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The Diagnosis and Treatment


Jess P. Shatkin, MD, MPH

Vice Chair for Education
NYU Child Study Center
New York University School of Medicine
Learning Objectives
Residents will be able to:
1. Identify symptom criteria for ADHD.
2. State the major rule-out diagnoses.
3. Identify the primary comorbidities.
4. Describe the diagnostic process.
5. Choose between various treatment options
based upon their risk/benefit profiles.
The Story of Fidgety Phillip
--Dr. Heinrich Hoffman, 1844
"Let me see if Philip can
Be a little gentleman;
Let me see if he is able
To sit still for once at table."
Thus spoke, in earnest tone,
The father to his son;
And the mother looked very grave
To see Philip so misbehave.
But Philip he did not mind
His father who was so kind.
He wriggled
And giggled,
And then, I declare,
Swung backward and forward
And tilted his chair,
Just like any rocking horse;-
"Philip! I am getting cross!"
History of ADHD
 Minimal Brain Dysfunction (damage): 1900 – 1950
 Hyperkinetic/Hyperactivity Syndrome (DSM-II of
1968): 1950 – 1969
 Recognition of Attentional impairment and
Impulsivity: 1970 – 1979
 Diagnostic Criteria (DSM-III) and “ADD” with or
without Hyperactivity: 1980
 ADD becomes ADHD (DSM-IIIR) w/mixed criteria:
 ADHD (inattentive, hyperactive, combined subtypes)
in DSM-IV: 1994
Differential Diagnosis
 Mood and/or Psychotic Disorder
 Anxiety Disorder
 Learning Disorder
 Mental Retardation/Borderline IQ
 ODD/Conduct Disorder
 Pervasive Developmental Disorder
 Substance Abuse
 Axis II Disorders
 Psychosocial Cx (e.g., abuse, parenting, etc.)
Differential Diagnosis
 Seizure Disorder (e.g., Absence, Complex-Partial)
 Chronic Otitis Media
 Hyperthyroidism
 Sleep Apnea
 Drug-Induced Inattentional Syndrome
 Head Injury
 Hepatic Illness
 Toxic Exposure (e.g., lead)
 Narcolepsy
DSM-IV Diagnostic Criteria
 Makes careless mistakes/poor attention to detail
 Difficulty sustaining attention in tasks/play
 Does not seem to listen when spoken to directly
 Difficulty following instructions
 Difficulty organizing tasks/activities
 Avoids tasks requiring sustained mental effort
 Loses items necessary for tasks/activities
 Easily distracted by extraneous stimuli
 Often forgetful in daily activities
DSM-IV Diagnostic Criteria
 Fidgets
 Leaves seat
 Runs or climbs excessively (or restlessness)
 Difficulty engaging in leisure activities quietly
 “On the go” or “driven by a motor”
 Talks excessively
 Blurts out answers before question is completed
 Difficulty waiting turn
 Interrupts or intrudes on others
DSM-IV Functional Criteria
 6 of 9 symptoms in either or both categories
 Code as: Inattentive; Hyperactive-
Impulsive; or Combined Type
 Persisting for at least 6 months
 Some symptoms present before 7 y/o
 Impairment in 2 or more settings
 Social/academic/occupational impairment
Epidemiology (1)
 Most commonly diagnosed behavioral disorder
of childhood (1 in 20 worldwide)
 3 – 7% of school children are affected in U.S.
 Males:Females = 2 – 9:1
 Virtually all neurodevelopmental disorders are
more common in boys prior to age 10 years; by
adulthood, we get closer to 1:1 ratios
Epidemiology (2): Gender Paradox
 Girls typically show less hyperactivity, fewer
conduct problems, & less externalizing behavior
 Yet we see a gender paradox
– The group with the lower prevalence will show a
more severe clinical presentation, along with
severity/greater levels of comorbidity (Loeber &
Keenan, 1994)
– Consistent with multifactorial/polygenic conditions:
 The idea is that it takes a greater accumulation of
vulnerability and risk factors to put an individual from the
lower-afflicted group “over the top”
Epidemiology (3)
 At least 30 – 50% maintain diagnosis for ≥ 15 yr
 Strongest predictor of poor prognosis is pre-
pubertal aggression
 Over 80% of psychotropics are Rx by PCPs:
stimulants (>50%), antidepressants (30%), mood
stabilizers (13%), anxiolytics (7%), &
antipsychotics (7%)
 ADHD related outpatient visits to PCPs
increased from 1.6 – 4.2 million between 1990 -
Too Much of a Good Thing?
 Between 1991 – 2000, the annual production of
MPH rose by 740%; production of amphetamine
increased 25x during this same period.
 In 2000, America used 80% of the world’s
stimulants; most other industrialized countries
use 1/10 the amount we do. Canada uses
stimulants at 50% of the US rate.
 Rates vary by states and regions: Hawaii has the
lowest per capita MPH use by a factor of 5.
“Hot spots” are mostly in the east near college
campuses and clinics that specialize in Dx/Rx.
But wait, there’s more!
 Approximately 2.5 million children in the
US (ages 4 – 17) took medication for
ADHD in 2004
 Sales of medications used to treat ADHD
rose to $3.1 billion in 2004 from $759
million in 2000
Medical Expenditure Panel
Survey, 2008
 3.5% of US children (2.8 million kids) aged
18 and younger received a stimulant
medication in 2008, up from 2.9% in 1996
 Stimulant use in girls increased over 10
years from 1.1% to 1.6%
 Stimulant use in preschoolers decreased,
stayed the same for 6 – 12 y/o, and
increased for adolescents
Hey, Kids Can’t Have All the
 Adult use of these medications increased 90%
between March 2002 and June 2005…can you
say Strattera?!
 Use of meds to treat ADHD in adults aged 20 –
44 rose 19% in 2005
 An estimated 1.7 million adults aged 20 – 64
and 3.3 million children under 19 took
medication for ADHD in 2005
– Use increased 2% for those 10 – 19
– Use decreased by 5% for those under 10
ADHD is Familial
 Family studies: (1) sibling risk increases 2-5x;
(2) 3-5x increased likelihood that parent is
affected (9 – 35%)
Symptom Evolution



