ADHD
Prof. M. Danckaerts UZ-KULeuven
1
Ambivalentie Alom • Media-aandacht overwegend negatief • Steeds suggestie dat – Teveel kinderen de diagnose krijgen – Teveel kinderen medicatie krijgen – Medicatie niet nodig is; er betere manieren zijn om de problemen aan te pakken – Medicatie allerlei nefaste nevenwerkingen heeft – Ouders de gemakkelijke weg kiezen – Artsen beïnvloed zijn door de geneesmiddelenindustrie
2
CASE DESCRIPTION ADHD core symptoms
Inattention
Hyperactivity
Impulsivity ©Döpfner
et al 2002
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CLINICAL PICTURE ADHD/ HKD core symptoms Inattention a
1. Often fails to give close attention to details, or makes careless mistakes in schoolwork, work, or other activities 2. Often has difficulty in sustaining attention in tasks or play activities 3. Often does not seem to listen when spoken to directly 4. Often fails to follow through on instructions or to finish schoolwork, chores, or duties in the workplace (not because of oppositional behaviour or failure to understand instructions) 4
CLINICAL PICTURE ADHD/ HKD core symptoms Inattention 5. Often has difficulty in organising tasks and activities 6. Often avoids, dislikes, or is reluctant to engage in, tasks that require sustained mental effort (such as schoolwork or homework) 7. Often loses things necessary for tasks or activities (eg toys, school assignments, pencils, books, or tools) 8. Is often easily distracted by extraneous stimuli 9. Is often forgetful in daily activities 5
CLINICAL PICTURE ADHD/ HKD core symptoms Hyperactivity 1. Often fidgets with hands or feet or squirms in seat
2. Often leaves seat in classroom or in other situations in which remaining seated is expected 3. Often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, this may be limited to subjective feelings of restlessness) 4. Often has difficulty playing or engaging in leisure activities quietly 5. Often ‘on the go’ or often acts as if ‘driven by a motor’. 6
CLINICAL PICTURE ADHD/ HKD core symptoms Impulsivity 1. Often blurts out answers before questions have been completed 2. Often has difficulty awaiting turn. Often interrupts or intrudes on others (eg butts into others' conversations or games) 3. Often talks excessively
4. Often interrupts or intrudes on others (e.g. butts into others' conversations or games) 7
ADHD CLASSIFICATION DSM-IV DIAGNOSES (ADHD) Inattention
+ Hyperactivity/ impulsivity
ADHD: combined subtype ADHD: predominantly inattentive subtype
Inattention Hyperactivity/ impulsivity
ADHD: predominantly hyperactive/impulsive subtype
DSM-IV requires that at least 6/9 symptoms are present for both the inattentive and hyperactive/ impulsive subtypes (for combined subtype it requires a combination of both) 8
CLINICAL PICTURE Core symptoms Additional diagnostic criteria a Duration
symptom criteria must have been met for the past 6 months Age of onset some symptoms must have been present before 6-7 years of age Pervasiveness present in 2 or more settings (eg school, work or home)
9
CLINICAL PICTURE Core symptoms Additional diagnostic criteria Impairment
symptoms must have led to significant impairment (social, academic, or occupational) Discrepancy symptoms are excessive in comparison to other children of the same age and IQ Exclusion symptoms must not be solely attributable to other mental disorders 10
CLINICAL PICTURE
DSM 5: aanpassingen ADHD • • • • •
Symptomen: 4 extra impulsiviteitscriteria Nieuw subtype: restrictieve onaandachtige type Beginleeftijd: vòòr 12 jaar (i.p.v. 7 jaar) Vanaf 17j: 4/9 symptomen Informatie: van ouders en leerkrachten of derde waar mogelijk • Impact: “duidelijke bewijs van weerslag op kwaliteit van sociaal, schools, werk-functioneren” • Exclusie: ASS is geen exclusiecriterium meer
DSM 5: aanpassingen ADHD DSM-IV (1994) DSM-5 (2013)
Inattention symptoms
9
Gecombineerd Onaandachtig / hyperactief-impulsief type
6/9
Hyperactive -impulsive
9
+4
impulsive
Overwegend Onaandachtige type
Overwegend onaandachtig Restrictief onaandachtig < 3 HI criteria
6/9 Overwegend Hyperactiefimpulsieve type
DSM 5: aanpassingen ADHD
Examples of dev. adaptations
DSM-IV
DSM-5
Difficulty sustaining attention in tasks or play activities
Idem (eg. during lectures, conversation or during lengthy readings)
Is forgetful
