The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium

Figures & data

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.