The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium

ABSTRACT

Introduction

Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on norepinephrine, dopamine, and serotonin neurotransmission, they benefit both ADHD and comorbid disorders and have some other advantages including longer duration of action and fewer adverse effects compared to stimulants. There is continued interest in these agents with novel mechanisms of action in treatment of ADHD.

Areas covered

The authors conducted a PubMed literature search using the following key words: ‘ADHD’ AND ‘adrenergic reuptake inhibitors’ OR ‘nonstimulants’ OR ‘atomoxetine’ OR ‘Viloxazine’ OR ‘Dasotraline’ OR ‘Centanafadine’ OR ‘PDC-1421’ OR ‘Reboxetine’ OR ‘Edivoxetine’ OR ‘Bupropion’ OR ‘Venlafaxine’ OR ‘Duloxetine.’ They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD.

Expert opinion

Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor affinities and modulating effects support the unique benefits of individual agents.

KEYWORDS:

• Adrenergic agents
• non-stimulants
• adrenergic neurotransmitter reuptake inhibitors
• ADHD
• medication

1. Overview

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with an estimated prevalence of 5% worldwide in children aged 6–18 years [1], up to 9.4% in the U.S.A [2]. Stimulant medications are first-line treatments in current guidelines; between 2012 and 2021, overall stimulant prescriptions in the U.S.A increased by 45.5% [3]. However, a substantial minority of patients with ADHD have an inadequate response to the stimulants or have tolerability problems. Typical side effects, including insomnia, appetite suppression, growth delay, and rebound irritability in the evenings, are usual causes for discontinuation of stimulants or switching to alternatives even when the stimulants are effective. Children and adolescents with ADHD and comorbidities, including depression, anxiety, and tics, may suffer exacerbation of comorbid symptoms, or stimulant side effects such as insomnia and elevated heart rate may interfere with recognizing the comorbid illnesses. In patients requiring 24-hour symptom coverage, there is a risk of nonmedical use, drug diversion, or abuse of these Schedule II drugs. In addition, it is challenging to obtain 24-hour symptom coverage with stimulants. Therefore, interest in non-stimulant medications for ADHD and comorbid psychiatric conditions is reflected in a growing literature.

Until recently, there were three FDA-approved non-stimulants: atomoxetine (Strattera^©), guanfacine extended release (Intuniv^©), and clonidine sustained release (Kapvay^©). Viloxazine (Qelbree^©) is the newest non-stimulant to receive FDA approval, in April 2021, for ADHD in children ages 6–17 years old. There is a continuous search for non-stimulant medications, especially those with novel mechanisms of action, as viable alternatives in the treatment of ADHD. Several agents are either in clinical development or repurposed for new indications and have successfully completed phase 2 and/or phase 3 studies. On the basis of their pharmacological profiles, the non-stimulant medications are broadly classified as follows: 1. Monoamine reuptake (transporter) inhibitors, (e.g. atomoxetine), 2. Receptor modulators (guanfacine ER, clonidine ER), and 3. Multimodal agents (viloxazine). The alpha-adrenergic agonists (guanfacine and clonidine) act by modulating the balance of phasic and tonic activity of locus coeruleus neurons by acting on the neuronal autoreceptors by direct stimulation of post-synaptic alpha_2A autoreceptors [4]. Due to their distinct mechanism of action, which does not involve reuptake inhibition and hence effects on other neurotransmitter systems, clonidine and guanfacine were not included in this paper.

2. Mechanism of action

Core symptoms of ADHD are linked to dysfunction in the cortico-striato-thalamo-cortical circuits. Dysregulation in the dopaminergic and noradrenergic systems underlies the disruption of normal tuning of neurons in the prefrontal cortex (PFC) and basal ganglia, leading to inattention, impulsivity, and hyperactivity. The inhibition of dopamine (DA) and norepinephrine (NE) reuptake is an important mechanism of action of current therapeutic agents for ADHD [5].

The norepinephrine transporter, NET, which transports NE back into the presynaptic neuron for catabolic destruction, is found in the plasma membrane of norepinephrinergic neurons and especially in the prefrontal cortex. The reuptake of both DA and NE into the presynaptic neuron is modulated by NET (Hohmann et al. [6]; Zhou [7]. While NE is the main substrate of NET and DA is mainly transported by DA transporter in most parts of the brain, in the prefrontal cortex, NET also mediates the reuptake of DA. This allows a NE-reuptake inhibitor to more specifically target the PFC than the DA-reuptake inhibiting stimulants. According to Zhou, the treatment of ADHD targets both DA and NE in balanced equilibration Zhou [7].

Table 1 summarizes the agents with alpha-adrenergic neurotransmitter reuptake inhibition currently approved for treatment of ADHD along with drugs that are in the pipeline.

Table 1. Comparing the alpha-adrenergic neurotransmitter reuptake inhibitors in ADHD with current approval and in the pipeline.

