Working with difficult children: Recent advances in ADHD

Working with difficult children: Recent advances in ADHD

Eric TaylorEric Taylor

King’s College London Institute of PsychiatryKing’s College London Institute of Psychiatry

There are many ways in which children can be ‘difficult’: ADHD is just one. Behaviour is dysregulated : inattention, executive

dysfunction, altered response to reward, poor time perception, and response disorganisation can all be involved. Assessment can guide

education, help counselling, and lead to treating ADHD.

Lessons from researchLessons from research

It’s not their faultIt’s not their fault Psychological treatments workPsychological treatments work Medicines help the worst affectedMedicines help the worst affected Increasing range of medicinesIncreasing range of medicines

More ‘diagnoses’ for child troubles

BBC to apologise for child drug program

Born mad or made bad? Crime and

the child

Conflicts in understanding ADHD*Conflicts in understanding ADHD* Genetic influences 80%;Genetic influences 80%; Frontal, striatal, Frontal, striatal,

cerebellar parts of brain cerebellar parts of brain are smallare small

Same structures Same structures underactivateunderactivate

Psychological deficitsPsychological deficits

Great differences over Great differences over timetime

Great differences in Great differences in prevalence between prevalence between countriescountries

Emotional & Emotional & behavioural problemsbehavioural problems

Performance variablePerformance variable

Persistent and pervasive abnormalities in : Attention (distractible, forgetful, disorganised); Activity (restless, fidgety) and Impulsiveness

(acting without thinking)

Where does ADHD come from?Twin studies show high heritabilityWhere does ADHD come from?Twin studies show high heritability

Twin

correlations

DZ MZ

Median heritability (13 studies) 0.82 (0.52-0.98)

Search for high-risk allelesSearch for high-risk alleles DRD4DRD4

metaanalysis p< .00000001metaanalysis p< .00000001 Odds ratio (averaged): 1.32Odds ratio (averaged): 1.32

DAT1DAT1 metaanalysis p<.0001metaanalysis p<.0001 Odds ratio (averaged): 1.13Odds ratio (averaged): 1.13

8 candidate genes well established to be associated with ADHD:

mostly affecting dopamine or serotonin neurotransmission

7 (vs 2-5 or 8) copies of 48 bp VNTR on 11p.15.5

9 vs 10 copies of 40 bp VNTR on 5p15.3

Geographical variations in the number of repeats of the variable 48-bp sequence in DRD4

Chang et al

Genome scan identifies a spot on Chr 16: Cadherin 13Genome scan identifies a spot on Chr 16: Cadherin 13

Cadherins mediate cell adhesion and play a fundamental role Cadherins mediate cell adhesion and play a fundamental role in normal development. They participate in the maintenance in normal development. They participate in the maintenance of proper cell-cell contactsof proper cell-cell contacts

CDH13 also implicated in substance misuse:CDH13 also implicated in substance misuse:

Nicotine dependenceNicotine dependence

Substance dependenceSubstance dependence

Plays a role in cell adhesion, cell-cell contacts and cell-Plays a role in cell adhesion, cell-cell contacts and cell-migrationmigration

What is inherited?What is inherited?

NotNot ADHD: ADHD: genetic influences on continuum*genetic influences on continuum* NotNot a unitary trait: influences vary with context a unitary trait: influences vary with context Dispositions to react:Dispositions to react:

gene-environment interactions and correlationsgene-environment interactions and correlations early physical environmental associationsearly physical environmental associations parenting influences on developmentparenting influences on development MAOA multiplies effects of violence, DRD4.7/DAT10 of MAOA multiplies effects of violence, DRD4.7/DAT10 of

smokingsmoking

*(with possible exception at highest level of severity & possible latent classes)

Probable environmental associationsProbable environmental associations

PregnancyPregnancy nicotine, alcohol, anticonvulsants, cocainenicotine, alcohol, anticonvulsants, cocaine lead, mercury; thyroid, immune rejectionlead, mercury; thyroid, immune rejection stress; infections; toxaemia;APHstress; infections; toxaemia;APH

