ADHD Persistence into Adolescence and Childhood

Biederman et al, 1996

Hart et al, 1995

Barkley et al, 1990

Lambert et al, 1987

Wiss et al, 1985

10

20

30

40

50

60

70

80

90

100

Percent Persistence

Neuroanatomy
Reduction brain volume: 5 % Diminution size of: Frontal right lobule Corpus callosum Cerebellum Caudate head Globus pallidus Putamen Central white matter deficits in left hemisphere

Prefrontal and Executive Attention Network Lesions and the Development of Attention-Deficit /Hyperactivity Symptomatology

Method:
Twenty-nine children with focal stroke lesions were studied with standardized psychiatric assessments and anatomical brain magnetic resonance imaging. The pattern of lesion overlap in subjects with ADHD symptomatology was determined.

Jeffery Max J.AM.ACD CHILD ADOLESC.PSYCHIATRY ,44:5 ,May 2005

Results Fifteen of 29 subjects with no prestroke

ADHD were diagnosed with ADHD symptomatology at the time of assessment. The extent of lesions within the executive attention network was marginally related to ADHD symptomatology (p=.088; effect size=0.66),

Jeffery Max J.AM.ACD CHILD ADOLESC.PSYCHIATRY ,44:5 ,May 2005

Results cont! whereas the extent of lesions in the

specific frontal region of interest was significantly related to ADHD symptomatology. (p=.040; effect size=0.82). Orbitofrontal gyrus lesions predicted the development of ADHD in the first 6 months after traumatic brain injury
Jeffery Max J.AM.ACD CHILD ADOLESC.PSYCHIATRY ,44:5 ,May 2005

Summary of Changes in Revised Texas CMAP Algorithm

Algorithm Stage 1998-2004 Algorithm
1 Stimulant (MPC or AMP)

2005 Algorithm
Same, but additional longlong-acting formulations and dextrodextro-MPH

Alternative Stimulant

ADHD
3 4 Pemoline Bupropion or tricyclic antidepressant Alternative not used in stage 4 Alpha Agonist eg Clonidine

Same, but may attempt different formulations of stimulant within stage Atomoxetine (Pemoline (Pemoline eliminated) eliminated) Same

Same

Same

Stimulants
Methylphenidate (Ritalin) Mixed amphetamines (Adderall) Dextroamphetamine (Dexedrine) Magnesium pemoline (Cylert) Amphetamine Concerta (Methylphenidate) extended release Focalin dexmethylphenidate HCI tablets Adderall XR Strattera atomoxetine HCI (Non stimulant)

OROS# methylphenidate HCl Formulation

Laser-Drilled Hole MPH Compartment #1

MPH Overcoat
(Provides an immediate release of 22 % of the entire dose within 1 hour)

MPH Compartment #2

Tablet Shell

Push Compartment

Plasma Profiles Following Ritalin# tid and OROS# methylphenidate

OROS
Concentration (ng/mL) 20 16 12 8
l

methylphenidate provides:

IR MPH 10 mg tid (n=15) CONCERTA! 36 mg qd (n=15)

Immediate release followed by extended release of methylphenidate1 Minimized fluctuations in peak and trough plasma concentrations compared to methylphenidate tid2

4 0 0 2 4 6 8 10 12

Time (h)

Swanson J et al. Arch Gen Psychiatry 2002

1. Modi et al. J Clin Pharmacol 2000. 2. Modi et al. Biopharm Drug Dispos 2000.

OROS# Methylphenidate HCI Laboratory School Studies1,2

Objective
" Study efficacy and duration of effect of CONCERTA# in controlled environment

Design
" Double-blind, randomised, cross-over study " CONCERTA#, IR methylphenidate, placebo " Children with ADHD (n = 133) " Each treatment 1-week duration " Assessment: multiple raters, settings, and scales
Study 1: Swanson et al. Pediatrics 2004; 113: e206; Study 2: Pelham et al. Pediatrics 2001; 107: e105

OROS# Methylphenidate HCI Laboratory School Studies1,2: Magnitude of Effect

IOWA Conners I/O Score

Maximum Symptoms

14 12 10 8 6 4 2 0
CONCERTA# qd MPH tid

Laboratory school study community school teacher,parents IOWA Conners I/O results: CONCERTA# statistically significantly better than placebo
Placebo

No Symptoms

Study 1: Swanson et al. Pediatrics 2004; 113: e206; Study 2: Pelham et al. Pediatrics 2001; 107: e105 I/O= Inattention Overactivity

OROS# Methylphenidate HCI Laboratory School Studies1,2 : Magnitude of Effect

Community school teacher IOWA Conners Oppositional/Defiance mean scores in patients aged 6 12 years* Maximum Symptoms Opposition/Defiance

7 6 5 4 3 2 1 0
Study 1 n=61 Study 2 n=68

CONCERTA! qd Placebo p<0.001

CONCERTA significantly reduced symptoms on the IOWA Conners Oppositional/ Defiance subscale All patients were known responders to stimulants

No Symptoms

Study 1: Swanson et al. Pediatrics 2004; 113: e206 Study 2: Pelham W, et al. Pediatrics 2001;107:E105.

