Attention-Deficit/Hyperactivity Disorder: Pharmacologic Treatment Options

Attention-deficit/hyperactivity disorder (ADHD) is a disorder characterized by difficulties with inattentiveness, hyperactivity, or impulsivity. ADHD symptoms may be identified as early as 3 years of age and can continue throughout development and into adulthood.¹ The mean overall prevalence of ADHD worldwide in children and adolescents is 2.2%, with a higher mean overall prevalence of 8.1% in USA children.²

What is Attention-Deficit/Hyperactivity Disorder (ADHD)?

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) outlines the specific symptoms and diagnostic criteria for ADHD. ADHD “severity” is defined as mild, moderate, or severe, with each category indicating the presence of symptoms and the impact on impairment. In order to be diagnosed with ADHD:^3:4

• Symptoms must be present for ≥6 months in ≥2 settings, which include, but are not limited to, school, home, and work.
• Symptoms must hinder one’s academic performance, social skills, and/or occupational functioning.
• Symptoms must be present prior to the age of 12 and must not occur due to other psychiatric disorders (e.g., anxiety disorder, personality disorder).
• In those <17 years of age, 6 or more symptoms must be present for each ADHD subtype. For those ≥17 years old, 5 or more symptoms must be present for diagnosis.

Based on symptoms and presentation, individuals can be classified as having ADHD inattentive type, hyperactive/impulsive type, or combined type. For combined type, criterion for both inattentive and hyperactive/impulsive type must be met over the past 6 months.³

While the core diagnostic symptoms of ADHD are consistent across age groups, clinical presentation may differ between children and adults. A meta-analysis of 97 studies demonstrated that the inattentive-predominant subset of ADHD was the most common subset in all age groups except ages 3-5, where the hyperactive/impulsive-predominant subset was most common.²

How is ADHD Treated in Pediatrics?

The American Academy of Pediatrics’ Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of ADHD in Children and Adolescents splits treatment approaches into the following three age-related categories:⁵

• Preschool-aged children (4 years old to 6th birthday)
• School-aged children (6 years old to the 12th birthday)
• Adolescents (12 years old to the 18th birthday)

For preschool-aged children, parent training in behavior management (PTBM) and/or behavioral classroom interventions are the first-line treatment options. If behavioral interventions are not effective then methylphenidate may be considered.⁵

For school-aged children, FDA-approved medications for ADHD should be prescribed simultaneously with PTBM and/or behavioral classroom interventions. The guidelines note “particularly strong” evidence for stimulant medications, and “sufficient, but not as strong” evidence for medications such as atomoxetine, extended-release guanfacine, and extended-release clonidine.⁵

For adolescents, FDA-approved medications for ADHD should also be prescribed first-line with evidence-based training and/or behavioral interventions.⁵

How is ADHD Treated in Adults?

For adults, treatment with FDA-approved medications is recommended as first-line over non-pharmacological interventions. Both the British Association for Psychopharmacology (BAP) and the National Institute for Health and Care Excellence (NICE) recommend the use of stimulants as the first-line medications in the adult population.^6,7

Non-stimulant medication options may be considered when stimulants are intolerable or when symptoms have not improved with adequate trials of stimulant medications. Furthermore, non-pharmacological interventions should be considered when patients have difficulty adhering to medications, medication is found to be ineffective or intolerable, or if the patient chooses not to use medications.^6,7

Pharmacotherapy of ADHD: Dopaminergic Stimulants

It is hypothesized that the core symptoms of ADHD result from abnormalities in various prefrontal cortex circuits and/or dysregulation of dopamine and norepinephrine. Central nervous system stimulants are the mainstay pharmacologic treatment option for ADHD in both children and adults. Dopaminergic stimulants like methylphenidate and amphetamine enhance the actions of dopamine and norepinephrine in several brain regions, including those important for focus and hyperactivity. They exert their effects by blocking the transporters that are responsible for the reuptake of dopamine and norepinephrine or by increasing the release of these messengers, thus leading to an increase in synaptic availability of both catecholamines.⁸

Methylphenidate blocks the dopamine transporters (DAT) and norepinephrine transporters (NET) allosterically and has no known action on the vesicular monoamine transporters (VMAT). Amphetamine is a competitive inhibitor of DAT, NET, and VMAT. These differences in the actions of methylphenidate and amphetamine are very small when used at the recommended dosage range for ADHD.⁸

