Psichiatria di TransizioneLa complessità dell’ADHD
Bolzano , 5-6 dicembre 2016
La fenomenologia dell’ADHDdal bambino all’adolescente
Alessandro ZuddasClinica di Neuropsichiatria dell’Infanzia e dell’Adolescenza
Sezione di Neuroscienze e Farmacologia ClinicaDipartimento di Scienze Biomediche, Università di Cagliari
Ospedale Pediatrico “A. Cao”, AO “G.Brotzu”, Cagliari
AO Brotzu
Financial Disclosure (2013-2016)
Research grants• Shire• Vifor• Roche• Lundbeck• EU 7 Framework Program (PERS, STOP, ADDUCE, MATRICS)• AIFA-Farmacovigilanza (Agenzia Italiana del Farmaco), • Assessorato Sanità Regione Sardegna
RoyaltiesGiunti.OS, Oxford University Press
Speaker or advisory relationship with: Angelini, Lilly, Otsuka, Shire, Takeda, Vifor.
Member of Data Safety Monitory BoardsOtsuka, Lundbeck,
Executive function deficits in children with ADHD
ADHD is an heterogeneous disorder
ADHD & executive functions
Neuro-economic models
Psychological intervention
Attention Deficit Hypercetivity Disorder: a brief definitionAttention Deficit Hypercetivity Disorder: a brief definition
Developmentally inappropriate level of inattention and/ or hyperactivity-
impulsivity present before the age of 7 (12) years
must be more severe than those seen in other children of the same age
must be more severe than those seen in other children at the same
developmental level
must be present in several settings (eg family, school)
must create serious problems in everyday life
will change with age and can be life-long
Disruptive, Impulse-Control
& Conduct Disorders
Oppositive Defiant Disorder
Intermittent Explisive Disorder
Conduct Disorder
Antisocial Personality Disorder
Pyromania
Kleptomania
Neurodevelopmental Disorders
Intellectual Disabilities
Communication Disorders
Autism Spectrum Disorder
ADHD
Specific Learning Disorders
Motor Disorders
Others
DSM 5, APA 2013
DSM 5
1. Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or during
other activities (e.g. overlooks or misses details, work is inaccurate).
2. Often has difficulty sustaining attention in tasks or play activities (e.g., has difficulty remaining
focused during lectures, conversations, or lengthy reading).
3. Often does not seem to listen when spoken to directly (e.g., mind seems elsewhere, even in the
absence of any obvious distraction).
4. Often does not follow through on instructions and fails to finish school work, chores, or duties in the work
place (e.g., starts tasks but quickly loses focus and is easily sidetracked).
5. Often has difficulty organizing tasks and activities (e.g., difficulty managing sequential tasks;
difficulty keeping materials and belongings in order; messy, disorganized work; has poor time
management; fails to meet deadlines).
6. Often avoids or is reluctant to engage in tasks that require sustained mental effort (e.g. schoolwork or
homework; for older adolescents and adults, preparing reports, completing forms, reviewing
lengthy papers).
7. Often loses things necessary for tasks or activities (e.g., school materials, pencils, books, tools,
wallets, keys, paperwork, eyeglasses, mobile telephones).
8. Is often easily distracted by extraneous stimuli (e.g., for older adolescents and adults may include
unrelated thoughts).
9. Is often forgetful in daily activities (e.g., doing chores, running errands; for older adolescents and
adults, returning calls, paying bills, keeping appointments).
Inattention
1. Often fidgets with or taps hands or squirms in seat.
2. Often leaves seat in situations when remaining seated is expected (e.g., leaves his or her place in the
classroom, in the office or other workplace, or in other situations that require remaining
in place).
3. Often runs about or climbs in situations where it is inappropriate (e.g., in adolescents or adults, may
be limited to feeling restless).
4. Often unable to play or engage in leisure activities quietly;
5. Is often “on the go” acting as if “driven by a motor” (e.g., is unable to be or uncomfortable being still
for extended time, as in restaurants, meetings; may be experienced by others as being restless
or difficult to keep up with).
