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Attention Deficit Hyperactivity Disorder (ADHD): Medication Treatment

Attention Deficit Hyperactivity Disorder (ADHD): Medication Treatment. Tim Wigal, Ph.D. Pediatrics University of California, Irvine. ADHD: Historical Timeline. Hyperkinetic Reaction of Childhood (DSM-II). Attention Deficit Hyperactivity Disorder (DSM-III-R). Minimal Brain Damage. 1930.

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Attention Deficit Hyperactivity Disorder (ADHD): Medication Treatment

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  1. Attention Deficit Hyperactivity Disorder (ADHD):Medication Treatment Tim Wigal, Ph.D. Pediatrics University of California, Irvine

  2. ADHD: Historical Timeline Hyperkinetic Reaction of Childhood (DSM-II) Attention Deficit Hyperactivity Disorder (DSM-III-R) Minimal Brain Damage 1930 1960 1968 1980 1987 1994 1902 Minimal Brain Dysfunction ADHD-like syndrome first described Attention Deficit Disorder + or - Hyperactivity (DSM-III) Attention Deficit/Hyperactivity Disorder (DSM-IV)

  3. Inattention Impulsivity/Hyperactivity ADHD: DSM-IV Subtypes • ADHD Predominantly Inattentive Type • Criteria met for inattention but not for impulsivity/hyperactivity • ADHD Predominantly Hyperactive-Impulsive Type • Criteria met for impulsivity/hyperactivity but not for inattention • ADHD Combined Type • Criteria are met for both inattention and impulsivity/hyperactivity Inattention Impulsivity/Hyperactivity

  4. Proper Steps in Diagnosis • Assessment • History • DSM-IV criteria • Interview — parents, teachers, and patient • Determine functional impairment in home and school/job settings • Rating scales to corroborate clinical diagnosis • Physical exam, vital signs, physical explanation for disorder, secondary conditions, drug contraindications • Make assessment for comorbid conditions AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S.

  5. Potential Areas of Impairment Academic limitations Children Relationships Occupational/ vocational Adults ADHD Low self esteem Legal difficulties Motor vehicle accidents Injuries Smoking and substance abuse Adolescents

  6. Worldwide Prevalence of ADHD Is 3% to 7% Studies of ADHD prevalence United States (Shaffer et al 1996) Tennessee (Wolraich et al 1996) Mannheim, Germany (Esser et al 1990) London, England (Esser et al 1990) Germany (Baumgaertel et al 1995) Iowa (Lindgren et al 1990) Pittsburgh, Pa (Costello et al 1988) US inner city (Newcorn et al 1989) Ontario (Szatmari et al 1989) New Zealand (Anderson et al 1997) 0 5 10 15 20 Incidence of ADHD (%) in school-age children Goldman, et al. JAMA.1998;279:1100-1107.

  7. ADHD: Etiology ADHD is a heterogeneous behavioral disorder with multiple possible etiologies Neuroanatomicalneurochemical Environmentalfactors ADHD CNSinsults Geneticorigins CNS = central nervous system

  8. Neuroimaging and ADHD Normal control ADHD 1 x 10-2 1 x 10-2 y = +21 mm y = +21 mm -3 -3 1 x 10 1 x 10 Frontal Striatal Insular network Anterior Cingulate Cortex • fMRI shows decreased blood flow to the anterior cingulate and increased flow in the frontal striatum • PET imaging shows decreased cerebral metabolism in brain areas controlling attention • SPECT imaging shows increased DAT protein binding MGH-NMR Center & Harvard-MIT CITP. Adapted from Bush, et al. Biol Psychiatry. 1999;45:1542-1552.

  9. 0 0.2 0.4 0.6 0.8 1 Twin Studies Show ADHD Is a Genetic Disorder Asthma Schizophrenia Height Breast cancer Hudziak, 2000 Nadder, 1998 Levy, 1997 Sherman, 1997 Silberg, 1996 Gjone, 1996 Thapar, 1995 Schmitz, 1995 Edelbrock, 1992 Gillis, 1992 Goodman, 1989 Willerman, 1973 Average genetic contribution of ADHD based on twin studies ADHD Mean Faraone. J Am Acad Child Adolesc Psychiatry. 2000;39:1455-1457. Hemminki. Mutat Res. 2001;25:11-21.Palmer. Eur Resp J. 2001;17:696-702.

