ADHD-Focus-On-Medications-Timothy-E.-Wilens.Pdf
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ADHD: Focus on Medications Timothy E. Wilens, M.D. Chief, Child & Adolescent Psychiatry, Director, Center for Addiction Medicine, Massachusetts General Hospital Professor of Psychiatry, Harvard Medical School 1 Disclosures* Source Advisory Consultant Honoraria for this Research Royalties Board meeting Support AACAP Alcobra x Bay Cove Human Services x Cambridge Press x Elsevier Press Neurovance/Otsuka x x Guilford Press x Ironshore x x x KemPharma x National Institute of Drug Abuse x x Phoenix/Gavin (Clinical Services) x National Institute on Drug Abuse x US Minor/Major League Baseball x US National Football League (ERM) * Past 2 years. Some of the products discussed are not FDA approved for ADHD or other psychopathology; and may not be FDA approved in the manner discussed (e.g. dosing, combination therapy) 2 Page 1 Learning Objectives • 1) Understand strategies for addressing basic ADHD • 2) Understand strategies for addressing refractory ADHD including mono- and combined therapies • 3) Understand the management of common side effects associated with medications used in the treatment of ADHD 3 ADHD Overview • ADHD prevalence among 8- to 15-year-olds: 8.7% • ADHD prevalence among 18- to 44-year-olds: 4.4% • Associated with chronic course » Circa 75% persistence from childhood into adolescence » Circa 50% persistence from childhood into adulthood • Associated with high degrees of psychiatric comorbidity • Associated with impairment in multiple domains ADHD = attention-deficit/hyperactivity disorder. (Froehlich TE, et al. Arch Pediatr Adolesc Med. 2007;161(9):857-864. Kessler RC, et al. Am J Psychiatry. 2006;163(4):716-723. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109; Faraone et al, Nature Neuroscience, 2015) 4 Page 2 Spencer TJ, et al. J Clin Psychiatry. 2013;74(9):902-917. 5 fMRI in Adults With ADHD MGH NMR Center and Harvard-MIT CITP fMRI, functional magnetic resonance imaging. Bush G et al. Biol Psychiatry. 1999;45(12):1542-1552; Bush G et al. Arch Gen Psychiatry. 2008;65(1):102-114. 6 Page 3 Dose of OROS® MPH (Concerta) Increases Over Two Years to Maintain Effectiveness (Wilens et al. JAACAP: 2005) Mean daily dose/body weight weight (mg/kg)Mean daily dose/body Mean Daily Dose (MG) Mean daily dose/body weight (mg/kg) Mean dose dose Mean (mg) MTA: 26% increase in MPH dose by 14 months Month 7 Protective Effect of Medication Treatment on Later Comorbidity N=140 boys with ADHD at entry; 10-year follow-up data n=82 participants receiving stimulants [mean duration of 6 yrs], n=30 not on stimulants Biederman J et al. Pediatrics. 2009;124(1):71-78. 8 Page 4 Medication for ADHD Reduces Criminality Swedish national registers (N=25,656 with ADHD, about 50% on medications). 40% of convictions related to drug offenses (Tx OR=0.6). No difference in type of ADHD medication (stimulants, nonstimulants) or level of crime. Lichtenstein P et al. N Engl J Med. 2012;367(21):2006-2014. 