores remaining between −1 and 1 for all assessment timepoints, compared to Centers for Disease Control and Prevention (CDC) normal growth curves [106].

Table 4. Adverse events (≥5% in any treatment group) from the phase II and III trials in children and adolescents (ages 6–17 years old) [86–90].

		Viloxazine ER
	Placebo	100 mg	200 mg	300 mg	400 mg	600 mg	All viloxazine ER
	(n = 487)	(n = 202)	(n = 415)	(n = 48)	(n = 354)	(n = 99)	(N = 1117)*
Somnolence	17 (3.5)	23 (11.4)	54 (13.0)	11 (22.9)	55 (15.5)	19 (19.2)	162 (14.5)
Headache	32 (6.6)	19 (9.4)	45 (10.8)	6 (12.5)	42 (11.9)	9 (9.1)	121 (10.8)
Decreased appetite	4 (0.8)	13 (6.4)	36 (8.7)	4 (8.3)	32 (9.0)	6 (6.1)	91 (8.1)
Fatigue	11 (2.3)	8 (4.0)	21 (5.1)	1 (2.1)	33 (9.3)	10 (10.1)	73 (6.5)
Nausea	13 (2.7)	4 (2.0)	17 (4.1)	5 (10.4)	22 (6.2)	9 (9.1)	57 (5.1)
Vomiting	7 (1.4)	9 (4.5)	15 (3.6)	3 (6.3)	22 (6.2)	4 (4.0)	53 (4.7)
Irritability	6 (1.2)	5 (2.5)	12 (2.9)	2 (4.2)	16 (4.5)	5 (5.1)	40 (3.6)
Diarrhea	2 (0.4)	3 (1.5)	4 (1.0)	3 (6.3)	5 (1.4)	0	15. (1.3)

Values are presented as n (%). *Two individuals participated in both the phase II and a phase III trial. One participant received viloxazine ER 100 mg/day in phase II and placebo in phase III, and AEs on each treatment are counted in their respective columns; the other participant received viloxazine ER 400 mg/day in phase II and viloxazine ER 200 mg/day in phase III and AEs from each trial are counted their respective columns; this patient is counted once for determining the total viloxazine ER sample size, with AEs from both trials considered in determining total incidence rates.

AE = adverse event, ER = extended-release.

Given the nonclinical evidence suggesting that viloxazine has the pharmacologic potential to inhibit cardiac sodium channels, a thorough QT interval study was conducted to assess potentially associated drug-induced cardiovascular risks [107]. Results from that phase I study demonstrated supratherapeutic doses (1800 mg; i.e. 3 times the maximum recommended adult dose or 4.5 times the maximum recommended pediatric dose) had no effect on cardiac repolarization (QT interval), conduction (PR interval or QRS duration), or clinically relevant effect on heart rate in healthy adult volunteers [48,107].

Other FDA-approved nonstimulant treatment options for pediatric ADHD include atomoxetine (Strattera®, Eli Lilly and Company), clonidine ER (Kapvay®, Concordia Pharmaceuticals Inc.), and guanfacine ER (Intuniv®, Shire US Inc.). The most common adverse reactions (defined as ≥5% of participants and at least twice the rate of the placebo treatment group) for these treatments in pediatric trials are summarized in Table 5. Of note, somnolence and fatigue are the most common adverse reactions reported for all nonstimulant treatments.

Table 5. Common (≥5% and at least twice the rate of placebo) adverse reactions at approved doses in pediatric trials [43–45,48].

	Viloxazine ER (Qelbree®)*	Atomoxetine (Strattera®)^†	Clonidine ER (Kapvay®)^‡		Guanfacine ER (Intuniv®)^§
	Monotherapy(N = 826)	Monotherapy(N = 1597)	Monotherapy(N = 154)	Adjunct + stimulant(N = 102)	Monotherapy Fixed Dose(N = 513)	Monotherapy Flexible Dose(N = 221)	Adjunct+ stimulant(N = 302)
Somnolence	X	X	X	X	X	X	X
Fatigue	X	X	X	X	X	X	X
Lethargy					X
Insomnia			X				X
Irritability		X				X
Dizziness		X		X			X
Hypotension					X	X
Decreased appetite	X	X		X
Nausea		X			X	X
Vomiting						X
Abdominal pain						X	X

