Overview of ADHD and its Pharmacotherapy

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Overview of ADHD and its Pharmacotherapy

• Andrew D. Mosholder, M.D., M.P.H.
• FDA Division of Drug Risk Evaluation

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Topics

• Overview of diagnosis and clinical
  characteristics of attention deficit
  hyperactivity disorder (ADHD)
• Treatment of ADHD, including pharmacotherapy
• Recent data on ADHD from CDC survey (National
  Survey of Childrens Health)
• Patterns of ADHD drug use from Verispan database

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Attention Deficit Hyperactivity Disorder

• Diagnostic criteria
• (American Psychiatric Association Diagnostic and
  Statistical Manual (DSM-IV))
• gt 6 of 9 symptoms of inattention X gt 6 mos.
• And/Or
• gt 6 of 9 symptoms of hyperactivity-impulsivity X
  gt 6 mos.
• Onset prior to age 7 years
• Impairment in more than one setting (e.g., both
  school and home)
• Social, academic, or occupational impairment
• Symptoms not accounted for by another mental
  disorder such as a psychotic disorder, mood
  disorder, anxiety disorder, etc.
• Subtypes
• Inattentive
• Hyperactive-Impulsive
• Combined (most common)

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ADHDDifferential Diagnosis (from DSM-IV)

• Age-appropriate activity
• Cognitive impairment
• Reaction of child to disorganized, chaotic
  environment
• Oppositional behavior without ADHD
• Other psychiatric disorders (see above)
• Adverse drug reactions

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ADHDSome common psychiatric comorbidities
(source DSM-IV)

• Oppositional Defiant Disorder
• Conduct Disorder
• Mood disorders
• Anxiety disorders
• Tic disorders
• Learning disorders

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ADHD overview, continued

• Malefemale ratio from 41 to 91 (DSM-IV)
• Estimates of prevalence in school age children
  range from 3-5 (DSM-IV) to 8-12 (Biederman and
  Faraone 2005)
• Etiology not known (environmental, genetic,
  developmental, family dysfunction)
• Diagnosis is clinical (no pathognomonic physical
  or laboratory findings)
• Diagnosis applies to different levels of severity

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Adult ADHD

• Diagnostic criteria originally developed for
  children
• DSM-IV specifies ADHD In Partial Remission for
  presence of residual symptoms without full
  disorder
• Adult ADHD increasingly recognized and treated
• Two drug products now approved specifically for
  adult ADHD
• National Comorbidity Survey Replication
  persistence of retrospectively diagnosed ADHD
  into adulthood (ages 18-44) was estimated at 36
  (Kessler et al. Biol Psychiatry
  20055714421451)

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ADHD Associated Morbidity

• Impairment in academic, familial/social,
  occupational settings
• Delinquent, antisocial behaviors
• Motor vehicle accidents
• More frequent among drivers with ADHD (Barkley et
  al. Pediatrics 1993, 92212-218)
• Driving simulator study showed improvement with
  methylphenidate (Cox et al. J Nerv Ment Dis.
  2000, 188230-4)
• Injuries (DiScala et al., Pediatrics
  1998,1021415-1421)

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ADHD Associated Morbidity

• Substance abuse (alcohol, drug)
• Perhaps mitigated by pharmacotherapy (Wilens et
  al. Pediatrics 2003111179-185)
• Tobacco use
• In one prospective study, tobacco and cocaine
  dependence roughly double that of non-ADHD
  control group (Lambert and Hartsough, J Learn
  Disabil. 199831533-44)
• Stimulant medication itself may increase use of
  tobacco (Rush et al. Psychopharmacology (Berl).
  2005 181 781-9)

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Treatment of ADHD in children

• Pharmacotherapy (to be discussed)
• Behavioral, psychosocial, educational
  interventions
• Recommended by American Academy of Pediatrics
  (Pediatrics 2001, 1081033-1044), American
  Academy of Child and Adolescent Psychiatry
  (www.aacap.org), and current product labels
• However, the efficacy of behavioral treatments
  above and beyond that of medication has been
  difficult to demonstrate in long term trials
• Abikoff et al. J. Am. Acad. Child Adolesc.
  Psychiatry, 200443802811
• MTA Cooperative Group, 1999 Arch Gen Psychiatry
  5610731086)

