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          Attention-Deficit Hyperactivity                                                            The material presented at this activity is being made available by the American Academy of Family Physicians for
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                                                                                                     procedure appropriate for the medical situations discussed but, rather, is intended to present an approach, view,

         Disorder – Child: Assessment,                                                               statement or opinion of the faculty that may be helpful to others who face similar situations.

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                                                                                                     FACULTY DISCLOSURE


                          Mary N. Cook, MD                                                           The AAFP has selected all faculty appearing in this program. It is the policy of the AAFP that all CME planning
                                                                                                     committees, faculty, authors, editors, and staff disclose relationships with commercial entities upon nomination or
                                                                                                     invitation of participation. Disclosure documents are reviewed for potential conflicts of interest and, if identified,
                                                                                                     they are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or
                                                                                                     who agreed to an identified resolution process prior to their participation were involved in this CME activity.

           CME #214 Friday, 10:30-11:30 a.m. Location: Korbel Ballroom 1D                            Mary N. Cook, M.D., returned a disclosure indicating that he has no affiliation or financial interest in any
                                                                                                     organization(s).

            CME #215 Friday, 3:00-4:00 p.m. Location: Korbel Ballroom 1D




                      Learning Objectives/                                                                  Epidemiologic Studies
                       Search References
•       Analyze the prevalence of ADHD among children in your practice.                             • ADHD rates among school-aged youth
•       Utilize DSM-IV criteria to assess or diagnose ADHD in symptomatic
        patients.                                                                                     range from 5%-8%
•       Counsel parents and/or patients on successful management of ADHD.
•       Prepare or modify pharmacologic treatment modifications based on evolving                   • Boys diagnosed 2.5x more often than girls
        evidence and recommendations.
                                                                                                    • 9.2% of males and 2.9% of females
    •       Attention Deficit Hyperactivity Disorder. National Institute of Mental Health (NIMH),
                                                                                                    • School-aged children more likely
            National Institutes of Health (NIH). NIH Publication No. 08-3572. June 2009.              diagnosed than preschoolers or teens
    •       Attention-Deficit/Hyperactivity Disorder. CDC National Center for Birth Defects and      Polanczyk G, Jensen P. Epidemiologic considerations in attention deficit hyperactivity
            Developmental Disabilities (NCBDDD), Division of Human Development and                   disorder: a review and update. Child Adolesc Psychiatr Clin N Am. 2008;17(2):245-
            Disabilities. March 2009.                                                                260, vii.
    •       Symptoms and Diagnostic Criteria. National Resource Center on ADHD.




            Epidemiologic Studies                                                                           Epidemiologic Studies
• 50% of children who receive the diagnosis                                                         • ADHD is considered a lifelong condition
  are treated with medication                                                                       • 60-80% of adolescents with ADHD, first
• ADHD often unrecognized or untreated                                                                diagnosed as children, meet criteria into
         – Of 3082 patients, 52.1% of children who met                                                adulthood
           criteria for ADHD had been undiagnosed                                                   • Among preschoolers diagnosed with
         – 68% of them had not received drugs for                                                     ADHD,
           treatment of ADHD for the majority of the
           previous year                                                                              < 50% continue into childhood
        Centers for Disease Control and Prevention (CDC). Mental health in the United
                                                                                                      Polanczyk G, Jensen P Epidemiologic considerations in attention deficit hyperactivity
        States. Prevalence of diagnosis and medication treatment for attention-
                                                                                                      disorder:a review and update. Child Adolesc Psychiatric Clin N Am 2008;17:245–260
        deficit/hyperactivity disorder – United States, 2003. MMWR Morb Mortal Wkly Rep.
        2005;54(34):842-847.
        DSM-IV Diagnostic Criteria                                                                                              DSM-IV Diagnostic Criteria
Diagnostic Criteria for Attention-Deficit/Hyperactivity Disorder (A, B, C, D, E)                                   Diagnostic Criteria for Attention-Deficit/Hyperactivity Disorder
A. Either 1 or 2                                                                                                   A. Either 1 or 2
1. 6 or more of the following symptoms of inattention have persisted for at least 6                                2. 6 or more of the following symptoms of hyperactivity-impulsivity have persisted
    months to a degree that is maladaptive & inconsistent with developmental                                           for at least 6 months to a degree that is maladaptive & inconsistent with
    level:                                                                                                             developmental level:
• Inattention                                                                                                      • Hyperactivity
    –   1. Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or             –   1. Often fidgets with hands or feet or squirms in seat
        other activities                                                                                                 –   2. Often leaves seat in classroom or in other situations in which remaining seated is expected
    –   2. Often has difficulty sustaining attention in tasks or play activities                                         –   3. Often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or
    –   3. Often does not seem to listen when spoken to directly                                                             adults, may be limited to subjective feelings of restlessness)
    –   4. Often does not follow through on instructions and fails to finish school work, chores, or duties in           –   4. Often has difficulty quietly playing or engaging in leisure activities
        the workplace (not due to oppositional behavior or failure to understand instructions)                           –   5. Often is “on the go” or acts as if “driven by a motor”
    –   5. Often has difficulty organizing tasks and activities                                                          –   6. Often talks excessively
    –   6. Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such
        as schoolwork or homework)
                                                                                                                   •    Impulsivity
    –   7. Often loses things necessary for tasks or activities (eg, toys, school assignments, pencils, books,           –   7. Often blurts out answers before the questions have been completed
        tools)                                                                                                           –   8. Often has difficulty awaiting turn
    –   8. Often is easily distracted by extraneous stimuli                                                              –   9. Often interrupts or intrudes on others (eg, butts into conversations or games)
    –   9. Often is forgetful in daily activities
        Reprinted from American Psychiatric Association. Diagnostic and Statistical Manual of                                Reprinted from American Psychiatric Association. Diagnostic and Statistical Manual of
        Mental Disorders: DSM-IV-TR. 4th ed, text revision. Washington, DC: American Psychiatric                             Mental Disorders: DSM-IV-TR. 4th ed, text revision. Washington, DC: American Psychiatric
        Association; 2000:83-85.                                                                                             Association; 2000:83-85.




