Attention deficit hyperactivity disorder (ADHD) is a persistent neurodevelopmental disorder that affects more than 5% of children and adolescents and 2.5% of adults worldwide.1 ADHD is diagnosed clinically based on criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) that includes inattention and/or hyperactivity that is inconsistent with the individual’s level of development for at least six months.2 Additionally, symptoms must be present before the age of 12 and occur in multiple settings. Symptoms of ADHD present as a wide range depending on the individual but can impair functioning in many aspects of the individual’s well-being including physical health, academic, social, and occupational functioning.3 Individuals with ADHD, especially those that are diagnosed in adulthood, are often diagnosed with comorbidities such as mood disorders, anxiety disorders, substance use disorders, and conduct disorders.4 The cause of ADHD is multifactorial due to genetic, social, economic, and environmental factors. However, it is important to note that the genetic component is very prominent with an estimated heritability of 60-80%.2
Currently, stimulants such as methylphenidate and dextroamphetamine-amphetamine are considered first-line therapy for ADHD. However, nonstimulant drugs such as viloxazine, atomoxetine, guanfacine, and clonidine are becoming more popular due to minimal adverse effects when compared to stimulants.3 As prevalence of ADHD is increasing, different pharmacological therapies continue to be an opportunity for research to minimize the wide variety of symptoms that patients being treated for ADHD with stimulants may experience.
Epidemiology, Pathophysiology, Risk Factors, and Presentation of ADHD
When initially determining prevalence in the 1970s and 1980s, the number of children being treated for ADHD was rapidly increasing. This led to concerns that ADHD was being overly diagnosed or possibly a cultural product of competitive developed societies.3 However, more recent studies have determined that ADHD has a worldwide prevalence of about 7.2%, which is equivalent to 5.4 million children.5 According to the 2011 National Health Interview Survey, prevalence in males was nearly double the prevalence in females, most likely because males present as disruptive while females are more inattentive.2 The median age of diagnosis is 7 years old and usually persists into adulthood. Recent studies have estimated the prevalence of ADHD in adults above 18 years old to be 2.5%.3
ADHD is considered a multifactorial disorder because numerous causes contribute to its development including genetics, lifestyle, and environment. However, genetics is currently considered the primary component due to an estimated 60-80% heritability as determined by multiple family-based studies.2 Additional risk factors include birth complications, traumatic brain injury, maternal alcohol or tobacco consumption, maternal stress during pregnancy, prematurity, toxin exposure, family adversity, low income, and severe deprivation in childhood.2
Although the pathophysiology of ADHD is not entirely clear, it is believed that a combination of neurotransmitter dysfunction, differing brain structures (though research has been inconsistent), and decreased cognitive functioning precipitate the development of symptoms in ADHD. Regarding neurotransmitter dysfunction, it has been hypothesized that a decrease in the catecholamines, dopamine and norepinephrine, lead to a delay in the communication between neurons. In children with ADHD, early neuroimaging has shown maturational abnormalities with a 2-3-year delay in reaching peak thickness of the cerebrum and prefrontal cortex.3 Additionally, structural deficits in the frontal lobe, thalamus, and striatum (key components of the cortico-striato-thalamo-cortical loop for attention and cognitive processing) have been associated with the emergence of ADHD.2 Imaging is similar in adults, which indicates smaller volumes in the frontal cortex, cerebellum, and subcortical structures.6
Presentation of ADHD
As previously stated, symptoms of ADHD come in a wide variety and can present differently in every patient. Diagnosis is made clinically via DSM-5 criteria that includes inattention and/or hyperactivity for at least six months, must be present before 12 years of age, and must be present in at least two settings.3 In boys, ADHD predominantly presents as hyperactive behaviors such as restlessness, excessive talking, and difficulty waiting their turn.5 However, girls exhibit inattentiveness via becoming easily distracted, not listening when spoken to, or working in a disorganized fashion. As they enter adolescence, hyperactivity and impulsivity decline and inattentive symptoms become more prominent. Moreover, adults present with deficient executive functions such as working memory, shifting tasks, initiation, and self-inhibition.7
Current treatment options for ADHD
Over the years, much has been known about the pathophysiology of this disease entity and the ability to treat ADHD. Multiple centers of excellence including the American Academy of Pediatrics and Child and Adolescent Psychiatry have formulated guidelines in managing ADHD according to the age group.8,9 Though the main stay of treatment for ADHD remains behavioral therapy techniques for pre-school children; medications are the first-line management for children ≥ 6 years.10–15 ADHD is a multifactorial disorder which incorporates neuropsychological, behavior-based, and emotional-based abnormalities, not just the symptoms; as a result, multiple management strategies are based on a combination of medications, behaviorial therapy, and combined interventions.16–19
For over eight decades, stimulant medications have been the mainstay of management in ADHD. Stimulants lead to an increase in release of catecholamines through dopaminergic and noradrenergic pathways, but the exact mechanism remains unknown.13 In 1937, benzedrine sulfate, an amphetamine, became the first FDA medication approved for the treatment of ADHD. It was noticed that administration of benzedrine sulfate led to an increase in emotional responses and improvements in interactions, engagements, and school performances.20 This eventually led to a formulation of methylphenidate - a stimulant medication, commonly known as Ritalin – being approved by the FDA in 1955.8 Now, stimulant medications such as methylphenidate (Ritalin, Methylin, Metadate, and Concentra) and amphetamines (Adderall, Dexedrine, and Dextrostat) are the first-line medications for ADHD.16,19,21,22 Both methylphenidate and amphetamines are available in different forms (tablet, capsules, patch, oral suspension, or disintegrating tablets) and variety of formulations such as short, immediate or long-acting.17–19 Response rate to dosing are highly variable. Guidelines to the dosage according to different formulations are represented in Tables 1A & B.