OROS# Methylphenidate HCI Laboratory School Studies1,2 : Magnitude of Effect

Community school teacher SNAP-IV mean scores in patients aged 6 12 years (n=61)* CONCERTA! qd IR MPH tid Placebo

Maximum Symptoms Mean SNAP-IV score

2.4 2.1 1.8 1.5 1.2 0.9 0.6 0.3

Study 1, n=61
p<0.001 for CONCERTA! vs placebo

No Symptoms

Inattention

Hyperactivity /Impulsivity

All patients were known responders to stimulants

Study 1: Swanson et al. Pediatrics 2004; 113: e206 Study 2: Pelham W, et al. Pediatrics 2001;107:E105. SNAPS-IV Teacher!s assessment questioners

OROS# Methylphenidate HCI Laboratory School Studies1,2 : Duration of Effect

Less attentive SKAMP Combined Attention Score, Studies 1 & 2 3 2.5 2 1.5 1 0.5 0 CONCERTA# Placebo

N = 133
2 4 6 8 10 12

SKAMP ratings from Studies 1 and 2 showed that CONCERTA! provided sustained improvement in attention and behaviour for 12 hours

More attentive

Hours Post Initial Dose

Study 1: Swanson et al. Pediatrics 2004; 113: e206; Study 2: Pelham et al. Pediatrics 2001; 107: e105

OROS# Methylphenidate HCI Laboratory School Studies2 : Duration of Effect

Mean percentage math problems completed by patients aged 6 12 years, as reported by laboratory school teachers (n=68)

Mean percentage math problems completed

60 50 40 30 20 10

CONCERTA! qd Placebo p<0.05

8:00

9:20 10:30 12:30 14:05 Time

16:00 17:15 18:20 19:10

Pelham W, et al. Pediatrics 2001;107:E105

OROS# Methylphenidate HCI Laboratory School Studies1,2 : Parent Preference

60

Percentage (%) of Parents/Caregivers

Study 1 Study 2

50 40 30 20 10 0
CONCERTA# Ritalin# tid tid Previous MPH Treatment

Since tablets (OROS MPH, Ritalin, placebo) were taken tid throughout the study, preference does not reflect convenience of once-daily dosing, which would be expected to favour OROS MPH

No Preference

Placebo

Study 1: Swanson et al. Pediatrics 2004; 113: e206; Study 2: Pelham et al. Pediatrics 2001; 107: e105

OROS# Methylphenidate HCI

Preference in Children2,3
Parent/caregiver treatment preferences for children aged 6 12 years (n=133)*
60 Oros Methylphenidate! 50 Percentage of parents/caregivers 40 30 20 10 0 Study 1 Study 2 MPH tid Previous MPH treatment No preference Placebo *All patients were known responders to stimulants

Study 2: Pelham W, et al. Pediatrics 2001;107:E105 Study 3: Wigal S, et al. Poster presentation at American Psychological Association, Chichago, IL, August 22-25,2003

OROS# Methylphenidate HCI Long-

term
Percentage of children rated with good or excellent sleep quality

Study: Sleep
oros# (MPH) MPH tid Placebo

100 80 60 40 20
0

Day 0

Day 14

Day 28

No significant differences in sleep quality between the treatment groups

Stein, Swanson. Poster presented at NCDEU, 2001.

OROS# Methylphenidate HCI Long-

Term Study: Impact on Tics

CONCERTA once daily not appear to induce or worsen tics during the 1 - y ear open - label study.
" 62.5% of children with a history of tics reported either no tics or improvements in their tics during the study " Only 6.3% of children with a history of tics experienced exacerbation of tics " 6.4% of those with no history of tics developed tics during the study

Wilens. Neurology 2000; 54 (7)

OROS# Methylphenidate HCI LongTerm Study: Growth

100 90 80

% subjects

70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 Ate same as usual Ate less then usual Ate more than usual

Effects of CONCERTA# on appetite decrease over time

Months
Wilens. Neurology 2000; 54 (7)

CONCLUSION
Decision to treat with medication should be based
on persistent target symptoms sufficiently severe to cause functional impairment in home, school, work, or peer related activities, on continuing efficacy of medication, and on family/ parent performance.

Patients treated pharmacologically should have their

height and weight monitored throughout treatment.

Limitations in pharmacologic and behavioral

treatment arise from lack of maintenance if treatment discontinued and /or failure in setting where treatment has not been well applied.

Should Treatment Change as Patients Age?

Differences in metabolism

" Younger children may metabolize medication faster, requiring "

higher doses than adults. As younger children age, downward dose adjustment may therefore be necessary

More control over own treatment: may not want to continue medication

" Help them develop a plan (tutors, etc.) " Drug holidays " Simplified medication regimens " School/work schedules
Wolraich et al. Pediatrics 2005.

Environmental parameters differ for young children vs. adolescents vs. adults.

Summary
ADHD is a neurobehavioral disorder with:
A complex etiology A neurobiologic basis A strong genetic component

ADHD
Affects millions of people of both genders Persists through adolescence and adulthood in a high percentage of cases Can have negative impact on multiple areas of functioning