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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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