  10. Molecular Genetics of ADHD • Specific genes associated with ADHD • Dopamine receptor D4 gene (DRD4) on chromosome 11 • Dopamine transporter gene (DAT1) on chromosome 5 • D2 dopamine receptor gene • Dopamine-beta-hydroxylase gene • Uncertain about the association ofnoradrenergic genes • There are several genes involved and their effects are cumulative Sunohara G, et al. J Am Acad Adolesc Psychiatry. 2000;39:1537-1592. Giros B, et al. Nature. 1996;379:606-612.

  11. Three Components of ADHD Treatment • Education • Psychosocial interventions • Pharmacotherapeutic interventions

  12. American Academy of Pediatrics: Guidelines for the Treatment of ADHD • Establish a treatment program that recognizes ADHD as a chronic condition • Specify appropriate target outcomes to guide management • Prescribe stimulant medication and/or behavior therapy to improve target outcomes in children with ADHD • If the treatment program has not met target outcomes, evaluate: • Original diagnosis • Use of all appropriate treatments • Adherence to the treatment plan • Presence of coexisting conditions • Using information from parents, teachers, and the child, follow-up to evaluate target outcomes and adverse effects AAP. Pediatrics. 2001;108:1033-1043.

  13. Prevalence, Diagnosis, and Treatment of ADHD in US Across All Ages 91.7% of diagnosed patients are treated with medication 9,000 7,660 8,000 7,000 6,000 5,000 Thousands 4,135 3,790 4,000 3,000 2,000 1,000 0 Prevalence Diagnosed Treated Sources: Prevalence - Equinox, Diagnosed & Treated - PDDA, Drug - NDC

  14. MTA Sites and Collaborators UC Irvine Duke U Swanson, Wigal Conners, Wells, March U Pittsburgh LIJ/Montreal CC Pelham, Hoza Abikoff, Hetchman Columbia U UC Berkeley Greenhill, Newcorn Hinshaw, Elliott NIMH/US Dept Education/Stanford Jensen, Severe, Arnold, Richters, Vitiello, Vereen/Shiller/Kraemer

  15. Summary of the MTA Design • 4 randomly assigned groups • Med management (MedMgt, n=144) • Behavior modification (Beh, n=144) • Combined multimodal (Comb, n=145) • Routine community care (CC, n=146) • First 3 groups treated 14 months • All assessed at baseline, 3, 9, and 14 months

  16. Combination Therapy Is More Effective in the MTA • All treatment arms improved symptoms on an absolute basis • Medication management with behavior management for ADHD symptoms showed the most improvement • Behavior management was slightly superior to community-based treatment (2/3 Medication) MTA Cooperative Group. Arch Gen Psych. 1999;56:1073-1086.

  17. Questions about the MTA from a Clinician • “What is the chance of clinical success rate if I adopt the MTA behavioral algorithm?” • about 34% will show “loss of symptoms” • “What is the chance of clinical success rate if I adopt the MTA medication algorithm?” • about 56% will show “loss of symptoms” • “What additional benefits are expected if I also recommend intensive psychosocial treatment? • an increase of about 12%, from 56% to 68%

  18. Education of Patients and Family • Understanding the disorder • Medical cause • Not due to poor parenting • Environmental restructuring • Classroom changes • ADHD-friendly modifications in family, work, leisure activities • Structure, lists, delegating • Parent support groups: for example, www.chadd.org, www.add.org AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S.

  19. Psychosocial Interventions in ADHD Treatment • Parent education • Use naturally occurring consequences to teach social skills • Reinforce positive behaviors and correct negative behaviors • Establish and maintain house rules • Social skills training • Target specific behaviors, ie, playground aggression • More effective in groups and natural environments like school or camp • Stress conflict-resolution • Academic skills training • Individual or group training • Focus on following directions, time management, and study skills AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S.

  20. Classes of Medication Used to Treat ADHD • FDA-approved • Stimulants (methylphenidate, amphetamine) • Off-label • Antidepressants (tricyclics, bupropion) • -adrenergic agonists (clonidine) AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36(suppl):85S-121S.

  21. Probable Mechanism of Action of Methylphenidate Presynaptic Neuron v v Storage vesicle Cytoplasmic DA DA Transporter Methylphenidate Synapse Wilens T, Spencer TJ. Handbook of Substance Abuse: Neurobehavioral Pharmacology. 1998;501-513.

