Pharmacologic Treatment of ADHD in Children

Educational Objectives

The goal of this program is to improve the pharmacologic treatment of attention-deficit/hyperactivity disorder (ADHD). After hearing and assimilating this program, the clinician will be better able to:

1. Characterize the changes of symptoms of ADHD with age.

2. Elaborate on the amphetamine and methylphenidate formulations available for treatment of ADHD.

Summary

Developmental impact of attention-deficit/hyperactivity disorder (ADHD): preschool children — presenting symptoms often include behavioral disturbances, aggression, or acting out; school age — additional concerns include academic difficulties, difficulties in peer relationships, and self-esteem issues; high school — self-esteem issues continue; additional issues include drug abuse and smoking; risk-taking behavior can lead to injuries; potential for criminal behavior and legal problems; college age and adulthood — academic difficulties, job and occupational issues, and increased risk of motor vehicle accidents and injuries

ADHD developmental trends by age: impulsivity and hyperactivity decrease with age; inattention remains steady or may worsen in adulthood and becomes more prevalent with age; rates of comorbidity increase

Medications for ADHD: nonstimulant medications may be used as monotherapy or as adjuncts; stimulant medications are the most common first-line treatment; effect size ≈1 for stimulants compared with ≈0.7 for atomoxetine and α agonists; methylphenidate and amphetamine are the core stimulants used for treatment of ADHD; comparable efficacy; ≈40% preferably respond to one of these, ≈40% respond to both, and 20% may not respond at all or have an adverse effect; subtype of ADHD is not a predictor of response to a specific agent; bupropion (Wellbutrin) and tricyclic antidepressants have lower efficacy

Mechanism of action: primary action of stimulants is to increase the synaptic availability of dopamine and norepinephrine; methylphenidate and amphetamine inhibit dopamine and norepinephrine transport or reuptake; unlike methylphenidate, amphetamine is transported into the presynaptic cell and displaces dopamine and norepinephrine from intracellular storage

Pharmacokinetics: onset of action ≈30 to 45 min; duration of action ≈3 to 4 hr for methylphenidate and ≈4 to 6 hr for amphetamine; both are racemic mixture; l-amphetamine is the therapeutically active isomer; d-amphetamine has a greater impact on dopamine and l-amphetamine on norepinephrine; d-methylphenidate is the therapeutically active isomer; variations in activity of different formulations are related to difference in delivery and mixtures of isomers

Methylphenidate oral formulation: available as oral solution and chewable tablet; both are bioequivalent to Ritalin immediate release (IR) methylphenidate formulation; both are racemic mixtures of d- and l-methylphenidate

Methylphenidate (Adhansia XR): approved for children aged ≥6 yr; mixture of d and l particles; biphasic release; 20% immediate release (IR) and 80% extended release (XR); first peak at ≈1.5 hr; second peak at ≈10 hr; effect lasts ≈12 to 14 hr; starting dose 25 mg; can be increased 10 to 15 mg/wk; disproportionate increase of certain side effects (eg, insomnia, decreased appetite) occurs at doses ≥70 mg in pediatric patients; should be consumed immediately if sprinkled on food

Methylphenidate (Aptensio XR): composed of composite multilayered beads, 30% IR and 70% XR; rapid initial release followed by a drop during lunchtime, then a second controlled release; levels gradually decrease into the evening; response comparable to other XR formulations; onset of action 1 to 1.5 hr; manufacturer reports effects last for ≈12 hr; other source suggests duration of 7 to 8 hr; starting dose 10 mg; can be increased 10 mg/wk

Methylphenidate (Contempla XR): orally disintegrating tablet (ODT); approved for children aged 6 to 17 yr; equal racemic mixture; 30% IR and 70% XR; starting dose 17.3 mg; speaker starts with 8.6 mg for younger children or children naïve to stimulants; significant clinical response lasts 8 to 12 hr; high-fat meals can decrease peak concentration and bioavailability; maximum dose 51.8 mg

Methylphenidate (QuilliChew ER): 30% IR and 70% XR; starting dose 10 mg; food delays time to peak concentration; effect lasts ≈8 hr with gradual loss between 8 and 10 hr

Methylphenidate (Quillivant XR): liquid; 30% IR and 70% XR; IR onset of action ≈45 min; gradual XR lasts ≈8 hr; loss of effect between 8 to 12 hr; recommended starting dose 20 mg for children aged ≥6 yr; consider 10 mg for young children

Methylphenidate (Jornay PM): dl-methylphenidate is the generic form; first evening dose stimulant medication; administered at bedtime; onset of action starts the following morning, ≈8 to 10 hr post-ingestion, followed by a period of XR through the day; starting dose 20 mg; can be increased 20 mg/wk; recommended time of dose 8 PM; speaker states timing can be adjusted from 6:30 to 9:30 PM; does not interfere with sleep onset; can cause early morning awakening

Methylphenidate (Daytrana): transdermal patch; onset of action ≈2 hr after application; total dose depends on the size of the patch and total time of application; recommended time for application ≤9 hr; absorption continues for ≈2 to 3 hr after removal; contact dermatitis is a frequent side effect; treated with cortisone cream; recommended to place on hip and alternate sides; avoid skin contact with the active surface after removal; ensure proper disposal

Amphetamine: newer IR formulations are Evekeo, Procentra, and Zenzedi; XR formulations are also available

