ADHD-Focus-On-Medications-Timothy-E.-Wilens.Pdf

Timothy E. Wilens, M.D. Chief, Child & Adolescent Psychiatry, Director, Center for Addiction Medicine, Massachusetts General Hospital

Professor of Psychiatry, Harvard Medical School

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)

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

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)

Page 2 Spencer TJ, et al. J Clin Psychiatry. 2013;74(9):902-917.

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.

Page 3 Dose of OROS® MPH (Concerta) Increases Over Two Years to Maintain Effectiveness (Wilens et al. JAACAP: 2005) Mean daily dose/body daily dose/body Mean (mg/kg) weight Mean Daily Dose (MG)

Mean daily dose/body weight (mg/kg) Mean dose (mg)Mean dose

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.

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.

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

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)

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)

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.

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.

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.

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.

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

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)

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

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

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

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

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. SKAMP, Swanson, Kotkin, Agler, M- Flynn, and Pelham. Lower scores denote more change

Childress AC, Brams M, Cutler AJ, et al.. J Child Adolesc Psychopharmacol. 2015;25(5):402-414

Page 13 ADHD and Methylphenidate: Dose Effects on Attention in Clinic and Classroom

65 CPT 55 ADHD Comprehensive Teachers Rating Score 45 % Academic 35 Efficiency Weekly T-Score % On Task 25

15 Rapport, et al. 1987 placebo 5 10 15 20 Methylphenidate Dose

Higher Doses of Methylphenidate (Concerta) and Blood Levels Study

MPH Levels Mean=27.3 ± 10.0 ng/mL 280 10

240 8 200 6 160

Ng/Ml 4 120 169.4 193.5 2 Mean MPH (mg)DoseMean MPH 80 ±31.2±37. 40 1 0 10-19.920-29.930-39.940-49.950-59.9 0 MPH Serum Level (ng/mL) Children Adults (Stevens, et al. JCAP 2010) 28

Page 14 NIMH Preschool ADHD Treatment Study (PATS): Study Design

• Patients – Ages 3-5.5 years • Parent Training (10 weeks) • Open-label Safety Lead-in (1 week) • Double-blind Crossover Titration (5 weeks) – Placebo and 4 doses of MPH (1.25, 2.5, 5, 7.5 mg tid*) • Double Blind Parallel Phase (4 weeks) – Random assignment to placebo or best dose from crossover • Open-label Maintenance (10 months) • Placebo Discontinuation (6 weeks) *tid=three times a day

Kollins S, et al. JAACAP. 2007; Greenhill LL, et al. JAACAP. 2007

Treatment of ADHD in Preschoolers: PATS Study

Greenhill et al. J.Am. Acad. Child Adolesc. Psychiatry, 2006; 45(11): 1284-1293

Page 15 Early Administration of Methylphenidate Improves Before School Functioning (Before School Functioning Scale)

(N=50, 4 wk RCT)

Severe

P<0.05 vs PTS P<0.01 vs PTS P<0.01 vs PTS P<0.05 vs PTS

None

MTS = methylphenidate transdermal system PTS = placebo transdermal system (Wilens et alJ Clin Psychiatry. 2010. 71(5):548–556. )

MAS XR Study in Youth with ADHD: Frequently Reported Adverse Effects

% of Subjects Reporting

Page 16 STIMULANT CONTROVERSIES

• Adverse cardiovascular (CV) outcomes • Growth suppression • Development of tics

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) 34

Page 17 ADHD Meds are Not Associated with Adverse CV Outcomes:Children

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

ADHD Meds are Not Associated with Adverse CV Outcomes: Adults

Habel et al. JAMA 2011; 306(24) 2673-2683.

