Attention-Deficit /Hyperactivity Disorder

Attention-Deficit
/Hyperactivity
Disorder
Workshop
Vineyard Hotel
Prof. A. Venter
Department of Paediatrics and Child Health
University of the Free State
Departement Sentrum • Department Centre
UNIVERSITEIT VAN DIE VRYSTAAT • UNIVERSITY OF THE FREE STATE • YUNIVESITHI YA FREISTATA
Tel (051) 401 3000 • E-mail: [email protected] • www.ufs.ac.za
DECLARATION OF INTERESTS
Advisory
Board
Lecturer
Eli-Lilly


Novartis


Janssen-Cilag


2
ADHD
PATHOPHYSIOLOGY
3
ADHD IS NO MONKEY BUSINESS
4
ADHD IS NOT A BENIGN
DISORDER
•
•
•
•
32-40%: Drop out of school
70-80%: Under-achieve
40%: Teen pregnancies
20-30%: Depressed
5
ADHD – THE BACK TO FRONT
CONDITION
6
7
8
9
Sir Alexander Critchton
(1763-1856)
• Scottish physician
• Studied at the University of Leuven
• Wrote 3 books – 1798 (published again
2001)
• Described inattentativeness but not
hyperactivity
10
11
Heinrich Hoffmann (1809-1894)
12
Struwwelpeter
by Heinrich Hoffmann
The Story of Fidgety Philip
13
Heinrich Hoffman
• General practitioner and obstetrician in
Frankfurt – 1835
• In 1851 employed at a mental hospital became a psychiatrist
• In 1844 wrote and illustrated
“Struwwelpeter” for his 3 year old son
• Describes the hyperactive type ADHD
• Probably described a naughty boy!
15
Franz Kramer & Hans Pollnow
• Reported “On a hyperkinetic disease of
infancy” - 1932
• Vey accurate description of hyperactive
behaviour:
– Cannot stay still for a second
– Run up and down the room
– Climb about, preferring high furniture
– Displeased when deterred
17
Leandro Pannizon
• Synthesized Methylphenidate in 1944
• Ritalin derives from “Marguerite” or “Rita”
– his wife!
• Initially developed for chronic fatigue,
lethargy, depressive states, senile
behaviour and narcolepsy
• Ciba-Geigy markets Ritalin in 1954
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20
21
ADHD: Proposed Etiologies
• ADHD is a heterogeneous behavioral disorder with
multiple possible etiologies
Genetic
origins2
Neuroanatomic
Neurochemical1
ADHD
CNS
insults3
1 Swanson
Environmental
factors4
J, et al. Curr Opin Neurobiol. 1998;8:263-271. 2 Hauser P, et al. N Engl J Med.
1993;328:997-1001. Cook EH, et al. Am J Hum Genet. 1995;56:993-998. Swanson JM, et al. Mol
Psychiatry. 1998;3:38-41. 3 Milberger S, et al. Biol Psychiatry. 1997;41:65-75. 4 Castellanos FX, et
22
al. Arch Gen Psychiatry. 1996;53:607-616. Swanson JM, et al. Lancet. 1998;351:429-433.
Overview of Areas in the Brain
Implicated in ADHD
sensory organs and
parietal lobe
Perception and localization
limbic system
Emotional significance
prefrontal cortex
Delay, analysis and judgment
hippocampus
Association and recognition
locus ceruleus
reticular activating system
Arousal and alerting
nucleus acumbens and
striatum
Relay and interruption
23
Anterior and Posterior
Attentional Systems
Posterior Attentional System
NE Mediated
Right
Frontal
Posterior
Parietal
Anterior Attentional System
DA & NE Mediated
Dorsolateral
Frontal Cortex
LC
24
Dopamine
Transporter DAT
D4 Receptor
AD/HD
25
Neurotransmitter Systems
NE
Norepinephrine Neuron
Norepinephrine
Dopamine
DOPA
(NE) MAO NE
decarboxylase Dopamine- hydroxylase
MHPG
DOPA
NE
NE
NE
Transporter
Dopamine Neuron
DOPA
DOPA
decarboxylase
DA
DA
Dopamine
(DA)
MAO
DA
DA
Dopamine
Transporter
Presynaptic Neuron
Postsynaptic Neuron
26
27
ETIOLOGY
28
29
Etiology
-Genetic
- Maternal anxiety/stress
-Prematurity
- Maternal deprivation
-Birth asphyxia
- Post concussion/injury
-Teratogens
- Post encephalitis
= Smoking
- Post meningitis
= Alcohol
- Post asphyxiation
= Cocaine
- FFA deficiencies
30
Etiology What’s new:
Prematurity:
SGA status and lower birth weight,
rather then prematurity have increased
risk for ADHD
Heinonen, Raikkonen, Pesonen et al, 2010