For adolesc. & adults:returning calls, paying bills, keeping appointments Tends to act without thinking Often impatient
New impulsiveness items
Uncomfortable doing things slowly and systematic Difficult to resist temptations or opportunities
ADHD: Restrictief onaandachtige type ? • Tot op heden: weinig verschil te vinden in – Neuropsychologische – Neurofysiologische bevindingen tussen gecombineerde / onaandachtige subtype
• “Sluggisch-cognitive” type Lijkt heel anders
CLINICAL PICTURE Core symptoms Diagnostic issues – interpreter bias a • Phrasing of core symptoms • Interpretation of words such as ‘often’ • Interpretation of phrases such as ‘significant impairment’ • Discrepant information from different sources
Investigator bias and training bias 16
Prevalence rates 90 80 70 60 50 40 30 20 10 0
Bv. ADHD
diagnostische cut-off
The best estimate based on current DSM-IV criteria is a prevalence of 2-5% 17
EPIDEMIOLOGY Prevalence and impairment Prevalence is lower when impairment is considered 25
Prevalence (%)
20
Males without impairment considered Females without impairment considered Males & females without impairment considered Males & females with impairment considered
15 10 5 0 AHCPR 1999
18
VOORKOMEN: WERELDWIJD: 5 %
Polanczyk ea 2007
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COMORBIDITY Very frequent (more than 50%) Oppositional defiant or conduct disorder Frequent (up to 50%) Specific learning disorders Anxiety disorder Developmental coordination disorder Less frequent (up to 20%) Tic disorders Depressive disorder Infrequent Autism spectrum disorders Mental retardation Over 85% of patients have at least one comorbidity and approximately 60% of patients have at least two comorbidities 20
CLINICAL PICTURE Course of the disorder – Psychosocial impairments Symptom domains
Functional impairments Self
Inattention Hyperactivity Impulsivity
+
Lead to
Psychiatric comorbidities Disruptive behavioural disorders (conduct disorder and oppositional defiant disorder) Anxiety and mood disorders
Low self-esteem Accidents and injuries Smoking/ substance abuse Delinquency
School/ work
Academic difficulties/ underachievement Employment difficulties Home Family stress Parenting difficulties
Social
Poor peer relationships Socialisation deficit Relationship difficulties 21
Psychopathology risk Lifetime prevalences: Cumulative risk by age 21 Significantly increased risk MDD MDD Bipolar Bipolar disorder disorder
No significant increase of risk
Cont. Cont. ADHD ADHD 7 7 46 46 3 3 29 29
Cont.
ADHD
Psychosis
2 2
8 8
Gen. Anx. Dis.
5 5
8 8
Social ODD phobia OCD CD
10 20 3 16
29 78
Social phobia
10
29
14 46
OCD
3
14
ODD ASPD CD Tics
20 9 16 7
78 29
Alcohol dep.
16
29
46 35
Drug dep.
10
21
ASPD Nicotine dep. Tics
9 21 7
29 43
Nicotine dep.
21
43
Alcohol dep.
16
29
Drug dep.
10
21
35
Significantly increased risks remaining after controlling for baseline psychopathology
M.Danckaerts UPC-KULeuven
Biederman ea 2006 22
ADHD and comorbidity
Major Depressive Disorder
Developmental Disorders
Biederman M.Danckaerts UPC-KULeuven
ea 2006, Biederman ea232008
ADHD and comordity
M.Danckaerts UPC-KULeuven
Biederman ea 2006 24
Comorbidities aggregate
4-year follow-up of 6-17y ADHD M.Danckaerts UPC-KULeuven
Biederman ea 1996 25
Genen
Executieve functies
Hersenfuncties
Aberrant bekrachtigingsys teem
Inhibitie
Gedrag
Tijdsperceptie
ADHD
Toestands regulatie
B i o l o g i s c h e
M a a t s c h a p p e l ij k e
O m g e v i n g
26
naar Taylor 2005
AETIOLOGY Behavioural genetics Family studies
High prevalence of ADHD and other mental disorders in the relatives of patients (25-30%)
Adoption study
Higher prevalence of ADHD in biological parents than in adoptive parents
Twin study
Concordance for ADHD symptoms: MZ > DZ Heritability coefficients: 0.65-0.91 27
AETIOLOGY Molecular genetics • Associated genes: – – – – – – –
pooled odds ratios
DRD4 Dopamine-D4-receptor DRD5 Dopamine-D5-receptor DAT Dopamine Transporter DBH Dopamine-beta-hydroxylase 5-HTT Serotonine Transporter HTR1B Serotonine-1B-receptor SNAP-25 Synaptosomal-assoc. protein 25
1.16-1.45 1.24 1.13 1.33 1.31 1.44 1.19
• Most children with gene polymorphisms do not have ADHD and most children with ADHD do not have any of the known gene polymorphisms Faraone & Kahn 2006