ADHD: Course of the Disorder

Why More ADHD?

 Improved recognition by physicians?

 Increase in prevalence?
 An easing of standards for making the diagnosis?
 An easing of standards for prescribing
medication?...or the “Prozac” connection?
 Increased scholastic demands?
 Changing parental habits?
 Managed care and the pharmaceutical industry?
 1991 amendments to IDEA?
Potential Areas of Impairment
Occupational/ Relationships

Legal Low self

difficulties ADHD esteem

Motor vehicle
accidents Injuries
Smoking and
substance abuse
Comorbidities (1)
 2/3 of children with ADHD present with ≥ 1
comorbid Axis I disorder:
Comorbidities (2)
 ≥ 84% of children with ADHD demonstrate
psychopathology as adults
 Adolescents w/ADHD Rx w/stimulants have
lower rates of substance abuse than untreated
adolescents w/ADHD
 Educational impairments
 Employment problems
 Greater sexual-reproductive risks
 Greater motor vehicle risks
Natural History
 Rule of “thirds”:
– 1/3  complete resolution
– 1/3  continued inattn, some impulsivity
– 1/3  early ODD/CD, poor academic achievement,
substance abuse, antisocial adults
 Age related changes:
– Preschool (3-5 y/o) – hyperactive/impulsive
– School age (6-12 y/o) – combination symptoms
– Adolescence (13-18 y/o) – more inattn w/restlessness
– Adult (18+) – largely inattn w/periodic impulsivity
Brain Imaging and ADHD
 Numerous imaging studies have now
demonstrated the following:
– The caudate nucleus and globus pallidus (striatum)
which contain a high density of DA receptors are
smaller in ADHD than in control groups
– ADHD groups have smaller posterior brain regions
(e.g.,occipital lobes)
– Areas involved in coordinating activities of multiple
brain regions are (e.g., rostrum and splenium of
corpus collosum and cerebellar vermis) are smaller in
Developmental Trajectories of Brain Volume
Abnormalities in Youth with ADHD
 Smaller brain volumes in all regions regardless
of medication status (cortical white & gray
 Smaller total cerebral (-3.2%) and cerebellar (-
3.5%) volumes
 Volumetric abnormalities (except caudate)
persist with age
 No gender differences
 Volumetric findings correlate with severity of
• Castellanos et al, 2002
Cortical Thickness in ADHD: Cingulate Cortex
Makris et al.

