Getting Over the ADHD Treatment Hurdles
An Information Session for Pharmacists
Leslie JocelynMD FRCPC Pediatrics & Psychiatry
Developmental Pediatrician
Child & Adolescent Psychiatrist
February 2, 2010
Disclosures and Acknowledgment
Speakers Bureau : Janssen, Lilly, Purdue, Shire
Research Grants : Janssen
Advisory Board: Lilly, Purdue, Shire
Thanks to Jill Bojarski and Purdue Canada for their financial support of this evenings program
This presentation is for educational purposes only. The opinions expressed in this
presentation are not necessarily those of the sponsor and neither product
descriptions nor opinions expressed should be attributed to the sponsor. The
sponsor does not recommend any use of its products that is inconsistent with the
product monograph
Objectives: At the conclusion of this program the
pharmacist will be able to clear the following hurdles:
1. Recognize the symptoms of ADHD across the lifespan
2. Outline the evidence for a biological etiology for ADHD
3. Communicate the importance of ADHD treatment to
parents.
4. Appreciate what factors influence choice of medication
5. Serve as a valuable and informed resource for patients
with ADHD and their families.
How many times a week do parents ask you “Does my child really need ADHD medication?”
A. No one ever asks me that
B. Once a week
C. Five times a week
D. Ten times a week
E. Virtually every parent asks this
Reluctant parents seem most concerned about?
A. Safety of the med (i.e. serious side effect)
B. General concerns about giving medication to children
C. Belief treatment should be limited to “school time”
D. The stigma of ADHD
E. The cost of medication
F. Potential for addiction
Making the diagnosis across the lifespan
Hurdle # 1
What should an assessment for ADHD consist of ?
Physical
Exam
AssessmentLearning
Testsprn
Mental Status Exam
Rating Scales
DSM 1V Diagnosis ADHD Based on Type of Symptoms
Inattentive Type
Hyperactive/Impulsive Type
DSM 1V Criteria continued
Duration of 6+ months
Not due to developmental delay
Onset before age 7 yrs
2+ settings (home, school, social)
Impairment in function
Not due to another mental D/O
Adapted from American Psychiatric
Association, DSM-IV TR, 2000.
Prevalence of ADHD
The most common psychiatric diagnosis in children and adolescents
• Affects 8 – 10% of males < 18 years old *
• Affects 3 – 4 % of females < 18 years old *
You’ll see it even in adults
• 80% remain symptomatic into adolescence
• 60% remain symptomatic into adulthood
• 4.4% adults meet full DSM 1V criteria
*CADDRA guidelines 2008 (Canadian ADHD Resource Alliance)
ADHD Symptoms Change Over the Life Span
Inattention
Time
Hyperactivity
Impulsivity
Persistence greatest in those with symptomatic parent, co-morbidity & social adversity.
Biederman J. et al. Am J Psychiatry. 2000 May;157(5):816-8.
•Lack attention to details
•Avoids paperwork / paralyzing procrastination
•Starts but does not finish projects
•Poor time management
•Changes gear in middle of tasks
•Misses appointments or late
•Careless mistakes
•Difficulty sustaining attention
•No follow-through
•Can’t organize
•Easily distractible
•Forgetful
•Can’t sit through meetings
•Can’t wait in line, tolerate frustration
•Drives too fast
•Talks excessively,
•Makes inappropriate comments
•Interrupts
•Squirming, fidgeting
•Can’t wait turn
•On the go/driven by motor
•Blurts out answers
Hurdle #2
ADHD is a Real Diagnosis
What’s the
evidence to
support a biologic
basis for ADHD ?
Willerman, 1973
Goodman, 1989
Gillis, 1992
Edelbrock, 1992
Schmitz, 1995
Thapar, 1995
Gjone, 1996
Silberg, 1996
Sherman, 1997
Levy, 1997
Nadder, 1998
Hudziak, 2000
0 0.2 0.4 0.6 0.8 1
HeightBreast cancer Asthma Schizophrenia
ADHD is InheritedAverage genetic contribution to ADHD
0 means no genetic effect1 means 100% due to genetics
ADHD
ADHD: MRI Studies
Swanson JM et al. Lancet. 1998;351:429–433. Castellanos FX et al. Arch Gen Psychiatry. 2001;58:289–295.
