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ADHD: Diagnosis and Treatment of More Than One Disorder

ADHD: Diagnosis and Treatment of More Than One Disorder. Steven R. Pliszka, MD. Faculty Disclosure.

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ADHD: Diagnosis and Treatment of More Than One Disorder

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  1. ADHD: Diagnosis and Treatment of More Than One Disorder Steven R. Pliszka, MD

  2. Faculty Disclosure • Steven R. Pliszka, MD, was a member of the Speakers Bureau for Shire US Inc. and Ortho-McNeil Pharmaceuticals, Inc. He has received grants/research support from Shire US Inc., Cephalon, Inc., McNeil, and Eli Lilly and Company, and is a consultant for Shire US Inc. He has received honoraria from Shire US Inc., McNeil and Cephalon, Inc.

  3. Topics To Be Covered • ADHD “simplex” • Adverse events of treatment (e.g., cardiovascular, psychiatric) • ADHD with comorbidity • ODD/CD • Tics • Aggression • Bipolar Disorder CD = conduct disorder

  4. Adverse Events of Stimulants Update on the Controversy

  5. Estimated Reporting Rates (1992-2004): Pediatric Sudden Death (18 Years Old) 1IMS Health, National Prescription Audit Plus, January 1992 through December 2004. Data Extracted April 2005; 2Total person-years (p-y) times the percentage of drug appearances in the pediatric subgroup population (IMS Health, National Disease and Therapeutic Index, January 1993 to December 2004, Data Extracted June 2005); 3N = sudden death cases identified in FDA AERS database received from January 1992 through February 2005; Available at: www.fda.gov/ohrms/dockets/AC/06/briefing/2006_42106_06_Gelperin.pdf. Accessed Jan. 29, 2007

  6. Psychiatric Side Effects of Stimulants? Duration Psychosis Type of No. of of trials Category Patient- /mania Suicidal Aggression trial trials (range) of exposure N years events events events Drugs Concerta DB 4 6-28 dys Placebo 317 10.20 0 0 0 Drug DB 321 12.68 0 0 0 < 12 mos. OL 7 Drug OL 2824 1397.40 8 6 52 Metadate CD DB 4 7-21 dys Placebo 572 19.44 0 0 3 Drug DB 493 19.13 0 0 3 OL 2 NS Drug OL 322 19.55 0 0 6 MTS DB 8 1-49 dys Placebo 464 23.84 0 0 1 Drug DB 471 30.26 4 0 6 OL 4 NS Drug OL 617 341.97 6 1 7 Modafinil DB 6 1-9 wks Placebo 366 39.87 0 0 5 Drug DB 722 85.50 2 4 9 < 1 yr OL 3 Drug OL 924 383.53 2 0 14 Adderall XR DB 7 1-4 wks Placebo 678 28.00 0 0 6 Drug DB 1236 77.18 0 1 20 < 2yrs OL 6 Drug OL 5177 1767.47 14 8 166 < 78 wks Atomoxetine DB 20 Placebo 1443 350.73 0 4 18 Drug DB 2459 654.87 4 9 49 < 96 wks OL 10 Drug OL 5270 5095.27 12 44 198 Ritalin LA DB 5 1-14 dys Placebo 259 11.31 0 1 0 Drug DB 383 25.66 2 0 2 OL 1 NS Drug OL 125 25.95 0 1 0 < 49 dys d-MPH DB 8 Placebo 468 53.24 0 0 0 Drug DB 588 64.75 4 0 1 < 1 yr OL 5 Drug OL 740 362.09 3 1 13 Gelperin K (2006). Available at: www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-Index/htm. Accessed Feb. 1, 2007

  7. Growth and Stimulants • Spencer (1996) compared growth in 3 cross-sectional samples of patients with ADHD controls: children, early pubertal adolescents and young adults • No difference in height in child and young adult samples, adolescents with ADHD were shorter than control ADHD; no relationship of treatment history to height • This study lead to view that stimulants do not effect growth at all, drug holidays not necessary Spencer TJ et al. (1996), J Am Acad Child Adolesc Psychiatry 35(11):1460-1469

  8. Growth and Stimulants (Cont.) • 1-2 year trials of long-acting stimulants showed small, but generally clinically insignificant effects on height z score1 • Poulton (2005) reviewed all studies, concluded that stimulants induce a 1-3 cm deficit in expected height early in treatment2 1Faraone SV et al. (2005), J Child Adolesc Psychopharmacol 15(2):191-202; 2Poulton A (2005), Arch Dis Child 90(8):801-806

