Lecture presented as part of an ADHD symposium at Walsh University in North Canton, OH on April 16, 2008. The lecture was sponsored by Mercy Medical Center and the Child and Adolescent Service Center of Stark County

1. Optimizing Medication Treatment
in Children, Adolescents and
Adults with ADHD
Stephen Grcevich, M.D.
CWRU School of Medicine, Cleveland, Ohio
Family Center by the Falls, Chagrin Falls, OH
Presented at: Barrett Business and Community Center
Walsh University
North Canton, Ohio
April 16, 2008
E-mail: drgrcevich@fcbtf.com Web: www.fcbtf.com Phone: 440.543.3400
Special Needs Ministry: www.keyministry.org

2. Objective: Equip participants with an
evidence-based model to guide
prescribing decisions for ADHD patients
To meet this objective, participants will:
 Review current practice parameters and
recommended strategies for initiating ADHD
pharmacotherapy
 Explore a systematic approach for optimizing
treatment of individual patients with ADHD
 Discuss treatment strategies for ADHD patients
with comorbid conditions
Medication uses not currently approved by the FDA will be discussed
Brand names may be used during the presentation for purpose of clarity

3. Potential Conflicts of Interest:
(Complete disclosure for 2006-08 available at www.fcbtf.com)
Source of conflict: Company:
Consultant: Shire US (2006, 2007)
Grant/research support: No current ADHD
research support
Major shareholder: N/A
Other financial/material Independent Contractor: Medscape
Consultant: MEDACorp/ Leerink-
support: Swann, Porter Novelli
Speakers’ bureau: Shire US (through March, 2006)
None in last 24 months

4. Revised TMAP* Algorithm for
Pharmacotherapy of ADHD
 Consensus conference of academic clinicians and
researchers, practicing clinicians, administrators,
consumers, families
 Revised algorithms based upon new research
developed for treatment of ADHD, with and
without common comorbid conditions
 Children treated according to earlier algorithms
achieved better outcomes and were exposed to
less polypharmacy than controls
TMAP=Texas Medication Algorithm Project
*
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.

5. Algorithm for the Pharmacological Treatment of ADHD
(with no significant comorbid disorders), Revised 2005
Pliszka SR, et al. J Am Acad
Diagnostic Assessment and Family Child Adolesc Psychiatry.
Stage 0 Consultation Regarding Treatment 2006;45:642-657.
Alternatives
Non-Medication
Any stage(s) can be skipped Treatment Alternatives
depending on the clinical picture
Stage 1 Methylphenidate or Amphetamine
Response
Stage 1A
Partial
(Optional)
Response Response
(if MAS or Formulation not
DEX used used in Stage 1 Continuation
Partial Response in Stage 1)
or Non-response Partial Response
or Non-response
Stage 2 Stimulant not used in Stage 1
DEX = Dextroamphetamine
MAS = Mixed amphetamine salts

6. Pliszka SR, et al. J Am Acad
Stage 2 Stimulant not used in Stage 1 Child Adolesc Psychiatry.
2006;45:642-657.
Response
Stage 2A
Partial (Optional) Response
Response Continuation
Formulation not
(if MAS or used in Stage 2
DEX used
in Stage 2)
Stage 3 Partial Response Partial Response
or Non-response or Non-response
Atomoxetine
Response
Stage 3A
Partial (Optional) Response
Response
Combine stimulant Continuation
to stimulant or
atomoxetine and atomoxetine
Partial Response
or Non-response Partial Response
or Non-response
Stage 4 Bupropion or TCA
TCA = Tricyclic antidepressant

7. Pliszka SR, et al. J Am Acad
Child Adolesc Psychiatry.
Stage 4 Bupropion or TCA 2006;45:642-657.
Response
Continuation
Partial Response
or Non-response
Stage 5 Agent not used in Stage 4
Response
Continuation
Partial Response
or Non-response
Stage 6 Alpha agonist
Clinical
Consultation
Maintenance

8. Factors in Selecting Medication
for Individual ADHD Patients:
 What’s the best drug (molecule) for the patient?
Do they respond best to AMP or MPH?
 What’s the best dose for them? Are you giving
them enough to get the desired result?
 What’s the necessary duration of action? Does the
medication work when it needs to later in the day?
 And the best delivery 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

9. Factors in Selecting Medication
for Individual ADHD Patients:
Other Considerations:
 TMAP suggests amphetamine (AMP) or
MPH as first-line Rx, but which one?
 Side effect/safety issues
 Cost
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-657.

10. Approved stimulant products for ADHD:
Immediate- Long-Acting, Long-Acting,
Release Formulated Non- Prodrug
Stimulants Stimulants Stimulants Stimulants
Lisdexamfetamine
Amphetamine Amphetamine SR Atomoxetine
dimesylate
D-methylphenidate Dexmethylphenidate XR
Methylphenidate Methylphenidate CD
Mixed
amphetamine Methylphenidate LA
salts
Methylphenidate patch
Mixed amphetamine salts
XR
OROS* methylphenidate
OROS=osmotic release oral system
*

11. Differential Response to
Stimulants
Meta-Analysis of Within-subject Comparative Trials
Evaluating Response to Stimulant Medications
50
40
Best 41%
response
30
(percent)
28%
20
10 16%
0
AMP MPH Equal response to
either stimulant
AMP=amphetamine
MPH=methylphenidate
Arnold et al. J Attention Dis 2000;3:200-211.