Adrenergic reuptake inhibitor	Pharmacological action	ADHD approval status	Dosing	Special considerations/Adverse effects
Atomoxetine	NET inhibitor	FDA approved in children 6 years and above, and adults	1.2 mg/kg/day in Children 80 mg/day for adults Max approved dose: 1.4 mg/kg, 100 mg/day. Safety & effect shown up to 1.8 mg/kg. Dosed once or twice a day
Viloxazine	5-HT, NE, DA modulating agent Antagonistic activity at 5-HT-2B and agonistic activity at 5-HT-2C receptors. Moderate inhibitory effects on the NET and elicited moderate activity at NE and DA systems. Lacks binding Affinity at the dopamine transporter DAT	FDA Approved for ADHD 6–17 years. 5 RCTs in children, N = 1605,	100 mg/day in children 200 mg/day in adolescents- Maximum dose 400 mg/day.	Minimal effect on dopamine transporter - > low substance abuse liability. Supratherapeutic doses −1800 mg/day – No increase in QTc interval. No clinically significant changes in the HR, PR interval and QRS duration- indicates a large cardiac safety margin. Major AE- somnolence Major SAEs- syncope, suicidal ideation, and suicide attempt.
Dasotraline	Triple reuptake inhibitor with potent inhibition of DA NE reuptake and (weaker) 5-HT reuptake	Not approved 2 RCTs in children 6–12 years N = 342 and N = 112	1^st- Improvement noted at 4 mg/day. Serious AEs with 6 mg/day	May be associated with a reduced risk of abuse due to long half-life (t½, 47–77 h) and lack of direct DA stimulation. Frequent AEs included- insomnia, decreased appetite, decreased weight, irritability and nonserious psychotic symptoms. 6 mg/day arm discontinued due to serious AEs- Hallucinations, Insomnia, affective lability, weight loss.
Centanafadine	Triple reuptake inhibitor with preferential potency for NE and DA and mild effect on 5-HT	Not approved Phase-3 trials currently underway by Otsuka pharmaceuticals in adults
Edivoxetine	NE Reuptake inhibitor	Not approved One RCT (Children 6–17, N = 340)	0.2 mg/kg/day and 0.3 mg/kg/day doses had more improvement in ADHD-RS scores than placebo. Effect sizes of d = 0.51, 0.54	Increases in SBP, DBP, and HR, decrease in weight, nausea, sedation, somnolence, irritability.
Reboxetine	NET	Not approved 2 open labeled trials Available in the Europe. Not approved for use in the United States.	1 mg/day- titrated up to 3.8 mg a day in 1^st study. Fixed dose of 4 mg/day in second study	Evidence is inconclusive, regarding use in pediatric population for treatment of ADHD. Side effects- headache, low appetite, somnolence, irritability, butterfly sensation and bruxism
Mazindol	DA and NE reuptake inhibitor, 5-HT1A and 5-HT7 receptor agonist & partial agonist at orexin-2 receptors	Not approved Open labeled study of IR Mazindol in children 9–12 years (N = 21) RCT in adults of Mazindol Controlled release	Dose 1 mg in children 1–3 mg in adults Large Effect size (d = 1.09)	Originally approved for the treatment of obesity Adverse effects reported include decreased appetite, drowsiness, intestinal distension and upper abdominal pain. No sleep problems. 3 mg/day caused more elevation in Heart rate.
Bupropion	NE and DA transport inhibitor	Not approved 2 studies of children, Bupropion vs MPH for 6 weeks One study over 12 weeks	100–150 mg/day	No significant differences, similar efficacy between Bupropion and MPH. Some evidence on the beneficial effect in children with comorbid ADHD and substance use or mood disorders. Serious adverse events such as ‘“serum sickness-like”’ reaction, seizures. Rate of seizure is 0.4% at doses of 300 to 450 mg/day.
Venlafaxine	SNRI	Approved for depression, not ADHD One RCT of 38 Children (6-13yo) with ADHD Comparing low dose Venlafaxine (50–75 mg/day) with Methylphenidate (20–30 mg/day)	50–75 mg/day	Comparable efficacy as Methylphenidate with improvement in parent/teacher ADHD-RS Venlafaxine had favorable side effect profile; Methylphenidate caused more headaches, Insomnia. Evidence poor quality due to small sample
Duloxetine	SNRI	Not approved One open labeled trial in children- N = 17 One RCT in adults n = 30	60 mg/day over 6 weeks, Symptom reduction noted by week 4	Not enough evidence for use in ADHD 24–40% drop out due to AEs- decreased appetite, dry mouth, insomnia, headaches, nausea
Tricyclic antidepressants	Block the serotonin and norepinephrine transporters	Approved for depression, not ADHD Cochrane Review 6 RCTs in children and adolescents, 5 on Desipramine, 1 on Nortriptyline. N = 216	Desipramine 200 mg/day, studies over 2–6 weeks. Studies on children with ADHD and tics and Tourette disorder Desipramine found superior to Clonidine. Nortriptyline studied over 9 weeks	Low quality evidence of TCAs in ADHD in children and adolescents Considered third- or fourth-line options. Adverse effects- appetite suppression, headaches, dry mouth, constipation, increases in mean diastolic blood pressure and heart rate. Risk of cardiotoxicity and potential for sudden death in children
Solriamfetol	Dopamine and norepinephrine reuptake inhibitor	Not approved One adult RCT, 6 weeks	Solriamfetol 75–150 mg in adults with ADHD- greater improvement than placebo	No data in children Adverse effects- : decreased appetite, headaches, insomnia, increased energy, gastrointestinal (nausea, vomiting, diarrhea), cardiac and neurologic side effects
Modafinil	Dopamine, norepinephrine reuptake inhibitor	Approved for narcolepsy, not ADHD One crossover study in adults randomized to Modafinil, dextroamphetamine or placebo	Modafinil (mean dose 206.8 mg/day) Vs dextroamphetamine (mean dose 21.8 mg/day) No difference found between treatment groups.	Common side effects include anxiety, headache, nausea

Abbreviations: NE= Norepinephrine, DA= Dopamine, 5 HT- Serotonin, NET= Norepinephrine Transporter, SNRI= Serotonin−Norepinephrine reuptake inhibitor, RCT= Randomized controlled trial.

3. Adrenergic reuptake (transporter) inhibitors

3.1. Atomoxetine (Strattera®, Eli Lilly)

Atomoxetine is a selective noradrenergic reuptake inhibitor with high specificity for the presynaptic norepinephrine transporter. It was approved for the treatment of ADHD in children and adolescents 6 years and older in the United States in 2002 and in the UK and other European countries in 2003 and 2004 [8,9].

