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Response to treatment in ADHD: Prediction and
Compliance
Eric Taylor
King’s College London– Institute of Psychiatry
South London & Maudsley NHS Trust
A complex disorder, multiply caused
Goals of treatment
• Reduce core symptoms• Impulsiveness, inattentiveness, restlessness
• Alleviate comorbid problems• Aggression-anger, anxiety, emotional lability,
autism spectrum, Tourette
• Promote realistic learning goals• Reduce rejection by others• Understanding of disability, valuing of self
and of authority
WHY PREDICT RESPONSE?
(A treatment trial will often give a clearer answer than even a “significant” prediction)
• To understand the treatment• To influence choice of treatment
- therapy helpful only for a small minority- hazardous or expensive therapy- many therapies available
• To influence treatment regime- dynamics, kinetics, adherence
Value of a predictive marker(Assuming 70% response rate & c. 80% sensitivity & specificity)
Improved Treated Utility
unnecessarily (+1 v. -1) 100
70 30 40 No pretest
100 Positive 60 48 12 36
Pretest Negative 40 0 0
+1 v -3
-20
12
So a marker becomes useful if treatment is hazardous; or very costly (or if there are many possible treatments and response is slow)
Future of pharmacotherapy:iInternational licences now being
sought• Guanfacine
• Dexamfetamine complex
• Modafinil
• Focalin
• Risperidone for “irritability”
Coming later: percutaneous delivery; nicotine & GABA analogues; AMPAkines & CREBS?
Predicting outcome
• Single dose
• Clinical profile• Subtypes• Comorbidity
• Pharmacogenomics
• Brain function
• Compliance
UNDERSTANDING THE TREATMENT
• Measure the marker at baseline and outcome• Correlate change in marker with clinical outcome• Avoid confounders
- regression to mean, recovery, placebo, fluctuations
• Compare with placebo
- crossover
- regression• Fixed v variable dose; absolute or relative outcome
REVIEW OF REPLICATED PREDICTORS
• Psychophysiology = high or low skin conductance normal or abnormal EEG high or low heart rate
• Neurology = presence of soft signs
• Familial = good management
• Age = younger or older
• Clinical = high severity: (IQ inconsistent); poor attention
Barkley (1976) Journal of Abnormal Child Psychology
PREDICTING % (DRUG – PLACEBO) CHANGE
Responder Non-responder Iambda N=22 N=16
Age (months) 95 111 .85
IQ 90 98 .84
PACS/Hyperactivity 1.2 0.4 .75
Attention -1.5 +0.6 .72
Clumsiness 14 8 .70
Significant predictors in crossover double-blind R.C.T in boys with disruptive behaviour; Taylor et al (1987) Psychological Medicine, 17, 121
What predicts “good response”?
Taylor et al Buitelaar et al
High severity Low severity
Low IQ High IQ
Young age Young age
Low anxiety Low anxiety
Differences between studies
Taylor et el Buitelaar et al
Disruptive behaviour ADHD
Optimal dose Fixed low dose
Marked improvement Normalised(“improved” was not predicted)
Crossover placebo Regression subtraction
Measuring outcome: normalisation v. effect size
Unmedicated ADHD
General population
Medicated ADHD
CLUSTERING IN BOYS WITH DISRUPTIVE BEHAVIOUR
Cluster Medication response*Hyperkinetic 73%Conduct 14%Anxious/depressed 8%
* “Marked improvement” in drug and not placebo; N=38 in crossover double- blind R.C.T.
Taylor et al (1986) British Journal of Psychiatry, 149, 760-777
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 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
Subtyping
ANXIETY / DEPRESSION
HKDHKDHYPHYP3/53/5INATINAT
6/96/9
IMPIMP1/41/4
SCHOOLSCHOOL HOMHOMEE
IMPAIRMENTIMPAIRMENT
ADHD versus HKD
ANXIETY / DEPRESSION
HKDHKDHYPHYP3/53/5INATINAT
6/96/9
IMPIMP1/41/4
SCHOOLSCHOOL HOMHOMEE
IMPAIRMENTIMPAIRMENT
HKD AS A MODERATOR
Using the same analysis as the original MTA report, HKD emerged as a significant moderator of treatment outcome on
– SNAP HYPERACTIVITY/IMPULSIVITY (P)
– SSRS TOTAL SOCIAL SKILLS SCORE (P)
– SSRS INTERNALISING SCORE (P)
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
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)
Treatment Decision Making - HKD
Hyperkinetic Disorder
STIMULANTSSTIMULANTS
Treatment decisionsTreatment decisions
• Severe, pervasive, disabling?
