ADHDIN

CHILDHOOD

Highlights in Psychiatry, 2007

Marina Danckaerts, UPC-K.U.Leuven

Disclosure

• Have served in Advisory Boards of Cephalon, Janssen, Lilly, Medice, Novartis, Pfizer, UCB

• Have received support for public speaking from Astra-Zeneca, Janssen, Lilly, Novartis, UCB

• Have received research support from Janssen, Lilly

Highlights in ADHD research in childhood and adolescence

• Linking neuroscience to neuropsychology and to behaviour

• Gene-environment interactions• Treatment guidelines• Medication side-effects• Long term treatment outcome• Early psychosocial treatment • Other treatments

• ADHD = disorder of self-control• Prefrontal cortex is central in

regulating behaviour (top-down), but subcortical and posterior systems are critical in signaling this system to engage (bottom-up)

• Control functions may function well when they are “on-line”, but may not be brought on-line when needed

• Most puzzling: – variability in performance– heterogeneous findings

Neuroscience-neuropsychology-behaviourCasey ea 2007, Curr Opin Neurol; Swanson ea 2007, Neuropsychol Rev

MRI and fMRI studies systematically show abnormalities

in prefrontal cx, n.caudatus, cerebellum & parietal cx

Increased long-range and decreased short range connectivity with age

Fair et al., 2007

Delay or interruption in these developmental processes might be associated with cognitive deficits in ADHD.

Neuroscience-neuropsychology-behaviourDevelopment

Neuroscience-neuropsychology-behaviour

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

Neuroscience-neuropsychology-behaviourDevelopmental theories

• Model: dopamine reinforcement learningCasey ea 2007, Curr Opin Neurol; Tripp & Wickens 2007, Eunethydis Meeting

Normal development ADHD

Learning to “expect” Reward dependent

Highlights in ADHD research in childhood and adolescence

• Linking neuroscience to neuropsychology and to behaviour

• Gene-environment interactions• Treatment guidelines• Medication side-effects• Long term treatment outcome• Early psychosocial treatment • Other treatments

Genes / Environment

• Heritability 0.6-0.9• Meta-analysis:

– DRD4: 7-repeat allele ~ ADHD

– DAT1: less reliable association

• Prenatal smoking, alcohol

• Family adversity• Low birth weight,

prematurity

• Low-level Lead exposure

Li ea 2006, Hum Mol Genet

Nigg ea 2007, Biol. Psychiatry

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)

Highlights in ADHD research in childhood and adolescence

• Linking neuroscience to neuropsychology and to behaviour

• Gene-environment interactions• Treatment guidelines• Medication side-effects• Long term treatment outcome• Early psychosocial treatment• Other treatments

ADHD Treatment Guidelines

• 1998: Clinical Guidelines for hyperkinetic disorder (Taylor E et al. Eur Child Adolesc Psychiatry 1998)

• 2004: European Clinical Guidelines for hyperkinetic disorder – first upgrade (Taylor E et al. Eur Child Adolesc Psychiatry 2004)

• 2006: NICE guidelines (www.NICE.org.uk)

• 2006: Long-acting medications for the hyperkinetic disorders – a systematic review and European treatment guideline(Banaschewski T et al. Eur Child Adolesc Psychiatry 2006)

• 1997: AACAP (American Academy of Child and Adolescent Psychiatry, J Am Acad Child Adolesc Psychiatry 1997)

• 2000: Texas Children’s Medication Algorithm(Pliszka GR et al. J Am Acad Child Adolesc Psychiatry 2000)

• 2000: NIH (National Institute of Health, J Am Acad Child Adolesc Psychiatry, 2000)

• 2001: AAP (American Academy of Pediatrics, Pediatrics 2000)

• 2006: Revision of Texas Children’s medication Algorithm (Pliszka GR et al. J Am Acad Child Adolesc Psychiatry 2006)

• 2007: AACAP(American Academy of Child and Adolescent Psychiatry, J Am Acad Child Adolesc Psychiatry)