  9. Growth and Stimulants: Recent Studies Preschool ADHD Treatment Study (PATS) • 140 preschoolers started treatment with methylphenidate (MPH) at a mean age of 4.4 for 1 year • z height and z weight assessed serially, no control group • Preschoolers with ADHD were bigger than average at baseline (z height = +0.45, z weight = +0.78) Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

  10. Growth and Stimulants: Recent Studies (Cont.) • Annual growth rates were reduced compared to that predicted by growth charts: • -1.38 cm/year lower expected height • -1.32 kg/year lower expected weight • Cannot say this pattern will continue Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

  11. Growth and Stimulants: Recent Studies (Cont.) • Multimodal Treatment Study of Children with ADHD (MTA) • Followed MTA sample 3-year follow up: • 65 children with ADHD never medicated • 70 children with ADHD consistently medicated • 147 children with ADHD inconsistently medicated • 88 children with ADHD newly medicated Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

  12. Growth and Stimulants: Recent Studies (Cont.) 0.6 0.5 0.4 No meds 0.3 Controls z Height 0.2 New meds Incons 0.1 Cons meds 0 BSL 14 Mo. 24 Mo. 36 Mo. -0.1 -0.2 BSL = baseline; MTA data; Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

  13. Growth and Stimulants: Recent Data • 66 children treated with mixed amphetamine salts (MAS) and 113 treated with MPH for at least 1 year (mean 2.7 years of treatment) • Treated with stimulant monotherapy, no switching from 1 stimulant to another • No effect of z height or weight, no difference between medications on height • Drug holidays averaging 31% of the time during treatment Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(5):520-526

  14. Revised CMAP Algorithm for Pharmacotherapy of ADHD • Consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, families • Revised algorithms based upon new research developed for treatment of ADHD, with and without common comorbid conditions • Children treated according to earlier algorithms achieved better outcomes and were exposed to less polypharmacy than controls Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657; Pliszka SR et al. (2003), J Am Acad Child Adolesc Psychiatry 42(3):279-287

  15. CMAP Algorithm for Pharmacologic Management of ADHD Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657

  16. Multimodal Treatment of ADHD Study: Change Scores Jensen PS, et al. J Am Acad Child Adolesc Psychiatry. 2004;43(11):1334-1344.

  17. ADHD—Childhood Common Comorbid Diagnoses Approximate Prevalence Rate in Children With ADHD (%) Male Female Biederman J et al. (1996), J Am Acad Child Adolesc Psychiatry 35(3):343-351; Pliszka SR (1998), J Clin Psychiatry 59(suppl 7):50-58; Biederman J et al. (1999), J Am Acad Child Adolesc Psychiatry 38(8):966-975; Spencer T et al. (1999), Pediatr Clin North Am 46(5):915-927

  18. Nature of ODD and CD • A descriptive diagnosis, does not imply etiology • ODD may be secondary to ADHD • ODD or CD may occur even without ADHD • ODD/CD are sometimes due to environmental factors (late onset) • Most likely has multiple causes

  19. Meta-Analyses of the Effects of Stimulants on Aggression • Connor et al. (2002) • 1970-2001, 28 studies • Mean effect size of stimulants—0.84 for overt and 0.69 for covert aggression • Pappadopulos et al. (2006) • 1989-2004, 19 studies, >1,000 participants • Mean effect size of 0.78 Connor DF et al. (2002), J Am Acad Child Adolesc Psychiatry 41(3):253-261; Pappadopulos E et al. (2006), J Cdn Acad Child Adolesc Psychiatry 15(1):27-39

  20. Psychopharmacology of ODD/CD • ADHD children with ODD/CD respond to stimulants as well at those without ODD/CD • No evidence that stimulants increase aggression at appropriate doses • Relative to placebo, ADHD children on stimulants engage in less antisocial behavior

  21. ADHD-ODD/CD Issues With Stimulants Pharmacotherapy and Substance Abuse • Fear: stimulant therapy may lead to substance abuse • Fact: untreated ADHD is a significant risk factor for substance abuse in adolescence • Pharmacotherapy for ADHD may have protective effects