PerinatalPerinatal low birth weight, O.C.s, perinatal care, [season of birth]low birth weight, O.C.s, perinatal care, [season of birth]

Infancy Infancy attachment problems, neglect, injuryattachment problems, neglect, injury socioeconomic adversity, nutritionsocioeconomic adversity, nutrition

ChildhoodChildhood Course influenced by exclusion, hostility, injury, schoolCourse influenced by exclusion, hostility, injury, school

Embryonic Postnatal

Week: 0 6 12 18 24 30 36 Month: 0 6 12 18 24 30 36 Year: 4 8 12 16 20 24

Cell Birth

Migration

Axonal/Dendritic Outgrowth

Programmed Cell Death

Myelination

Majority of Neurons

Fewer Neurons, primarily in cortex

Synaptic Production

Synaptic Elimination/Pruning

10 cm

But, if ADHD is so neurological, how come it varies so much in different places? Isn’t it really a social disorder? What about the rise of television and the decline of the family?

Prevalence of disorderPrevalence of disorder

Administrative prevalence from local surveys; HKD in approx 105,000 nationally

0

10

20

30

40

50

Nu

mb

ers

pe

r 1

00

0

US'80 UK'80 US'98 UK'99

Admin prevalence Hyperkinetic disorder

ADHD /1000

Real prevalence

Prevalence of disorderPrevalence of disorder

Same survey method in Hong Kong and East London

0

10

20

30

40

50

60

70

Nu

mb

ers

pe

r 1

00

0

HKratings

UKdiag

HK ratings UK ratings HK diag UK diag

Is it a Social Problem?Is it a Social Problem?Is it a Social Problem?Is it a Social Problem?

Does society determine the presence of ADHD?Does society determine the presence of ADHD? No, shared environment plays little partNo, shared environment plays little part

Does society alter the rate?Does society alter the rate? Only small differences between societiesOnly small differences between societies Little increase over timeLittle increase over time

Does society determine what is recognised?Does society determine what is recognised? Yes, substantial cultural differencesYes, substantial cultural differences

Patterson - OSLC

Is it a Treatable Problem?

Interventions in the classroomInterventions in the classroom

Proximity to teacherProximity to teacher Managed transitionsManaged transitions Pacing & letting off energyPacing & letting off energy Classroom aideClassroom aide

operant conditioningoperant conditioning peer advicepeer advice

Rule governmentRule government Clarity of goal & speed of feedbackClarity of goal & speed of feedback Understanding disorder (eg projects)Understanding disorder (eg projects) Monitoring medicationMonitoring medication

Some common-sense procedures – avoiding distractors and short-chunk learning – don’t yet have trial evidence

Specific treatmentsSpecific treatments

Psychological therapies:Psychological therapies: Parent training, behaviour mod, social skillsParent training, behaviour mod, social skills

Licensed drugs:Licensed drugs:Methylphenidate, dexamfetamine, Methylphenidate, dexamfetamine,

atomoxetineatomoxetine Unlicensed drugs:Unlicensed drugs:

Trial evidence:Trial evidence: pemoline, imipramine, clonidine, bupropion, pemoline, imipramine, clonidine, bupropion, “Adderall”, modafinil, guanfacine“Adderall”, modafinil, guanfacine

Anecdotal: Anecdotal: moclobemide, risperidone, sertraline moclobemide, risperidone, sertraline

Diet: Diet: eliminations and supplementseliminations and supplements

Include non-specific interventions - education, support, advice

Xavier, aged 11, has been out of the control of his parents after an episode of meningoencephalitis at age 4. He is dangerously aggressive to his sister and younger brother and has been excluded from a special unit at school. He sets fires, steals from shops, and puffs cannabis with a group of older boys.He can’t concentrate in class, is very forgetful and disorganised; and teachers have believed that this comes from a chaotic home background.