        DSM-IV Diagnostic Criteria
                                                                                                                                      Assessment ADHD
Diagnostic Criteria for Attention-Deficit/Hyperactivity Disorder
                                                                                                                       • Look for comorbidity or “masqueraders”
B. Some hyperactive-impulsive symptoms or inattentive symptoms that caused
    impairment were present before 7 years of age
                                                                                                                             – Environmental
C. Some impairment from the symptoms is present in 2 or more settings (eg, at
    school or at home)
                                                                                                                             – Psychiatric
D. There must be clear evidence of clinically significant impairment in social,
    academic, or occupational functioning
                                                                                                                             – Developmental
E. The symptoms do not occur exclusively during the course of a pervasive
    developmental disorder, schizophrenia, or other psychotic disorder and are not
                                                                                                                       • 67% youth with ADHD have comorbid psych
    better accounted for by another mental disorder (eg, mood disorder, anxiety                                              – Oppositional defiant (35%), conduct disorder (30%),
    disorder, dissociative disorder, or personality disorder)
                                                                                                                               anxiety (25%), mood (18%)
        Reprinted from American Psychiatric Association. Diagnostic and Statistical Manual of
        Mental Disorders: DSM-IV-TR. 4th ed, text revision. Washington, DC: American Psychiatric                       • 12%-60% have learning disorder
        Association; 2000:83-85.                                                                                               Floet AM, Scheiner C, Grossman L. Attention-deficit/hyperactivity disorder.
                                                                                                                               Pediatr Rev. 2010;31(2):56-69 [Review].




               Assessment ADHD                                                                                                      Rationale Focus of Rx
• Standardized diagnostic scales
    –   Conners (2-18, $)
                                                                                                                       • MTA study findings
    –   SNAP (5-11, no teacher, limited norm data)                                                                     • Genetic study findings
    –   ADHD-RS (5-18, ADHD only)                                                                                      • Neurobiological study findings
    –   Vanderbilt (Teachers, Parents, comorbidity,
        impairment, free, AAP “Tool Kit”)
• Multiple Sources (Parents, teachers, day)
• Letter templateÆrequest “educational
  assessment,” “consideration” special ed
        Floet AM, Scheiner C, Grossman L. Attention-deficit/hyperactivity disorder.
        Pediatr Rev. 2010;31(2):56-69 [Review].
                                                   MTA Study                                                                                   Genetic Factors
                                             Hyperactive Impulsive Symptoms
                                                    (Teacher Reports)
                              70
                              65                          60%
                                                                                                                              • D4 receptor & DAT1 consistently replicated
                              60          56%                                                                                    – Individually, each make weak contribution
                                                                                                                                 – 1.1% of variance inattentive, 3.6% in hyperactivity
                      o th




                              55
       p vem t at 14 M n




                              50                                                45%
                                                                                                                                 – Neither is necessary or sufficient for ADHD
                              45
                              40                                                                 36%
                                                                                                                                   Brookes K, Xu X, Chen W, et al. The analysis of 51 genes in DSM-IV combined
            en




                              35                                                                                                   type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and
                              30                                                                                                   16 other genes. Mol Psychiatry. 2006;11(10):934-953. Erratum in Mol Psychiatry.
                              25                                                                                                   2006;11(12):1139.
     Im ro




                              20
                              15                                                                                              • Twin studies Æ heritability estimates of
                              10
                               5
                                                                                                                                approximately 0.8 (range 0.6-0.9)
                               0                                                                                                 – Height 0.9, schizophrenia 0.7
                                    Medication     Com bination        Behavioral            m
                                                                                         Com unity-
                                   Managem  ent      Therapy           Treatment            based                                  Kieling C, Goncalves RR, Tannock R, et al. Neurobiology of attention deficit
                                                                                          Treatment                                hyperactivity disorder. Child Adolesc Psychiatry Clin N Am. 2008;17(2):285-307,
                                                                                                                                   viii.
Information from A 14-month randomized clinical trial of treatment
strategies for attention-deficit/hyperactivity disorder. The MTA
Cooperative Group. Multimodal Treatment Study of Children with
ADHD. Arch Gen Psychiatry 1999;56(12):1073-1086.




