ADHD

1. ADHD New Developments in Pharmacological and Therapeutic Interventions Gabriel Kaplan, M.D. Bennett Silver, M.D.

2. Your Faculty: Gabriel Kaplan, M.D. • President, New Alliance Academy • Medical Director, Bergen Regional Medical Center • Board Certified Psychiatrist • Kaplan G., Ivanov I., and Newcorn J.H. Pharmacological Management of ADHD in Children and Adolescents. Int J Child Adolesc Health 2010; 3(2):143–61 • IvanovI., Pearson A., Kaplan G., and Newcorn J.H. Management of Comorbid ADHD and SUD Int J Child Adolesc Health 2010; 3(2):163-177 • Kaplan G. and Newcorn J.H. Pharmacological Management of ADHD Ped Clinics North Am. 2011; 58:99–120 • Kaplan G. “Attention deficit hyperactivity disorder in adolescence.” in Child Health and Human Development Yearbook 2012 Greydanus DE, Merrick J, eds Nova Biomedical Books, New York 2012

3. Your Faculty: Bennett Silver, M.D. • Board Member, New Alliance Academy • Medical Director, Adolescent PHP and Consultation Liaison, St. Mary Hospital • Board Certified Psychiatrist • Editor Nationwide Newsletters • Psychiatry Drug Alerts • Child Psychiatry Drug Alerts • Psychiatry NOS • Readership over 22,000 psychiatrists

4. Conference Agenda Dr. Gabriel Kaplan • ADHD Epidemiologic and Diagnostic Considerations Dr. Bennett Silver • Stimulants Dr. Gabriel Kaplan • Non Stimulants and New Approaches Dr. Bennett Silver • Non Medication Approaches

5. Epidemiological and Diagnostic Considerations Gabriel Kaplan, M.D.

6. Perceptions of ADHD: “Then” and “Now” Hill, Schoener. Am J Psychiatry. 1996;153(9):1143-1146. Klorman et al. J Am Acad Child Adolesc Psychiatry. 1987;26(3):363-367. J Am Acad Child Adolesc Psychiatry. 1991;30(3):I-III. Adler et al. J AttenDisord. 2008;11(6):720-727. Rostain. Postgrad Med. 2008;120(3):27-38. Weiss, J Clin Psychiatry. 2004;65(suppl 3):27-37. Barkley et al. J Abnorm Psychol. 2002;111(2):279-289.

7. Executive Functions Perception of Time Inhibit Responses Working Memory Internalize Speech Self Regulation

8. ADHD DSM-IV-TR CriteriaAdapted from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. A Either 1 or 2: 1. Six or more of a list of nine symptoms of inattentionhave been present for at least 6 months, to a degree that is maladaptive 2. Six or more of a list of nine symptoms of hyperactivity-impulsivity have been present for at least 6 months, to a degree that is maladaptive B Some symptoms that cause impairment were present before age 7 years. C Some impairment from the symptoms is present in two or more settings (e.g. at school/work and at home). D There must be clear evidence of significant impairment in social, school, or work functioning. E The symptoms are not better accounted for by another mental disorder

9. ADHD DSM-IV-TR Criteria Inattention (a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities (b) often has difficulty sustaining attention in tasks or play activities (c) often does not seem to listen when spoken to directly (d) often does not follow through on instructions and fails to finish school work, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) (e) often has difficulty organizing tasks and activities (f) often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) (g) often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) (h) is often easily distracted by extraneous stimuli (i) is often forgetful in daily activities  Hyperactivity -Impulsivity (a) often fidgets with hands or feet or squirms in seat (b) often leaves seat in classroom or in other situations in which remaining seated is expected (c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) (d) often has difficulty playing or engaging in leisure activities quietly(e) is often "on the go" or often acts as if "driven by a motor" (f) often talks excessively (g) often blurts out answers before questions have been completed (h) often has difficulty awaiting turn(i) often interrupts or intrudes on others (e.g., butts into conversations or games) 

10. Is ADHD Real? • One of the most studied disorders of childhood with several thousand publications in peer refereed journals • Affects 5% to 8% of US children • Statistics replicated throughout the world • However, there is a small but vocal segment that insists ADHD was invented by pharmaceutical companies to sell drugs

11. Jan Steen - The Village School- 1665 Kast & Altschuler; The earliest example of the hyperactivity; 2008 South African medical journal

12. Jan Steen - The Village School - 1670

13. Sir Alexander Crichton (Scottish MD) • In 1798 in the chapter of Attention in his book: An inquiry into the nature and origin of mental derangement • Described a mental state with al the essential features of the inattentive subtype of ADHD, the restlessness, problems with attention, the early onset and how it can affect the ability to perform in school.

14. ADHD is highly heritableAccording to a metastudy by Faraone et al in Biol Psych 2005;57:1313-1323, ADHD mean heritability is 0.75 reaching almost the heritability of height.

