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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
Attention-Deficit
/Hyperactivity
Disorder
Workshop
Vineyard Hotel
Prof. A. Venter
Department of Paediatrics and Child Health
University of the Free State
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
19
20
21
ADHD: Proposed Etiologies
• ADHD is a heterogeneous behavioral disorder with
multiple possible etiologies
ADHD
Neuroanatomic
Neurochemical1
CNS
insults3
Genetic
origins2
Environmental
factors4
1 Swanson 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 al. Arch Gen Psychiatry. 1996;53:607-616. Swanson JM, et al. Lancet. 1998;351:429-433. 22
Overview of Areas in the Brain
Implicated in ADHD sensory organs and
parietal lobe Perception and localization
locus ceruleus reticular activating system
Arousal and alerting
limbic system Emotional significance
nucleus acumbens and
striatum Relay and interruption
prefrontal cortex Delay, analysis and judgment
hippocampus Association and recognition
23
Anterior and Posterior
Attentional Systems
LC
Posterior Attentional System
NE Mediated
Anterior Attentional System
DA & NE Mediated
Posterior
Parietal
Right
Frontal
Dorsolateral
Frontal Cortex
24
AD/HD
Dopamine
Transporter DAT
D4 Receptor
25
Neurotransmitter Systems
Presynaptic Neuron Postsynaptic Neuron
Dopamine Norepinephrine (NE)
NE
MHPG
DOPA decarboxylase Dopamine- -
hydroxylase NE
DOPA
NE Transporter
Dopamine (DA)
DA
DA DOPA decarboxylase
DA
DOPA
Dopamine
Transporter
Norepinephrine Neuron
Dopamine Neuron
NE
NE
DA
MAO
MAO
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, Landeros-
Weisenberger 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
– Approximations in reading and writing
– Reckless behavior
– Accident proneness
– Impaired sphincter control (?inattentive)
– Inability to delay gratification
CLINICAL
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
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
METHYLPHENIDATE
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)
RITALIN LA
• Releases Ritalin in two peaks
• Adverse events similar to placebo
• Second dose released 4 hrs after the first
• Available 20mg, 30mg, 40mg
METHYLPHENIDATE
Each Ritalin® LA capsule contains 50% immediate-release
beads and 50% extended-release beads
Immediate-release bead
Extended-release polymer coated bead Polymer
coating
Ritalin®
layer
Inactive
core
EXTENDED RELEASE DELIVERY VIA SODASTM TECHNOLOGY
SODASTM is a trademark of Elan Corporation, PLC
EXTENDED-RELEASE DELIVERY
• Same rapid onset as Ritalin® & school day duration
• 50/50 bimodal release mimics Ritalin BID dosing
METHYLPHENIDATE
CONCERTA
Principle of increased doses
MPH
Overcoat
Tablet Shell Push
Compartment
MPH
Compartment
#2
Laser-Drilled
Hole
MPH
Compartment
#1
CONCERTA: OROS®
Formulation
Swanson J, et al. Arch Gen Psychiatry 2003;60:204–211.
20
16
12
8
4
0
0 2 4 6 8 10 12
Time (h)
Co
nc
en
tra
tio
n (
ng
/mL
) The unique ascending
profile is designed to
maintain a consistent,
12-hour therapeutic
effect, providing a
reduction of symptoms
throughout the day
CONCERTA: Treatment
IR MPH 10 mg tid (n=15)
CONCERTA 36 mg qd (n=15)
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
Manuzza, Klein, Truong et al,
2008 Brook, Brook, Zhang et
al, 2010
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)
40 mg single dose of Atomoxetine:
effect of body weight on Pharmacokinetic
profile is notable
Time From Dose (hr)
Ato
mxe
tin
e P
lasm
a C
on
cen
trat
ion
(n
g/m
L)
0 3 6 9 12 15 18 21 24
0
100
200
300
400 26.3 kg
29.6 kg
35.3 kg
43.6 kg
70.0 kg
Effect of Weight on Plasma
Exposure
Witcher et al. 2001. Population Pharmacokinetics Analysis. Lilly Research Laboratories
1 mg/kg single dose of
Atomoxetine: effect of body
weight is minimised
0 3 6 9 12 15 18 21 24
0
100
200
300
400
26.3 kg
29.6 kg
35.3 kg
43.6 kg
70.0 kg
Adjusting for Weight Normalizes
Plasma Exposure A
tom
xeti
ne
Pla
sma
Co
nce
ntr
atio
n (
ng
/mL
)
Time From Dose (hr)
Witcher et al. 2001. Population Pharmacokinetics Analysis. Lilly Research Laboratories
18
23
28
33
38
1 3 5 7
Me
an
AD
HD
RS
Sc
ore
Weeks of Treatment
*p<.05. **p<.001. Weiss et al . Poster presented at CCNP, Quebec, Canada, 2003
*
** **
**
Once-Daily Efficacy: School Setting
-8.7
-18.7
ADHD-RS Teacher Total Score
Placebo (n=52)
Atomoxetine (n=101)
-17.8
-8.5-9.9-9.3
-19.4
-9.5
-22
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
*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.