Corpus
Callosum
Cerebellum
Frontal lobes
Several brain areas
are 10% smaller in
patients with ADHD
compared to
controls
Bush G et al. Biol Psychiatry. 1999;45:1542-1552.
1 x 10 -3
1 x-2y = +21 mm
Normal Controls
1 x 10 -2
1 x 10 -3
y = +21 mm
ADHD
Dorsal Anterior Cingulate Cortex (Cognitive
Division) Fails to Activate in ADHD on fMRI Study
During Stroop Test
PET Scans show Global and Regional glucose Metabolism Reduced in Adults with ADHD
Global & regional glucose consumption reduced in
ADHD
Increased glucose consumption with Ritalin
Zametkin AJ et al, N Eng J Med1990;323:1361-6
Hurdle # 3
The Consequences of Not Treating
Side effects of the
ADHD meds are well
know but are the
consequences of not
treating ADHD as
well appreciated ?
How to Help Parents Understand the Need for ADHD Treatment
1. De-stigmatize ADHD
2. Emphasize the risks associated with
non-treatment
3. Emphasize the protective effect treatment
can have
4. Reassure that the abuse potential for most
ADHD medications is low
5. Address specific concerns about the safety
of a medication
Treatment: The ADHD Tool Belt
1. Education
Verbal, written, local & web info
www.caddra.ca
2.Behavioral/Environmental
ChangesClassroom interventions
Behavioral interventions
3. MedicationsEffective and safe
Treat the core symptoms
If you only have a hammer you better hope you only need a nail
0% 10% 20% 30% 40% 50% 60%
Fired from job
Incarcerated
Arrested
Serious car accident
Accident prone
Substance abuse
STD
Teen pregnancy
< high school
Repeat a grade
Subjects (%)
ADHD
Normal
1. Barkley. Attention-deficit hyperactivity disorder. A handbook for diagnosis and treatment, 1998; 2. Barkley et al. JAACAP 1990; 3. Biederman et al. Arch Gen Psych1996; 4. Weiss et al. JAACAP 1985; 5. Satterfield, Schell. JAACAP 1997; 6. Biederman et al. Am J Psych 1995.
Functional Impairment in Untreated ADHD vs Controls
3x
9x
4x
3x
4x
11x
2x
Stimulants Protect Against Psychiatric Disorders in Youth with
ADHD. A 10 yr Follow up study
Case-control study of male children aged 6-18 with ADHD
Disorder P value
Major depression <0.001
Conduct disorder <0.001
Multiple (≥2) anxiety disorder <0.001
Oppositional defiant disorder <0.001
Bipolar disorder 0.063
Repeated a grade in school <0.001
Biederman J, et al. Pediatrics 2009;124(1):71-8
ADHD and Driving: A Dangerous Mix
• MVAs are #1 cause of death in teens
• ADHD increases the risk. (1)
• Adolescents with ADHD:
• 2-4 x more car accidents ( 2-4)
• 3 x more injuries (3)
• 4 x more at fault (2)
• 6-8 x more license suspensions (2,3)
• Meds decrease risk for MVAs (4,6)
1.National Highway Traffic Safety Administration, Ann Emerg Med 1997:29:546-9.
2. Barkley RA, Pediatrics1993:92:212-218. 3. Barkley RA, Pediatrics 1996:98:1069-1095.
4. Cox DJ, J Nerv Ment Dis 2000:188:230-234. 5. Neda-Rajas, JAACAP 1997:36:515-32
6. Cox DJ, JAACAP.2004:43(3):269-75
Do Stimulants Increase Risk of Later Drug Abuse?
NOMedication treatment of ADHD decreases drug use by teens with ADHD by 6 times
Wilens et al. Pediatrics 2003;111:179-185
Things to keep in mind if you’re concerned about abuse of ADHD medication...
1. These meds have approval from Health Canada.
2. Some ADHD medications can only be abused if
they are snorted or injected. There is no risk if
they are taken orally.