Extreme preterm children are at risk for ADHD and autism
Johnson, Hollis, Kochhar et al, 2010
Maternal smoking: Yes: Biedernan, Monuteaux, Faraone, Mick, 2009
Motlagh, Sukhodolsky, LanderosWeisenberger et al, 2010.
No:
Ball, Gilman, Mick et al, 2010
31
Etiology What’s new:
Lead:
even at low levels
Kim, Cho, Kim, Hong et al, 2010
Eubig, Aguiar, Schatz 2010
Nicolescu, Petcu, Cordeanu et al, 2010
Zinc deficiency:
Lipping, Huber 2010
32
Co-morbid medical conditions:
-Epilepsy
-Mental retardation
-Autistic spectrum disorders
-Learning disorders
-Fragile X etc.
-FAS
33
Diagnosis
34
35
36
IMPAIRED ATTENTION
1. Unable to listen or follow instructions
2. Unable to finish work
3. Unable to sequence (Auditory or visual stimuli)
4. Attend to detail
5. Work alone
6. Distracted
7. Daydream
8. Have poor organizational skills
9. Perseverative on task
37
38
39
40
41
42
43
44
45
46
47
48
49
CLINICAL
• DISINHIBITION/IMPULSIVENESS
– React before they have understood a
problem clearly, heard the complete
question or before they have given
sufficient thought to possible
solutions
– Make many careless mistakes
– Low frustration tolerance
– Antisocial behavior
– Poor planning and judgement
– Failure to finish tasks
– Sloppy work
50
CLINICAL
– Approximations in reading and writing
– Reckless behavior
– Accident proneness
– Impaired sphincter control (?inattentive)
– Inability to delay gratification
51
52
53
54
55
56
57
Criticisms of DSM-IV ADHD
1. Are subtypes useful?
2. What about the Inattentive ADHD with no
hyperactivity.
3. Representation of 3 key features are uneven
-impulsivity is underrepresented.
4. Manifestation of adult ADHD not well reported.
5. Age of onset was set arbitrarily at 7 years.
6. Criteria are sparsely described.
7. Large number of criteria is difficult for clinicians to
remember.
APA 2010
Swanson, Wigal, Lakes 2009
Bell 2010
58
Some suggested improvements:
Elaboration of criteria
Example I - Inattention
Existing:
Often has difficulty organising tasks and activities
Elaboration:
(messy, disorganized work, difficulty managing
sequential tasks, keeping accurate records, keeping
clothes or belongings in order, organizing time,
recurrent latenesses and failure to meet deadlines).
59
Elaboration of Criteria Example II
Existing:
Is often “on the go” or often acts as if “driven by a
motor”
Elaboration:
(is adverse to being still for extended time, feels has
to get going when in restaurant, during lectures, is
perceived as being hard to keep up with, as being
too restless, has difficulty unwinding or relaxing).
60
Expanding criteria for impulsiveness
Existing:
1. Blurts out answers
2. Difficulty waiting turn
3. Interrupts others
Expression:
4. Acts without thinking
5. Impatient
6. Rushes through activities or tasks
7. Difficult to resist temptations
61
Age criterion
Suggestion:
Increase age of onset of symptoms to be
present on or before age 12
62
Use of EEG’s in the diagnosis of ADHD controversial
1. 25% of non-epileptic children with ADHD had epileptiform
discharges on EEG.
>50% focal ? Relevance
Millichap, Stack, Millichap 2010
2. Pilot study:
No correlation between focal
noctural epileptiform activity on
EEG (FNEA) and severity of ADHD
symptoms
Wannay, Eriksson, Larsson 2010
3. Theta/beta ratio identified ADHD 87% sensitivity and 94%
specifically
Not influenced by co-morbidity
Snyder, Quintana, Sexson et al, 2008
63
Use of EEG’s in the diagnosis of ADHD controversial
4. Childhood EEG as a predictor of adult ADHD.
Adult ADHD groups had global relative beta,
reduced frontal relative theta, increased frontal absolute
and relative beta
Clark, Barry, Dupuy et al, 2010
5. Epileptiform abnormalities more common in girls with
ADHD-I
Socanski, Heigstad, Thomson et al, 2010
64
MANAGEMENT OF ADHD
MANAGEMENT