  22. In ADHD: Stimulants Found to Improve • Other Symptoms • Noncompliance • Impulsive aggression • Social interactions • Academic efficiency • Academic accuracy • Family dynamics • Core Symptoms • Inattention • Impulsivity • Hyperactivity ADHD Practice Parameters. J Am Acad Child Adolesc Psychiatry. 1997;36:85S. Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry. 1999;38:503-512.

  23. Stimulants: Potential Side Effects • Mild increase in pulse, blood pressure • Psychiatric effects, irritability, dysphoria, and rebound • Appetite loss,abdominal pain • Insomnia • Nervousness (Effects occurring in >5% of patients and >placebo) Controversies: growth deficits, tic exacerbation, seizures, abuse AACAP Clinical Practice Guidelines. J Am Acad Child Adolesc Psychiatry. 1997;36(suppl):85S-121S.

  24. New Formulations for ADHD • Methylphenidate • Amphetamine

  25. History of Stimulant Formulations • 1937 – IR d, l-amphetamine • 1940 – IR d-amphetamine • 1950 – IR methylphenidate • 1970 – IR pemoline • 1980 – SR methylphenidate • 2000 – New formulations

  26. FIRST LINE TREATMENTS: STIMULANTS AMPHETAMINE Adderall XR Shire Pharmaceuticals 10 hr 10-30mg (X1) Desoxyn Ovation Pharmaceuticals 4 -5 hr 10-25 mg (X2) Dexedrine Spansule Glaxo-Smith-Kline 7 hr 5-15 mg (X2) Dexedrine Glaxo-Smith –Kline 5 hr 5-14mg (X3) Vyvanse Shire 10-12 hr 30, 50, 70 mg (X1)

  27. METHYLPHENIDATE Concerta McNeil Pharmaceuticals 9-10 hr 18-72mg (X1) Metadate CD UCB Pharmaceuticals 8 hr 20-60 mg (X1) Ritalin LA Novartis 7-8 hr 10 – 60 mg (X1) Methylin ER Mallinckrodt 6 hr 20-30 mg (X2) Focalin Novarits 4 hr 2.5 – 15 mg (X3) FocalinXR Novarits 8 hr 5, 10, 15 & 20mg (X1) Ritalin Novartis 4 hr 5-30 mg (X3) Daytrana Shire Methylphenidate patch 12 hr (Patches are 10, 15, 20 and 30 mg)

  28. SECOND LINE TREATMENTS: ANTI- DEPRESSANTS Strattera Eli Lilly 8-10 hr 10-60 mg (X2) (Wellbutrin SR Glaxo-Smith-Kline 6-8 hr 100-150 mg (X2) Tricyclics: Pamelor, Norpramin &Tofranil (Imipramine) All by Novarits 4-6 hr 10-30mg (X3)

  29. SECOND LINE TREATMENTS: OLDER MEDICATIONS Cylert – made by Abbott – discontinued due to liver toxicity; stimulant-like drug Clonidine - Less used due to concerns about side effects (sedation) and sudden death when used in conjunction with stimulant therapy; beta blocker drug (antihypertensive). MEDICATIONS STILL UNDER DEVELOPMENT Provigil Cephalon Modafinil (Anti-narcoleptic) –not FDA approved Guanfacine ER Shire Anti-hypertensive – Approvable letter issued

  30. Laboratory School Staff

  31. MPH Overcoat The Final Formulation of OROS®-MPH for Concerta™ Laser-Drilled Hole MPH Compartment #1 MPH Compartment#2 Tablet Shell Push Compartment

  32. FOCALIN: Dexmethylphenidate

  33. H H H H H H N N 2’ 2’ 2’ CH3OOC CH3OOC 2 2 Ph Ph CHOOC3 2 Ph H H H Dexmethylphenidate D-methylphenidate N D (+) Methylphenidate (2R, 2’R) l (-) Methylphenidate (2S, 2’S)

  34. 5mg 2.5mg 10mg DEXMETHYLPHENIDATE DOSE METHYLPHENIDATE DOSE 5 mg 2.5 mg 10 mg 5 mg 20 mg 10 mg FOCALIN Dosing • Recommended conversion doses Data on file

  35. Ritalin® LA—Bimodal Release for Once-daily Dosing

  36. Bead Core Bead Core Drug Layer Drug Layer Overcoating Release-Delaying Polymer Overcoating 50% 50% Overcoating ADDERALL XR™ Pulse Delivery System Delayed-Release Bead Immediate-Release Bead ADDERALL XR™ Capsule Available in 10 mg , 20 mg, and 30 mg capsules