• Problems at home?
• Problems at school?
• Persistent after treatment?
• Comorbid problems?
Home CBT
Liaison+ self-instruction
Medication
?
Medical treatment in “comorbidity”
• Mental retardation• Autism spectrum• Coordination problems• Conduct disorders• Anxiety• Tourette• Bipolar disorder• Epilepsy• Attachment disorder
As in simple ADHD; more AEs; enhanced monitoring needed
}Treat as usual
Predicts poor response but not contraindicated Nonstimulants sometimes needed
Differentiate pattern; cause does not determine response
Caution ++ in BP I or II; stimulants useful in “PBD”
Stimulants are not contraindicated and may be useful
Predict by genetics?
• CYP2D6 polymorphisms for atomoxetine; esterase for methylphenidate
• DRD4.7 findings contradictory
• DAT 10/10 may predict nonresponsiveness*
• glutamate receptor 7 gene (GRM7) & norepinephine transporter suggested in genome scan**
* Eg Keun-Ah Cheon, Young-Hoon Ryu, Jae-Won Kim and Dae-
YeonCho(2005)Eur Neuropsychopharm 15,,95-101;**Mick et al (2008) Am J Med Genet B
Neuropsychiatr Genet. 2008 5:1412-8.
Stimulants raise dopamine levels
Atomoxetine raises frontal dopamine levels
By inhibiting the noradrenaline transporter
Adherence to Medication Regime (from baseline to 3 years in MTA trial)
Percentage of Children Using Medication Over 50% of Days by Time Period and Treatment Group
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36Month
% M
ed U
se
Comb Med Beh CC
Adherence and attitudes• Tom is 15. Professional parents. White British.
• Mixed neuropsychiatric presentation:– Presented at age 10 with history of impulsive overactivity
throughout his life; asked to leave nursery; multiple suspensions from primary school and three changes of school (all mainstream) due to mother’s perception of school failing him
– Reading age then was 7; WISC IQ 106; noncompliant with tasks seen as difficult
– Increasingly unpopular; steals to give to other kids– Violent to his younger sister, not otherwise
• Treated with Concerta (in spite of tics appearing); good response, maintained in mainstream with facilitator, friendless.
Problems now
• Age 14 increasing cannabis use; agreed to continue Concerta (54 mg daily) none the less; off medication at weekends and holidays; discussions in motivational interviewing format.
• Age 15 behaviour at school deteriorated. Concerta increased; clonidine added; not helpful; admitted not taking medicines
• Wont accept a self-monitored trial; “dunno” and “don’t like it” on his objections.
Patients taking stimulants (General Practice Research Database)
30
7 6 5 6
211
66
20 13
73
25 1936
241
42
0
50
100
150
200
250
300
16 17 18 19 20 to 21
Age, years
Nu
mb
er o
f p
atie
nts
Female Male Total
Common reasons for nonadherence
• Forget• Stigma• Not real self• Losing funny side• Adverse effects
• Physical; sex; tension; feared brain damage• Incompatible with misused substances
• Inconvenience• Don’t need it• Up to me• No point
Attitudes of young people to stimulants
• Harpur (2006, PhD thesis Southampton)• Predominantly positive• “Adherence” is complex – individually chosen
regimes, often by parents (Singh, 2006, Am J Med Ethics: “authenticity”) – adherence to what?
• Ferrin (2007, MSc, London)• Questionnaire from Childrens Health Beliefs
model: locus of control, self-esteem, general beliefs on medicine, knowledge perceived threat and benefit doctor-patient relationship
Outcome and adherence
• Simpson et al BMJ 2006 333 15– Metaanalysis: good adherence in about 50%;
predicts good outcome, even for placebo. (“healthy adherer”)
• Charach et al J Amer Acad CAP 43 559– Adherence to stimulants over 5 years predicts
good outcome, is predicted by youth, severity of ADHD, no ODD
Attitudes of young people to stimulants
• Project commissioned from LSE (Singh)
• Qualitative interviewing
• Attitudes predominantly positive
• Negative aspects acknowledged• Inconvenient• Stigmatising for some• Sleep/appetite problems
• Better for some activities, worse for others
Conclusions
• Prediction of stimulant response depends upon the outcome desired.
• Greatest change happens in children with a pattern of inattentiveness, pervasive hyperkinesis and low anxiety
• Future possibilities for pharmacogenomics and fMRI
• Good compliance goes with good response and good communication