6. Often talks excessively.
7. Often blurts out answers before questions have been completed (e.g., completes people’s sentences;
cannot wait for turn in conversation).
8. Often has difficulty awaiting turn (e.g., while waiting in line).
9. Often interrupts or intrudes on others (e.g. butts into conversations, games, or activities. may start
using other people’s things without asking or receiving permission; for adolescents and adults,
may intrude into or take over what others are doing).
Hyperactivity/ impulsivity
- Massimo grado di iperattività
- Crisi di rabbia (“tempeste affettive”)
- Litigiosità, provocatorietà
- Assenza di paura, tendenza a incidenti
- Comportamenti aggressivi
- Disturbo del sonno
“ADHD” in età prescolare
- Comparsa di disattenzione, impulsività
- Difficoltà scolastiche
- Possibile riduzione della iperattività
- Evitamento di compiti prolungati
- Comportamento oppositivo-provocatorio
ADHD in età Scolare
- Disturbo dell’attenzione:
difficoltà scolastiche,
di organizzazione della vita quotidiana (pianificazione)
- Riduzione del comportamento iperattivo
(sensazione soggettiva di instabilità)
- Instabilità scolastica, lavorativa, relazionale
- Mancanza di Savoir faire Sociale
- Bassa autostima, ansietà
- Condotte rischiose
ADHD in Adolescenza
Transizione dell’ADHD dall’infanzia all’età adulta
L’iperattività motoria diminuisce: si può manifestare
come irrequietezza psichica
L’inattenzione spesso persiste: si può manifestare come
difficoltà nel portare a termine i compiti (es.: rispettare
appuntamenti, scadenze o focalizzarsi su una singola attività).
Può interferire significativamente con vari aspetti della
vita quotidiana.
Volkow & Swanson 2013
La definizione DSM 5 di ADHD si focalizza sul deficit
di attenzione, ma le manifestazioni cliniche includono
una minore percezione delle gratificazioni con
conseguente deficit di motivazione.
Adulti con ADHD mostrano una ridotta le risposta alle
ricompense premi e appaiono meno motivati a
impegnarsi ed a portare a termine le attività.
ADHD in età adulta:
Wolkow & Swanson NEJM 2013
Demotivation
Poor school achievement
School withdrawn
Conduct disorder
Antisocial behaviour
Substance abuse
Oppositional disorder
Defiant behaviour
Mood disorder
Low self-esteem
Poor social skills
Learning problems
Disruptive behaviour
Disturbed family relations
ADHD
only
AgeAge
ADHD Developmental outcome
Banaschewski et al. 2010
Comorbidità: Kadesjö & Gillberg 2001Comorbidità: Kadesjö & Gillberg 2001
ADHD
40%Reading/ writing
disorder
13%Mental
retardation
47%Developmental coordination
disorder
ADHD
33%Tic
60%Oppositional
defiant disorder(ODD)
Developmental disorders Psychiatric disorders
7%Asperger’s
Mood and anxiety disorders not included
AntisocialPersonalityDisorder
AnxietyMood
Disorders
Childhood Adolescence Young Adult
SubstanceUse Dis.
OppositionalDefiantDisorder Conduct
Disorder
ADHD
Loeber et al. 2000
Disturbo Oppositivo Provocatorio (DSM 5)