Page 18 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

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

Page 19 Onset of Tic Disorders in ADHD Boys Stratified by Stimulant Treatment (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

Medication Strategies for Stimulant-Induced Side Effects

(Wilens & Hammerness. Straight Talk about Psychiatric Medications for Kids, Guilford Press, 2016)

Page 20 Medication Strategies for Stimulant-Induced Side Effects (continued)

Talk

(Wilens & Hammerness. Straight Talk about Psychiatric Medications for Kids, Guilford Press, 2016)

ADHD: Focus on Medications II

Timothy E. Wilens, M.D. Chief, Child & Adolescent Psychiatry, Director, Center for Addiction Medicine, Massachusetts General Hospital

Professor of Psychiatry, Harvard Medical School

Page 21 Previous MPH Exposure Influences Outcomes for Some Nonstimulants (Huss et al., Neuropsychiatric Disease Tx, 2016: 12; 1085-1101)

Atomoxetine Uses • Uncomplicated ADHD • Refractory ADHD • Comorbid ADHD • Anxiety or depressive disorders • Tic disorders • Disruptive disorders • Substance use disorders Safety Rare hepatitis reported Rare possibility -NO LFTs necessary Slight increase in irritability & suicidal ideation reported in clinical trials 0.037% Atomoxetine vs. 0.0% placebo One suicide attempt/1,357 cases; no suicides

Page 22 The Ventromedial Prefrontal Cortex (PFC): Emotional Regulation

Ventromedial PFC is thought to regulate emotion1–3

Ventromedial

Basal PFC Ganglia

Amygdala

Hypothalamus Impairment may lead and Brainstem to aggressive and oppositional behavior

1Anderson SW, et al. Nat Neurosci. 1999;2:1032-1037. 2Arnsten AFT, et al. J Child Adolesc Psychopharmacol. 2007;17:393-406. 3Price JL, et al. Prog Brain Res. 1996;107:523-536.

Guanfacine or Clonidine: When to Use

• Monotherapy • Stimulant or nonstimulant nonresponders • Medication partial responders (adjunctive therapy) – Improved ADHD in majority of subjects – Tolerable AE: abd pain, fatigue & irritability most common – CV: typically BP/HR dose dependent decreases; no CV symptoms reported • Adverse effects to stimulants or nonstimulants • Comorbid ADHD plus – Oppositional disorder/ “Emotional dysregulation” – Anxiety – Tics • Potentially younger children (needs to be studied)

(Wilens et al. J Am Acad Child Adoles Psych 2012) 46

Page 23 Guanfacine Extended-Release in ADHD (N=324 [51 sites]; 6 weeks active*, Mean Age 11±3 yrs)

Effect size: 0.41-0.89

*, + P < .05

*3 weeks titration 3 weeks maintenance (endpoint) Sallee et al. J AM Acad Child Adolesc Psychiatry, 48: 155-165; 2009 3 weeks taper 47

Extended-release Guanfacine Has Similar Efficacy with AM or PM Administration ( 6-12 years, dosing 1-4 mg/day; Samples size of GXR AM (107), GXR PM (114), or placebo (112)

Total Score Hyper/Imp

Inattention

Newcorn et al. JAACAP 2013; 52; 921-930. 48

Page 24 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 Clinical Global Impressions–Improvement of 1 or 2

(Wilens et al. J Am Acad Child Adoles Psych 2015; 54 (11) 916–925.e2) 49

Guanfacine XR in Adolescent ADHD

(Wilens et al. J Am Acad Child Adoles Psych 2015; 54 (11) 916–925.e2)

Page 25 Non-FDA Approved, Non-Stimulants in ADHD • Bupropion – RCTs in Children (and adults) – Generally smaller effect size (ES) vs stimulants • Modafinil – Multiple RCTs positive in children (careful with SJS) – Failed RCTs in adults • Tricyclics (imipramine, nortriptyline, desipramine) – Multiple RCTs in children/adolescents and adults – Longer term persistent effect without tolerance – Serum levels, ECG monitoring recommended • Memantine – Mainly open; RCT underway

Adler, Spencer, Wilens (ed); ADHD in Children and Adults, Cambridge Press, 2015

Modafinil in ADHD*

• Modafinil research – 2 RCT in adults » Negative studies – 4 RCT in Pediatric groups » 200 mg / 100 mg; once daily ca 400 mg (Biederman et al Pediatrics: 2005) » Good tolerability » Effect size around 0.60 – May be useful for arousal of attention, motivation – Careful with rare serious rash – Stimulant-like mechanism & adverse effects