A range of presentations: XavierA range of presentations: Xavier

A complex disorder, multiply causedA complex disorder, multiply caused

Not just genetic: The Environmental Risk Longitudinal Twin Study interviewed the mothers of 565 five-year-old monozygotic (MZ) twin pairs : the twin receiving more maternal negativity and less warmth had more antisocial behavior problems. (Moffitt et al 2008)

Not just bad parents: Medication of child reduces parental EE

Not just complications:Not just complications:In never-medicated adults:In never-medicated adults:Recent findings of low Recent findings of low dopamine and DATdopamine and DATRecent findings of Recent findings of persisting hypoactivationpersisting hypoactivation

A range of presentations: MatteoA range of presentations: Matteo

Matteo is regarded by his parents as a charming 8-year-old who has recovered from injury but is now encountering bullying. His teachers, however, refer him to the clinic with a very different story: he does not listen to them, he does not concentrate as he should, he has low academic self-esteem and big tempers when frustrated, he is inclined to lose his way, he is clumsy and his handwriting is terrible.

He was popular when he started at school, but now is teased a great deal. His teachers are frustrated because in individual sessions he shows good understanding and creativeness.

A complex disorder, multiply causedA complex disorder, multiply caused

Inattention creates an increasingly unstimulating environment

Effect sizes on ADHD scalesEffect sizes on ADHD scales

0

0.2

0.4

0.6

0.8

1

1.2

MPH- IR Concerta Equasym ATOMOX

Parent effectTeacher effect

Psychological interventionsPsychological interventions

Type Delivery Costed as:

Parent training Group

Individual

Group + child

10 sessions

10 sessions

Cognitive Individual n/a [no effect]

Educational Class information

Screening

Delivery to teacher

n/a

Principles of psychological treatmentPrinciples of psychological treatment Identify specific problems Analyse contingencies Enhance adult attending Teach effective instruction Token economy + response cost (frequent)

or time-out + rapid novel rewards Include self- management

A school-based trialA school-based trial

Tymms & Merrill (2009)86 schools & 2,584 pupils in randomised trial

Year 2 behaviour in schools receiving an Information Booklet was improved (ES = 0.26)Pupil attitudes to school and reading were improved (ES = 0.17)No effect of screening programme.

Cost of booklet £2.55

(similar booklet in Taylor E (ed) People with Hyperactivity. CDM 171; MacKeith Press)

Learning social skills in peer groupLearning social skills in peer group

Listen to others Join play gradually Learn the rules

Avoid intrusiveness and excessive demands

Figure out why others react Control anger Learn how to refuse kindly

Especially drugs

But do behavioural treatments work? Metaanalysis

But do behavioural treatments work? Metaanalysis

Pelham & Fabiano (2008) review: Behavioural parent training Behavioural classroom management Intensive intervention in recreational settings

Journal of Clinical Child and Adolescent Psychiatry 37 184

Table 5. Databases searched and inclusion/exclusion criteria for clinical evidence

Electronic databases CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO

Date searched Database inception to 18.12.08

Study design RCT

Patient population Children diagnosed with ADHD

Interventions Any non-pharmacological intervention used to treat ADHD symptoms and/or associated behavioural problems

Outcomes ADHD symptoms*; conduct problems*; social skills*; emotional outcomes*; self-efficacy*; reading; mathematics; leaving study early due to any reason, non-response to treatment.

*Separate outcomes for teacher, parent, self, and independent ratings.

