ADHD

Attention Deficit Hyperactivity Disorder (ADHD): Overview:

Attention Deficit Hyperactivity Disorder (ADHD): Overview Saad A. Shakir, MD,DFAPA,FACIP Adjunct Clinical Associate Professor Emeritus of Psychiatry and Behavioral medicine Stanford University

Worldwide Prevalence of ADHD Is 3% to 7%:

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

ADHD: Historical Timeline:

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

Prevalence of ADHD in Adults:

Prevalence of ADHD in Adults

Adult ADHD Remains Largely Undiagnosed*:

Adult ADHD Remains Largely Undiagnosed*

Why May ADHD in Adults Go Undiagnosed or Untreated?:

Why May ADHD in Adults Go Undiagnosed or Untreated?

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Coexisting Conditions in Adults with ADHD

Erroneous Beliefs/Assumptions About ADHD:

Erroneous Beliefs/Assumptions About ADHD Minor disorder if it even exists Affects almost solely males Has little impact beyond the classroom Disappears spontaneously after grade school

Erroneous Beliefs/Assumptions About ADHD :

Erroneous Beliefs/Assumptions About ADHD Overdiagnosed Diagnosis made about any energetic or “different” child Medication is only a form of chemical control Misdiagnosed in cases of Poor parenting Rigid, misguided teachers Overtreated by physicians who used powerful and potentially addicting drugs for a minor, temporary ailment

Erroneous Beliefs/Assumptions About ADHD :

Erroneous Beliefs/Assumptions About ADHD Produced a pattern of treatment in which clinicians did not use medications OR Used low doses of medications Only Monday through Friday Only during school hours Gave "drug holidays" Stopped medications in adolescence

Erroneous Beliefs vs Evidence:

Erroneous Beliefs/Assumptions Are False Erroneous Beliefs vs Evidence Evidence Exists to Invalidate Them ADHD

Evidence:

Evidence In the beginning, the diagnosis of ADHD was unclear due to Different names Inconsistent nature of impairments Feedback from 3 rd parties (ie, children are poor historians) Media controversy Lack of validated diagnostic instruments But by 1998, the AMA called ADHD “…one of the best-researched disorders in medicine, and the overall data on its validity are far more compelling than for many medical conditions.” Goldman et al. JAMA 1998;279:1100.

Evidence Genetics:

Evidence Genetics Numerous twin studies report the average heritability index to be approximately 0.75 across various sets of diagnostic criteria Adoption and family studies further support the genetic basis for ADHD Stressors and bad parenting can exacerbate impairment but do not cause ADHD Todd. Am J Med Genetics 2000;96:241. Faraone and Biederman. Biol Psychiatry 1998;44:951.

Twin Studies Show ADHD Is a Genetic Disorder:

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. Willerman, 1973 Goodman, 1989 Gillis, 1992 Edelbrock, 1992 Schmitz, 1995 Thapar, 1995 Gjone, 1996 Silberg, 1996 Sherman, 1997 Levy, 1997 Nadder, 1998 Hudziak, 2000 Average genetic contribution of ADHD based on twin studies 0 0.2 0.4 0.6 0.8 1 Height Breast cancer Asthma Schizophrenia Twin Studies Show ADHD Is a Genetic Disorder ADHD Mean

Molecular Genetics of ADHD :

Sunohara G, et al. J Am Acad Adolesc Psychiatry. 2000;39:1537-1592. Giros B, et al. Nature. 1996;379:606-612. 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 of noradrenergic genes There are several genes involved and their effects are cumulative

ADHD: Course of the Disorder :

Hyperactivity —Age— Impulsivity Inattention ADHD: Course of the Disorder

ADHD Diagnosis :

ADHD Diagnosis

Proper Steps in Diagnosis:

AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S. 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

Diagnostic Criteria for ADHD: DSM-IV-TR:

Diagnostic Criteria for ADHD: DSM-IV-TR Persistent symptoms of inattention Onset of symptoms before age 7 Impairment in 2 or more settings (eg, school, work, home) Evidence of clinically significant impairment in social, academic, or occupational functioning Symptoms not a result of other disorders APA. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Association; 2000.

DSM-IV Diagnostic Criterion Symptoms for ADHD:

American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders. 4th edition. Text Revision. 2000, Washington DC. DSM-IV Diagnostic Criterion Symptoms for ADHD Inattention Is careless Has difficulty sustaining attention in activity Does not listen Does not follow through with tasks Is disorganized Avoids/dislikes tasks requiring sustained mental effort Loses important items Is easily distracted Is forgetful in daily activities

DSM-IV Diagnostic Criterion Symptoms for ADHD (cont’d):

Impulsivity Blurts out answers Cannot wait turn Intrudes/interrupts others American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders. 4th edition. Text Revision. 2000, Washington DC. DSM-IV Diagnostic Criterion Symptoms for ADHD (cont’d) Hyperactivity Squirms and fidgets Cannot stay seated Runs/climbs excessively Cannot play/work quietly Is on the go/driven by a motor Talks excessively

ADHD: DSM-IV Subtypes:

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 Inattention Impulsivity/Hyperactivity

ADHD: Core Symptom Areas:

ADHD: Core Symptom Areas Inattention Impulsivity/Hyperactivity

ADHD: Core Symptom Area:

ADHD: Core Symptom Area Six or more of the following - manifested often*: Inattention Inattention to details/ makes careless mistakes Difficulty sustaining attention Seems not to listen Fails to finish tasks Difficulty organizing Avoids tasks requiring sustained attention Loses things Easily distracted Forgetful * DSM-IV, 1994.

ADHD: Core Symptom Areas:

ADHD: Core Symptom Areas Impulsivity/Hyperactivity Six or more of the following - manifested often* Impulsivity Blurts out answer before question is finished Difficulty awaiting turn Interrupts or intrudes on others Hyperactivity Fidgets Unable to stay seated Inappropriate running/climbing (restlessness) Difficulty in engaging in leisure activities quietly “On the go” Talks excessively *DSM-IV, 1994.

Progression of Executive Functions from Childhood to Adulthood:

Slide provided by T. Spencer, MD Progression of Executive Functions from Childhood to Adulthood Early childhood Simple responses to limited demands in a protective environment Late childhood into adulthood: executive functions become more important Juggling competing tasks, independence, organization, and planning

ADHD: Diagnosis:

ADHD: Diagnosis DSM-IV Diagnostic Criteria List of symptoms must be present for past 6 months Some symptoms present before 7 years of age Some impairment from symptoms must be present in 2 or more settings (e.g. school and home) Significant impairment: social academic occupational Exclude other mental disorders (e.g. Mood Disorder, Anxiety Disorder, PDD/Autism, etc.) American Psychiatric Association 1994; 83-85.

