Attention-Deficit/Hyperactivity Disorder

1. Attention-Deficit/Hyperactivity Disorder John D. McLennan, MD, PhD, FRCPC Child Psychiatry Consultant University of Calgary Pediatric Resident Seminar Jan 17, 2013

2. Acknowledgements/Disclosures I have no conflict of interest to declare • None to declare

3. Why a whole lecture focused on ADHD? • Common • Significant Impact • Risk for scholastic problems • academic underachievement, grade retention, drop out • Risk for relationship/social problems • Risk for employment problems • Risk for physical health problems • E.g., motor vehicle accidents

4. Outline • Diagnostic aspects • Intervention aspects • Other

5. A. Diagnostic aspects ADHD as a categorical disorder ADHD as a dimensional phenomenon Prevalence/etiology/prognosis ADHD and comorbidity Recommended diagnostic approach mi9.com

6. Diagnostic Criteria for ADHD(American Psychiatric Association, 1994)

7. DSM-IV ADHD subtypes • Combined • Predominately, hyperactive-impulsive • Likely just a precursor of combined type or just milder form • Predominately, inattentive • Some previously combined type • Some sub-threshold combined type • Some sluggish cognitive tempo? • Not-otherwise-specified (NOS)

8. Sluggish Cognitive Tempo • Forgetful, daydreams, sluggish, drowsy • Hypoactive • “in a fog” • Slow to process information/ more errors with information processing • Socially passive, withdrawn • McBurnett et al., 2001

9. Proposed changes in DSM-5 for ADHD (May 2012) SEE www.dsm5.org for more details (..release date May 2013?)

10. Categorical vs. Dimensional • While ADHD is often conceptualized or promoted as a categorical entity, it probably better fits on a spectrum • Consider degrees of attentional weakness and poor impulse control • Setting a diagnostic cut-point on a spectrum • Hypertension analogy (≥140/90, not 139/89) Attention regulation

11. The Dimension of ADHD • Strengths and Weaknesses of ADHD-symptoms and Normal-behaviour (SWAN rating scale) (www.adhd.net) • Support provided by a study of the heritability of attention problems in a Norwegian twin study (Gjone et al , 1996) • No change in relative genetic influence across severity • Lacking evidence of a taxon (Coghill & Sonuga-Barke, 2012)

12. Social construction? The dimensional nature of ADHD and indistinct boundaries with a normal range of behaviours may result in the notion of it being a socially constructed disorder……..although this is true of well-established medical disorders as well

13. Prevalence • DSM-IV criteria • Estimated about 5% prevalence (Polanczky et al., 2007) • Higher in clinical samples • Boys>girls (more pronounced in clinical samples) • Inattentive type>combined type?

14. Etiology Points: Genetics • Family aggregation studies • If parent has ADHD, risk to offspring about 57% • Risk to sibling approximately 32% • Twin Studies • Average heritability: 80% • Shared environment contribution: 0-13% • Non-shared environment: 9-20% • Also support from adoption research • Molecular genetic research • DRD4 (gene for dopamine 4 receptor) – 7 repeat version? • 13p16 region of chromosome 16? (Barkley, 2006)

15. Etiology Points: Brain structure & function • Some studies identified smaller brain regions: total brain volume, prefrontal volume, caudate nucleus, cerebellum-vermis (Barkley, 2006; Steinhausen 2009) • Evidence of dysfunction of the frontostriatal networks and possible other networks/regions (Cherkasova & Hechtman 2009) • Developmental lag in cortical grey matter thickening/maturation in childhood (Shaw et al., 2007) • Decreased cortical thinning in adolescents (Shaw et al., 2011) • Others (Barkely 2006) • Deficits on neuropsychological testing (e.g., executive functioning) • Quantitative EEG – increased slow wave in frontal lobe & decreased beta activity • Decreased blood flow to prefrontal regions • Low birth weight, white matter abnormalities, brain injuries (though likely only small subgroup)

16. Etiology Points: Other • Environmental Toxins? • Lead, alcohol, nicotine (Linnet et al., 2003) • Psychosocial Factors? • Not etiologic, parenting behaviour may contribute to maintenance/worsening of oppositional behaviours • Other? • Sugar (no) • Additives (maybe): Artificial food colours (Schab & Trinh, 2004) • Medication (Phenobarbital) • Streptococcal infection (Barkley 2006)