Almeno 4 dei seguenti sintomi (significativamente più frequenti che nei
coetanei ) negli ultimi 6 mesi
Angry/Irritable Mood
1. Scoppi d’ira (Loses temper)
2. Permaloso e infastidito dagli altri.
3. Irritabile e risentito
Defiant/Headstrong Behavior
4. Polemico con gli adulti
5. Sfida o rifiuta attivamente di seguire le indicazioni
6. Disturba volutamente gli altri
7. Scarica sugli altrui i propri errori o responsabilità
Vindictiveness / Hurtfull
8. Dispettoso e vendicativo
Significativa compromissione funzionale (sociale, accademica, lavorativa)
Se >18 aa. escludere Dist. Antisociale di Personalita’
Irrit. 8 Irrit. 10 Irrit. 13
Depr. 16
Head 8ConductProb 16
Head 10 Head 13
Hurt 8 Hurt 13Hurt 10Callous16
JAACAP 2013
0.58 0.43
0.65
0.42
-0.18
0.34
0.78
0.21
0.20
0.66
0.36
ALSCPAvon Longitudinal Study of Children and Parents
13867 GRAVIDANZEApril 1991, December 1992Follow-up 19-22 anni
DAWBADevelopment and WellBeing Assessment
Parent and teacher rating
2.07ParentsRatings & interview
UKICD-9Taylor et al (1991)
4.02.0
813
ParentsRatings & interview
GermanyICD-9Esser et al (1990)
3.76.5-7.5TeacherParents
Ratings & interview
SwedenDSM-III-RKadesjö & Gillberg (2001)
Teacher 5.7 Parent 4.7
6-8TeacherParents
RatingsIcelandDSM-IVMagnusson et al (1999)
17.85-12TeacherRatingsGermanyDSM-IVBaungaert el et al(1995)
4.0-TeacherParents
Ratings & interview
SwedenDS-IIIRLandgren et al (1996)
1.813-18TeacherParents
Ratings & interview
NetherlandsDSM-IIIRVerhulst et al (1997)
6.68-9ParentsRatings & interview
FinlandDSM-IIIRPuura et al (1998)
3.98-10TeacherRatings & interview
ItalyDSM-IIIRGallucci et al (1993)
10.95-12TeacherRatingsGermanyDSM-IIIRBaungaert el et al(1995)
16.66-8TeacherRatingsUKDSM-IIITaylor et al.(1991)
9.58 & 11TeacherParents
Ratings & interview
NetherlandsDSM-IIIVerhulst et al (1985)
6.45-12TeacherRatingsGermanyDSM-IIIBaungaert el et al(1995)
PrevalenceAge-rangeSourceProcedureCountryCriteriaStudy
ADHD in Europe: Prevalence rates
ICD-10 DiagnosisMTA study re-analysis
579 ADHD - Combined
Without Anxiety/Depression432
Pervasive161
Borderline ADHD 71
Anxiety/Depression147
3 Symptom domains361
Home -P134
School -P66
Impairment
HKD 145
Santosh et al. 2006
Polanczyk et al. AJP 2007
Factor structure and cultural factors of disruptive behaviour disorders symptoms in Italian children
ADHD ODD CDADHD
+ODD
ADHD
+CD
Parents 2.5 % 0.7 = 0.7 0.3
Teachers 8.6 0.8 = 2.2 0.6
Parents
AND
Teachers1.4 0.2 = 0.1 =
Zuddas et al. Eur.Psychiatry 2006
1575 parent’s & 1085 teacher’s Questionnaires
ADHD prevalence estimates as afunction of time
Polanczyk et al. Int J Epidemiol 2014;43(2):434-42
ADHD is an heterogeneous disorder
Clinical Presentations
Inattentive
Hyperactive/Impulsive
Combined
Neuropsychology Models
Executive Dysfunction
Motivational Dysfunction
Time percetion
Delay Adversion
Response Variability
Speed in Cognition & Arausal
DSM-5 ADHD
vs ICD-10 (11?) Hyperkinetic Dis.
Comorbidities
Developmental: Specific Learning Disorders
Motor D. (Tics & Tourette S.)
Autism spectrum disorder
Social(Pragmatic) Communication D.
Disruptive behaviours (ODD, CD)
Anxiety
Depression
Dysruptive Mood Disregulation Disorder
Substance Use Disorder
Deficit delle funzione esecutivenei bambini con disturbo da deficit di attenzione e iperattività
ADHD is an heterogeneous disorder
ADHD & executive functions
Neuro-economic models
Psychological intervention
Funzioni Esecutive:
Funzioni cognitive che servono a raggiungere un obbiettivo futuro:
Inibizione
di una risposta “prepotente” --> Change Task (MRT, SD,SSRT)
di una risposta in atto --> Circle Tracing
controllo interferenza --> Opposite Worlds of TEA-Ch
Memoria di lavoro --> Self Order.Pointing Task (SOP)
Pianificazione --> Torre di Londra
Flessibilita’ (Set-Shifting) --> Wisconsin Card Sorting Task
Fluenza --> Liste di Parole
ADHD & Executive dysfunctionEF concept Tasks Dependent Measures Non-EF concept Tasks Dependent Measures
Inhibition prepotent response ongoing response
Change task Circle Drawing task
SSRT Circle time difference
Response Execution Motor Control
Change Task Visual Motor Integrat. T.
