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Est presentacin tiene derechos de autor.Queda prohibido su distribucin y venta.
www.congresotdah.mx
www.cerebrofeliz.org
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Chronic Effects of Chronic Treatment of
ADHD: Focus on Pharmacotherapy
Timothy E. Wilens, M.D.
Chief, Division of Child and AdolescentPsychiatry
Director of Center for Addiction MedicineMassachusetts General Hospital
Harvard Medical School
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Faculty Disclosure
Dr. Wilens: Grant SupportNIH (NIDA, NIMH); ConsultantEuthymics/Neurovance, NIH (NIDA), Theravance, TRIS;
Published BooksStraight Talk About Psychiatric
Medications for Kids (Guilford Press),ADHD Across the
Lifespan (Cambridge University Press), Comprehensive
Clinical Psychiatry (Elsevier).
Some of the medications discussed may not be FDA-
approved in the manner in which they are discussed
including diagnosis(es), age groups, dosing, or in contextto other disorders (eg, substance abuse).
Brand names are included in this presentation forparticipant clarification purposes only. No product
promotion should be inferred.
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Abbreviations Used
! MPH = methylphenidate (active constituent of
Ritalin, Focalin, Concerta, Metadate)
OROS MPH = Osmotic release methylphenidate
(Concerta)
! AMPH = amphetamine (active constituent of
Dexedrine, Adderall, Biphetamine)
MAS = Mixed amphetamine Salts (Adderall,
Adderall XR)
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ADHD in the United States
ADHD prevalence among 8- to 15-year-olds: 8.7%
Percentage of children with ADHD who have been treatedconsistently during the past year: 32%
ADHD prevalence among 18- to 44-year-olds: 4.4%
Percentage of adults with ADHD who received treatment within theprevious 12 months: 11%
Associated with high degrees of psychiatric comorbidity
Associated with impairment in multiple domains
Associated with chronic course
Circa 75% persistence from childhood into adolescence
Circa 50% persistence from childhood into adulthood
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.
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Barbaresi WJ, et al. Pediatrics. 2013;131(4):637-644.
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Need for Long-Term Safety Studies
! To establish long-term effectiveness of medicationfor ADHD (tolerance? Dosing?)
! To address positive and negative effects on braindevelopment
! To address positive and negative effects on thedevelopment of other problems
! To address concerns that exist about effects oflong-term treatment on:
Growth
Tics
Cardiovascular
Substance abuse
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Psychostimulants Improve CorticalDevelopment in ADHD Growing Up
Prospective study utilizing two neuroanatomic MRI scans in 43 youths (age 9-20 years) with ADHD.
Shaw et al.Am J Psychiatry. 2009;166:58-63.
Mean baseline and endpoint raw cortical thickness (SEM)
in the left middle/inferior frontal gyrus
Thickness(mm)
4.8
4.1
3.8Time 1
(mean age,
12.5 years)
Time 2(mean age,
16.4 years)
For most participants, cognitive data was not collected at both timepoints. Increased cortical thinning in the groupthat stopped taking stimulants was not associated with any difference in clinical outcome. Effects of treatment with
nonstimulants cannot be excluded, although prevalence of nonstimulant use was low
*Derived from 620 scans of 294 typically developing youths
On psychostimulants (n = 19)Typically developing cohort*
Off psychostimulants (n = 24)
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Spencer TJ, et al. J Clin Psychiatry. 2013;74(9):902-917.
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Representative Studies of Chronic
Pharmacotherapy in ADHD! Study of Amphetamine (Gillberg et al. Arch Gen
Psych, 1997; 54:857-864)
Controlled study of d-amphetamine vs.
placebo 2 year follow-up
Findings of improved outcome with
amphetamine for ADHD, functioning
Relapse with controlled-discontinuation fromd-amphetamine at end of study
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Representative Studies of Chronic
Pharmacotherapy in ADHD
!
Study of Methylphenidate (MPH) (Abikoff, Hechtman et al.JAACAP:2004)
Collaboration of Canada and U.S. (initially presented in
1996) Use of immediate release MPH
Multimodal study of MPH alone (n=50) vs MPH +Multimodal treatment (N=50)
Findings at 2 years: Excellent response for both groups
No additive effect of psychotherapy (ies)
Noncomorbid ADHD
Comorbid ADHD
Relapse with discontinuation
(Abikoff et al, JAACAP, 2007)
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Medication management +
behavioral treatment
ADHD: Multimodal Treatment of ADHDResults at 14 Months
Medication
management alone
Behavioral treatment alone Community based treatment
All treatment arms found to be effective on an absolute basis
Nearly equally effectiveand superior to both:
(MTA Study Group, Arch Gen Psych, 1999)
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ADHD: Multimodal Treatment of ADHDResults at 14 Months
! Continued improvement to 24 months
! Majority with continued ADHD symptoms; not
clearly in remission
! Combined treatment
More useful in comorbid ADHD cases (ADHD plus
anxiety)
More subjects in remission
Slightly lower methylphenidate doses
(MTA Group, 1999a, 1999b; Swanson et al. JAACAP 2003)
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OROS MPH: Subject Retention
0
10
20
30
40
50
60
70
80
90
100
_ _
%Su
bjectsreceiving
medication
289 subjects completed 12 months on study. 278 subjects enrolled in extension study.