Shaw et al., Arch Gen Psychiatry 2006

Specific Genes Associated w/ADHD
 Rare mutations in the human thyroid receptor β
gene on chromosome 3
 Symptoms suggestive of ADHD are found among those w/a
general resistance to thyroid hormone (Hauser et al, NEJM,
 Dopamine Transporter gene (DAT) on
chromosome 5
 A “hyperactive” presynaptic DAT (Gill et al, Mol Psych,
 Dopamine Receptor D4 gene (DRD4) on
chromosome 11
 Postsynaptic malfunction do not allow signal transmission
(Swanson et al, Mol Psych, 1998)
Thickness &
Shaw et al.
AGP 2007
Potential Non-Genetic Causes
 Non-genetic causes of ADHD are also
neurobiological in nature
– Perinatal stress
– Low birth weight
– Traumatic brain injury
– Maternal smoking during pregnancy
– Severe early deprivation (extreme)
• Nigg, 2006
Executive Functioning
 Most children with ADHD have
impairments in executive functioning,
– Response inhibition
– Vigilance
– Working memory
– Difficulties with planning
• Wilcutt et al, 2005
Neuropsychological Testing
 Nigg (2005) in a meta-analysis identified the most
common abnormalities in various neuropsych tasks
in ADHD (listed by Effect Size):
– Spatial working memory (0.75)
– CPT d-prime (0.72)
– Stroop Naming Speed (0.69)
– Stop Task Response Suppression (0.61)
– Full Scale IQ (0.61)
– Mazes, a planning measure (0.58)
– Trails B Time (0.55)
Establishing a
Convincing Diagnosis (1)
 There is no single test to identify ADHD
 Available “tests” are primarily Continuous
Performance Tests (CPTs):
– TOVA (Test of Variables of Attention)
– Conner’s CPT
– Gordon Computerized Diagnostic System
– I.V.A. CPT
 Diagnosis must be multi-factorial
Establishing a
Convincing Diagnosis (2)
 Clinical Interview:
– Diagnostic Assessment of Primary Complaint
– Review of Psychiatric Systems (e.g., attention,
hyperactivity/impulsivity, oppositional & conduct
difficulties, mood, anxiety, psychosis, trauma,
neurovegetative systems, tics, substance abuse, etc.)
– Medical, Psychiatric, & Developmental History
– Detailed Educational History
– Detailed Family & Social History
Establishing a
Convincing Diagnosis (3)
 Collateral interviews:
– Patient
– Primary Caregivers (parents, grandparents, etc.)
– Teachers
– School Counselors
– Sunday School Teachers
– Coaches
– Music Teachers
– Camp Counselors (e.g., Boys & Girls’ Club)
Establishing a
Convincing Diagnosis (4)
 “Some” symptoms by age 7 years
 This criterion has been maintained in 3 versions of the
DSM, despite a lack of empirical support
 Likely leads to increased false-negatives
 DSV-IV field trials demonstrated that inattentive subtype
exhibited a later onset (Applegate et al, 1997)
 An adult population survey found that only 50% of
individuals with clinical features of ADHD retrospectively
reported symptoms by age 7, but 95% reported symptoms
before age 12 & 99% before 16 (Kessler et al, 2005)
 DSM-V will possibly reset age to 12 years to decrease rate
of false negatives (Kieling et al, 2010)
Establishing a
Convincing Diagnosis (5)
 Symptoms in ≥ 1 setting:
– Never diagnose ADHD in a 1:1 interview
– Individuals with ADHD can often function well in
certain settings with no signs of symptoms when they
are interested and maintain total focus (e.g., playing
Nintendo, watching videos, etc.)
– Symptoms in group settings are a must!
Establishing a
Convincing Diagnosis (6)
 Rating scales:
– SNAP – IV (for parents & teachers)
– Conners (for teachers, parents, and affected adults)
– ACTeRS (for teachers & parents)
– Child Behavior Checklist
– Behavior Assessment System for Children (BASC)
– ADHD Rating Scale – IV
– Brown ADD Scales
Establishing a
Convincing Diagnosis (7)
 Treatment trial:
– Risk of adverse effects is significant
– Not necessarily “diagnostic” even if effective
– At least 2 – 3 medications should be attempted
before patient deemed non-responder
– Very low placebo response with treatment of
Who “Gets” ADHD?
 Children without insurance receive less
attention (e.g., care) in all domains
 Latino and black children are less likely to
be diagnosed with ADHD by parent report
than are white children
 Black children with ADHD are less likely to
receive stimulants than white children
*1997 – 2001 National Health Interview Surveys
*1997 – 2000 Medical Expenditure Panel Survey
Treatment (1)
 Medication
 Behavioral Therapy
– Cognitive/Behavioral Therapy
– Parent Management Training
– Social Skills Training
 Educational Support
– 504
– Individual Educational Plan (IEP)
Treatment (2):
The MTA Study of 1999
 Over 550 school-aged children with
ADHD were followed for 14 months:
1) Community Treatment
2) Rigorous Medication Protocol
3) Rigorous Behavioral Protocol
4) Combined Behavioral and Medication
Treatment (3)
 The MTA Study demonstrated:
– Medication (stimulants) treatment effective
– Behavioral treatment not effective for core
ADHD symptoms (useful for some related
– More frequent & higher dosing led to greater
– Increased physician contact improved outcome
Treatment (4)
 After 14 month initial MTA study, all follow ups were
naturalistic (patients could choose any treatment)
 2-Year Follow Up of MTA Study:
– Modest advantages for Meds & Combined Rx over Behavior
Rx & Community Care (effect sizes were reduced by about ½
in comparison to 14 month follow up)
 3-Year Follow Up of MTA Study:
– 485 of original 579 subjects participated
– No differences between groups at 36 months on any measure
(parent/teacher ADHD & ODD symptoms, reading
achievement scores, social skills, & functional impairment)
– Note: Compliance waned over time for med group (used IR
meds, not ER); medication treatment intensity group was
dropped after 14 months; initial medication only group
decreased medication use (91% to 71%) & behavioral only
group increased medication use (14% to 45%)
• Jensen et al 2007
Treatment (5)
 8-Year Follow Up of MTA Study:
– 436 of original 579 subjects participated
– No differences between groups at 6 & 8 years on any measure
(parent/teacher ADHD & ODD symptoms, reading
achievement scores, social skills, & functional impairment,
along with new variables: grades, arrests, & psych
– Note: Medication use decreased by 62%, but adjusting for this
did not change the outcome. Type or intensity of treatment in
the first 14 months did not predict functioning at 6 and 8 years
later. ADHD symptom trajectory over the first 3 years did
predict 55% of the outcomes. Children with behavioral and
sociodemographic advantage and with the best response to any
treatment will have the best long-term prognosis.
• Molina et al 2009
Comorbidity in the MTA Study

ADHD alone ODD

179 126

Tic 15
4 1
2 67
3 Mood
Conduct 5
Stimulants (1):
Mechanism of Action
 Reuptake inhibition of NE & DA
 Cause increased release of presynaptic NE/DA
 Amphetamine promotes passive diffusion of NE
and DA into synaptic cleft
 Amphetamine promotes release of NE and DA
from cytoplasmic pools
 Amphetamine & Methylphenidate are mild
inhibitors of MAO
Mechanism of Action of Stimulants
Presynaptic Neuron


vv Storage
Cytoplasmic DA

blocks DA Transporter Methylphenidate
reuptake blocks
Synapse reuptake

Wilens T, Spencer TJ. Handbook of Substance Abuse: Neurobehavioral Pharmacology. 1998;501–513

