Attention-deficit Hyperactivity Disorder – ADHD · Attention-deficit Hyperactivity Disorder – ADHD Jan Buitelaar Radboud University Nijmegen Medical Center Donders Institute for

Attention-deficit Hyperactivity Disorder – ADHD

Jan Buitelaar Radboud University Nijmegen Medical Center Donders Institute for Brain, Cognition and Behavior Department of Cognitive Neuroscience, and Karakter Child and Adolescent Psychiatry University Center Nijmegen, The Netherlands

Symposium 19 mei 2018 Amsterdam

Conflict of interest

Speaker Advisory Board Research Support Involved in clinical trials

Lilly X X X X

Janssen Cilag X X X

UCB X

Organon X

Medice X

Shire X X

Medice X

Novartis X

Roche X

Servier X

Declaration of Interest Jan Buitelaar

Take home message

•  ADHD is a disorder of brain development with a strong genetic loading

•  Environmental and GxE factors play additional roles •  ADHD is a very persistent disorder, 24 hours/day •  It is important to identify and treat ADHD as a disorder

on itself and as a risk factor for other disorders •  A comprehensive treatment approach includes a

combination of medical and psychological interventions •  Treatment should be

–  Systematic –  24 hours / day –  Long-term

Inattention

Impulsivity/Hyperactivity

ADHD - Core Symptom Areas

Case description Aetiology Classification Emergence of a concept Comorbidity Cost Core symtoms Epidemiology Implications

CORE SYMPTOMS of ADHD

§ must be more severe than those seen in other

children of the same age § must be more severe than those seen in other

children with 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

Core symtoms

Figure 1 The history of attention-deficit/hyperactivity disorder

Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20


Mortality in ADHD versus non-ADHD

Dalsgaard et al. Lancet 2015, , http://dx.doi.org/10.1016/ S0140-6736(14)61684-6

Mortality in ADHD versus non-ADHD -mechanisms

Faraone. Commentary in Lancet 2015, http://dx.doi.org/10.1016/ S0140-6736(14)61822-5

Thapar et al. Lancet Psychiatry, 2016

ADHD – the broader clinical picture

10

Neurodevelopmental disorders

This is different from a cerebral lesion in a mature brain

Wide spread ramifications of neural dysfunction towards a variety of clinical symptoms

The developmental “snowball” rolls downhill over time……

“Outcome”?

…….gathering speed and mass (loadings for psychopathology and atypicality).

“Outcome”?

…….gathering speed and mass (loadings for psychopathology and atypicality).

Environmental Influences

Genetic Predispositions

Maturation

Time

Birth

“Outcome”

Child’s Own Behavior

The developmental pathway of an individual child reflects not only genetic endowment and environmental effects, but also the interactions among these and the child’s own activity over time.

Time

Protective and Supportive Conditions and Adverse Events Risks and

Protective Factors

Behavior Birth

“Outcome”

Maturation and Maturational Vulnerabilities

Genetic Predispositions

Environmental Influences

Adaptive and Maladaptive Behaviors

Influences on development are both positive and adverse. Likewise, the individual’s behaviors over time are both adaptive and maladaptive.

Impairment through the lifespan

Childhood ⇒ Adolescence

Difficulties at school Becomes Underachievement, no high school graduation

Impulsivity Becomes Carelessness, substance abuse,

unwanted pregnancy

Repetitive failure Becomes Hopelessness, frustration, depression,

anxiety

ODD Becomes Criminal involvement

Multiple injuries Becomes Risk taking, accidental injuries

Parent stress

Family conflict

Accidents and injuries

Smoking and substance abuse

Legal difficulties

Poor peer relationships

School failure

Psychiatric comorbidity

Impairment in ADHD

Comorbidity – the full spectrum

sleep problems

motor problems (DCD)

learning disorders

ODD en CD

tics and OCDbipolar disorder

substance use gambling obesity

autism spectrum

disorder (ASD)

anxiety and depression ADHD

Global Prevalence of ADHD

0 5 10 15 20 Prevalence of ADHD (%)

Puerto Rico

New York City

Pittsburgh

Iowa

Tennessee

Minnesota

Oregon

Missouri

Virginia

N. Carolina

NY, MI, WI

India China

Netherlands New Zealand

Japan Brazil

Ukraine Germany

Netherlands/Belgium Switzerland

Israel United Kingdom

Ireland Canada

New Zealand Spain

0 5 10 15 20 Prevalence of ADHD (%)

WWorldwide prevalence in childhood 5.3% (Polanczyk et al., 2007)

Figure 1 The history of attention-deficit/hyperactivity disorder


Is ADHD in Adults a Valid Diagnosis?