  22. Pharmacotherapy and Substance Abuse: Adolescents With ADHD Unmedicated Medicated 45 40 35 30 25 Rate of SA (%) 20 15 10 5 0 EtOH Ab/Dep Drug Ab/Dep Ab = alcohol or drug abuse; Dep = dependence; Wilens TE et al. (2002), Annu Rev Med 53:113-131

  23. Treatment Plan for ADHD/ODD • Optimize treatment of ADHD • Stimulants, atomoxetine, bupropion (Wellbutrin) • If good response of ADHD, add behavioral interventions • If behavior interventions fail, consider guanfacine, clonidine (Catapres) • Severe aggression, mood lability, consider mood stabilizers and SGAs

  24. Risperidone in Conduct Disorder:Study Design • 6-week, double-blind, placebo-controlled study • 110 children aged 5-12 with subaverage IQ (5-12 years) • 0.02-0.06 mg/kg/day (0.98 mg/kg/day) mean dose Snyder R et al. (2002), J Am Acad Child Adolesc Psychiatry 41(9):1026-1036

  25. Efficacy of Risperidone in Conduct Disorder: Change in Aggression Score Baseline Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk. 5 Wk. 6 0 -2 Placebo (N=57) -4 Risperidone (N=52) -6 Mean Reduction in Conduct Scores -8 -10 -12 -14 -16 -18 Snyder R et al. (2002), J Am Acad Child Adolesc Psychiatry 41(9):1026-1036

  26. Treatment Plan for ADHD/ODD • Serotonin reuptake inhibitors (e.g., fluoxetine [Prozac], paroxetine [Paxil]) not helpful for ADHD per se, rarely help ODD in absence of depression • Rational and irrational polypharmacy

  27. CMAP Algorithm for Pharmacologic Management of ADHD and Aggression Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657

  28. Tics and ADHD • Many children with tics and ADHD can tolerate stimulants without an increase in tics • Law and Schachar (1999): 12-month study, 91 children • MPH treatment did not produce significantly more tics than placebo in children with or without mild-to-moderate pre-existing tic disorder • Gadow et al. (1999): 24-month study, 34 children with ADHD and tic disorder or Tourette’s syndrome • Stimulant treatment was effective in controlling ADHD symptoms without adversely affecting tics • Lipkin et al. (1994), in a review of 122 children treated with stimulant medication found 9% developed transient tics and <1% developed chronic tics Law SF, Schachar RJ (1999), J Am Acad Child Adolesc Psychiatry 38(8):944-951; Gadow KD et al. (1999), Arch Gen Psychiatry 56(4):330-336; Lipkin PH et al. (1994), Arch Pediatr Adolesc Med 148(8):859-861

  29. Induction or Exacerbation of Tics • Tics are usually transient; only very rarely do patients develop a chronic tic disorder • When tics occur or increase • Decrease dose • Switch to another stimulant • Adjunct agent to treat tics • Try nonstimulant medication

  30. Controlled Trial of MPH and Clonidine Week 0 Week 4 Week 8 Week 12 Week 16 0 -2 -4 PLA Change in Y-GTSSTotal Score -6 MPH CLON -8 MPH + CLON -10 -12 -14 Y-GTSS = Yale Global Tic Severity Scale; Tourette Syndrome’s Study Group (2002), Neurology 58(4):527-536

  31. CMAP Algorithm for Pharmacologic Management of ADHD With Comorbid Tic Disorder Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657

  32. Depressive Disorders • Major depressive disorder • Dysthymia • Adjustment disorder with depressed mood • Chronic dysphoria of adolescence (Non-DSM) • Ethical aspects of diagnosis—do really help people by broadening or ignoring our diagnostic criteria?

  33. Children and Adolescents With MDD: Score on the CDRS-R Adjusted Mean CDRS-R Score Visit Week CDRS-R = Children’s Depression Rating Scale-Revised; Wagner KD et al. (2003), JAMA 290(8):1033-1041

  34. Important Issues • Only mildly depressed patients in trials • Suicidal patients/inpatients excluded • Drugs studied long after they have been on the market • Enrollment pressures

  35. Treatment of Adolescent Depression Study (TADS) • FLX + CBT: 71% response • FLX alone: 61% • CBT alone: 43% • Placebo: 35% • SI present in 29% at baseline, all groups improved significantly March J et al. (2004), JAMA 292(7):807-820