Stimulants (2):
Response Rates
 70% response rate w/a single stimulant
(DEX/MPH); 90% respond if both tried
 No significant differences between Dexedrine,
Adderall, and Methylphenidate overall
 Behavioral rebound
 6 of 8 studies (involving 241 children ) in
preschool age (3 - 6 y/o) found MPH effective;
no studies w/ADD & DEX (paradoxically
FDA approved for preschool children)
Stimulants (3): Tachyphylaxis
Serum Level
Methylphenidate IR

Ritalin SR

Time (Hours)
Stimulants (4): Tachyphylaxis &
Successful Long Acting Stimulants
Serum Level
Methylphenidate IR
Long Acting Stimulant

Ritalin SR

Time (Hours)
Stimulants (5): Dosage &
 Routine PE prior to initiation of stimulants; Vitals
checked periodically
 Long-acting treatments (e.g., Concerta, Ritalin
LA, Adderall XR, Metadate CD) are good
options given concerns about tachyphylaxis
 Dosing averages: 30 mg/d MPH, 20 mg/d AD
 Ritalin LA & Adderall XR are good long-acting
choices for those with difficulty swallowing pills
Stimulants (6): Dosage and
Administration Continued
 Weight based dosing (not generally utilized)
– Methylphenidate @ 1 mg/kg
– Adderall @ 0.6 mg/kg
 Dose to clinical response
 Forced Dosage Titration
– E.g., for a 100+ pound child: Concerta: 18 mg/d
week #1; 36 mg/d week #2; and 54 mg/d week #3
– E.g., for a 50 pound child: Adderall XR: 5 mg/d
week #1; 10 mg/d week #2; and 15 mg/d week #3
Long Term Effects on Academic Success
 Mayo Clinic 18 year study (2008) of >5,000 children from birth
(370 with ADHD, 277 boys & 93 girls) found that treatment with
prescription stimulants is associated with improved long-term
academic success of children with ADHD.
 Girls and boys with untreated ADHD were equally vulnerable to
poor school outcomes.
 By age 13, on average, stimulant dose was modestly correlated with
improved reading achievement scores.
 Both treatment with stimulants and longer duration of medication
were associated with decreased absenteeism.
 Children with ADHD who were treated with stimulants were 1.8
times less likely to be retained a grade than children with ADHD
who were not treated.
– Barbaresi et al, 2008
Are Stimulants Protective?
 Certainly with regard to SUDS
 10-year, prospective study of 112 white males with ADHD ages 6 to 17
 82 (73%) had received stimulant treatment, with a mean treatment
duration of six years
 In comparison with those who never took stimulants, participants who
had received stimulant medication were significantly less likely to
subsequently develop MDD (24% versus 69% for those who were
stimulant naïve), conduct disorder (22% versus 67%), oppositional
defiant disorder (40% versus 88%) and multiple anxiety disorders (7%
versus 60%)
 Children receiving stimulant therapy also had significantly lower lifetime
rates of grade retention as compared to their counterparts who never
received stimulants (26% versus 63%)
--Biederman et al, 2009
Stimulants (7): Side Effects &
 Side Effects: Nausea, headache, early insomnia,
decreased appetite; tics, anxiety, HTN/tachycardia,
 Preschool Study of ADHD (PATS) demonstrated a
20% decrease in expected height and 55% decrease
in expected weight over 1 year of treatment
 Contraindications: HTN, symptomatic
cardiovascular disease, glaucoma, hyperthyroidism,
tics/Tourette’s (relative), drug abuse (relative),
psychosis (relative)
Stimulants (8): Sudden Cardiac Death
 Concerns about the cardiac safety of stimulants peaked in
2005 when Health Canada discontinued sales of Adderall
 FDA discovery of 25 reports of death among users of
stimulants between 1999 and 2003 and 54 cases of serious
CV problems (e.g., strokes, MI, arrhythmia).
 Based on 110 million Rx for MTP written for 7 million
kids between 1992 – 2005, the estimated rate of SCD
among treated patients was 2 – 5 times below the rate in
the general population
 The risk of dying of a sudden cardiac event is still under
1/1,000,000 and no more than is expected in an untreated
AHA/AAP Recommendations
 The American Heart Association released on April 21, 2008 a statement about
cardiovascular evaluation and monitoring of children receiving drugs for the treatment of
Attention Deficit Hyperactivity Disorder (ADHD).
 1. The scientific statement included a review of data that show children with heart
conditions have a higher incidence of ADHD.
 2. Because certain heart conditions in children may be difficult (even, in some cases,
impossible) to detect, the AAP and AHA feel that it is prudent to carefully assess children
for heart conditions who need to receive treatment with drugs for ADHD.
 3. Obtaining a patient and family health history and doing a physical exam focused on
cardiovascular disease risk factors (Class I recommendations in the statement) are
recommended by the AAP and AHA for assessing patients before treatment with drugs
for ADHD.
 4. Acquiring an ECG is a Class IIa recommendation. This means that it is
reasonable for a physician to consider obtaining an ECG as part of the evaluation of
children being considered for stimulant drug therapy, but this should be at the
physician's judgment, and it is not mandatory to obtain one.
 5. Treatment of a patient with ADHD should not be withheld because an ECG is not
done. The child's physician is the best person to make the assessment about whether
there is a need for an ECG.
 6. Medications that treat ADHD have not been shown to cause heart conditions nor have
they been demonstrated to cause sudden cardiac death. However, some of these
medications can increase or decrease heart rate and blood pressure. While these side
effects are not usually considered dangerous, they should be monitored in children with
heart conditions as the physician feels necessary.
Conflicting Data…sort of…