End of studyYear 1 Year 2
(Wilens et al. JAACAP:2005)
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Global Assessment: % Parents and Teachers Assessing
OROSMPH Treatment as Good/Excellent
0
10
20
30
40
50
60
70
80
90
100
Month 6 (T, n = 254; P, n = 320) Month 12 (T, n = 173; P, n = 287)
Month 21/24 (P, n = 210)
%A
ssessingtreatm
ent
good/excellent
Teacher Parent
(Wilens et al. JAACAP:2005)
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Dose of OROSMPH (Concerta) Over 2 Years
20
25
30
35
40
45
50
1 3 12 21 24
Month
Meandose(m
g)
Mean Daily Dose (MG):
Increase of 30% over 2 yrs
(Wilens et al. JAACAP: 2005)
MTA study increase in MPH
of 26% over 14 months
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Dose of OROSMPH (Concerta) Over 2 Years
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
Meandose(m
g)
Meandailydose/bodyweigh
t(mg/kg)
Mean Daily Dose (MG)
(Wilens et al. JAACAP: 2005)
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Drug Holidays
OROS MPH Data:22% of children took a drug holiday of between and
29 consecutive days
17% children took a drug holiday of 30 or more
consecutive daysDrug holidays associated with return of ADHD
symptoms & poorer response
European consortium (IACAP, Berlin 2005):
5/6 studies of drug holidays indicated deleteriouseffects
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MAS XR Effectiveness:
Parented-rated Conners Global Index Scores
0
2
4
6
8
10
12
14
Q 1 Q 2 Q 3 Q 4 Q 5 Q 6 Q 7 Q 8
Mean scores for ITT population.
Baseline
N=560 N=463 N=402 N=359 N=308 N=297
Note: A lower CGIS-P score indicates better response to treatment.
N=259 N=267N=568
Year 1 Year 2
CGIS-PSco
re No change in weight corrected dose was found
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Atomoxetine in Young children with ADHD(Kratchovil, Wilens et al. J Am Acad Child Adoles Psych; 2006)
! Study of 448 children at 6-7 years; 97 followed to twoyears
! Mean dose = 1.47 mg/kg/day
!
Findings! Significant sustained effectiveness
Sustained effectiveness up to 2 years
No increase in dose evident (e.g. tolerance developing)
! Adverse effects
Low discontinuation rate (4%) Increases in pulse (+5 bpm) and blood pressure (5 mmHg
each for systolic and diastolic)
20% with decreased appetite
Significant effect on decreased weight over two years
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Atomoxetine in Adolescents
! N=13 studies; 610 subjects, 269 followed over twoyears
! Ages 12-18
!
Mean dose = 1.4 mg/kg/day! Findings (see next slide)
! Reduced ADHD RS scores over two years
16% discontinued secondary to lack of effectiveness
! Adverse events
5% drop secondary to effectiveness No clinically significant BP, height, weight, psychiatric, or
laboratory findings
(Wilens et al. J Pediatrics:2006)
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Effectiveness of Atomoxetine in Adolescents
ean ase - ota core easurements ver mPatients age 12 and older
Output: \\tiger\tiger.grp\ATMX_RMP\data mining\adolescent\LOCF AD4PITLI adol GRAPH_kb_1.cgm.
Program: \\mc1stat02\mc1stat02.grp\rmp\b4zs\Data Mining\adolescent\LOCF AD4PITLI adol GRAPH_kb_1.sas.
Population: Enrolled patients age 12 and older with at least one dose Atomoxetine.
0
5101520253035404550
Duration (Months)0 1 2 3 6 9 12 15 18 21 24
(Wilens et al. J Pediatrics:2006)
(N=882)
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What is the relationship of side effects
and medication dose to side effects
over time?