EU GuidelinesEU Guidelines US GuidelinesUS Guidelines

Treatment Guidelines

• Growing armamentarium

• More evidence based

• Growing literature on side-effects

• Choice stimulants and non-stimulant

Effect size 10% larger

Full effect after days

Lower cost

Effect gradual over weeks

Long-lasting effect

May be preferred in comorbid cases with tics, anxiety, risk of substance abuseSpencer ea 2007, Geller ea 2007,

Kelsey ea 2007, ESCAP Posters

Highlights in ADHD research in childhood and adolescence

• Linking neuroscience to neuropsychology and to behaviour

• Gene-environment interactions• Treatment guidelines• Medication side-effects• Long term treatment outcome• Early psychosocial treatment • Other treatments

• 2006: FDA data review adverse events to ADHD medications (Mosholder 2006)

• 2006: postmarketing safety data review (Gelperin, 2006)

– Box warning US: Atx: suicidal thinking in 4/1000 versus 0 in placebo

• 2006: FDA data review on sudden deaths in patients using stimulants (Villalaba, 2006)

– 20 on amphetamine, 14 on MPH: does not exceed base rate of sudden death in general population

– Advise: not to be used in children with pre-existing cardio-vascular risk without cardiologist’s advise

Medication Side-effects/Safety

Conclusion: closer monitoring

Highlights in ADHD research in childhood and adolescence

• Linking neuroscience to neuropsychology and to behaviour

• Gene-environment interactions

• Treatment guidelines

• Medication side-effects

• Long term (treatment) outcome

• Early psychosocial treatment

• Other treatments

MTA: NIMH landmark study

EarlyTreatment

(3 m)

Mid-treatment

(9 m)

EndTreatment

(14 m)

Follow-up(24 m)

14-m Treatment Stage

10-m Follow-up After

Treatment

22-m Follow-up After

Treatment

0 362414Month

RandomAssignment

579 ADHD Subjects

Medication Only144 Subjects

Psychosocial (Behavioral)Treatment Only

144 Subjects

Combined Medication & Behavioral Treatment

145 Subjects

Community ControlsNo Treatment from Study

146 Subjects

Recruitment of LNCG Cohort

36 m FU

0

0,5

1

1,5

2

2,5

3

0 100 200 300 400

CC

Beh

MedMgt

Comb

Time x Tx: F=10.6, p<.0001Site x Tx: F=0.9, nsSite: F=2.7, p<.02

Comb, MedMgt > Beh, CC

Ave

rag

e S

core

Assessment Point (Days)

MTA: 14-month outcomeTeacher SNAP-Inattention

MTA: 36 month Follow-Up

Initial treatment does not seem to make a difference.

All did better.

Continuous Med (> 50% of days) versus non-continuous Med : no difference

Stop study Tr.

Influential study, but hard to interpret at this point in time !

Jensen ea 2007

Outcome research

ADHD + CD Controls OR *p<.001

Arrests 44% 15% 4.57*

Convictions 29% 8% 4.68*

Incarcerations 26% 8% 4.08*

All children had 3y.multimodal treatment between 6-12y

Preschool identificationPoor outcome

At 11-13y and 12-14y, fewer children with preschool ADHD were well-adjusted (17,7%) than controls (71.4%)

Medication works less well in preschoolers: PATS-study: 21% normalized with medication, 13% with placebo (Daley,

2007, Eunethydis)

Highlights in ADHD research in childhood and adolescence

• Linking neuroscience to neuropsychology and to behaviour

• Gene-environment interactions• Treatment guidelines• Medication side-effects• Long term treatment outcome• Early psychosocial treatment • Other treatments

Psychosocial treatmentParent Management Training

• New Forest Parent Training for preschool ADHD children (UK)

• Positive Parenting Plan (Triple P- US)

• Incredible Years (UK)All work (3-P somewhat less),

so far no external validation (only parent ratings)

Self-administration packages

Pelham ea, in press; VandenOord ea, in press; Jones ea 2007;

Other therapies

• EEG-biofeedback (Hirschberg, 2007)

• Food supplements (Johnson ea 2007)

• Cognitive rehabilitation

Conclusions

Genes/Environment

Neuro-anatomy/ Brain development

Neurophysiology/Neuropsychology

Behaviour

Treatment

Outcome