Optimizing Medication Treatment in Children,

Adolescents and Adults with ADHD

Stephen Grcevich, M.D.Stephen Grcevich, M.D.CWRU School of Medicine, Cleveland, CWRU School of Medicine, Cleveland,

OhioOhioFamily Center by the Falls, Chagrin Falls, Family Center by the Falls, Chagrin Falls,

OHOH

Presented at: Barrett Business and Community Presented at: Barrett Business and Community CenterCenter

Walsh UniversityWalsh UniversityNorth Canton, OhioNorth Canton, Ohio

April 16, 2008 April 16, 2008 E-mail: drgrcevich@fcbtf.com Web: www.fcbtf.com Phone: 440.543.3400

Special Needs Ministry: www.keyministry.org

Review current practice parameters and Review current practice parameters and recommended strategies for initiating ADHD recommended strategies for initiating ADHD pharmacotherapy pharmacotherapy

Explore a systematic approach for optimizing Explore a systematic approach for optimizing treatment of individual patients with ADHDtreatment of individual patients with ADHD

Discuss treatment strategies for ADHD Discuss treatment strategies for ADHD patients with comorbid conditionspatients with comorbid conditions

Objective: Equip participants with an evidence-based model to guide prescribing decisions for ADHD patients

To meet this objective, participants will:

Medication uses not currently approved by the FDA will be discussed Brand names may be used during the presentation for purpose of clarity

Potential Conflicts of Interest:Potential Conflicts of Interest:(Complete disclosure for 2006-08 available at (Complete disclosure for 2006-08 available at

www.fcbtf.com)www.fcbtf.com)

Source of conflict:Source of conflict: Company:Company:

Consultant:Consultant: Shire US (2006, 2007)Shire US (2006, 2007)

Grant/research Grant/research support:support:

No current ADHD No current ADHD research supportresearch support

Major shareholder:Major shareholder: N/AN/A

Other Other financial/material financial/material support:support:

Independent Contractor: Independent Contractor: MedscapeMedscape

Consultant: MEDACorp/ Consultant: MEDACorp/ Leerink-Swann, Porter NovelliLeerink-Swann, Porter Novelli

Speakers’ bureau:Speakers’ bureau: Shire US (through March, Shire US (through March, 2006)2006)

None in last 24 monthsNone in last 24 months

Revised TMAPRevised TMAP** Algorithm Algorithm for Pharmacotherapy of for Pharmacotherapy of

ADHDADHD Consensus conference of academic clinicians Consensus conference of academic clinicians

and researchers, practicing clinicians, and researchers, practicing clinicians, administrators, consumers, familiesadministrators, consumers, families

Revised algorithms based upon new research Revised algorithms based upon new research developed for treatment of ADHD, with and developed for treatment of ADHD, with and without common comorbid conditionswithout common comorbid conditions

Children treated according to earlier Children treated according to earlier algorithms achieved better outcomes and were algorithms achieved better outcomes and were exposed to less polypharmacy than controls exposed to less polypharmacy than controls

Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006;45:642-657.Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2003;42:279-287.

*TMAP=Texas Medication Algorithm Project

Partial Response or Non-response

Response

PartialResponse (if MAS or DEX used in Stage 1)

Algorithm for the Pharmacological Treatment of ADHD (with no significant comorbid disorders), Revised 2005

Stage 0Diagnostic Assessment and Family Consultation Regarding Treatment

Alternatives

Non-MedicationTreatment Alternatives

Response

Continuation

Stage 1A(Optional)

Formulation not used in Stage 1

Stage 1

Any stage(s) can be skipped depending on the clinical picture

Stimulant not used in Stage 1Stage 2

Partial Response or Non-response

Continuation

Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006;45:642-657.

DEX = DextroamphetamineMAS = Mixed amphetamine salts

Methylphenidate or Amphetamine

Partial Response or Non-response

Partial Response or Non-response

Response

ResponsePartial

Response (if MAS or

DEX used in Stage 2)

Partial Response or Non-response

PartialResponse

to stimulant or atomoxetine

Partial Response or Non-response

Response

Response

Stage 3

Continuation

Stage 3A(Optional)

Combine stimulantand atomoxetine

Continuation

Stage 2A(Optional)

Formulation not used in Stage 2

Bupropion or TCAStage 4

Stage 2 Stimulant not used in Stage 1

TCA = Tricyclic antidepressant

Atomoxetine

Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006;45:642-657.

