Attention Deficit Hyperactivity Attention Deficit Hyperactivity Disorder (ADHD):Disorder (ADHD):

Medication TreatmentMedication Treatment

Tim Wigal, Ph.D.Tim Wigal, Ph.D.

PediatricsPediatrics

University of California, IrvineUniversity of California, Irvine

Minimal Brain Dysfunction

Minimal Brain Damage

Hyperkinetic Reaction of Childhood (DSM-II)

Attention Deficit Disorder + or - Hyperactivity (DSM-III)

Attention Deficit Hyperactivity Disorder (DSM-III-R)

19601960 1980198019681968 19871987 19941994

Attention Deficit/Hyperactivity Disorder (DSM-IV)Attention Deficit/Hyperactivity Disorder (DSM-IV)

19301930

ADHD: Historical TimelineADHD: Historical Timeline

ADHD-likesyndromefirst described

19021902

ADHD: DSM-IV SubtypesADHD: DSM-IV Subtypes ADHD Predominantly Inattentive TypeADHD Predominantly Inattentive Type

– Criteria met for inattention but not for Criteria met for inattention but not for impulsivity/hyperactivityimpulsivity/hyperactivity

ADHD Predominantly Hyperactive-Impulsive TypeADHD Predominantly Hyperactive-Impulsive Type– Criteria met for impulsivity/hyperactivity Criteria met for impulsivity/hyperactivity

but not for inattentionbut not for inattention

ADHD Combined TypeADHD Combined Type– Criteria are met for both inattention and Criteria are met for both inattention and

impulsivity/hyperactivityimpulsivity/hyperactivityInattention

Impulsivity/Hyperactivity

Inattention

Impulsivity/Hyperactivity

AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S.

Proper Steps in DiagnosisProper Steps in Diagnosis AssessmentAssessment

– HistoryHistory– DSM-IV criteriaDSM-IV criteria– Interview — parents, teachers, and patientInterview — parents, teachers, and patient

Determine functional impairment in home and school/job settingsDetermine functional impairment in home and school/job settings

– Rating scales to corroborate clinical diagnosisRating scales to corroborate clinical diagnosis– Physical exam, vital signs, physical explanation for Physical exam, vital signs, physical explanation for

disorder, secondary conditions, drug contraindicationsdisorder, secondary conditions, drug contraindications– Make assessment for comorbid conditionsMake assessment for comorbid conditions

ADHD Low selfesteem

Academiclimitations

Relationships

Smoking andsubstance abuse

InjuriesMotor vehicle

accidents

Legaldifficulties

Occupational/vocational

Children

Ad

ult

s

Adolescents

Potential Areas of ImpairmentPotential Areas of Impairment

Goldman, et al. JAMA.1998;279:1100-1107.

Worldwide Prevalence of Worldwide Prevalence of ADHD Is 3% to 7%ADHD Is 3% to 7%

0 5 10 15 20

New Zealand (Anderson et al 1997)

Ontario (Szatmari et al 1989)

US inner city (Newcorn et al 1989)

Pittsburgh, Pa (Costello et al 1988)

Iowa (Lindgren et al 1990)

Germany (Baumgaertel et al 1995)

London, England (Esser et al 1990)

Mannheim, Germany (Esser et al 1990)

Tennessee (Wolraich et al 1996)

United States (Shaffer et al 1996)

Incidence of ADHD (%) in school-age children

Studies of ADHD prevalence

ADHD: EtiologyADHD: Etiology

ADHD is a heterogeneous behavioral disorder with multiple possible etiologies

CNS = central nervous system

CNSinsults

Geneticorigins

Neuroanatomicalneurochemical

ADHD

Environmentalfactors

MGH-NMR Center & Harvard-MIT CITP. Adapted from Bush, et al. Biol Psychiatry. 1999;45:1542-1552.