NICE approach: Systematic literature review

Cost-effectiveness calculationCost-effectiveness calculation

Table 10. Cost-effectiveness of parent training versus no treatment in children with ADHD - results of the base-case analysis over 1 year

Intervention

Total QALYs / child

Total cost / child ICER

Parent training

0.803 £168 Parent training versus no treatment: £6,608/QALYNo

treatment0.785 0

Sensitivity analyses for differing assumptions

Economic conclusionEconomic conclusion

According to this analysis, and after assuming an 80% uptake of such programmes, the group clinic-based programme resulted in a cost per responder of £10,060 and £1,006 at a 5% and 50% success (response) rate, respectively; and a cost per QALY of £12,575 and £3,144 at a 5% and 20% improvement in HRQoL, respectively.

Clinical conclusionsClinical conclusions

The results of the economic analysis indicate that group-based parent training programmes (or CBT for children of school age) are likely to be cost-effective for children with ADHD, if the mode of delivery of such programmes does not affect their clinical effectiveness. Individual parent training is unlikely to be a cost-effective option

Neurofeedback trials meta-analysisNeurofeedback trials meta-analysis

Assessment Points

Baseline EarlyTreatment

(3 m)

Mid-Treatment

(9 m)

End ofTreatment

(14 m)

FirstFollow-up

(24 m)

SecondFollow-up

(36 m)

14-m Treatment

Phase

10-m Follow-up

Phase

22-m Follow-up

Phase

0 362414

Month

RecruitmentScreeningDiagnosis

RANDOM

ASSIGNMENT

579 Subjects7 to 9 yrs old

ADHD-Combined

MedMgt144 Subjects

Beh144 Subjects

Comb 145 Subjects

CC 146 Subjects

Observation 1 LNCG Group

Pre-Baseline

Observation 2 LNCG Group

Comparing Therapies:Conclusions from MTA StudyComparing Therapies:Conclusions from MTA Study

Medication is more powerful than behavioural treatment at 14 months

Research treatment better than routine

Many advantages in adding medicationto behavioural treatment; few in adding behavioural treatment to medication

Comparing therapies:MTA TimelineComparing therapies:MTA Timeline

Study

Treatments

Basel

ine,

7-9

.9 y

rs

8 Yea

rs

6 Yea

rs

36 M

os, 1

0-14

yrs

24 M

os, 9

-12

yrs

14 M

os, 8

-12

yrs

10 Y

ears

Randomisation ends

36 Month Findings on Substance Use

Molina et al

Jensen et al, 2007Intent-to-treat (ITT) Analysis Jensen et al, 2007Intent-to-treat (ITT) Analysis

Randomized Clinical Trial at 14-month assessment: Transition to Naturalistic Follow-up at the 24-month & 36-month Assessment

MTA Group, 1999a,b

MTA Group, 2004a,b

Equifinality of Interventions: How Should Clinical Services React?Equifinality of Interventions: How Should Clinical Services React?

Results underestimate treatment effects?

Treatments lack long-term benefit?

Extra benefits of intensive therapy fade?

Self-selection makes good outcomes

SubtypingSubtyping

ANXIETY / DEPRESSION

HKDHKDHYPHYP3/53/5INATINAT

6/96/9

IMPIMP1/41/4

SCHOOLSCHOOL HOMHOMEE

IMPAIRMENTIMPAIRMENT

ADHD versus HKDADHD versus HKD

ANXIETY / DEPRESSION

HKDHKDHYPHYP3/53/5INATINAT

6/96/9

IMPIMP1/41/4

SCHOOLSCHOOL HOMHOMEE

IMPAIRMENTIMPAIRMENT

SNAP Hyperactivity-Impulsivity (Parent)SNAP Hyperactivity-Impulsivity (Parent)

HYPERKINETIC DISORDER (n=145)

0.60

0.85

1.10

1.35

1.60

1.85

2.10

2.35

D 3 m 9m 14m

ASSESSMENT POINTS

Combined

MedMgt

Psychosocial

Community

ADHD without HYPERKINETIC DISORDER (n=434)

0.60

0.85

1.10

1.35

1.60

1.85

2.10

2.35

D 3m 9m 14m

ASSESSMENT POINTS

Combined

MedMgt

Psychosocial

Community

SNAP Hyperactivity-Impulsivity (Parent)SNAP Hyperactivity-Impulsivity (Parent)