Growth should be continuously monitored as common side effects include poor growth, anorexia, weight loss, social withdrawal, jitteriness, and sleep disturbances. Other side effects such as increase in heart rate and blood pressure, headaches, dizziness, priapism, tics, and peripheral vasculopathy such as Raynaud’s phenomenon have been noted; furthermore, symptomatic cardiovascular disease is a contraindication to stimulant use due to its increase in heart rate and blood pressure.26–33 Moreover, stimulants have an addictive tendency with a potential of misuse to achieve euphoria in high-school and college-age students.34,35
To avoid the use of stimulants, the use of FDA-approved nonstimulants can be employed such as selective norepinephrine (NE) reuptake inhibitors (NRI), atomoxetine and viloxazine. They function by blocking the reuptake of NE in the nerve terminals, increasing the concentration of NE in the synapse.15,36 The dose of atomoxetine (Strattera) depends on the child’s weight; it is administered once or twice a day lasting 10-12 hours with a typical onset of action between 6-12 weeks.15,23,37–39 The side effect profile of atomoxetine is similar to stimulants with the differences being that it can cause severe liver injury and an increase in suicidal ideations and behaviorial problems.
Metabolism is via the CYP450 system, and care should be taken when given with other medication that are metabolized by the same system as it can either increase or decrease serum concentrations.15,27,40–47 For those who have contraindications, severe side effects, or poor response to stimulants or NRIs; alpha-2-adrenergic agonists such as extended-release clonidine and guanfacine can be prescribed for age groups 6-17. These drugs have been shown to improve ADHD symptoms but not to the same extent as stimulants alone and were not superior to stimulants; in fact, combination therapy has proven to be more beneficial in improving ADHD symptoms, tic disorders, and improving working memory.13,48–58
Due to their similar mechanism of action, tricyclic antidepressants (TCAs) such as imipramine, desipramine, nortriptyline; and dopaminergic re-uptake inhibitors (bupropion) have also been indicated for use in ADHD as reserve agents to those who respond poorly, have unacceptable side effects, or contraindications to stimulants.59–61 Other investigational drugs for the treatment of ADHD, including cholinesterase inhibitors (tacrine and donepezil) and nicotinic analogues (ABT-418), are under investigation.62
Viloxazine Drug Info
Viloxazine (Qelbree by Supernus Pharmaceuticals) is a recently FDA approved non-stimulant drug for ADHD.63 Previously used for its anti-depressive effects, viloxazine has been now shown to have effects on blocking the noradrenergic reuptake and has a low abuse potential; it now represents an alternative to stimulants for managing ADHD.63–68
Viloxazine is available as an extended-release capsule to be taken once daily (OD) with recommended dosing based on the age group. For ages 6-11, recommended starting dosage is 100 mg titrating upwards to a maximum dosage of 400mg.69 For ages 12-17, recommended starting dosage is 200mg and titrating up to a maximum of 400 mg.69 Patients receiving viloxazine should be very closely monitored for any evidence of suicidal behavior or thoughts as there is an FDA black box warning.69 Viloxazine can be associated with adverse effects such as increase in heart rate and blood pressure, exacerbation of manic or hypomanic episodes in patients with concomitant bipolar disorder, excessive somnolence, and fatigue.69 The concomitant use of viloxazine and monoamine oxidase inhibitors (MAOIs), or initiation of viloxazine within 14 days of discontinuing MAOIs, should be avoided as there is an increased risk of hypertensive crisis.69 The use of viloxazine in pregnancy is limited but is based on the animal representation model studies; thus, it is recommended to discontinue viloxazine once pregnancy is identified.69
Mechanism of Action of Viloxazine