                                          Perinatal Risk Factors                                                                Environment/Gene Interactions
                                                                                                                               • Children exposed to nicotine AND homozygous
                                                                                                                                 for DAT1 10-repeat allele were at increased risk
                                                                                                                                 for ADHD (neither factor alone was associated
                                                                                                                                 significantly)
                                                                                                                                   Kahn RS, Khoury J, Nichols WC, et al. Role of dopamine transporter genotype
                                                                                                                                   and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive,
                                                                                                                                   and oppositional behaviors. J Pediatr. 2003;143(1):104-110.
                                                                                                                               • Prenatal alcohol exposure AND the DAT1 gene
                                                                                                                                 linked to an increased risk for ADHD
                                                                                                                                  Brookes KJ, Mill J, Guindalini C, et al. A common haplotype of the dopamine
                                                                                                                                  transporter gene associated with attention-deficit/hyperactivity disorder and
                                                                                                                                  interacting with maternal use of alcohol during pregnancy. Arch Gen Psychiatry.
                                                                                                                                  2006;63(1):74-81.


Reprinted from Spencer TJ. Neurobiology and
genetics of ADHD in adults. CNS Spectr. 2008;13(9
Suppl 13):5-7.




                                Neuroimaging and ADHD
                                                                                                                                       Neuroimaging and ADHD
                                                                                                                               • Reduction in total brain size that persists into
                             Normal control                                                  ADHD                                adolescence and young adulthood
                                                                            -                                             -
                             y = +21 mm                           1 x 10        y = +21 mm                      1 x 10
                                                                  2                                             2

                                                                                                                               • Reduced dimensions of caudate, prefrontal cortex
                                                                                                                                 white matter, corpus callosum and the cerebellar
                                                                                                                                 vermis
                                                                  1 x 10-                                       1 x 10-              Kieling C, Goncalves RR, Tannock R, et al. Neurobiology of attention deficit
                                                                  3                                             3

                                     Anterior Cingulate                                      Frontal Striatal                        hyperactivity disorder. Child Adolesc Psychiatry Clin N Am. 2008;17(2):285-307,
                                                                                             Insular network                         viii.
                                           Cortex

                                                                                                                               • A recent meta-analysis confirms these findings
        • fMRI shows decreased blood flow to the anterior cingulate and
          increased flow in the frontal striatum                                                                                     Valera EM, Faraone SV, Murray KE, et al. Meta-analysis of structural imaging
                                                                                                                                     findings in attention-deficit/hyperactivity disorder. Biol Psychiatry.
    MGH-NMR Center & Harvard-MIT CITP.                                                                                               2007;61(12):1361-1369.
    Reprinted from Bush G, Frazier JA, Rauch SL, et al. Anterior cingulate cortex
    dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the
    Counting Stroop. Biol Psychiatry. 1999;45(12):1542-1552.
                   Neuroimaging and ADHD                                                                      Pharmacologic Treatment

                                                                                                         StimulantsÅ-------------------First-line
                                                                                                         AtomoxetineÅ----------------Second-line
                                                                                                         AntihypertensivesÅ---------Third-line
                                                                                                         AntidepressantsÅ------------Fourth-line
                                                                                                         MiscellaneousÅ---------------Alternative
                                                                                                             Modafinil, venlafaxine, MAOIs, combined,
                                                                                                             donepezil
                                                                                                             Faraone SV. Using meta-analysis to compare the efficacy of medications for
                                                                                                             attention-deficit/hyperactivity disorder in youths. P T. 2010;34(12):678-694.
Reprinted from Adler LA. Best practices in adult ADHD.
Neurobiology, pharmacology, and emerging treatment.
CNS Spectr. 2008;13:9(Suppl 13):4.
                                                                                                   19




             Relative Effect Sizes                                                                                Relative Effect Sizes
         – ATX: 0.63
         – BUPR: 0.22                                                                                         – LA stimulants:
                                                                                                                   • d-AMP ER: 1.13
         – CLN: 0.03
                                                                                                                   • LDX: 1.52
         – GXR: 0.8                                                                                                • MAS XR: .77
         – IR stimulants:                                                                                          • OROS MPH: .9
              • MAS: 1.34                                                                                          • MPH ER/SR: .85
              • d-AMP: 1.24                                                                                        • MPH LA: .96
              • IR MPH: 0.92
                                                                                                                 Faraone SV. Using meta-analysis to compare the efficacy of medications for
              • IR d-MPH: 0.76                                                                                   attention-deficit/hyperactivity disorder in youths. P T. 2010;34(12):678-694.
            Faraone SV. Using meta-analysis to compare the efficacy of medications for
            attention-deficit/hyperactivity disorder in youths. P T. 2010;34(12):678-694.