Go MRT VMI
Interference control Opposite Worlds
of the TEA-Ch TEA-Ch time difference
Rapid Naming TEA-Ch TEA-Ch Same world
condition
Working Memory Self-Ordered Pointing
Task SoP errors
Visual short term memory
Benton Visual Retention Test
Number of correct designs
Planning Tower of London ToL score
ToL decision time
ToL execution time
Spatial Span Memory Corsi Block Tapping T.
Span level
Flexibility
Wisconsin Card Sorting T.
Change task
WCST % perseverative
responses
Change MRT
Change number of errors
Semantic
categorization
Response Execution
Wisconsin Card Sorting
Test
Change Task
WCST non-
perseverative
responses Go MRT Go number of errors
Fluency
Semantic Fluency
Letter Fluency Words produced
Words produced Semantic categoriz
Phonolog. awareness Son-R
Letter Fluency Number correct items
Letter Rule – Breaks
Marzocchi, Oosterland, Zuddas et al. JCPP 2008
Groups
NC
(n=30)
ADHD
(n=35)
RD
(n=22)
Effect of group Effect of IQ Effect of Non-
EF
measures
Contrasts between
groups
after covariation
EF Measure M SD M SD M SD F(1,84) F(1,84) F(1,84) Tukey
Prepotent Inhibition
SSRT
278.5
107
299
91.8
286.8
102.1
0.296
Ongoing Inhibition
Circle time difference
86.4
50.7
42.3
42.8
70.2
109.5
3.649*
Interference Control
TEA-Ch time difference
5.3
4.0
9.1
7.8
7.9
4.7
3.509*
Working memory
SoP errors
16.5
6.9
23.6
7.3
21.3
6.8
8.062**
Planning
ToL total score*
ToL planning time/item*
ToL – total time/item)
28.6
5.1
9.0
2.7
1.8
1.7
24.7
3.5
9.7
5.2
1.5
4.1
29.1
4.9
9.9
2.9
1.9
3.2
12.105***
7.067**
0.561
Flexibility
Change MRT
Change Errors
WCST % perseverative
responses
587
8.2
13.5
161
1.5
8.7
563
8.0
26.9
118
1.2
14.5
552
8.6
21.7
72
1.5
12.8
0.464
0.115
10.017***
Fluency
Semantic number correct
Letter number correct
26.2
16.4
4.9
6.0
25.4
10.4
7.8
5.1
24.6
11.0
10.3
4.6
0.308
11.688***
0.322
0.049
0.983
1.842
4.013*
0.023
1.447
0.318
0.020
4.137*
1.876
0.452
1.361
3.005
1.811
19.199***
4.761*
14.355***
42.507***
0.131
5.927*
4.278*
n.s.
n.s.
ADHD<NC
ADHD<NC
ADHD<RD,NC
ADHD<NC n.s.
n.s.
n.s.
ADHD,RD<NC
n.s.
ADHD,RD<NC
Note. ADHD = Attention Deficit Hyperactivity Disorder; RD = Reading Disorder; NC = Normal Controls; MRT = Mean Reaction Time; SoP = Self Ordered
Pointing Task; SSRT = Stop Signal Reaction Time; TEA-Ch = Test of Every Day Attention for Children; ToL = Tower of London; WCST = Wisconsin Card
Sorting Test.
ADHD & Executive dysfunction
Groups
NC
(n=30)
ADHD
(n=35)
RD
(n=22)
Effect of group Group
contrasts
Non-EF Measure M SD M SD M SD F(1,84) p < .017
Response Execution
Go-MRT
Go-Errors
484.9
4.54
150.9
4.38
426.2
7.83
253.4
9 . 95
504.6
7 . 00
78.7
7 . 78
1.270
1.119
n.s.
n.s.
