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Timothy E. Wilens, M.D.
Chief, Child & Adolescent Psychiatry,
Director, Center for Addiction Medicine,
Massachusetts General Hospital
Professor of Psychiatry,
Harvard Medical School
ADHD:
The Stimulants
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* 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)
Disclosures*
Grant support (Research): NIH (NIDA)Consulting Fees: Alcobra, Neurovance/Otsuka, Ironshore, and KemPharmRoyalties (Published author/ co-editor/co-owner ofcopyrighted diagnostic questionnaire, licensing agreement): Guilford Press, Cambridge University Press, Elsevier, IronshoreConsulting Fees (clinical consultant): US National Football League (ERM Associates), U.S.Minor/Major League Baseball; Phoenix/Gavin House and BayCove Human Services
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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*
(Adler, Spencer, Wilens, ADHD in Children and Adults, Cambridge Press, 2016)
*Denotes not FDA approved for use in ADHD
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Suspected Mechanism of Action of Medications for ADHD
Wilens TE. J Clin Psychopharmacol. 2008;28(3 Suppl 2):S46-S53. Markowitz et al JCAP, 2017)
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fMRI in Adults With ADHD
MGH NMR Center and Harvard-MIT CITPfMRI, 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.
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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.
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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; Zhu et al. Clin Pharm 2009 270: 59-65.
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Methylphenidate (MPH) in ADHD: Optimizing Dosing & Duration
Medication Starting DoseMaximum Dose*
Usual DosingDuration
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(disintegrating tab)
8.6 mg QD 51.8 mg 12 hr/once
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.
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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.
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Amphetamine
• Redundant hepatic metabolism (p448 inhibitors do not adversely alter AMPH levels)
• No pharmacokinetic drug interactions
• Linear pharmacokinetics
• Food effects noted (absorption delay; excretion enhancement)
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
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Amphetamine (AMPH) in ADHD: Optimizing Dosing & Duration
*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.
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
Dexedrine Tablets® 2.5–5 mg BID 1.5 mg/kg/day3–5 hr / BID–QID
Evekeo® 2.5–5 mg BID 3–5 hr / BID–QID
Dexedrine Spansule® 5 mg QD 6 hr / QD–BID
Dyanavel XR™
(suspension) 2.5–5 mg QD 1.5 mg/kg/day 12 hr / QD
Adzenys XR™
(disintegrating tab) 6.3–12.5 mg QD 12.5 mg (adolescents) 12 hr / QD
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Extended-Release Methylphenidate (Jornay PM)
Consider in early-morning ADHD dysfunction
(Drugs.com; Wilens et al., APSARD 2018; Wigal et al. AACAP 2018)
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
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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
Extended Release MPH Solution and Chewable Preparations
Consider for micro-titration, difficulty with pills
Rx list.com; PI
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Extended-Release Oral Disentegrating Methylphenidate (Contempla XR)
Consider with difficulty with pills
Drugs.com
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
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Amphetamine extended-extended release
Extended release mixed amphetamines: Mydayis Consider for extended duration in adult/
adolescent ADHD
Drugs.com
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)
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Amphetamine oral disintegrating tabs (Adzenys XR) Consider for difficulty with pills
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
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Amphetamine suspension (Dynavel XR)
Consider for titration, difficulty with pills
Drugs.com
Amphetamine suspension
Composition: 3.2 to1 ratio of d- to l-amphetamine
Dosing: 2.5 to 5 mg QD
Duration of action: 12 hours
D,L Amphetamine (Evekeo) for Pediatric ADHD
Consider for easier titration
Childress AC, Brams M, Cutler AJ, et al.. J Child Adolesc Psychopharmacol. 2015;25(5):402-414
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
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ADHD and Methylphenidate:Dose Effects on Attention in Clinic and Classroom
15
25
35
45
55
65
placebo 5 10 15 20
Wee
kly
T-S
core
Methylphenidate Dose
CPT
ADHD Comprehensive
Teachers Rating Score
% Academic
Efficiency
% On Task
Rapport, et al. 1987
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Higher Doses of Methylphenidate (Concerta) and Blood Levels Study
0
40
80
120
160
200
240
280
Mean
MP
H D
ose
(m
g)
Children Adults
169.4
±31.2
193.5
±37.