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AETIOLOGY Acquired biological factors –Intrauterine exposure to alcohol or nicotine or stress –Extreme prematurity and low birth weight –Brain disorders (eg encephalitis, brain trauma) –Food allergies, colourings –Lead poisoning and high lead levels 29
Gene-environment interactions • Genotype as a resilience factor in the presence of psychosocial adversity (Nigg ea 2007) • DAT1 only associated with ADHD in those exposed to prenatal smoking (Kahn ea 2003; not confirmed by Langley ea 2007) • Stronger association with DAT1 when mother consumed alcohol during pregnancy (Brookes ea 2006) • DRD2 x marital status interaction (Waldman, 2007)
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AETIOLOGY Neuroanatomy •Smaller brain (4%): right frontal lobe (8%) •Smaller basal ganglia (6%) normalisation (18 yrs) •Smaller cerebellum (12%) more pronounced (18 yrs) •Volumetric differences – manifest early (6 years) – correlate with ADHD severity – are irrespective of medication status – are irrespective of comorbidities
31
AETIOLOGY Neuroanatomy – total brain volume Controls > ADHD P<0.003
ml
1100
1000
900
Control males ADHD males Control females ADHD females
5
7
9
11
13
15
Age (years)
17
19
21
Castellanos et al 2002
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Neuroscience-neuropsychologybehaviour / Development
Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development with normalization of the right parietal cortical region.
Shaw ea 2007, Arch Gen Psychiatry 34
ADHD persistence Brain Development
ADHD ~ delay in cortical maturation And: differential clinical outcome ~ differential trajectories M.Danckaerts UPC-KULeuven
35
Shaw ea 2007
AETIOLOGY Neuroanatomy - developmental
Persistent anatomical differences in persistent ADHD / worse outcome
Shaw ea 2006
AETIOLOGY Neurophysiology
Reduced metabolism/ blood flow in • frontal lobe • parietal cortex
• striatum • cerebellum
Increased blood flow/ electrical activity in • sensorimotor cortex
Activation of other neuronal networks
Deficits in neuronal focusing 37
AETIOLOGY Neurophysiology - blood flow SPECT Normal
ADHD
Frontal lobe
Sensory-motor cortex
Cerebellum
Kuperman et al 1990
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AETIOLOGY Neurophysiology – PET Activation of other neuronal networks
Normal Normal
ADHD ADHD
Stroop test in adults with ADHD Bush et al 1999
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AETIOLOGY Psychosocial factors Modulating factors include family instability partner conflict
parental mental disorders lack of parenting competence
negative parent-child relationship low socioeconomic status (?)
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Genen
Executieve functies
Hersenfuncties
Aberrant bekrachtigingsys teem
Inhibitie
Gedrag
Tijdsperceptie
ADHD
Toestands regulatie
B i o l o g i s c h e
M a a t s c h a p p e l ij k e
O m g e v i n g
42
naar Taylor 2005
Neuropsychology • Response inhibition deficit • Executive functioning / Working memory deficit • Shortened delay gradient • Temporal processing • Cognitive energetic dysfunction
43
Barkley’s unitary theory of response-inhibition / executive function deficit Response Inhibition (ability to inhibit an inappropriate prepotent response)
Executive fucntions
Working memory
Internal Speech
Speech fluency
Behavioural output
Barkley 1998
e.a.
Shortened delay gradient • Aversie voor uitstel • Kiezen voor kleinere onmiddellijke bekrachtiging eerder dan grotere bekrachtiging met uitstel • Bekrachtiging met uitstel heeft veel sneller minder effect • Greater motor activity when delay is unavoidable (compensatory?) • fMRI activation n.accumbens / cerebellar vermis • Volumetric abnormalities of n.caudatus / cerebellar vermis in ADHD • Excessive striatal DAT in ADHD
120 100 80 controle ADHD
60 40 20 0
tijd
47
Cognitive energetic dysregulation • Task performance variability dependent on situational demands – Length of time interval, self pacing – Supervision, threat
• “underaroused” • ERP-studies
48
REDUCED POSTERIOR P300 ACTIVATION DURING ORIENTING TO SALIENT STIMULI
GFP ERP strength in µV
P300 G:\MM6\MM_P1\Tn148.DAT
6.0
P1 4.0
N1
2.0
Posterior Cue P300 Sources
0.0 - 0.1
0.4
0.9
1.4
Cue P300
1.9
+7.0 µV
• • • ••• • •••• ••
cue A P1
N1
distractor -7.0 µV 0.1
Activity ->
0.25
•^ • • • • • • •• • • • •• • • • •
back
0.4 s 49
“Executive Deficient” and “Delay Averse” Subtypes?
