1. ADHD Attention Deficit Hyperactivity Disorders Jonathan Ponesse MD FRCPC Developmental Pediatric Neurologist CHEO & OCTC Assistant Professor University of Ottawa

2. Objectives 1.Describe the presentation of ADHD in children. 2.Recognize the impact of ADHD on child emotional and social development. 3.Identify the comorbidities associated with ADHD. 4.List the treatment options for children with ADHD. 6/10/20162

3. Case Jennifer had no problems in preschool. In kindergarten, she seemed to learn her letters and numbers, and could read a dozen words on sight. Her teacher said that she was doing well, but her parents noticed that she seemed more disorganized and inattentive than her older sister was at the same age. They often had to repeat instructions, and she left half-finished drawings all over her room. In first grade, Jennifer had mild difficulty with arithmetic, but now the teacher was concerned that she seemed to not be listening much of the time. Jennifer's school work was inconsistent and often she failed to finish assignments. The teacher suggested that Jennifer's parents have her tested for ADHD. 36/10/2016

4. 4 Presentation

5. Presentation of ADHD in children may have its onset in infancy, but rarely recognized until a child is at least toddler age sensitive to stimuli and easily upset by noise, light, temperature and other environmental changes infants with ADHD are active in the crib, sleep little, and cry a lot 6/10/20165

6. Presentation of ADHD in children In school Cannot follow instructions and often demand extra attention from teachers Cannot follow instructions and often demand extra attention from teachers Attack a test rapidly but answer only the first few questions Attack a test rapidly but answer only the first few questions Unable to wait to be called on and may respond before everyone else Unable to wait to be called on and may respond before everyone else 6/10/20166

7. Presentation of ADHD in children At home Cannot be put off for even a minute Cannot be put off for even a minute Do not comply with their parents’ requests Do not comply with their parents’ requests Often explosive or irritable Often explosive or irritable The irritability may be set off by relatively minor stimuli The irritability may be set off by relatively minor stimuli Impulsive and unable to delay gratification Impulsive and unable to delay gratification Often accident prone Often accident prone 76/10/2016

8. Clinical Features 2 categories of core symptoms: Hyperactive and impulsive behaviors occur together Hyperactive and impulsive behaviors occur together Inability to sit still or inhibit behavior Observed by age 4, peaks age 7-8, then hyperactive symptoms decline but impulsive symptoms persist Inattention Inattention Reduced ability to focus attention, reduced speed of cognitive processing and responding Apparent at 8-9 years old, usually lifelong

9. Diagnostic Criteria DSM-5  Age <17 years: ≥6 symptoms in 1 or both categories  Age ≥17 years, ≥5 symptoms of in 1 or both categories  Present > 1 setting  Persist > 6mo  Present before age 12  Inconsistent with developmental level child  Impair functioning  Exclude psychiatric disorders

10. DSM-4 vs DSM-5 New overall diagnostic category Neurodevelopmental disorders (DSM-5) vs Disorders usually first diagnosed in infancy, childhood and adolescence (DSM-4) Neurodevelopmental disorders (DSM-5) vs Disorders usually first diagnosed in infancy, childhood and adolescence (DSM-4)

11. DSM-4 vs DSM-5 ADHD across lifespan Not only a disorder of childhood Not only a disorder of childhood Adding new examples to apply criteria across lifespan Adding new examples to apply criteria across lifespan Lower age cutoff for diagnosis in adults Lower age cutoff for diagnosis in adults Age of onset changed from 7 to 12 Removal of PDD/ASD from exclusion criteria Allows for diagnosis of ADHD with comorbid PDD/ASD Allows for diagnosis of ADHD with comorbid PDD/ASD 116/10/2016

12. Changes from subtypes to presentations: DSM-4 vs DSM-5 Combined subtype Inattention + hyperactive- impulsivity Predominantly inattentive type Predominantly hyperactive-impulsive type Combined presentation Predominantly inattentive 6 inattentive and 3-5 hyperactive/impulsive symptoms Inattentive (restrictive) 6 inattentive and no more than 2 hyperactive/impulsive symptoms Predominantly hyperactive/impulsive DSM-4DSM-5

13. Impact 136/10/2016

14. 146/10/2016 Without treatment or improper treatment Substance abuse Gang allegiance Depression/low self-esteem School absenteeism Unstable employment record Marital discord Sexual promiscuity Increased MVAs

15. 156/10/2016 Associated Impairment Is ADHD ever found in isolation? Mimicry or comorbidity?