Response

Response

Partial Response or Non-response

Partial Response or Non-response

Stage 4

Continuation

Continuation

Clinical Consultation

Stage 5

Stage 6

Maintenance

Bupropion or TCA

Agent not used in Stage 4

Alpha agonist

Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006;45:642-657.

Factors in Selecting Medication for Individual ADHD Patients:

What’s the best What’s the best drugdrug (molecule) for the (molecule) for the patient? patient? Do they respond best to AMP or MPH?

What’s the best What’s the best dosedose for them? for them? Are you Are you giving them enough to get the desired result?giving them enough to get the desired result?

What’s the necessary What’s the necessary durationduration of action? of action? Does the medication work when it needs to later in the day?

And the best And the best delivery systemdelivery system? ? When do you most need the peak effect from medicine? What are they least likely to misuse? What if they can’t swallow pills?

Grcevich S. Future Neurology 2006; 1(5) 525-534

Factors in Selecting Medication for Individual ADHD Patients:

Other Considerations:Other Considerations:

TMAP suggests amphetamine (AMP) TMAP suggests amphetamine (AMP) or MPH as first-line Rx, but which or MPH as first-line Rx, but which one?one?

Side effect/safety issuesSide effect/safety issues CostCost

Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-657.

Approved stimulant products for ADHD:

Immediate- Release

Stimulants

Long-Acting, FormulatedStimulants

Non- Stimulants

Long-Acting,Prodrug

Stimulants

Amphetamine Amphetamine SR AtomoxetineLisdexamfetamine dimesylate

D-methylphenidate Dexmethylphenidate XR

Methylphenidate

Methylphenidate CD

Mixed amphetamine salts

Methylphenidate LA

Methylphenidate patch

Mixed amphetamine salts XR

OROS* methylphenidate

*OROS=osmotic release oral system

Differential Response to Stimulants

Arnold et al. J Attention Dis 2000;3:200-211.

0

10

20

30

40

50

Best response(percent)

Meta-Analysis of Within-subject Comparative Trials Evaluating Response to Stimulant Medications

AMP=amphetamine MPH=methylphenidate

AMPAMP MPHMPH Equal response to Equal response to either stimulanteither stimulant

28%

16%

41%

Implications of Arnold Study: Patients with uncomplicated ADHD Patients with uncomplicated ADHD

should receive a trial of an alternate should receive a trial of an alternate stimulant molecule if they fail an initial stimulant molecule if they fail an initial trialtrial

Suboptimal responders (improved, but Suboptimal responders (improved, but not normalized) to a given stimulant may not normalized) to a given stimulant may benefit from an alternative stimulant benefit from an alternative stimulant

Problem:Problem: Physicians are often reluctant Physicians are often reluctant to increase medication dose or consider to increase medication dose or consider alternative molecules when results are alternative molecules when results are less than optimal less than optimal

Faraone 2006 Metanalysis(29 controlled studies, 4465 children, adolescents)

Drug:Drug: Effect Size:Effect Size:

Amphetamine 0.92

Methylphenidate 0.80

Atomoxetine 0.73

Modafinil 0.49

Buproprion 0.32

Faraone SV, Spencer TJ: Presented at APA Annual Meeting, Toronto, Canada (2006)

Atomoxetine (ATX) vs OROS-MPH

0

10

20

30

40

50

60

70

PriorStim

Tx. Naïve TotalSample

ATXOROS

Per

cen

t R

esp

on

se

to T

reat

men

t

Michelson, D. Presented at AACAP Annual Meeting, Washington, DC, October 21, 2004

Math Problems by Hour Math Problems by Hour (ITT) MAS-XR vs. (ITT) MAS-XR vs.

AtomoxetineAtomoxetine

*P<0.0001 MAS XR® compared with ATX for both number attempted and correct (ANCOVA); †P<0.05 for number attempted.