3. Other ADHD medications haven’t shown any
ability to give a high, even if injected or snorted.
4. Short acting meds are more likely to be abused
5. Diversion is most common in patients with
substance use disorders/conduct disorder
Choosing a Medication
Factors That Influence Choice of Medicationfor A Specific Patient
Medical Considerations
• Treatment guidelines
• Urgency of treatment
• Duration of effect
• Patient preference
• Co-morbid symptoms
• Previous treatment success
• History of drug abuse (individual or family)
Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-57.
Practical Considerations
• Adherence
• Stigma
• Cost / insurance
• Administration:
• By parent
• By teacher
COMORBIDITY: The Rule not the Exception in ADHD
ADHD andOppositional
Defiant Disorder
ADHD only
n = 579 Does not include 30-40% with LDs
Jensen P, et al. Arch Gen Psychiatry 1999;56:1073-1086. MTA study
*Note that the total is greater than 100% due to listing some patients with more than one diagnosis
ADHD and Oppositional Defiant Disorder
ADHD only
n = 579 Does not include 30-40% with LDs
ADHD and anxiety /mood disorders
ADHD and Conduct Disorder
ADHD and tics
Medication Guidelines
CADDRA
Guidelines
2008
www.caddra.ca
Canadian ADHD Resource Alliance
1st line 2nd line 3rd line
2008 CADDRA Guidelines Medication Treatment of ADHD
"Off label"
if drugs fail
Imipramine
Wellbutrin®
Short Acting
Dexedrine®
Dex-Spansules®
Ritalin IR®
Ritalin SR®
Long Acting
Adderall
XR®
Biphentin ®
Concerta ®
Strattera ®
All trade-marks mentioned in this presentation are the property of their respective owners.
Reasons for using Long-acting Medication First-line
1. Improves tolerability
2. Improves compliance
3. Preserves confidentiality & avoids legal/logistic issues of taking meds at school
4. Improves function in many areas • Home life (i.e., relationships with family)
• Interaction with friends
• Extracurricular activities (e.g., sports, peer groups)
Medication Active Agent Delivery System Duration
Adderall® XRMixed-
amphetamine salts
Beaded double-
pulse delivery10-12 h
Biphentin® MethylphenidateMulti-Layer
ReleaseTM 10-12 h
Concerta® Methylphenidate
Osmostic-controlled
release oral system
(OROS®)
10-12 h
Strattera® Atomoxetine
24 hOnce at
therapeutic
dose
4-6 weeks
Sti
mu
lan
tsN
on
S
tim
ula
nts
Long-Acting ADHD Agents Currently Available
Respective Product Monographs
What portion of the parents ask you how ADHD medications work?
A. Virtually none
B. Close to 25%
C. Close to 50%
D. Close to 75%
E. Nearly all
The Long Acting
Methylphenidates
• Osmostic-controlled release
oral system (OROS®)
• 22% immediate release
• Efficacy maintained through 12
hours after dosing
• Doses: 18, 27, 36, 54 mg
• Pharmacare coverage
• Generic????
CONCERTA ® Product Monograph, Janssen-Ortho Inc, August 14, 2007
CONCERTACONCERTA**: OROS Technology : OROS Technology
to Clinical Efficacyto Clinical Efficacy
CONCERTA ®
Methylphenidate HCl
22% released
immediately-
peaks 1-2 hrs.
Second peak 1-
2 hrs later
Generic Equivalency? • Health Canada has approved an generic MPH that is being marketed as a
“long acting” stimulant medication “equivalent “ to Concerta
• When Health Canada determines whether or not 2 medications are
“equivalent” they look at Bioequivalency not Clinical Equivalency
• Health Canada uses 2 pharmacokinetic parameters of the plasma-
concentration curve to determine whether new product is bioequivalent:
• Total-area-under-the-curve (AUCo-∞ )
• Maximum-concentration (Cmax)
• If AUC and Max concentration is 80-125% of reference product the new
product meets Health Canada Criteria for Bioequivelence
Health Canada Guidance Document: Guidance for Industry, Conduct and Analysis of Bioavailability and
Bioequivalence Studies - Part B: Oral Modified Release Formulations, 1996
Cmax 4.32 ng/mlAUC 41.8ngh/ml
Cmax 3.73ng/mlCmax 3.73 ng/mlAUC 41.8ngh/ml
Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as OROS®
(methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999
Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as OROS®
(methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999
Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as
OROS® (methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999
Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as
OROS® (methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999
Bioequivalence ≠ Clinical Equivalence
Thus even though bioequivalence may be
established between a second- entry product and a
current product , it can not be assumed that the
second- entry product will provide the same clinical
benefit as the original medication
Recommend advising physician and patients if
substitution occurs so that clinical efficacy can be
monitored.