ADHD: Adolescents:

ADHD: Adolescents Childhood ADHD persists into adolescence Adolescents with ADHD are frequently undertreated One-third of adolescents with ADHD will develop Conduct Disorder or Substance Abuse Disorder 1 Adolescent ADHD will persist into adulthood in 40% of cases Estimated prevalence: ~9% children 2 ; ~6% of adolescents 3 ; ~5% of adults 4 Adolescents and adults with symptoms of ADHD display significant impairments in adaptive functioning, vocational achievement, and are at high risk for comorbid disorders 5 1 Brown TE. Attention-deficit and comorbidities in children, adolescents and adults. Presented at the American Psychiatric Association, Washington, DC: 2000. 2 American Academy of Pediatrics. Diagnostic and Statistical Manual for Primary Care (DSM-PC) Child and Adolescent Version. Elk GroveVillage, IL: AAP, 1998. 3 Barkley et al. J Am Acad Child Adolesc Psychiatry 1990;29(4):546–57. 4 Murphy, Barkley. Comprehensive Psychiatry 1996;37:393–401. 5 Weiss, Jain. ADHD Report 2000;8(6):4.

ADHD May Result in Performance Limitations:

Despite similar educational levels and IQ scores, non-medicated adults with ADHD display: Significantly more academic difficulty in school (25% repeat a grade) Lower levels of occupational advancement Faraone S, et al. Biol Psychiatry. 2000;48:9-20. Biederman, et al. Am J Psychiatry. 1993;150:1792-1798. ADHD May Result in Performance Limitations

ADHD: Adolescents:

Study Age of patients and follow-up Findings at follow-up Barkley et al, 1990 1 6 years, follow-up at 14 years 72% with ADHD Biederman et al, 1996 2 6–17 years, 4 year follow-up 85% with ADHD Gittelman et al, 1995 3 16–23 years 68% with ADHD in adolescence Weiss et al, 1985 4 5–12 years, 5, 10 and 15 year follow-up 66% with at least 1 core symptom of ADHD by adulthood ADHD: Adolescents Evidence for persistence of symptoms into adolescence and adulthood is shown in longitudinal follow-up studies 1 Barkley et al. J Am Acad Child Adolesc Psychiatry 1990;29(4):546–57. 2 Biederman et al. Arch Gen Psychiatry 1996;53(5):437–46. 3 Gittelman et al. Arch Gen Psychiatry 1985;42(10):937–47. 4 Weiss et al. J Am Acad Child Psychiatry 1985;24(2):211–20.

ADHD: Adolescents:

ADHD: Adolescents Issues in the management of adolescent ADHD ADHD symptoms, particularly hyperactivity, may be less obvious Treatment should NOT be discontinued prematurely Common domains of impairment include: Academic underachievement Driving Early sexual behavior Family functioning Major issue is compliance with treatment Who manages ADHD symptoms? (parent, patient, school) Psychosocial treatments

ADHD: Adults:

ADHD: Adults Issues in diagnosis: Few validated instruments Adults with ADHD are poor historians Negative findings on interview Possible comorbidities Medical mimics: Not all attention problems are ADHD Social mimics: ADHD as an excuse Barkley AR. Attention-Deficit Hyperactivity Disorder . 2nd ed. New York, NY: The Guilford Press, 1998.

ADHD: Adults:

ADHD: Adults Suggested evaluation procedures: Interview with patient Review of previous medical/educational records Corroborating data from parent, spouse, employer Physical examination Rating scales (CAARS, WURS) Barkley AR. Attention-Deficit Hyperactivity Disorder . 2nd ed. New York, NY: The Guilford Press, 1998.

ADHD: Adults:

ADHD: Adults Multimodal treatment targeting: ADHD symptoms (stimulant vs non stimulant) Impairments (vocational counseling) Comorbid conditions (CBT for mood symptoms) Identify strengths and focus on positive aspects (e.g. sporting achievements, social capabilities) Barkley AR. Attention-Deficit Hyperactivity Disorder . 2nd ed. New York, NY: The Guilford Press, 1998.

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DSM-IV-TR Diagnosis of ADHD in Adults

Symptoms: Assessing the Adult for ADHD:

Symptoms: Assessing the Adult for ADHD

Awareness and Recognition of ADHD in Adults :

Awareness and Recognition of ADHD in Adults

Awareness and Recognition of ADHD in Adults :

Awareness and Recognition of ADHD in Adults

The Adult ADHD Self-Report Scale (Adult ASRS): Screener and Symptom Checklist:

The Adult ADHD Self-Report Scale (Adult ASRS): Screener and Symptom Checklist

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Adult ASRS Screener

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Adult ASRS Screener

Adult ASRS Screener:

Adult ASRS Screener

Adult ASRS Symptom Checklist:

Adult ASRS Symptom Checklist

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Adult ASRS Symptom Checklist

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Adult ASRS Symptom Checklist

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Adult ASRS Symptom Checklist

ADHD: Etiology:

ADHD: Etiology ADHD is a heterogeneous behavioral disorder with multiple possible etiologies CNS = central nervous system CNS insults Genetic origins Neuroanatomical neurochemical ADHD Environmental factors

Neurochemistry of ADHD:

Neurochemistry of ADHD Both dopaminergic (DA) and noradrenergic (NE) systems are strongly implicated in the pathophysiology of ADHD Maximal effectiveness may be produced by those agents that act on both the DA and the NE neurotransmitter systems Stimulants potentiate the actions of both dopamine and norepinephrine in the synapse Solanto. Behav Brain Res 1998;94:127.

Neurotransmitters and Normal Behavior:

MOOD MODULATION IMPULSE CONTROL Neurotransmitters and Normal Behavior PLEASURE DRIVE LIBIDO APPETITE AGGRESSION ACTIVATION AFFECT COGNITION ENERGY ATTENTION MOTIVATION STRESS TOLERANCE MODULATION Serotonin Norepinephrine Dopamine Adapted from Healy D et al. J Psychopharmacol 1997;11(4 Suppl):S25-31.