15. According to Shaw, Arch GenPsychiatry. 2006;63:540-549, cortical thickness in ADHD compared with controls is significantly thinner regions in the ADHD group.

16. Academic Impairment • Very well documented • Failure to perform academically is the single most common source of referral for children and adolescents • Children with ADHD • Perform poorly on achievement tests and fail grades / courses significantly more often than children without ADHD • Complete 3 fewer years of education than matched controls • More likely not to graduate from high school (35%) • Academic impairment more profound when learning disabilities are present Weiss & HechtmanHyperactive Children Grown Up 1993 Manuzza & Klein The Economics of Neuroscience, 2001:47-53

17. Social Impairment • Social problems begin in childhood, persist into adolescence • Fewer friends, more limited social skills • Lower self esteem on assessment scores • 3X’s as likely to have trouble getting along with peers • ½ as likely to have good friends • 2Xs as likely to get picked on by peers • 3Xs as likely to have problems that limit after school activities Suppl. JAACAP Practice Parameters for Use of Stimulant Medications 2002;41:26S-49S I.M.P.A.C.T. Survey;NYU Child Study Center;2001

18. Diagnostic Approach • Despite significant advances in anatomical/genetic research, there is NO current validated biological marker • Psychiatric interview and history remain the best diagnostic tools • Rule in (ADHD) • Rule out (Mimics)

19. Rule in Approach • Psychiatric Interview • Family (family hx of ADHD) • Child (school/social performance) • Parents (marital/parental function) • Collateral Information • Rating Scales from Teacher (most reliable guide of treatment progress) • Discussion with teacher if available • Discussion with grandparents if involved

20. Psychiatric Mimics of ADHD Adapted from Searight et al. Am Fam Physician. 2000;62(9):2077-2086.

21. Medical Mimics of ADHD • Thyroid disease • Medication adverse effects • Antiasthmatics • Anticonvulsants • Benzodiazepines • Antihistamines • Seizure disorder and other neurologic disorder • Excessive caffeine consumption • Sleep apnea • Hearing impairment • Chronic disease Stein. CNS Spectr. 2008;13(10 suppl 15):14-16.

22. Differential Diagnosis Tools • Physical Exam • Specialists if necessary (Neurologist, Endochrinologist,etc) • Rating Scales for current symptoms • Conners’ ADHD Rating Scale • Laboratory testing • Chemistries (CBC, TFTs, etc) • Sleep Lab • EEG • Psychological testing • Not pathognomonic but helpful Brown, ed. ADHDComorbidities: Handbook for ADHD Complications in Children and Adults. Washington, DC: American Psychiatric Press; 2009.

23. Dopamine • Enhances signal • Improves attention • Focus • Vigilance • Acquisition • On-task behavior • On-task cognition Solanto. Stimulant Drugs and ADHD. Oxford; 2001.

24. Norepinephrine • Dampens noise • Decreases shifting • Executive operations • Increases inhibition • Behavioral • Cognitive • Motoric Solanto. Stimulant Drugs and ADHD. Oxford; 2001.

25. Trends in Prevalence of Stimulant Use 1987–2008 Zuvekas Am J Psychiatry. 2012;169(2):160-166Since 1987, there has been a signficant increase overall for ages 0-17. However, the largest increase has been for ages 12-17 while there was a decrease for ages 0-5.

26. Stimulant Treatment Bennett Silver, MD

27. Societal and Workplace Impact of ADHD • ADHD cost the U.S. economy between 143 billion and 266 billion in 2010 • That is roughly $2,000 per household • Although commonly thought of as a childhood disorder, adults with ADHD accounted for 73% of those estimated costs • The majority of these costs were the result of lost productivity (62%), healthcare (26%), education (10%), and the criminal justice system (2%) • Effective treatment plans can improve the outcome of ADHD and reduce these costs to society *Congressional briefing on societal and workplace impact of untreated ADHD, November 30,2011

28. Stimulants • Gold standard, first line treatment • There are two chemical families with almost identical therapeutic properties • Amphetamines (AMPH) • Methylphenidates (MPH) • Amphetamines first used in 1937 • Stimulants are very effective (80%) and very safe. • Only difference amongst multiple preparations is duration of action

29. Short Acting Stimulants (up to 4hrs) • MPH products • Ritalin • Methylin • Focalin • AMPH products • Dexedrine • Dextrostat • Adderall

30. Long Acting Stimulants (More recently approved) • MPH products • Oral (6-10 hrs) • Methylphenidate-SR • Ritalin (SR or LA) • Methylin-ER • Metadate (CD or ER) • Concerta (8-10 hours) • Focalin XR (8-10 hours) • Patch (duration depends on length of time patch on) • Daytrana • AMPH products • Adderall XR (8-10 hours) • Vyvanse (at least 13 hours in children)

31. Choice of Stimulant • It does not matter which MPH or AMPH starts first • Most children will respond to one or the other • If one is not effective or induces side effects, the child is switched to the other one • This strategy improves over 80% of patients • Over 70% of psychiatrists prefer long acting formulations • Avoids having to see the nurse at noon • Longer duration helps with homework • Avoids rebound emotional lability as dose wears off

