ADHD. Prof. M. Danckaerts UZ-KULeuven

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1 ADHD Prof. M. Danckaerts UZ-KULeuven 1

2 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

3 CASE DESCRIPTION ADHD core symptoms Inattention Hyperactivity Impulsivity Döpfner et al

4 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

5 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

6 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

7 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

8 ADHD CLASSIFICATION Inattention Inattention + DSM-IV DIAGNOSES (ADHD) Hyperactivity/ impulsivity ADHD: combined subtype ADHD: predominantly inattentive subtype 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

9 Duration CLINICAL PICTURE Core symptoms Additional diagnostic criteria a Age of onset symptom criteria must have been met for the past 6 months 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

10 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 CLINICAL PICTURE Core symptoms Additional diagnostic criteria symptoms must not be solely attributable to other mental disorders 10

11 CLINICAL PICTURE

12 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

13 Hyperactive -impulsive Inattention symptoms DSM 5: aanpassingen ADHD impulsive 6/9 6/9 DSM-IV (1994) DSM-5 (2013) Gecombineerd Onaandachtig / hyperactief-impulsief type Overwegend Onaandachtige type Overwegend onaandachtig Restrictief onaandachtig < 3 HI criteria Overwegend Hyperactiefimpulsieve type

14 DSM 5: aanpassingen ADHD Examples of dev. adaptations New impulsiveness items DSM-IV Difficulty sustaining attention in tasks or play activities Is forgetful DSM-5 Idem (eg. during lectures, conversation or during lengthy readings) For adolesc. & adults:returning calls, paying bills, keeping appointments Tends to act without thinking Often impatient Uncomfortable doing things slowly and systematic Difficult to resist temptations or opportunities

15 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

16 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

17 Prevalence rates Bv. ADHD diagnostische cut-off The best estimate based on current DSM-IV criteria is a prevalence of 2-5% 17

18 Prevalence (%) EPIDEMIOLOGY Prevalence and impairment Prevalence is lower when impairment is considered Males without impairment considered Females without impairment considered Males & females without impairment considered Males & females with impairment considered AHCPR

19 VOORKOMEN: WERELDWIJD: 5 % Polanczyk ea

20 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

21 CLINICAL PICTURE Course of the disorder Psychosocial impairments Symptom domains Inattention Hyperactivity Impulsivity + Psychiatric comorbidities Disruptive behavioural disorders (conduct disorder and oppositional defiant disorder) Anxiety and mood disorders Lead to Functional impairments Self 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

22 Psychopathology risk Lifetime prevalences: Cumulative risk by age 21 Significantly increased risk Cont. Cont. ADHD ADHD MDD Bipolar disorder Social ODD phobia OCD ODD ASPD CD Tics ASPD Nicotine dep Tics 7 35 Nicotine dep Alcohol dep Drug dep No significant increase of risk Cont. ADHD Psychosis Gen. Anx. Dis Social phobia OCD 3 14 Alcohol dep Drug dep Significantly increased risks remaining after controlling for baseline psychopathology Biederman ea 2006 M.Danckaerts UPC-KULeuven 22

23 ADHD and comorbidity Major Depressive Disorder Developmental Disorders Biederman ea 2006, Biederman ea 2008 M.Danckaerts UPC-KULeuven 23

24 ADHD and comordity M.Danckaerts UPC-KULeuven Biederman ea

25 Comorbidities aggregate 4-year follow-up of 6-17y ADHD M.Danckaerts UPC-KULeuven Biederman ea

26 Genen Hersenfuncties Gedrag O m g e v i n g naar Taylor 2005 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 ADHD Aberrant bekrachtigingsys teem Tijdsperceptie Executieve functies Toestands regulatie Inhibitie 26