It is absorbed when administered with or without food, and maximum plasma level is achieved 1–2 hours after the dosing. ATX is metabolized to 4-hydroxy ATX in the liver via the CYP 2D6 pathway. Nearly 5−7% of individuals have a genetic polymorphism, which makes them poor metabolizers, and a small number of individuals are ultrarapid metabolizers. In ultrarapid metabolizers, the half-life is about 5 hours, and in slow metabolizers, the half-life increases to around 21.6 hours. Due to its interaction via CYP 2D6, coadministration of fluoxetine or paroxetine elevates mean peak plasma concentrations of atomoxetine [10].

Dosing: The target dose of atomoxetine is 1.2 mg/kg/day for children and 80 mg/day for adults. The FDA maximum approved is 1.4 mg/kg/day with a 100 mg cap. It is effective with either once a day or split twice daily dosing. Atomoxetine shows a graded dose−response between 0.5 mg/kg/day and 1.2 mg/kg/day doses. Greater improvements are noted in psychosocial functioning when the dose is increased to 1.8 mg/kg/day with no significant increase in the rate of adverse effects. However, studies that looked into the tolerability and utility of higher doses up to 2.4–3.0 mg/kg/day did not show further improvement in ADHD-RS scores or the percentage of patients converting to responders [11,12].

A systematic review and meta-analysis of atomoxetine (2014) in ADHD included 25 double-blind RCTs of atomoxetine, with a total of 3928 youths over an average duration of 8.6 weeks (4–18 weeks); it noted significant decreases in total inattentive and hyperactive parent-rated and total teacher-rated ADHD symptom scores with a medium effect size (ES) of d = 0.59 to 0.67 [13].

Patients treated with atomoxetine show a bimodal response, with 44.6% showing >40% improvement and a 39.9% not responding (i.e. failure to improve by 25%). The effect size (ES) (close to d = 0.7 in children) includes both responders and nonresponders, so is not a good representation of the response for responders, who have effects nearly equal to stimulants. An early onset of response by 4 weeks predicts excellent response to atomoxetine [13].

In placebo-controlled studies comparing the differential treatment response of children with ADHD to atomoxetine and methylphenidate OROS, by 6 weeks, both Atomoxetine and Methylphenidate OROS showed significantly greater improvement than placebo, with response rates of 45% with atomoxetine and 56% with methylphenidate and moderate to large effects for each treatment [14]. A study comparing mixed amphetamine extended-release salts to atomoxetine in children 6–12 years old with ADHD found mixed amphetamine extended-release salts to be more effective than atomoxetine with similar rates of adverse effects in both groups [15].

Differential effects are observed with atomoxetine based on a sequence of treatment. In stimulant naïve patients, the response rates to atomoxetine (57%, p = 0.004) and methylphenidate (64%, p ≤ 0.001) were superior to the placebo and not significantly different from each other. Treatment effect size for atomoxetine in stimulant naïve patients was d = 0.9 compared to d = 0.5 in patients previously treated with stimulants. OROS methylphenidate’s effect size in stimulant naïve patients was d = 1.0 compared to d = 0.8 in patients previously treated with a stimulant [14].

Benefits in addition to ADHD effects: In addition to improvement in ADHD symptoms, atomoxetine treatment has also shown decreases in ODD symptoms (ES d= −0.33) even in patients not meeting full criteria for ODD/CD, advantages in functional outcomes, including parent-rated child total QoL (ES d = 0.39), effects on family activity, parent and child emotional state, and self-esteem using the corresponding Child Health Questionnaire (CHQ-50) sub-scores (ES d = 0.25–0.48) [16,17]. Atomoxetine caused significantly greater decreases in tic severity based on the Yale Global Tic Severity Scale (YGTSS; p = 0.027) in children with ADHD and comorbid Tourette’s syndrome [18]. In children with enuresis, atomoxetine increased the average number of dry nights per week by 1.47 compared with 0.60 for placebo (p = 0.01) [19].

Safety: Atomoxetine has a black box warning regarding the increased risk of suicidal ideation in children and adolescents treated for ADHD. The initial safety warnings were based on a meta-analysis of 2208 patients between 6 and 18 years treated with atomoxetine, which noted the significantly higher frequency of suicidal ideation and behavior (0.44%, 6 out of 1357) in children treated with atomoxetine compared to children treated with placebo (0%, 0 out of 851) [20,21]. A large Swedish registry-based study of both pediatric and adult patients (total of 37,936 of which 26.1%, 6818 received atomoxetine) followed over 4 years comparing ‘non-treatment periods’ with ‘treatment periods’ found no increase in suicide-related events in non-stimulant/mixed users (Hazard ratio of 0.96) compared to stimulant users (Hazard ratio of 0.93) [22]. A meta-analysis (2014) of 23 placebo-controlled studies (N = 3883) showed no completed suicides, and suicidal behavior was noted only in 1 out of 2445 patients treated with atomoxetine (0.04%) and none out of 1438 patients treated with placebo (0%) [23]. Based on the data so far, children treated with atomoxetine should be carefully monitored for the emergence and worsening of suicidality, along with the consideration of comorbid depression which could also predispose to suicide.

Aggression and hostility events are more frequently reported in atomoxetine-treated patients compared to placebo in clinical trials. A meta-analysis of 14 trials found no significant difference in aggression/hostility events in atomoxetine-treated children (1.6%, 21/1308 patients) compared to placebo (1.1%, 9/806 patients) (Risk ratio 1.33, 95% confidence interval (CI) 0.67–2.64) [24]. Symptoms of psychosis and mania are rarely reported in children treated with atomoxetine, mainly in children with comorbid bipolar disorder or major depression.

