Pharmacotherapy of Attention-Deficit/Hyperactivity 49 Disorder across the Life Span Jefferson B. Prince, MD, Timothy E. Wilens, MD, Thomas J. Spencer, MD, and Joseph Biederman, MD KEY POINTS www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/DrugSafetyInformation • Attention-deficit/hyperactivity disorder (ADHD) is a forHeathcareProfessionals/ucm165858.htm for the most common disorder in children, adolescents, and recent recommendations by the Food and Drug Administra- adults. tionA] [FD about monitoring for children and http://www.fda .gov/drugs/drugsafety/ucm279858.htm for the most recent • While the phenotype of ADHD changes across the recommendations about monitoring for adults). Clinicians life span, ADHD persists in many children, and patients/families should select an initial treatment, either adolescents, and adults. a stimulant or a non-stimulant; decide on a target dose (either • Formulations of stimulant and non-stimulant absolute or weight-based) titration schedule; and decide how medications are Food and Drug Administration- to monitor tolerability and response to treatment (using rating approved as pharmacological treatments for ADHD in scales, anchor points, or both). Patients should be educated children, adolescents, and adults. about the importance of adherence, safely maintaining medi- • Co-morbid psychiatric and learning disorders are cations (e.g., as in college students), and additional types of common in patients with ADHD across the life span. treatment (e.g., coaching and organizational help) that may be helpful. • When treating ADHD and co-morbid disorders, clinicians must prioritize and treat the most severe condition first, and regularly re-assess the symptoms STIMULANTS of ADHD and the co-morbid disorder. For over 60 years stimulants have been used safely and effec- tively in the treatment of ADHD21 and they are among the most well-established treatments in psychiatry.22,23 The stimu- lants most commonly used include methylphenidate (MPH), a mixture of amphetamine salts (MAS) and dextroampheta- OVERVIEW mine (DEX). The recent development of various novel delivery systems has significantly advanced the pharmacotherapy of Attention-deficit/hyperactivity disorder (ADHD) is a common ADHD (see Table 49-1 for a list of these medications). psychiatric condition shown to occur in 3% to 10% of school- age children worldwide, up to 8% of adolescents and up to 4% of adults.1–5 The classic triad of impaired attention, impul- Pharmacodynamic Properties of Stimulants sivity, and excessive motor activity characterizes ADHD, Stimulants increase intra-synaptic concentrations of dopamine although many patients may manifest only inattentive symp- (DA) and norepinephrine (NE).24–27 MPH primarily binds to toms.6,7 ADHD usually persists, to a significant degree, from theA D transporter protein (DAT), blocking the re-uptake of childhood through adolescence and into adulthood.8,9 Most DA, increasing intra-synaptic DA.25,27 While amphetamines children, adolescents, and adults with ADHD suffer significant diminish pre-synaptic re-uptake of DA by binding to DAT, functional impairment(s) in multiple domains,10 as well as these compounds also travel into the DA neuron, promoting co-morbid psychiatric or learning disorders.5,11–18 release of DA from reserpine-sensitive vesicles in the pre- Studies demonstrate that ADHD is frequently co-morbid synaptic neuron.25,26 In addition, stimulants (amphetamine > with oppositional defiant disorder (ODD), conduct disorder MPH) increase levels of NE and serotonin (5-HT) in the inter- (CD), multiple anxiety disorders (panic disorder, obsessive- neuronal space.24Although group studies comparing MPH and compulsive disorder [OCD], tic disorders), mood disorders amphetamines generally demonstrate similar efficacy,19,20 their (e.g., depression, dysthymia, and bipolar disorder [BPD]), pharmacodynamic differences may explain why a particular learning disorders (e.g., auditory processing problems and patienty ma respond to, or tolerate, one stimulant preferen- dyslexia), and substance use disorders (SUDs) and often com- tially over another. It is necessary to appreciate that while the plicates the development of patients with autism spectrum efficacy of amphetamine and MPH is similar, their potency disorders (ASDs). Co-morbid psychiatric, learning, and devel- differs, such that 5 mg of amphetamine is approximately opmental disorders need to be assessed in all patients with equally potent to 10 mg of MPH. ADHD and the relationship of these symptoms with ADHD 1,19,20 delineated. Methylphenidate