16. 166/10/2016 “Non-diagnosable” Associated Impairments Academic underachievement >90% >90% But may be bright intellectually But may be bright intellectually Up to 35% drop out rate Up to 35% drop out rate Poor occupational outcome

17. 176/10/2016 “Non-diagnosable” Associated Impairments Poor driving practices 6x more likely to be involved in accidents 6x more likely to be involved in accidents Difficulty dealing with multiple distractions Difficulty dealing with multiple distractions 50% increase in bike accidents 50% increase in bike accidents Increased risk of accidents 33% increase in ER visits 33% increase in ER visits

18. 186/10/2016 “Non-diagnosable” Associated Impairments Poor parenting practices Substance use disorders 2x risk 2x risk Earlier onset Earlier onset Less likely to quit in adulthood Less likely to quit in adulthood

19. 196/10/2016 Comorbid Diagnoses

20. 206/10/2016 Comorbid Diagnoses Only 1/5 has ADHD alone Comorbidity profile changes through the life span Language issues in preschool Language issues in preschool Mood disorders in adolescence Mood disorders in adolescence

21. 216/10/2016 Comorbid Diagnoses Comorbidity profile differs for different ADHD subtypes Ie combined form has higher rates of conduct disorder and tics Ie combined form has higher rates of conduct disorder and tics Disruptive/Externalizing disorders are more common in hyperactive-impulsive subtype than inattentive Internalizing disorders more common in inattentive

22. 226/10/2016 Developmental Disorders Developmental Coordination Disorder Aka Clumsy Child Syndrome Aka Clumsy Child Syndrome 5-15% of those with ADHD have significant motor disorder 5-15% of those with ADHD have significant motor disorder High incidence in prems May present with hypotonia in infancy Later, poor performance in athletics Poor motor speed in classroom affecting penmanship Co-occuring NVLD

23. 236/10/2016 Developmental Disorders Communication Disorders Ie articulation Ie articulation Rate of comorbidity at 3-5 yo is 30% Rate of comorbidity at 3-5 yo is 30% Then decreases thereafter Then decreases thereafter Reading Disability ….25% Phonological processing Phonological processing RD and ADHD represent separate disorders that frequently co-occur RD and ADHD represent separate disorders that frequently co-occur

24. 246/10/2016 Developmental Disorders Other Learning Disability ….50% Tourette Syndrome 50% have ADHD symptoms which predate tics 50% have ADHD symptoms which predate tics Presence of tics has little impact on outcome Presence of tics has little impact on outcome ASD (Autism Spectrum Disorder)

25. 256/10/2016 Externalizing Psychiatric Disorders Oppositional Defiant Disorder……50% Only in 30-40% of cases does it lead to conduct disorder Only in 30-40% of cases does it lead to conduct disorder More common ADHD-HI type Conduct Disorder….20% Leads to antisocial personality disorder in adults Leads to antisocial personality disorder in adults

26. 266/10/2016 Internalizing Psychiatric Disorders Anxiety …..20% Presence will alter response to medication and increase incidence of adverse responses Presence will alter response to medication and increase incidence of adverse responsesDepression….5%

27. 276/10/2016 Possible Impacts on learning Problem following directions Poorly selective memory Tendency to retain irrelevant while forgetting pertinent Tendency to retain irrelevant while forgetting pertinent Reading, spelling, writing errors reflecting poor visual attention to detail reflecting poor visual attention to detail

28. 286/10/2016 Possible Impacts on learning Illegible handwriting possibly due to impulsivity possibly due to impulsivity Difficulty conforming to classroom routines Poor social adjustment in school Difficulties completing tasks

29. 296/10/2016 Other Common Associated Impairments Verbal, physical aggression Social rejection & Demoralization Irritability Enuresis, encopresis Poor sleep, physical complaints

30. 306/10/2016 Burden of suffering… Parents Guilt Guilt Stress (marital, time for self) Stress (marital, time for self) 3-5x increase parental divorce or separation 3-5x increase parental divorce or separationSibs Disrupted lives Disrupted lives The limited resource of attention The limited resource of attention

31. 316/10/2016 Treatment of ADHD

32. 326/10/2016 Treatment of ADHD Multimodal BEAM BEAMBehavioralEmotionalAcademic School-based/cognitive School-based/cognitiveMedical biologic biologic