12. Implications of Arnold Study:
 Patients with uncomplicated ADHD should
receive a trial of an alternate stimulant
molecule if they fail an initial trial
 Suboptimal responders (improved, but not
normalized) to a given stimulant may
benefit from an alternative stimulant
Problem: Physicians are often reluctant
to increase medication dose or consider
alternative molecules when results are less
than optimal

13. Faraone 2006 Metanalysis
(29 controlled studies, 4465 children,
adolescents)
Drug: 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)

14. Atomoxetine (ATX) vs OROS-MPH
70
60
Percent Response
50
to Treatment
40
30 ATX
OROS
20
10
0
Prior Tx. Naïve Total
Stim Sample
Michelson, D. Presented at AACAP Annual Meeting, Washington, DC, October 21, 2004

15. Math Problems by Hour (ITT)
MAS-XR vs. Atomoxetine
MAS XR® Change in Attempted ATX Change in Attempted
MAS XR® Change in Correct ATX Change in Correct
80 75.6* 77.2*
Change in Number of Math Questions
70.1* 79*
70 75* 67.5*
72.3*
68.4* 56.8*
60
56.9*
50
40.7
40 34.2 36.3 44.6
31.9
35.1 38.4
30 23.3 34.3
20 24.0† 13.7 16.6
18.6
10 12.1
0
0 2 4.5 7 9.5 12
Time (hr)
*P<0.0001 MAS XR® compared with ATX for both number attempted and correct (ANCOVA); †P<0.05
for number attempted.
Wigal SB et al. J Atten Disord 2005; 9(1) 275-289

16. Studies Comparing d- and L-AMP:
 Arnold (1976)-randomized, crossover study
(N=31): d- and L- isomers are equally
efficacious, (non-significant trend toward d-AMP
> L-AMP)-trend toward L-AMP more effective in
“undersocialized, aggressive” children. 28% of
drug responders preferred L-AMP
 James (2001)-randomized, crossover study
(N=35) comparing d-AMP IR, d-AMP ER, MAS-
IR. MAS-IR produced most robust effects in AM,
only d-AMP improved cognitive performance in
analog classroom after 4 hours
 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

17. LDX vs. MAS-XR in Children:
SKAMP LS Mean Across Assessment Day – ITT
Population
3–
– LDX *** p<0.001 compared to placebo
–
MAS-XR
–
2– Placebo
Mean Score
–
–
– *** ***
1 –
*** ***
–
–
–
0–
Deportment (primary endpoint) Inattention
Biederman J. et al. Poster presented at Annual APA Meeting, May 24, 2006, Toronto, Ontario, Canada

18. OROS-MPH/MPH Patch Parallel
Group Study:
MPH Patch OROS MPH Placebo
0
-5
Mean Change Scores
-10
-15 -10.3
-20
-25 -21.6 *
-24.2
-30 *
-35
-40
-45
-50
Change from Baseline
* 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

19. Dosing Issues
 FDA marketing guidelines for new products
reflect smallest possible effective dose, not
optimal dose
 FDA doesn’t take into account variability in
dose response between individual patients
when determining approved dose
 Open-label or dose-optimization studies often
suggest higher-than-approved doses are
beneficial for individual patients
 Notion of ‘approved’ vs ‘clinical’ dose in
practice parameters
 Response to stimulants is highly
individualized

20. Selecting the Right Delivery
System:
 Can the person swallow pills?
 Risk of drug diversion, abuse
 How soon does the product work?
 When does maximum benefit occur?
 How often do you need to administer?
(Increased frequency=decreased
adherence)
Steinhoff K et al. Presented at 53rd Annual Meeting of AACAP, San Diego, CA, October 27, 2006

21. Maximum Change in Subject Liking
Scores after LDX Oral Administration
6 Placebo *
Mean Maximum Change
4.9
5 LDX 100 mg
in DRQ-S Scores
d-amphetamine 40mg
4
3 2.6 †
2
1 0.4
0
Treatment
 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
DRQ-S=Drug Rating Questionnaire-Subject.; *P<.01 vs placebo; †P<.05 vs d-amphetamine
Jasinski D, Krishnan S. Poster presentation at US Psychiatric & Mental Health Congress Annual Meeting,
New Orleans, Nov 18, 2006.

