Update in ADHD: Focus on Longer Term Medication Outcomes
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Pharmacological Strategies in ADHD Timothy E. Wilens, MD Update in ADHD: Focus on Longer Term Medication Outcomes Timothy E. Wilens, MD Massachusetts General Hospital Harvard Medical School 1 Disclosures Source Consultant Employee Grant Royalties Support Bay Cove Human Services X Cambridge University Press X Gavin Foundation X Guilford Press X Ironshore Pharmaceuticals Inc. X X KemPharm, Inc. X Massachusetts General Hospital X National Institute on Drug Abuse X Otsuka America Pharmaceutical, Inc. X US Minor/Major League Baseball X US National Football League (ERM Associates) X Vallon X Some of the medications discussed may not be FDA approved in the manner in which they are discussed including diagnosis(es), combinations, age groups, dosing, or in context to other disorders. 2 Pharmacological Strategies in ADHD Timothy E. Wilens, MD Learning Objectives At the conclusion of this continuing medical education activity, the participant will be able to: 1. Learn the new stimulant preparations 2. Compare the longer-term outcomes of treated versus untreated samples of ADHD. 3. Learn longer term adverse outcomes of medications for 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 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 Pharmacological Strategies in ADHD Timothy E. Wilens, MD Diagnosis of ADHD • Developmentally inappropriate symptoms • 6/9 Symptoms of Inattention, Hyperactivity or Combination • 5/9 if > 17 years of age (adult) • 95% of cases are either combined or inattentive subtype • Age of onset < 12 years • Not accounted for by other disorder • Can make diagnosis of Autism Spectrum and ADHD • Diagnosis Clinically Derived • Rating Scales Helpful (Parent, School) • Narrow: Vanderbilt (AAP), others • Broadband: Child Behavior Checklist 5 5 Developmental Impact of Untreated ADHD Academic difficulties Self-esteem issues Occupational failure Legal issues Self-esteem Behavioral Smoking Relationship problems disturbance Injuries Injuries/accidents Preschool Adolescent Adult School-age College-age Behavioral disturbance Academic failure Academic difficulties Occupational difficulties Peer relationships Self-esteem Self-esteem issues Substance abuse Injuries/accidents Pliszka S; AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894- 921. Brown TE, et al. Postgrad Med. 2010;122(5):42-51. Adler, Spencer, Wilens ADHD in Children and Adults, 2015, Cambridge Press 6 Pharmacological Strategies in ADHD Timothy E. Wilens, MD Medications: Attention-Deficit/Hyperactivity Disorder Pharmacological Treatment Stimulants FDA Approved Methylphenidate Amphetamines Atomoxetine FDA Approved Alpha Agonists Guanfacine (XR) FDA Approved Clonidine (XR) Guan XR or Clon XR + stimulants FDA Approved Antidepressants Bupropion Tricyclics Combination/others Modafinil Memantine ADHD in Children & Adults. Adler, Spencer, Wilens (eds), Cambridge Press; 2015 7 Medication Starting Dose Maximum Dose* Duration ® Methylphenidate Ritalin IR 5 mg QD/BID 2 mg/kg/day 4 hr /BID (MPH) in ADHD 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 Contempla XR 8.6 mg QD 51.8 mg 12 hr/once (dissolve tab) Aptensio XR 10 mg QD 2 mg/kg/day 12 hr/once Adhansia XR 25 mg QD To 16 hr/once Jornay 20 mg QD 100 mg 12 hr/once (delayed release) *May exceed FDA approved dose. Listed above are brand names for methylphenidate in various forms QD = 1 time a day; BID = 2 times a day; TID = 3 times a day Wilens TE, et al. CNS News. 2007. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. Adler, Spencer, Wilens ADHD in Children and Adults, Cambridge Press, 2015 www.drugs.com. 8 Pharmacological Strategies in ADHD Timothy E. Wilens, MD Maximum Medication Starting Dose Dose* Duration Amphetamine Usual Dosing (AMPH) in ADHD 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 50/25 mg Mydayis® 12.5 mg QD To 16 hr/QD (adults/adol) Dexedrine 3–5 hr / BID– 2.5–5 mg BID 1.5 mg/kg/day Tablets® QID 3–5 hr / BID– Evekeo® 2.5–5 mg BID QID Dexedrine 5 mg QD 6 hr / QD–BID Spansule® Dyanavel XR™ 2.5–5 mg QD 1.5 mg/kg/day 12 hr / QD (suspension) Adzenys XR™ 12.5 mg *May exceed FDA 6.3–12.5 mg QD 12 hr / QD (dissolve tab) (adolescents) approved dose (e.g., > 20 to 30 mg/day). Listed above are brand names for mixed amphetamine in various forms Wilens TE, et al. CNS News. 2007. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. Adler, Spencer, Wilens ADHD in Children and Adults, Cambridge Press, 2015 www.drugs.com. 9 Night-Time Administered Delayed/Extended Release MPH for ADHD: Jornay Consider for early-morning difficulties, parents who work in early AM Mean Observed MPH Plasma Concentration Newly approved (± S.E.M.) Following a Single Evening extended-release methylphenidate Administration of HLD200 (54 mg) Formulation: PM administration AM release Dosing: 20 – 100 mg QD Children Capsules: 20, 40, 60, 80, 100 mg (n=11) Duration of action: 12+ hours Adolescents (n=18) ADHD-RS-IV Total Score at Visit 2 and Visit 8 BSFQ Total Score at Visit 2 and Visit 8 45 45 40 40 35 35 30 30 25 25 20 P=0.0001 20 38.2 36.2 P=0.0001 15 15 10 10 5 12.5 Score BSFQ Total 5 10.1 ADHD-RS-IV Total Score 0 0 Baseline (V2) Treatment Optimized (V8) Baseline (V2) Treatment Optimized (V8) Visit Visit Ironshore Pharmaceutical 6-week open study (presented) followed by controlled trial (not shown) n=43 children aged 6-12 years Findings: Improvement in ADHD RS, Before School Functioning Scale, DPRMB Adverse effects: Stimulant like—no major effects on sleep Drugs.com; Plizka et al, J Child Adolesc Psychopharm 2017; Wilens et al., APSARD 2018; Wigal et al. AACAP 2018 10 Pharmacological Strategies in ADHD Timothy E. Wilens, MD Extended Release MPH Solution and Chewable Preparations Consider for difficulty swallowing pills Quillivant XR QuilliChew ER • Chewable tablet • Suspension • 8 hour duration • 12 hour duration • 20 s, 30 s, 40 mg tablets • 25 mg/5 cc (tsp) • Dosing to 60 mg daily • Dosing to 60 mg daily • Approved in pediatrics • Approved in pediatrics Rx list.com; PI 11 Extended-Release Oral Disintegrating Methylphenidate: Contempla XR Consider for difficulty swallowing pills • Extended-release methylphenidate • Formulation: oral disintegrating tablets • Dosing: 8.6 – 25.9 mg QD • Tablets: 8.6, 17.3, 25.9 mg • Duration of action: 12 hours Drugs.com 12 Pharmacological Strategies in ADHD Timothy E. Wilens, MD Extended-Extended Release AMPH [Mydayis®] or MPH [Adhansia XR] for Adult / Adolescent ADHD Consider for Very Extended Coverage • Mydais: Extended mixed AMPH (eg, XR2) • Composition: Mixed AMPH salts • Dosing: 12.5 to 25 mg QD (> 13 years old) or 50 mg (adults) • Capsules: 12.5, 25, 37.5, 50 mg • Duration of action: 16 hours (onset at 2 to 4 hours) • Adhansia XR: MPH product • Capsules: 25, 35, 45, 55, 70, or 85 mg (up to 100 mg tested in adults) • Duration of action: 16 hours (onset within 1 hr) US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. 13 Amphetamine Oral Disintegrating Tabs: Adzenys XR for Pediatric ADHD Consider for difficulty swallowing pills Mixed amphetamine formulation (3:1 ratio of d- to l-amphetamine) Duration of action to 12 hours Equivalent Dosing Amph ER disintegrating (Adzenys XR) Mixed Amph salts ER 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg (Adderall XR) Drugs.com 14 Pharmacological Strategies in ADHD Timothy E. Wilens, MD Previous Methylphenidate Exposure Influences Outcomes Mean change from baseline in ADHD-RS-IV total score by treatment for prior MPH or stimulant-naïve subgroups at endpoint (full-analysis set). Notes: *P<0.05, **P<0.001 versus placebo. Nominal statistical differences based on ANCOVA of placebo-adjusted LS means in the RCT only. Statistics not performed for RWS. Not all patients had ADHD-RS-IV total score data available at end point. Abbreviations: ADHD-RS-IV, ADHD Rating Scale version IV; ANCOVA, analysis of covariance; ATX, atomoxetine; GXR, guanfacine extended release; LOCF, last observation carried forward; LS, least squares; MPH methylphenidate; RCT, randomized controlled trial; RWS, randomized-withdrawal study. Huss et al., Neuropsychiatric Disease Tx, 2016: 12; 1085-1101 15 Guanfacine XR in Adolescent ADHD GXR, n=157; Placebo, n=157; Dosing to 7 mg/day. Percentage of responders (full analysis set). Response was defined as a percentage reduction from the baseline visit in the ADHD-RS-IV total score of ≥ 30% and a CGI-I of 1 or 2. CGI-I = Clinical Global Impressions–Improvement Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 2015;54(11):916-925.e2. 16 Pharmacological Strategies in ADHD Timothy E. Wilens, MD What Do We Know About Long‐term Outcomes in Medication Treated ADHD Youth Growing Up? 17 Discontinuing Treatment Leads to ADHD Relapse LDX = lisdexamfetamine Treatment failure = 50% or greater increase in ADHD-RS-IV total score and a 2 point or greater increase in CGI-S score at any double-blind visit relative to start of randomized withdrawal period.