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Pharmacotherapy

• Drugs approved for ADHD
• Stimulants (sympathomimetic)
• Methylphenidate (e.g., Ritalin)
• Dexmethylphenidate (Focalin, Focalin XR)
• Amphetamine (Adderall, Adderall XR)
• Dextroamphetamine (Dexedrine)
• Pemoline (Cylert) --no longer marketed due to
  liver toxicity
• Methamphetamine (Desoxyn) --little used
• Atomoxetine (Strattera)
• selective norepinephrine reuptake inhibitor

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Pharmacotherapy, continued

• Under review for ADHD indication
• Modafinil (Provigil)--stimulant
• Drugs used off label for ADHD
• Tricyclic antidepressants
• Bupropion
• Alpha-2 agonists (e.g., clonidine)

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Stimulants

• Used for decades
• Principle compounds in use currently
• Amphetamines
• Adderall 25 l-amphetamine, 75 d-amphetamine
• Dextroamphetamine
• Methylphenidate and d-methylphenidate
• Available in extended release formulations
• Adverse effects abuse/dependence (Schedule
  C-II), tics, cardiovascular, CNS, growth
• Adderall XR approved for adult ADHD

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Other compounds

• Atomoxetine
• NE reuptake inhibitor
• Adverse effects hepatotoxicity, suicidal events,
  cardiovascular (increased p, bp), growth
• Not scheduled
• Approved for adult ADHD
• Modafinil
• Stimulant
• Approved for excessive sleepiness
• Under review for ADHD
• May have some cardiovascular effects
• Schedule C-IV

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Drugs used for ADHD and some related compounds
with known cardiovascular effects
Amphetamine
Methamphetamine
Methylphenidate
Atomoxetine
Modafinil
Ephedrine
Fenfluramine
Phenylpropanolamine
Source National Library of Medicine ChemIDPlus
Aminorex
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CDC 2003 NSCH SurveyMMWR 200554842-847

• National Survey of Childrens Health (NSCH)
• Telephone survey conducted 2003-4
• 100K subjects ages 4-17 years
• Parents or guardians in household responded to
  questions about diagnosis and treatment of ADHD
• Statistical projections to national and state
  level

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Source Centers for Disease Control and
Prevention. Prevalence of diagnosis and
medication treatment for attention-deficit/hyperac
tivity disorder United States, 2003. MMWR
200554842-847.
18
Source Centers for Disease Control and
Prevention. Prevalence of diagnosis and
medication treatment for attention-deficit/hyperac
tivity disorder United States, 2003. MMWR
200554842-847.
19
Source Centers for Disease Control and
Prevention. Prevalence of diagnosis and
medication treatment for attention-deficit/hyperac
tivity disorder United States, 2003. MMWR
200554842-847.
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CDC 2003 NSCH SurveyConclusions

• High prevalence of ADHD diagnosis and medication
  use in children and adolescents
• Estimated 2.5 mil children aged 4-17 years
  receiving medication for ADHD
• 4.3 of all children in that age group
• Males gt females
• Regional variation in ADHD diagnosis and
  medication use
• Medication use peaks around ages 9-12
• 9.3 of boys aged 12
• 3.7 of girls aged 11
• Limitations survey data, dependent upon parental
  recall

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ADHD Drug Use in the U.S.

• Data source Vector One National (VONA)
• Collects data on prescription activity from
  retail pharmacies from multiple sources
• Includes data on prescriber specialty, patient
  age, gender
• Data available for gt1.8 bil Rxs per year, for 150
  million patients in the U.S.
• Does not provide data on indication for Rx, or
  duration of treatment

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Source Vector One National (VONA)
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Source Vector One National (VONA)
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U.S. Prescriptions by Active Ingredient, Jan-Jun
2005, for Selected Drugs Source Vector One
National (VONA)
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Total Retail Prescriptions Dispensed (in
thousands) for 8 Selected Drugs by Patient Age
January 2002 to June 2005 by Quarter
Source Vector One National (VONA)
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Source Vector One National (VONA)
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U.S. Drug Use Data from Vector One National
(VONA)Conclusions

• Increasing use of drugs for ADHD by both adults
  (19) and children (0-18)
• For adults above the age of 19, 90 increase in
  quarterly Rxs between Mar 2002 and Jun 2005
• Currently, 1 mil. Rxs monthly for adults and 2
  mil Rxs monthly for children
• Methylphenidate products most frequently
  prescribed, followed by amphetamine, atomoxetine
• 10 of use is by adults over 50 y.o.

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Acknowledgements

• Susanna Visser, MS and Ruth Perou, PhD
• National Center on Birth Defects and
  Developmental Disabilities, Centers for Disease
  Control and Prevention
• Carol Pamer, R.Ph.
• FDA Office of Drug Safety