# Presentation: 780143

## Overview of ADHD and its Pharmacotherapy

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

## 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 Children’s Health)
- Patterns of ADHD drug use from Verispan database

## Attention Deficit Hyperactivity Disorder

- Diagnostic criteria
- (American Psychiatric Association Diagnostic and Statistical Manual (DSM-IV))
- _>_ 6 of 9 symptoms of inattention X _>_ 6 mos.
- 		*And/Or*
- _>_ 6 of 9 symptoms of hyperactivity-impulsivity X _>_ 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)

## ADHDDifferential 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

## ADHDSome common psychiatric  comorbidities (source: DSM-IV)

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

## ADHD overview, continued

- Male:female ratio from 4:1 to 9:1 (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

## 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 2005;57:1442–1451)

## 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, 92:212-218)
- Driving simulator study showed improvement with methylphenidate (Cox et al. J Nerv Ment Dis.  2000, 188:230-4)
- Injuries (DiScala et al., Pediatrics 1998,102:1415-1421)

## ADHD: Associated Morbidity

- Substance abuse (alcohol, drug)
- Perhaps mitigated by pharmacotherapy (Wilens et al. Pediatrics 2003;111;179-185)
- Tobacco use
-  In one prospective study, tobacco and cocaine dependence roughly double that of non-ADHD control group (Lambert and Hartsough, J Learn Disabil. 1998;31:533-44)
- Stimulant medication itself may increase use of tobacco (Rush et al. Psychopharmacology (Berl). 2005; 181: 781-9)

## Treatment of ADHD in children

- Pharmacotherapy (to be discussed)
- Behavioral, psychosocial, educational interventions
- Recommended by American Academy of Pediatrics (Pediatrics 2001, 108:1033-1044), 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, 2004;43:802–811
- MTA Cooperative Group, 1999; Arch Gen Psychiatry 56:1073–1086)

## 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

## 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)

## 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

## 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

## Drugs used for ADHD and some related compounds with known cardiovascular effects

- Amphetamine

- Phenylpropanolamine

- Methylphenidate

- Atomoxetine

- Methamphetamine

- Fenfluramine

- Source: National Library of Medicine ChemIDPlus

- Modafinil

- Ephedrine

- Aminorex

- Drugs used for ADHD and some related compounds with known cardiovascular effects

## CDC 2003 NSCH SurveyMMWR 2005;54:[842-847]

- National Survey of Children’s 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

## Source: Centers for Disease Control and Prevention. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder – United States, 2003. MMWR 2005;54:[842-847].

*Source: Centers for Disease Control and Prevention. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder – United States, 2003. MMWR 2005;54:[842-847].*

**Notes:**
3:1 Sex ratio of males to females; age effect with medication most common among 9-13 year olds.
Several racial and ethnic differences previously noted for diagnosis and treatment around ADHD

## Source: Centers for Disease Control and Prevention. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder – United States, 2003. MMWR 2005;54:[842-847].

**Notes:**
3:1 Sex ratio of males to females; age effect with medication most common among 9-13 year olds.
Several racial and ethnic differences previously noted for diagnosis and treatment around ADHD

## Source: Centers for Disease Control and Prevention. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder – United States, 2003. MMWR 2005;54:[842-847].

**Notes:**
3:1 Sex ratio of males to females; age effect with medication most common among 9-13 year olds.
Several racial and ethnic differences previously noted for diagnosis and treatment around ADHD

## CDC 2003 NSCH SurveyConclusions

- 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 > 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

## 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 >1.8 bil Rxs per year, for 150 million patients in the U.S.
- Does not provide data on indication for Rx, or  duration of treatment

## Source: Vector  One®:  National (VONA)

## Source: Vector  One®:  National (VONA)

## U.S.  Prescriptions by Active Ingredient, Jan-Jun 2005, for Selected Drugs

- Source: Vector  One®:  National (VONA)

## 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)

## Source: Vector  One®:  National (VONA)

## 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.

## 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