Stimulant Treatment of Pediatric ADHD - media-ns.mghcpd...
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Thomas J. Spencer, MD Massachusetts General Hospital
Harvard Medical School
Stimulant Treatment of Pediatric ADHD
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Disclosures
Dr. Spencer receives research support from Royalties and Licensing fees on copyrighted ADHD scales through MGH Corporate Sponsored Research and Licensing.
Dr. Spencer has a US Patent Application pending (Provisional Number 61/233. 686), through MGH corporate licensing, on a method to prevent stimulant abuse.
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3 nida.gov
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Effects of Methylphenidate (3 mg/kg i.p.) on Extracellular Levels of Monoamines in the Rat Prefrontal Cortex
Time in hours
-1 0 1 2 3 4
% B
ase
line
0
50
100
150
200
250
300
350
400 Dopamine Norepinephrine
Methylphenidate 3 mg/kg i.p.
*=P<0.05 versus baseline
* *
From Bymaster et al., Neuropsychopharmacology, 2002
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Mechanism of Action MPH: Insights from PET Imaging Studies
(Volkow et al. J Att Dis. 2002;(suppl)1)
– Because DA enhances task-specific neuronal
signaling and decreases noise, MPH-induced
increases in DA could improve attention and
decrease distractibility
– Since DA modulates motivation, the increases in
DA would also enhance the saliency of the task
facilitating the “interest it elicits” and thus
improving performance
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Superior Parietal Cortex
DLPFC
DLPFC
Dorsal ACC
VLPFC
Methylphenidate (Concerta) Increases dACC & DLPFC fMRI Activation in ADHD during MSIT
Bush et al. AGP - 2008
Concerta (N=11) vs Placebo (N=10)
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ADHD Practice Parameters. JAACAP 1997;36:85S. Zametkin and Ernst. N Eng J Med 1999;340:40.
In ADHD Stimulants Found to Improve
• Inattention
• Impulsivity
• Hyperactivity
• Noncompliance
• Impulsive aggression
• Social interactions
• Academic efficiency
• Academic accuracy
AND Core Symptoms
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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-Sc
ore
Methylphenidate Dose
CPT
ADHD Comprehensive Teachers Rating Score
% Academic Efficiency
% On Task
Rapport, et al. 1987
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––– CC ––– Beh ––– MedMgt ––– Comb
Parent Teacher
Assessment Point (Days)
0
0.5
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1.5
2
2.5
3
0 100 200 300 400
0
0.5
1
1.5
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2.5
3
0 100 200 300 400
MTA: Treatment Effects on Inattention Scores (SNAP) [MTA Group, Arch General Psychiatry, 1999]
Ave
rage
Sco
re
Ave
rage
Sco
re
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Effectiveness Factors in MTA Randomized Treatment Groups on Meds
Variable
MedMGt (n=131)
CC Group (n=94)
t value P
Severity CTQ-Total
52.4(17.4) 51.1 (16.6) -0.65 NS
% Time on MPH
89.0 (28.3) 41.1 (39.7) -11.70 <.0001
Average doses/day
2.9 (0.4) 2.1 (0.6) -11.61 <.0001
Total Daily Dose
32.8 (12.9) 18.7 (12.8) -7.75 <.0001
Total Visits 10.3 (4.3) 2.7 (3.5) -16.07 <.0001
Months on MPH
9.9 (3.9) 5.5 (5.4) -7.58 <.0001
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Indirect Effects of Medication on Parents, Teachers and Peers
(Barkley et al., Cunningham et al.)
• Social changes in Parents and Teachers • (Barkley et al., Pelham et al., Whalen et al.)
– Decreased rate of commands and degree of supervision
– Increased praise and positive responsiveness
• Social changes in Peers • (Cunningham et al., Whalen et al.)