1 x 10-3

1 x 10-2

1 x 10-3

y = +21 mm y = +21 mm

Normal control ADHD

Anterior Cingulate Cortex

Frontal StriatalInsular network

• fMRI shows decreased blood flow to the anterior cingulate and increased flow in the frontal striatum

• PET imaging shows decreased cerebral metabolism in brain areas controlling attention

• SPECT imaging shows increased DAT protein binding

Neuroimaging and ADHDNeuroimaging and ADHD

1 x 10-2

Faraone. J Am Acad Child Adolesc Psychiatry. 2000;39:1455-1457. Hemminki. Mutat Res. 2001;25:11-21.Palmer. Eur Resp J. 2001;17:696-702.

Willerman, 1973

Goodman, 1989

Gillis, 1992

Edelbrock, 1992

Schmitz, 1995

Thapar, 1995

Gjone, 1996

Silberg, 1996

Sherman, 1997

Levy, 1997

Nadder, 1998

Hudziak, 2000

Average genetic contribution of ADHD based on twin studies0 0.2 0.4 0.6 0.8 1

HeightBreast cancer Asthma Schizophrenia

Twin Studies Show ADHD Twin Studies Show ADHD Is a Genetic DisorderIs a Genetic Disorder

ADHD Mean

Sunohara G, et al. J Am Acad Adolesc Psychiatry. 2000;39:1537-1592.Giros B, et al. Nature. 1996;379:606-612.

Molecular Genetics of ADHD Molecular Genetics of ADHD

Specific genes associated with ADHDSpecific genes associated with ADHD– Dopamine receptor D4 gene (DRD4) on Dopamine receptor D4 gene (DRD4) on

chromosome 11chromosome 11– Dopamine transporter gene (DAT1) on Dopamine transporter gene (DAT1) on

chromosome 5chromosome 5– D2 dopamine receptor geneD2 dopamine receptor gene– Dopamine-beta-hydroxylase geneDopamine-beta-hydroxylase gene– Uncertain about the association ofUncertain about the association of

noradrenergic genesnoradrenergic genes There are several genes involved and their effects There are several genes involved and their effects

are cumulativeare cumulative

Three Components of Three Components of ADHD TreatmentADHD Treatment

Education Education Psychosocial interventions Psychosocial interventions Pharmacotherapeutic interventionsPharmacotherapeutic interventions

American Academy of Pediatrics: Guidelines American Academy of Pediatrics: Guidelines for the Treatment of ADHDfor the Treatment of ADHD

Establish a treatment program that recognizes ADHD as a Establish a treatment program that recognizes ADHD as a chronic conditionchronic condition

Specify appropriate target outcomes to guide managementSpecify appropriate target outcomes to guide management Prescribe Prescribe stimulant medicationstimulant medication and/or and/or behavior therapybehavior therapy to to

improve target outcomes in children with ADHDimprove target outcomes in children with ADHD If the treatment program has not met target outcomes, If the treatment program has not met target outcomes,

evaluate:evaluate:– Original diagnosisOriginal diagnosis– Use of all appropriate treatmentsUse of all appropriate treatments– Adherence to the treatment planAdherence to the treatment plan– Presence of coexisting conditionsPresence of coexisting conditions

Using information from parents, teachers, and the child, Using information from parents, teachers, and the child, follow-up to evaluate target outcomes and adverse effectsfollow-up to evaluate target outcomes and adverse effects

AAP. Pediatrics. 2001;108:1033-1043.

Sources: Prevalence - Equinox, Diagnosed & Treated - PDDA, Drug - NDC

Th

ou

san

ds

91.7% of diagnosed patients are treated with medication

7,660

4,1353,790

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

Prevalence Diagnosed Treated

Prevalence, Diagnosis, and Treatment of Prevalence, Diagnosis, and Treatment of ADHD in US Across All AgesADHD in US Across All Ages

MTA Sites and CollaboratorsMTA Sites and Collaborators

UC IrvineUC Irvine Duke UDuke USwanson, Wigal Swanson, Wigal Conners, Wells, MarchConners, Wells, March

U PittsburghU Pittsburgh LIJ/Montreal CCLIJ/Montreal CCPelham, HozaPelham, Hoza Abikoff, HetchmanAbikoff, Hetchman