Methylphenidate (n=40)
Atomoxetine (n=178)
Comparability Relative to
Methylphenidate (cont.)
Mean Final Dose (mg/kg/day) Atomoxetine=1.4 Methylphenidate=0.9
Hyperactive/ Impulsive Subscale
Inattentive Subscale ADHD-RS Total
Mea
n C
han
ge
in A
DH
D-R
S S
core
* *
* * * *
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
-3.7
-0.8
-5
-4
-3
-2
-1
0
Mea
n C
han
ge
in C
GI-
T
*p=.008. **p=.025. Weiss et al . Poster presented at CCNP, Quebec, Canada, 2003
Conners’ Global Index-Teacher (CGI-T)
-5.3
-2.0
-8
-6
-4
-2
0
Mea
n C
han
ge
in T
each
er
Pro
ble
m B
ehav
ior
Sca
le
Placebo (n=42)
Atomoxetine (n=74)
Teacher Problem Behavior Scale
Placebo (n=45)
Atomoxetine (n=76) *
**
Once-Daily Efficacy: School Setting (cont.)
Evening Behaviours Completing homework Sitting through dinner Playing quietly Distractibility Arguing/struggling
excessively Transitioning activities Settling at bedtime Falling asleep -5.4
-3.3
-6
-5
-4
-3
-2
-1
0
Placebo (n=58)
Atomoxetine (n=126)
Evening Subscale
*
Mea
n C
han
ge
in
Dai
ly P
aren
t R
atin
g S
cale
*p<.005. Kelsey D, et al. Poster presented at AACAP, Miami, 2003.
Once-Daily Efficacy:
Symptom Control in the Evening
Early Morning Behaviours
Getting out of bed
Getting ready for school
Arguing/struggling
excessively -0.9
-1.7
-2.0
-1.6
-1.2
-0.8
-0.4
0.0
Placebo (n=58)
Atomoxetine (n=126)
Early Morning Subscale
*
*p<.02. Kelsey D, et al. Poster presented at AACAP, Miami, 2003
Mea
n C
han
ge
in
Dai
ly P
aren
t R
atin
g S
cale
Once-Daily Efficacy: Symptom Control Early
the Next Morning
What does this mean – Strattera offers 24 hours Continuous Symptom Relief
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
Michelson D, Bangs ME, Zhang S, et al. Poster presented at the American Academy of Adolescent Psychiatry (AACAP) annual meeting, Washington, October 2004.