Motor Control VMI 19.07 3.38 17.02 3.36 18.00 4.21 2.595 n.s.
Rapid Naming TEA-Ch baseline 26.07 4.11 26.49 7.34 29.52 8.07 1.984 n.s.
Visual short term memory
BVRT
Spatial Short term memory
Corsi Span Task
6.13
4.70
1.89
0.75
4.69
4.09
1.95
0.95
5.19
4.41
1.79
0.73
4.797*
4.406*
ADHD<NC
ADHD<NC
Semantic categorization
WCST % non-pers. responses
SON-R
10.96
11.37
6.42
3.76
22.91
8.03
12.71
4.09
17.75
10.23
9.14
6.68
11.475***
4.106*
ADHD<NC
ADHD<NC
Phonological awareness
Letter – rule breaks
2.20
3.36
1.34
1.81
0.14
0.35
5.145**
NC < RD
Note. ADHD = Attention Deficit Hyperactivity Disorder; RD = Reading Disorder; NC = Normal Controls BVRT = Benton Visual Retention Test;
Corsi = Corsi Block Tapping Test; MRT = Mean Reaction Time;; SON-R = Snijders-Oomen Non-verbal Intelligence Test Revised.
WCST = Wisconsin Card Sorting Test.
Marzocchi, Oosterland, Zuddas et al. JCPP 2008
ADHD & Non-Executive dysfunction
ADHD & Executive dysfunction
Nigg 2005
ADHD & Executive dysfunction
Nigg 2005
ADHD & Executive dysfunction
Sonuga-Barke 2009
Funzioni Esecutive alterate in ADHD
Inibizione
di una risposta “prepotente” --> Stop Task (MRT,SD,SSRT)*
* Risposta esecutiva lenta e variabile
* Processi inibitori non alterati
* Peggioramento delle alterazioni per basso event rate
Effetto della ricompensa
Reazione più lenta
Inibizione più rapida
maggiore % di inibizione
Meno errori
Scheres et al. 2002
DUAL PATHWAY MODELDUAL PATHWAY MODEL
Meso-limbicrewardcircuits
Meso-limbicrewardcircuits
Meso-corticalcontrolcircuits
Meso-corticalcontrolcircuits
Shortendeddelay
gradient
Shortendeddelay
gradient
InhibitorydysfunctionInhibitory
dysfunction
DelayaversionDelay
aversionExecutive
dysfunctionExecutive
dysfunction
HYP/IMPHYP/IMP IAIA
Disruptedtask
engagement
Disruptedtask
engagement
DUAL PATHWAY MODEL (revised)DUAL PATHWAY MODEL (revised)
Meso-limbicrewardcircuits
Meso-limbicrewardcircuits
Severe earlydeprivationSevere earlydeprivation
Meso-corticalcontrolcircuits
Meso-corticalcontrolcircuits
Severe earlydeprivationSevere earlydeprivation
Shortendeddelay
gradient
Shortendeddelay
gradient
InhibitorydysfunctionInhibitory
dysfunction
Cultural delayrelated
demands
Cultural delayrelated
demands
DelayaversionDelay
aversionExecutive
dysfunctionExecutive
dysfunction
HYP/IMPHYP/IMP IAIA
Disruptedtask
engagement
Disruptedtask
engagement
????D1D1D2D2DAT1DAT1
Sonuga-Barke 2007
A TRIPLE PathwayHypothesis
CORTICO-DORSAL
STRIATAL
LOOP
DISTURBANCE
INHIBITORY
DEFICITS
EXECUTIVE
DEFICITS
CORTICO-VENTRAL
STRIATAL
LOOP
DISTURBANCE
IMPAIRED
SIGNAL
DELAYED
REWARD
DELAY
AVERSION
ADHD
CORTICO-
CEREBELLAR
LOOP
DISTURBANCE
TEMPORO-
SENSORY-
MOTOR
INTEGRATI’N
DEFICITS
MOTOR
ASYNCHRONY
Simplified Functional Neuroanatomy
DLPFC
DORSAL
STRIATUM
Caudate
Nucleus
THALAMUS
MOTOR
CORTICES
NEO
CEREBELLUM
VENTRAL
STRIATUM
Nucleus
Accumbens
OFC
AMYGDALA
ANTERIOR
CINGULATE
Sonuga Barke et al. 2010
Sonuga-Barke et al. JAACAP 2010
Delayn=25 (32%)
Inhibitn=16 (20%)
Timingn=34 (44%)
5 (6,4%)
5 (6,4%)
6 (7.8%)
1 (1.3%)
15 (19,5%)
19 (24.7%)
4 (5.2%)
No Deficit n= 22 (28%)
N=77
Familial effect for inhibition and timingless for delay