Solanto et al., 2001: school
23%
23%
15%
INHIB Delay Aversion Neither Both
39%
51
MULTIMODAL ASSESSMENT Diagnosis – Clinical interview (parents) – Information (teacher) – Observation
•Comorbidities – Clinical interview (parents) – Neuropsychological examination – Physical examination
Differential diagnosis – Clinical interview (parents, child)
•Severity rating/ treatment response – Questionnaires (parents and teachers) – Rating of impairment
Aetiology – Physical examination – Clinical interview (parents, child) – Neuropsychological examination
52
ASSESSMENT Behavioural observation ADHD may not be observable
in highly structured settings in novel situations when patient is engaged in interesting activities when patient is receiving oneto-one attention in a controlled and supervised context where there are frequent rewards
ADHD typically worsens
in unstructured situations during repetitive activity in boring situations where there is a lot of distraction under minimal supervision when sustained attention or mental effort is required during self-paced activities
Observation in varying contexts is important 53
PSYCHOLOGICAL ASSESSMENT
Testing IQ (most always indicated) Achievement • reading
•
mathematics
spelling Neuropsychological core functions • attention • perception •
•
learning
•
memory
•
speech and language
•
motor skills
Five domains of executive function Tests should be performed only where indicated. There is no specific test for ADHD! 54
Behandeling
55
Ambivalentie Alom
56
Europese Richtlijnen 2004 Psychosociale Aanpak versus Medicatie ADHD or hyperkinetic disorder diagnosed Psychoeducation, advice, and support to child, family and teacher Child under 6 years?
No Pervasive, severe disability
Yes
No
Good response
Psychosocial intervention Parent Training
Significant impairment persist
Problems at home? Parent training and advice to child
Significant impairment exists
Try second stimulant Significant impairment persist
Problems at school? School liaison and advice to child Significant impairment persists
Stimulant medication
Yes
Good response
Review, add behaviour therapy, treat comorbidity, try second line drugs e.g. noradrenergic
Maintain treatment Review and if necessary treat coexistent problems
Specialist review, identification of stressors and/or associated problems, consider medication
57
Psycho-education for children / parents / teachers Distribute scientifically sound information Pitfal: pseudo-science
Change maladaptive ideas Enhance self-management Inform all services
58
Counceling Adjustment of the child, the family, teacher to the
new situation
Mourning for the lost ideal Adaptation of expectations Adaptation of environment Adaptation of reactions
Treatment plan Identify treatment aims and priorities
Directly related to ADHD Associated problems 59
Behaviour Modification • Parent Management Training • Teacher Training Use: • Core ideas: – Enhance attending skills – Enhance compliance
Effective Communication Positive reinforcement Continuous monitoring Adequate negative reinforcement Token economy / time out
60
Oudertraining UPC-Leuven Toolkit voor leerkrachten Verwachtingsniveau ouders = norm
Werkingsprincipe
Niveau kind
Aanvangssituatie
Aanpassing 61
Oudertraining UPC-Leuven Toolkit voor leerkrachten Proces
Aanmoedigen Dagelijks oefenen Hulpmiddelen gebruiken Dispenseren 62
Medicatie Anno 2009 Dopaminerg Methylfenidaat Rilatine® Rilatine MR® Concerta® Equasym XL Daytrana (patch)
Amfetamine D-amphetamine Adderal-XR Vyvanse
Noradrenerg Atomoxetine Strattera® (TCA) Pertofran®, Nortrilen®
(Clonidine) Dixarit® 63
Gebruik methylfenidaat in België Jongens: 2% Meisjes: 0,5%
Vlaanderen: 1,9 % W-Vlaanderen: 3,1% Wallonië: 0,5% Luxemburg: 0,4%
Hoe werkt medicatie ?