– Decreased negative and aggressive behavior on stimulants
– Leads to greater acceptance by peers
– Leads to further positive benefit to the child
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Methylphenidate (MPH) in ADHD: Optimizing Dosing
*May exceed FDA approved dose. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. www.drugs.com.
Medication StartingDoseMaximumDose*UsualDosing
Duration
RitalinIR® 5mgQD/BID 2mg/kg/day 4hr/BID
Focalin® 2.5mgQD/BID 1mg/kg/day 4–5hr/BID–TID
FocalinXR® 5mgQD 1mg/kg/day 10–12hrQD
Daytrana® 10mg
6–16hr
Concerta® 18mgQD 2mg/kg/day 12hr/once
MetadateCD® 20mgQD
8hr/once
RitalinLA® 20mgQD
8hr/once
Quillivant® <10mgQD
12hr/once
Quillichew™ <10mgQD
8hr/once
AptensioXR 10mgQD
12hr/once
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Long Acting MPH formulations
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Bioavailability from two MPH extended-release formulations . Gonzalez et al. Int J Clin Pharmacol Ther 40(4):175–184
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MPH ER Individual PK Plots
0
5
10
15
20
0 2 4 6 8 10
Co
nc (
ng
/mL
)
Time (hrs)
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Pharmacological Dissociation Between The Robust Effects Of Methylphenidate On ADHD Symptoms And Weaker Effects On Working Memory
Biederman et al. Eur Neuropsychopharmacol 2011
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Amphetamine (AMPH) in ADHD: Optimizing Dosing
*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*
Usual Dosing 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
Dexedrine Tablets® 2.5–5 mg BID 1.5 mg/kg/day 3–5 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 Not established 12 hr / QD
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Best Response
(Percent)
Dextroamphetamine Methylphenidate Equal response to either stimulant
Meta-analysis of Within-Subject Comparative Trials Evaluating Response to Stimulant Medications
0
10
20
30
40
25% 23%
52% 50 6 studies N=274
Spencer et al. Arch of Gen Psych 2001
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MAS XR Efficacy: Academic Productivity
Randomized, Double-Blind, Placebo-Controlled Study
Placebo
MAS 10 mg
MAS XR 30 mg
MAS XR 10 mg
MAS XR 20 mg
McCracken JT, et al. J Am Acad Child Adolesc Psychiatry. 2003;42(6):673-683.
Number of Math Problems Completed Correctly
40
60
80
100
120
140
0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time Postdose (h)
PER
MP
Nu
mb
er C
orr
ect
N = 49
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-10
-5
0
5
10
15
Adderall XR Study in Youth with ADHD: CGIS-T Mean Total Score Afternoon
Placebo Add XR
10 mg
Add XR
20 mg
Add XR
30 mg
Baseline
Endpoint
Change
ITT Population
* *
* *P<0.001 (Dunnett test compared to placebo following ANCOVA with baseline score as covariate)
-1.2
-5.4 -6.8 -7.2
(Biederman et al., Pediatrics 2003)
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LDX Chemistry
LDX
Site of cleavage
l-lysine d-amphetamine
H N 2
O
N H
NH 2
CH 3 H N 2
O
OH
NH 2
H N 2
CH 3
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LDX Extraction, Pharmacokinetic and Abuse Liability Studies: Results
• Amphetamine is very difficult to extract from LDX prodrug
• Intravenous administration does not result in appreciable serum amphetamine levels in rat and human studies
• Intranasal administration does not result in appreciable serum amphetamine levels in rat and human studies
• Apparent “saturation” of LDX in gut limits ultimate serum amphetamine levels (e.g., overdose implications)
• Marginally less likeability in human studies
Jasinski D, et al. Posters presented at CPDD Meeting, June, 2006, Scottsdale, AZ.; Biederman J, et al. Poster presented at Annual APA Meeting, May 24, 2006, Toronto, Ontario, Canada. Boyle L, et al. Presented at NCDEU, June 12-15, 2006, Boca Raton, FL.