*Not FDA approved for ADHD

Page 26 Nortriptyline* for Pediatric ADHD (Prince, et al., J Child Adolesc Psychopharm, 2000)

40 Placebo 30

20 * * * * * * Nortriptyline 10 0 2 4 6789 Week

*Not FDA approved for ADHD

Bupropion versus Methylphenidate: Analyses

Ng QX. J Child Adolesc Psychopharmacol.2017 Mar;27(2):112-116 54

Page 27 Omega -3/Omega-6 Fatty Acids for ADHD* • Types – EPA (eicosapentaenoic acid) - Omega 3 – DHA (docosahexaenoic acid) - Omega-3 – g-linoleic acid (Omega-6) • Metanalysis of 10 studies; N= 699 children – Indicating mild-modest improvement in ADHD overall with good tolerability » Effect size = 0.28 monotherapy » Effect size = 0.18 adjunct – Potential dose response effect of EPA – Efficacy/effectiveness in mood • MGH Study showing improvement in treated ADHD youth (moodiness) *Not FDA approved for ADHD (Bloch MH, Qawasmi A, J Am Acad Child Adoles Psych 2011; Wilens et al. JCAP 2017)

MGH Open Study: Fish Oils Are Effective in Reducing Emotional Dysregulation in Med-Treated ADHD Children (N=10)

CGI-S Score 75% of Patients Were Improved in Mood

Markedly ill Moreimprovement

*P<0.0001 Mildly ill

Normal

No Effect on ADHD Observed (Wilens et al., JCAP 2017)

Page 28 Strategies for Common Nonstimulant- Induced Side Effects • Alpha Agonists – Sedation » Monitor (improves with time), lower dose, change formulation, change to alternative alpha agonist, add stimulant or modafinil – Wear off » Administer multi doses daily, change formulation to XR – Early AM difficulties » Administer XR at night, administer med very early in AM – Depression/moodiness » Reassess for comorbidity, change formulation, change to other alpha agonist, discontinue – Insomnia » Change to shorter acting preparation, change to other alpha agonist, avoid nighttime administration

Strategies for Common Nonstimulant- induced Side Effects

• Atomoxetine – Initial sedation » Monitor as improves over time, administer initial 2 week dosing qHS (then move to qAM), consider qHS dosing – Wearoff » Administer BID, increase dose – Low efficacy » Add stimulant, alpha agonist

Page 29 Strategies for Common Nonstimulant- induced Side Effects

• Bupropion – Agitation/activation » Lower dose, change preparation (e.g. to IR form) – Insomnia » Administer earlier in day, change to QD dosing, add adjunct agent (e.g. melatonin, alpha agonist, mirtazpine) – Lower efficacy » Add stimulant, modafinil, atomoxetine

Case

• Joey is an 11 year old with ADHD, prominent executive dysfunction, severe mood dysregulation, and tics • Atomoxetine resulted in minor improvements in ADHD, executive functioning, and tics • Treatment with stimulants had positive effect on attention with tic exacerbation • What next? • What if the mood instability = bipolar disorder?

Page 30 Refractory ADHD Prominent Executive Function Deficits

• Organizational training/coaching (focus on specific dysfunction) • Use of Norepi agent - ATMX, alpha agonist, TCA, bupropion (alone or combined with stimulant, modafinil)* • Memantine* (alone, in combination with other ADHD meds) • Vortioxetine* (anecdotal only) • Investigational: – Nicotinic/ cholinergic agents* » Indirect: Donepezil, galantamine • Systematic data negative • Case reports positive » Direct: Nicotinic agents/gum/patch* – Triamine reuptake inhibitors*

*Not FDA approved for ADHD

(Adler, Spencer, Wilens (eds) ADHD Across Lifespan: Cambridge Press 2015) 61

MGH Randomized Controlled Trial of CBT for ADHD in Medication Treated Adolescents (N=46)