Sibling impairmentintermediate betweencontrols and probandsNo evidence of cosegregation
Timing associated withreading problemsDelay associated with low IQ
Proportion of ADHD cases with neuropsychological impairments (A) or impairments in neuropsychological and emotional functioning (B)
Neuropsychological Deficits in Treatment Naïve Boys with ADHD
• 83 Drug naïve boys (6 – 12 years) with DSM IV ADHD
• 66 Healthy control boys matched for age
• All completed all tasks in one session with breaks
• Tasks were counterbalanced across two orders
Coghill, Seth, Matthews, 2013
0 10 20 30 40
Variability
Timing
Decision making
Delay Aversion
Inhibition
Memory
% with deficit
0 0,2 0,4 0,6 0,8 1
Variability
Timing
Decision making
Delay Aversion
Inhibition
Memory
Effect Size
Deficit delle funzione esecutivenei bambini con disturbo da deficit di attenzione e iperattività
ADHD is an heterogeneous disorder
ADHD & executive functions
Neuro-economic models
Psychological intervention
Reward
Punishment
Reinforcement Motivational-independent
Monitoring Punishment
Monitoring Reward
Dorsolatereral prefrontal CtxExecutive
Default Mode network
Orbito ( Ventral) prefrontal CtxReward/punishment
Anterior CingulateChoice
Fair et al. 2013
Default network associato con:- ricordare il passato, - pianificare - anticipare futuri eventi
“ A set of processes by which mental simulation is used adaptively to imagine events beyond those that emerge from the immediate environment”.“Ricordare il passato, pianificare e anticipare futuri eventi” Buckner et al. 2008
Incapacità ad “esplorare” correttamente, anticipare e valutare correttamente le relazioni tra un’azione presente ed una ricompensa futura.
Compromissione dei processi di salienza, motivazione e percezione della ricompensa ( affettività)
oPFC vmPFC dlPFC
AMG ACC
Davidson et al., Science 2000
Emotion Processing Neural Circuits
Everitt & Robbins, Nat Rev Neurosci 2005
Decision Making: a neuro-economic model
Integration of information on: valence, magnitude, timing, probability
Utility matrix
Choice:Working memory & Inhibition
Goal attainment:Planning, inhibition, self organization
Utility Matrix & autobiografical memory
JCPP Sonuga-Barke et al. 2016
Decision Making: a neuro-economic model
JCPP Sonuga-Barke et al. 2016
Decision Making: a neuro-economic model
JCPP Sonuga-Barke et al. 2016
Decision Making: a neuro-economic model
JCPP Sonuga-Barke et al. 2016
Decision Making: a neuro-economic model
JCPP Sonuga-Barke et al. 2016
Decision Making: a neuro-economic model
JCPP Sonuga-Barke et al. 2016
Evaluation Decision &Managemnent
Appraisal &Accomodation
Self referential(Default Mode Network-DMN)
Reducte integrity of DMN: impaired prospection
DMN interference linked to attentional laspes
Executive Dorsal fronto-striatal / fronto-parietal deficits reduce decision speed & efficiency
Reinforcement Ventral fronto-striatal deficits impair utility estimate and with Delay adversion produce preference for immediacy
Disconnectivity inOrbito-frontal Ctxaffects computation in predicting errors , impairing learning
ADHD Neuroeconomic Model:
Inefficiency, inconsistency, impulsiveness
Sonuga-Barke et al. JCPP 2016
Evaluation Decision &Managemnent