Viloxazine was originally used in Europe to treat depression in adults with activity in both the noradrenergic as well as serotonergic pathways. It initially garnered attention as a potential nonstimulant treatment for ADHD due to its different inhibitory potency for norepinephrine (NE) and 5-HT and reuptake of NE.70–72 Viloxazine functions by increasing the availability of both NE and 5-HT in the prefrontal cortex of patients by inhibiting the neurotransmitter transporters specific to these chemicals, resulting in an improvement of ADHD related symptoms including impulsivity, hyperactivity, and attention deficit.73 Viloxazine exhibited a moderate inhibitory activity on norepinephrine transporter (NET) with an IC50 (half maximal inhibitory concentration) around 0.3 μM; this relatively low IC50 on NET in relation to other drugs of this class is responsible for the marked decrease in cardiac related side effects traditionally seen in NRIs such as atomoxetine and reboxetine.74–77 Increased extracellular concentrations of NE and 5-HT in the prefrontal cortex, nucleus accumbens, and amygdala have been shown as a result of viloxazine administration in rodent models.77,78 Double-blind placebo controlled clinical trials in children revealed a significant alleviation of ADHD symptoms as determined by ADHD Rating Scale 5 (ADHD-RS-IV) rating scores in200mg, 300mg, and 400mg extended release dose ranges.79,80
Viloxazine has also demonstrated agonistic activity on 5-HT2C receptors and antagonistic activity on 5-HT2B receptors expressed in the central nervous system. These G-protein coupled receptors are expressed widely within areas of the central nervous system, including the prefrontal cortex, amygdala, nucleus accumbens, and hypothalamus. These serotonin receptors modulate neurotransmitter release in these areas of the brain and produce effects on mood, anxiety, behavior, and locomotion.77,81–83 Pre-clinical animal trials have demonstrated increased levels of dopamine in the prefrontal cortex, nucleus accumbens, and amygdala as a result of viloxazine administration.77 Elevated extracellular dopamine levels in the nucleus accumbens have been implicated in the pathophysiology of addiction and substance abuse.84,85 Notably, dopamine levels in the nucleus accumbens after treatment with viloxazine are elevated considerably less in comparison with traditional stimulant ADHD treatments such as methylphenidate and amphetamine suggesting the potential for a lowered chance of substance abuse, drug dependance, and withdrawal symptoms upon the cessation of therapy in patients taking this medication.77,86 High rates of substance abuse among adults with ADHD have been documented, and the potential for use of these non-stimulant treatments could make viloxazine beneficial to these patients.87,88
Pharmacokinetics/pharmacodynamics of Viloxazine
Viloxazine was initially offered in an instant release formulation to be administered orally two to three times daily in adults for the treatment of depression. Current formulations to treat ADHD in pediatric patients and adults are now offered in once daily oral doses and were approved for its first use in the United States in April of 2021. These extended-release treatments are now offered in 100-600 mg dosages.72,73
Viloxazine is predominantly metabolized via the 5-hydroxylation by cytochrome P450 isoenzyme CYP2D6, with the majority of its metabolites excreted renally through urine; it has exhibited reversible inhibition of CYP1A2, 2B6, 2D6, and 3A4/5 with an IC50 of 0.269,184,141,221 µM respectively.89 Volume of distribution of viloxazine following IV dosing is 0.73 ± 0.28 L/kg, and its absolute oral availability has been determined to be 85 ± 13%.90 In a clinical trial examining the pharmacokinetics of viloxazine in healthy adults, the Cmax (maximum measured plasma concentration of participants) of a 700 mg extended-release dose was determined as 4.73 ± 0.86 µg/mL and occurred 5 hours after dose administration. The half-life elimination for viloxazine ranges from 3 to 9 hours with a clearance rate of 6.29 ± 6.89 L/h in children and 7.88 ± 7.01 L/h in adolescents. Body weight has been identified as a prospective source for variability in the pharmacokinetics of viloxazine with a linear correlation between body mass index and drug exposure levels; however, further studies will be necessary to shed more light on this trend.91,92
Drug holidays are days or periods of time in which patients skip doses of medications and are often utilized by patients undergoing long-term ADHD therapy. These holidays as well as treatment adherence should be considered by physicians prior to beginning ADHD treatments, particularly in children and adolescents. The primary purpose of these holidays is to increase tolerability of the drug and to decrease the severity of adverse side effects such as insomnia and weight loss common in patients prescribed stimulants. Drug holidays typically coincide with school holidays or weekends and typically terminate with the resumption of school related activities.92–94 The pharmacological effects