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Side Effects Lessen Over Time: MixedAmph Salts XR (Adderall XR) Side Effects
Occurrence Over Time
0
5
10
15
20
25
30
35
40
45
Q 1 Q 2 Q 3 Q 4 Q 5 Q 6 Q 7 Q 8+TotalTreatment-emergentAEs(%)
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Adverse Events Probably or Possibly Related
to OROSMPH (Concerta) by Dose Level
%S
ubjectswithindosagegroup
0
5
10
15
20
25
Headache Abdominalpain
Decreasedappetite
Insomnia Tics
18 mg (n = 215)36 mg (n = 337)
54 mg (n = 261)
(Wilens et al. JAACAP: 2005)!5% Subjects Overall
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14
9
5
0 0
21
0
20
10
32
12 2
0
6
3
1 1 10 0
1
0
2
4
68
10
12
14
16
18
20
Q 1 Q 2 Q 3 Q 4 Q 5 Q 6 Q 7 Q 8
Adderall XR 10 mg Adderall XR 20 mg Adderall XR 30 mg
Amphetamine Extended-release (Adderall XR)Adverse Events Leading to Withdrawal (n=84)
Dose at Withdrawal
Time When Patient Withdrew from Study
NumberofPatients
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Does ADHD Treatment Effect the
Development of Psychiatric
Comorbidity?
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N = 140 boys with ADHD at entry; 10-year follow-up datan = 82 participants receiving stimulants [mean duration of 6 yrs], n = 30 not on stimulants
Biederman J, et al. Pediatrics. 2009;124(1):71-78.
Protective Effect of Medication Treatment on
Later Comorbidity
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Does ADHD Treatment Beget Later
Cigarette Smoking or Substance
Abuse ?
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MGH Study of Adolescent Girls with ADHDStimulant Tx Reduces Later Substance Use Disorders
Wilens TE, et al.Arch Pediatr Adolesc Med. 2008;162(10):916-921.
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Groenman AP, et al. Br J Psychiatry. 2013; 203(2):112-119.
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Groenman AP, et al. Br J Psychiatry. 2013; 203(2):112-119.
Cumulative Lifetime Risk for Any Substance Use
Disorder
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Swedish national registers (N = 25,656 with ADHD, about 50% on medications). 40% ofconvictions related to drug offenses (Tx OR = .6). No difference in type of ADHDmedication (stimulants, nonstimulants) or level of crime.
Lichtenstein P, et al. N Engl J Med. 2012;367(21):2006-2014.
Medication for ADHD Reduces Criminality
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Chang Z, et al. JAMAPsychiatry. 2014;71(3):
319-325.
Serious Transport Accidents in Adults with ADHD
and the Effect of Medication: A Population-Based Study
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Are ADHD treatments associated with
growth problems over time?
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(Wilens et al. JAACAP: 2005; Spencer et al. JAACAP:2006)
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OROS MPH: Effects on Height
Heightz-score
-1.0
-0.8
-0.6-0.4
-0.2
0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20
Months
z-height
(Wilens et al. JAACAP: 2005; Spencer et al. JAACAP:2006)
Open label two-year study of 407 children
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Effect of Stimulants on Height and Weight: A Reviewof the LiteratureSTEPHEN V. FARAONE, PH.D., JOSEPHI BIEDERMAN, M.D.,
CHRISTOPHE P. MORLEY, M.A., AND THOMAS J. SPENCER, M.D.ABSTRACTObjective: Stimulant medications are effective treatments for attention-deficit/hyperactivity disorder, butconcerns remain about their effects on growth. Method: We provide a quantitative analysis of longitudinalstudies about deficits in expected growth among children with attention attention-deficit/hyperactivity disordertreated with stimulant medication. Study selectioncriteria 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. Forissues not suitable for quantitative analyses, we provide a systematic, qualitative review. Results: Thequantitative analyses showed that treatment with
stimulant medication led to statistically significant delays in height and weight. This review found statisticallysignificant evidence of attenuation of these deficits over time. The qualitative review suggested that growthdeficits 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 thatattention deficit/hyperactivity disorder itself maybe associated with dysregulated growth.
Conclusions:Treatment with stimulants in childhood modestly reduced expectedheight and weight. Although these effects attenuate over time and some datasuggest that ultimate adult growth parameters are not affected, more work isneeded to clarify the effects of continuous treatment from childhood to adulthood.Although physicians should monitor height, deficits in height and weight do notappear 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
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Schwartz BS, et al. Pediatrics. 2014;133(4):668-676.
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Similar Effects of Methylphenidate andAmphetamine on Growth
! No differences between MPH and AMPH after threeyears of treatment (Gross, 1976)
! No significant differences in height found betweenMPH and AMPH groups after three years of treatment
(Kaffman et al. 1979)
! No significant differences in height found betweenMPH and AMPH groups after five years of treatment
(Sund et al. 1979)
! No differences between MPH and AMPH after one year
of treatment (Schwartz, 1976)
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-5
-4
-3
-2
-1
0
1
2
3
4
0 to 6 6 to 18 18 to 30 30 to 42
Height Velocity by Duration ofMPH & AMPH Treatment
(Poulton A, Cowell CT. J Paediatr Child Health2003;39:180-185.)