HYPERKINETIC DISORDER (n=145)

0.60

0.85

1.10

1.35

1.60

1.85

2.10

2.35

D 3 m 9m 14m

AS S ES S MENT P OINTS

MedMgt

P sychosocial

ADHD w ithout HYPERKINETIC DISORDER (n=434)

0.60

0.85

1.10

1.35

1.60

1.85

2.10

2.35

D 3m 9m 14m

AS S ES S MENT P OINTS

MedMgt

Psychosocial

HYPERKINETIC DISORDER (n=145)

0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30

D 3m 9m 14m

ASSESSMENT POINTS

Combined

MedMgt

Psychosocial

Community

ADHD without HYPERKINETIC DISORDER (n=434)

0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30

D 3m 9m 14m

ASSESSMENT POINTS

Combined

MedMgt

Psychosocial

Community

SSRS Total Social Skills (Parent)SSRS Total Social Skills (Parent)

Economic modellingEconomic modelling

Methylphenidate

Parent training

Continue

MethylphenidateParent training

Continue

QoL £

Severe casesSevere cases

Methylphenidate

Parent training

Continue

MethylphenidateParent training

Continue

Relative effect of medication to behavioural interventions greater in hyperkinetic subtype

Treatment decisionsTreatment decisions

Severe, pervasive, disabling?

Problems at home? Problems at school?

Persistent after treatment?

Comorbid problems?

Home CBT

Liaison+ self-instruction

Medication

?

Key recommendations from NICEKey recommendations from NICE

ADHD should be recognised and referred Comprehensive specialist assessment; impairment req’d

Trusts to set up lead group Adult services to be developed First choice usually group parent training Severe cases go straight to medication First choice medication usually MPH Shared care expected

Drugs or behaviour therapy?Conclusions so farDrugs or behaviour therapy?Conclusions so far Both are effective Both are cost-effective Medication hazards:

Growth suppression (manageable) Hypertension (avoidable with monitoring) Unknown risks to CVS

ADHD is heterogeneous in severity and course

Specific approaches: cognitive therapySpecific approaches: cognitive therapy

Effective for coexistent anxiety/ depressionFor Core ADHD symptoms, little effect:

Learning to STOP AND THINK Recognising and managing anger

Teaching others to be self-controlledTolerating waiting

So far, trial evidence suggests no effect on core ADHD. What are we doing wrong?

Perhaps teaching cognitive control is hard because there are many routes into impaired control/ impulsiveness

Perhaps teaching cognitive control is hard because there are many routes into impaired control/ impulsiveness

Varieties of “inattention”Varieties of “inattention”

Attention domainsAttention domains Executive functionExecutive function AlertingAlerting Sustaining vigilanceSustaining vigilance Resisting distractionResisting distraction Altering focusAltering focus Allocating resourceAllocating resource Modify responsivenessModify responsiveness

Planning

Reaction time,

Continuous performance tests

CPT with distractors

Central-incidental learning

Dual task

“Inhibition”, preparedness, Sternberg, cognitive energetics

A continuous performance testA continuous performance test

Press

A sustained attention deficit?A sustained attention deficit?

02468

1012

Beginning oftask

End of task

% e

rror

s

ADHDControl

Number of errors are high and responses slow throughout the test

eg Sergeant et al 1990

Slowing the presentation rateSlowing the presentation rate

0123456789

2 seconds 8 seconds

% c

omm

issi

on e

rror

s

ADHDControl

Van der Meere et al 1995

A preparation deficit?A preparation deficit?