Dopamine Neurotransmission Relative to ADHD:

Dopamine Neurotransmission Relative to ADHD Enhances signal Improves attention Focus On-task behavior On-task cognition Solanto. Stimulant Drugs and ADHD. Oxford; 2001. Nigrostriatal Pathway Mesolimbic Pathway Substantia nigra Ventral tegmental area Mesocortical Pathway Dopamine

Norepinephrine Neurotransmission Relative to ADHD:

Locus Ceruleus Frontal Limbic Norepinephrine Neurotransmission Relative to ADHD Dampens noise Executive operations Increases inhibition Solanto. Stimulant Drugs and ADHD. Oxford; 2001. Norepinephrine

Norepinephrine /Dopamine Comorbidities:

Norepinephrine /Dopamine Comorbidities ADHD* Smoking Obesity DEPRESSION Fatigue Sexual Dysfunction § *Attention Deficit Hyperactivity disorder

Neuroimaging and ADHD:

MGH-NMR Center & Harvard-MIT CITP. Adapted from Bush, et al. Biol Psychiatry. 1999;45:1542-1552. 1 x 10 -3 1 x 10- 2 1 x 10 -3 y = +21 mm y = +21 mm Normal control ADHD Anterior Cingulate Cortex Frontal Striatal Insular network 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 Neuroimaging and ADHD 1 x 10- 2

Potential Areas of Impairment:

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

Domains of Impairment:

Domains of Impairment Impairments Academic/ Occupational Health/Injury Substance Abuse Sexual Behavior Criminality Social Functioning Self-esteem

Impairment:

Impairment DSM-IV-TR: ADHD symptoms must be consistently and persistently impairing in at least 2 areas of life functioning Much more than personality traits and quirks Must significantly impair major aspects of day-to-day life Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. 2000.

Academic Impairment:

Academic Impairment Very well documented Failure to perform academically is the single most common reason for referral of children and adolescents Children with ADHD Perform poorly on achievement tests and failed grades/ courses significantly more often than children without ADHD Complete 3 fewer years of education than matched controls Are more likely not to graduate from high school Academic impairment more profound when learning disabilities are present Weiss and Hechtman. Hyperactive Children Grown Up. 2 nd ed. New York: Guildford Press; 1993. Mannuzza and Klein. The Economics of Neuroscience . April 2001:47-53.

Health and Injury:

Health and Injury Accidents, such as motor vehicle crashes, are the leading cause of death until 44 years of age in the US Without treatment, adolescents with ADHD have 4 times as many serious injuries and 3 times as many motor vehicle accidents than those without ADHD or those with ADHD who consistently take medication 9-year study of medical utilization shows that persons with ADHD have more than double the cost of care as compared to controls Barkley et al. Pediatrics 1993;92:212. Leibson et al. JAMA 2001:285:60.

Sexual Behavior:

Sexual Behavior Longitudinal follow-up at young adulthood of a cohort of children (ongoing Milwaukee follow-up study) with ADHD compared to controls Sexual intercourse at earlier age (15 vs 16 years) More sexual partners (19 vs 7) More pregnancies (38% vs 4%) More sexually transmitted diseases (17% vs 4%) Tested for HIV (54% vs 21%) Barkley. ADHD: A Handbook for Diagnosis and Treatment. New York: Guilford Press; 1998:209.

Criminality:

Criminality ADHD has high comorbidity with ODD and CD Coupled with an impulsive, high-risk lifestyle — increases risk for legal problems Long-term study reports that persons with ADHD more likely to be Arrested (39% vs 20%) Arrested more than once (23% vs 8%) Convicted (28% vs 11%) Jailed (9% vs 1%) Biederman et al. Arch Gen Psychiatry 1996;53:437. Mannuzza et al. Arch Gen Psychiatry 1989:46:1073.

Social Functioning and Self-Esteem:

Social Functioning and Self-Esteem Social problems begin in childhood, persist into adolescence Fewer friends, poorer social skills Lower self-esteem assessment scores Adults “Just don’t seem to get it” Lack intuitive understanding Tactless, blurt out things before thinking Barkley. ADHD: A Handbook for Diagnosis and Treatment. New York: Guilford Press; 1998:209.

ADHD Affects Socialization:

AACAP. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S. Barkley RA. J Am Acad Child Adolesc Psychiatry. 1991;30:752-762. ADHD Affects Socialization Children are stigmatized by their behavior Disruptive behavior Troublemakers • Bad sportsmanship Excessive talking • Cannot sit still Unfocused, not responsive to others • Impulsive aggression Immaturity and impulsiveness Center of attention • Breaks the rules Blurting out answers • Peer rejection Adolescents continue to demonstrate social problems Poor participation in group activities Few friends Vulnerable to antisocial groups, drug abuse

Increased Traffic Violations and Motor Vehicle Accidents in Adolescents and Adults with ADHD:

Increased Traffic Violations and Motor Vehicle Accidents in Adolescents and Adults with ADHD 0 10 20 30 40 50 60 70 80 90 Traffic violations Speeding violations Drunk driving License suspended Driver-caused accidents Subjects (%) ADHD n=25 Control n=23 Barkley RA, et al. Pediatrics. 1996;98:1089-1095. P =0.004 P =0.07 P =0.07 P =0.01

ADHD Is Associated with Increased Medical Costs:

ADHD Is Associated with Increased Medical Costs Leibson CL, et al. JAMA . 2001;285:60-66. 26% 41% 81% 18% 33% 74% 0 10 20 30 40 50 60 70 80 90 Inpatient hospital admission Outpatient hospital admission Emergency admission ADHD (n=309) Non-ADHD (n=3810) P <0.001 P <0.006 P <0.005 $4306 $1944 $0 $500 $1000 $1500 $2000 $2500 $3000 $3500 $4000 $4500 ADHD Non-ADHD Overall medical costs P <0.001 N=4119 1987 to 1995 % total cohort Medical cost (1995 national avg. dollars)

Common Associations:

Anxiety Addiction Attention deficit Depression Common Associations

ADHD: Comorbid Conditions:

ADHD: Comorbid Conditions ADHD frequently occurs with other psychiatric conditions: Anxiety disorders: e.g. Generalized Anxiety Disorder, Obsessive Compulsive Disorder (OCD) Disruptive behavior disorders: Oppositional Defiant Disorder (ODD), Conduct Disorder (CD) Mood disorders: Bipolar disorder, depression Specific learning disabilities Tic disorders including Tourette's syndrome

