This is a 2007 presentation on the topic of how to select medication for patients with ADHD once a diagnosis has been established.

1. E-mail: drgrcevich@fcbtf.com Web: www.fcbtf.com Phone: 440.543.3400
Special Needs Ministry: www.keyministry.org

2. Objective: To help participants develop
an evidence-based model to guide
prescribing decisions for individual
patients with ADHD
To meet this objective, participants will:

4. Capone NM, McDonnell TP. Presented at the APA Annual Meeting, Toronto, ON (2006)

5. More Frequent Office Visits May Help
ADHD Medication Adherence
A B
Patients (%)
Patients (%)
Office Visits ADHD Rxs Filled
Data shown are the rate (%) of patients with the indicated number of office visits
or prescriptions filled over the 12-month study period.
Grcevich S, et al. Presented at: AACAP Annual Meeting, San Diego, CA, October 27, 2006.

6. Monthly Persistence With OROS-MPH (N=2398)
% of Patients
Capone N, et al. Presented at the CHADD International Conference (2005) Dallas, TX.

7. Monthly Persistence With MAS-XR (N=1626)
100%
90%
80%
70%
% of Patients
60%
50%
40%
30%
20%
10%
0% Sep-03 Oct-03 Nov-03 Dec-03 Jan-04 Feb-04 Mar-04 Apr-04 May-04 Jun-04 Jul-04 Aug-04
MAS-XR Category
Capone N, et al. Presented at the CHADD International Conference (2005) Dallas, TX.

8. Monthly Persistence With ATX (N=1292)
100%
90%
80%
70%
% of Patients
60%
50%
40%
30%
20%
10%
0%
Sep-03 Oct-03 Nov-03 Dec-03 Jan-04 Feb-04 Mar-04 Apr-04 May-04 Jun-04 Jul-04 Aug-04
ATX Category
Capone N et al. Presented at the CHADD International Conference, Dallas, 2005.

9. Grcevich S, et al. Presented at: AACAP Annual Meeting, San Diego, CA, October 27, 2006.
Wolraich ML, et al. Pediatrics. 2005;115:1734-1746.

10. *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.

11. 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

12. 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

13. 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

14. Factors in Selecting Medication
for Individual ADHD Patients:
Grcevich S. Future Neurology 2006; 1(5) 525-534
Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-657.

15. 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-
Dexmethylphenidate XR
methylphenidate
Methylphenidate Methylphenidate CD
Mixed
Methylphenidate LA
amphetamine salts
Methylphenidate patch
Mixed amphetamine salts
XR
OROS* methylphenidate
*OROS=osmotic release oral system

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

18. Percent Response
to Treatment
Michelson, D. Presented at AACAP Annual Meeting, Washington, DC, October 21, 2004

19. 0.33†
‡
‡ ‡ ‡ ‡
*
–0.47†
–0.74† –0.78†
–0.81†
–0.86†
*P<0.05; †P<0.0001 compared with baseline by 1-sample t test.
‡ P<0.0001 MAS-XR compared with ATX by ANCOVA.
Wigal et al. Poster presented at the 157th Annual Meeting of the American Psychiatric Association, New York, May 4, 2004.

20. Meta-Analysis of Within-subject Comparative Trials
Evaluating Response to Stimulant Medications
Best 41%
response
(percent)
28%
16%
AMP=amphetamine
MPH=methylphenidate
Arnold et al. J Attention Dis 2000;3:200-211.

21. Implications of Arnold Study:

22. 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

23. 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

24. OROS-MPH/MPH Patch Parallel
Group Study:
*
*
* 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

26. Selecting the Right Delivery System:
Steinhoff K et al. Presented at 53rd Annual Meeting of AACAP, San Diego, CA, October 27, 2006

27. New Delivery Systems: LDX
O! CH!3 O!
H 2 N! H 2 N!
N! OH! CH!
3
Rate-limited!
H! +
Hydrolysis
! H 2 N!
Site of cleavage!
NH!2 NH!2
Lisdexamfetamine l-lysine! d-amphetamine
(Prodrug)
! (active)
!

28. Maximum Change in Subject Liking
Scores after LDX Oral Administration
Placebo *
Mean Maximum Change
LDX 100 mg
in DRQ-S Scores
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
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.

30. 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
* * *
* *
Mean Change From Predose,
* *
Mean Change From Predose,
* * * * *
* * * *
Improvement
* *
Improvement
* *
Math Attempted
Math Correct
* *
* *
* *
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

31. 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.

32. Analog Classroom Study of Transdermal
MPH: Impact on Math Performance
Laboratory Classroom Mean Change from Pre-Dose in Number of
Math Problems Correct
Transdermal * * *
MPH * *
* *
Improvement
* * P < .001 Transdermal MPH vs
placebo at all measured post-dose
time points.
Placebo
N=79
Patch applied Patch removed
Wigal et al. Poster presented at the AACAP Annual Meeting, Toronto, October 21, 2005.

33. Comparison of Frequently
Prescribed Stimulant Preparations:
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

34. 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.

35. 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.

36. ADHD-RS: Mean Total Score at Endpoint and
Change in LS Mean from Baseline (ITT Population)
40
ADHD-RS Total
30 Baseline
Endpoint
Score
20 Change in Least
Square (LS)
10
0
Mean Change in
ADHD-RS Total
-10
Score
-20 ** ** ***
-30
Placebo 2 mg 3 mg 4 mg
*8-week, double-blind, placebo-controlled, parallel-group safety and efficacy study; **p<..
001; *** p<.0001 (adjusted Dunnett test compared to placebo following ANCOVA with
baseline score as covariate)
Bear Stearns. Presented at London Healthcare Conference, London, March 2004.

37. Comorbidity: A Diagnostic
Consideration
Lifetime Prevalence of Comorbid Conditions in
Pediatric Population With ADHD
Boys (N = 140)
Girls (N = 140)
Major Multiple Conduct Bipolar
ODD Enuresis Depression Disorder Disorder
(>2)
Anxiety
Biederman J. J Clin Psychiatry. 2004;65(suppl 3):3-7.

38. Correlates of ADHD Among Children
in Pediatric and Psychiatric Clinics
Referral Site
Psychiatric Pediatric
(N=139) % (N=141) %
CD 14 15
ODD 55 45
MDD 50 42
BPD 13 9
Anxiety disorders 33 29
(≥2)
SUD* 13 15
Tics 10
*SUD includes cigarettes and psychoactive substances. 6
Busch et al. Psychiatric Services. 2002;53:1103.

39. 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

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

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

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