Data from database and registry studies found no significant association between atomoxetine treatment and seizure risk [25].

Both the European and U.S.A regulatory authorities describe rare, spontaneous liver injury with elevated liver enzymes, bilirubin, and jaundice. The liver injury occurred within 120 days of initiation of atomoxetine with marked elevation of liver enzymes (>20 × upper limit of normal (ULN)) with jaundice and significant elevation of bilirubin levels (>2 × ULN) and recovery upon discontinuation. Atomoxetine was listed as a ‘probable cause’ of three hepatic adverse events (AEs) (all reversible hepatitis) out of 351 reports of AEs in children and adolescents, and 133 children with hepatic AEs had possible confounding factors and were ‘possibly related.’ Routine laboratory tests are not recommended, but laboratory tests to measure liver enzymes should be done on the first sign or symptoms of liver dysfunction [26].

Cardiac effects: A review of cardiovascular safety data of atomoxetine reported that 8–12% of children and adolescents treated with atomoxetine had pronounced changes in heart rate (≥20 beats per minute (bpm)) and blood pressure (≥15–20 mmHg) and approximately 15–26% of those with more pronounced changes in blood pressure and heart rate had ‘sustained or progressive increases.’ Atomoxetine is contraindicated in children and adolescents with severe cardiac and vascular diseases. It is recommended to measure pulse and blood pressure at baseline, with dose increases, and periodically during treatment to detect clinically important increases [27,28].

In a comprehensive review of a clinical trials database (N = 8417 received atomoxetine), most pediatric patients experienced modest increases in heart rate and blood pressure, and 8–12% experienced more pronounced changes (≥20 bpm, 15–20 mmHg). However, in three long-term analyses (≥2 years), blood pressure was within age norms, and few patients discontinued due to cardiovascular AEs [27].

There is a small risk of QT interval prolongation with atomoxetine. In an open-label study extending ≥3 years, 1.4% (N = 10/711) of children and adolescents treated with atomoxetine developed prolonged QTc intervals (≥450 ms in males, ≥470 ms in females), and there was no statistically significant change in QTc (0.6 ms; p = 0.506). The European summary of product characteristics (SPC) warns about potential QT interval prolongation in patients with a personal or family history (e.g. congenital or acquired long QT), or if atomoxetine is administered with other drugs that potentially affect the QT interval [29].

Similar to stimulants, growth retardation in both weight and height gain is observed early in therapy with atomoxetine. This (weight and height gain) occurred greatest in patients of above average weight and height but appeared to recover over 2–5 years of atomoxetine treatment [30].

3.2. Viloxazine extended-release capsules (Qelbree^®, Supernus)

Viloxazine is distinct from other ADHD medications targeting norepinephrine reuptake and is better described as a serotonin and norepinephrine modulating agent. It has antagonistic activity at 5-HT-2B and agonistic activity at 5-HT-2C receptors and increases serotonin levels in the prefrontal cortex. It has moderate inhibitory effects on the norepinephrine transporter and moderate activity in noradrenergic and dopaminergic systems. This finding is consistent with the low rate of cardiac effects clinically [31].

Viloxazine lacks binding affinity to the dopamine transporter (DAT) and does not directly interact with dopamine receptors D1 and D2. Based on its minimal effect on dopamine in the nucleus accumbens, it is expected to have low substance abuse liability. The immediate-release Viloxazine formulation was first marketed as an antidepressant in Europe and was later discontinued due to reasons unrelated to safety or efficacy. Data from over two decades of research in adults demonstrated its safety and tolerability compared to the TCAs, with fewer cardiovascular effects and minimal effects on BP.

The median time to reach the maximum concentration (Tmax) for viloxazine ranges between 6 and 9 hours while the half-life is 7 hours. Viloxazine is mainly metabolized by CYP2D6, UGT1A9, and UGT2B15 enzymes, and 90% of the drug has renal elimination including 12–15% of unchanged drug and the remaining as inactive metabolites. In adult studies, coadministration of Viloxazine ER and Methylphenidate or Lisdexamphetamine did not impact the pharmacokinetics of either drug and the combination appeared to be safe and well tolerated.

Efficacy studies-: Four phase 3 double-blind placebo-controlled trials included a total of 1354 subjects (761 children 6–11 years and 593 adolescents 12–17 years of age) [32–34]. Viloxazine ER showed significantly greater improvements in ADHD symptoms than placebo in 3 out of the 4 studies. In the fourth study, Viloxazine ER 400 mg/day but not 600 mg/day was separated from the placebo. Viloxazine ER 100 mg showed improvement in inattention and hyperactivity scores compared to placebo at week 1 extending into week 6, while 200 mg and 400 mg doses showed improvement at week 2 extending to week 6. Viloxazine 600 mg dose showed improvement in inattention scores at week 6 and hyperactivity scores at week 4. The 50% responder rate at week 6 was 37.8% for placebo; 53.2% for 100-mg/day viloxazine ER (p = 0.0014); 50.3% for 200-mg/day viloxazine ER (p = 0.0007); 56.2% for 400-mg/day viloxazine ER (p < 0.0001); and 53.1% for 600-mg/day viloxazine ER (p = 0.0104).

Tolerability for Viloxazine was poorer, as it had 23–33% dropouts compared to 12.5% for placebo, not dose-dependent. The most frequent adverse effects were somnolence, headaches, decreased appetite, fatigue, nausea, and nearly 20% incidence of psychiatric adverse effects, including irritability, which occurred in >5%. The adverse effects mostly occurred within the first month of treatment and resolved in those who continued treatment.