Exclude any medical causes for
symptoms (eg. Medication, allergies,
epilepsy)
 Check development
 Behavioral management
 Social support for children and parents
 Medication
MEDICAL
MANAGEMENT OF
ADHD
METHYLPHENIDATE
METHYLPHENIDATE
MULTIMODAL TREATMENT
STUDY OF CHILDREN WITH
ADHD (MTA)
579 Children
7-9.9 Years
ADHD Combined Type
4 Modalities of treatment
METHYLPHENIDATE
MTA STUDY
MODALITIES OF TREATMENT
Medication management (n=144)
(titration followed by monthly visits)
Intensive behavioural treatment (n=144)
The two combined (n=145)
Standard community care (n=145)
METHYLPHENIDATE
THE EFFECT OF DIFFERENT
DOSAGE REGIMENS
PHARMACOKINETICS
Absorption - Ritalin 10mg:
 Rapid absorption of active substance
 Food ingestion accelerates absorption, but no
influence on amount absorbed
 First-pass metabolism  only 30% systemic
availability
 Peak plasma concentrations reached on average 1
to 2 hours after administration
(vary from person to person)
METHYLPHENIDATE
RITALIN LA
• Releases Ritalin in two peaks
• Adverse events similar to placebo
• Second dose released 4 hrs after the first
• Available 20mg, 30mg, 40mg
EXTENDED-RELEASE DELIVERY
Each Ritalin® LA capsule contains 50% immediate-release
beads and 50% extended-release beads
Ritalin®
layer
Inactive
core
Immediate-release bead
Extended-release polymer coated bead
Polymer
coating
EXTENDED RELEASE DELIVERY VIA SODASTM TECHNOLOGY
SODASTM is a trademark of Elan Corporation, PLC
•
Same rapid onset as Ritalin® & school day duration
•
50/50 bimodal release mimics Ritalin BID dosing
METHYLPHENIDATE
CONCERTA
Principle of increased doses
CONCERTA: OROS®
Formulation
Laser-Drilled
Hole
MPH
Compartment
#1
MPH
Overcoat
MPH
Compartment
#2
Tablet Shell
Push
Compartment
CONCERTA: Treatment
Concentration (ng/mL)
20
IR MPH 10 mg tid (n=15)
CONCERTA 36 mg qd (n=15)
The unique ascending
profile is designed to
maintain a consistent,
12-hour therapeutic
effect, providing a
reduction of symptoms
throughout the day
16
12
8
4
0
0
2
4
6
Time (h)
Swanson J, et al. Arch Gen Psychiatry 2003;60:204–211.
8
10
12
PRECAUTIONS