65
Hoe werkt medicatie ? Catecholamine Neuron
Presynaptic neuron Stimulants/NSRI block reuptake
Dopamine/ Norepinephrine
Transporter Synapse
X
Postsynaptic Increased neurotransmitter Receptors neuron Wilens and Spencer, Amph Pharm in Handbook of Substance Abuse, 1998 Biederman 2004
66
Korte termijn effecten
Percent Responders
“Normalisatie” op Stimulantia / Strattera na 8 weken 80 70 60 50 40 30 20 10 0
64% Strattera
57%
56%
51%
Concerta
45%
37% 24%
Alle Patienten (n = 492)
Placebo
23%
Voorheen Stimulantia gebruikt (n = 301)
25%
Voorheen geen Stimulantia (n = 191)
“Normalisatie” = aandacht / impulsiviteit / hyperactiviteit terug binnen normale verwachting 67
Korte termijn effecten Meetbare herseneffecten tijdens “afrem”-taak
Ouders met ADHD: vooral verschil in de hersenkernen
Epstein ea. 2007, J Child Psychol Psychiatry
Kinderen met ADHD: verschil in de hersenkernen en de Rezijkwab 68
Korte termijn effecten • Grootte-orde effecten: – Gedrag – Leerprestaties – Psychometrische Testen: – Sociaal gedrag ? – Gezinsfunctioneren ?
0.6 – 1.2 0.4 – 0.5 0.3
69
Lange termijn effecten MTA-studie
Total Screened = 4541
Study Group = 579
Community Care 144
Behavioural Management 145
Medication Management 145
Combined Treatment 145 70
Lange termijn effecten Medicatie versus Psychosociale behandeling na 14 mnd
SNAP Hyperactiviteit-Impulsiviteit (beoordeeld door Ouders) Reanalysis by Santosh et al 2005
71
Lange termijn effecten MTA Studie Symptoom “Normalisatie”
Normalisation rate (%)
80
68
70 56
60 50 40
34 25
30 20 10 0
Community treatment
Behavioural treatment
MED
MED + Behavioural treatment
Swanson et al 2001 72
Lange termijn effecten MTA na 36 maanden stop studie
Maakt niet uit wat je aanvankelijk kreeg; je behoudt de voordelen. Na de studie begonnen velen te switchen.
Jensen 2007
73
Nevenwerkingen • Frequenter voorkomend, maar relatief banaal: – Stimulantia: eetlustremming, inslaapproblemen – Atomoxetine: misselijkheid, agitatie, slaperigheid
• Zeldzaam, niet-bewezen, maar potentieel beangstigend: – – – –
Epilepsie Hartritmestoornissen Leverbeschadiging Suicidedreiging
• Medicatievigilantie nu veel groter
74
Klassieke medicatieschema’s • Rilatine: werkingsduur 4u – start ½ co : 8u en 12u – Optitreren op geleide van effect /nevenwerkingen – Klassiek: 1 co: 8u – 12u – 16u
• Rilatine MR: werkingsduur 8u – Pas vanaf schema 2 x 10 mg: te vervangen door: • MR 20 mg 1co om 8u
• Concerta: werkingsduur 12u • Strattera: werkingsduur 24u ?
Geen terugbetaling 75
Behandeling ADHD • Medicatie • Gedragstherapie – Via Ouders – Via School
• Individual therapy – Neurofeedback – Sociale vaardigheids training – Cognitive training – Zelfinstructie
• Supplementen (Ώ3,..) • Dieet
Bewijs
Restricted EliminationDiet = individualized hypoallergenic diet 5 w e e k s
u p
Few food diet (Water, Rice, Turkey, Lamb, Vegetables, Pear)
Improvement = Re-introduction of products one by one
No improvement = Other treatment options
t o
1 y e a r
Worsening = identification of allergen
Eliminate the trigger
Eliminate all triggers -Individually different -Usually +/- 5 products
Pelsser & Buitelaar 2011
Restricted Elimination Diet • www.ADHDenvoeding.nl • Artikel stelt: 2/3 goed geholpen, MAAR: – Sterk gemotiveerde ouders die er zelf voor kozen – Slechts bij (al bij) de helft was er nadien herval – Geen allergisch mechanisme aangetoond
• Voorlopig niet in de richtlijnen • Voorlopig niet terugbetaald
Cognitieve trainingen Werkgeheugen deficit bij ADHD ? – Verbaal Werkgeheugen: • 50% studies vindt afwijking
– Spatiaal Werkgeheugen: • 75% studies vindt afwijking
Effect van trainingen ? – In onderzoek – Mogelijks effect op aandacht, planning, hyperactiviteitimpulsiviteit
Martinussen ea 2005, Beck ea 2010, Klingberg ea 2005
Neurofeedbacktraining • Training via feedback op computerscherm over de verhouding snelle/trage hersengolven • Wisselende resultaten: positieve invloeden vooral op aandacht en impulsiviteit gemeld (Arns ea 2009) • Recente studie met nepinterventie: geen meerwaarde van neurofeedback (Logemann ea 2010)