It is important to recognize that all stimulant products are schedule II-controlled substances (C-II) due to the potential for abuse and dependence. Methylphenidate and amphetamine-based products have similar adverse effect profiles, including but not limited to:^9:12

• Abdominal pain
• Decreased appetite
• Dry mouth
• Headache
• Hypertension
• Insomnia
• Irritability
• Tachycardia
• Weight loss

Pharmacotherapy of ADHD: Non-Stimulant Medications

Non-stimulant options are available for treating ADHD. Atomoxetine (Strattera®) and viloxazine (Qelbree®) both work by selectively inhibiting the reuptake of norepinephrine, with very little to no activity at other neuronal reuptake transporters. Atomoxetine can be used in children ≥ 6 years, adolescents, and adults. Viloxazine was recently FDA-approved for use in patients ages 6-17 years old and is currently under review for use in adults with ADHD.^13,14

Both atomoxetine and viloxazine have boxed warnings for suicidal thoughts and behaviors in pediatric patients. Therefore monitoring should occur frequently in this population. The adverse effects of both medications include somnolence, decreased appetite, fatigue, nausea and vomiting, insomnia, and irritability.^13,14

Guanfacine (Intuniv®) and clonidine (Kapvay®) are also non-stimulant medications that are FDA-approved for treating ADHD. These medications are centrally acting alpha 2-adrenergic agonists. Both have similar adverse effects such as somnolence, headache, fatigue, abdominal pain, and nausea. These medications are also capable of inducing hypotension, bradycardia, and syncope, so caution should be used in patients at risk for these conditions.^15,16

Cortese and colleagues published a meta-analysis that assessed the efficacy and tolerability of medications used for the management of ADHD in children, adolescents, and adults. The findings from the meta-analysis support the use of methylphenidate in children/adolescents and amphetamines in adults as first-line pharmacological treatment options. In children/adolescents, although amphetamines were superior in efficacy, methylphenidate presented better acceptability than placebo and was non-inferior to placebo regarding tolerability. Atomoxetine was inferior to methylphenidate and amphetamine in both adults and pediatrics and was equal to placebo regarding tolerability.¹⁷

Pharmacogenetics and ADHD

A one-size-fits-all plan does not work for many psychiatric disorders, including ADHD. It has been estimated that roughly 30% of patients with ADHD do not achieve optimal symptom reduction or do not tolerate stimulants.¹⁸ One factor that could play a role in personalizing ADHD medications is pharmacogenetics. The next article, “Management of Attention Deficit Hyperactivity Disorder (ADHD) with a Focus on Pharmacogenetics | Part One: Pharmacodynamic Genes,” will explore how variations in the pharmacodynamic genes are associated with pharmacologic treatments for ADHD.

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References

1. National Institute of Mental Health (2021). Attention-Deficit/Hyperactivity Disorder.
2. Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics 2012; 9: 490-499.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American Psychiatric Publishing: Arlington, VA, USA, 2013.
4. Fayyad et al; WHO World Mental Health Survey Collaborators. The descriptive epidemiology of DSM-IV Adult ADHD in the World Health Organization World Mental Health Surveys. Atten Defic Hyperact Disord. 2017 Mar;9(1):47-65.
5. Wolraich et al. SUBCOMMITTEE ON CHILDREN AND ADOLESCENTS WITH ATTENTION-DEFICIT/HYPERACTIVE DISORDER. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019 Oct;144(4):e20192528.
6. Bolea-Alamañac et al. British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014 Mar;28(3):179-203.
7. National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: diagnosis and management. NICE. Epub 2018 Mar.
8. Stahl, S. M. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press. 2013.
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10. Concerta [package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ. Dec 2013.
11. Daytrana [package insert]. Noven Pharmaceuticals, Inc. Miami, FL. Mar 2007.
12. Adderall [package insert]. DSM Pharmaceuticals, Inc. Greenville, NC. Mar 2007.
13. Strattera [package insert]. Eli Lilly and Company. Indianapolis, IN. 2003. 
14. Viloxazine [package insert]. Supernus Pharmaceuticals. Winchester, KY. 2021. 
15. Intuniv [package insert]. Shire Pharmaceuticals. Wayne, PA. Aug 2009. 
16. Kapvay [package insert]. Amdipharm Limited. Dublin, Ireland. Feb 2020.
17. Cortese et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018 Sep;5(9):727-738.
18. Treatment of adults with attention-deficit/hyperactivity disorder. (2008, April). PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518387/