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ADHD: Comorbid Conditions 1 NIMH 2 Milberger S et al. J Am Acad Child Adolesc Psychiatry 1997;36:37-44. 3 Biederman et al. J Am Acad Child Adolesc Psychiatry 1997;36:21-29. 60 55 50 45 40 35 30 25 20 15 10 5 0 (%) Oppositional Defiant Disorder 1 Anxiety disorders 1 Learning difficulties 1 Mood disorders 1 Conduct disorder 1 Smoking 2 Substance Use Disorder 3 Language disorder 40% 30-35% 20-25% 15-20% 15-20% 15-20% 19% 15%

ADHD: Comorbid Conditions:

ADHD: Comorbid Conditions Disruptive Behavior Disorders (ODD and CD): ODD: Characterized by bullying, failure to comply with adult requests, and defiance of authority CD: Characterized by aggression and non-aggression (stealing, truancy) ODD and CD may be related to hyperactivity There is generally a developmental progression from ODD to CD with increasing age Reeves JC et al. J Am Acad Child Adolesc Psychiatry 1987;26:144-155. Anderson JC et al. Arch Gen Psychiatry 1987;44:69-76. Szatmari P et al. J Am Acad Child Adolesc Psychiatry 1989;28:865-872.

ADHD: Comorbid Conditions:

ADHD: Comorbid Conditions Mood Disorders (depression): Juvenile depression: Characterized by irritability, dysphoria, boredom, social withdrawal, fatigue, abnormal sleep patterns, and diminished ability to concentrate Approximately 20% of initial presentations of depression in childhood will represent the first episode of a bipolar disorder Depression is observed equally among males and females up to adolescence; into adulthood approximately two-thirds of cases are in females Biederman J et al. J Affect Disorder 1998;47:113-122.

Depressed Patients with ADHD (%):

Depressed Patients with ADHD (%) Wender PH. Psychiatric Times 1996;13. Alpert JE, et al. Psychiatry Res 1996;62:213-9. Depressed Control Childhood ADHD 16 3-10 Adult ADHD 12 1-6

ADHD: Comorbid Conditions:

ADHD: Comorbid Conditions Learning difficulties: Learning disorders include motor skills and communication disorders Children with ADHD and comorbid learning difficulties generally respond to ADHD treatment; this improves school performance, but not the learning difficulty 1 Anxiety disorders: Follow-up studies show ADHD and anxiety symptoms are both chronic, persisting or increasing into adolescence and adulthood 2,3 The MTA study demonstrated that ADHD children with anxiety were more likely to benefit from psychosocial treatments than non-anxious ADHD children 4 1 Tannock R, Brown TE. In: Attention-Deficit Disorders and Comorbidities in Children, Adolescents and Adults. Brown Ed, APA Press: Washington, DC, 231-95. 2 Biederman et al. J Am Acad Child Adolesc Psychiatry 1996;35:1193–1204. 3 Fischer et al. J Abnorm Child Psychol 1993;21:315–337. 4 Jensen et al. JAACAP 2001; 402:134-136.

Substance Abuse:

Substance Abuse Many people with untreated ADHD try to self-medicate to improve functioning Smoking ADHD adults smoke more and have more difficulty quitting Children with ADHD start younger and smoke more Substance use disorders (SUDs) Fear: stimulant therapy may lead to substance abuse Fact: untreated ADHD is a significant risk factor for substance abuse in adolescence and adulthood A longitudinal study found ADHD medication was associated with an 85% reduction in risk for SUD in ADHD youth Stimulants are known to be associated with dependence and abuse in “at-risk” populations Biederman et al. Pediatrics 1999;104:e20. Pomerleau et al. J Subst Abuse 1995;7:373. Milberger et al. JAACAP 1997;36:38.

Increased Smoking with ADHD:

Pomerleau, et al. J Subst Abuse. 1995;7:373-378. *Smokers Quit ratio Current smokers Adult patients with ADHD; n=71 0% 10% 20% 30% 40% 50% * P <0.01 48.5% ADHD General population 40.8% 25.8% 29% Increased Smoking with ADHD

Earlier Initiation of Smoking with ADHD:

Earlier Initiation of Smoking with ADHD 6- to 17-year-old boys 0.6 0.5 0.4 0.3 0.2 0.1 0 Smoking probability 0 2 4 6 8 10 12 14 16 18 20 22 24 P <0.003 ADHD n=128 Control n=109 Milberger S, et al. J Am Acad Child Adolesc Psychol. 1997;36:37-44.

Increased Lifetime Substance Abuse in Untreated Adults with ADHD:

Biederman, et al. Biol Psychiatry. 1998;44:269-273. Lifetime rate of substance abuse in referred ADHD adults 0 10 20 30 40 50 60 Increased Lifetime Substance Abuse in Untreated Adults with ADHD 27% 55% Control (n=268) ADHD (n=239) P <0.001

ADHD: Impact of Untreated & Under-Treated ADHD:

ADHD: Impact of Untreated & Under-Treated ADHD Patient Family 3-5x  Parental Divorce or Separation 11,12 2-4 x  Sibling Fights 13 Society Substance Use Disorders: 2 X Risk 8 Earlier Onset 9 Less Likely to Quit in Adulthood 10 School & Occupation 46% Expelled 6 35% Drop Out 6 Lower Occupational Status 7 Health Care System 50%  in bike accidents 1 33%  in ER visits 2 2-4 x more motor vehicle crashes 3-5 Employer  Parental Absenteeism 14 and Productivity 14 1. DiScala et al., 1998. 2. Liebson et al., 2001. 3. NHTSA, 1997. 4-5. Barkley et al., 1993; 1996. 6. Barkley, et al., 1990. 7. Mannuzza et al., 1997. 8. Biederman et al., 1997. 9. Pomerleau et al., 1995. 10. Wilens et al., 1995. 11. Barkley, Fischer et al., 1991. 12. Brown & Pacini, 1989. 13. Mash & Johnston, 1983. 14. Noe et al., 1999.