22. Duration of Action
 Extracurricular activities, homework, driving
render concept of school- or work-day
coverage obsolete
 Why do patients tell you XR stimulants don’t
last as long as they should?
 Every ADHD product currently issued
“approvable” letter lasts at least as long (if
not considerably longer) than the products
they are intended to replace

23. Analog classroom study of d-MPH XR:
Impact upon math performance
Change From Predose in Number Change From Predose in Number of
of Math Test Problems Attempted Math Problems Correctly Solved
* * 70 *
70 * *
Mean Change From Predose,
* *
Mean Change From Predose,
* * * 60 * *
60 * *
* 50 *
Improvement
50 * *
Improvement
* *
Math Attempted
40 40
Math Correct
* 30 *
30 * *
20 * 20 *
10 10
0 0
-10 -10
-20 -20
-30 -30
0 0.5 1 2 3 4 5 6 7 8 9 10 11 12 0 0.5 1 2 3 4 5 6 7 8 9 10 11 12
Hours Postdose Hours Postdose
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

24. Analog classroom study of OROS MPH:
Impact upon math performance
Change in number of math problems completed
50
45
40
35
30
25
20
15 Placebo
10 OROS MPH (all doses)
TID MPH (all doses)
5
0
8:15 9:20 10:30 12:30 14:05 16:00 17:15 18:20 19:10
Class period
Pelham WE et al. Pediatrics 2001; 107(6) e105.

25. Analog Classroom Study of Transdermal
MPH: Impact on Math Performance
Laboratory Classroom Mean Change from Pre-Dose in Number of
Math Problems Correct
40
Transdermal * * *
35
30 MPH * *
*
Mean Change Score
25 *
20
Improvement
15 * * P < .001 Transdermal MPH vs
10 placebo at all measured post-dose
5 time points.
0
-5
-10
-15 Placebo
-20
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hr) N=79
Patch applied Patch removed
Wigal et al. Poster presented at the AACAP Annual Meeting, Toronto, October 21, 2005.

26. Comparison of Frequently
Prescribed Stimulant Preparations:
Dose Delivery
Product: Molecule: Range: Duration: System: Advantages:
MAS-XR d,l-AMP 5-30 Up to 12 Biphasic Rapid onset,
mg/day hours release effective for ODD,
adults
LDX d-AMP 30-70 12 hours Prodrug Less appeal to
mg/day addicts, more
consistent
duration?
OROS-MPH MPH 18-72 12 hours Osmotic Prolonged effects
mg/day release on driving
D-MPH XR MPH 5-20 12 hours Biphasic Rapid onset
mg/day (claimed) release
Transdermal MPH 10-30 Variable, Patch Potentially longest
MPH mg/day based on acting, most
wear time flexible duration

27. Bupropion XL in Adults With ADHD:
Percent Responders*
60
** **
50 †
** Bupropion XL (N = 81)
Responders (%)
40
30
20 Placebo (N = 81)
10
0
1 2 4 5 8
Time in Study (wk)
*≥30% reduction from baseline; **p≤0.01, †p<0.05
Wilens T, et al. Biol Psychiatry. 2005;57:793-801.

28. Guanfacine in the Treatment of
Children with Tic Disorders and ADHD
Improvement in Outcome
Measures
Measure Guanfacine Placebo P-
0.5-4.5 (n =17) value
mg/d
(n =17)
ADHD-RS total score 37% 8% <0.001
CGI Global Improvement Scale 47% 0% <0.001
(rated much improved or very much
improved)
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
Scahill L, et al. Am J Psychiatry. 2001;158:1067–1074.

29. Comorbidity: A Diagnostic
Consideration
Lifetime Prevalence of Comorbid Conditions in
Pediatric Population With ADHD
Boys (N = 140)
70 66
Girls (N = 140)
60
50
40 35
%
32 33
29
30 25
28
21
20 15
11 11
10 8
0
Major Multiple Conduct Bipolar
ODD Enuresis Depression Disorder Disorder
(>2)
Anxiety
Biederman J. J Clin Psychiatry. 2004;65(suppl 3):3-7.

30. 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

31. TMAP algorithm for pharmacologic management of
ADHD and comorbid anxiety disorder:
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

32. TMAP algorithm for pharmacologic management of
ADHD with comorbid tic disorder:
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

33. Bottom line: What is most important to
you as physician, to the parent/patient?
 Efficacy: AMP (slight advantage)>MPH>ATX
 Duration of action: Transdermal MPH (with
extended wear time)>OROS MPH=LDX> MAS-
XR>d-MPH XR
 Flexible duration: Transdermal MPH
 Rapid onset: IR stimulant>d-MPH XR>OROS
MPH>Transdermal MPH
 Abuse Potential: ATX, evidence for less abuse
potential with LDX, OROS-MPH, transdermal
MPH, indirect evidence of less abuse potential
with other ER stimulants

34. Conclusions:
 Optimizing treatment for individual patients with
ADHD is likely a critical factor in improving
treatment adherence
 Key considerations for each patient include:
identifying the molecule they respond to
optimally (drug), prescribing an adequate dose
to normalize symptoms, treating functional
impairment all day long (duration), and using
the best delivery system to provide peak effects
when necessary while improving adherence