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0.0
0.5
1.0
1.5
2.0
2.5
3.0
1.0 2.0 3.0 4.5 6.0 8.0 10.0 12.0 1.0 2.0 3.0 4.5 6.0 8.0 10.0 12.0
LDX Adderall XR Placebo
LDX : Duration of Action SKAMP Time Course
LS
Mean S
KA
MP
Score
* * * * * *
* ** ** ** ** ** **
**
*P < .0001, **P < .01, LDX and Adderall XR vs placebo;
LS = Least Square.
Postdose (h)
N=50
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Adverse Effects of Stimulants
• Adverse effects (AEs) are similar for all stimulants
- Decreased appetite
- Insomnia
- Headache
- Stomachache
- Irritability/rebound phenomena
• Rates of these “Aes” may be high prior to any medical intervention; thus, baseline levels should always be obtained
Wilens T, Spencer T. In: Child and Adolescent Psychiatric Clinics of North America. Philadelphia, Pa:
Saunders Press; 2000:573-604.
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Blood Pressure and Heart Rate
Over 10 Years in the MTA
(Vitiello et al. JAMA 2012)
No significant treatment-by-time effect was observed on systolic or diastolic blood pressure.
A significant treatment-by-time effect was observed on heart rate (p=0.02), with significantly higher mean heart rates in the groups receiving medication at 14 months, but not afterward.
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Cooper et al. 2011 NEJM
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Gutgesell H, et al. Circulation. 1999:99:979-982.
Schubiner H, et al. J Atten Disord. 2006;10:205-211.
Screening for Cardiac Risk: AHA Guidelines
• Medical history − Personal congenital or acquired cardiac disease history
− Family history of cardiac disease (<50 years of age)
− Palpitations, chest pain, fainting, seizures, post-exercise symptoms
− Ask about other medications (including OTC)
• Routine medical exam
• Monitor BP and pulse at baseline and follow-up, especially in adults
• ECG is reasonable but not mandatory
• Routine check of Holter, ECHO is not necessary
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-2
-1
0
1
Year Prior to Tx First Year Tx Second Year Tx Third Year Tx
Boys (n = 68)
Girls (n = 16)
Growth Over Time in Children Treated With MPH
Lisska MC, Rivkees SA. J Pediatr Endocrinol Metab. 2003;16:711-718.
Gro
wth
Vel
oci
ty Z
Sco
res
Duration of Tx
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30
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25
Stimulant Treated
Not Stimulant Treated
Onset of Tic Disorders in ADHD Probands Stratified by Stimulant Treatment
Age in Years (Spencer et al., Arch Gen Psych, 1999)
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0
5
10
15
20
25
0 1 2 3 4 5 6 7 8 9 10
Time (hrs)
Feel
an
Eff
ect
IR-MPH
OROS-MPH
Feel an Effect (average±SEM)
a
a
a b
a p < 0.05 b P < 0.01
Spencer, Biederman et al. Am J Psych 2006.
a
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Early ADHD Treatment Reduces Marijuana Use
Population risk
Stimulant use started prior to 9 years of age
Stimulant use started between 10-14
years of age
Stimulant use started after 15 years of age
20% 30% 40% 50% 60%
Past Year Use
15 year follow-up study (N=40,358; 10% with ADHD)
* p<0.001 vs controls
*
*
McCabe, West, Dickinson, Wilens. J Am Acad Child Adoles Psych 2016: 55:479-486
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Protective Effect of Stimulants on Comorbidity
Biederman et al. Pediatrics. 2009.
2(1) = 19.7, p < 0.001 2
(1) = 17.8, p < 0.001
2(1) = 3.5, p = 0.063
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Psychostimulant Treatment and the Developing Cortex in ADHD
Shaw et al 2009
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www.mghcme.org
PI: Thomas Spencer, MD
Sarah Kassabian, at (617) 726-0481 [email protected].
FDA PK/PD Classroom Study