How ADHD Affects Parents:

Murphy D, Barkley B. Am J Orthopsychiatry. 1996;66:93-102. How ADHD Affects Parents Increased stress Worry — Anxiety Frustration — Anger Lower self-esteem Self-blame — Depression Social isolation Increased employment disruption Increased marital disruption Increased alcohol/substance abuse

American Academy of Pediatrics: Guidelines for ADHD Assessment:

AAP. Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics . 2000;105:1158-1170. American Academy of Pediatrics: Guidelines for ADHD Assessment Evaluate children (age 6 to 12 years) who exhibit the following: Inattention Hyperactivity Impulsivity Academic underachievement Behavioral problems DSM-IV criteria Evidence from parents/caretakers and teachers/school professionals of core symptoms of ADHD in school, home, and social settings Assessment for co-existing conditions Other diagnostic tests are not routinely indicated

ADHD: Conclusions:

ADHD: Conclusions Characterized by inattention, hyperactivity, and impulsivity The worldwide prevalence is estimated to be 3% to 7% Specific guidelines employ DSM-IV criteria for diagnosis Impairments often occur in home, school, and job settings and persist from childhood through adulthood Genetic factors often contribute to the etiology Neuroimaging research demonstrates significant differences in the brains of individuals with ADHD Affected brain areas such as the cortical-striatal-thalamic-cortical circuit are known to control attention, motoric output, impulsivity, and executive functions

ADHD Treatment Strategies :

ADHD Treatment Strategies

Treatment Requires Understanding:

Treatment Requires Understanding Neurotransmitters offer a crucial conceptual bridge between the mind and the brain .

Reduced Neurotransmission and Neural Adaptability:

SEROTONIN NOREPINEPHRINE DOPAMINE IMPAIRED MODULATION IMPAIRED ACTIVATION DEPRESSION Metzner, 2000 Fatigue Apathy Anhedonia Hypersomnia Lack of initiative Inability to concentrate Decreased productivity Anxiety Irritability Hostility Impulsivity Agitation Hypochondriasis Suicidality Reduced Neurotransmission and Neural Adaptability

Three Components of ADHD Treatment:

Three Components of ADHD Treatment Education Psychosocial interventions Pharmacotherapeutic interventions

Non-Pharmacological Treatment of ADHD:

Non-Pharmacological Treatment of ADHD Education of family and child Formal psychosocial intervention (behavioral modification involves setting goals, defining progress, determining incentives) Social skills training Dietary, herbal, and homeopathic treatments (limited benefits) Biofeedback, meditation, and perceptual stimulation/ training

Pharmacological Treatment of ADHD:

Pharmacological Treatment of ADHD CNS stimulants Methylphenidate D-amphetamine, mixed salts amphetamines Pemoline Selective norepinephrine reuptake inhibitor Atomoxetine Other agents under investigation Antihypertensives (e.g., clonidine) Antidepressants (e.g., desipramine, bupropion) Wake-promoting agent (e.g., modafinil)

Treatment Adherence:

Education Communication Collaboration Nierenburg. J Clin Psychiatry. 1999; Delgado. J Clin Psychiatry. 2000 Treatment Adherence

Education of Patients and Family:

AACAP. J Am Acad Child Adolesc Psychiatry . 1997;36:85S-121S. 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

Treatment Strategies for ADHD:

MTA Cooperative Group. Arch Gen Psych. 1999;56:1073-1086. Treatment Strategies for ADHD The multimodal treatment study of children with ADHD (MTA) — 14-month clinical trial of treatment strategies — 579 children with ADHD — Subjects randomized to one of 4 treatment conditions Medication management Behavior management Medication management and behavior management Community-based treatment

Long-term Outcomes of Therapies for ADHD in the MTA Study:

Long-term Outcomes of Therapies for ADHD in the MTA Study Hyperactive Impulsive Symptoms (Teacher Reports) 0 10 20 30 40 50 60 70 Medication management Combination therapy (medication + behavior therapy) Behavioral treatment Community-based treatment Improvement at 14 months (%) 65 55 45 35 25 15 5 56% 60% 45% 36%

Medication Management or Combination Therapy Is More Effective in the MTA:

MTA Cooperative Group. Arch Gen Psych. 1999;56:1073-1086. Medication Management or Combination Therapy Is More Effective in the MTA All treatment arms improved symptoms on an absolute basis Medication management alone or medication management with behavior management for ADHD symptoms were almost equally effective Medication management alone or medication management with behavior management were superior to behavior management or community-based treatment

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. Psychosocial Interventions in ADHD Treatment

Psychotherapy:

Psychotherapy

American Academy of Pediatrics: Guidelines for the Treatment of ADHD:

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.

Strattera® (atomoxetine HCl) for the Treatment of Attention-Deficit/ Hyperactivity Disorder: Clinical Perspectives:

Strattera ® (atomoxetine HCl) for the Treatment of Attention-Deficit/ Hyperactivity Disorder: Clinical Perspectives

Controlled Studies of Medication in ADHD:

Antihypertensives Neuroleptics Antidepressants Stimulants N=6472 children, adolescents, and adults. Controlled Studies of Medication in ADHD Spencer et al. JAACAP 1996;35:409. 155 21 12 3

Treating ADHD: What Works? :

Treating ADHD: What Works? Of the pharmacologic options available for ADHD, stimulant medications are the Most studied Most commonly used Most effective First-line agents for treatment Spencer et al. JAACAP 1996;35:409. ADHD Practice Parameters. JAACAP 1997;36:85S. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. 2000.

ADHD: Stimulant Treatment:

ADHD: Stimulant Treatment Safety profile for stimulants Stimulants have been studied as psychotropic medications since the 1930s 1 Side-effects are generally mild, short-lived, and responsive to dose or timing adjustment 1,2 No consistent reports of behavioral rebound, motor tics or dose-related growth delays have been found in controlled studies 2 Tactics exist to deal with side effects such as insomnia and appetite loss 1 1 Greenhill L et al. J Am Acad Child Adolesc Psychiatry 2002;41(Suppl 2):26S-49S. 2 American Academy of Pediatrics. Pediatrics 2001;108:1033-1044.

In treatment of ADHD, stimulants improve::

Swanson et al. Except Child 1993;60:154. In treatment of ADHD, stimulants improve: Inattention Impulsivity Hyperactivity Impulsive aggression Social interactions Academic productivity and accuracy AND Core Symptoms ADHD and Stimulant Medication

In ADHD: Stimulants Found to Improve:

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. In ADHD: Stimulants Found to Improve Core Symptoms Inattention Impulsivity Hyperactivity Other Symptoms Noncompliance Impulsive aggression Social interactions Academic efficiency Academic accuracy Family dynamics

Stimulants: Potential Side Effects:

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

ADHD: Stimulant Treatment:

ADHD: Stimulant Treatment Abuse potential of stimulant medications Adolescents treated with stimulants have a lower risk of substance use disorder than ADHD adolescents not receiving stimulant medication 1 Orally administered MPH does not induce euphoria 2 CONCERTA ® has minimal potential for abuse and diversion, as the tablet cannot be readily crushed and the MPH is in a form which cannot be ground up or snorted 1 1 Greenhill L et al. J Am Acad Child Adolesc Psychiatry 2002;41(Suppl 2):26S-49S. 2 Volkow ND et al. Arch Gen Psychiatry 1995; 52 (6):456-463.