27 Family studies AETIOLOGY Behavioural genetics 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:

28 AETIOLOGY Molecular genetics Associated genes: pooled odds ratios DRD4 Dopamine-D4-receptor DRD5 Dopamine-D5-receptor 1.24 DAT Dopamine Transporter 1.13 DBH Dopamine-beta-hydroxylase HTT Serotonine Transporter 1.31 HTR1B Serotonine-1B-receptor 1.44 SNAP-25 Synaptosomal-assoc. protein 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

29 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

30 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) 30

31 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

32 ml AETIOLOGY Neuroanatomy total brain volume Controls > ADHD P< Age (years) Control males ADHD males Control females ADHD females Castellanos et al

33 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

34 ADHD persistence Brain Development ADHD ~ delay in cortical maturation And: differential clinical outcome ~ differential trajectories M.Danckaerts UPC-KULeuven 35 Shaw ea 2007

35 AETIOLOGY Neuroanatomy - developmental Persistent anatomical differences in persistent ADHD / worse outcome Shaw ea 2006

36 Reduced metabolism/ blood flow in frontal lobe parietal cortex striatum cerebellum AETIOLOGY Neurophysiology Increased blood flow/ electrical activity in sensorimotor cortex Activation of other neuronal networks Deficits in neuronal focusing 37

37 AETIOLOGY Neurophysiology - blood flow SPECT Normal ADHD Frontal lobe Sensory-motor cortex Cerebellum Kuperman et al

38 AETIOLOGY Neurophysiology PET Activation of other neuronal networks Normal ADHD Stroop test in adults with ADHD Bush et al

39 AETIOLOGY Psychosocial factors Modulating factors include family instability partner conflict parental mental disorders lack of parenting competence negative parent-child relationship low socioeconomic status (?) 41

40 Genen Hersenfuncties Gedrag O m g e v i n g naar Taylor 2005 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 ADHD Aberrant bekrachtigingsys teem Tijdsperceptie Executieve functies Toestands regulatie Inhibitie 42

41 Neuropsychology Response inhibition deficit Executive functioning / Working memory deficit Shortened delay gradient Temporal processing Cognitive energetic dysfunction 43

42 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 e.a. Behavioural output Barkley 1998

43 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 tijd controle ADHD 47

44 Cognitive energetic dysregulation Task performance variability dependent on situational demands Length of time interval, self pacing Supervision, threat underaroused ERP-studies 48

45 REDUCED POSTERIOR P300 ACTIVATION DURING ORIENTING TO SALIENT STIMULI GFP ERP strength in µv 6.0 P300 G:\MM6\MM_P1\Tn148.DAT 4.0 P1 N Posterior Cue P300 Sources Cue P µv Activity -> cue A distractor P1 N s -7.0 µv ^ back 49

46 Executive Deficient and Delay Averse Subtypes? Solanto et al., 2001: school 23% 23% 15% INHIB Delay Aversion Neither Both 39% 51

47 MULTIMODAL ASSESSMENT Diagnosis Clinical interview (parents) Information (teacher) Observation Comorbidities Clinical interview (parents) Neuropsychological examination Physical examination Differential diagnosis Clinical interview (parents, child) Aetiology Physical examination Clinical interview (parents, child) Neuropsychological examination Severity rating/ treatment response Questionnaires (parents and teachers) Rating of impairment 52

48 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

49 PSYCHOLOGICAL ASSESSMENT Testing IQ (most always indicated) Achievement reading spelling Neuropsychological core functions attention learning speech and language mathematics perception memory motor skills Five domains of executive function Tests should be performed only where indicated. There is no specific test for ADHD! 54

50 Behandeling 55

51 Ambivalentie Alom 56

52 Europese Richtlijnen 2004 Psychosociale Aanpak versus Medicatie ADHD or hyperkinetic disorder diagnosed Psychoeducation, advice, and support to child, family and teacher No Child under 6 years? Yes Pervasive, severe disability No Yes Stimulant medication Significant impairment persist Good response Psychosocial intervention Parent Training Problems at home? Parent training and advice to child Try second stimulant Significant impairment exists Problems at school? School liaison and advice to child Significant impairment persists Good response Significant impairment persist Review, add behaviour therapy, treat comorbidity, try second line drugs e.g. noradrenergic Specialist review, identification of stressors and/or associated problems, Maintain consider medication treatment Review and if necessary treat coexistent problems 57