Not indicated in all cases of ADHD history and evaluation of prime
importance! Correct assessment

Use with caution in epilepsy
•
can increase seizure frequency
•
if seizure frequency increases,
discontinue use of Ritalin
CONTRA-INDICATIONS

Hypersensitivity to methylphenidate or any
of the excipients of ritalin

Anxiety, tension, agitation

Tics, tics in siblings, family history or
diagnosis of Tourette’s syndrome

Hyperthyroidism

Cardiac arrhythmia's, severe angina pectoris
Side-effects
Most common side-effects are:
1.
Decreased appetite - usually transient
2.
Headache, drowziness, dizziness
3.
Nervousness, insomnia
4.
Social withdrawal
Other:
1.
Blurred vision, difficulties with
accommodation
Impact on height and weight
There is a small deceleration of height velocity –
the magnitude related to duration of treatment
No significant influence on weight
Zhang, Du, Zhuang, 2010
Goldman, 2010
Cardiovascular effects
1.
Minor increases in BP and heart rate
2.
No strong data to suggest an increase in QT
interval
3.
Sudden death very rare - ? Linked to stimulants
4.
Atomoxitine may increase BP long-term
5.
Children with heart conditions have a higher rate
of ADHD
Stiefel, Besag, 2010
Merkul, 2010
Hennessy, Solellerman, Daniel
et al, 2010
Recommendation:
1.
Obtain a patient and family health history – poor
exercise tolerance, fainting spells, family history of
unexplained death, dysrhythmias
2.
Do a cardiovascular physical exam
3.
It is reasonable to consider doing an EEG in
specific cases, but not mandatory
4.
Checklists are available
5.
Children with cardiac lesions should be treated by
experts in conjunction with cardiologists
Elia, Venter, 2010
Silva, Skimming, Munig, 2010
Substance abuse
1.
No association between stimulant treatment and
later substance abuse
2.
There is an increase when conduct disorder is
factored in
3.
Treatment with stimulants may decrease the risk of
substance abuse
Willens, Adamson, Monuteau et
al, 2008
2008
al, 2010
Manuzza, Klein, Truong et al,
Brook, Brook, Zhang et
Safety of stimulant therapy in
ADHD
-
Majority of treatment complications are quickly
reversible or easily manageable
-
Consequences of untreated ADHD clearly outweigh
the risks of the stimulant
Merkel, 2010
STRATTERA
(ATOMOXETINE)
Effect of Weight on Plasma
Exposure
26.3 kg
Atomxetine Plasma
Concentration (ng/mL)
400
40 mg single dose of
Atomoxetine:
effect of body weight
on Pharmacokinetic
profile is notable
29.6 kg
35.3 kg
300
43.6 kg
200
70.0 kg
100
0
0
3
6
9
12
15
18
21
24
Time From Dose (hr)
itcher et al. 2001. Population Pharmacokinetics Analysis. Lilly Research Laboratories
Adjusting for Weight Normalizes
Plasma Exposure
1 mg/kg single
dose of
Atomoxetine:
effect of body
weight is
minimised
Atomxetine Plasma
Concentration (ng/mL)
400
26.3 kg
29.6 kg
300
35.3 kg
43.6 kg
70.0 kg
200
100
0
0
3
6
9
12
15
18
21
Time From Dose (hr)
Witcher et al. 2001. Population Pharmacokinetics Analysis. Lilly Research
Laboratories
24
Once-Daily Efficacy: School Setting
ADHD-RS Teacher Total Score
Placebo (n=52)
Atomoxetine (n=101)
Mean ADHD RS Score
38
33
28
*
-8.7
**
23
**
**
18.7
18
1
3
Weeks of Treatment
*p<.05. **p<.001.
Weiss et al . Poster presented at CCNP, Quebec, Canada, 2003
5
7
Comparability Relative to
Methylphenidate (cont.)
Mean Change in ADHD-RS Score
ADHD-RS Total
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
-20
-22
Hyperactive/
Impulsive Subscale
-8.5
*
-17.8
*
Inattentive
Subscale
-9.5
-9.3
-9.9
*
*
*
-19.4
*
Methylphenidate (n=40)
Atomoxetine (n=178)
Mean Final Dose (mg/kg/day)
Atomoxetine=1.4
Methylphenidate=0.9
*p<.001 within treatment group, baseline to endpoint. p=NS between groups.
Kratochvil CJ, et al. J Am Acad Child Adolesc Psychiatry. 2002;41(7):776-784.
NEW RESEARCH: EFFICACY
GENERAL:
 Spain
2009
 151 treatment naive (113 children, 38
adolescents)
 Dosage up titrated from 0.5mg/kg to 1.2mg/kg
 Double blind, randomized placebo controlled
study over 12 weeks
NEW RESEARCH: EFFICACY
 Effect
size of 0.8 [95% CI: -11.0 to -4.8]
 Most improvement between 3-6 weeks
 Side effects – somnolence and decreased
appetite (no patient discontinued)
Montoya, Hervas, Artigas et al. (2009). Curr Med
Res Opin;,25(11): 2745
NEW RESEARCH: EFFICACY
Japan,
2009
Double blind, placebo controlled
245 children and adolescents received
0.5mg/kg. 1.2 mg/kg and 1.8 mg/kg over
8weeks
235 completed study
NEW RESEARCH: EFFICACY
 Only
1.8mg/kg was significantly superior to
placebo in reducing symptoms
 Side effects: decreased appetite and vomiting (no
difference between groups). Two stopped due to
affect lability and headache.
Takahashi, Takita, Yamazaki et al. (2009) A
randomized, double-blind, placebo-controlled study
of Atomoxitine in Japanese children and
adolescents with ADHD. J of Child & Adolesc
Psychopharm; 19(4): 341-350
ADOLESCENTS:
Wietecha, Williams, Herbert et al. (2009)
Atomoxitine Treatment in Adolescents with ADHD.
J of Child & Adolesc Psychopharmacology; 19(6):
719-730
 Slow
and fast titration scales equally effective up
to 1.2mg/kg, but not less side effects (8 weeks) –
267 subjects
 Lower maintenance dose (0.8mg/kg) less
effective than 1.4 mg/kg (40 weeks) – 178
subjects
ADULTS
Durell, Adler, Wilens, Paczkowski, Schuh (2009).
Atomoxitine treatment for ADHD. Younger adults
compared with older adults. J of Attention
Disorders
 Meta
analysis: aged < and > 25 years
 Response rates 56.4% and 47.8% over 10
weeks. Dosage 60- 90- 120mg
 Tolerability similar, more sexual side effects
reported in older group
 Effect size greater in younger group
Once-Daily Efficacy: School Setting (cont.)
Conners’ Global Index-Teacher (CGI-T)
0
-0.8
-2
-3
-4
-5
-3.7
Placebo (n=42)
Atomoxetine (n=74)
*
Mean Change in Teacher
Problem Behavior Scale
Mean Change in CGI-T
0
-1
Teacher Problem Behavior Scale
-2.0
-2
-4
-6
-8
-5.3
Placebo (n=45)
Atomoxetine (n=76)
*p=.008. **p=.025.
Weiss et al . Poster presented at CCNP, Quebec, Canada, 2003
**
Once-Daily Efficacy:
Symptom Control in the Evening
Evening Behaviours
excessively
 Transitioning activities
 Settling at bedtime
 Falling asleep
Evening Subscale
0
Mean Change in
Daily Parent Rating Scale
 Completing homework
 Sitting through dinner
 Playing quietly
 Distractibility
 Arguing/struggling
-1
-2
-3.3
-3
-4
-5
-6
Placebo (n=58)
Atomoxetine
(n=126)
*p<.005.
Kelsey D, et al. Poster presented at AACAP, Miami, 2003.
-5.4
*
Once-Daily Efficacy: Symptom Control Early
the Next Morning
Early Morning Behaviours
 Getting
Mean Change in
Daily Parent Rating Scale
out of bed
 Getting ready for school
 Arguing/struggling
excessively
Early Morning Subscale
0.0
-0.4
-0.9
-0.8
-1.2
-1.6
-2.0
Placebo (n=58)
Atomoxetine
(n=126)
*p<.02.
Kelsey D, et al. Poster presented at AACAP, Miami, 2003
-1.7
*
What does this mean –
Strattera offers 24 hours Continuous Symptom Reli
Atomoxetine Tolerability in Combined
Child/Adolescent Studies

Gastrointestinal side effects (decreased
appetite, vomiting, abdominal discomfort and
dyspepsia) and sedation/somnolence were the
adverse events most of note in the placebo
controlled studies