Pharmacotherapy Significantly Reduces Substance Abuse in Adults with ADHD:

Biederman J, et al. Pediatrics. 1999;104:e20-e25. 40 30 20 10 0 % of study population Unmedicated ADHD Medicated ADHD Control 32 12 10 Effect of pharmacotherapy P <0.001 Pharmacotherapy Significantly Reduces Substance Abuse in Adults with ADHD (N=56) (N=19) (N=137)

ADHD: Stimulant Treatment:

ADHD: Stimulant Treatment Stimulants: Methylphenidate (MPH) First-line treatment for ADHD Unsurpassed efficacy 1 Superior tolerability 1 Available as formulations with different durations of effect: Short-acting (3–4 hours) Intermediate-acting (3–8 hours) Long-acting (9–12 hours) d-Isomer (6-7.5 hours) 1 Greenhill L et al., J Am Acad Child Adolesc Psychiatry 2002;41(Suppl 2):26S-49S.

ADHD: Stimulant Treatment:

ADHD: Stimulant Treatment Short-acting MPH e.g. Ritalin ® , Methylin ® Requires bid or tid dosing Intermediate-acting MPH e.g. Ritalin ® SR, Metadate ® ER, Methylin™ ER Metadate ® CD: Uses Diffucaps technology, to achieve a biphasic dose (30% immediate-release and 70% controlled-release) with 8 hour duration of effect 1 Ritalin ® LA: Uses SODAS technology (50% immediate-release and 50% extended-release beads) to achieve 6–9 hour duration of effect 1 . Ideally requires bid dosing to achieve symptom control throughout the day. 1 Greenhill L. Are new stimulants really better? Presented at the American Academy of Child and Adolescent Psychiatry, Honolulu, HI: Oct. 2001.

ADHD: Stimulant Treatment:

ADHD: Stimulant Treatment Long-acting MPH e.g. CONCERTA ® (methylphenidate HCI) CII Extended-release formulation using OROS ® technology to achieve 12-hour duration of action Designed to maintain a smooth effect through 12 hours Dex-MPH 1 e.g. Focalin ® (previously Ritadex ® ) d-isomer of MPH having a duration of action for 2-5 hours Active at approximately half the dose required for mixed isomer MPH therapies 1 Greenhill L. Are new stimulants really better? Presented at the American Academy of Child and Adolescent Psychiatry, Honolulu, HI: Oct. 2001.

Probable Mechanism of Action of Methylphenidate:

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

ADHD: Stimulant Treatment:

ADHD: Stimulant Treatment Stimulants: Amphetamines (AMP) Can also be chosen as first-line treatment for ADHD, however, problems with appetite and sleep are greater on average Short-acting (4–6 hours) e.g. Dexedrine ® , Dextrostat ® Intermediate-acting (6–8 hours) e.g. Adderall ® , Dexedrine ® Spansule Long-acting (10-12 hours) e.g. Adderall ® XR uses SODAS technology (50% immediate-release and 50% extended-release beads) to achieve estimated duration of effect Stimulants: Pemoline (PEM) Long-acting stimulant with gradual onset of action Not recommended for first- or second-line treatment of ADHD Greenhill L et al., J Am Acad Child Adolesc Psychiatry 2002;41(Suppl 2):26S-49S. American Academy of Pediatrics, Pediatrics 2001;108(4):1033–44.

Stimulants’ Proposed Mechanism of Action:

Adapted from Wilens & Spencer. Child Adolesc Psych Clin N Am 2000;9:573. NT Transporter (reuptake pump) Presynaptic Neuron Postsynaptic Neuron Neurotransmitter Transporter Neurotransmitter Output Storage Vesicle AMPH = NT = neurotransmitter; dopamine or norepinephrine AMPH = amphetamine MPH = methylphenidate Stimulants’ Proposed Mechanism of Action

WELLBUTRIN SR,XL,IR(Non FDA approved)® (BUPROPION HCl) CLINICAL EXPERIENCE IN ADHD :

WELLBUTRIN SR,XL,IR(Non FDA approved) ® (BUPROPION HCl) CLINICAL EXPERIENCE IN ADHD

Use for the Treatment of ADHD:

Use for the Treatment of ADHD Not indicated for ADHD Data indicate: Efficacy in adults and children Efficacy comparable to Ritalin Efficacy in Ritalin responders Efficacy in ADHD with unipolar depression/substance abuse Efficacy in ADHD with bipolar depression Generally well-tolerated §

WELLBUTRIN (bupropion HCL) FOR ADHD:

WELLBUTRIN (bupropion HCL) FOR ADHD Bupropion vs methylphenidate Data in adults and children Bupropion vs placebo Data in adults and children Bupropion open-label Data in adults and children Clinical Experience

WELLBUTRIN (Bupropion HCL) FOR ADHD IN CHILDREN:

WELLBUTRIN (Bupropion HCL) FOR ADHD IN CHILDREN Bupropion vs methylphenidate (n=15) Comparable efficacy No significant difference between treatments Bupropion vs placebo (n=109) Efficacy superior to placebo Bupropion open-label (n=56) Significant improvement over baseline Bupropion generally well-tolerated in all studies Summary of Published Studies

Slide 113:

Results Efficacy of bupropion and methylphenidate comparable No significant difference between treatments on any efficacy measure Significant improvement over baseline with both treatments Safety Adverse events minimal for both treatments No adverse event led to discontinuation of treatment Bupropion vs Methylphenidate WELLBUTRIN (Bupropion HCL) FOR ADHD IN CHILDREN Barrickman, J Am Acad Child Adolesc Psychiatry 1995

WELLBUTRIN (Bupropion) FOR ADHD IN CHILDREN:

WELLBUTRIN (Bupropion) FOR ADHD IN CHILDREN Study design Open label (with single-blind placebo lead-in) 10-week treatment phase Patients ADHD with depression (n=17) Age range - 11 to 16 years Treatment Wellbutrin SR 2 to 6 mg/kg/day Daviss, Poster presented at APA Annual Meeting 1999 ADHD with Comorbid Depression

WELLBUTRIN (Bupropion HCL) FOR ADHD IN CHILDREN:

WELLBUTRIN (Bupropion HCL) FOR ADHD IN CHILDREN ADHD with Comorbid Depression Results Significant improvement in ADHD and depressive symptoms 63% (n=10) responders * for ADHD symptoms 88% (n=14) responders * for depressive symptoms Wellbutrin SR generally well-tolerated No adverse event led to discontinuation of treatment No serious adverse events reported * Response = CGI-I of much improved or very much improved Daviss, Poster presented at APA Annual Meeting 1999

Slide 116:

Conners, J Am Acad Child Adolesc Psychiatry 1996 WELLBUTRIN (Bupropion HCL) FOR ADHD IN CHILDREN Results Bupropion significantly superior to placebo Significantly greater improvement in hyperactivity, restlessness, and impulsivity Significantly greater improvement in conduct Significantly greater improvement in memory retrieval Bupropion generally well-tolerated No clinically significant changes in vital signs 4 patients discontinued bupropion due to adverse events Bupropion vs Placebo

WELLBUTRIN SR FOR ADHD IN CHILDREN:

Efficacy comparable to methylphenidate Efficacy superior to placebo Effective in ADHD with comorbid depression Significant improvement in ADHD and depressive symptomatology Effective in ADHD responsive to methylphenidate Generally well-tolerated WELLBUTRIN SR FOR ADHD IN CHILDREN Summary

WELLBUTRIN SR FOR ADHD IN CHILDREN:

Objective To determine if Wellbutrin SR would be effective and well-tolerated for the treatment of ADHD in adolescents who were responsive to Ritalin Hudziak, Presented at APA Annual Meeting 2000 WELLBUTRIN SR FOR ADHD IN CHILDREN ADHD Responsive to Methylphenidate

WELLBUTRIN SR FOR ADHD IN CHILDREN:

Study design Open-label 8-week treatment phase Patients ADHD currently responsive to methylphenidate (n=20) Age (mean) - 14 years Treatment Initiated 1 day after methylphenidate discontinued Wellbutrin SR titrated to 150 mg BID (150 mg QD x 1 week; then 150 mg BID) Hudziak, Presented at APA Annual Meeting 2000 WELLBUTRIN SR FOR ADHD IN CHILDREN ADHD Responsive to Methylphenidate

WELLBUTRIN SR FOR ADHD IN CHILDREN:

Results 95% (19/20) of patients improved following switch from methylphenidate to Wellbutrin SR ADHD and hyperactivity improved with Wellbutrin SR Aggression and anxious/depressed problems improved with Wellbutrin SR Fewer patients exhibited social, anxious/depressed, and attention problems with Wellbutrin SR Wellbutrin SR generally well-tolerated No serious adverse events reported Hudziak, Presented at APA Annual Meeting 2000 WELLBUTRIN SR FOR ADHD IN CHILDREN ADHD Responsive to Methylphenidate

WELLBUTRIN SR FOR ADHD IN ADULTS:

Study design Placebo-controlled 6-week treatment phase Patients ADHD (n=40) Age (mean) - 38 years Treatment Wellbutrin SR up to 400 mg/day Placebo WELLBUTRIN SR FOR ADHD IN ADULTS Wellbutrin SR vs Placebo Wilens, Poster presented at NCDEU 1999

WELLBUTRIN SR FOR ADHD IN ADULTS:

Results Wellbutrin SR significantly superior to placebo 76% of patients responded * to Wellbutrin SR 37% of patients responded * to placebo Wellbutrin SR was generally well-tolerated No serious adverse events reported No adverse event led to discontinuation of treatment WELLBUTRIN SR FOR ADHD IN ADULTS Wellbutrin SR vs Placebo Wilens, Poster presented at NCDEU 1999 * Response defined as  30% reduction in DSM IV ADHD symptom checklist scores

WELLBUTRIN SR FOR ADHD IN ADULTS:

% of Patients * p=0.012 Wilens, Poster presented at NCDEU 1999  30% Improved ADHD Symptom Checklist WELLBUTRIN SR FOR ADHD IN ADULTS Wellbutrin SR vs Placebo

WELLBUTRIN SR FOR ADHD IN ADULTS:

% of Patients * p=0.005 Wilens, Poster presented at NCDEU 1999 CGI Scores WELLBUTRIN SR FOR ADHD IN ADULTS Wellbutrin SR vs Placebo Much or Very Much Improved at week 6

WELLBUTRIN SR FOR ADHD:

Further investigation needed to clarify role of Wellbutrin SR in treating ADHD Data suggest efficacy superior to placebo Data suggest efficacy comparable to methylphenidate Data suggest efficacy in treating ADHD with comorbid depression Data suggest efficacy in treating ADHD responsive to methylphenidate WELLBUTRIN SR FOR ADHD Summary

Treatment of Adult ADHD with Bupropion, Methylphenidate, and Placebo:

Kuperman S, et al. Ann Clin Psychiatry 2001;13:129-34. Treatment of Adult ADHD with Bupropion, Methylphenidate, and Placebo 0 10 20 30 40 50 60 70 Bupropion Methylphenidate Placebo % Improved (CGI)

The Need for Once-Daily Dosage Options:

The Need for Once-Daily Dosage Options Extended medication coverage needed After school, extracurricular activities Social interactions Homework hours Problems with in-school dosing Privacy issues Ridicule by peers; decreased self-esteem Storage of controlled medications Security; potential for diversion

New Stimulant Formulations:

New Stimulant Formulations Concerta™: methylphenidate formulated for effective 12 h dosing Metadate ® CD: methylphenidate formulated for effective 8 to 9 h dosing Adderall XR™: once-daily, extended-release formulation of mixed amphetamines Focalin™: a refined form of Ritalin, isolating only the effective isomer Long Acting Ritalin ® : new product in development and awaiting FDA approval; designed to last the school day

Slide 129:

CONCERTA ® : Treatment Extended-release CONCERTA ® Once-a-day dosing Eliminates the need for in-school and after-school dosing, and may improve compliance Immediate-release overcoat Efficacy that lasts through 12 hours Parents and physicians prefer 12-hour duration 1 Standard of care established by MTA Study 2 Ascending plasma profile Minimizes fluctuations in peak and trough plasma concentrations associated with methylphenidate dosed 3 times a day 3 1 Data on file 2 MTA Cooperative Group Study, Arch Gen Psychiatry 1999; 56:1073-1086. 3 Lerner et al. Poster presentation at PAS/AAP, Boston, MA, May 2000.