Columbia UColumbia U UC BerkeleyUC BerkeleyGreenhill, NewcornGreenhill, Newcorn Hinshaw, ElliottHinshaw, Elliott

NIMH/US Dept Education/Stanford NIMH/US Dept Education/Stanford Jensen, Severe, Arnold, Richters, Vitiello, Vereen/Shiller/Kraemer Jensen, Severe, Arnold, Richters, Vitiello, Vereen/Shiller/Kraemer

Summary of the MTA DesignSummary of the MTA Design

4 randomly assigned groups

Med management (MedMgt, n=144)Behavior modification (Beh, n=144)Combined multimodal (Comb, n=145)Routine community care (CC, n=146)

First 3 groups treated 14 monthsAll assessed at baseline, 3, 9, and 14 months

MTA Cooperative Group. Arch Gen Psych. 1999;56:1073-1086.

Combination Therapy Is More Effective in the Combination Therapy Is More Effective in the MTAMTA

All treatment arms improved symptoms on an All treatment arms improved symptoms on an absolute basisabsolute basis

Medication management with behavior Medication management with behavior management for ADHD symptoms showed the management for ADHD symptoms showed the most improvementmost improvement

Behavior management was slightly superior to Behavior management was slightly superior to community-based treatment (2/3 Medication)community-based treatment (2/3 Medication)

Questions about the MTA from a Questions about the MTA from a Clinician Clinician

““What is the chance of clinical success rate if I What is the chance of clinical success rate if I adopt the MTA behavioral algorithm?”adopt the MTA behavioral algorithm?”– about 34% will show “loss of symptoms”about 34% will show “loss of symptoms”

““What is the chance of clinical success rate if I What is the chance of clinical success rate if I adopt the MTA medication algorithm?”adopt the MTA medication algorithm?”– about 56% will show “loss of symptoms”about 56% will show “loss of symptoms”

““What additional benefits are expected if I also What additional benefits are expected if I also recommend intensive psychosocial treatment? recommend intensive psychosocial treatment? – an increase of about 12%, from 56% to 68%an increase of about 12%, from 56% to 68%

AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S.

Education of Patients and FamilyEducation of Patients and Family

Understanding the disorderUnderstanding the disorder– Medical causeMedical cause– Not due to poor parentingNot due to poor parenting

Environmental restructuringEnvironmental restructuring– Classroom changesClassroom changes– ADHD-friendly modifications in family, work, leisure activitiesADHD-friendly modifications in family, work, leisure activities– Structure, lists, delegatingStructure, lists, delegating

Parent support groups: for example, Parent support groups: for example, www.chadd.org, www.add.orgwww.chadd.org, www.add.org

Parent educationParent education– Use naturally occurring consequences to teach social skillsUse naturally occurring consequences to teach social skills

– Reinforce positive behaviors and correct negative behaviorsReinforce positive behaviors and correct negative behaviors

– Establish and maintain house rulesEstablish and maintain house rules Social skills trainingSocial skills training

– Target specific behaviors, ie, playground aggressionTarget specific behaviors, ie, playground aggression

– More effective in groups and natural environments like school or campMore effective in groups and natural environments like school or camp

– Stress conflict-resolutionStress conflict-resolution Academic skills trainingAcademic skills training

– Individual or group trainingIndividual or group training

– Focus on following directions, time management, and study skillsFocus on following directions, time management, and study skills

AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S.

Psychosocial Interventions in Psychosocial Interventions in ADHD TreatmentADHD Treatment

AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36(suppl):85S-121S.

Classes of Medication Used Classes of Medication Used to Treat ADHDto Treat ADHD

FDA-approved FDA-approved – Stimulants (methylphenidate, amphetamine)Stimulants (methylphenidate, amphetamine)

Off-labelOff-label– Antidepressants (tricyclics, bupropion)Antidepressants (tricyclics, bupropion) -adrenergic agonists (clonidine)-adrenergic agonists (clonidine)

v v Storagevesicle

DA Transporter

Cytoplasmic DA

Methylphenidate

Presynaptic Neuron

Synapse

Probable Mechanism of Action Probable Mechanism of Action of Methylphenidateof Methylphenidate

Wilens T, Spencer TJ. Handbook of Substance Abuse: Neurobehavioral Pharmacology. 1998;501-513.