Incidence of insomnia comparable to placebo

No evidence of symptom rebound or adverse
events suggesting a withdrawal syndrome
Atomoxetine Summary of Product Characteristics
Effect on Vital Signs
Mean Increase
Vital Sign
Atomoxetine
Methylphenidate
Heart Rate
6.1 bpm
5.7 bpm
Systolic Blood Pressure
2.7 mm Hg
3.4 mm Hg
Diastolic Blood Pressure
2.6 mm Hg
3.0 mm Hg
Kratochvil CJ, et al. J Am Acad Child Adolesc Psychiatry. 2002;41(7):776-784
Atomoxetine: Unlikely to affect growth
Changes in weight and height over 36 months
Michelson D, Bangs ME, Zhang S, et al. Poster presented at the American Academy of Adolescent Psychiatry (AACAP) annual meeting,
Washington, October 2004.
ECG Evaluations
 Extensive
ECG monitoring conducted on all
subjects
 No
effects on QTc interval
 No
requirement for ECG monitoring
outside of routine medical care
Wernicke et al, Drug Safety 2003 26(10): 729-740
Perceived Strattera Patient Profile
Physicians struggle with providing a cohesive Strattera patient profile
As an alternative to
stimulants
• If the patient doesn’t, or
is unlikely to tolerate
stimulants
For a variety of
psychological conditions
and ADHD
• If the patients/patient’s
parents wishes to avoid
stimulants
•anxiety,
•mood disorders,
•irritability, or any manner
of „emotional‟ or
„psychological‟ issues
• To prevent abuse of
stimulants
• To reduce the level of
stimulants
• To avoid the ups and
downs of stimulants
For the patient with
patience, typically adults
For complex ADHD (comorbid) or mild symptoms
For the non-compliant
or low-compliant
patient
• In children or adults
Qualitative Study – Hypotheses generated which must be validated/tested via quantitative study
Who is the Strattera patient…
Naïve
Patient
Strattera
treated but
needs add-on
Potential
“Whole Life”
TARGET
Crisis –
immediate
symptom
resolution
needed
NO
Responding
well but could
do better
Not
Dissatisfied
responding
with stimulants
well
Responding
well
Switch
Patient
Atomoxetine Dosing Guidelines
How to switch Current patients to
Strattera
“…transitioning patients from one medication to another can be
an important strategy for finding the most effective regimen for an
individual patient”
 “when transitioning to atomoxetine, a gradual cross-taper of
medications over a 2-3 week period is suggested to minimize any
disruption in the control of the symptoms of ADHD

-Therapeutic Focus, Attention-Deficit Disorder: Pharmacotherapy
Challenges and Practical Solutions for the Treatment of Children
and Adolescents - A Roundtable Discussion 2003
Week 1
Example*: For
Illustrative
Purposes only
Stimulant
Strattera
Week 2
Full
½ dose
dose
0.5mg/k 1.2mg/k
g
g
10 mg
25mg
Week 3
DC
Week 4
DC
1.2mg/k 1.2mg/k
g
g
25mg
25mg
*Recommendations to prescribers by the S.A. Advisory Board Members of Atomoxetine – Nov 06 2004
Ref: Quintana, Kelsey – presented at AACAP Oct 18-23,2005, Toronto, Canada
Prescribing information (South Africa, July
2005)
S5 STRATTERA® (atomoxetine) 10 mg, 18 mg, 25 mg, 40 mg and
60 mg oral capsules containing atomoxetine hydrochloride equal to 10
mg,
18 mg, 25 mg, 40 mg or 60 mg atomoxetine respectively.
INDICATIONS: For treatment of Attention-Deficit/Hyperactivity
Disorder (ADHD) in children 6 years of age or older, adolescents and
adults.
PHARMACOLOGICAL CLASSIFICATION: A1.2: Psychoanaleptics
CONTRAINDICATIONS: Hypersensitivity to atomoxetine or to any of
its excipients, and patients with uncontrolled hypertension, narrow angle
glaucoma, impairment of liver function or in combination with MAOIs.
WARNINGS: Allergic reactions may occur. Discontinue in patients with
jaundice or laboratory evidence of liver injury; do not restart. Liver
enzyme
levels and bilirubin should be tested at the first sign or symptom of
possible liver involvement. STRATTERA® may increase the risk of
mood
swings, including hostility and emotional lability. STRATTERA® lacks
efficacy
as a treatment modality in depression.
INTERACTIONS: Administer with caution in patients taking
betaadrenergic
receptor agonists (e.g. salbutamol), pressor agents and medicines
affecting norepinephrine.
DOSAGE AND DIRECTIONS FOR USE: See package insert for
details.
Dosing of children and adolescents up to 70 kg body weight: Initial
daily dose: 0,5 mg/kg, for at least 7 days prior to upward dose titration
according to clinical response and tolerability. Recommended maintenance
dose: 1,2 mg/kg/day with or without food.
Dosing: Children and adolescents > 70 kg body weight and adults:
Initial dose: 40 mg daily, for at least 7 days prior to upward titration
according to clinical response and tolerability. Recommended maintenance
dose: 80 mg/day with or without food. (Maximum dose: 100 mg).
General dosing information: Titrate cautiously to the desired clinical
response in patients with hepatic insufficiency or end-stage renal disease.
SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Children and adolescent patients: Mydriasis, GI, CNS and cardiac
symptoms, influenza, dermatitis, pruritis, and abnormal LFTs.
Adult patients: Cardiac, GI and CNS symptoms, decrease in weight,
urinary and reproductive system symptoms and dermatitis.
Monitor weight gain and longitudinal growth during treatment. Use
cautiously in patients with CVS symptoms. Caution must be used when
driving a car or operating hazardous machinery until it is reasonably certain
that performance is not affected by STRATTERA®.
REGISTRATION NUMBERS: 10 mg, 18 mg, 25 mg, 40 mg and 60 mg
capsules: 38/1.2/0520 - 0524
Eli Lilly (S.A.) (Pty) Limited, 1 Petunia Street, Private Bag X119, Bryanston
2021, Gauteng.
Manipulating the dose:
(i) Side-effects:
-give at night
-decrease the dose temporarily
(ii)Not effective:
-increase the dose (1,2-1,8 mg/kg)
-stimulants as add-on
-remember to increase dose as weight
increases
Stimulants as add on
Wilens, Hammerness, Utzinger et al. (2009). An
open study of adjunct OROS-methylphenidate in
children who are Atomoxitine partial responders: I
Effectiveness
Hammerness, Georgipoulos, Doyle et al. (2009).
An open study of adjunct OROS-methylphenidate
in children who are Atomoxitine partial responders:
II Tolerability and pharmacokinetics
Stimulants as add on
Good news:
•
On combination - a 40% reduction in
ADHD symptoms
• Improvements in executive function
• No ECG changes
• LFT remained normal
Stimulants as add on
Bad news:
• More
insomnia, irritability, loss of
appetite
• Sign but small increase in blood
pressure
Stimulants as add on
Limitations:
•
Open study
• Non-responders diagnosed after 4
weeks of ATMX
• Combination therapy assessed after 3
weeks
• OROS doses increased from 18mg to
54mg in that time
ATOMOXITINE AND CO-MORBID
CONDITIONS
Review:
1.
2.
3.
4.
Efficacy of ATMX unaffected by co-morbid
conditions
Improves oppositional defiant disorder (in
most studies)
Potential for improving co-occurring
symptoms of anxiety
Useful in Tourette‟s syndrome
ATOMOXITINE AND EXECUTIVE FUNCTION
Improvements in:
 Non-verbal
executive functions (n=30):
• Shifting & flexibility of attention
• Spatial short-term memory
• Sustained attention
• Response inhibition
• Spatial working memory
• Spatial planning
• Problem solving
Gau & Shang (2009). Int J of Neuropsychopharmacol
Atomoxetine: Available Capsules
10 mg
18 mg
25 mg
PRICE - SEP : R476
40 mg
60 mg
Availability: 1st August 2005
Available in packs of 28‟s
STRESS…
HOW TO KEEP SANE WHEN THERE’S
AN ADHD CHILD IN THE FAMILY
GENERAL RULES FOR PARENTS