Slide 130:

CONCERTA ® : OROS ® Formulation MPH Overcoat Tablet Shell Push Compartment MPH Compartment #2 Laser-Drilled Hole MPH Compartment #1

CONCERTA®: Dosing:

CONCERTA ® : Dosing CONCERTA is available in the following doses for the treatment of ADHD: The 27mg tablet is now available for increased dosing flexibility

ADDERALL XR™ Pulse Delivery System:

ADDERALL XR™ Pulse Delivery System Adderall is registered in the US patent and trademark office.

ADDERALL XR™ Formulation Study:

ADDERALL XR™ Formulation Study Adderall XR™ QD is designed to follow a time-course similar to BID Adderall ® with a 4-hour interval Tested in 20 healthy adult volunteers in a randomized, crossover design: Adderall XR™ 20 mg QD Adderall ® 10 mg BID with a 4-hour interval Blood was collected at multiple points over a 48-hour post-dose period Subjects were crossed over to the alternate dosing condition separated by at least a 1-week period Adapted from data on file and package insert, 2002.

ADDERALL XR™ Dosing:

ADDERALL XR™ Dosing ADDERALL XR ™ can be taken with or without food Capsules can be taken whole or the capsule may be opened and the entire contents sprinkled on applesauce Capsule Strength 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg Released Upon Ingestion 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg 15 mg Released at 4 Hours 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg 15 mg

Focalin™ (dexmethylphenidate HCl):

Focalin ™ (dexmethylphenidate HCl) A Refined Form of Ritalin ®

Focalin™: A Refined Form of Ritalin®:

H N H H Ph CH 3 OOC 2’ 2 D (+) Methylphenidate Dexmethylphenidate H H H Ph COOCH 3 2’ 2 l (-) Methylphenidate N Focalin ™ : A Refined Form of Ritalin ®

Focalin™: A Refined Form of Ritalin®:

Focalin ™ : A Refined Form of Ritalin ® Ritalin ( d,l -methylphenidate HCl) is an asymmetric molecule made up of 2 optical isomers Pharmacodynamic activity of Ritalin ® resides mostly with the d-isomer (right half) Focalin was created by isolating the effective d-isomer

Focalin™ PET Scans: d-Methylphenidate vs l-Methylphenidate:

Focalin ™ PET Scans: d -Methylphenidate vs l -Methylphenidate Quinn, DMP, in Ritalin Theory and Practice . 1999; 369-374. [11C] dexmethylphenidate [11C] l-threo-methylphenidate

Focalin™: Dosing Flexibility:

Flexible control Focalin provides a short duration of effect for flexible dosing needs Easy to Start Recommended starting dose: 2.5 mg BID Dose at least 4 hours apart May be taken with or without food Focalin ™ : Dosing Flexibility Data on file. Easy to Convert Recommended conversion doses from other methylphenidates are half the dose of racemic methylphenidate 5 mg 10 mg 20 mg 2.5 mg 5 mg 10 mg METHYLPHENIDATE DOSE FOCALIN DOSE 2.5 mg 5 mg 10 mg

Focalin™: Summary:

Focalin ™ : Summary Focalin is the refined form of Ritalin, created by isolating the effective d-isomer (right half) of d , l -methylphenidate (Ritalin) Focalin provides short duration of action for flexible control of ADHD symptoms Focalin was proven to be efficacious in controlling the symptoms of ADHD Focalin was shown to have a favorable safety and tolerability profile, with minimum adverse effects

Straterra (atomoxetine HCI):

Straterra (atomoxetine HCI) Treatment of Attention-Deficit/ Hyperactivity Disorder: Clinical Perspectives

Indication:

Indication Straterra is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder in Children aged 6 and older, adolescents, and adults

Strattera® (atomoxetine HCl) for the Treatment of Attention-Deficit/ Hyperactivity Disorder: Clinical Perspectives:

Strattera ® (atomoxetine HCl) for the Treatment of Attention-Deficit/ Hyperactivity Disorder: Clinical Perspectives

Strattera® (atomoxetine HCl) Overview:

Strattera ® (atomoxetine HCl) Overview

Indication:

Indication

Strattera® (atomoxetine HCl): A Norepinephrine Reuptake Inhibitor (NRI):

Strattera ® (atomoxetine HCl): A Norepinephrine Reuptake Inhibitor (NRI)

Strattera® (atomoxetine HCl) Mechanism of Action:

Strattera ® (atomoxetine HCl) Mechanism of Action

Strattera® (atomoxetine HCl) Pharmacokinetics:

Strattera ® (atomoxetine HCl) Pharmacokinetics

Strattera® (atomoxetine HCl) Effects on Dopamine (DA)*:

Strattera ® (atomoxetine HCl) Effects on Dopamine (DA)*

Strattera® (atomoxetine HCl) Pharmacodynamics:

Strattera ® (atomoxetine HCl) Pharmacodynamics

Efficacy of Strattera® (atomoxetine HCl) Adults:

Efficacy of Strattera ® (atomoxetine HCl) Adults

Strattera® (atomoxetine HCl) Efficacy in Adults:

Strattera ® (atomoxetine HCl) Efficacy in Adults

Strattera® (atomoxetine HCl) Efficacy in Adults: Conners’ Rating Scale :

Strattera ® (atomoxetine HCl) Efficacy in Adults: Conners ’ Rating Scale

Strattera® (atomoxetine HCl) Adverse Events: Adult Studies :

Strattera ® (atomoxetine HCl) Adverse Events: Adult Studies

Drug Interactions :

Drug Interactions

Drug Interactions (cont.) :

Drug Interactions (cont.)

Ease of Dosing: Choose starting dose and maintain for minimum of 3 days Proceed to target dose thereafter:

Ease of Dosing: Choose starting dose and maintain for minimum of 3 days Proceed to target dose thereafter Patient Weight Range Starting Dose (minimum of 3 days) Target Dose 40-62 lbs 18mg 25mg 63-93 lbs 25mg 40mg 94-126 lbs 40mg 60mg 127+ lbs 40mg 80mg

Ease of Dosing:

Ease of Dosing

Conclusions:

Conclusions Provides continuous symptom relief dosed QD School Home Improves measurements of functional outcomes Incidence of insomnia comparable to placebo in children/adolescents Extended safety data (up to 18 months) Not contraindicated in patients with tics or anxiety Convenient for patient/parent/physician Nonstimulant, noncontrolled Ease of dosing

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