Based on adult treatment manuals, adapted for adolescents

1. Organizing and planning (4) 2. Coping with distractibility (2) 3. Cognitive restructuring (2) 4. Parent/adolescent sessions (2) 5. Relapse prevention (1) 6. Parents included for 10 min each session optional 4. Application to procrastination (1) 5. Parent-only sessions (2)

Page 31 MGH Randomized Controlled Trial of CBT for ADHD in Medication Treated Adolescents (N=46) 4 Month Responder Status (% responders)

30% reduction on the ADHD rating scale=categorical responder, (Chi Sq (1) = 8.98, p=.00 for parent; Chi Sq (1) = 5.87, p=.02 for adolescent)

(Sprich et. al., J Child Psychology & Psychiatry. 2016) 63

Combination of Guanfacine XR plus Stimulants in the Treatment Of ADHD (N=455)

Wilens et al. J Am Acad Child Adolesc Psych: 2012 64

Page 32 Combination of Guanfacine XR plus Stimulants in the Treatment Of ADHD

Adverse effects (cont)

Serious adverse effects -all unrelated to medication: 1) syncope, 2) poison ivy, 3) emotional outbursts

Cardiovascular indices at endpoint Heart rate: -5.6 bpm Systolic blood pressure: -2.2 mm Hg Diastolic BP: -1.2 mm Hg No ECG abnl, no QT prolongation

Wilens et al. J Am Acad Child Adolesc Psych: 2012

Combined (COMB) stimulant and guanfacine for ADHD: Comparative Study (McCracken et al, JAACAP, 2016 doi 10.1016/j.jaac.2016.06.015)

8 week, RCT, 3-arm trial in 207 participants of 7-14 year olds treated with IR guanfacine (1-3 mg/day), IR d-MPH 5-20 mg/day), or the combination (COMB) with fixed flexible dosing (e.g. using CGI to guide dosing).

Response rate (CGI-I + ADHD RS IV): 62% (guan), 63% (D-MPH), 75% (COMB)

Page 33 Combination of Clonidine XR plus Stimulants for ADHD

• Study of clonidine XR coadministration to partial responders on stimulants (>ADHD RS 26 score) • Dosing to 0.4 mg daily (in 0.2 mg BID dosing) • Duration: 5 weeks (then taper)

Kollins et. al. Pediatrics June 2011. epub 67

Combination of Atomoxetine plus Stimulants in the Treatment Of ADHD • Qualitative analysis of existing studies • N= 3 prospective (1RCT)+ 7 retrospective reports • Predominately children/adolescent with inadequate response to stimulants • Most often used stimulant = methylphenidate • Conclusions • Small sample sizes • “Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success”.

Truer et. al. J Child Adolesc Psychopharmacol. 2013 Apr; 23(3): 179–193

Page 34 OROS MPH plus ATMX*: Improvement Characterized by the BRIEF: Initiation Results 80 More 75 Disturbed n=38 70 65 60 vs w4: p<0.001 SD10 SD13 SD11 55 SD11 50 45 40 35 30 Baseline ATMX ATMX+OROS MPH Alone *Not FDA approved for ADHD MPH (Historical) (Wilens et al. J Child Adolesc Psychopharm: 2009) 69

Memantine for ADHD*: MGH Open Trial AISRS Total, Inattentive & Hyperactive /Impulsive Scores

35 30 Total score 25 20 Inattentive score 15 Hyperactive/impulsive 10 score 5 0 N= 28 adults (LOCF) 0 1 2 3 4 6 81012 12 week trial Titrated to 10 mg BID Week (LOCF)

*Not FDA approved for ADHD (Surman et. al. World J Biol Psych Mar 2012).

Page 35 Sonuga-Barke EJ, et al. Am J Psychiatry. 2013;170(3):275-289.