In a recent study involving healthy adults ages 18–45 years, supratherapeutic doses of Viloxazine (1800 mg/day) had no clinically significant effect on cardiac repolarization, Qtc interval, heart rate, PR interval, and QRS duration, suggesting a large cardiovascular safety margin of Viloxazine [35].

3.3. Dasotraline

Dasotraline is a triple reuptake inhibitor with potent inhibition of Dopamine and Norepinephrine reuptake and weaker serotonin reuptake inhibition. It is a stereoisomer of an active metabolite of sertraline. Its pharmacokinetic profile is characterized by slow absorption (tmax, 10–12 h) and a long elimination half-life (t½, 47–77 h), resulting in stable plasma concentrations around the clock permitting once-daily dosing. Its pharmacodynamic profile (absence of direct stimulation of dopamine release) and PK profile (delayed tmax and long elimination half-life) suggest that dasotraline will be associated with a reduced risk of abuse [36].

A double-blind trial of children 6–12 years with ADHD (n = 342) randomized to dasotraline versus placebo showed significantly more improvement in ADHD symptoms than placebo with dasotraline 4 mg/day (d = 0.48 by week 6) but not 2 mg/day. Dropout rates were higher in both active treatment arms (20–24%). Discontinuation due to adverse effects was higher with dasotraline 4 mg/d (12.2%) compared to 2 mg/d (6.3.%) and placebo (1.7%). The most frequent AEs associated with dasotraline were insomnia, decreased appetite, decreased weight, irritability, and nonserious psychotic symptoms [37,38].

A second double-blind study evaluated children 6–12 years with ADHD (n = 112) using fixed doses of dasotraline, 4 mg or 6 mg, or placebo in a laboratory classroom setting. The 6 mg/day arm was discontinued due to a high rate of nonserious, neuropsychiatric adverse events such as insomnia, hallucinations, affective lability, and weight loss [39].

Dasotraline was developed by Sunovion Pharmaceuticals Inc. as a promising novel therapeutic agent for ADHD treatment. However, due to a lack of clinical data to secure approval, the company withdrew the new drug applications (NDAs) for Dasotraline in May 2020 [40].

3.4. Centanafadine

This is a triple reuptake inhibitor with preferential potency for NE and DA and a mild effect on 5-HT. Phase 2 studies indicated therapeutic effectiveness. The sustained release form of centanafadine, developed by Otsuka Pharmaceuticals, is in phase 3 trials for adult ADHD. There are two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo in adults (18–55 years) both of which demonstrated the efficacy of Centanafadine in relieving ADHD symptoms in as little as 1 week [41,42].

Centanafadine seems to be safe and well tolerated, with a limited abuse potential across the clinical trial program. The overall rate of treatment-emergent adverse events (TEAEs) was low, but there was a small increase in treatment-emergent adverse effect (TEAE) occurrence with increasing doses.

3.5. PDC-1421

PDC-1421 Capsule is a botanical investigational new drug containing the extract of Radix Polygalae (Polygala tenuifolia Willd.) as the active ingredient. PDC-1421 is an antidepressant that functions as a norepinephrine reuptake inhibitor. The phase 2 study of PDC-1421 for treatment of ADHD showed therapeutic potential and found it safe in six adult patients. This is being tested to determine effective dose and treatment duration in a larger cohort of ADHD patients [43].

3.6. Reboxetine

Reboxetine is a specific NRI with potential uses in ADHD. It is available in Europe as an antidepressant but was never approved for use in the United States. In an open-label study of children 6–16 years with ADHD and comorbid anxiety disorders, Reboxetine started at 1 mg/day and was titrated daily to an average dose of 3.8 mg/day. It showed a reduction in the severity of ADHD symptoms as early as 2 weeks, and a reduction of anxiety scores from baseline to the end point at 4 weeks. Side effects included headache, low appetite, somnolence, irritability, butterfly sensation, and bruxism. The most common complications were headache and anorexia [44].

In a prospective, open-label study of children and adolescents aged 8–18 years with ADHD resistant to methylphenidate, treated with fixed doses of reboxetine 4 mg orally once daily, 70% showed an improvement (defined as a reduction of 25% of DSM-IV ADHD scale (DAS) scores) by 2 weeks of treatment. However, by 6–8 weeks, there was a significant mean increase in DAS total for all patients [45]. The most common adverse events included gastrointestinal events (abdominal pain, constipation, nausea, and decreased appetite). Evidence is inconclusive regarding Reboxetine for treatment of ADHD.

3.7. Edivoxetine

Edivoxetine is a selective norepinephrine reuptake inhibitor. A fixed-dose 8-week double-blind trial randomized children aged 6–17 years (n = 340) by 2 strata (prior stimulant use or not): the first stratum (prior stimulant use) to Edivoxetine 0.1 mg, 0.2 mg, and 0.3 mg or Placebo in 1:1:1:1 ratio, and the second stratum (stimulant naïve subjects) to placebo, edivoxetine 0.1 mg, 0.2 mg, 0.3 mg, or osmotic-release oral system methylphenidate (OROS MPH) (18–54 mg/day based on body weight) in a 1:1:1:1:1 ratio [46].

The edivoxetine 0.2 mg/kg/day and 0.3 mg/kg/day arms had significantly greater improvement than placebo in mean ADHD-RS total score with medium effect sizes d = 0.51 and d = 0.54, respectively. In addition, there was a significant improvement in the Conners CBRS oppositional defiant disorder and generalized anxiety symptom scores for the edivoxetine 0.3 mg/kg/day arm compared with the placebo.

Treatment-emergent adverse effects with edivoxetine included nausea, decreased appetite, sedation, somnolence, irritability, and elevation in systolic and diastolic blood pressure and heart rate compared to placebo.