 Retrospective, case-control study; children who died of

sudden unexplained death were matched to children who died
in MVAs
 Medical, historical, and toxicology info was collected
 Children with identified heart abnormalities and family
history of SCD were excluded
 Of 564 cases, 10 (1.8%) of cases of sudden unexplained death
were treated with a stimulant at the time of death, as
compared with only two (0.4%) who died by MVA
 Gould et al, 2009
Stimulants (9): Pros & Cons
 Methylphenidate (Ritalin), Adderall, Dexedrine
 Pros:
– Highly effective
– Long history of use
 Cons:
– Limited duration of action
– Side effects [e.g., Nausea, headache, insomnia, decreased
appetite, tics (up to 65% w/MPH), anxiety, HTN/tachycardia,
– Contraindications [HTN, symptomatic cardiovascular disease,
glaucoma, hyperthyroidism, tics/Tourette’s (relative), drug
abuse (relative), psychosis (relative)]
Stimulants (10): Standard Care
 Routine Treatment with Stimulants and Atomoxetine
– Prior to treatment
 Height, weight, Blood Pressure & Heart Rate
 Cardiac Exam
 Family history of sudden cardiac death and/or personal or family
history of syncope, chest pain, shortness of breath, or exercise
intolerance warrants an ECG and pediatric cardiology referral for an
– During Treatment
 At least annual height & weight (compare to published norms); if
height for age decreases by > 1 standard deviation while on
stimulants, refer to a pediatric endocrinologist (re: possible growth
hormone deficiency or hypothyroidism)
 Repeat blood pressure and heart rate at least twice annually and
anytime prior and subsequent to a dosage increase
Tic Disorders
 Up to 65% of children initiating Rx with
MPH may develop a transient tic
 Simple Motor, Complex Motor, or Vocal
 Stimulants may cause or “unmask” tics
 Treatment: Alteration in stimulant dose,
discontinuation of stimulant, change of
stimulant, α-2 agonists, antipsychotics,
CBT, Strattera(?)
-2 Agonists (1): Mechanism of Action
 Increased basal activity of the locus coeruleus noradrenergic cell
bodies in patients with ADHD may decrease the response of the
 Consequently, treatments that reduce locus coeruleus activity (e.g,.
clonidine, guanfacine) have been hypothesized to improve
attentional, arousal, and cognitive processes (Pliszka et al, 1996)
 Clonidine binds to the three subtypes of alpha (2) -receptors, A, B
and C, whereas guanfacine binds more selectively to post-synaptic
alpha (2A) - receptors, which appears to enhance prefrontal
 Stimulation of the post-synaptic alpha-2A receptors is thought to
strengthen working memory, reduce susceptibility to distraction,
improve attention regulation, improve behavioral inhibition, and
enhance impulse control
-2 Agonists (2): Dosage,
Treatment, and Side Effects
 Useful for residual hyperactivity & impulsivity,
insomnia, treatment emergent tics, & aggression
Clonidine (0.1 – 0.3 mg/d) & Guanfacine (1 – 3 mg/d)
 Routine PE/VS prior to initiation of Rx
 Contraindications: CAD, impaired liver/renal function
 Side Effects: Rebound HTN/tachycardia, HOTN,
sedation, dizziness, constipation, H/A, fatigue
 Dosage: Start with HS and titrate toward morning
 Monitor BP, but ECG not routinely necessary
-2 Agonists (3):Supporting Data
 Clonidine (Catapres)
– DBPC (age range, 7–12 years) randomized to 4 groups
(clonidine, methylphenidate, clonidine plus
methylphenidate, or placebo) found at 16 weeks that
teachers did not find improvement in the clonidine-only
group but did indicate statistically significant
improvement in both methylphenidate groups. Parents of
children in the clonidine-only group, but not the
methylphenidate-only group, reported significant symptom
improvement (Palumbo et al, 2008, n =122)
– DBPC shows benefit with and w/out MPH in children with
Tourettes in reducing ADHD & tics (Tourette’s Study
Group 2003, n = 136)
– DBPC shows benefit in children w/comorbid MR
(Agarwal et al 2001, n = 10)
– Conners et al 1999 meta-analysis shows decreased effect
size compared to stimulants
-2 Agonists (4):Supporting Data
 Guanfacine (Tenex)
– RDBPC trial of 345 patients shows benefit in
treatment of ADHD in children (6-17) using long-
acting Tenex at 2, 3 & 4 mg/day; greatest benefit at
highest dose. The change from baseline in patients
with the inattentive ADHD subtype was not
statistically significant. Younger children (age range,
6–12 years) had greater responses to guanfacine than
did adolescents (age range, 13–17 years). Only 62% of
all enrolled patients completed the study largely due to
fatigue, somnolence, and sedation (Biederman et al,
2008, n = 345)
– DBPC shows benefit in treatment of ADHD in
children w/comorbid tic d/o (Scahill et al 2001 n = 34)
– DBPC shows benefit in adults w/ADHD comparable
to dexedrine (Taylor et al 2001, n = 17)
 Guanfacine ER (Shire)
 Nonscheduled, alpha-2A receptor agonist indicated for ADHD
 Indicated for children and adolescents, ages 6 – 17 years, as solo
treatment or as augmenting medication to stimulants
 Available in November of 2009
 Dosages of 1, 2, 3, and 4 mg once daily
 In clinical trials, Intuniv significantly reduced ADHD symptoms across
a full day as noted by teachers (10 AM and 2 PM) and doctors
(throughout the day) and as measured by parents at 6 PM, 8 PM, and 6
AM the following morning
 Two randomized, DBPC trials: the first trial incorporated 345 children
on either placebo or a 2, 3, or 4 mg dose once daily for 8 weeks; the
second was a DBPC trial in which 324 children were given placebo or 1
– 4 mg per day for 9 weeks (1 mg given to children <50 kg). Doses
increased in both trials at 1 mg per week to treatment effect. Clinically
significant improvement noted in 1-2 weeks.
α-2 Agonists (5): Pros & Cons
 Clonidine (Catapres) and Guanfacine (Tenex)
 Pros:
– Moderately effective (residual hyperactivity & impulsivity,
insomnia, treatment emergent tics, & aggression)
 Cons:
– Side Effects: Rebound HTN/tachycardia, HOTN, sedation,
dizziness, constipation, H/A, fatigue, sudden death in
combination with stimulants?
– Contraindications: CAD, impaired liver/renal function
Combination Treatment
 Stimulant + α-2 Agonist:
– Concern related to 4 reported deaths in children
taking both MPH & Clonidine (each with
extenuating circumstances)
– No FDA limitations
– AACAP recommends against routine ECGs
 Stimulant + TCA:
– 9 deaths reported in children taking TCAs
– recent report of 10 y/o on DEX and IMI who died
by cardiac arrhythmia
Tricyclics for ADHD
 DBPC trials:
– Desipramine in adults w/68% positive responses (Wilens
et al 1996, n = 41)
– Desipramine w/comorbid tic d/o in children &
adolescents (Spencer et al 2002 n = 41); 71% of pts
w/ADHD responded positively; 30% decrease in tics,
42% decrease in ADHD symptoms
– Desipramine statistically better than clonidine for ADHD
with comorbid tourettes in children and adolescents;
neither exacerbated tics (Singer et al 1995 n = 34)
– Desipramine in children & adolescents (Biederman et al
1989, n = 62); 68% responded positively “much or very
much” improved
Wellbutrin for ADHD
 Adults
– DBPC positive (Wilens et al 2001, n = 40)
– BPP v. MPH v. placebo all negative (Kuperman et al
2001, n = 30)
 Children and Adolescents
– DBPC positive (Conners et al 1996, n = 109)
– BPP v. MPH both positive (Barrickman et al 1995, n
= 15)
– BPP for ADHD w/adolescents w/comorbid MDE
62% response rate to ADHD, 85% for MDE; no
statistical improvement in ADHD per teachers
(Daviss et al 2001, n = 24)
Effexor for ADHD
 Effexor - contradictory open label data in children
and adults
 By example, Motavalli & Abali (2004)
demonstrated efficacy in an open label study of
13 children and adolescents (average age = 10
y/o) dosed venlafaxine to an average of 40 mg
(+/- 7 mg); Connors parent rating scales and CGI
ratings both showed significant improvement
Modafinil (Provigil, Sparlon)
 FDA approved for narcolepsy, EDS associated with
sleep apnea, & shift work sleep disorder
 Variable open label results with higher doses suggested
to possibly improve symptoms of ADHD
 One RDBPC Trial, 189 children (ages 6-17), 7 weeks
randomized to modafinil (dosed for weight; <30 kg =
340 mg/d & >30 kg = 425 mg/d) w/2 week blinded
withdrawal (no discontinuation syndrome noted)
demonstrated statistical separation by week #1 (Effect
Size = 0.76)
 Side Effx = insomnia (24% vs. 1%), H/A (17% vs.
14%), decreased appetite (14% vs. 2%), rare risk of
Stevens- Johnson Syndrome
Modafinil (2): Provigil, Sparlon