32. Stimulant Side Effects • FREQUENT • Decrease appetite • Difficulty falling asleep • Mood lability • Stomach upset • Dry Mouth • Irritability • INFREQUENT • Clinically significant increased pulse or blood pressure • Motor tics, Tourette’s • Weight loss, slowed growth • Psychosis • Do not use in those with arrhythmias or other heart abnormalities • Can be used as substance of abuse, to be avoided in active SA

33. Incomplete Diagnosis Can Lead to Inadequate Treatment • Sometimes ADHD is correctly diagnosed, appropriate treatment and proper medication are initiated, but the student only partially responds • When this occurs it is necessary to look for co-existing psychiatric disorders that may also require treatment • As many as two thirds of children and adolescents with ADHD have at least one other co-existing condition

34. ADHD and Co-Existing Disorders • Learning Disabilities (30%-50%) • Disruptive Behavior Disorders- ODD/CD (40%-50%) • Depression (15%-30%) • Bipolar Disorder (15%-20%) • Anxiety (25%-30%) • Substance Abuse (30%-35%) • Sleep Disorders (30%-75%)

35. Is Substance Abuse More Common in Teenagers Who Are or Were Treated with Stimulants? • Youths with ADHD are at increased risk for substance abuse; about one-and-a-half times greater risk than non-ADHD youths* • Current research documents that those adolescents with ADHD prescribed stimulant medication are less likely to subsequently use illegal drugs than are those not prescribed medication ** *Wilens, T, et al. (2011). Does adhd predict substance-use disorders? A 10-Year follow-up study of young adults with adhd. Journa of the American Academy of Child and Adolescent Psychiatry 543-553: v50, i6 **Biederman, J, et al. (1999). Pharmacotherapy of attention deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 104:e20

36. Non-Stimulants and New Approaches Gabriel Kaplan, MD

37. Stimulants vs. Non-Stimulants • Stimulants strengths • Act right away • Very effective • Gold standard • Many preparations, multiple dosage strengths • Well tolerated • Stimulants weaknesses • Controlled substances • 20% non response • Some patients do not tolerate AEs

38. When to use a Non Stimulant • A Stimulant trial has failed • Non effective or intolerable side effects • Parents do not want to use a controlled substance • There is active drug abuse in the patient or family • There is a contraindication • Sensitivity, heart problems • Presence of Co-morbidities: ODD, Anxiety

39. Strattera • Takes 3-4 weeks to work • Selective Norepinephrine Reuptake Inhibitor SNRI (it makes more NE available) • Once per day dosage • Although studies proved efficacy, in clinical practice, physicians have been disappointed and is used less and less often

40. Strattera Side Effects • FREQUENT • Upset stomach • Decreased appetite • Nausea or vomiting • Dizziness • Tiredness • Irritability • Insomnia • INFREQUENT • Liver failure • Suicidal thoughts • Urine retention • Cardiac complications • Psychosis

41. Intuniv • Guanfacine Extended Release • Approved 9/2009 • Acts on the same receptor as Norepinephrine (Selective Alpha 2A) • Its action, thus, mimics increased NE • Taken once per day • Takes a minimum of 2 weeks but most likely up to 4 weeks to work

42. Intuniv Side Effects • FREQUENT • Sedation • Somnolence • Fatigue • Headache • Increased appetite • INFREQUENT • Clinically significant low BP or heart rate • Syncope • Dizziness

43. Kapvay • Clonidine Extended Release • Approved 10/2010 • Acts on the same receptor as Norepinephrine (Alpha 2 non selective) • Its action, thus, mimics increased NE • Taken twice per day • Takes a minimum of 2 weeks but most likely up to 4 weeks to work

44. Kapvay Side Effects • FREQUENT • Sedation • Somnolence • Fatigue • Headache • Increased appetite • INFREQUENT • Clinically significant low BP or heart rate • Syncope • Dizziness

45. How do you know the medication works • Executive Functions have improved • Decreased impulsivity and motor behavior • Increased attention • As shown by teacher reports (the most reliable outcome measure) • Via Rating scales: Conner's, etc or phone contact with the provider directly or via parents • And there are no significant side effects

46. Newly Approved Combination Therapy • Use a stimulant and a non stimulant at the same time • Approved recently for Kapvay (2010) and Intuniv (2011) but in use for decades with IR preparations • For stimulant partial responders

47. Newly Approved Combination Therapy • Stimulant Side Effects • Anorexia • Insomnia • Hypertensive • Non Stimulant Kapvay/Intuniv Side Effects • Increased appetite • Sedation • Hypotension

48. Omega-3 fatty acid supplementation improves ADHDBloch, JAACAP, 2011 50, 10:991-1000

49. Restriction Diet improves ADHDNigg JAACAP 51:1; 2012

50. Non- Medication Approaches Bennett Silver, MD