                                Stimulants                                                                                           Stimulants
 • Stimulants discovered 1937                                                                            • Average effect sizes:
 • 1000+ controlled trials, primarily ST +                                                                    – 3-5 yo: 0.5-0.6
   school-aged + efficacy                                                                                     – 6-12 yo: 0.8-1.2
         Merkel RL Jr, Kuchibhatla A. Safety of stimulant treatment in attention deficit                      – 13-17 yo: 0.94
         hyperactivity disorder: Part I. Expert Opin Drug Saf. 2009;8(6):655-668.
                                                                                                              – Adults: 0.9
 • MPH approved for ADHD by FDA in 1955
                                                                                                         • 70%-80% response rate in 6-12 yo
 • MPH and AMP available in 19 formulations                                                                      Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central
                                                                                                                 nervous system stimulant formulations in children and adolescents
         Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system                             with attention-deficit/hyperactivity disorder. Ann Pharmacother.
         stimulant formulations in children and adolescents with attention-deficit/hyperactivity                 2009;43(6):1084-1095.
         disorder. Ann Pharmacother. 2009;43(6):1084-1095.                                                       Faraone SV. Using meta-analysis to compare the efficacy of
                                                                                                                 medications for attention-deficit/hyperactivity disorder in youths. P
                                                                                                                 T. 2010;34(12):678-694.
                                                                                                        24
                                                                                                                         Mechanisms of Action
                                                     Stimulants
                                                                                                             •   MPH: blocks reuptake NE & DA (indirect)
 An NIMH report reviewing long-term effects of
                                                                                                             •   AMP: binds with DA transporter (direct)
 stimulants in children with ADHD found the
 “general effectiveness and safety of these                                                                  •   ATX: inhibits reuptake NE (indirect)
 medications over the short and intermediate                                                                 •   BUPR: inhibits reuptake NE & DA
 term has been well documented…stimulants                                                                    •   GUAN & CLN: stimulant alpha-2 NE
 can be considered among the most effective                                                                      autoreceptors, thereby dec release NE (indirect)
 and well-tolerated drugs in pediatric                                                                               Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
 psychopharmacology.”                                                                                                stimulant formulations in children and adolescents with attention-
                                                                                                                     deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.
 Vitiello B. Long-term effects of stimulant medications on the brain: possible relevance to
 the treatment of attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol
 2001;11(1):25-34 [Review].




                                  Stimulant Comparison
     Information from Spencer T, Biederman J, Wilens T, et al. Efficacy of mixed
     amphetamine salts compound in adults with attention-deficit/hyperactivity disorder. Arch
                                                                                                                       Methylphenidate (MPH)
     Gen Psychiatr. 2001;58(8):775-782.


                          50
                                                                                                             • MPH approved by FDA for ADHD in 1955
                                   6 studies                                     52%
                                   N=274                                                                     • All MPH formulations, except patch are
Best Response (percent)




                          40                                                                                   approved for > 6 years of age
                          30                                                                                 • MPH patch and dexMPH approved for use
                                       25%                                                                     in 6-12 yo
                                                           23%
                          20
                                                                                                                     Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
                          10                                                                                         stimulant formulations in children and adolescents with attention-
                                                                                                                     deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.

                          0      Dextroamphetamine   Methylphenidate   Equal response to either
                                                                              Stimulant




                                          IR Methylphenidate                                                 First-Generation MPH Preps
              • ADVANTAGES
                          – 3 forms-tabs, chewable tabs, oral solution
                          – The IR tabs can be crushed, given in applesauce                                  • Overcoming “tachyphylaxis”
                          – Chewable tabs & liquid appeals to patients who
                            cannot swallow tabs or caps
                                                                                                             • Methylphenidate ER
                          – Fine tune dosing, tighter control and precision
                                                                                                             • Methylphenidate SR
              • DISADVANTAGES
                          – Inconvenient, multiple daily doses                                                   Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
                                                                                                                 stimulant formulations in children and adolescents with attention-deficit/hyperactivity
                          – Greater potential diversion                                                          disorder. Ann Pharmacother. 2009;43(6):1084-1095.
                               Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
                               stimulant formulations in children and adolescents with attention-
                               deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.
                                                                                                 Long-Acting MPH Caps
       Second-Generation MPH
                                                                                            • Methylphenidate LA
• Osmotic-release oral system                                                                   Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
                                                                                                stimulant formulations in children and adolescents with attention-deficit/hyperactivity

  (OROS) MPH                                                                                    disorder. Ann Pharmacother. 2009;43(6):1084-1095.




  Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
  stimulant formulations in children and adolescents with attention-deficit/hyperactivity
  disorder. Ann Pharmacother. 2009;43(6):1084-1095.




  Methylphenidate ER Caps                                                                   MPH Transdermal System
                                                                                            •   Newest
                                                                                            •   Patch
 • Methylphenidate CD                                                                       •   Approved 6-12 yo
                                                                                            •   10 mg (= 15 mg IR), 15 mg (= 22.5 mg IR),
       Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
       stimulant formulations in children and adolescents with attention-
                                                                                                20 mg (= 30 mg IR), 30 mg (= 45 mg IR)
       deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.
                                                                                                    Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
                                                                                                    stimulant formulations in children and adolescents with attention-
                                                                                                    deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.




 MPH Transdermal System                                                                            Dexmethylphenidate
• Minimal skin irritation at application                                                    • IR and XR
• Apply hip, below underwear, rotate                                                        • Isolated d-enantiomer of racemic d, l-MPH
• Placement on other parts of body (arm, leg)                                               • L-MPH probably doesn’t contribute
  leads to more absorption variability                                                      • Using only d-enantiomer allows doses to
• Optimal abspn deps hygiene, skin integrity                                                  be halved but still be equally effective,
• A child could remove the patch                                                              claim increase tolerability
                                                                                            • Expensive, ? advantage
 Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system                        Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
 stimulant formulations in children and adolescents with attention-                                 stimulant formulations in children and adolescents with attention-
 deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.                            deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.
                                                                                                               Amphetamines
                                                                                             •   Mixed amphetamine Salts, IR and ER
                                                                                             •   IR-MAS indicated ADHD in children > 3 yo
                                                                                             •   Tablets can be crushed
                                                                                             •   At higher doses, MAS stimulate the rel DA
                                                                                                 – Reinforcing properties
                                                                                                 – Increased potential psychosis
                                                                                                 – Possible exacerbation tics
                                                                                                    Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
                                                                                                    stimulant formulations in children and adolescents with attention-
                                                                                                    deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.