of drug holidays consisting of 1-4 missed daily doses in patients taking viloxazine after steady state has been achieved have been analyzed. After cessation of therapy, drug levels dipped below the level of quantification (0.01µg/mL) and were achieved within three days, regardless of drug dose. Upon resuming therapy, steady state plasma concentrations were achieved on average within two doses. This suggests viloxazine plasma concentrations can quickly return to therapeutic levels in patients who have taken a drug holiday or who have simply missed a dose, which is common in adolescents who self-administer medication making it a good option for patients that fall into this category.92,95,96
Clinical Studies: Safety and Efficacy of Viloxazine
A phase III randomized control trial sought to measure the safety and efficacy of a viloxazine extended release (ER) formulation (SPN-812) in male and female children diagnosed with ADHD between the ages of 6-11 years old.97 A double-blind method was utilized to randomize 477 individuals into a placebo, 100 mg, or 200 mg SPN-812. The effectiveness of the SPN-812 was measured through ADHD-RS-5, Clinical Global Impression-Improvement (CGI-I), Conners 3–Parent Short Form (Conners 3–PS), and Weiss Functional Impairment Rating Scale–Parent (WFIRS–P) by evaluating changes in scores obtained throughout the 6-week study.97 The researchers reported a significant improvement in ADHD-RS-5 scores in impulsive, hyperactive, and inattentive behaviors in both the 100 mg/daily and 200 mg/daily groups versus placebo. Similar improvements were seen in the mean scores from the CGI-I, Conners 3-PS, and WFIRS–P assessment (p = 0.0020 and p < 0.0001), (p = 0.0003 and p = 0.0002), and (p = 0.0019 and p = 0.0002), respectively in comparison to the placebo.97 When compared to the placebo, the frequent side effects were headaches, somnolence, and decreased appetite in ≥5% of the participants indicating an overall safe drug profile.97
Another phase III randomized control trial assessed the safety and efficacy of SPN-812; however, the treatment groups received either 200 mg/daily, 400 mg/daily, or placebo over an 8 week period.98 A total of 313 children between the ages 6-11 years were recruited and had their change from baseline (CFB) to end of study (EOS) scores from the ADHD-RS-5, CGI-I, Conners 3-PS, WFIRS-P analyzed to further assess the drug profile of SPN-812. Both 200 mg/daily and 400 mg/daily SPN-812 groups when compared to placebo revealed significant improvement in the ADHD-RS-5 scores (p = 0.0038, p=0.0063), CGI-I scale (p = 0.0028, p = 0.0099).98 While there was a significant reduction in symptoms in all categories of the Conners 3-PS T-scores for the 200 mg/daily group, the 400 mg/daily treatment arm saw a reduction in hyperactivity (p = 0.0030) only. The frequent adverse events (AEs) were headaches, somnolence, decreased appetite in addition to fatigue (7.2%) and upper abdominal pain (4.8%) with only 1 participant in the 400 mg/daily group experiencing an increased heart rate and blood pressure.97,98
Similar results were obtained in a phase II randomized placebo-controlled trial which assessed the safety and efficacy of viloxazine ER in children diagnosed with ADHD between the ages of 6 to 12 years old.99 ADHD-RS-5, CGI-S, and CGI-I scales were employed to analyze the different viloxazine groups 100 mg, 200 mg, 300 mg, or 400 mg/daily. A significant improvement in was seen in 200 mg, 300 mg, and 400 mg treatments with an effect size of 0.547, 0.596, and 0.623 respectively (p < 0.5). While the CGI-I scores only saw an improvement in the 300 mg treatment arm, the CGI-S scores did not result in significant ADHD symptom reductions in the 100 mg group.99
Two clinical trials were performed to examine the effects of dosing with one trial evaluating 200 and 400 mg/daily viloxazine ER in adolescents (12-17 years old) and the second trial evaluted 400 and 600 mg/daily.100,101 When compared to placebo the 200 mg and 400 mg/daily saw an improvement in the ADHD-RS-5 (p = 0.0232, p = 0.0091), CBI-I (p = 0.0042, p = 0.0003) and no improvement in the Conners 3-PS and WFIRS-P scales.100 The second trial demonstrated a significant change from baseline in the ADHD-RS-5 score for the 400 mg/daily (p = 0.0082) only when compared to placebo.101 There was no significant improvement in the 600 mg/daily group, which the researchers attributed to an abnormally high response rate to the placebo. Both studies exhibited the same the adverse events in ≥ 5% of the participants including somnolence, fatigue, headache, nausea, and decreased appetite.100,101