  37. 3 2.5 2 1.5 1 0.5 0 1.5 3 4.5 6 7.5 9 10.5 12 Placebo ADDERALL XR 30 mg ADDERALL XR 10 mg ADDERALL XR 20 mg Analog Classroom Study: Mean SKAMP Deportment scores More symptoms Fewer symptoms Time post dose (hr)

  38. Summary • MPH formulations are the “gold standard” of stimulant medications used to treat ADHD • Both MPH and Amphetamine preparations help • Dose Dependent results are typical • Coverage throughout the day depends on the formulation, the needs of each child and individual brain chemistry

  39. MEDICATION TREATMENT Adverse Events in PATS

  40. Summary of Vital Signs and Adverse Events Relating to Hypertension and Tachycardia Dosage during titration at time of the Hypertension/ Tachycardia AEs 7.5mg TID- 2 Hypertension 1 Tachycardia AE 5mg TID- 2 Hypertension AEs 2.5mg TID- 3 Hypertension AEs 1.25mg TID- 1 Hypertension AE Placebo- 0 AEs (Mild tachyardia is 2 measurements of HR at 120-130 for ages 3-5.) (Mild hypertension is a systolic or diastolic reading above the 95th percentile based on age: 3 is 110/072, 4 is 112/72, 5 is 114/73, and 6 is 115/74) * No statistically significant differences were found.

  41. Side effects in PATS with statistically significant linear decreases Crabby, Irritable 0.5 Prone to Crying Tearful, Sad, Depressed 0.45 Listless 0.4 Side Effect Frequency 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0 1 2 3 4 5 6 7 8 9 10 (14.17) (15.86) (16.54) (17.07) (17.85) (18.16) (18.77) (18.88) (19.54) (20.51) Monthly visit and mean daily dose (in mg)

  42. 0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 Appetite Loss Picking at Skin 0.1 Trouble Sleeping Worried/ Anxious 0.05 0 1 2 3 4 5 6 7 8 9 10 (14.17) (15.86) (16.54) (17.07) (17.85) (18.16) (18.77) (18.88) (19.54) (20.51) Common side effects with no significant decrease Side Effect Frequency Monthly visit and mean daily dose (in mg)

  43. 0.5 Stomach ache 0.35 Social Withdrawal 0.45 Motor Tics 0.3 BLM 0.4 Headache 0.25 0.2 0.15 0.1 0.05 0 1 2 3 4 5 6 7 8 9 10 (19.54) (17.85) (14.17) (15.86) (16.54) (17.07) (18.88) (20.51) (18.16) (18.77) Rare side effects Side Effect Frequency Monthly visit and mean daily dose (in mg)

  44. Standardization of Weight and HeightBased on CDC 2000 National Norms Mean values at BaselineMonth 12-14 percentile z-score 175 170 165 160 155 150 145 140 135 130 125 120 70 65 60 55 50 45 40 35 30 25 20 15 95th 1.65 90th 1.28 75th 0.67 50th 0.0 25th -0.67 10th -1.28 Weight (kg) Height (kg) 5th -1.65 Age in Months Age in Months Age (yrs) Age (yrs) Population standard deviations for 7 to 12 year old children = 6.5 cm for height and 5.5 kg for weight

  45. A z-score is expressed in population SD units.  For normal growth rates, z-scores are not expected to change over time.  • At Baseline, the average z-scores for the PATS sample were positive (z-wt = +0.71 and z-ht = +0.44).  • CDC preschool norms for SD (2.75 kg and 4.8 cm) can be used to transform the z-score back to absolute values (kg and cm). • At Baseline, compared to CDC norms the PATS sample was: • 0.71 x 2.75 kg = 1.95 kg heavier than expected • 0.44 x 4.8 cm = 2.11 cm taller than expected

  46. Z-Scores and Percentiles for PATS and MTA z-score percentile 5 yr norms 8 yr norms (cm) (cm) -1.88 3rd -1.65 5th -1.28 10th -0.67 25th 0.00 50th +0.18 62nd 131.1 (MTA) +0.47 70th 110.5 (PATS) +0.67 75th +1.04 85th +1.28 90th +1.65 95th +1.88 97th

  47. Mean Height and Weight at Phases of the PATS(z-scores and percentiles)

  48. Question & Answer Session

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