Adverse events shown here are based on those listed in the Section 6 Adverse Reactions, 6.1 Clinical Trials Experience of the FDA-approved prescribing information as occurring at ≥ 5% and at least twice the placebo rate for all doses. Specific adverse event terms related to abdominal pain, hypotension, fatigue, insomnia, or somnolence may be combined for reporting in prescribing information and therefore rates may differ from those reported in individual studies. Consult product prescribing information for specific information on adverse events for individual doses. *The somnolence term includes somnolence, lethargy, and sedation; the abdominal pain term includes abdominal discomfort, abdominal pain, abdominal pain lower, and abdominal pain upper; the insomnia term includes initial insomnia, insomnia, middle insomnia, poor quality sleep, sleep disorder, and terminal insomnia. ^†The somnolence term includes somnolence and sedation; the abdominal pain term includes abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, and epigastric discomfort. ^‡The somnolence term includes somnolence sedation; the fatigue term includes fatigue and lethargy. ^§The somnolence term includes somnolence, sedation, and hypersomnia; the abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness; the hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, and blood pressure systolic decreased.

ER = extended-release, FDA = US Food and Drug Administration.

5.2. Real-world evidence

A retrospective chart review reported the clinical outcome of 50 patients (35 children; 15 adults) with a primary diagnosis of ADHD who received viloxazine ER (100–600 mg once daily for up to 4 weeks) following an inadequate experience with atomoxetine (25–100 mg once daily for up to 4 weeks) given alone (n = 24) or in combination with a stimulant (n = 26) [108]. This treatment pattern was guided by participants’ insurer mandates that a generic trial of atomoxetine precede clinical access to viloxazine ER. Statistical comparisons of ADHD-RS-5 outcomes were performed using a within-subject, 2-tailed t-test analysis. ADHD-RS-5 total score improvements were significantly greater following viloxazine ER treatment (t = −10.12, p < 0.00001) compared to the atomoxetine treatment period. ADHD-RS-5 subscales also showed greater improvement after viloxazine ER treatment in both the inattention (t = −8.57, p < 0.05) and hyperactivity/impulsivity (t = −9.87, p < 0.05) subscales. Among children who received viloxazine ER, 89% were reported to have a positive response by 2 weeks, which was consistent with the response patterns seen in the phase II/III trials (14% were reported to have a positive response on atomoxetine). The inability to tolerate atomoxetine did not predict the inability to tolerate viloxazine ER. Of these 50 patients, 36% discontinued atomoxetine for adverse events (primarily gastrointestinal upset, irritability, and fatigue) prior to completing week 4 of treatment, whereas 4% discontinued viloxazine ER for adverse events (namely fatigue) prior to completing week 4 of treatment. In total, 96% of patients preferred viloxazine ER over their prior atomoxetine treatment and 85% (24 of the 26) who were also using stimulants chose to taper these medications following stabilization on viloxazine.