Appraisal &Accomodation
Self referential(Default Mode Network-DMN)
Executive
Reinforcement Impaired evaluationof negative futureevents exacerbatedby amygdalaorbitofrontalcortex dysregulation
Limbic hypoactivationreduces sensitivity toaversive outcomes; impairedlearning fromnegative feedback due to deficient aversiveprediction error signalling
Conduct disorder Neuroeconomic Model:Reckless, insensitive to negative outcomes
Sonuga-Barke et al. JCPP 2016
Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation
Shaw P et al. PNAS 2007;104:19649-19654
ADHD vs Controls
DRD4 /7
DRD1
DAT 1
Polymorphisms of the Dopamine D4 Receptor, ClinicalOutcome, and Cortical Structure in Attention-Deficit/Hyperactivity Disorder Shaw at al. Arch Gen.Psych. 2007
Polymorphisms of the Dopamine D4 Receptor, Clinical Outcome, and Cortical Structure in Attention-Deficit/Hyperactivity Disorder
Shaw at al. Arch Gen.Psych. 2007
Genetica molecolare dell’ADHD
Whole genome linkage: Ampie regioni di genoma che possono contenere geni di suscettibilità
Nessuna regione specifica per ADHD, ma 16q23 [CDH13 (SUD)].
Studio dei geni candidatiDAT-1, DRD 4, DRD-5, COMT, SNAP 25, 5HTTR, 5HT1B,
Genome Wide Asociation Studies (GWAS)Nessuno SNPs ha raggiunto la significatività statistica.
Nei top-25: Cannabinoid Receptor 1 (CNR1)
Caderina 13 (CDH 13)
Tollloid-like (TTLs)
Glucose-fructose oxidoreductase domain 1 (GFOD1)
Sodium Hydrogen exchanger 9 (SLC9A9)
Copy Number Variants (CNVs)
Poelmans et al. AJP 2011
- Normalità
- Problemi ambientali
inadeguato supporto scolastico (lieve ritardo / particolare vivacità intellettiva)
inadeguato supporto familiare (ambiente caotico, divorzio, abuso, abbandono)
- Disturbi neurologici e patologie mediche
Disturbi sensitivi (sordità , deficit visivi)
Epilessia
Dist. Tiroidei
Trauma Cranico
Ascessi / neoplasie lobo frontale
Abuso di sostanze
Intossicazione da piombo
Farmaci (Antistaminici, benzodiazepine,beta-agonisti, antiepeilettici)
- Altri disturbi psichiatrici
ADHD: Diagnosi differenziale
La trasmissione dell’ADHD non segue un modello mendeliano:
l’ADHD deve esere considerato un disturbo geneticamente
complesso (diversi geni, ognuno con basso rischio).
La classificazione basata sui sintomi non e’ utile per la ricerca dei
genidi suscettibilità per l’ADHD (probabilmente la rende più difficile).
Esiste un notevole interesse per marker quantitivi in grado di predire
la suscettibilita per il disturbo in maniera simile a quella con cui
lipidemia e pressione arteriosa possono predire la comparsa di
patologie cardio- e cerebro-vascolare (endofenotipi)
Genetica molecolare dell’ADHD
- Normalità
- Problemi ambientali
inadeguato supporto scolastico (lieve ritardo / particolare vivacità intellettiva)
inadeguato supporto familiare (ambiente caotico, divorzio, abuso, abbandono)
- Disturbi neurologici e patologie medicheDisturbi sensitivi (sordità , deficit visivi)
EpilessiaDist. TiroideiTrauma CranicoAscessi / neoplasie lobo frontaleAbuso di sostanze Intossicazione da piomboFarmaci (Antistaminici, benzodiazepine,beta-agonisti, antiepeilettici)
- Altri disturbi psichiatrici
ADHD: Diagnosi differenziale
Dist.