ADHD Practice Parameters. J Am Acad Child Adolesc Psychiatry. 1997;36:85S.Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry. 1999;38:503-512.

In ADHD: In ADHD: Stimulants Found to ImproveStimulants Found to Improve

Core SymptomsCore Symptoms– InattentionInattention– ImpulsivityImpulsivity– HyperactivityHyperactivity

Other SymptomsOther Symptoms– NoncomplianceNoncompliance– Impulsive aggressionImpulsive aggression– Social interactionsSocial interactions– Academic efficiencyAcademic efficiency– Academic accuracyAcademic accuracy– Family dynamicsFamily dynamics

AACAP Clinical Practice Guidelines. J Am Acad Child Adolesc Psychiatry. 1997;36(suppl):85S-121S.

Controversies: growth deficits, tic exacerbation, seizures, abuse

(Effects occurring in >5% of patients and >placebo)

Stimulants: Potential Side EffectsStimulants: Potential Side Effects

Appetite loss,Appetite loss,abdominal painabdominal pain

InsomniaInsomnia NervousnessNervousness

Mild increase in pulse, Mild increase in pulse, blood pressureblood pressure

Psychiatric effects, Psychiatric effects, irritability, dysphoria, irritability, dysphoria, and reboundand rebound

New Formulations for ADHDNew Formulations for ADHD

MethylphenidateMethylphenidate AmphetamineAmphetamine

History of Stimulant FormulationsHistory of Stimulant Formulations

1937 – IR d, l-amphetamine1937 – IR d, l-amphetamine 1940 – IR d-amphetamine1940 – IR d-amphetamine 1950 – IR methylphenidate1950 – IR methylphenidate 1970 – IR pemoline1970 – IR pemoline 1980 – SR methylphenidate1980 – SR methylphenidate 2000 – New formulations2000 – New formulations

FIRST LINE TREATMENTS: STIMULANTSAMPHETAMINE

Adderall XR Shire Pharmaceuticals 10 hr10-30mg (X1)

Desoxyn Ovation Pharmaceuticals 4 -5 hr10-25 mg (X2)

Dexedrine Spansule Glaxo-Smith-Kline 7 hr 5-15 mg (X2)

Dexedrine Glaxo-Smith –Kline 5 hr 5-14mg (X3)

Vyvanse Shire 10-12 hr 30, 50, 70 mg (X1)

METHYLPHENIDATEConcerta McNeil Pharmaceuticals 9-10 hr 18-72mg (X1)

Metadate CD UCB Pharmaceuticals 8 hr 20-60 mg (X1)

Ritalin LA Novartis 7-8 hr 10 – 60 mg (X1)

Methylin ER Mallinckrodt 6 hr 20-30 mg (X2)

Focalin Novarits 4 hr 2.5 – 15 mg (X3) FocalinXR Novarits 8 hr 5, 10, 15 & 20mg (X1)

Ritalin Novartis 4 hr 5-30 mg (X3)

Daytrana Shire Methylphenidate patch 12 hr

(Patches are 10, 15, 20 and 30 mg)

SECOND LINE TREATMENTS: ANTI- DEPRESSANTSStrattera Eli Lilly 8-10 hr 10-60 mg (X2)

(Wellbutrin SR Glaxo-Smith-Kline 6-8 hr 100-150 mg (X2)

Tricyclics: Pamelor, Norpramin &Tofranil (Imipramine) All by Novarits 4-6 hr 10-30mg (X3)

SECOND LINE TREATMENTS: OLDER MEDICATIONS

Cylert – made by Abbott – discontinued due to liver toxicity; stimulant-like drug

Clonidine - Less used due to concerns about side effects (sedation) and sudden death when used in conjunction with stimulant therapy; beta blocker

drug (antihypertensive).