Reprinted from Markowitz J, Straughn AB, Patrick, KS. Advances in the
pharmacotherapy of attention-deficit-hyperactivity disorder: focus on
methylphenidate formulations. Pharmacotherapy. 2003;23(10):1281-
1299 [Review].




                       Amphetamines                                                                             Amphetamines
                                                                                             •   MAS ER comparable MAS IR bid
  • Higher doses MAS                                                                         •   2-pulsed, micro-bead delivery system
       – Decreased fatigue, increased motor, mental                                          •   50:50 ratio of IR and ER beads (0 hr, 4 hr)
         alertness, mild euphoria
                                                                                             •   Duration 10-12 hr
       – In PNS, direct stimulant action on a- and b-NE
                                                                                             •   Max conc is 7 hr (4 hr longer IR)
         Rs, inc BP, RR, weak bronchodilation
                                                                                             •   Starting dose 10 mg, kids > 6
       – HR decreases in reflex response in BP
                                                                                             •   Max dose FDA recommends 30 mg/day
           Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system              Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
           stimulant formulations in children and adolescents with attention-                       stimulant formulations in children and adolescents with attention-
           deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.                  deficit/hyperactivity disorder. Ann Pharmacother. 2009;43(6):1084-1095.




             Dextroamphetamine                                                                             Lisdexamfetamine
                                                                                         •   Pharmacologically inactive
  • DextroAMP sulfate IR & SR spansules                                                  •   Prodrug = l-lysine + dextroAMP
  • Approved for the treatment of ADHD in                                                •   After ingestion, hydrolysis to rel dextroAMP
    1997                                                                                 •   Dec risk toxicity, abuse, diversion
  • 2 randomized trials MPH v. sextroAMP                                                 •   Approved ADHD children aged 6-12 yo
  • Comparable efficacy                                                                  •   Dose equivalents:
  • AEs > DextroAMP v. MPH (p < 0.01)                                                              • 30 mg=10 mg mixed AMP,
  • Insomnia, irritability, proneness to crying,                                                   • 50 mg=20 mg mixed AMP,
                                                                                                   • 70 mg=30 mg AMP
    sadness/unhappiness, and nightmares                                                      Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system stimulant
      Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on                                   formulations in children and adolescents with attention-deficit/hyperactivity disorder. Ann
      central nervous system stimulant formulations in children                              Pharmacother. 2009;43(6):1084-1095.
      and adolescents with attention-deficit/hyperactivity
      disorder. Ann Pharmacother. 2009;43(6):1084-1095.
                Lisdexamfetamine                                                                                  Lisdexamfetamine
•   Lisdex comparable efficacy MAS XR
•   Longer duration lisdex compared MAS XR                                                       • Time to max conc 3.7 hr Æ dec potential
•   Lisdex > efficacy at 1800 (p < 0.01)                                                           abuse
•   Tolerability similar other AMP products                                                      • DextroAMP 40 mg scored much higher on
     – Insomnia, decreased appetite, irritability,                                                 the Drug Rating Questionnaire-Subject Liking
       dizziness, headache, and weight loss                                                        Scale than lisdex 50 or 100 mg
• ½-life 10 hr Æ once-daily dosing, efficacy                                                     • Evidence reduction in abuse potential
  persisting into the early pm
                                                                                                  Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system stimulant
      Chavez B, Sopko MA Jr, Ehret MJ, et al. An update on central nervous system
                                                                                                  formulations in children and adolescents with attention-deficit/hyperactivity disorder. Ann
      stimulant formulations in children and adolescents with attention-deficit/hyperactivity
                                                                                                  Pharmacother. 2009;43(6):1084-1095.
      disorder. Ann Pharmacother. 2009;43(6):1084-1095.




                                                                                                    Stimulants in Preschoolers
                 AEs Newer MPH/AMP
                                                                                                 • PATS Study by NIMH (2006-present)
    • High rate AEs most studies, but several                                                    • Response rates/effect sizes lower (50%-
      with no statistical difference with placebo                                                  60% v. 70%-80%, 0.4-0.6 v. 0.9-1.3), less
    • Discontinuation rates 0%-10%                                                                 well tolerated
    • 8 studies discontinuation below 6%                                                         • More preschoolers d/c bec Aes (11% v.
    • Stat sig AEs: anorexia, nervousness, dry                                                     1% in MTA)
      mucosa, anxiety, jitteriness, insomnia,                                                    • Common: emotional outbursts, insomnia,
                                                                                                   dec appetite, tired, dull, listless, social
      stomach pain (dose related)                                                                  w/d, reptve movt
    • HAs NOT sig in either                                                                      • Greater red growth (20% less HT, 55%
     Merkel RL Jr, Kuchibhatla A. Safety of stimulant treatment in attention
     deficit hyperactivity disorder: Part I. Expert Opin Drug Saf. 2009;8(6):655-                  less WT), 70 wk
                                                                                                    Merkel RL Jr, Kuchibhatla A. Safety of stimulant treatment in attention deficit
     668.                                                                                           hyperactivity disorder: Part I. Expert Opin Drug Saf. 2009;8(6):655-668;
                                                                                                    Greenhill L, Kollins S, Abikoff H, et al. Efficacy and safety of immediate-
                                                                                                    release methylphenidate treatment for preschoolers with ADHD. J Am Acad
                                                                                                    Child Adolesc Psychiatry. 2006;45(11):1284-1293. Erratum in J Am Acad
                                                                                                    Child Adolesc Psychiatry. 2006;46(1):141.