Be organized in all daily activities

Be one step ahead- never be at a loss

Don’t jump surprises, but don’t give warning
too far in advance

Make time for yourself

Make time for yourself and your spouse,
together & alone
GENERAL RULES FOR PARENTS

Don’t neglect the other children in the family

Be strict about time allocation, but be
flexible within this time

Remember, you are not the teacher, but the
parent

Be reasonable in your expectations

Get your child involved in extramural
activities (that they enjoy, if possible)
DISCIPLINE

Both parents have to be involved in the disciplining
of these children

Both parents have to discuss the disciplining of
these children

Both parents have to agree on the disciplining of
these children

Both have to be consistent as far as their
disciplining is concerned

Decide which specific behaviours have to be
targeted
DISCIPLINE

Both parents have to agree on how to target
these behavioural problems

Don’t argue with the child regarding
discipline

Your word is law, and not to be challenged.
On the other hand you have to be reasonable

Don’t shout at these children. They stop
listening
DISCIPLINE

Corporal punishment has little effect

Think your discipline through. Never be at a loss of
what to do next!

Feedback for good behavior & not only for bad
behavior

Keep instructions short, speak in a soft, clipped &
detached way

Use affection only as a reward for good behavior or
for correcting bad behavior
SYSTEMS

The rules of three

Rewards and punishments (bribes if necessary)

Time out!

Punish sibling fighting decisively, immediately,
impassionately and don’t ask for details

(both children involved should be punished
immediately, irrespective of who started what with
whom)
SYSTEMS