23.3

70.1*77.2*

67.5*

56.8*

13.7

34.2 36.340.7

31.9

16.6

75.6*

0

10

20

30

40

50

60

70

80

0 2 4.5 7 9.5 12

Time (hr)

Ch

ang

e i

n N

um

ber

of

Mat

h Q

ues

tio

ns

ATX Change in AttemptedATX Change in Correct

MAS XR® Change in AttemptedMAS XR® Change in Correct

24.0†

12.1

35.1

75*

38.444.6

34.3

18.6

72.3*79*

68.4*

56.9*

Wigal SB et al. J Atten Disord 2005; 9(1) 275-289

Studies Comparing d- and L-Studies Comparing d- and L-AMP:AMP:

Arnold (1976)-randomized, crossover study Arnold (1976)-randomized, crossover study (N=31): d- and L- isomers are equally (N=31): d- and L- isomers are equally efficacious, (non-significant trend toward d-efficacious, (non-significant trend toward d-AMP > L-AMP)-trend toward L-AMP more AMP > L-AMP)-trend toward L-AMP more effective in “undersocialized, aggressive” effective in “undersocialized, aggressive” children. 28% of drug responders preferred L-children. 28% of drug responders preferred L-AMPAMP

James (2001)-randomized, crossover study James (2001)-randomized, crossover study (N=35) comparing d-AMP IR, d-AMP ER, MAS-(N=35) comparing d-AMP IR, d-AMP ER, MAS-IR. MAS-IR produced most robust effects in AM, IR. MAS-IR produced most robust effects in AM, only d-AMP improved cognitive performance in only d-AMP improved cognitive performance in analog classroom after 4 hoursanalog classroom after 4 hours

Biederman (2006) LDX vs. MAS-XR Biederman (2006) LDX vs. MAS-XR Arnold LE et al. Arch Gen Psychiatry, 1976;33(3):292-301 James RS et al. J Am Acad Child Adolesc Psychiatry 2001;40(11):1268-76

LDX vs. MAS-XR in Children:SKAMP LS Mean Across Assessment Day –

ITT Population

Biederman J. et al. Poster presented at Annual APA Meeting, May 24, 2006, Toronto, Ontario, Canada

Deportment (primary endpoint) Inattention

Mea

n Sc

ore

3 – –– –

2 – –– –

1 – – – –

0 –

LDX

MAS-XR

Placebo

*** p<0.001 compared to placebo

*** ***

*** ***

OROS-MPH/MPH Patch Parallel Group Study:

-24.2-21.6

-10.3

-50-45-40-35-30-25-20-15-10-50

Change from Baseline

Mea

n C

han

ge

Sco

res

MPH Patch OROS MPH Placebo

**

* P < .0001 vs placebo.

Study was not powered for comparison between transdermal and OROS MPH.Findling and Lopez. Poster presented at the AACAP Annual Meeting. Toronto. Oct. 20, 2005. N=270

Dosing Issues FDA marketing guidelines for new FDA marketing guidelines for new

products reflect smallest possible products reflect smallest possible effective dose, not optimal doseeffective dose, not optimal dose

FDA doesn’t take into account variability FDA doesn’t take into account variability in dose response between individual in dose response between individual patients when determining approved dosepatients when determining approved dose

Open-label or dose-optimization studies Open-label or dose-optimization studies often suggest higher-than-approved doses often suggest higher-than-approved doses are beneficial for individual patientsare beneficial for individual patients

Notion of ‘approved’ vs ‘clinical’ dose in Notion of ‘approved’ vs ‘clinical’ dose in practice parameterspractice parameters

Response to stimulants is highly Response to stimulants is highly individualized individualized

Selecting the Right Delivery System:

Can the person swallow pills?Can the person swallow pills? Risk of drug diversion, abuseRisk of drug diversion, abuse How soon does the product work?How soon does the product work? When does maximum benefit When does maximum benefit

occur?occur? How often do you need to How often do you need to

administer? (administer? (Increased Increased frequency=decreased adherence)frequency=decreased adherence)

Steinhoff K et al. Presented at 53rd Annual Meeting of AACAP, San Diego, CA, October 27, 2006

Maximum Change in Subject Liking Scores after LDX Oral Administration

0.4

2.6

4.9

0

1

2

3

4

5

6

Treatment

DRQ-S=Drug Rating Questionnaire-Subject.; *P<.01 vs placebo; †P<.05 vs d-amphetamineJasinski D, Krishnan S. Poster presentation at US Psychiatric & Mental Health Congress Annual Meeting, New Orleans, Nov 18, 2006.