          Cardiovascular Adverse                                                                        Long-Term Impact Growth
                  Effects                                                                       • MTA at 36 months
                                                                                                  – Significant red HT, WT for newly medicated v.
    • No correlation btn dose v. EKG changes                                                        unmedicated, avg 2 cm HT, 2 kg WT
    • Most studies show no significant diffs                                                      – Red max first year, reduced second, absent third
    • Those studies that show inc BP &/or P v.                                                    – No decrease in group with prior hx tx meds
      plc, judge change NOT clinically significant                                                – Growth supp assoc aggressive and continuous dosing
                                                                                                  – Growth monitoring key
    • A sl increase P more likely than inc BP
                                                                                                  – Dec growth may not be clin imp enough to preclude tx
    • There are no consistent changes in EKG                                                      – Medication holidays may help although not rigorously
                                                                                                    tested
         Merkel RL Jr, Kuchibhatla A. Safety of stimulant treatment in attention deficit
         hyperactivity disorder: Part I. Expert Opin Drug Saf. 2009;8(6):655-668.                   Jensen PS, Arnold E, Swanson JM, et al. 3-year follow up of the NIMH MTA study
                                                                                                    J Am Acad Child Adolesc Psychiatry. 2007;46(8):989-1002.
       Overall Conclusion Growth                                                                       Stimulants and Tics
             Metaanalysis (Faraone 2008)                                                    – Meta-analysis 9 studies, 477 subjects
           • 20 studies of stimulants                                                       – Meds: AMP, MPH, CLN, GUAN, DES, ATX, DPRL
           •              All show impact HT, WT (WT>HT)                                    – MPH, CLN, GUAN, DESI, ATX all efficacious for
           •              Avg after 3 years - 2 cm HT, 2 kg WT (MTA)                          ADHD with comorbid tics
           •              Significantly larger effect, preschoolers
                                                                                            – CLN, GUAN, ATX significantly improved tics
           •              Attenuates with time
           •              Probably secondary dec appetite                                   – Supratherapeutic doses dextroAMP may worsen tics
           •              Dose effect                                                       – No evidence MPH worsened tics in the short term
                                                                                                Bloch MH, Panza KE, Landeros-Weisenberger A, et al. Meta-analysis: treatment of
                                                                                                attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad
           Faraone SV, Biederman J, Morley CP, et al. Effect of stimulants on height and        Child Adolesc Psychiatry. 2009;48(9):884-893.
           weight: a review of the literature. J Am Acad Child Adolesc Psychiatry.
           2008;47(9):994-1009 [Review].




                               Stimulants and Tics                                                    Risk SUDs with ADHD
• The Tourette Syndrome Association                                                         • Up to 45% of adult patients with ADHD
  Medical Advisory Board Guidelines:                                                          meet criteria for EtOH abuse or dep
     – ‘‘Given the added disability attributable to ADHD in
       children and adolescents with TS, aggressive                                         • Up to 30% meet for abuse or
       treatment of ADHD in these cases is warranted. After                                   dependence of other substances
       a review of the alternatives and the family’s                                              Wilens TE. Attention deficit hyperactivity disorder and substance use disorders. Am
       preference, treatment may start with an alpha-2                                            J Psychiatry. 2006;163(12):2059-2063.

       agonist or stimulant medication. Combined treatment                                  • Untreated patientsÆrisk increased 2x
       with an alpha-2 agonist and stimulant may produce
       better outcomes than either treatment alone.’’                                       • Risk SUD 2x in adults with ADHD
               Scahill L, Erenberg G, Berlin CM Jr, et al. Contemporary assessment and      • Risk SUD in ADHD inc if CD and Mood
               pharmacotherapy of Tourette syndrome. NeuroRx. 2006;3(2):192-206 [Review].     Faraone SV, Wilens TE. Effect of stimulant medications for attention-deficit/hyperactivity
                                                                                              disorder on later substance abuse and the potential for stimulant misuse, abuse and
                                                                                              diversion. J Clin Psychiatry. 2007;68 Suppl 11:15-22 [Review].




                           Stimulants and SUDs                                                        Risk SUDs with ADHD
Information from Wilens TE, Faraone SV, Biederman, J, et al. Does stimulant therapy of
ADHD beget later substance abuse? A meta-analytic review of the literature. Pediatrics.
2003;111(1):179-185.                                                                        • Most common is nicotine
                          40
                                                  p<0.001                                   • Earlier onset, heavier cig smoking
                                                                                            • Nicotine effective in red sx ADHD
       Percent of Group




                          30

                                                                                              Faraone SV, Wilens TE. Effect of stimulant medications for attention-
                          20                                                                  deficit/hyperactivity disorder on later substance abuse and the potential for stimulant
                                                                                              misuse, abuse and diversion. J Clin Psychiatry. 2007;68 Suppl 11:15-22 [Review].