1
(Stevens, et al. JCAP 2010)
0
2
4
6
8
10
10-19.9 20-29.9 30-39.9 40-49.9 50-59.9
MPH Serum Level (ng/mL)
Ng/M
l
MPH Levels
Mean=27.3 ± 10.0 ng/mL
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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)
Kollins S, et al. JAACAP. 2007; Greenhill LL, et al. JAACAP. 2007
*tid=three times a day
Greenhill et al. J.Am. Acad. Child Adolesc. Psychiatry, 2006; 45(11): 1284-1293
Treatment of ADHD in Preschoolers: PATS Study
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Early Administration of Methylphenidate Improves Before School Functioning (Before School Functioning Scale)
Severe
None
P<0.05 vs PTSP<0.01 vs PTS
(N=50, 4 wk RCT)
(Wilens et alJ Clin Psychiatry. 2010. 71(5):548–556. )
P<0.01 vs PTS P<0.05 vs PTS
MTS = methylphenidate transdermal system
PTS = placebo transdermal system
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ADHD Part II Stimulants:Longer Term Outcomes & Adverse
Effects
Dose of OROS® MPH (Concerta) Increases Over Two Years to Maintain Effectiveness
20
25
30
35
40
45
50
1 3 12 21 24
1
1.05
1.1
1.15
1.2
1.25
1.3
Mean daily dose/body
weight (mg/kg)
Month
Mean
dose
(m
g)
Mean
daily
dose/b
od
y w
eigh
t (mg/k
g)
Mean Daily Dose (MG)
(Wilens et al. JAACAP: 2005)
MTA: 26% increase in
MPH dose by 14 months
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Spencer TJ, et al. J Clin Psychiatry. 2013;74(9):902-917.
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
Protective Effect of Medication Treatment on Later Comorbidity
Biederman J et al. Pediatrics. 2009;124(1):71-78.
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.
29Early ADHD Treatment Reduces Marijuana Use
Population risk
Stimulant use started prior to 9 years
of age*
Stimulant use started between 10-14
years*
Stimulant use started after 15 years
of age**
20% 30% 40% 50% 60%
Past Year Use
10 Cohorts of senior years 2005 to 2014
(N=40,358; ca. 10% with ADHD)
•McCabe, West, Dickinson, Wilens.. J Am Acad Child Adoles Psych 2016: 55:479-486
p<0.001 vs controls
p<0.001 vs controls
* > 6 years of treatment
** > 3 years of treatment
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ADHD Medication Reduce SUDUS 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)
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.
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MAS XR Study in Youth with ADHD: Frequently Reported Adverse Effects
% of Subjects Reporting
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STIMULANT CONTROVERSIES
• Adverse cardiovascular (CV) outcomes
• Growth suppression
• Development of tics
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Mixed Amph Salts: Mean Blood Pressure and Heart Rate
50
60
70
80
90
100
110
120
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Time in Study
(months)
Heart Rate (bpm)
Baseline
(Findling, Biederman, Wilens et al. J Ped:2006)
Cooper et al. The New England Journal of Medicine 2011; 365(20) 18960-1904.
ADHD Meds are Not Associated with Adverse CV Outcomes:Children
www.mghcme.orgHabel et al. JAMA 2011; 306(24) 2673-2683.
ADHD Meds are Not Associated with Adverse CV
Outcomes:
Adults
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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)
Effect of Stimulants on Height and Weight: A Review
of the LiteratureSTEPHEN 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
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25
Stimulant Treated
Not Stimulant Treated
Stimulants Not Related to New Onset
Tic Disorders in ADHD Boys(Spencer et al. Arch Gen Psych, 1999; N=128 ADHD and 110 controls)
Age in Years
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(Wilens & Hammerness. Straight Talk about Psychiatric Medications for Kids, Guilford Press, 2016)
Medication Strategies for Stimulant-Induced Side Effects
(Wilens & Hammerness. Straight Talk about Psychiatric Medications for Kids, Guilford Press, 2016)
Talk
Medication Strategies for Stimulant-Induced Side Effects (continued)
MGH Open Study: Fish Oils Are Effective in Reducing Emotional Dysregulation in Med-Treated ADHD Children (N=10)
CGI-S
Score
Mo
re im
pro
ve
me
nt
*P<0.0001
Markedly ill
Mildly ill
Normal
75% of Patients Were Improved in Mood
(Wilens et al., JCAP 2017)
No Effect on ADHD Observed
www.mghcme.orgWilens et al. J Am Acad Child Adolesc Psych: 2012
Combination of Guanfacine XR plus
Stimulants in the Treatment Of ADHD (N=455)
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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)
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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
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Viktorin A, et al. Am J Psychiatry. 2017 Apr 1;174(4):341-348.
Stimulants Do Not Activate Mania in Mood-Stabilized
Adults with Bipolar and ADHD
Results from the Swedish Registry Study (N=2307)
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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”
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Stimulants: Summary
• Most effective agents for ADHD
•
• Short- and long-term effectiveness,
tolerability, and safety established
• Efficacy established through the lifespan
• Consider dose and adjunct therapies in non-
responsive cases
• Most side effects can be managed
• Stay tuned for newer preparations
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QUESTIONS ?