  36. TADS—Suicidal Ideation March J et al. (2004), JAMA 292(7):807-820

  37. TADS—Harm and Suicide Related Events No SSRI SSRI 12 10 8 Intent to Treat Cases 6 4 2 0 Harm Suicide Related March J et al. (2004), JAMA 292(7):807-820

  38. FDA Meta-Analysis • Pooled all studies, published and unpublished • Blinded reviewers at Columbia assessed each adverse event as to its self harm potential • N ~4,000 • No suicides • 4% SI on drug, 2% on placebo, statistically significant Hammad TA et al. (2006), Arch Gen Psychiatry 63(3):332-339

  39. Relationship of Suicide and SSRI Prescription Rate 1.8 1.6 1.4 1.2 Number of Suicides per 100,000 1.0 0.8 0.6 0.4 0.2 0 1 2 3 4 5 6 7 8 9 10 Higher SSRI Prescription Rate Gibbons RD et al. (2006), Am J Psychiatry 163(11):1898-1904

  40. Trends in Completed Suicide Since Boxed Warning Hamilton BE et al. (2007), Pediatrics 119(2):345-360

  41. Recent Meta Analysis • Reviewed 27 studies of MDD, OCD and anxiety disorders in children and adolescents • 15 MDD studies • 6 OCD studies • 6 anxiety studies • Included studies not in FDA review • Number of participants • MDD: 3,430 • OCD: 718 • Anxiety: 1,162 Bridge JA et al. (2007), JAMA 297(15):1683-1696

  42. Recent Meta Analysis (Cont.) Bridge JA et al. (2007), JAMA 297(15):1683-1696

  43. Clinical Guidelines • Based on FDA meta-analysis, we tell families there is a 2-4% of SI vs. 1-2% on placebo; TADS study shows 60-70% chance of improvement of MDD • Tell families to watch for and report increase in agitation or SI • Use alternative SSRI (sertraline, citalopram) if fluoxetine fails, NRI after that1 1CMAP: Hughes et al. (in press), J Am Acad Child Adolesc Psychiatry

  44. Algorithm for ADHD and depression

  45. Issues in Pediatric Bipolar Disorder • What is the prevalence of BD in childhood and adolescence? • How should diagnostic criteria differ from adults, if at all? • What is the role of the comorbidity of ADHD with pediatric BD? • Aggression and BD • Controversies in treatment

  46. Different Developmental Trajectories? Pediatric Euphoric BPs Mood State ? Adult Subtype Manic BP NOS? Euthymic ADHD Rx Adolescent Subtype BP II or I Depressed 0 2 4 6 8 10 12 14 16 18 20 22 Age/Years

  47. Mood Stabilizers • Classic mood stabilizers • Lithium, divalproex, carbamazepine—despite use in adults, limited studies in children • Negative studies • Gabapentin (Neurontin) • Tiagabine (Gabitril) • Oxcarbazepine (Trileptal) • Topiramate (Topamax) • Lamotrigine (Lamictal)—an emerging treatment

  48. Lithium vs. Placebo Efficacy for Acute Treatment of Adolescents With BD and Substance Dependency 60 UrineDrug Assays 40 % Positive 20 Lithium Placebo 0 3 4 5 6 65 Lithium Children’s Global Assessment Scale (CGAS)Scores Placebo 55 Mean CGAS Score 45 35 Baseline 1 2 3 4 5 6 Study Week Geller B et al. (1998), J Am Acad Child Adolesc Psychiatry 37(2):171-178

  49. Lithium, Divalproex Sodium and Carbamazepine in the Treatment of Bipolar Disorder: Study Design • 42 outpatient participants • Mean age = 11.4 ± 3.0 years • 6-8 week monotherapy period • Randomized to lithium, divalproex or carbamazepine • Assessed weekly for 6-8 weeks • Low dose chlorpromazine allowed as “rescue medication” Kowatch RA et al. (2000), J Am Acad Child Adolesc Psychiatry 39(6):713-720

  50. Lithium, Divalproex Sodium and Carbamazepine in the Treatment of BD: Response Rates and Effect Size Medication ITT Response Rate (%) Effect Size Valproate 46 1.63 Lithium 42 1.06 Carbamazepine 34 1.00 p=0.66; Kowatch RA et al. (2000), J Am Acad Child Adolesc Psychiatry 39(6):713-720

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