SYNDROMATIC CONTINUITY

Family- Genetic Studies

Treatment Effectiveness

Comorbidity and Neuropsych Deficits

Impairments

Imaging Studies

Onset versus Persistence vs Remission

Genes, E

GxE

Onset

Remission

Persistence

Genes, E GxE

Genes, E GxE

Dynamics of Genetic and Environmental Risk Factors

Chang et al. JAMA Psychiatry 2013

Onset versus Persistence vs Remission

Genes, E

GxE

Onset

Remission

Persistence

Genes, E GxE

Genes, E GxE

Different factors that influence onset and

that influence remission

Revisiting the Role of the Prefrontal Cortex in ADHD (Halperin et al. 2006, 2008)

Subcortical dysfunction (dopamine, noradrenaline)

• Automatic processing

• Less effortful processing

Early onset

Enduring

Cortical dysfunction (PFC)

•  Secundary

•  Compensatory

Clinical severity

Course

Trends In Cognitive Sciences, 2012

Familialaggrega*onofADHDSwedishCaseRegistrystudy

Chen et al. J Child Psychology Psychiatry 2016

Rare and common variants - integration

vv

Rare and common variants converge into the same gene-protein networks

300-1000causalgenes

20-40genenetworks

5-10biologicalpathways

Neurite outgrowth gene-protein network Poelmans et al. Am. J Psychiatry 2011

Enhancing Neuro Imaging Genetics through Meta-Analysis

http://ENIGMA.ini.usc.edu

Cross-disorder analysis of ADHD and ASD Based on mega-analysis results of 3242 people from ADHD sample (1713 cases) and 2090 people from ASD sample (1036 cases)

Daan van Rooij

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

Thalamus Caudate Putamen Pallidum Hippocampus Amygdala Accumbens ICV

Coh

en’s

d

ASD

ADHD * * *

*

*

*

*

*

* *

*indicates a significant difference between cases and controls in ADHD or ASD

Martine Hoogman

Figure 4 Brain mechanisms in attention-deficit/hyperactivity disorder Brain Imaging – Neural Heterogeneity


Dorsolateral PFC – working memory Ventromedial PFC – decision making Parietal cortex - attentional orientation


Ventral and dorsal ACC, together with the accumbens and the caudate – affective and cognitive control Fronto-striatal circuits



Reward networks – OFC, Ventromedial PFC and striatrum (anticipation and receipt of reward Thalamus and amygdala also involved


Alerting network – frontal and parietal cortex and the thalamus


Default-mode network – Mediale frontale cortex, posterior cingulate cortex, mediale temporal lobe and lateral parietal cortex

Context

Brain Cogni=on Behaviour

Genes

Environment

✖

Context

Brain Cogni=on Behaviour

Genes

Environment

✖

Context

Brain

Cogni=on

Behaviour

Genes

Environment

✖

Context

Brain

Cogni=on

Behaviour

Genes

Environment

✖

Context

Brain Behaviour Cogni=on

Genes

Environment

✖

Aboutsymptomsandbiology

Bleeding disorder

Few / Abnormal platelets

Abnormal / low amount of clotting proteins

Abnormal vessels

Factor VIII Factor IX

Inherited versus acquired

Intermediate phenotypes as stratification markers

Cognitive profile – across domain - as stratification marker

Executive functioning (Inhibition, WM) Reward processing Timing RT variability XX

Cognitive and Neural Mechanisms •  ADHD is very heterogeneous at the

cognitive and neural level

•  There are multiple cognitive pathways and multiple structural and functional brain abnormalities

•  Challenge: how to define valid cognitive and neural subtypes?

Treatment – General approach

Aims and objectives of treatment

– Reduce symptoms of ADHD – Reduce comorbid symptoms – Reduce risk of further complications – Educate the patient and the environment about the

disorder – Adapt the environment to the patient’s needs – Enhance patient, parent, teacher et al’s coping skills – Change maladaptive views

– Go beyond symptoms – Address functional impairments

More care than cure

Overview Algorithm Psychoeducation Psychopharmacotherapy QA Conclusions Efficacy of interventions Behaviour modification Overview

EFFICACY OF INTERVENTIONS a

• Psychopharmacotherapy – Proven short-term effects – Long-term effects well documented for up to

2 years • Parent management training

– Proven short-term effects (however ......) – Proven short- and long-term effects in

children with oppositional disorder

Overview Algorithm Psychoeducation Psychopharmacotherapy QA Conclusions Efficacy of interventions Behaviour modification Efficacy of interventions

Non-pharmacological treatments; the importance of a good design

Edmund Sonuga-Barke

Non-pharmacological treatments; the importance of a good design

SMD=0.40, p<.0001

SMD=0.02, p=.92

JAACAP, 2014, 53, 835 - 847

32 papers were analyzed (versus 15 in Sonuga-Barke et al. 2013)

Significant effects on other domains – parents and children

SMD=0.63, p<.001 SMD=0.43, p<.001 SMD=0.31, p<.001

Thus

•  Parent training is more effective for comorbid or associated problems than for the core ADHD symptoms

Non-pharma treatments

■ Behavior treatment ? ■ Cognitive training ?? ■ EEG-Neurofeedback ?? ■ Diet + (but small)

MTA 16 yr follow-up

Take home message

•  ADHD is a disorder of brain development with a strong genetic loading

•  Environmental and GxE factors play additional roles •  ADHD is a very persistent disorder, 24 hours/day •  It is important to identify and treat ADHD as a disorder

on itself and as a risk factor for other disorders •  A comprehensive treatment approach includes a

combination of medical and psychological interventions •  Treatment should be

–  Systematic –  24 hours / day –  Long-term

Documents

Attention-deficit Hyperactivity Disorder – ADHD · Attention-deficit Hyperactivity Disorder – ADHD Jan Buitelaar Radboud University Nijmegen Medical Center Donders Institute for