BIPHENTIN® (CR Methylphenidate MLR™)
• Multi-Layer Release (MLRTM)• Immediate-release layer (40% total MPH)
• Controlled-release layer (60% total MPH)
• Efficacy shown to last 10-12 hours
• Capsules should be swallowed whole;
contents may be sprinkled
• Patients currently receiving IR MPH may
be converted to the same daily dose of
Biphentin, as a single daily dose in AM
• Private payers or EDS
Biphentin ® Product Monograph, Purdue Pharma, June 19, 09
0
5
10
15
20
0 4 8 12 16 20 24
Time (hours)
Co
ncen
trati
on
(n
g/m
L)
Biphentin Child (fed) IR-MPH Child (fed)
Mean Dose – 38.6 mg
D Quinn, T Bode, JL Reiz, GA Donnelly, and AC Darke, 2007. "Single-dose pharmacokinetics of multilayer-release methylphenidate and immediate-release
methylphenidate in children with attention-deficit/hyperactivity disorder." J Clin Pharmacol. 47 (6): 760-66.
Biphentin® Single-Dose Plasma
Concentration Time Profile in Children
The Long Acting
Amphetami
ADDERALL XR ®(mixed salts amphetamine)
• Capsule contains beads designed
to give double-pulse delivery
• Behavioural improvements both
in morning and afternoon
assessments
• May be taken whole or sprinkled
• Single dose of Adderall XR
provided comparable plasma [ ]’s
to IR Adderall administered 4
hours apart
• Private plansAdderall XR® Product Monograph, March, 2009
4 hrs later
Patients Who Fail One Stimulant Should be Tried on Another
28%
16%
41%
83%
0%
20%
40%
60%
80%
100%
Response to
AMPH only
Response to MPH
only
Equal response to
AMPH and MPH
Response to at
least one
Arnold LE. J Attention Dis 2000;3(4):200-11.
Meta-analysis of 6 within-subject comparative trials (n=174) evaluating response to stimulant medications
AMPH, amphetamine; MPH, methylphenidate.
% P
ati
en
t re
sp
on
se
Some patients respond
preferentially to one
stimulant
Most Common Stimulant AEs
• Decreased appetite
• Sleep difficulties
• Headache
• Irritability
• Tics
• Growth effects
Specific Norepinephrine Reuptake Inhibitor
Atomoxetine (Strattera®)
STRATTERA® (atomoxetine)
• Effective when administered once daily in the morning• Can be discontinued without being tapered• Capsules not intended to be open, should be taken whole • Not associated with pattern of response that suggested
stimulant or euphoriant properties• 3 step titration • Paxil, Prozac increase steady state blood levels of Strattera
in extensive metabolizers• No precautions for co-morbid disorders (Bipolar, tics or anxiety)• Private Plans
Strattera ® Product Monograph, October 30, 2007
Side Effects of Strattera® :
• Common:• Nausea & vomiting (take with meal)
• Sedation • Appetite decreased
• Rare:• Hepatitis
• Suicidal thoughts: greater in 7-12 yr old boys on Strattera than controls 5/1357 (0.37%) vs 0/851 (0%) p<.016
Strattera ® Product Monograph, October 30, 2007
Atomoxetine and Methylphenidate:Effects on Extracellular Dopamine in Rat Prefrontal Cortex, Nucleus Accumbens, and Striatum