Condotta
Tourette HF Autismo
DAMP
Dist.
Apprendimento
Dist.
dell’Umore
ADHD
Dist.
d’ansia
Comorbidità psichiatrica e Diagnosi differenziale
Disturbo oppositivo- provocatorio
Disturbo di Condotta
Disturbi Depressivi
Disturbo Bipolare
Disturbi d’Ansia
Disturbo Ossessivo-Compulsivo
Disturbi Adattamento (con sintomi emotivi e di condotta)
Sindrome di Tourette
Disturbi Specifici dell’apprendimento
Ritardo Mentale
Disturbi Pervasivi dello Sviluppo
Deficit delle funzione esecutivenei bambini con disturbo da deficit di attenzione e iperattività
ADHD is an heterogeneous disorder
ADHD & executive functions
Neuro-economic models
Psychological intervention
Inclusion criteria
Age 3-18Diagnosis ADHD ( any subtype)Symptom measured by validated rating ScaleAppropriate control groupStable medication allowed (sensitivity analysis)Rare comorbidity (i.e. Fragile X) excluded
Outcome measure : ADHD symptoms scaleMost proximal assessmentProbably blinding assessment
Study quality independently assessed (Jadad et al. criteria for randomization,
blinding and missing data)
Misure di efficacia delle terapie
Effect Size
Basaline EndPoint
Farmaco 38.5 + 5.8 25.5 + 4.2
Placebo 40.4 + 6.1 32.7 + 5.0
d= (38.5-25.5) - (40.4-32.7) = 13.0 -7.7 = ES 1.1
(4.2+5.0)/2 4,6
Differenza nei cambiamenti dal baseline tra due trattamenti (es. farmaco
e placebo), diviso la media delle dev. standard (es. placebo e farmaco ad
end point).
L’effect size standardizza le unità di misura nei diversi studi.
Secondo la definizione di Cohen, ES > 0.2 è considerato basso,
ES > di 0.5 è considerato medio; oltre 0.8 è considerato alto
Behavioral interventions in attention-deficit/hyperactivity
disorder: a meta-analysis of randomized controlled trials across multiple outcome domains. Daley et al. JAACAP 2014
Dimension MPROX PBLIND
Positive parenting 0.68 0.63
Negative parenting 0.57 0.43
Parental self-concept 0.37
Parental Mental Health 0.09
Dimension MPROX PBLIND
ADHD 0.35 0.02
Conduct problem 0.26 0.31
Social skills 0.47
Academic Achievement 0.28
Take home message
ADHD is an heterogeneous disorder
Executive dysfunction do NOT always explain ADHD symptoms and impairment
Neuro-economic models (dysfunction of executive, default, reward and time perception systems) may be more useful to explain ADHD psychopathology
Treatments that only improve cognitive aspects of ADHD, may not be effective to completely normalize ADHD-related impairment
Both symptoms and cognition treatment approaches may be required
Grazie per l’attenzione
Intervention Most proximal assessment (SMD)
Probably blinding assessment (SMD)
Restricted EliminationDiet
1.48 0.51
Artificial food color exclusion
0.32 0.42
Free fatty acid supplementation
0.21 0.16
Cognitive training 0.64 0.24
Neurofeedback 0.59 0.29
Behavioral intervention 0.40 0.02
Sonuga-Barke et al. AJP 2013
MPROX PBLIND
Sonuga-Barke et al. AJP 2013
JAACAP 2015
JAACAP 2015
JAACAP 2015
JAACAP 2015
ES in General Medicine
Aspirine for prevention cardiovascular disease 0.06
Antypertensive on long term mortality 0.11
Corticosteroids for asthma 0.54
Antypertensive for high blood pressure 0.55
Interferone for Chronic Hepatitis C 2.27
ES in General (Adult) Psychiatry
SGA for schizophrenia (PANS) 0.51
SSRI for depression (HAMD) 0.32
SSRI/ Bdz for Panic 0.41
SSRI for OCD 0.44
Leucht et al.2012
ADHD