6. Completed, ongoing, and future clinical trials

Four studies have been completed since the commercial launch of viloxazine ER. These include the randomized, double-blind, placebo-controlled phase III trial mentioned above that expanded the viloxazine ER approval to adult ADHD (NCT04016779), two long-term, phase III, open-label extension trials in pediatrics (NCT02736656; N = 1100) and adults (NCT04143217; N = 159) that were open to individuals who completed a prior double-blind trial, and one 8-week, phase IV, open-label trial (NCT04786990) that evaluated the use of viloxazine ER adjunctively with stimulants for pediatric ADHD (N = 56). In the adult phase III, double-blind trial, participants were titrated to viloxazine ER 400 mg/day (or matching placebo) by week 2 [91]. Investigators could then adjust the dose to 200, 400, or 600 mg/day at their discretion. Statistically significant improvement in ADHD symptoms was observed on the Adult ADHD Investigator Symptom Rating Scale (AISRS; primary outcome) starting from week 2. At week 6/EOS, AISRS reductions were −15.5 viloxazine ER vs −11.7 placebo (p = 0.004). Significant improvement was also seen in secondary outcomes, including clinical global impression measures, AISRS inattention and hyperactivity/impulsivity subscores, and certain executive function measures. Open-label extension studies showed no new safety signals and reported maintenance of effect for the duration of exposure (out to over 5 years in pediatrics and over 2 years in adults). Open-label extension studies have also enabled analysis of growth trajectories beyond the shorter-duration, double-blind, placebo-controlled trials. In placebo-controlled trials, children treated with viloxazine ER gained an average of 0.2 kg compared to a gain of 1 kg in placebo-treated subjects, and adolescents treated with viloxazine ER lost an average of 0.2 kg compared to a gain of 1.5 kg in placebo-treated patients [48]. In the open-label extension, mean z-scores for weight remained between −1.00 and 1.00 over a 12-month evaluation period, indicating that, as a whole, pediatric subjects taking viloxazine ER daily for 12 months maintained weight within the normal expected range [106]. The phase IV trial also reported good safety and tolerability of viloxazine ER administered with stimulant administration, with improvement in both morning and evening ADHD symptoms over that seen with stimulant alone, regardless of whether viloxazine ER was administered in the morning or in the evening. Ongoing trials include a double-blind, placebo-controlled study (NCT04781140) to assess viloxazine ER efficacy and safety in children 4–5 years old with ADHD, and a study in lactating women to evaluate viloxazine concentration in breast milk, potential effects on milk production, and on the breastfed infant (NCT06259331).

7. Regulatory affairs

The viloxazine ER formulation was approved by the FDA in 2021 for children and adolescents, and shortly thereafter in 2022 for adults as a nonstimulant treatment option for ADHD. Available in 100-, 150-, and 200-mg capsules, the recommended starting dosage for children (6–11 years old) and adolescents (12–17 years old) is 100 and 200 mg orally once daily, respectively, with a maximum recommended dosage of 400 mg once daily, depending on response and tolerability [48]. For adults (≥18 years old), the recommended starting dosage is 200 mg orally once daily, with a maximum recommended dosage of 600 mg once daily [48]. As of October 2023, viloxazine ER is only available in the US.

8. Conclusion

The pharmacologic profile of viloxazine ER as a NET inhibitor with a serotonergic effect represents a novel treatment option for ADHD. The therapeutic utility of viloxazine ER for pediatric ADHD is substantiated by safety and efficacy data obtained in five double-blind phase II and III clinical trials. Symptoms rapidly improved relative to placebo-treated participants, and this improvement appeared sustained throughout the (over 5-year) period of participation in a subsequent long-term extension trial. Viloxazine ER is a nonstimulant option for clinical consideration when treating children, adolescents, and adults with ADHD.

9. Expert opinion

Despite the abundance of potential treatment options, there is an unmet need among many individuals suffering from ADHD with respect to inadequate relief and/or difficulty tolerating currently available treatments. Although approximately 40% of individuals with ADHD may not initially respond to stimulant treatment [109], approximately 91% may eventually respond after multiple classes of stimulants are attempted [110]. However, tolerability/adverse drug reactions, treatment adherence, and patient satisfaction are a considerable issue for stimulant ADHD treatments [111,112]. Although nonstimulants often have lower response rates when compared to stimulants, this class of ADHD treatment is associated with therapeutic utility and reduced abuse potential in individuals with various comorbidities [23]. The results from a retrospective study of real-world ADHD treatment data suggest an optimal treatment course in the future may be the combination of a stimulant and nonstimulant to facilitate long-term treatment adherence, but further studies are needed to support this initial finding [113].

Convergent genetic, biochemical, and advanced imaging studies have demonstrated both the physiologic importance of the 5-HT receptors and its potential pathogenic role in ADHD (i.e. serotonergic hypothesis of ADHD) [114]. The prefrontal cortex, densely populated with excitatory and inhibitory 5-HT receptors, is the principal brain region that regulates attention, cognitive control, emotion, and motivation [114,115]. The serotonergic hypothesis postulates, therefore, that any alterations in 5-HT signaling within this region can have profound effects on related behaviors and may underly the hyperactivity, inattentiveness, emotional dysregulation, and impulsive aggression observed among individuals with ADHD [114]. On this basis, pharmacotherapies that modulate dopamine, norepinephrine, and 5-HT signaling and/or levels can be considerably advantageous, at least in a subgroup of children, adolescents, and/or adults with ADHD. As substantiated directly by microdialysis studies in freely moving rodents and indirectly by a primate positron emission tomography scan study, pharmacodynamic evidence supports a putative mechanism of action for viloxazine involving NET inhibition and direct modulation of 5-HT_2B, 5-HT_2C, and 5-HT₇ receptors resulting in increased downstream release of norepinephrine, dopamine, and 5-HT in the prefrontal cortex [82,85].