17. Prognosis • Increasingly recognized as a chronic disorder • Estimate that 50-70% of childhood ADHD persists into adolescence cases (could be higher depending on criteria/measurement) • Significant heterogeneity • Substantial co-morbidity influences prognosis and course

18. ADHD & comorbidities • Comorbidity: the presence of one or more disorders • It is often ADHD “AND” ____ rather than ADHD “OR” _____ • Common types of co-morbidities: • Oppositional Defiant Disorder [or symptom cluster of] • Learning Disorder [or symptom cluster of] • Conduct Disorder [or symptom cluster of] • Anxiety Disorder [or symptom cluster of] • Depressive Disorders [or symptom cluster of] • Tic Disorders [or symptom cluster of]

19. The spectrum of ADHD + co-morbidities ADHD Alone ADHD + symptoms of another disorder ADHD + Other disorder Other disorder + some symptoms of ADHD Dr. Gabrielle Carlson, Stony Brook University Medical Centre

20. ADHD & Comorbidity • Kadesjö & GiIlberg, 2001 (Swedish population study)

21. Poor emotional regulation • Common in children with ADHD • May be (Wehneier et al, 2010): • Inherent in the disorder • Associated with comorbidity • Secondary/consequence of ADHD • Emotional impulsiveness (Barkley 2010)

22. What strategies would you use to obtain information to make a diagnosis of ADHD? dlc-ubc.ca

23. Some ADHD diagnostic points • You must get teacher data • Use standardized checklists • Consider patterns on the checklists • Child’s behaviour in the office • Remember comorbidities

24. Teacher data/information (Essential) • To make an ADHD diagnosis, you must have school data • Relying exclusively on parent report about school-behaviour is inadequate • Parents don’t have systematic data from school • Parent-teacher agreement is moderate to low • If a child is not manifesting ADHD behaviour in the classroom, they don’t have ADHD • Teachers… • typically have access to a normative sample to inform their ratings • Have a relatively “standardized” setting • At least some experience with typical development • Often substantial observation periods to draw from

25. Use standardized checklists • A best practice recommendation • Provides systematic coverage of ADHD items (and symptoms of comorbidities) • Greater reliability than clinical interview, but not a substitute for a clinical interview • Parent AND TEACHER

26. Standardized Ratings • Narrow/focussed (e.g., primarily measure ADHD symptoms) • MTA-SNAP-IV • ACTors • “Short” Connors • Broad-band (could help cover potential comorbidities) • Child Behavioral Checklist (CBCL)[Achenbachs] • Behavior Assessment System for Children (BASC) • Informant types • Parent/Caregiver • Teacher • Child • Disagreement between informants common

30. Child behaviour in office • Don’t use behaviour in the office as a proxy for behaviour at school or home • Beware of “false negatives” • Novel stimulating environment

31. Remember comorbidities fineartamerica.com

32. Questions about diagnosis, assessment, etc blog.pe.com

33. B. Interventions dissertationhelponline.blogspot.com

34. Evidence-based treatments • What are the evidence-based interventions for ADHD? • Only 2 interventions with rigorous evidence of effectiveness for ADHD • Certain behavioural modification techniques • Certain medication • Many other interventions out there: • some with a little evidence • some with no evidence

35. Stimulant options in Canada • Methylphenidate – based products • Immediate release (Ritalin, generic) • Extended release • CR (Biphentin) • OROS (Concerta; generic?) • SR (Ritalin SR) • Amphetamine – based products • Immediate release dextroamphetamine (Dexedrine, generic) • Sustained release dextroamphetamine (Dexedrine Spansules) • Extended release - mixed salts of amphetamine (Adderall XR) • dextroamphetamine sulfate • dextroamphetamine saccharate • amphetamine aspartate monohydrate • amphetamine sulfate • Lisdexamfetamine (Vyvanse) • Lysine + dextroamphetamine (pro-drug)

36. Methylphenidate mechanism • A CNS stimulant • Mechanism(?): increase intra-synaptic concentration of dopamine and noradrenaline in frontal cortex and subcortical brain regions associated with motivation and reward (Volkow et al., 2004, in NICE guidelines) • Blocks presynaptic membrane dopamine transporter (DAT) inhibits reuptake of dopamine and noradrenaline into presynaptic neurons

