Update in ADHD: Focus on Longer Term Medication Outcomes

Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Timothy E. Wilens, MD Massachusetts General Hospital Harvard Medical School

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.

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

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

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/.

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?

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. Coghill et al. J Am Acad Child Adolesc Psychiatry.2014;53(6):647-657.

18 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

MAS XR Effectiveness Parent-Rated Conners Global Index Scores

CGI-P Total Score 14 YEAR 1 YEAR 2 12

10 No change in weight corrected dose was found 8

0 Baseline Q 1 Q 2 Q 3 Q 4 Q 5 Q 6 Q 7 Q 8 N=568 N=560 N=463 N=402 N=359 N=308 N=297 N=259 N=267

Mean Conners Global Index – Parent scores for ITT population. Note: A lower CGI-P score indicates better response to treatment. 19

Dose of OROS® MPH Increases Over Two-Year Study MTA: 26% increase in MPH dose by 14 months

MG MG/KG 50 1.30 Mean Daily Dose (MG) LEFT SCALE 45 1.25

Mean Daily Dose / Body Weight (MG/KG) 40 1.20 RIGHT SCALE

35 1.15

30 1.10

25 1.05

20 1.00 1 3 12 21 24 Month

Wilens et al. JAACAP: 2005 20 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Spencer TJ, et al. J Clin Psychiatry. 2013;74(9):902-917. 21

Spencer TJ, et al. J Clin Psychiatry. 2013;74(9):902-917. 22 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Long-Term Studies of ADHD Stimulant Treated (Tx) vs. Untreated (UnTx) and Subsequent Mood Disorders Main Findings Study Country Total: N ADHD: N Age Tx vs. UnTx Chang et al. Sweden Not specified 38,752 8 – 46 yrs Depression 2016 Lee et al. Mean Taiwan 150,655 71,080 Depression 2016 9.5 yrs Wang et al. Taiwan 22,800,000 144,920 All ages Bipolar 2016 Jerrell et al. Mean US Not specified 22,452 Depression 2015 7.8 yrs

(from Boland, et al , Psychiatric Research 2020)) ) 24 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Long-Term Studies of ADHD Stimulant Treated vs. Untreated and Subsequent Suicidality

Main Findings Study Country Total: N ADHD: N Age Tx vs. UnTx Liang et al Taiwan Not specified 84,898 <18 yrs 2018 Man et al China Not specified 25,629 7 – 19 yrs 2017 Chen et al Sweden Not specified 37,936 13 – 28 yrs 2014*

*Included nonstimulants (nonstimulants did not reduce suicide risk) (from Boland, et al , Psychiatric Research 2020)) ) 25

Long-Term Studies of ADHD Periods On versus Off Stimulant Medication and Criminality

Main Findings Study Country Total: N ADHD: N Age Tx vs. UnTx Mohr-Jensen Denmark 23,826 4,231 15 – 34 yrs et al 2019 Dalsgaard et Sweden 25,656 > 15 yrs al 2014 Lichtenstein Denmark 4,556 10 years et al. 2012*

*Included nonstimulants (from Boland, et al , Psychiatric Research 2020)) 26 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

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. 27

Long-Term Studies of ADHD Stimulant Treated vs. Untreated and Subsequent Substance Use Disorders Main Findings Study Country Total: N ADHD: N Age Tx vs. UnTx Quinn et al. Within USA 146,000,000 2,993,887 15 – 42 yrs 2017 group Sundquist et Mean Between Sweden 551,164 9,424 al. 2015 15 yrs group Chang et al. Between Sweden 38,753 8 – 46 yrs 2014 group Steinhausen et Between & Denmark 20,742 11 – 20 yrs al. 2014 Within groups

(from Boland, et al , Psychiatric Research 2020))

28 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

ADHD Medication and SUD US Claims Data Conclusions • Largest US database examining ADHD medication treatment and later SUD • Almost 3 million with 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 29