0

0.2

0.4

0.6

0.8

1

1.2

1 second 15 sec 30 sec

ADHDControl

Warning Signal ResponseRT

Sonuga Barke et al 1993

GONOGOGONOGO STOPSTOP GONOGOGONOGO STOPSTOP

press press inhibitinhibit

Selective inhibition of a Selective inhibition of a motor response/response motor response/response selectionselection

ISI: 1.6spress inhibit

Withholding of a planned motor response

REVERSALREVERSAL

press inhibit

SWITCH TASKSWITCH TASKSWITCH TASKSWITCH TASK

Modification of Meiran Switch task: Cognitive flexibility. Switching between two dimensions.

Delay of gratificationDelay of gratification

Useful clinical test in preschool children; needs to be subtler for older children (Mischel).

Post - reward delayPost - reward delay

?

1 p 1 p

?

2 p

?

30 sec

Experiments by Edmund Sonuga-Barke

Delay aversion v inhibitionDelay aversion v inhibition

Evidence for both; inhibitory failure in more severe cases

Combination of both predicts behavior much more strongly than either alone (Solanto et al)

Inhibition (5-choice serial RT; 5HT2A,C) and preference for delayed reward (5HT2C,B) show double dissociation with 5-HT receptor (Talpos et al)

Reward & Social Influences

Time scales of reward effectsTime scales of reward effects

Response to reward

Anticipation Effects

Choice between alternatives

Expectation

Previous reward historyReinforcement schedules

Pairing

Rapid change of activity

REWARDED CPTREWARDED CPTREWARDED CPTREWARDED CPT

FMRI: respond to “X” and “O”. ISI: 900ms

Specific dysfunctions in CD vs ADHDSpecific dysfunctions in CD vs ADHD

Sustained Attention

Reward

‘Reward’ Problems presented in psychopathology‘Reward’ Problems presented in psychopathology Misbehaviour (“oppositional/conduct disorders”) Anhedonia Misery Addiction Hunger for novelty/sensation/reward/dopamine Apparently dysfunctional choices (risky or

punished activities) Insensitivity to reward schedules

Clinicians use of reward mechanismsClinicians use of reward mechanisms Parent Training

Clarity, consistency, speed

Premack principle Reward schedules

enuresis training reward frequency before training

Reward novelty [Density, predictability, reward/punishment ratios]

Clinicians’ use of punishment mechanismsClinicians’ use of punishment mechanisms Reduction of naturalistic punishment Response cost (Time-out)

Conceptualised as extinction

What is it like to be inattentive/ impulsive?What is it like to be inattentive/ impulsive?

““My thoughts are in a muddle”My thoughts are in a muddle” (usually only after treatment shows the difference)(usually only after treatment shows the difference)

““I get into trouble a lot, I don’t know why”I get into trouble a lot, I don’t know why” ““Other kids pick on me”Other kids pick on me” ““Ive got a bad temper”, “I cant concentrate”, “Ive Ive got a bad temper”, “I cant concentrate”, “Ive

got ADHD” got ADHD” (usually repeating what they have been told)(usually repeating what they have been told)

ConclusionsConclusions

There are several testable cognitive dysfunctionsThere are several testable cognitive dysfunctions Response organisation, switching, reward, timingResponse organisation, switching, reward, timing

They are found in several presentationsThey are found in several presentations Attention deficit, impulsiveness, irritabilityAttention deficit, impulsiveness, irritability

Useful for individual analysis, not diagnosisUseful for individual analysis, not diagnosis But most tests are unstandardisedBut most tests are unstandardised

Could help to guide teaching Could help to guide teaching Treatment does not usually depend on causeTreatment does not usually depend on cause

Consider behaviour modification and medicationConsider behaviour modification and medication

Research knowledge on ADHDResearch knowledge on ADHD

Common, persistent, risk for mental health Neurobiology becoming clearer

Low dopamine levels in striatum (PET) Frontostriatal (& other) brain changes (MRI) Genetic and environmental causes

• Allelic variants associated, esp genes in dopamine system

Effective treatments Stimulants, atomoxetine, behaviour therapy Efficacy is not related to cause