The NRI edivoxetine showed good efficacy, but the safety profile was similar to that of atomoxetine (with nausea, vomiting, and somnolence) though it is better than MPH on sleep and appetite effects.

3.8. Mazindol

Mazindol is a dopamine and norepinephrine reuptake inhibitor that was originally approved for the treatment of obesity. It also acts as an agonist for 5-HT1A and 5-HT7 receptors and a partial agonist at orexin-2 receptors. A pilot open-labeled study of Mazindol immediate release 1 mg/day for 7 days and follow-up over 3 weeks in children with ADHD aged 9–12 years (N = 21) found >90% improvement of ADHD RS-IV total score from baseline (−24.1, 95% confidence interval (CI) −28.9 to −18.29, p < 0.0001). Adverse effects reported included decreased appetite, drowsiness, intestinal distension, and upper abdominal pain. No sleep problems were reported, and blood pressure, heart rate, and ECG parameters were unchanged. Free fat mass (FFM) and age are found to be significant covariates for Mazindol’s pharmacokinetic variability in children [47].

A controlled-release formulation of Mazindol is developed which has a half-life of 10 hours. In an RCT in adults, Mazindol CR 1–3 mg showed significant improvement in ADHD-RS scores by day 42 compared to placebo and had a large effect size (ES d = 1.09) comparable to the stimulants. 42.9% of subjects on Mazindol-CR had a 50% reduction in the target scores compared to 11.9% on placebo. Mazindol CR 3 mg/day caused more elevation in HR compared to lower doses.

3.9. Bupropion

This is an amino ketone primarily used for treatment of depression and smoking cessation. Its primary mechanism of action is the inhibition of norepinephrine and dopamine transport Paul [48]. Its active metabolite, hydroxy bupropion, seems to play a key role in the antidepressant effects of bupropion, possibly through the enhancement of noradrenergic functional activity.

Studies comparing the effect of bupropion with placebo in ADHD have shown promising results in both children and adults. A meta-analysis of five placebo-controlled studies showed superior efficacy and similar tolerability of Bupropion compared to placebo in the treatment of adults with ADHD Maneeton et al. [49].

In a 6-week, randomized, double-blind, parallel-group clinical trial of children aged 6–17 years (n = 44), randomized to Bupropion 100–150 mg/day depending on weight, or MPH 20–30 mg/day for 6 weeks, no significant differences were noted between Bupropion and MPH. Both bupropion and methylphenidate improved the ADHD symptoms [50,51].

In a placebo-controlled study of 109 children with ADHD, bupropion at a mean dose of 3 to 6 mg/(kg/day) showed significant benefit over placebo. Teacher rating scales showed a significant decrease in hyperactivity and aggression in this group of children with conduct and attention problems and observed treatment effects as early as day 3 of Bupropion treatment [52].

Bupropion is shown to be beneficial in children with comorbid ADHD and substance use or mood disorders [53–55]. However, several adverse effects such as agitation, palpitations, and paresthesias were more frequently seen with Bupropion than the placebo. Some studies report rare serious adverse events such as ‘serum sickness-like’ reactions Hack [56] and seizures Ross and Williams [57]. With the immediate-release formulation, the rate of seizure is 0.4% at doses of 300 to 450 mg/day.

Adult studies: A 7-week double-blind placebo-controlled study failed to show the superiority of bupropion over placebo [58]. A 6-week double-blind placebo-controlled trial showed the superiority of bupropion (400 mg/day) in improving ADHD symptoms [59]. These results were also confirmed in a larger randomized placebo-controlled trial with a high dose of bupropion (450 mg/day). Bupropion is at least as effective as traditional treatments, especially at higher doses (400–450 mg/day) [60]. However, it should be used cautiously in those with medical comorbidities, e.g. seizures, anxiety disorders, and bipolar disorders.

3.10. Venlafaxine

Venlafaxine has a dose-dependent specificity. It acts as a SSRI at low doses (75 mg/day), but at higher doses (150–225 mg/day), it acts as a serotonin−norepinephrine reuptake inhibitor (SNRI) with a weak effect on dopamine uptake.

In a 6-week double-blind RCT of Venlafaxine in 38 children (6–13-year-old) with ADHD, Venlafaxine at 50–75 mg/day was compared with MPH 20–30 mg/day [61]. Both Venlafaxine and MPH had significant improvement in ADHD compared to baseline. In a head-to-head comparison, no significant differences were noted in parent and teacher ratings of ADHD symptoms and in the percentage of responders, which was 63% with Venlafaxine compared to 68.42% with MPH. Venlafaxine showed a tolerable profile compared to MPH, especially with regard to headaches and insomnia [62,63].

Venlafaxine was also tested in adults in a 6-week randomized double-blind trial with 75 mg three times a day compared to placebo, but the results failed to show the superiority of venlafaxine over placebo. The common side effects reported by the venlafaxine group included dry mouth, decreased appetite, insomnia, nausea, vertigo, constipation, anxiety, stomachache, irritability, and sexual dysfunction [64].

3.11. Duloxetine

The SNRI antidepressant Duloxetine has two small studies evaluating its effects on ADHD.

In a 6-week open-label study of 17 adolescents aged 11–18 years with ADHD, starting at 30 mg/day in week 1 and 60 mg/day from week 2 to the end of the study, Duloxetine showed improvement of ADHD symptoms starting at week 4, significantly greater than baseline at week 6 [65]. Anxiety symptoms and depressive symptoms measured by the RCMAS and CDI, respectively, did not change significantly. Four (24%) of participants dropped out due to side effects. Frequent side effects at week 2 assessment were decreased appetite (46%); dry mouth (30%); insomnia, headache, nausea, somnolence, anxiety, and nervousness.

