Response to treatment in ADHD: Prediction and Compliance

1. Response to treatment in ADHD: Prediction and Compliance Eric Taylor King’s College London– Institute of Psychiatry South London & Maudsley NHS Trust

2. A complex disorder, multiply caused

3. 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

4. WHYPREDICT 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

5. Value of a predictive marker(Assuming 70% response rate & c. 80% sensitivity & specificity) ImprovedTreatedUtility unnecessarily (+1 v. -1) 100 70 30 40 No pretest 100 Positive 60 48 12 36 PretestNegative 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)

6. 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?

7. Predicting outcome • Single dose • Clinical profile • Subtypes • Comorbidity • Pharmacogenomics • Brain function • Compliance

8. 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

9. 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

10. 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

11. What predicts “good response”? Taylor et alBuitelaar et al High severity Low severity Low IQ High IQ Young age Young age Low anxiety Low anxiety

12. Differences between studies Taylor et elBuitelaar et al Disruptive behaviour ADHD Optimal dose Fixed low dose Marked improvement Normalised (“improved” was not predicted) Crossover placebo Regression subtraction

13. Measuring outcome: normalisation v. effect size General population Unmedicated ADHD Medicated ADHD

16. CLUSTERING IN BOYS WITH DISRUPTIVE BEHAVIOUR ClusterMedication 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

17. Month 36 0 14 24 10-m Follow-up Phase 22-m Follow-up Phase 14-m Treatment Phase R A N D O M A S S I G N M E N T MedMgt 144 Subjects Recruitment Screening Diagnosis Beh 144 Subjects 579 Subjects 7 to 9 yrs old ADHD-Combined Comb 145 Subjects CC 146 Subjects End of Treatment (14 m) First Follow-up (24 m) Second Follow-up (36 m) Early Treatment (3 m) Mid- Treatment (9 m) Baseline Pre-Baseline Observation 2 LNCG Group Observation 1 LNCG Group Assessment Points

18. 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

19. Subtyping ANXIETY / DEPRESSION IMP 1/4 SCHOOL HOME HKD HYP 3/5 INAT 6/9 IMPAIRMENT

20. ADHD versus HKD ANXIETY / DEPRESSION IMP 1/4 SCHOOL HOME HKD HYP 3/5 INAT 6/9 IMPAIRMENT

21. 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)

22. SNAP Hyperactivity-Impulsivity (Parent)

23. SSRS Total Social Skills (Parent)

24. Treatment Decision Making - HKD Hyperkinetic Disorder STIMULANTS

25. Treatment decisions • Severe, pervasive, disabling? • Problems at home? • Problems at school? • Persistent after treatment? • Comorbid problems? Home CBT ? Liaison + self-instruction Medication

26. Medical treatment in “comorbidity” As in simple ADHD; more AEs; enhanced monitoring needed • Mental retardation • Autism spectrum • Coordination problems • Conduct disorders • Anxiety • Tourette • Bipolar disorder • Epilepsy • Attachment disorder }Treat as usual Predicts poor response but not contraindicated Nonstimulants sometimes needed Caution ++ in BP I or II; stimulants useful in “PBD” Stimulants are not contraindicated and may be useful Differentiate pattern; cause does not determine response

27. 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** **Mick et al (2008) Am J Med Genet B Neuropsychiatr Genet. 2008 5:1412-8. * Eg Keun-Ah Cheon, Young-Hoon Ryu, Jae-Won Kim and Dae-YeonCho(2005)Eur Neuropsychopharm 15,,95-101;

28. Stimulants raise dopamine levels

29. Atomoxetine raises frontal dopamine levels By inhibiting the noradrenaline transporter

30. Adherence to Medication Regime (from baseline to 3 years in MTA trial)

31. 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.

32. 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.

33. Patients taking stimulants (General Practice Research Database)

34. 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

35. 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

36. 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

37. 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

38. 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