33. 336/10/2016 Treatment of ADHD – general comments Biological Medication Medication Herbals, EEG biofeedback etc Herbals, EEG biofeedback etc There is a bit of evidence for omega fatty acids, sensorimotor training and neurofeedback (EEG) There is a bit of evidence for omega fatty acids, sensorimotor training and neurofeedback (EEG)

34. 346/10/2016 Treatment of ADHD – general comments Psychosocial CBT CBT Parent training, support and education Parent training, support and education Behavioral management Behavioral management Parent support groups Parent support groups Self-monitoring training Self-monitoring training Social skills training Social skills training Teacher training for classroom management Teacher training for classroom management

35. 356/10/2016 Treatment of ADHD – general comments School-based Behavior modification Resource-based modifications Note-taking, EA, classroom withdrawal etc. Note-taking, EA, classroom withdrawal etc. Social skills “Microphone” to help student remember who the speaker is “Microphone” to help student remember who the speaker is Taking turns Reduce working memory load Chunking, list of steps Chunking, list of steps Simple, familiar words, begin with action words

36. 366/10/2016 Treatment of ADHD – general comments Other Allow kids to blow off steam at recess! Allow kids to blow off steam at recess! Know the triggers! Junk food doesn’t cause ADHD but the context in which one receives them aggravates symptoms Junk food doesn’t cause ADHD but the context in which one receives them aggravates symptoms Ie. B-day party No evidence to support the idea that food makes kids hyper (sugar, aspartame) No evidence that diets help with ADHD

37. 376/10/2016 Multimodal treatment Behavior modification alone is difficult for parents, hard on kids and only partially effective at best Multimodal treatment is superior to single therapy for the comorbid behavioral problems but not for core ADHD symptoms Ie anxiety, disruptive behavior disorders, social skills, aggression/oppositionality Ie anxiety, disruptive behavior disorders, social skills, aggression/oppositionality

38. 386/10/2016 Multimodal treatment Stimulants alone never really sufficient but often serves as keystone in comprehensive thx Stimulants allow patients to respond more appropriately to environmental and social cues

39. 396/10/2016 An Ideal ADHD medication… Effective in all areas of impairment Safe Benign side-effect profile Once a day dosing Day and evening coverage No diurnal variation, rebound No diurnal variation, rebound Lacking abuse potential Accessible

40. 406/10/2016 Stimulant Medication

41. 416/10/2016 Historical Stimulants discovered by accident Benzedrine given to decrease headache in kids having undergone pneumoenephalograms Improved attention

42. 426/10/2016 Myths about Ritalin and other psychostimulants “cure” for ADHD Only controls symptoms Only controls symptoms “lifelong treatment” As adolescence approaches, strategies for more internal control may surface As adolescence approaches, strategies for more internal control may surface Trials off Ritalin may be done to see if still needed Trials off Ritalin may be done to see if still needed However, 80% of those needing meds as kids still need as teenagers and 50% need as adults However, 80% of those needing meds as kids still need as teenagers and 50% need as adults

43. 436/10/2016 Myths about Ritalin and other psychostimulants “physically addictive” Little risk Little risk In fact, higher risk of substance abuse in untreated ADHD whereas medicated ADHD approached baseline (normal) risk “causes tics” No production of more tics than placebo in kids with or without preexisting tics with careful titration No production of more tics than placebo in kids with or without preexisting tics with careful titration

44. 446/10/2016 Myths about Ritalin and other psychostimulants “higher doses work better” Amount is individualized Amount is individualized Maximize efficacy, minimize side effects Maximize efficacy, minimize side effects Too much has negative effects on emotional development and creative learning Too much has negative effects on emotional development and creative learning “doses need to be increased as age” Dose not based on age and weight but on improvement in symptoms Dose not based on age and weight but on improvement in symptoms Usually as child ages and “grows a frontal lobe”, need for medication decreases Usually as child ages and “grows a frontal lobe”, need for medication decreases

45. Why Stimulants? Why “stimulate” a child that can’t sit still?! ADHD “brains” have increased number of dopamine transporters Clear dopamine too quickly Dopamine is an inhibitory force Dopamine is an inhibitory force Stimulants increase extracellular dopamine Stimulants increase extracellular dopamine: In striatum and prefrontal cortex By blocking dopamine reabsorption at synapse By blocking dopamine reabsorption at synapse Hence we are stimulating an inhibitor Hence we are stimulating an inhibitor Like making the brakes on a car work better 456/10/2016