In a 6-week double-blind trial in adults with ADHD (n = 30), duloxetine 60 mg daily showed better scores on CGI-Severity at week 6 than placebo (3.00 vs. 4.07, p < .001), greater improvement on CGI-Improvement (2.89 vs. 4.00 at Week 6, p < .001), and greater decreases on five of eight subscales of the CAARS. No improvements were noted in depression or anxiety scores. Nearly 40% of patients dropped out of the Duloxetine arm due to adverse effects [66].

3.12. Tricyclic antidepressants

The tricyclic antidepressants (TCAs) primarily act by blockade of the serotonin and norepinephrine transporters. They increase the inhibitory effects of frontal cortical activity on subcortical structures through dopaminergic or noradrenergic pathways or both. A Cochrane meta-analysis of TCAs that included 6 randomized clinical trials (5 on desipramine and 1 on nortriptyline) for children and adolescents including 216 participants showed that TCAs led to greater improvement of core ADHD symptoms than placebo (OR 18.50, 95% CI 6.29 to 54.39, 3 trials, 125 participants, low-quality evidence) [67]. One of these studies involved desipramine in children with ADHD and comorbid tic disorder or Tourette disorder. Most of these studies were short duration, 2–6 weeks for desipramine and 9 weeks for nortriptyline. Using active comparators, desipramine was found to be superior to clonidine in one study. In another study, MPH was superior to both desipramine and clomipramine.

Similar to children, there are positive studies on the effectiveness of desipramine in treatment of ADHD in adults, notable one being a 6-week placebo-controlled study of desipramine 200 mg/day in adults with ADHD (N = 41) which found that 68% of desipramine-treated adults were considered very much improved, and treatment effects noted as early as week 2 sustained into week 6. The study failed to show an association between dose and clinical response [68–70].

The available evidence seems to support the efficacy of the TCAs in reducing ADHD symptoms. However, tricyclics are usually considered a third- or fourth-line option in the treatment of ADHD because of the small number of studies, small sample sizes, and the overall low quality of evidence, as well as their adverse effect profiles. The findings should be interpreted with caution and not extrapolated to the entire TCA group.

The common side effects of TCAs include appetite suppression, headaches, dry mouth, constipation, and mild increases in mean diastolic blood pressure and heart rate. Most importantly the use of TCAs in children is limited by their cardiotoxicity and potential for sudden death. If TCAs are considered in ADHD, guidelines recommend use by a specialist with experience in their use, using EKG monitoring at baseline and during chronic therapy, and after all other treatments have failed.

3.13. Solriamfetol

Solriamfetol is a dopamine and norepinephrine reuptake inhibitor, which is FDA-approved for treatment of excessive daytime sleepiness in patients with narcolepsy and obstructive sleep apnea [71]. A 6-week double-blind randomized controlled trial of dose optimization to solriamfetol 75–150 mg in adults with ADHD found greater improvement than placebo with solriamfetol based on both clinician and participant measures of ADHD with improvements noted from week 3 through the end of the study (week 6 effect size, d = 1.09) [72]. Changes in heart rate and systolic and diastolic blood pressures were not significantly different between the treatment and placebo groups, and the following adverse effects were noted as more common in the solriamfetol group: decreased appetite, headaches, insomnia, increased energy, gastrointestinal (nausea, vomiting, diarrhea), and cardiac and neurologic side effects.

3.14. Modafinil

Modafinil is a dopamine, norepinephrine reuptake inhibitor and increases histamine levels to improve attention. Common side effects include anxiety, headache, and nausea.

In a crossover study, 21 patients with adult ADHD were randomized to modafinil (mean dose 206.8 mg/day), dextroamphetamine (21.8 mg/day), or placebo for 2 weeks. Modafinil and dextroamphetamine both improved ADHD symptoms over placebo with no difference between active treatment groups. However, a larger study failed to demonstrate the superiority of modafinil over placebo using higher doses of modafinil (510 mg/day) [73,74].

4. Limitations

While the initial studies on the newer adrenergic reuptake inhibitors have promising results in children and adolescents, these findings need to be replicated in larger samples evaluating their long-term efficacy and safety. They need studies comparing their effectiveness and safety with existing first-line medications in both stimulant classes. Their safety and utility in treating ADHD in special populations such as those with intellectual disabilities, autism spectrum disorders, and with comorbidities such as substance use disorders, anxiety, and depression need to be investigated. Where they are used with comorbidities, we need to know their role in changing the course of comorbid conditions.

5. Conclusion

Adrenergic reuptake inhibitors are gaining recognition as ADHD treatment options. The wide variety of stimulant medications has limitations due to short duration of effect, adverse effects on growth, appetite, and sleep, abuse/dependence liability, and possible exacerbation of comorbid conditions such as tics and anxiety. The recent rise in stimulant prescriptions and supply shortage issues have also sparked interest in non-stimulant alternatives for ADHD.

6. Expert opinion

Norepinephrine plays an important physiological role in the regulation of mood, sleep, behavior, general alertness, and arousal and exerts control over endocrine and autonomic systems. Norepinephrine transporter (NET) located on the plasma membrane of norepinephrinergic neurons is critical in the inactivation of norepinephrine signals and dopaminergic signals in the prefrontal cortex. To date, there are two norepinephrine reuptake inhibitors (atomoxetine (Strattera©) and viloxazine (Qelbree©)) that are approved in the treatment of ADHD, and there are several other agents in different stages of development.

Looking at ADHD as a life-long neurodevelopmental disorder with a high rate of complex comorbidities, there is always a search for novel treatments in both children and adults. We need innovative drugs that compare to stimulants in their effectiveness for ADHD, with minimal to no effects on growth, sleep, and appetite. The adrenergic reuptake inhibitors fit the diverse needs of children, adolescents, and adults with 1) poor tolerability to stimulants due to growth suppression, insomnia, rebound irritability, comorbid depression, anxiety and/or tic disorders, and substance abuse or diversion concerns, 2) cardiac risks, and/or 3) need for extended duration of action.