PlaceboLDX 100 mg

d-amphetamine 40mg

Oral administration of 150 mg of LDX produced increases in positive subjective responses that were statistically indistinguishable from the positive subjective responses produced by 40 mg of oral immediate-release d-amphetamine

Mea

n M

axim

um

Ch

ang

e in

DR

Q-S

Sco

res

†

*

Duration of ActionDuration of Action Extracurricular activities, homework, Extracurricular activities, homework,

driving render concept of school- or driving render concept of school- or work-day coverage obsoletework-day coverage obsolete

Why do patients tell you XR stimulants Why do patients tell you XR stimulants don’t last as long as they should?don’t last as long as they should?

Every ADHD product currently issued Every ADHD product currently issued “approvable” letter lasts at least as “approvable” letter lasts at least as long (if not considerably longer) than long (if not considerably longer) than the products they are intended to the products they are intended to replacereplace

Analog classroom study of d-MPH XR: Impact upon math

performanceChange From Predose in Number of Math Test Problems Attempted

All P values, d-MPH XR versus placebo. *P<0.001. Pooled data; Studies US08 and US09.Turnbow JM et al. US Psychiatric and Mental Health Conference; 2005; Las Vegas, NV

Change From Predose in Number of Math Problems Correctly Solved

-30-20-10

01020

3040506070

0 0.5 1 2 3 4 5 6 7 8 9 10 11 12

Mea

n C

han

ge

Fro

m P

red

ose

,M

ath

Co

rrec

tHours Postdose

*

**

** *

* **

**

**

Imp

rov

em

en

t-30-20-10

010203040506070

0 0.5 1 2 3 4 5 6 7 8 9 10 11 12

Mea

n C

han

ge

Fro

m P

red

ose

,M

ath

Att

emp

ted

Hours Postdose

*

**

** *

* **

**

**

Imp

rov

em

en

t

Analog classroom study of OROS MPH:Impact upon math performance

0

5

10

15

20

25

30

35

40

45

50

8:15 9:20 10:30 12:30 14:05 16:00 17:15 18:20 19:10

Placebo

OROS MPH (all doses)

TID MPH (all doses)

Class period

Change in number of math problems completed

Pelham WE et al. Pediatrics 2001; 107(6) e105.

Laboratory Classroom Mean Change from Pre-Dose in Number of Math Problems Correct

Analog Classroom Study of Transdermal MPH: Impact on Math Performance

-20-15-10-505

10152025303540

0 1 2 3 4 5 6 7 8 9 10 11 12Time (hr)

Mea

n C

han

ge

Sco

re

Placebo

Transdermal MPH

Patch applied Patch removed

Wigal et al. Poster presented at the AACAP Annual Meeting, Toronto, October 21, 2005.

Imp

rove

me

nt

* P < .001 Transdermal MPH vs placebo at all measured post-dose time points.

*

*

**

* **

*

N=79

Comparison of Frequently Prescribed Stimulant Preparations:

Product:Product:MoleculeMolecule::

Dose Dose Range:Range:

DurationDuration::

Delivery Delivery System:System: Advantages:Advantages:

MAS-XR d,l-AMP 5-30 mg/day

Up to 12 hours

Biphasic release

Rapid onset, effective for ODD, adults

LDX d-AMP 30-70 mg/day

12 hours Prodrug Less appeal to addicts, more consistent duration?