46. 466/10/2016 Principles of stimulant usage Act on noradrenergic system by decreasing locus ceruleus firing by decreasing locus ceruleus firing by acting on alpha-adrenergic receptors by acting on alpha-adrenergic receptors Norepinephrine is involved in Maintaining alertness and attention Maintaining alertness and attention Norepinephrine containing neurons are quiescent during sleep Norepinephrine containing neurons are quiescent during sleep

47. 476/10/2016 Principles of stimulant usage Act on dopaminergic system by blocking dopamine re-uptake Dopamine is essential for Regulation of learning Regulation of learning Maintaining trained responses Maintaining trained responses Maintaining motivated behaviors Maintaining motivated behaviors Working memory Working memory Prefrontal-subcortical system Prefrontal-subcortical system

48. 486/10/2016

49. Most common side effects Dopaminergics DopaminergicsHeadache Stomach ache Loss of appetite InsomniaDizziness Noradrenergics Noradrenergics Loss of appetite DizzinessDermatitisDyspepsiaSomnolence EKG/cardiac conduction 496/10/2016

50. Medication Treatment Algorithm Start low and go slow Stimulant medications begin to work within 0.5-1.5 hours after administration Start with methylphenidate or amphetamine-based medication if nonpharmacologic treatments have not been successful on their own. If one is not successful after titrating to maximum effectiveness or if not tolerated, switch to other category. Texas Children’s Algorithm (JAACAP, Pliszka, 2006; 45(6): 642-57) 6/10/201650

51. 516/10/2016 Treatment of ADHD Goal of therapy Full remission Agree on target outcomes with family Agree on target outcomes with family ie to monitor: ie to monitor: Improved peer relations Improved peer relations Improved academic performance Improved academic performance Improved rule following Improved rule following

52. Treatment of ADHD Co-morbid disorders may be aggravated by stimulants: Worsening of anxiety or depression Worsening of tics and habits Increase in irritability during the course of the day when medication active, or after it wears off. Diamond, I. et al. Response to MPH in children with ADHD and comorbid anxiety,”JAACAP 38: 402-9. 1999. Hence consider: Atomoxetine Alpha adrenergic agonists Clonidine, guanfacine 6/10/201652

53. 536/10/2016 Benefits of Current Psychostimulants Immediate beneficial effects Well-studied immediate effects Behavioral improvement Behavioral improvement Decreased restlessness and motor drive Attention span Better inhibition control Decreased impulsivity Compliance/obedience Reduced aggression Social interactions

54. 546/10/2016 Benefits of Current Psychostimulants Academic improvement: Academic improvement: Core symptoms Academic productivity Accuracy Perceptual efficiency Short-term memory Quality of interaction with parents Response to behavior modification program Quality of interaction with teachers and peers Sporting performance

55. 556/10/2016 Benefits of Current Psychostimulants No apparent adverse effects on growth*, self- competence, substance abuse * controversial * controversial Up to 85% response rate in hyperactive ADHD vs. 65% in inattentive kids School age children show highest percentage of responders Compared to preschool, adolescent and adult Compared to preschool, adolescent and adult Improved driving performance

56. Benefits of stimulants Quick onset, ability to titrate easily, targeting symptoms which are impairing patient. Many dosage strengths and forms to fit patient, and hopefully, pocketbook. No reported long-term side effects. Few interactions with other medications. Additional stimulants (caffeine, decongestants) may be additive re: side effects. 6/10/201656

57. 576/10/2016 Limitations of Current Psychostimulants “Rebound”OverfocusCompliance Significant placebo effect Ongoing controversies Sudden death/cardiac conduction Sudden death/cardiac conduction height height

58. 586/10/2016 Usage of stimulants (MPH) Blinded med vs. placebo trial recommended Best is randomized 2 placebo weeks and 1 low dose, 1 high dose weeks Best is randomized 2 placebo weeks and 1 low dose, 1 high dose weeks Changeover on weekends Changeover on weekends Connor’s rating questionnaires Connor’s rating questionnairesMonitoring Height Height Weight Weight Bp q3monthly Bp q3monthly Side effects Side effects

