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