OROS-MPH

MPH 18-72 mg/day

12 hours Osmotic release

Prolonged effects on driving

D-MPH XR MPH 5-20 mg/day

12 hours (claimed)

Biphasic release

Rapid onset

Transdermal MPH

MPH 10-30 mg/day

Variable, based on wear time

Patch Potentially longest acting, most flexible duration

Bupropion XL in Adults With ADHD:

Percent Responders*

*30% reduction from baseline; **p0.01, †p<0.05

Wilens T, et al. Biol Psychiatry. 2005;57:793-801.

0

10

20

30

40

50

60

1 2 4 5 8

Time in Study (wk)

Resp

onde

rs (%

) Bupropion XL (N = 81)

Placebo (N = 81)

**

** **†

Guanfacine in the Treatment of Children with Tic Disorders and

ADHD

Scahill L, et al. Am J Psychiatry. 2001;158:1067–1074.

Improvement in Outcome Measures

Measure Guanfacine

0.5-4.5 mg/d

(n =17)

Placebo

(n =17)P-

value

ADHD-RS total score 37% 8% <0.001

CGI Global Improvement Scale (rated much improved or very much improved)

47% 0% <0.001

Yale Global Tic Severity Scale total score

31% 0% 0.05

Double-blind, placebo-controlled, parallel design, 8-week study in 34 medication-free youths with ADHD plus tics; age 7-14

Guanfacine immediate release given TID; maximum allowable dose: 4mg/kg TID No serious side effects observed; no clinically meaningful cardiovascular changes One guanfacine discontinuation owing to sedation in week 4

35

25

29 28

33

21

811 11

66

32

15

0

10

20

30

40

50

60

70

%

Comorbidity: A Diagnostic Consideration

Lifetime Prevalence of Comorbid Conditions in Pediatric Population With ADHD

Biederman J. J Clin Psychiatry. 2004;65(suppl 3):3-7.

Boys (N = 140)Girls (N = 140)

ODD EnuresisMajor

DepressionMultiple

(>2)Anxiety

Conduct Disorder

Bipolar Disorder

TMAP Algorithm: Pharmacologic Management of ADHD and Comorbid Depressive Disorder

Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

TMAP algorithm for pharmacologic TMAP algorithm for pharmacologic management of ADHD and comorbid anxiety management of ADHD and comorbid anxiety

disorder: disorder:

Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

TMAP algorithm for pharmacologic TMAP algorithm for pharmacologic management of ADHD with comorbid tic management of ADHD with comorbid tic

disorder: disorder:

Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

Bottom line: What is most Bottom line: What is most important to you as physician, to important to you as physician, to

the parent/patient?the parent/patient? Efficacy: AMP (slight Efficacy: AMP (slight

advantage)>MPH>ATX advantage)>MPH>ATX Duration of action: Transdermal MPH (with Duration of action: Transdermal MPH (with

extended wear time)>OROS MPH=LDX> extended wear time)>OROS MPH=LDX> MAS-XR>d-MPH XR MAS-XR>d-MPH XR

Flexible duration: Transdermal MPHFlexible duration: Transdermal MPH Rapid onset: IR stimulant>d-MPH Rapid onset: IR stimulant>d-MPH

XR>OROS MPH>Transdermal MPHXR>OROS MPH>Transdermal MPH Abuse Potential: ATX, evidence for less Abuse Potential: ATX, evidence for less

abuse potential with LDX, OROS-MPH, abuse potential with LDX, OROS-MPH, transdermal MPH, indirect evidence of less transdermal MPH, indirect evidence of less abuse potential with other ER stimulantsabuse potential with other ER stimulants

Conclusions:Conclusions:

Optimizing treatment for individual patients Optimizing treatment for individual patients with ADHD is likely a critical factor in with ADHD is likely a critical factor in improving treatment adherenceimproving treatment adherence

Key considerations for each patient include: Key considerations for each patient include: identifying the molecule they respond to identifying the molecule they respond to optimally (optimally (drugdrug), prescribing an adequate ), prescribing an adequate dosedose to normalize symptoms, treating to normalize symptoms, treating functional impairment all day long functional impairment all day long ((durationduration), and using the best ), and using the best delivery delivery systemsystem to provide peak effects when to provide peak effects when necessary while improving adherence necessary while improving adherence