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

azuddas@unica.it

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