MEDICATIONS STILL UNDER DEVELOPMENTProvigil Cephalon Modafinil (Anti-narcoleptic) –not FDA approved

Guanfacine ER Shire Anti-hypertensive – Approvable letter issued

Laboratory School Staff

The Final Formulation of The Final Formulation of OROS®-MPH for Concerta™OROS®-MPH for Concerta™

MPH Overcoat

Tablet Shell

Push Compartment

MPH Compartment

#2

Laser-Drilled Hole

MPH Compartment

#1

FOCALIN: FOCALIN: DexmethylphenidateDexmethylphenidate

HN

H

H

PhCH3OOC

2’

2

D (+) Methylphenidate (2R, 2’R)

H

H

H

Ph CHOOC3

2’

2

l (-) Methylphenidate (2S, 2’S)

D-methylphenidate

N

DexmethylphenidateDexmethylphenidate

HN

H

H

PhCH3OOC

2’

2

FOCALIN DosingFOCALIN Dosing

Data on file

2.5mg 5mg 10mg

—Recommended conversion doses

5 mg

10 mg

20 mg

2.5 mg

5 mg

10 mg

METHYLPHENIDATE DOSE DEXMETHYLPHENIDATE DOSE

RitalinRitalin®® LA—Bimodal Release for LA—Bimodal Release for Once-daily DosingOnce-daily Dosing

Delayed-Release Bead

ADDERALL XR™ Pulse Delivery System

Immediate-Release Bead

Bead Core

Overcoating

Release-DelayingPolymer

Overcoating

ADDERALL XR™ Capsule

Overcoating

50% 50%

Drug LayerDrug Layer

Bead Core

Available in 10 mg , 20 mg, and 30 mg capsules

0.5

1

1.5

2

2.5

3

0 1.5 3 4.5 6 7.5 9 10.5 12

More symptoms

Fewer symptoms

Time post dose (hr)

Analog Classroom Study:Analog Classroom Study: Mean SKAMP Deportment scores Mean SKAMP Deportment scores

Placebo ADDERALL XR 30 mgADDERALL XR 20 mgADDERALL XR 10 mg

SummarySummary

MPH formulations are the “gold standard” of MPH formulations are the “gold standard” of stimulant medications used to treat ADHDstimulant medications used to treat ADHD

Both MPH and Amphetamine preparations helpBoth MPH and Amphetamine preparations help Dose Dependent results are typicalDose Dependent results are typical Coverage throughout the day depends on the Coverage throughout the day depends on the

formulation, the needs of each child and formulation, the needs of each child and individual brain chemistryindividual brain chemistry

MEDICATION MEDICATION TREATMENTTREATMENT

Adverse Events in PATSAdverse Events in PATS

Summary of Vital Signs and Adverse Events Summary of Vital Signs and Adverse Events Relating to Hypertension and TachycardiaRelating to Hypertension and Tachycardia

Dosage during titration at time of Dosage during titration at time of the Hypertension/ the Hypertension/ Tachycardia AEsTachycardia AEs

7.5mg TID- 2 Hypertension7.5mg TID- 2 Hypertension1 Tachycardia AE1 Tachycardia AE

5mg TID- 2 Hypertension AEs5mg TID- 2 Hypertension AEs

2.5mg TID- 3 Hypertension AEs2.5mg TID- 3 Hypertension AEs

1.25mg TID- 1 Hypertension AE1.25mg TID- 1 Hypertension AE

Placebo- 0 AEsPlacebo- 0 AEs (Mild tachyardia is 2 (Mild tachyardia is 2

measurementsmeasurementsof HR at 120-130 for ages 3-5.)of HR at 120-130 for ages 3-5.)