 A second trial of children ages 7 – 17 with

ADHD (9 weeks, double-blind, flexible dose [170
– 425 mg], randomized to once daily drug vs.
 Modafinil led to statistically significant
reductions in symptoms of ADHD at home and at
 Side Effx = insomnia, headache, decreased
appetite, and weight loss
Published Modafinil Studies To Date
 A randomized, double-blind and placebo-controlled trial of modafinil in children and adolescents
with attention deficit and hyperactivity disorder. Kahbazi et al, 2009
 Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in
children and adolescents. Biederman et al, 2008
 Modafinil as a treatment for Attention-Deficit/Hyperactivity Disorder in children and adolescents:
a double blind, randomized clinical trial. Amiri et al, 2008
 Efficacy and safety of modafinil film-coated tablets in children and adolescents with or without
prior stimulant treatment for attention-deficit/hyperactivity disorder: pooled analysis of 3
randomized, double-blind, placebo-controlled studies. Wigal et al, 2006
 A comparison of once-daily and divided doses of modafinil in children with attention-
deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study.
Biederman et al, 2006
 A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children
and adolescents with attention-deficit/hyperactivity disorder. Greenhill et al, 2006
 Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity
disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by
abrupt discontinuation. Swanson et al, 2006
 Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-
deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-
dose study. Biederman et al, 2005
Vyvanse (lisdexamfetamine)

