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