Treatment period (months)
HeightvelocityZ-
Score
n = 51 n = 9n = 14n = 36
P
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Height and Weight Are Similar in Treated andUntreated Adults with ADHD
50
75
100
125
150
175
200
Tx ADHD UnTx Brothers UnTx ADHD
Kramer, et al.J Am Acad Child Adolesc Psychiatry.2000;39:517-524.
Height
(cm)
N=97 N=77 N=37
50
60
70
80
90
Tx ADHD UnTx
Brothers
UnTx ADHD
Weight
(Kg)
N=97 N=77 N=37
Youth aged 4 -12 yrs
MPH exposure = 36 mo
Reeval @ 21-23 years
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Weight Over Time
Duration
0 5 10 15 20 25
WeightPercen
t
20
40
60
80
52
54
56
58
60
62
64
66
68
Weight Percent
Weight
Atomoxetine Has No Effect on Weight in Adolescents(2 years exposure to Atomoxetine)
(Wilens et al. J Pediatrics: 2006)
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Height Over Time
Duration
0 5 10 15 20 25
HeightPercent
35
40
45
50
55
60
156
158
160
162
164
166
168
170
172
Height Percent
Height
Atomoxetine Has No Effect on Height in Adolescents(2 years exposure to Atomoxetine)
(Wilens et al. J Pediatrics: 2006)
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What cardiovascular effects do
the stimulants and nonstimulants
have and are they safe ?
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Mixed Amphetamine 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
(Spencer et al. CNS Spectrums: 2005)
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OROS MPH Related Change in Vital Signs:Month 12 vs Baseline (N=407)
-1
0
1
2
3
4
5
6
7
8
9
10
18mg 36mg 54mg
Dose Level
MeanChange
Systolic PulseDiastolic
(Wilens, Biederman & Lerner, J Clin Psychopharm 2003)
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BP / Pulse over Time
Duration
0 5 10 15 20 25 30
0
20
40
60
80
100
120
140
Pulse
0
20
40
60
80
100
120
Systolic
Diastolic
Pulse
Adolescents with 2 years exposure to Atomoxetine
Wilens et al. J Pediatrics: 2006
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Adjusted Rates of Serious Cardiovascular Events, According to the Use of ADHD Drugs. Rates per100,000 person-years were adjusted by multiplying the rate in the reference group (nonusers) by thehazard ratios for former and current users. Hazard ratios were estimated with the use of Cox regressionmodels, which were adjusted for the site-specific propensity-score decile, study site, medical conditions(serious cardiovascular disease and serious chronic illness), psychiatric conditions (major psychiatricillness, substance abuse, and antipsychotic use), utilization variables (medical hospitalization and generalaccess to medical care), age, and calendar year. The I bars indicate 95% confidence intervals.
Cooper WO, et al. N Engl J Med. 2011;365(20):1896-1904.
ADHD Medications are Not Associated with
Adverse Cardiovascular Outcomes in Children
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Habel LA, et al. JAMA. 2011;306(24):2673-2683.
ADHD Medications are Not Associated with
Adverse Cardiovascular Outcomes in Adults
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Cardiopulmonary Exercise Testing on
Amphetamine: MGH Study
MGH Protocol - Electronically braked ergometer, 12-lead ECG Metabolic cart (MedGraphics)
Hammerness et al. World J Biol Psych, 2012; Early Online: 18
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Recommended Cardiovascular Monitoring
!American Heart Association Guidelines (Gutgesell etal., Circulation; 1999; J Am Acad Child Adoles Psych; 1999)
! Family History of SD (
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Issues in the Use of Stimulant Medication: Tics
Development and Exacerbation of Tics
! Current Research:
Most tics are transient and chronic tics are rare
Most individuals on stimulants experience an
improvement in ADHD symptoms with no
predictable effect on tics
Stimulants may exacerbate ticsobserved in
30% of ADHD and tic patients
Castellanos FX, et al.J Am Acad Child Adolesc Psychiatry.1997;36(5):589-596.
Gadow KD, et al.Arch Gen Psychiatry.1999;56:330-336.
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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, Biederman, Wilens Arch Gen Psych:1999)
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Offset of Tic Disorders in ADHD ProbandsStratified by Stimulant Treatment
Age in Years(Spencer et al., Arch Gen Psych, 1999)
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Summary: Chronic Effects of Treatment! Difficult to perform long-term studies of monotherapy
for ADHD! Continued effectiveness of stimulants and
nonstimulants
! Improvements in Brain Structure over time
! May have mild tolerance with methylphenidate
! All agents generally well tolerated longer term:
?Growth effects of MPH and AMPH attenuate > 2 years out
Reduce cigarette and substance risk
No deleterious effects of stimulants on tic onset or remission
No evidence of cardiovascular deleterious effects in medically
healthy children! Medications for ADHD are safe, improve long term
outcomes for ADHD and related disorders, and appearto have neurotropic effects
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QUESTIONS
OR
COMMENTS ?