 Dextro-Amphetamine
– Contrast to Adderall (25% L-Amp & 75% D-Amp)
 Pro-drug Stimulant (20, 30, 40, 50, 60, & 70 mg
 10-12 hour duration
 Lower “drug liking effects” among drug abusers
than amphetamine (diminishing at higher doses)
 Once daily dosing; can be dissolved in water
 Side Effx = as amphetamine
Daytrana (The “patch”)

 Methylphenidate
 10-12 hour duration
 One patch per day worn for 9 hours
 Dosages: 10 mg (27.5 mg @ 1.1 mg/hour), 15
mg (41.3 mg @ 1.6 mg/hour), 20 mg (55 mg @
2.2 mg/hour), & 30 mg (82.5 mg @ 3.3 mg/hour)
 Side Effx = as methylphenidate
Texas Medication Algorithm
 Revised (JAACAP, June 2006)
 Uncomplicated ADHD:
1. Stimulant
2. 2nd Stimulant
3. Atomoxetine
4. Bupropion or TCA
5. Alternate (BPA/TCA)
6. Alpha-2 agonist
Texas Medication Algorithm
 Revised (JAACAP, June 2006)
 ADHD with Depression:
1. Non-medication alternatives
2. If ADHD worse, begin ADHD algorithm
3. If depression worse, begin MDD algorithm
4. If ADHD improves but there is no change
in depression, begin MDD
5. If ADHD or MDD worsens, begin MDD
6. If MDD improves but ADHD remains
unchanged or worsens, begin ADHD
Texas Medication Algorithm

 Revised (JAACAP, June 2006)

 ADHD with Anxiety:
1. Atomoxetine or Stimulant for ADHD
2. If ADHD symptoms improve but not
anxiety, add an SSRI
3. If ADHD symptoms don’t improve or
anxiety persists, change to alternate ADHD
agent (atomoxetine or stimulant)
Texas Medication Algorithm
 Revised (JAACAP, June 2006)
 ADHD with Tics:
1. Begin ADHD algorithm
2. If nonresponse to ADHD treatment,
continue with algorithm
3. If ADHD improves but tics persist or
worsen, add alpha-2 agonist
4. If tics do not respond, try an atypical
5. If tics do not respond, try haloperidol or
Texas Medication Algorithm

 Revised (JAACAP, June 2006)

 ADHD with Aggression:
1. Begin ADHD algorithm
2. Add behavioral intervention
3. Add atypical antipsychotic to stimulant
4. Add LiCO3 or VPA to stimulant
5. Use alternate agent not tried in Step #4
Other Treatments

 Focalin (dex-MPH), use at 50% MPH dose

 Focalin XR
 Pemoline (Cylert)
 Methamphetamine (Desoxyn)
 Reboxetine
Atomoxetine HCl (Strattera):
Mechanism of Action
 Norepinephrine reuptake inhibitor; acts at
presynaptic neuron; primary mechanism
 Significant increase in dopamine noted in PFC
 No DA increase noted in nucleus accumbens
(limbic system)
 No DA increase noted in striatum
Mechanism of Action
A Norepinephrine Reuptake
Inhibitor (NRI)
Relative Monoamine
Transporter Affinities
Compound NE 5-HT DA

Atomoxetine 5 77 1451

MPH 339 >10,000 34

Desipramine 3.8 179 >10,000

Bupropion >10,000 >10,000 562

Imipramine 98 19 >10,000

Fluoxetine 1022 7 4752

Strattera: Pharmacokinetics/
 Rapidly absorbed following oral administration
 Maximal plasma concentrations reached 1–2 hrs p dose
 Metabolized via hepatic CYP P450 2D6
 Half-life (t½) ~ 5 hours
(~ 20+ hours in poor metabolizers)
 Observed duration of action with once-daily dosing
– Therapeutic effects may persist after drug is cleared and/or
– Brain concentration may differ from plasma concentration
Strattera: Pharmacodynamics Cont’d
Brain Concentration 10X Plasma Concentration*
Strattera Concentration (ng/mL or ng/g)