Changes in weight and height over 36 months
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
As an alternative to
stimulants
• If the patient doesn’t, or
is unlikely to tolerate
stimulants
• If the patients/patient’s
parents wishes to avoid
stimulants
• To prevent abuse of
stimulants
• To reduce the level of
stimulants
• To avoid the ups and
downs of stimulants
For a variety of
psychological conditions
and ADHD
•anxiety,
•mood disorders,
•irritability, or any manner
of „emotional‟ or
„psychological‟ issues
For complex ADHD (co-
morbid) or mild symptoms
• In children or adults For the non-compliant
or low-compliant
patient
For the patient with
patience, typically adults
Perceived Strattera Patient Profile
Physicians struggle with providing a cohesive Strattera patient profile
Qualitative Study – Hypotheses generated which must be validated/tested via quantitative study
Who is the Strattera patient…
“Whole Life”
Strattera
treated but
needs add-on
Crisis –
immediate
symptom
resolution
needed
Responding
well but could
do better
Responding
well
Not
responding
well
TARGETNaïve
PatientSwitch
Patient
NO
Potential
“Whole Life”
Strattera
treated but
needs add-on
Crisis –
immediate
symptom
resolution
needed
Responding
well but could
do better
Responding
well
Not
responding
well
TARGETTARGETNaïve
PatientSwitch
Patient
NO
Potential
Dissatisfied
with stimulants
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 Week 2 Week 3 Week 4
Stimulant Full dose
½ dose DC DC
Strattera
0.5mg/kg
10 mg
1.2mg/kg
25mg
1.2mg/kg
25mg
1.2mg/kg
25mg
Example*: For
Illustrative
Purposes only
*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. Efficacy of ATMX unaffected by co-morbid
conditions
2. Improves oppositional defiant disorder (in
most studies)
3. Potential for improving co-occurring
symptoms of anxiety
4. 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
40 mg
60 mg
Available in packs of 28‟s
PRICE - SEP : R476
Availability: 1st August 2005
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
Set rules beforehand
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
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
OPPOSITIONAL DEFIANT DISORDER
(DMS-IV)
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
OPERANT CONCEPTUALIZATION OF EXPLOSIVE /
NONCOMPLIANT BEHAVIOR
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)
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
EXPLOSIVE OUTBURSTS
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)
THREE OPTIONS
(COMMON APPROACHES TO PROBLEMS / UNMET EXPECTATIONS
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. Medical treatment – using medication under supervision of a medical professional
2. Psychosocial treatment – targets psychological and social aspects
3. Alternative treatment – Any treatment other than 1 & 2 that claims to treat ADHD with equal or more effective outcome
4. Complimentary treatment – not alternatives, but may improve treatment
5. 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. Claims are overstated and exaggerated
2. Treats a wide variety of ailments, often not
rigorously defined
3. Claims are made that treatment is suppressed
or unfairly attacked by the “medical
establishment”
4. 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
effects minimalized
6. Based on a „secret formula‟
7. Described as „astonishing‟, „miraculous‟,
„amazing breakthrough‟
8. Available from just one source
9. Promoted through infomercials, mail order,
media – not in peer review journals
Complimentary and alternative
medicines (CAM)
Be suspicious of treatment if:
10. 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
ADHD – alternative therapies
DIETARY INTERVENTIONS
A healthy balanced diet is the key to
having a happy and healthy life – true
for everyone!
DIETARY INTERVENTION
Feingold – 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
DIETARY INTERVENTION
Scant or no evidence for sugar free diets,
megavitamin therapy or amino acid therapy
Sawni, 2008
Mineral supplements – only if deficiency is
proven – e.g. some benefit if serum ferritin
levels are low
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
EPA supplementation [N=92] – placebo control. 15
weeks - ADHD improved
Gustafsson, Birberg-Thornberg, Duchèn
et al, 2010
PUFA & Mg & Zn [N=810] – Considerable
reduction in ADHD in 12 weeks.
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. Keep EFA in mind when FFA deficiency type
symptoms are present
2. Important when poor diet
3. If anything, then FFA
4. 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
1. 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)
Stevens, Kuczek, Burgess et al,
2010
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. Children may react adversely to common
foods and food additives, but these are not
the main cause of ADHD
2. Delay of conventional treatment to first try
alternatives carry the risk of leaving the
problem untreated
3. 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
al, 2010
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
Not 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
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…..
2. Green environment
3. Homeopathy
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. Cognitive-training programs
2. Mid ear “problems” – anti motion
sickness medication
3. Yeast overgrowth
4. Gingko bilboa
5. Chiropractic/kinesiology/neural
organization technique – not presently
recommended as a treatment for ADHD
Sawni, 2008
6. Optometric vision training
Other therapies
7. Chelation therapy (lead)
8. Thyroid therapy
9. Bach flower remedies (Pintov et al,
2005)
10. St John‟s Wart (Weber et al, 2008)
Enthusiasm is no substitute
for scientific evidence
www.help4adhd.org