53 Psycho-education for children / parents / teachers Distribute scientifically sound information Pitfal: pseudo-science Change maladaptive ideas Enhance self-management Inform all services 58

54 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

55 Behaviour Modification Parent Management Training Teacher Training Core ideas: Enhance attending skills Enhance compliance Use: Effective Communication Positive reinforcement Continuous monitoring Adequate negative reinforcement Token economy / time out 60

56 Oudertraining UPC-Leuven Toolkit voor leerkrachten Verwachtingsniveau ouders = norm Werkingsprincipe Niveau kind Aanvangssituatie Aanpassing 61

57 Oudertraining UPC-Leuven Toolkit voor leerkrachten Proces Aanmoedigen Dagelijks oefenen Hulpmiddelen gebruiken Dispenseren 62

58 Medicatie Anno 2009 Dopaminerg Methylfenidaat Rilatine Rilatine MR Concerta Equasym XL Daytrana (patch) Amfetamine D-amphetamine Adderal-XR Vyvanse Noradrenerg Atomoxetine (TCA) Strattera Pertofran, Nortrilen (Clonidine) Dixarit 63

59 Gebruik methylfenidaat in België Jongens: 2% Meisjes: 0,5% Vlaanderen: 1,9 % Wallonië: 0,5% W-Vlaanderen: 3,1% Luxemburg: 0,4%

60 Hoe werkt medicatie? 65

61 Hoe werkt medicatie? Catecholamine Neuron Dopamine/ Norepinephrine Presynaptic neuron Stimulants/NSRI block reuptake Synapse X Transporter Biederman 2004 Postsynaptic neuron Receptors Increased neurotransmitter Wilens and Spencer, Amph Pharm in Handbook of Substance Abuse,

62 Percent Responders Korte termijn effecten Normalisatie op Stimulantia / Strattera na 8 weken % 56% Alle Patienten (n = 492) 37% 51% 24% 23% Voorheen Stimulantia gebruikt (n = 301) 64% 57% 25% Voorheen geen Stimulantia (n = 191) Strattera Concerta Placebo Normalisatie = aandacht / impulsiviteit / hyperactiviteit terug binnen normale verwachting 67

63 Korte termijn effecten Meetbare herseneffecten tijdens afrem -taak Ouders met ADHD: vooral verschil in de hersenkernen Kinderen met ADHD: verschil in de hersenkernen en de Rezijkwab Epstein ea. 2007, J Child Psychol Psychiatry 68

64 Korte termijn effecten Grootte-orde effecten: Gedrag Leerprestaties Psychometrische Testen: 0.3 Sociaal gedrag? Gezinsfunctioneren? 69

65 MTA-studie Lange termijn effecten Total Screened = 4541 Study Group = 579 Community Care 144 Behavioural Management 145 Medication Management 145 Combined Treatment

66 Lange termijn effecten Medicatie versus Psychosociale behandeling na 14 mnd SNAP Hyperactiviteit-Impulsiviteit (beoordeeld door Ouders) Reanalysis by Santosh et al

67 Normalisation rate (%) Lange termijn effecten MTA Studie Community treatment Symptoom Normalisatie 34 Behavioural treatment MED MED + Behavioural treatment Swanson et al

68 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

69 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

70 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

71 Behandeling ADHD Medicatie Gedragstherapie Via Ouders Via School Individual therapy Neurofeedback Sociale vaardigheids training Cognitive training Zelfinstructie Supplementen (Ώ3,..) Dieet Bewijs

72 5 w e e k s u p Restricted EliminationDiet = individualized hypoallergenic diet 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

73 Restricted Elimination Diet 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

74 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

75 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)