59. Thank You! 6/10/201659

60. Extras! 606/10/2016

61. Amphetamine Mechanism of Action Increase dopamine and norepinephrine in the synaptic cleft Inhibits reuptake of dopamine diminishes enzymatic metabolism of dopamine 616/10/2016

62. 626/10/2016 Long-acting stimulants Concerta) OROS methylphenidate ( Concerta) 12 hr (3 pulse system) 12 hr (3 pulse system) osmotic release 1/5 of the medication is released immediately 4/5 then releases over the next 8-12 hours with a more robust release in the afternoon 18, 36, 54 mg T 18, 36, 54 mg T

63. Dual Beaded forms two peaks 50% released immediately 50% released immediately releases 50% as second dose in 4 hours releases 50% as second dose in 4 hours Biphentin (Methylphenidate) Adderal Mixed amphetamine salts (2 pulse system) Mixed amphetamine salts (2 pulse system) Dextro salt is more potent than levo Dextro salt is more potent than levo 12 hr 12 hr 10, 20, 30 mg T 10, 20, 30 mg T 230$ for 100 T 230$ for 100 T 636/10/2016

64. Lisdexamphetamine mesylate (Vyvanse) Dextroamphetamine sulphate appended to lysine molecule. Entire drug passes unchanged through gut to rbc’s, hydrolyzed, and lysine is removed rendering the active drug available to CNS. Smooth duration of action. Tmax reached at about same time in most patients. 646/10/2016

65. Lisdexamphetamine mesylate Long duration of action, up to 12 hours Advantages: low abuse potential. Smooth coverage many dosage strengths No feeling of jitteriness when it starts to work Powder soluble in many liquids not altered by dissolving it 656/10/2016

66. 666/10/2016 Long-acting products available Atomoxetine (Strattera) SNRI SNRI Effexor is an SSRI until high dose then is an SNRI 1-1.2 mg/kg/d 1-1.2 mg/kg/d Metabolized by CYT P450 Metabolized by CYT P450 Watch interactions

67. 676/10/2016 Long-acting products available Atomoxetine (Strattera) Highly selective NE reuptake inhibitor Highly selective NE reuptake inhibitor Increased NE, DA concentrations in prefrontal cortex Did not increase concentration of DA in striatum or nucleus accumbens Hence less addictive Hence less addictive Most notable effects on attention Most notable effects on attentionAdvantages Day and evening effects Children still under influence of medication in am Children still under influence of medication in am Mechanism of action different from Ritalin and Dex

68. 686/10/2016 Long-acting products available Atomoxetine (Cont’d) Safe No effect on sleep initiation No risk of addiction Still has appetite suppression, but weight loss negligible

69. Long-Acting Products available Atomoxetine (cont’d) Some effect on serotonin may act like mild SSRI (hence black box warning about increasing suicidal ideation). May take weeks to demonstrate efficacy. Only med. dosed acc. to wt. 6/10/201669

70. 706/10/2016 Long-acting products available Tricyclics Ie. Imipramine Ie. ImipramineObsolete But may be favored as 2 nd line for anxiety + ADHD, obsessive traits Lower response rate: 40-60% Dry mouth, constipation, orthostasis, need for EKG prior Risks of cardiovascular problems, sudden death Overdosage can be lethal.

71. Long-acting products available Alpha Agonists Clonidine, guanfacine Off-label modulate pre-synaptic and post-synaptic norepinephrine activity helps regulate basic adrenergic tone. positive neuropsychological effect on the prefrontal cortex. Wilens, T., “Mechanisms of Action of Agents Used in Attention-Deficit/Hyperactivity Disorder,”J. Clinical Psychiatry, 2006(67) Suppl 8: 32-37 6/10/201671

72. Long-acting products available Alpha Agonists (cont’d) Diffuse more slowly, less sedating, longer acting. Side effects Drowsiness, sedation, dizziness. Can be given in evenings and still have effects next morning Watch blood pressure. Sudden withdrawal may result in blood pressure alterations, sweating, dysphoria. 726/10/2016

73. 736/10/2016 Long-acting products available Alpha Agonists (cont’d) More for impulse control, hyperactivity and aggression More for impulse control, hyperactivity and aggression Hence helps socialization Limited influence on attention Adjunctive thx for Tourette’s + ADHD Adjunctive thx for Tourette’s + ADHD Aggressive ADHD Aggressive ADHD Explosive outbursts Explosive outbursts