COMORBIDITY IN ADHD

ADHD CONDUCT / Oppositional DISORDER

ANXIETY DISORDER

MOOD

Page 36 Pharmacotherapy of ADHD Comorbidity

• Evidence of improved ADHD outcome with treated comorbidity – Anxiety – Depression – Bipolar disorder – Substance Use Disorders

Atomoxetine in Adults with ADHD and Social Anxiety Disorder

Design • Double blind, placebo controlled study • Adults with DSM IV ADHD and Social Anxiety Disorder (SAD) • Dosing of atomoxetine of up to 100 mg/day • 2 week placebo washout followed by 14 week trial Results (versus placebo) • Significant effect on ADHD (2 scales) • Significant effect on Anxiety (3 scales) • Week to week improvement • Side effects: predictable ATX effects Conclusions: Atomoxetine effective for ADHD and Social Anxiety Disorder in adults

(Adler et al, Depress Anxiety. 2009;26(3):212-21)

Page 37 Atomoxetine for Youth with ADHD & Anxiety

ADHD RS Anxiety (PARS) N 55 58 55 58 Baseline 33.9 (8.9) 34.2 (10.7) 17.5 (3.0) 17.0 (2.5) 0.0

-2.0 -1.4

-4.0 -3.2

Atomoxetine -6.0 -5.5 Placebo

Improvement -8.0 ** effect size = 0.5 -10.0 * p<.001 Mean Mean Change from Baseline -10.5 ** p=.011 -12.0

effect size* = 1.0

Dose of ATMX = 1.26 mg/kg/day (Geller et al. JAACAP 2007) 75

Strategies for ADHD and SUD

In context to SUD, ADHD treatment should be considered If less severe SUD (e.g. weekend marijuana use), treat ADHD concomitantly

More severe SUD --> address SUD first

If unable to address or recalcitrant SUD then use CBT, nonstimulants, extended- release stimulants

• Wilens and Morrison, ADHD & SUD In ADHD in Children and Adults, Cambridge Press, 2015

Page 38 Effect of Methylphenidate on ADHD in Stabilized Youth with BPD: Measures at Baseline & After 1 Week of Treatment

N=16; Ages 4-17 P<0.05 vs PBO (mean 11 yrs) ADHD RS ES = 0.90 Euthymic-stable on thymoleptics 1 week Tx No effect on mania

Dose condition (BID)

*ARS-IV: parent-completed ADHD Rating Scale-IV

Findling R. et al., JAACAP 2007. 46:11:1445-1453 77

Stimulants Do Not Activate Mania in Mood-Stabilized Adults with Bipolar and ADHD Results from the Swedish Registry Study (N=2307)

Viktorin A, et al. Am J Psychiatry. 2017 Apr 1;174(4):341-348.

Page 39 Use of Stimulants and Second Generation Antipsychotics (SGA) (Penzner et al. J Child Adoles Psychopharm: 19: 2009)

Naturalistic study of metabolics of SGAs in children with mixed psychiatric disorders

Mixed SGAs: Risperidone (33%), aripiprazole (29%), quetiapine (18%), olanzapine (12%), ziprasidone (6%), and clozapine (1%)

N= 71 SGA + Stimulants vs 82 SGA – Stimulants

Metabolic characteristic outcomes: No significant differences for most outcomes between SGA + stimulants (BMI, GLU, Insulin, Chol, LDL, HDL, TG) No clinically significant differences between groups on overall “body composition”

NEW MEDICATION DEVELOPMENT IN ADHD

Page 40 New Representative ADHD Meds in Development

Stimulants: Abuse deterrence Novel delivery systems Various isomeric preparations

Nonstimulants: Dasatroline (NET>DAT uptake inhibitor) Centanafadine ( DAT>NET>5HT uptake inhibitor (triamine)) Mazandole (potentially regulating the orexins) Eltoprazine (5-HT1A/1B partial agonist) SPN-810 (Molindone HCl; indole-derivative; D2 receptor selective antagonist) AR-08 (Adrenergic receptor agonist)

Clintrials.gove; CNS Drugs 81

Summary

• Multiple agents available for the treatment of ADHD • Consider dose-response issues when using stimulants • Sequencing of ADHD treatment may influence nonstimulant response • Most side effects can be managed • Use of combined pharmacotherapy/psychotherapy may be necessary for refractory ADHD and/or ADHD with comorbidity • Stay tuned for new agents and preparations for ADHD!

Page 41 QUESTIONS ?

Page 42