1. Bymaster FP et al., Neuropsychopharmacology 2002;27: 699–711.
Prefrontal cortex (3 mg/kg)
Nucleus accumbens (3 mg/kg)Striatal dopamine (10 mg/kg)
Time (Hours)
-1 0 1 2 3 4%
Do
pam
ine B
aselin
e0
50
100
150
200
250
300
350
Time (Hours)
-1 0 1 2 3 4
% D
op
am
ine B
ase
lin
e
0
50
100
150
200
250
300
350 *p <.05 vs. baseline
Prefrontal cortex
Nucleus accumbensStriatum
***
AtomoxetineMethylphenidate
Methylphenidate 3 mg/kg ip Atomoxetine 1 mg/kg ip
**p <.05 curve vs. baseline
***
Have you heard of Vyvanse® yet?
A. Yes
B. No
A New Long-Acting ADHD Medication:
Lisdexamfetamine Dimesylate
Chemical Structure of Vyvanse
Therapeutically inactive until it is
converted to active d-amphetamine in the body
Lisdexamfetamine
(Prodrug)
H N2
O
NH
NH 2
CH 3
l-lysine
H N2
O
OH
NH 2
+
d-amphetamine
(active)
H N2
CH 3
Site of cleavage
Release of the active ingredient in Vyvanse does not rely on gastrointestinal factors such as GI transit time or gastric pH
Vyvanse Dosing
Dosages available in Canada: 30 mg and 50 mg
Designed as a once-daily capsule
Indicated for children ages 6 to 12
Starting treatment or switching from another agent
recommended dose 30 mg given in the morning
Therapeutically inactive until it is converted to active
d-amphetamine in the body
May be taken with or without food
The capsule may be opened and the entire contents
dissolved in a glass of water
Vyvanse ® Product Monograph, SHIRE LLC, May 29, 2009
Stability of Pharmacokinetics with Prodrug
* Data are individual subject Tmax and Cmax for the largest cohort
Ermer JC, et al. Presented at the 160th Annual Meeting of the American Psychiatric Association;
May 19-24; San Diego, CA.
0
50
100
150
200
250
0 1 2 3 4 5 6 7 8 9 10 11 12
Max
imu
m C
on
cen
tra
tio
n
d-A
mp
heta
min
e (
ng
/mL
) C
ma
x
Time (h) to Maximum Concentration (Tmax)
MAS XR 30 mg (n=9)
LDX 70 mg (n=8)
**
**
*
*
**
**
**
*
LDX MAS XR Placebo
Time Post-Dose (h)
* p<0.05 vs. placebo; N=50; † Average of all doses tested
Biederman J, Boeliner SW, Childress A, et al. Biol Psychiatry 2007.
LS
Mea
n S
KA
MP
-A S
co
re†
(Ch
an
ge F
rom
1s
tT
ime
Po
int
Me
as
ure
d)
8:00 a.m.
First
Assessment
7:00 p.m.
Last
Assessment
7:00 a.m.
Dose
Significant Improvements in Attention for Up to 12 Hours (SKAMP-A)
-0,8
-0,6
-0,4
-0,2
0,0
0,2
0,4
0,6
1 2 3 4.5 6 8 10 12
Vyvanse® -Incidence of Most
Commonly Reported AEs
26.1
11.9
2.2 2.8
17.4
2
5.43.9
8.7
2.50.5
2.22.8 3.5 3.82.2
0
5
10
15
20
25
30
1
(n=218)
2
(n=202)
3
(n=186)
4
(n=178)
Decreased appetite Insomnia
Abdominal pain Irritability
Pati
en
ts (
%)
WeekData on file, LDX 004. Shire US Inc.
1st Occurrence or Recurrence
15 min Break W
Pharmacists are often a patient’s 1st contact with the health care system.
They are considered unbiased experts on medication
They can play an important role in management of ADHD
Role of the Pharmacist
In Conclusion :1. ADHD is a clinical diagnosis with genetic
& neuroimaging findings.
2. Parents reluctant to treat ADHD must
understand the significant dangers of
non-treatment.
3. Parents who are interested should be
informed why a specific medication has
been prescribed and how it works.
4. Pharmacists have an important role in
educating & supporting patients with
ADHD and their families.
Questions…