                          10


                          0
                               Unmedicated   Medicated        Control
                                  ADHD         ADHD
              Mgt AEs, Stimulants                                                                                                         Guanfacine ER
   • Anorexia, weight loss, nausea                                                                            •    Strengths 1,2,3,4 mg
      – Meds with meals                                                                                       •    2 DBPC, 6-17 yo, 8 & 9 weeks, N=345, 324
                                                                                                              •    Titrated up 1 mg/wk, Only <50 kg got 1 mg
      – Caloric supplements, med holidays
                                                                                                              •    Wkly clinician administered ADHD-RS
      – Let kids eat when they’re hungry
                                                                                                              •    Significant for 6-12 yo, but not 13-17 yo
   • Insomnia
                                                                                                              •    25% adolescents randomized to fixed dose rather than
      – Meds earlier in day                                                                                        optimized by wt, so maybe dosing was too low for 13-
      – Switch to shorter acting                                                                                   17 yo
                                                                                                                   Sallee FR, McGough J, Wigal T, et al; SPD503 Study Group. Guanfacine extended release in
      – D/C later dose                                                                                             children and adolescents with attention-deficit/hyperactivity disorder: a placebo controlled trial. J
                                                                                                                   Am Acad Child Adolesc Psychiatry. 2009;48(2):155-165.
      – Consider adj tx (CLN, Remeron, TCAs)                                                                       Posey DJ, McDougle CJ. Guanfacine and guanfacine extended release: treatment for ADHD
            Daughton JM, Kratochvil CJ. Review of ADHD pharmacotherapies:                                          and related disorders. CNS Drug Rev. 2007;13(4):465-474 [Review].
            advantages, disadvantages, and clinical pearls. J Am Acad Child
            Adolesc Psychiatry. 2009;48(3):240-248 [Review].




                          Guanfacine ER                                                                                                       Atomoxetine
• Strong inverse correlation btn BW, pl levels
• Adverse effects:                                                                                        •       >20 DBPC, ES .5-.7
   – Serious-hypotension, bradycardia, syncope,                                                           •       0.5 mg/kg/d x 2 wk, then 1.2 mg/kg/d x 4 wk
     sedation                                                                                             •       Q day comparable to bid
   – Common-sedation, abdomenal pain,
     dizziness, hypotension, dry mouth,                                                                   •       Ok to combine with stimulants
     constipation                                                                                         •       Sedation most common adverse event
• Established efficacy for ADHD plus tics                                                                 •       Consider if wt loss, tics, bipolar, insomnia
• Less sedation than CLN, but more agitation,                                                                     w/stimulants
  insomnia, headaches                                                                                                Garnock-Jones KP, Keating GM. Spotlight on atomoxetine in attention-deficit hyperactivity
                                                                                                                     disorder in children and adolescents. CNS Drugs. 2010;24(1):85-88 [Review].
  Sallee FR, McGough J, Wigal T, et al; SPD503 Study Group. Guanfacine extended release in
  children and adolescents with attention-deficit/hyperactivity disorder: a placebo controlled trial. J
  Am Acad Child Adolesc Psychiatry. 2009;48(2):155-165.
  Posey DJ, McDougle CJ. Guanfacine and guanfacine extended release: treatment for ADHD
  and related disorders. CNS Drug Rev. 2007;13(4):465-474 [Review].




                              Atomoxetine

• Some combined trials underway
• Effect on anxiety shown
• Suicidality:
  – 0.44% v. 0% (placebo): 5 SI, 1 SIB in 6 of 1357
   – 7-12 yo males, w/in first month, no completed, black
     box
  Garnock-Jones KP, Keating GM. Spotlight on atomoxetine in attention-deficit
  hyperactivity disorder in children and adolescents. CNS Drugs. 2010;24(1):85-88
  [Review].
[Date]

Dear [Name of Principal or Director of Special Education Director]:

I am writing to request an Initial Educational Evaluation to determine whether [name of student,
date of birth], who attends [name of school, grade level] has a disability, and to determine
whether educational interventions or special education services may be appropriate. I am
concerned in particular about [student’s skills in a particular subject or student’s behavior in
certain settings]. Please let me know how I can best support the educational evaluation process.
I would be happy to provide any relevant information to help the school complete this
evaluation.

Please call me at [phone number] to respond to this request, and forward to me at [address] any
documents I need to sign to help the school begin this process.

Thank you in advance for your attention.


Sincerely,

[name of family member, clinician, or concerned other]
References for AAFP Talk-Oct 1st, 2010
Mary N. Cook, MD

Pediatric Attention Deficit Hyperactivity Disorder: Assessment, Treatment, Practical
Guidelines & Literature Updates


1. Polanczyk G, Jensen P. Epidemiologic considerations in attention deficit hyperactivity
disorder: a review and update. Child Adolesc Psychiatric Clin N Am. 2008;17:245–260

2. Visser SN, Lesesne, CA. Mental health in the United States:prevalence of diagnosis
and medication treatment for attention deficit/hyperactivity disorder – United States,
2003. MMWR Morbid Mortal Wkly Rep. 2005;54:842–847

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders Text-Revision (DSM IV). Washington, DC: American Psychiatric Association;
1994:83–85

4. Wilms Floet, A, Scheiner, C, & Grossman, L. Attention deficit hyperactivity disorder
Pediatr. Rev. 2010;31;56-69

5. MTA Cooperative Group. Multimodal treatment study of children with ADHD. A 14-
month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity
disorder. Arch Gen Psychiatry. 1999;56:1073–1086