9 10 Early ADHD Treatment Reduces Marijuana Use 10 Cohorts of senior years 2005 to 2014 (N=40,358; ca. 10% with ADHD) Population risk Stimulant use started prior to 9 years of age* Stimulant use started between 10-14 years* p<0.001 vs controls Stimulant use started after 15 years of age** p<0.001 vs controls 20% 30% 40% 50% 60% * > 6 years of treatment Past Year Use ** > 3 years of treatment •McCabe, West, Dickinson, Wilens.. J Am Acad Child Adoles Psych 2016: 55:479-486 10 Page 5 ADHD Medication and SUD; US Claims Data Conclusions • Largest US database examining ADHD medication treatment and later SUD (almost 3 million w ADHD) • Medicated ADHD was associated with lower SUD risk when compared to unmedicated ADHD groups – 24% and 6% reductions in males/females • Medication periods were generally associated with reduced risk of SUD events (30-35% reduction) • Most findings maintained long-term • SUD reductions associated with ADHD medication similar to Scandinavian and some US Studies • No evidence of worsened SUD (Patrick et al. Am J Psych 2017: 877-885) 11 Pharmacotherapy for ADHD • Stimulants (FDA approved) – Methylphenidate – Amphetamine compounds • Atomoxetine (FDA-approved) • Alpha agonists (FDA-approved) – Guanfacine extended-release – Clonidine extended-release • Combination therapy (FDA approved) – Alpha agonists + stimulants • Antidepressants* – Bupropion – Tricyclics • Modafinil* • Research* *Denotes not FDA approved for use in ADHD (Adler, Spencer, Wilens, ADHD in Children and Adults, Cambridge Press, 2016) 12 Page 6 Myers K, Vander Stoep A, Zhou C, McCarty CA, Katon W. Effectiveness of a telehealth service delivery model for treating attention-deficit/hyperactivity disorder: a community-based randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2015 Apr;54(4):263-74. 13 Methylphenidate • Low bioavailability (~20 – 25%) – (+)-MPH isomer much greater bioavailability than the (–)- MPH isomer • Typical therapeutic doses provide – Tmax = 1.5 – 2.5 h – Cmax = 6 – 15 ng/mL – T½ = 2 – 3.5 h Wilens and Spencer. Child Adolesc Psychiatr Clin N Am 2000;9:573-603. Patrick and Markowitz. Hum Psychopharmacol Clin Exp 1997;12:527-546. 14 Page 7 Methylphenidate • Primarily de-esterified-may be susceptible to genetic polymorphisms (ultra slow metabolizer) • Prominent metabolism (L-MPH) in intestinal wall • Stereo-isomeric metabolism (L>D) • Linear pharmacokinetics at moderate doses • No pharmacokinetic drug interactions • No food effects noted Wilens and Spencer. Child Adolesc Psychiatr Clin N Am 2000;9:573-603. Stevens and Wilens; ADHD Across the Lifespan, 2013 In press; Zhu et al. Clin Pharm 2009 270: 59-65. 15 Methylphenidate (MPH) in ADHD: Optimizing Dosing & Duration Maximum Dose* Medication Starting Dose Duration Usual Dosing Ritalin IR® 5 mg QD/BID 2 mg/kg/day 4 hr /BID Focalin® 2.5 mg QD/BID 1 mg/kg/day 4–5 hr / BID–TID Focalin XR® 5 mg QD 1 mg/kg/day 10–12 hr QD Daytrana® 10 mg 6–16 hr Concerta® 18 mg QD 2 mg/kg/day 12 hr / once Metadate CD® 20 mg QD 8 hr / once Ritalin LA® 20 mg QD 8 hr /once Quillivant® <10 mg QD 12 hr /once Quillichew™ <10 mg QD 8 hr /once Aptensio XR 10 mg QD 12 hr/once Contempla XR 8.6 mg QD 51.8 mg 12 hr/once (disintegrating tab) Jornay PM 20 mg QD 100 mg QD 12 hr/once *May exceed FDA approved dose. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. www.drugs.com. 16 Page 8 Amphetamine • High bioavailability (~75%) • Typical therapeutic doses of dextroamphetamine provide – Tmax = 2 – 3 h – Cmax = 40 – 70 ng/mL – T½ = 7 h Adler, Spencer, Wilens (eds), ADHD in Children and Adults, Cambridge Press 2016 Markowitz et al., J Child Adolesc Psychopharm 2017. 8:678-689. 17 Amphetamine • Redundant hepatic metabolism • Linear pharmacokinetics • No pharmacokinetic drug interactions • Food effects noted Wilens and Spencer. Child Adolesc Psychiatr Clin N Am 2000;9:573-603. Patrick and Markowitz. Hum Psychopharmacol Clin Exp 1997;12:527-546. Markowitz et al., J Child Adolesc Psychopharm 2017. 8:678-689 18 Page 9 Amphetamine (AMPH) in ADHD: Optimizing Dosing & Duration Medication Starting Dose Maximum Dose* Duration Adderall® 2.5–5 mg QD 1.5 mg/kg/day 6 hr / BID Adderall XR® 2.5–5 mg QD 12 hr / QD Vyvanse® 30 mg QD 12–14 hr / QD Mydayis® 12.5 mg QD 50/25 mg (adults/adol) To 16 hr/QD 3–5 hr / BID–QID Dexedrine Tablets® 2.5–5 mg BID 1.5 mg/kg/day Evekeo® 2.5–5 mg BID 3–5 hr / BID–QID Dexedrine Spansule® 5 mg QD 6 hr / QD–BID Dyanavel XR™ 2.5–5 mg QD 1.5 mg/kg/day 12 hr / QD (suspension) Adzenys XR™ 6.3–12.5 mg QD 12.5 mg (adolescents) 12 hr / QD (disintegrating tab) *May exceed FDA approved dose (eg, > 20 to 30 mg/day). Wilens TE, et al. CNS News. 2007. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109.www.drugs.com. 19 Extended-Release Methylphenidate (Jornay PM) Newly approved extended-release MPH Formulation: PM administration; AM release Dosing: 20 – 100 mg QD Capsules: 20, 40, 60, 80, 100 mg Duration of action: 12+ hours (Drugs.com; Wilens et al., APSARD 2018; Wigal et al. AACAP 2018) 20 Page 10 Extended Release MPH Solution and Chewable Preparations Quillivant XR QuilliChew ER Suspension Chewable tablet 12 hour duration 8 hour duration 25 mg/5 cc (tsp) 20 s, 30 s, 40 mg tablets Dosing to 60 mg daily Dosing to 60 mg daily Approved in pediatrics Approved in pediatrics Rx list.com; PI 21 Extended-Release Oral Disentegrating Methylphenidate (Contempla XR) Extended-release methylphenidate Formulation: Oral disintegrating tablets Dosing: 8.6 – 25.9 mg QD Capsules: 8.6, 17.3, 25.9 mg Duration of action: 12 hours Drugs.com 22 Page 11 Amphetamine extended-extended release (Mydayis) for Adult/ Adolescent ADHD Very extended mixed amphetamine (e.g. Adderall XR2) Composition: mixed-amphetamine salts Dosing: 12.5 to 25 mg QD (>13 yo) or 50 mg (adults) Capsules: 12.5, 25, 37.5, 50 mg Duration of action: 16 hours (onset at 2-4 hours) Drugs.com 23 Amphetamine oral disintegrating tabs (Adzenys XR) for Pediatric ADHD Mixed amphetamine (3 to 1 ratio of d- to l-amphetamine Duration of action to 12 hours Equivalent Dosing Amph ER disintegrating (Adzenys XR) 3.1 mg 6.3 mg 9.4 mg 12.5 mg 15.7 mg 18.8 mg Mixed Amph salts ER (Adderall XR) 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg Drugs.com 24 Page 12 Amphetamine suspension (Dynavel XR) for Pediatric ADHD Amphetamine suspension Composition: 3.2 to1 ratio of d- to l-amphetamine Dosing: 2.5 to 5 mg QD Duration of action: 12 hours Drugs.com 25 D,L Amphetamine (Evekeo) for Pediatric ADHD Newly approved mixed amphetamine Composition: 50% d- & l-amphetamine Duration of action to 10 hours Dosing: 5 & 10 mg tablets Laboratory classroom SKAMP-Combined scores.