Additionally, the same group of researchers investigated the effects of a maximum dose viloxazine ER on cardiac repolarization in adults.102 In a consecutive manner with appropriate 3-day washout periods, 22 participants received placebo, 400 mg moxifloxacin, and 1800 mg viloxazine ER. The corrected QT interval (ΔQTcI) was compared to viloxazine ER and 5-hydroxyviloxazine glucuronide (viloxazine metabolite) plasma concentrations resulting in a negative slope (p = 0.0012) and (p = 0.0007), respectively.102 The supratherapeutic doses of SPN-812 did not elicit abnormal cardiovascular parameters and in some cases, a minor decrease in the QT interval was observed indicating the overall safety of the pharmacotherapy.102
Exploring the pharmacokinetics of viloxazine alone but also in combination with previously approved stimulant modalities is vital.103,104 An open-label study assessed the bioavailability and safety of the stimulant used for ADHD methylphenidate (36 mg/daily) alone, viloxazine ER/SP-812 (700 mg/daily), and a combination of both drugs (36 mg + 700 mg/daily).105 The three treatment arms were administered to 34 healthy adults aged between 18 to 55 years old over a 13-day period. Blood samples were drawn and analyzed using a mass spectrometer to measure bioavailability and possible drug interactions. The geometric low square mean (LSM) ratios (viloxazine ER + methylphenidate/drug alone) with a 90% confidence interval (CI) for the maximum concentrations of viloxazine and methylphenidate were Cmax 100.98% (96.21–105.99), and 103.55% (97.42–110.07) respectively; which demonstrates no drug-drug interactions on bioavailability.105 Common AEs that were reported in ≥ 5% of participants included dizziness, nausea, somnolence, and a single patient displayed an abnormal ECG at EOS which was deemed to be an insignificant finding.105
A similar combination trial using lisdexamfetamine (psychostimulant) instead of methylphenidate was performed.106 The open label trial administered viloxazine ER alone (700mg), lisdexamfetamine alone (50mg), and a combination of both therapies. The researchers reported geometric LSM ratios with a 90% CI for viloxazine maximum concentration, area under concentration-time curve from time 0 to last measurable time and infinity; Cmax = 95.96% (91.33–100.82), (AUC0-t) = 99.19% (96.53–101.91), and (AUCinf) = 99.23% (96.61–101.93) respectively. These data suggest viloxazine has no drug interactions with lisdexamfetamine or methylphenidate (as seen in the previous study).105,106 The investigators reported one moderate AE where an individual experienced vomiting after receiving the combination therapy, and two participants were reported to have abnormal ECGs that were later deemed insignificant.106 (All studies are summaried in Table 2)
ADHD is a widely diagnosed neurodevelopmental disorder giving rise to symptoms of hyperactivity, impulsivity, and inattentiveness that can impair daily functioning. On average, ADHD is diagnosed before the age of 7 and can progress into adulthood.3 Since the 1930s, stimulant drugs including methylphenidate and amphetamines are considered first-line therapy for ADHD as they can block the transport of dopamine and norephinephrine.1 However, the side effect profiles are not ideal and response rate is only 70%.107 There have been reports of stunted height, increased likelihood of substance abuse, increased risk of cardiovascular events with long term use.1 Moreover, second-line medications fall under the category of “non-stimulants” and can be used if stimulants are not adequate. Viloxazine is an example of a non-stimulant medication that has been recently approved for the treatment of ADHD by inhibiting the uptake of norepinephrine.107 Adverse effects include decreased appetite, fatigue, insomnia, somnolence, nausea, vomiting, and irritability.107 In children, viloxazine can be given 100 mg daily with a maximum daily dose of 400 mg. As age increases, initial doses are increased to 200 mg/day and while the maximum dose remains 400 mg/day.107 Furthermore, patients on viloxazine should be closely monitored due to two significant adverse reactions: cardiovascular effects and suicidal ideation. Although there is need for more research for the safety and efficacy of viloxazine as a treatment for ADHD long-term, it has shown promise in patients who may not respond to first-line treatments.
All authors were involved in the writing and editing of the manuscript.
There are no conflict of interests with the authors.