Behavior in public places: set rules and
keep reminding and reward

Seek professional help if not coping

Above all else, try and have realistic
expectations and even more important, try
and see some humour within the situation!!
APPROACHES TO THE
OPPOSITIONAL AND
AGGRESSIVE ADHD CHILD
OPPOSITIONAL DEFIANT DISORDER
(DMS-IV)
A recurrent childhood pattern of
developmentally inappropriate levels
of negativistic, defiant, disobedient,
and hostile behaviour toward authority
figures; may include temper
outbursts, persistent stubbornness,
resistance to directions, unwillingness
to compromise, deliberate or
persistent testing of limits, and verbal
(and minor physical) aggression
OPERANT CONCEPTUALIZATION OF
EXPLOSIVE /
NONCOMPLIANT BEHAVIOR
Oppositional, explosive behaviour is
the byproduct of inept (inconsistent,
noncontingent) parenting practices;
the child has learned that
oppositional, explosive behaviour is
effective at coercing adults into
capitulating to his or her wishes
SPECIFIC COMPONENTS
OF OPERANT APPROACH
• List of target behaviours (priority is
compliance)
• Menu of rewards and punishments
(differential reinforcement)
• Currency system
COGNITIVE CONCEPTUALIZATION OF
EXPLOSIVE / NONCOMPLIANT
BEHAVIOUR
The child is delayed in the
development of the skills of flexibility /
adaptability and frustration tolerance
or has significant difficulty performing
these skills when they are most
necessary (it’s a learning disability)
EXPLOSIVE OUTBURSTS
An explosive outburst – like other
forms of disadvantageous
behaviour – occurs when the
cognitive demands being placed
upon a person outstrip the
person’s capacity to respond
adaptively
THREE OPTIONS
(COMMON APPROACHES TO PROBLEMS / UNMET
EXPECTATIONS
PLAN A: Impose adult will
PLAN B: Train lacking skills; collaborative
problem
solving (solve the problem together)
PLAN C: Drop it (for now, at least)
COLLABORATIVE PROBLEM
SOLVING TREATMENT GOALS
Reduce explosive outbursts
(stabilize)
•
• Pursue adult expectations
• Teach lacking skills (e.g. flexibility
and
frustration tolerance)
BASKET B ENTRY STEPS
1. Empathy (+ reassurance)
2. Define problem
3. Invitation
BASKET B APPLICATIONS
-Proactive B
-Emergency B
-Added heat, lower odds
ADHD
Controversial and
alternative therapies
DEFINITIONS
1.
2.
3.
4.
5.
Medical treatment – using medication under
supervision of a medical professional
Psychosocial treatment – targets
psychological and social aspects
Alternative treatment – Any treatment other
than 1 & 2 that claims to treat ADHD with
equal or more effective outcome
Complimentary treatment – not alternatives,
but may improve treatment
Controversial treatment – no known
published science
Complimentary and alternative
medicines (CAM)
Why do parents choose them?
 Minimizing
symptoms of ADHD
 Adding to conventional treatment
 Avoiding side effects
 Silver Bullet
 Guilt
(65% of parents: Sinha & Efron, 2005)
Complimentary and alternative
medicines (CAM)
Be suspicious of treatment if:
1.
2.
3.
4.
Claims are overstated and exaggerated
Treats a wide variety of ailments, often not
rigorously defined
Claims are made that treatment is suppressed
or unfairly attacked by the “medical
establishment”
Only case histories and testimonials as proof/
one study cures/ no control groups
Complimentary and alternative
medicines (CAM)
Be suspicious of treatment if:
5. Described as natural or harmless, adverse
6.
7.
8.
9.
effects minimalized
Based on a „secret formula‟
Described as „astonishing‟, „miraculous‟,
„amazing breakthrough‟
Available from just one source
Promoted through infomercials, mail order,
media – not in peer review journals
Complimentary and alternative
medicines (CAM)
Be suspicious of treatment if:
It is very expensive
11. It has to be used exclusively
12. The “guru” lives “overseas”
13. There are few disciples – often colleagues
who are very competent in their fields offers
therapies outside their field
10.
ADHD – alternative therapies
DIETARY INTERVENTIONS
A healthy balanced diet is the key to
having a happy and healthy life – true
for everyone!
DIETARY INTERVENTION
– salicylates in food dyes, preservatives
and colourants increase hyperactivity
 Much anecdotal
 Well-controlled studies have failed to find a
robust effect (<1%) - old studies
 Parent‟s rating scales more positive
 Might be more effective in a small subset of
children
 Feingold
DIETARY INTERVENTION
Scant
or no evidence for sugar free diets,
megavitamin therapy or amino acid therapy
Sawni, 2008
supplements – only if deficiency is
proven – e.g. some benefit if serum ferritin
levels are low
Mineral
Hurr, Volp, Staruss-Grobo, 2010; Juneja, Jain, Sigh, Mallilix,
2010;
Konofal et al, 2008; Lilienfield, 2005; Oner, Oner,
Bozkurt et al, 2010
DIETARY INTERVENTION
Fatty acids
Omega 3 & 6 and the brain:
 Crucial
for brain structure and function
 Provided by diet only
 EFA are converted to HUFA - essential for the
fluidity of neuronal membranes, essential for
optimal functioning of membrane-associated
proteins such as ion channels and
neurotransmitter substances
DIETARY INTERVENTION
Fatty Acids
Signs of deficiency:
 Excessive thirst, frequent urination
 Rough or dry skin and hair, dandruff
 Brittle nails
? Atopic tendencies (especially eczema)
? Visual symptoms (poor night vision, sensitivity to
bright light etc)
? Attentional problems
? Emotional sensitivity (mood swings, temper
tantrums)
? Sleep problems
DIETARY INTERVENTION
Fatty Acids
Possible reasons for functional deficiencies:
 EFA conversion to HUFA very slow in humans
 High intake of saturated or trans (hydrogenated)
FA (processed foods)
 Vitamin & co-factor deficiencies (Zn, Mg, Vit B3, B6
and C)
 Smoking, alcohol, caffeine
 High levels of stress hormones
 Gender - males at risk
 Constitutional - diabetes, eczema
DIETARY INTERVENTION
Fatty Acids
Evidence?
 Evening of primrose oil - equivocal results
 Omega 6 appears less important then 3, and then
EPA rather than DHA
 DHA proven to be essential for pre-and postnatal
brain development (Kidd, 2007)
 EPA more influential on behaviour and mood (Kidd,
2007)
DIETARY INTERVENTION
Fatty Acids
Evidence?
 RCT
(small numbers) - some improvement on
attention, concentration, working memory,
disruptive behaviour, hyperactivity, anxiety and
withdrawal (3 out of 14 scales)
(Richardson,
2001, 2005)
Newer studies:
 Meta
analysis PUFA 1980-2009 - Evidence is too
limited to reach definite conclusion
Transler, Eilander, Mitchell et al, 2010
supplementation [N=92] – placebo control. 15
weeks - ADHD improved
 EPA
Gustafsson, Birberg-Thornberg, Duchèn
et al, 2010
& Mg & Zn [N=810] – Considerable
reduction in ADHD in 12 weeks.
 PUFA
Huss, Volp, Strauss-Gorbo, 2010
DIETARY INTERVENTION
Fatty Acids
Recommendation
 Supplementation
will not help everyone
 Blood tests difficult to interpret
 EFA often normal, converting to HUFA a problem?
 Nutritional interventions to be seen as
complimentary
DIETARY INTERVENTION
Fatty Acids
Personal View:
1.
2.
3.
4.
Keep EFA in mind when FFA deficiency type
symptoms are present
Important when poor diet
If anything, then FFA
Treat long term (>6m)
DIETARY INTERVENTION
Glyconutritional supplements