37. Dextroamphetamine mechanism • More potent than MPH • In addition to blocking reuptake of dopamine and noradrenaline via the dopamine transporter (DAT) it also releases dopamine and noradrenaline into the extraneuronal space by blocking intraneuronal vesicular monamine transporter (VMAT)

38. Non- Stimulants • Atomoxetine (Strattera, generic) • Selective norepinephrine reuptake inhibitor • Approved in Canada for ADHD • Others (available but not approved for ADHD) • Bupropion (Wellbutrin SR and XL, Zyban, generics) • Nortriptyline (Aventyl, generics) • Imipramine (Tofranil, generics) • Clonidine (Catapres, Dixarit, generics) • Guanfacine (Tenex) [special order only] • Guanfacine extended release [Intuniv] under review in Canada • Desipramine and Pemoline are no longer used

39. Medication choice • What would you start with? • What would inform your decision? scienceprogress.org

40. Medication Choice/Order • Texas Algorithm Project (Pliszka et al., 2006) • 1st choice – stimulant • Methylphenidate or amphetamine • 2nd choice – stimulant from other class • Methylphenidate or amphetamine • 3rd choice atomoxetine • Are there exceptions where you would chose atomoxetine earlier? • 4th choice – other monotherapy

41. Factor informing choice • What period of time to cover? • School only vs. beyond school • Can the child swallow? • Have to be able to swallow for methylphendiate OROS (Concerta) and atomoxetine (Strattera) • Are non-generics affordable? • History of medication use/response (including family) • Genetic testing – not yet

42. Medication management: Stimulants • What do they do? • Increase attention span • Decrease hyperactivity • Decrease impulsivity • Sometimes… • Reduce aggression • Improve socialization • Some measures of school performance (short-term) • Reduce emotional dysregulation • Improve compliance

43. Stimulant side-effects: Physical • Gastrointestinal/Appetite/Growth • Decrease appetite (ensure balanced diet, calorie supplementation) • Weight loss (as above; monitor) • Upset stomach (take with food) • Decrease stature (mean of 1.2cm at 14 months in MTA study) • Cardiovascular • Increased pulse (monitor, not typically a problem) • Increased blood pressure (monitor, not typically a problem) • Sudden (Cardiac) Death – not evidence of increased risk but • Screen for family history of sudden cardiac death • Screen for factors increasing risk for unexpected cardiac death • Baseline physical/cardiovascular exam • ECG not required if normal exam and history ….but… • …could miss Long QT syndrome and WPW

44. Stimulant side-effects: Emotional and others • EMOTIONAL • Increased proneness to tears • Agitation/irritability • Too quiet/glassy eyed/“zombie” appearance, flat/depressed (dose too high) • Tics (obtain family history, monitor, possibly discontinue, controversy) • Other • Headaches • Insomnia (may be an issue with late dosing or longer-acting formulations) • Generally unfounded societal worries • Personality change • Entry to drug abuse & addiction

45. Atomoxetine • Selective norepinephrine reuptake inhibitor • Primarily metabolized in the liver via cytochrome P450 2D6 (CYP2D6 pathway) • Slower titration than the stimulants (as may be lag in the attainment of maximum response to a given dose) • Dose/body weight recommendations • “Maximum” of 1.4mg/kg/day (or 100mg, whichever is less) • Start dose recommendation 0.5mg/kg/day • Typically once per day dosing (but can spilt dose: am and late afternoon/early evening)

46. Atomoxetine- adverse effects Rare/black box warnings: liver involvement , suicidality *-Cheng et al 2007 Psychopharmacology 194: 197-209

47. Medication management: Titration • Systematic titration schedule • See Texas Algorithm approach (Pliszka et al) • Why? • Substantial variation in optimal response between individuals • Assist in determination of optimal dose • Avoid under and over dosing • In contrast to treatment as usual which may entail: • “Typical”: try 1-2 dose and adjust over-time as prompted by parent (or teacher) • This is inadequate and will not likely lead to optimal medication choice or dose selection

48. You have to get follow-up school data • ….parent reports of amount of change over time cannot serve as a substitute for an assessment of the amount of change that occurs in the classroom” (Lavigne et al., 2012 p. 341) • “Although it may be difficult and time-consuming, gathering teacher reports appears to be critical for the optimal treatment of ADHD” (Lavigne et al., 2012 p. 341) Parent-teacher correlations on ADHD symptoms in a primary care treatment study (Lavigne et al., 2012)

49. Medication treatment example (1)

50. Medication treatment example (2)