Evekeo: 50% racemic mixture; approved for use in children aged ≥3 yr; recommended to give on awakening with 1 to 2 additional doses at 4 to 6 hr intervals; recommended starting dose for children aged 3 to 5 yr 2.5 mg; can increase 2.5 mg/wk; recommended starting dose for children aged ≥6 yr 5 mg; can increase 5 mg/wk

Procentra: IR dextroamphetamine oral solution; contains 5 mg of d-amphetamine in each 5 ml

Zenzedi: short-acting; must be administered 2 or 3 times daily; starting dose for children aged 3 to 5 yr 2.5 mg; can increase 2.5 mg/wk; starting dose for children aged ≥6 yr 5 mg; can increase 5 mg/wk; maximum dose 40 mg

Amphetamine (Adzenys XR): available as an ODT and oral solution; peak concentration between 5 and 6 hr; starting dose 6.3 mg; can increase in increments of 3.1 or 6.3 mg; maximum dose 18.8 mg for children aged 6 to 12 yr and 12.5 mg for ≥13 yr; ODT should not be crushed or chewed; must be taken consistently with or without food; administration with high-fat meals can decrease and delay peak plasma levels

Switching between different amphetamine products: can directly switch from Adderall XR to Adzenys ER; when switching, discontinue the first drug and start the second drug at the recommended starting dose for the child’s age

Amphetamine (Dynavel XR): liquid; initial rapid absorption; levels peak at 4 to 5 hr; duration ≤13 hr; causes less appetite suppression than other formulations; starting dose 2.5 or 5 mg in children aged ≥6 yr; increase by 2.5 to 10 mg/day every 4 to 7 days; speaker recommends increments of ≈2.5 mg in a younger child and 5 mg in an older child; maximum dose 20 mg/day

Amphetamine (Mydayis): duration ≤16 hr; gradual release and steady concentration because of 3 small release spurts; approved for children aged ≥13 yr; starting dose 12.5 mg for children aged ≥13 yr and 25 mg for adults with weekly dose adjustments

Lisdexamfetamine (Vyvanse): only prodrug stimulant; the pharmacologically inactive parent molecule is hydrolyzed in red blood cells after absorption, liberating the pharmacologically active d-amphetamine, causing delayed onset of action of ≈1.5 hr; reported duration ≈13 hr; starting dose 30 mg in children aged ≥6 yr; speaker prefers to start at 10 or 20 mg; can increase 10 to 20 mg/wk; also available as chewable tablet

ADHD mediation guide: available at www.ADHDmedicationguide.com

Endeavour: video game approved by the Food and Drug Administration for children aged 8 to 12 yr with ADHD; activates parts of the brain that control attention; Kollins et al (2020) showed that participants demonstrated improvement in attention; no serious adverse events; common adverse events included frustration, headache, dizziness, emotional reaction, and aggression

Omega-3 fatty acids: level 1 evidence indicates they can reduce symptoms by ≈20%; recommended dose 1 to 2 g/day with ≥400 mg of eicosapentaenoic acid

Saffron vs methylphenidate for ADHD (Baziar et al [2019]): participants receiving methylphenidate responded more quickly, but response rates were equal at 6 wk

Audience question about how to progress with various formulations: speaker prefers to start with generic medications; considers newer formulations if generic products do not work or if requested by the parent

Readings

Baziar S et al. Crocus sativus L. versus methylphenidate in treatment of children with attention-deficit/hyperactivity disorder: a randomized, double-blind pilot study. J Child Adolesc Psychopharmacol. 2019;29(3):205-212; Cabral MDI et al. Attention-deficit/hyperactivity disorder: diagnostic criteria, epidemiology, risk factors and evaluation in youth. Transl Pediatr. 2020;9(Suppl 1):S104-S113. doi:10.21037/tp.2019.09.08; Cherkasova M et al. Developmental course of attention deficit hyperactivity disorder and its predictors. J Can Acad Child Adolesc Psychiatry. 2013;22(1):47-54; Epstein JN, Loren REA. Changes in the definition of ADHD in DSM-5: Subtle but important. Neuropsychiatry (London). 2013;3:455–458; Felt BT et al. Diagnosis and management of ADHD in children. Am Fam Physician. 2014;90:456-464; Jornay PM -- evening-dosed methylphenidate for ADHD. Med Lett Drugs Ther. 2019;61:126-128; Kollins SH et al. A novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a randomised controlled trial. Lancet Digit Health. 2020;2(4):e168-e178; Steingard R et al. New formulations of stimulants: an update for clinicians. J Child Adolesc Psychopharmacol. 2019;29:324-339; Pfiffner LJ, Haack LM. Behavior management for school aged children with ADHD. Child Adolesc Psychiatr Clin N Am. 2014;23:731–746; Wolraich ML et al. Clinical Practice Guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019:144:e20192528; DOI: https://doi.org/10.1542/peds.2019-2528. Accessed April 2, 2021.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In her lecture, Dr. Schmidt discusses the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Schmidt was recorded at the 15th Annual Pediatric Review, held virtually on October 23, 2020, and presented by the Oregon Health and Science University School of Medicine, Portland, OR. For information about upcoming CME opportunities from the Oregon Health and Science University School of Medicine, Portland, OR, please visit www.ohsu.edu/school-of-medicine/cpd. Audio Digest thanks the speakers and the Oregon Health and Science University School of Medicine for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PD671701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.