2500 Plasma





0 5 10 15 20 25 30
**Mouse half-life ~1 hour; (human half-life 5 hours).
Data on file, Eli Lilly and Company.
Strattera: Efficacy in Children
& Adolescents
 24-hour duration of action with once-daily
 Incidence of insomnia comparable with placebo
(for children/adolescents)
 Not contraindicated in patients with tics and
 Nonstimulant/noncontrolled substance
 May improve some measures of functional
outcome (not just core ADHD symptoms)
Comparability Relative to
Methylphenidate (cont.)
Strattera vs. Concerta
 RDBPC trial of 220 children (6 – 16 y/o), all subtypes, were randomly
assigned to 0.8 – 1.8 mg/kg/day of Strattera (n = 222) or 18 – 54 mg/day
fo Concerta (n = 220) or placebo (n = 74) for 6 weeks
 The a priori specified primary analysis compared response (at least 40%
decrease in ADHD Rating Scale total score) to Concerta with response
to atomoxetine and placebo.
 After 6 weeks, patients treated with methylphenidate were switched to
atomoxetine under double-blind conditions.
 The response rates for both atomoxetine (45%) and methylphenidate
(56%) were markedly superior to that for placebo (24%), but the
response to Concerta was superior to that for atomoxetine.
 Completion rates and discontinuations for adverse events not
significantly different from those for placebo.
 Of the 70 subjects who did not respond to methylphenidate, 30 (43%)
subsequently responded to atomoxetine. Likewise, 29 (42%) of the 69
patients who did not respond to atomoxetine had previously responded
to Concerta
– Newcorn et al, 2007
Relative Efficacy of ADHD Therapies:
Effect Size

Effect size: 2
a statistical
Effect Size

of the 1 Large (0.8)
magnitude of Moderate (0.5)
effect of a
treatment. 0
Small (0.2)
Large = 0.8
(Swanson et al,
2001) –1
Nonstimulant Stimulant Long-acting

Faraone SV et al. Poster presented at APA; May 17–22, 2003; San Francisco, CA.
Swanson JM et al. J Am Acad Child Adolesc Psychiatry. 2001;40:168–179.
Understanding Effect Size (1)
What Works Best?…or the Art
of Psychopharmacology
 Effect Size
– A measure of the “real” population difference between 2
groups; it measures the effectiveness of the treatment:
 0.2 = small; 0.5 = moderate; 0.8 = large
 Stimulants Effect Size in MTA Study = 1.2; in meta-
analysis of 62 stimulant studies = 0.78 (teacher) & 0.54
(parent); average response rate in 155 controlled studies
in children/adolescents & adults (Spencer, 1996) = 70%
 Strattera Effect Size = 0.7 (based on 6 pre-marketing
clinical trials in children/adolescents and adults); average
response rate in clinical trials = 70%
 α-2 Agonists Effect Size = 0.4
Understanding Effect Size (2)
Strattera: Side Effects
 Children and Adolescents:
– Decreased appetite (15%)
 Ave wt loss of 2 – 4 LB in first 3 months, then resume nl growth
– Dizziness (5%)
– Dyspepsia (5%)
– Sedation
 Adults:
– Anticholinergic side effects (dry mouth, constipation, urinary
– Sexual SEfx (decreased libido, erectile disrurbance, anorgasmia)
– Insomnia
– Nausea and decrease in appetite
 Liver Toxicity?...Suicide?
Published Studies in Adult ADHD
Study Year N Medication Duration*
Mattes et al 1984 26 Methylphenidate 3 weeks
Wender et al 1985 37 Methylphenidate 2 weeks
Gualtieri et al 1985 8 Methylphenidate 5 days
Shekim et al (open label) 1990 33 Methylphenidate 8 weeks
Spencer et al 1995 23 Methylphenidate 3 weeks
Iaboni et al 1996 30 Methylphenidate 2 weeks
Wilens et al 1996 42 Pemoline 4 weeks
Wilens et al 1999 35 Pemoline 4 weeks
Paterson et al 1999 68 Dextroamphetamine 4 weeks
Taylor et al 2000 21 Amphetamine 2 weeks
Horrigan et al (open label) 2000 24 Amphetamine 16 weeks
Spencer et al 2001 27 Amphetamine 3 weeks
Taylor et al 2001 17 Amphetamine 2 weeks
Michelson et al 2001 536 Strattera 10 weeks
*Active Treatment Period
Patients in Whom You Might
Consider Strattera
 History of adverse effect to stimulants
 Comorbid anxiety, depression, tics, enuresis or
 Require 24 hour symptom relief
 Severe stimulant rebound
 Personal or family history of substance abuse
 Concern about insomnia or appetite suppression
 Monthly prescriptions are a major hassle
 Any newly diagnosed patient for whom you determine
the treatment to be appropriate
Patients in Whom You Might
Consider Stimulants
 History of favorable response to stimulants
 Those who require “drug holidays”
 Obese/overweight patients
 Concern about manic activation
 Augmenting Strattera
 When you need a “powerful punch”
 Any newly diagnosed patient for whom you
determine the treatment to be appropriate
Organizational Skills Training
 Manualized Treatment, Flexibly Applied to
Individual Needs
 20 sessions conducted in 10 weeks
 Meet with child and parents
 Consult with teachers
 Focus on practical routines that children can use
over and over again
 Rewards and reinforcement used to motivate
students to change
Treatment Areas for
Organizational Skills Management
 Tracking Assignments  Time Management
 Organization of Settings – Time Estimation
 Materials Management – Scheduling
– Collection  Planning
– Storage – Single Time Period

– Transfer – Long-Term Projects

– Setting Priorities
– Determining Breaks
Parent Problems
Related to ADHD
 Parents of children w/ADHD are 3-5x more
likely to become separated or divorced
 Parents of children w/ADHD have a higher
incidence of depression & family discord
 Majority of parents of children w/ADHD report
making changes in work status
 9 – 35% risk that a parent of a given patient has