Viloxazine ER has established a relatively rapid onset of action in five short-term studies, sustained efficacy in an open-label extension study, and a balanced benefit for both inattentiveness and hyperactivity/impulsivity symptoms of ADHD [86–90]. Moreover, treatment with viloxazine has been associated with improved executive function as well as peer and social relationships. Finally, viloxazine treatment has demonstrated a favorable benefit–risk ratio, which is reflected by the positive NNT, NNH, and LHH values based on the four phase III clinical trials in children and adolescents. Beyond pharmacologic differences relative to stimulant treatment options, patients who have experienced suboptimal responses to atomoxetine achieved rapid improvement and greater tolerability upon transitioning to monotherapy viloxazine ER [108]. Viloxazine therefore represents an appropriate choice for individuals with ADHD who do not experience adequate response or who have tolerability issues with currently available stimulant and/or nonstimulant treatments.

Article highlights

• Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects approximately 9.4% to 10.5% of children in the US and is characterized by inattention, hyperactivity, and impulsivity.

• Current pharmacologic treatment options include stimulant and nonstimulant agents, yet some individuals experience suboptimal symptom improvement and/or tolerability issues.

• Viloxazine extended-release (ER) capsules (Qelbree®) represents an emerging, once-daily, US Food and Drug Administration–approved, nonstimulant treatment option for children and adolescents (6–17 years old) with ADHD.

• Randomized, placebo-controlled, phase II and III clinical trials demonstrated efficacy and safety in pediatric populations. ADHD symptom improvement was rapid and was maintained during subsequent open-label treatment.

• Although head-to-head data with other available agents for ADHD are lacking, post hoc analyses of pediatric clinical trial data further demonstrate the pharmacologic utility of viloxazine ER as an ADHD treatment option.

Declaration of interest

J Earnest is an employee of Supernus Pharmaceuticals. V Maletic is a consultant for Acadia Pharmaceuticals; Alfasigma U.S.A.; Alkermes; Allergan; Biogen; Boehringer Ingelheim; Cerevel Therapeutics; Corium; Eisai-Purdue; Intra-Cellular Therapies; Janssen Pharmaceuticals; Liva/Nova; Lundbeck; Neumora; Neurelis; Noven; Otsuka America Pharmaceutical; Pax Medica; Relmada; Sage Therapeutics Inc.; Sunovion; Supernus Pharmaceuticals, Inc.; and Takeda. He serves on the speakers’ bureau of AbbVie; Alfasigma; Alkermes; Allergan; Axsome; Corium; Ironshore; Intra-Cellular Therapies; Janssen; Lundbeck; Otsuka America Pharmaceutical; Sunovion, Supernus Pharmaceuticals Inc.; and Takeda. His spouse serves on the speakers’ bureau of Otsuka America Pharmaceutical. GW Mattingly has served as a consultant to Akili; Alkermes; Allergan (now AbbVie); Axsome, Intra-Cellular Therapies; Ironshore; Janssen; Lundbeck; Neos Therapeutics; Otsuka America Pharmaceutical; Purdue; Rhodes; Sage Therapeutics, Inc.; Sunovion; Takeda; and Teva. He has received research grants from Akili; Alkermes; Allergan (now AbbVie); Axsome; Boehringer Ingelheim; Janssen Pharmaceuticals; Lundbeck; Medgenics; NLS-1 Pharma (now NLS Pharmaceuticals); Otsuka America Pharmaceutical; Reckitt Benckiser; Roche; Sage Therapeutics, Inc.; Sunovion; Supernus Pharmaceuticals Inc.; Takeda; and Teva. He has received speaker/promotional honoraria from Alkermes; Allergan (now AbbVie); Ironshore; Janssen Pharmaceuticals; Lundbeck; Otsuka America Pharmaceutical; Sunovion; and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by Supernus Pharmaceuticals.