(Mild hypertension is a systolic or(Mild hypertension is a systolic ordiastolic reading above the 95diastolic reading above the 95thth

percentile based on age: 3 ispercentile based on age: 3 is110/072, 4 is 112/72, 5 is 114/73,110/072, 4 is 112/72, 5 is 114/73,and 6 is 115/74) and 6 is 115/74)

VisitVisit

PulsPulse e

(BP(BPM)M)

  

SystoliSystolic BP c BP

(mmH(mmHg)g)

  

DiastolDiastolic BP ic BP

(mmHg(mmHg))

  

  MeaMea

nnSDSD MEANMEAN SDSD MEANMEAN SDSD

Parallel- Parallel- Best Dose Best Dose

GroupGroup94.394.3 10.810.8 101.6101.6 9.49.4 61.861.8 8.48.4

Parallel- Parallel- Placebo Placebo GroupGroup

98.398.3 11.811.8 99.499.4 10.710.7 6161 10.810.8

1st Month 1st Month of of

MaintenancMaintenancee

9898 14.314.3 105105 12.812.8 62.462.4 8.48.4

10th Month 10th Month of of

MaintenancMaintenancee

99.399.3 1010 103.6103.6 1010 6161 9.89.8* No statistically significant differences were found.* No statistically significant differences were found.

Side effects in PATS with statistically significant linear decreases

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

(14.17) (15.86) (16.54) (17.07) (17.85) (18.16) (18.77) (18.88) (19.54) (20.51)

Crabby, Irritable

Prone to Crying

Tearful, Sad, Depressed

Listless

1 2 3 4 5 6 7 8 9 10

Monthly visit and mean daily dose (in mg)

Sid

e E

ffec

t F

req

uen

cy

Common side effects with no significant decrease

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

1(14.17)

2(15.86)

3

(16.54)

4

(17.07)

5

(17.85)

6

(18.16)

7

(18.77)

8

(18.88)

9

(19.54)

10

(20.51)

Appetite Loss

Picking at Skin

Trouble Sleeping

Worried/ Anxious

Monthly visit and mean daily dose (in mg)

Sid

e E

ffec

t F

req

uen

cy

Rare side effects

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

(14.17) (15.86)

(16.54) (17.07) (18.77) (18.88) (20.51)

Stomach ache

Social Withdrawal

Motor Tics

BLM

Headache

(19.54)10987654321

(17.85)(18.16)

Monthly visit and mean daily dose (in mg)

Sid

e E

ffec

t F

req

uen

cy

Standardization of Weight and HeightStandardization of Weight and HeightBased on CDC 2000 National NormsBased on CDC 2000 National Norms

Age (yrs)

70

65

60

55

50

45

40

35

30

25

20

15

Wei

ght (

kg)

Hei

ght (

kg)

175

170

165

160

155

150

145

140

135

130

125

120

Age (yrs)

Mean values at Baseline Month 12-14

50th 0.0

25th -0.67

5th -1.6510th -1.28

75th 0.6790th 1.28

95th 1.65

Age in Months

percentile z-score

Age in Months

Population standard deviations for 7 to 12 year old children = 6.5 cm for height and 5.5 kg for weight

A z-score is expressed in population SD units.  For normal growth rates, z-scores are not expected to change over time. 

At Baseline, the average z-scores for the PATS sample were positive (z-wt = +0.71 and z-ht = +0.44). 

CDC preschool norms for SD (2.75 kg and 4.8 cm) can be used to transform the z-score back to absolute values (kg and cm).

At Baseline, compared to CDC norms the PATS sample was:

a. 0.71 x 2.75 kg = 1.95 kg heavier than expectedb. 0.44 x 4.8 cm = 2.11 cm taller than expected

Z-Scores and Percentiles for PATS and MTAZ-Scores and Percentiles for PATS and MTA

z-score percentile 5 yr norms 8 yr norms(cm) (cm)

-1.88 3rd-1.65 5th-1.28 10th-0.67 25th 0.00 50th+0.18 62nd 131.1 (MTA) +0.47 70th 110.5 (PATS) +0.67 75th+1.04 85th+1.28 90th+1.65 95th+1.88 97th

Mean Height and Weight at Phases of the PATSMean Height and Weight at Phases of the PATS(z-scores and percentiles)(z-scores and percentiles)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

-200 -100 0 100 200 300 400 500

average number of days

av

era

ge

z-s

co

re

avghtz

avgwtz

Screening Titration Maintenance

Question & Answer SessionQuestion & Answer Session