Contain basic saccharides
Used for cell communication,
glycoproteins, glycolipids
Two small studies showed some
reduction in symptoms, one study found
no impact
Dietary sensitivities and ADHD
symptoms: 35 years of research
There is a subpopulation of children with ADHD
who improve significantly on an artificial food
colouring elimination diet
2. No challenge studies of artificial flavours or
natural salicylates alone
3. There may be a cross sensitivity to milk,
chocolate, soy, eggs, wheat, corn, legumes (no
salicylates) and grapes, tomatoes and orange
(salicylates)
1.
Stevens, Kuczek, Burgess et al,
Which children may respond to dietary
challenges?
1.
Children with IgE mediated allergies
2.
Younger children
3.
Children with irritability and sleep
problems
Summary:
1.
2.
3.
Children may react adversely to common
foods and food additives, but these are not
the main cause of ADHD
Delay of conventional treatment to first try
alternatives carry the risk of leaving the
problem untreated
No reason why children on medication
cannot be tested for food and additive
hypersensitivities
EEG biofeedback
 Based
on findings that ADHD is associated with
low levels of arousal of the frontal brain areas
 Treats ADHD by increasing the ratio of beta
activity to low frequency theta
 When this is learned it is expected that there will
be improvement in attention and reduction of
hyperactive/impulsive behaviour
 No persuasive scientific evidence
New studies:
1.
Double blind study including a sham neuro feedback
control
group [N=27] 15 weeks. Study ceased due to
lack of effect
Logemann, Lansberger, Os et al, 2010
2.
Randomized control trial – NF vs computer program
[N=94]
6
months: 25% reduction in 50% of children
in NF group –
limited effect
Gevensleben, Holl, Albrecht et al, 2010,2009
3.
Placebo controlled study – no significant sleep problems
or
adverse effects. Improvements was similar for both
groups.
75% of children in active NF group and 50% in
placebo
groups thought they were receiving
placebo
Lansberger, van Dongen-Boonsma, Buitelaar et
Interactive metronome training
 Computerized
version of a metronome
 Individuals attempt to match with hand or foot
tapping
 Auditory feed back is provided
 Presumed to improve motor planning and timing
skills
 One well conducted study in boys showed a wide
range of improvements
Binaural Auditory Beats reduce
ADHD symptoms RDB PCS
No significant reduction in attention in
experimental groups
Kemel, Taylor, Lyon et al, 2010
Sensory integration training
a treatment of ADHD, but of SI dysfunction –
brain is “overloaded” with sensory input, and
cannot respond normally
 Therapy helps the brain to integrate various
sensory messages better
 Practically no published clinical research
 Anecdotal support for tactile hypersensitivity
 Not
Dore program
 Developed
by paint tycoon Wynford Dore, with
NASA space technology.
 Involves some exercises, it‟s a secret how it
works, but has been proven by experts.
 Based on the cerebellar deficit of hypothesis of
dyslexia
 But……also works for ADHD, dyspraxia and
Asperger syndrome
Dore program
Flawed study:
- SUBJECTS WERE NOT RANDOMIZED
- MISMATCHED GROUPS
- “CONTROL” GROUP GOT „NOTHING‟
- PROGRESS MEASURED WITH
SCREENING TOOLS
- STATISTICS ARE FLAWED
- DETAILS OF TREATMENT NOT
DIVULGED AS IT WAS „COMMERCIALLY
SENSITIVE‟
- EVALUATORS NOT BLINDED
Dore program
NASA
- press release refutes claims
that any NASA space technology
used
From the internet…..
1.
Shelled hemp seed (cannabis)
1. Supported by traditional use
2. Little scientific support
3. Contains oil rich in Omega 3 & 6
4. No psychoactive effects
5. Laxative
From the internet…..
Green environment
3. Homeopathy
2.
There is no significant treatment effects of
homeopathy for the global symptoms, core
symptoms of inattention, hyperactivity or
impulsivity or related outcomes such as anxiety
in ADHD. Cochrane review
Coultera, Dean,
2007
Other therapies
1.
2.
3.
4.
5.
Cognitive-training programs
Mid ear “problems” – anti motion
sickness medication
Yeast overgrowth
Gingko bilboa
Chiropractic/kinesiology/neural
organization technique – not presently
recommended as a treatment for ADHD
Sawni, 2008
6.
Optometric vision training
Other therapies
7.
8.
9.
10.
Chelation therapy (lead)
Thyroid therapy
Bach flower remedies (Pintov et al,
2005)
St John‟s Wart (Weber et al, 2008)
Enthusiasm is no substitute
for scientific evidence
www.help4adhd.org