A large network meta-analysis of double-blind randomized controlled trials in children, adolescents, and adults, comparing stimulants, atomoxetine, bupropion, and modafinil to placebo, found atomoxetine and bupropion to be superior to placebo in both children and adolescents (SMD −0.56, 95% CI −0.66 to −0.45 for ATX, and SMD −0.96, 95% CI −1.69 to −0.22 for Bupropion) and adults (SMD −0.45, 95% CI −0.58 to −0.32 for ATX, and SMD 0.46, 95% CI −0.85 to −0.07 for Bupropion) [75]. The authors recommend caution in interpreting these data due to large confidence intervals, especially for Bupropion. Based on the differential effects of atomoxetine on the sequence of treatment with a greater effect size of atomoxetine in stimulant naïve youth than in those previously on stimulants, we might consider atomoxetine as a first-line agent in carefully selected patients. However, the risks of liver injury and suicide with atomoxetine need to be weighed along with its benefits in individual cases. In addition to the ADHD comorbidities (depression, anxiety, tics, and Tourette’s disorder) reported in the literature, atomoxetine is considered off-label to treat ADHD comorbid with bipolar disorder as the risks of mood destabilization are higher with the stimulants. We need long-term studies on the effectiveness of non-stimulant medication in treatment of ADHD with comorbid bipolar disorder.

As we navigate the complex comorbidities of ADHD across the lifespan, the clinical challenges lie in managing ADHD comorbid with bipolar disorders, substance use, pregnancy, and medical conditions. The Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline task force recommends Bupropion as a reasonable first-line treatment for bipolar disorder with comorbid attention-deficit/hyperactivity disorder [76] and for major depressive disorder with ADHD, with desipramine, nortriptyline, and venlafaxine as second-line options. Bupropion is also a preferred drug to manage ADHD in pregnancy based on reassuring data regarding its use in pregnancy [77]. Compared to the studies in children which showed moderate effectiveness, adult studies that used higher doses (400–450 mg/day) of Bupropion showed that it was as effective and tolerated as the stimulants in treatment of ADHD.

Among the SNRI antidepressants, a small short-term study suggested that venlafaxine showed comparable efficacy and tolerability to methylphenidate in treatment of ADHD but this needs replication in larger studies. Duloxetine, despite showing effectiveness, had a high rate of dropouts due to adverse effects. Though Dasotraline showed initial promise based on its efficacy, low affinity for dopamine release, and low abuse potential, it likely has a narrow therapeutic index based on safety risks at higher doses.

Despite their common effect on adrenergic reuptake inhibition, the agents have unique differences in their affinities and modulating effects on different receptors. For example, the moderate inhibitory effects of Viloxazine on the NET and its moderate activity at noradrenergic and dopaminergic systems support its low rate of cardiac effects and effects on HR and BP. Also, Viloxazine’s low affinity at the dopamine transporter (DAT) and lack of effect on dopamine receptors D1 and D2 should result in low abuse potential.

Several other Norepinephrine Dopamine reuptake inhibitors (NDRIs) such as Modafinil, Solriamfetol, and Mazindol have had phase 2 and phase 3 studies in adults with ADHD with initial promising results. However, these need to be replicated in larger samples, and effectiveness and safety need to be studied in children and adolescents.

Finally, the available evidence on the TCAs desipramine and nortriptyline supports their use as third-line agents in adults with ADHD, but the use in children and adolescents is limited by their low quality of evidence and risk of cardiovascular problems and sudden death.

If progress in developing new agents continues, in 5 years, there should be an enhanced armory of choices to personalize treatment. The challenge then will be finding biomarkers to distinguish those most likely to respond to each agent. It will also be necessary to educate prescribers and patients on how long is needed to judge results in individual patient trials, e.g. when atomoxetine first became available, some prescribers decided it was ineffective because they were used to the quick results from stimulants and did not know to give it a month or two to show results.

Article highlights

• The adrenergic reuptake inhibitors fit the diverse needs of children and adolescents with poor tolerability to stimulants, with cardiac risks, and a need for an extended duration of action.

• Atomoxetine (Strattera^©) and Viloxazine (Qelbree^©) are two approved non-stimulant medications that act by Adrenergic Reuptake (Transporter) Inhibition.

• Despite their common effect on adrenergic reuptake inhibition, the agents have unique differences in their affinities and modulating effects on different receptors leading to clinical benefits. For example, Viloxazine has minimal effect on dopamine transporter, which explains its low abuse liability and fewer cardiovascular effects. Dasotraline at lower doses (4 mg once daily) significantly improved ADHD symptoms, while higher doses (>6 mg daily) caused nonserious psychotic symptoms, mood lability, insomnia, and weight loss.

• Some agents (Centanafadine) are undergoing phase 3 trials for ADHD, while some (reboxetine) have no conclusive evidence for treatment of ADHD in children.

• Antidepressants bupropion, venlafaxine, and duloxetine showed improvement in ADHD symptoms with small effect sizes and can be beneficial for children with ADHD with comorbid depression and substance use.

Declaration of interest

L E Arnold has received research funding from Supernus Pharmaceuticals, Roche/Genentech Pharmaceuticals, Otsuka Pharmaceuticals, Axial, Yamo, and Maplight. Myndlift, YoungLiving Essential Oils, and the National Institute of Health (U.S.A., R01 MH 100144) have consulted with Pfizer Pharmaceuticals, Yamo, and CHADD, and have been on advisory boards for Otsuka and Roche/Genentech.

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.

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Funding

This paper was not funded.