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 P<0.001 vs. controls 10-14 years*

Stimulant use started after P<0.001 vs. controls 15 years of age**

20% 30% 40% 50% 60% Past Year Use

* > 6 years of treatment ** > 3 years of treatment McCabe, West, Dickinson, Wilens. J Am Acad Child Adoles Psych 2016: 55:479-486

30 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Long-Term Studies of ADHD Stimulant Treated vs. Untreated and Subsequent Traumatic Brain Injury Main Findings Study Country Total: N ADHD: N Age Tx vs. UnTx Liao et al Taiwan 124, 438 <18 yrs 2018 Liao et al Taiwan 72,181 3 – 29 yrs 2018*

* Included atomoxetine (from Boland, et al , Psychiatric Research 2020))

Long-Term Studies of ADHD Periods On vs. Off Stimulant Medication and Motor Vehicle Accidents

Main Findings Study Country Total: N ADHD: N Age Tx vs. UnTx Chang et al Mean USA 2,319,450 2017* 32.5 yrs Chang et al Sweden 17,408 18 – 46 yrs 2014*

* Included atomoxetine (from Boland, et al , Psychiatric Research 2020)) 32 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Long-Term Studies of ADHD Stimulant Treated vs. Untreated and Academic Achievement Findings: Study Country Total: N ADHD: N Age Tx vs. UnTx Jangmo et al. Sweden 657,720 29,128 GPA 2019 Kellow et al. Mean Denmark 577,551 6,444 GPA 2018* 16.1 yrs Mean Entrance Lu et al. 2017* Sweden 61,640 3,718 22 yrs Exams van der Schans School Netherlands 600,000 7,736 12 – 13 yrs 2017 Performance Currie et al. Academic Canada < 16 yrs 2014 Outcomes Zoega et al. Iceland 13,617 1,029 9 – 12 yrs Test scores 2012 Marcus et al. USA 3,543 GPA 2011 Barberesi et al. Mean Reading USA 5,718 370 2007 18.4 yrs Attendance

*Included nonstimulants (from Boland, et al , Psychiatric Research 2020)) 33

Effect of Stimulants on Height and Weight: A Review of the Literature STEPHEN V. FARAONE, PH.D., JOSEPHI BIEDERMAN, M.D., CHRISTOPHE P. MORLEY, M.A., AND THOMAS J. SPENCER, M.D.

ABSTRACT

Objective: Stimulant medications are effective treatments for attention-deficit/hyperactivity disorder, but concerns remain about their effects on growth. Method: We provide a quantitative analysis of longitudinal studies about deficits in expected growth among children with attention attention-deficit/hyperactivity disorder treated with stimulant medication. Study selection criteria were use of DSM criteria or clear operational definitions for hyperactivity or minimal brain dysfunction; outcome measures including raw, standardize standardized, or percentile measurement of change in height and/or weight; first assessment of effects on growth occurred during childhood; and follow-up for at least 1 year. For issues not suitable for quantitative analyses, we provide a systematic, qualitative review. Results: The quantitative analyses showed that treatment with stimulant medication led to statistically significant delays in height and weight. This review found statistically significant evidence of attenuation of these deficits over time. The qualitative review suggested that growth deficits may be dose dependent, deficits may not differ between methylphenidate date and amphetamine, treatment cessation may lead to normalization of growth, and further research should assess the idea that attention deficit/hyperactivity disorder itself maybe associated with dysregulated growth. Conclusions:Treatment with stimulants in childhood modestly reduced expected height and weight. Although these effects attenuate over time and some data suggest that ultimate adult growth parameters are not affected, more work is needed to clarify the effects of continuous treatment from childhood to adulthood. Although physicians should monitor height, deficits in height and weight do not appear to be a clinical concern for most children treated with stimulants. J. Am. Acad. Child Adolesc. Psychiatry, 2008;47(9) R E V I E W

34 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Mixed Amph Salts: Mean Blood Pressure and Heart Rate

Systolic BP (mm Hg)

Heart Rate (bpm)

Diastolic BP (mm Hg)

Time in Study Baseline (months)

(Findling, Biederman, Wilens et al. J Ped:2006) 35

ADHD Meds are Not Associated with Adverse CV Outcomes:Children

Cooper et al. The New England Journal of Medicine 2011; 365(20) 18960-1904.