6. Brookes et al. The analysis of 51 genes in DSM-IV combined type attention deficit
hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol.
Psychiatry 2006: 11, 934–953

7. Kieling, C, Goncalves, RR, Tannock, R, Castellanos, FX, 2008. Neurobiology of
attention deficit hyperactivity disorder. Child Adolesc Psychiatry Clin N Am 2008;17:285–
307 (viii)

8. Kahn, RS, Khoury, J, Nichols, WC, Lanphear, BP. Role of dopamine transporter
genotype and maternal prenatal smoking in childhood hyperactive- impulsive,
inattentive, and oppositional behaviors. J Pediatrics. 2003;143:104–110

9. Brookes et al. A common haplotype of the dopamine transporter gene associated with
attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol
during pregnancy. Arch Gen Psychiatry 2006;63:74–81

10. Casey, BJ, Nigg, JT, Durston, S. New potential leads in the biology and treatment of
attention deficit-hyperactivity disorder. Curr Opin Neurol. 2007; 20, 119–124

11. Valera, EM, Faraone, SV, Murray, KE, Seidman, LJ. Meta-analysis of structural
imaging findings in attention-deficit hyperactivity disorder. Biol Psychiatry. 2007;
61:1361–1369
12. Castellanos, FX, Lee, PP, Sharp, W, et al. Developmental trajectories of brain volume
abnormalities in children and adolescents with attention deficit/hyperactivity disorder.
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13. MGH-NMR Center & Harvard-MIT CITP. Adapted from Bush, et al. Biol Psychiatry.
1999;45:1542-1552.

14. Daughton, JM, Kratochvil, CJ. Review of ADHD Pharmacotherapies: Advantages,
Disadvantages, and Clinical Pearls J Am Acad Child Adolesc Psychiatry. 2009;48:3, pp.
240-248

15. Merkel, RL, Kuchibhatla, A. Safety of stimulant treatment in attention deficit
hyperactivity disorder. Expert Opin.Drug Saf. 2009; pp. 665-668

16. Chavez, B, et al. An update on central nervous system stimulant formulations in
children and adolescents with attention deficit hyperactivity disorder. The Annals of
Pharmacotherapy. 2009;43:1084-1095

17. Vitiello B. Long-term effects of stimulant medications on the brain: possible
relevance to the treatment of attention deficit hyperactivity disorder. J Child Adolesc
Psychopharmacol. 2001;11(1):25-34

18. Spencer et al. Meta-analysis of within-subject comparative trials evaluating
response to stimulant medications. Arch of Gen Psych. 2001

20. Modi, NB, Lindemulder, B, Gupta, SK. Single and multiple-dose pharmacokinetics of
an oral once-a-day osmotic controlled-release OROS. J Clin Pharmacol. 2000;40:379-388

21. Jensen PS, Arnold E, Swanson JM, et al. 3-Year follow up of the NIMH MTA study. J
Am Acad Child Adolesc Psychiatry. 2007;46(8):989-1002

22.Faraone SP, Biederman J, Morley Christopher P et al. Effect of stimulants on height
and weight: a review of the literature. J Am Acad Child Adolesc Psychiatry. 2008;47:994-
1009

23.Greenhill. L et al. J Am Acad Child Adolesc Psychiatry. 2002;41(Suppl 2): 265-495

24.Volkow, ND et al. Arch Gen Psychiatry. 1995; 52 (6) 456-463

25.Biederman, J, Monuteaux, MC, Spencer, T, et al. Stimulant therapy and risk for
subsequent substance use disorders in male adults with ADHD: a naturalistic controlled
10-year follow up study. AJP 2008;165:597-603

26.Wilens, TE. Attention deficit hyperactivity disorder and substance use disorders. AJP.
2006;163(12):2059-63
27.Faraone SV, Wilens, TE. Effect of stimulant medications for attention deficit
hyperactivity disorder on later substance abuse and the potential for stimulant misuse,
abuse and diversion. J Clin Psychiatry. 2007;(Suppl 11):15-22

28.Bloch, M, Panza, BA et al. Meta-analysis: treatment of attention-deficit/hyperactivity
disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry.
2009;48(9):884-893

29.Scahill, L, Erenberg, G, Berlin, CM Jr et al. Contemporary asessment and
pharmacotherapy of Tourette syndrome. NeuroRx. 2006;3:192-206

30.Salle, FR, McGough, J, Wigal, T, et al. Guanfacine extended release in children and
adolescents with attention deficit hyperactivity disorder: a placebo controlled trial. J Am
Acad Child Adolesc Psychiatrist. 2009;48(2):155-165

31.Posey, DG, McDougle, CJ. Guanfacine and guanfacine extended release: treatment
for ADHD and related disorders. CNS Drug Rev. 2007;13(4):465-474

32. Garnock-Jones, KP, Keating, GM. Spotlight on atomoxetine in attention-deficit
hyperactivity disorder in children and adolescents. CNS Drugs. 2010;24(1):85-88

33. Wolraich ML, Feurer ID, Hannah JN, et al. Obtaining systematic teacher reports of
disruptive behavior disorders utilizing DSM-IV. Journal of Abnormal Child Psychology.
1998; 26(2):141–152.

34. The Vanderbilt Scales (Parent and Teacher) are available at
http://peds.mc.vanderbilt.edu/VCHWEB_1/rating~1.html

				
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