Before using medications, clinicians should complete a through clinical evaluation that includes a complete history As originally formulated, MPH was produced as an equal of symptoms, a differential diagnosis, a review of prior mixture of d,l-threo-MPH and d,l-erythro-MPH. The erythro assessments/treatments, a medical history, and a description isomers of MPH appear to produce side effects, and thus MPH of current physical symptoms (including questions about the isw no manufactured as an equal racemic mixture of d,l-threo- physical history, including either a personal or family history MPH.28 Behavioral effects of immediate-release MPH peak 1 of cardiovascular symptoms or problems). Before treatment to 2 hours after administration, and tend to dissipate within with medications, it is usually important to measure baseline 3 to 5 hours. After oral administration immediate-release levels of height, weight, blood pressure, and pulse and to MPH is readily absorbed, reaching peak plasma concentra- monitor them over the course of treatment (see http:// tion in 1.5 to 2.5 hours, and has an elimination half-life of 538 Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Pharmacotherapy of Attention-Deficit/Hyperactivity Disorder across the Life Span 539 TABLE 49-1 Available FDA-approved Treatments for Attention-Deficit/Hyperactivity Disorder 49 Usual Absolute and (Weight- FDA-approved Generic Name Duration of based) Dosing Maximum Dose (Brand Name) Formulation and Mechanism Activity How Supplied Range for ADHD MPH (Ritalin)* Tablet of 50 : 50 racemic mixture 3–4 hours 5, 10, and 20 mg (0.3–2 mg/kg/day) 60 mg/day d,l-threo-MPH tablets Dex-MPH Tablet of d-threo-MPH 3–5 hours 2.5, 5, and 10 mg (0.15–1 mg/kg/day) 20 mg/day (Focalin)* tablets (2.5 mg Focalin equivalent to 5 mg Ritalin) MPH (Methylin)* Tablet of 50 : 50 racemic mixture 3–4 hours 5, 10, and 20 mg (0.3–2 mg/kg/day) 60 mg/day d,l-threo-MPH tablets MPH-SR Wax-based matrix tablet of 50 : 50 3–8 hours 20 mg tablets (0.3–2 mg/kg/day) 60 mg/day (Ritalin-SR)* racemic mixture d,l-threo-MPH Variable (amount absorbed appears to vary) MPH (Metadate Wax-based matrix tablet of 50 : 50 3–8 hours 10 and 20 mg (0.3–2 mg/kg/day) 60 mg/day ER)* racemic mixture d,l-threo-MPH Variable tablets (amount absorbed appears to vary) MPH (Methylin Hydroxypropyl methylcellulose 8 hours 10 and 20 mg (0.3–2 mg/kg/day) 60 mg/day ER)* base tablet of 50 : 50 racemic tablets mixture d,l-threo-MPH; no 2.5, 5, and 10 mg preservatives chewable tablets 5 mg/5 ml and 10 mg/5 ml oral solution MPH (Ritalin LA)* Two types of beads give bimodal 8 hours 20, 30, and 40 mg (0.3–2 mg/kg/day) 60 mg/day delivery (50% immediate-release capsules; can be and 50% delayed-release) of sprinkled 50 : 50 racemic mixture d,l-threo-MPH D-MPH (Focalin Two types of beads give bimodal 12 hours 5, 10, 15, 20, 25, 0.15–1 mg/kg/day 30 mg/day in XR) delivery (50% immediate-release 30, 35, and 40 mg youth; 40 mg/ and 50% delayed-release) of capsules day in adults d-threo-MPH MPH (Metadate Two types of beads give bimodal 8 hours 20 mg capsule; can (0.3–2 mg/kg/day) 60 mg/day CD)* delivery (30% immediate-release be sprinkled and 70% delayed-release) of 50 : 50 racemic mixture d,l-threo-MPH MPH (Daytrana)* MPH transdermal system 12 hours (patch 10, 15, 20, and 0.3–2 mg/kg/day 30 mg/day worn for 9 hours) 30 mg patches MPH (Concerta)* Osmotic pressure system delivers 12 hours 18, 27, 36, and (0.3–2 mg/kg/day) 72 mg/day 50 : 50 racemic mixture 54 mg caplets d,l-threo-MPH MPH (Quillivant Extended-release liquid 12 hours 25 mg/5 ml (0.3–2 mg/kg/day) 60 mg/day XR) AMPH† (Dexedrine d-AMPH tablet 4–5 hours 5 mg tablets (0.15–1 mg/kg/day) 40 mg/day Tablets) AMPH† d-AMPH tablet 4–5 hours 5 and 10 mg tablets (0.15–1 mg/kg/day) 40 mg/day (Dextrostat) AMPH† (Dexedrine Two types of beads in a 50 : 50 8 hours 5, 10, and 15 mg (0.15–1 mg/kg/day) 40 mg/day Spansules) mixture short and delayed- capsules absorption of d-AMPH Mixed salts of Tablet of d,l-AMPH isomers (75% 4–6 hours 5, 7.5, 10, 12.5, 15, (0.15–1 mg/kg/day) 40 mg/day AMPH† d-AMPH and 25% l-AMPH) 20, and 30 mg (Adderall) tablets Mixed salts of Two types of beads give bimodal At least 8 hours 5, 10, 15, 20, 25, (0.15–1 mg/kg/day) 30 mg/day in AMPH*‡ delivery (50% immediate-release (but appears to and 30 mg children (Adderall-XR) and 50% delayed-release) of last much longer capsules; can be Recommended 75 : 25 racemic mixture in certain sprinkled dose is d,l-AMPH patients) 20 mg/day in adults Continued on following page Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018.