36 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

What to Do at Evaluation (AHA Guidelines) • Medical History (essentially screening of sudden death risk) • Personal congenital or acquired cardiac disease • Palpitations, chest pain, syncope, seizures, post-exercise symptoms • Family history or premature cardiac disease (< 30 yrs of age) • Other meds (including OTC) • Routine med history (neurological, etc.) • BP / heart rate - particularly in adults • Peds: no ECG, Holter, or GXT • Adults: work-up as indicated • Suspicion of CV defect (e.g. IHSS, ARVD) --w/u as indicated • Monitor above during treatment • Issues of informed consent

Gutgesell H et al., Circulation 1999:99:979-982; AAP Guidelines 2008; Perrin et al Pediatrics, 2008; Wilens et al. Pediatrics 2006; Cooper et al. NEJM 2012; Cooper et al JAMA 2012) 37

Stimulants Not Related to New Onset Tic Disorders in ADHD Boys (Spencer et al. Arch Gen Psych, 1999; N=128 ADHD and 110 controls) 100 90 80 70 60 50 Stimulant Treated 40 30 20 Not Stimulant Treated 10 0 0 5 10 15 20 25 Age in Years

38 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Other Treatments?

Sonuga-Barke EJ, et al. Am J Psychiatry. 2013;170(3):275-289. 40 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

MGH Open Study: Fish Oils Reduce Emotional Dysregulation in Medication-Treated Children with ADHD

CGI-S Score 7 75% of Patients Improved 6 Markedly ill 5 More Improvement 4

*P<.0001 Mildly ill 3

1 Normal 0 Week 0 Week 12

N=10. CGI-S = CGI–Severity. Wilens TE, et al. J Child Adolesc Psychopharmacol. 2017;27(8):755-756. 41

Trigeminal Nerve Stimulation for ADHD

ADHD RS Over 4-week Trial Active (N=32) Versus Sham (N=30) Trigeminal Nerve Stimulation

McGough et al. J Am Acad Adolesc Psychiatry 2019;58(4):403-411

42 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

Representative Experimental Pharmaceuticals for ADHD* Effectiveness/efficacy demonstrated* • Evidoxetine – NET inhibitor Lin et al. J Child Adolesc Psy 2014 • Dasatroline – Biamine reuptake inhibitor 2 adult RCT positive Neuropsychopharm 2015 Pediatric RCT Findling et al. J Child Adoles Psychopharm 2019 • Centanafadine – Triamine reuptake inhibitor Wilens et al., Presentation at ASCP 2014 • Molindone – Impulse/ADHD; antipsychotic; child/adults

Phase 3 studies Britain et al, Neurol 2016 • SPN 812 (Viloxazone) – NET/ 5HT inhibitor 4 Phase III RCTs (N=1,397 children) positive Press release; Nasser et al., Presentation at ASENT 2019 • Mazindol – Catecholamine reuptake inhibitor Wigal et al.,CNS Drugs 2018 • New stimulant preparations (multiple) • Release systems • Abuse deterrence *Not FDA approved for ADHD

Summary

• Multiple agents available for the treatment of ADHD. • Consider dose-response issues when using stimulants. • New stimulant preparations may improve outcomes. • Use of combined pharmacotherapy/psychotherapy may be necessary for refractory ADHD and/or ADHD with comorbidity. • Long term outcomes more favorable with pharmacologically treated ADHD. • Stay tuned for new agents and preparations for ADHD!

44 Pharmacological Strategies in ADHD Timothy E. Wilens, MD

QUESTIONS?