The Diagnosis and Treatment

of ADHD

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:
1987
ADHD (inattentive, hyperactive, combined subtypes)
in DSM-IV: 1994

Differential Diagnosis
(Psychiatric)
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
(Medical)
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

(Inattention)
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

(Hyperactive/Impulsive)
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; HyperactiveImpulsive; 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 prepubertal 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 93

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 worlds
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, theres 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 Cant Have All the Fun!

Adult

use of these medications increased 90%

between March 2002 and June 2005can 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
Inattention

Hyperactivity
Impulsivity

Time

ADHD: Course of the Disorder

Inattention
Hyp
era

ctiv
ity

Imp
ulsiv
i

ty

Age

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

Academic
limitations

Relationships

Adults

Occupational/
vocational
Legal
difficulties

Motor vehicle
accidents

Ch
ildr
en

ADHD

Low self
esteem

Injuries
Smoking and
substance abuse
Adolescents

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

Neuroimaging

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
ADHD

Developmental Trajectories of Brain Volume

Abnormalities in Youth with ADHD
Smaller

brain volumes in all regions regardless of

medication status (cortical white & gray matter)
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
ADHD
Castellanos et al, 2002

Cortical Thickness in ADHD: Cingulate Cortex

Makris et al.
Cerebral
Cortex
2006

Shaw et al., Arch Gen Psychiatry 2006

Specific Genes Associated w/ADHD

Rare

mutations in the human thyroid receptor

gene on chromosome 3

Symptoms suggestive of ADHD are found among those w/a

general resistance to thyroid hormone (Hauser et al, NEJM,
1993)

Dopamine

Transporter gene (DAT) on

chromosome 5

A hyperactive presynaptic DAT (Gill et al, Mol Psych,

1997)

Dopamine

Receptor D4 gene (DRD4) on

chromosome 11

Postsynaptic malfunction do not allow signal transmission

(Swanson et al, Mol Psych, 1998)

Cortical
Thickness &
DRD4
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,
including:
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)

Conners 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
This

symptoms by age 7 years

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
ADHD

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

Protocols

Treatment (3)
The

MTA Study demonstrated:

Medication (stimulants) treatment effective

Behavioral treatment not effective for core

ADHD symptoms (useful for some related

impairments)
More frequent & higher dosing led to greater
responses
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

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
hospitalizations)
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

14
5

Conduct
43

12

8
4

67

11

Mood
5

26

Anxiety
58

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
Amphetamine
blocks

vv
Cytoplasmic DA

Amphetamine
blocks
reuptake

Storage
vesicle

DA Transporter

Synapse

Wilens T, Spencer TJ. Handbook of Substance Abuse: Neurobehavioral Pharmacology. 1998;501513

Methylphenidate
blocks
reuptake

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
3x/daily

Ritalin SR

Time (Hours)

Stimulants (4): Tachyphylaxis &

Successful Long Acting Stimulants
Serum Level
Long Acting Stimulant

Ritalin SR

Time (Hours)

Methylphenidate IR
3x/daily

Stimulants (5): Dosage &

Administration
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
years
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 nave), 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 &

Contraindications
Side

Effects: Nausea, headache, early insomnia,

decreased appetite; tics, anxiety, HTN/tachycardia,
psychosis
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/Tourettes (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
XR.
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
population.

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 Datasort 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,

psychosis]
Contraindications [HTN, symptomatic cardiovascular disease,
glaucoma, hyperthyroidism, tics/Tourettes (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
echo

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, -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
PFC
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
function
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, 712 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 (Tourettes 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, 612 years) had greater
responses to guanfacine than did adolescents (age
range, 1317 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)

Intuniv

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.

-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

+ -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 StevensJohnson 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. placebo)
Modafinil led to statistically significant
reductions in symptoms of ADHD at home and at
school
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 attentiondeficit/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 attentiondeficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexibledose 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

dosages)
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.
2.
3.
4.
5.
6.

Stimulant
2nd Stimulant
Atomoxetine
Bupropion or TCA
Alternate (BPA/TCA)
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 algorithm
5.
If ADHD or MDD worsens, begin MDD
algorithm
6.
If MDD improves but ADHD remains
unchanged or worsens, begin ADHD
algorithm

Texas Medication Algorithm

Revised

(JAACAP, June 2006)

ADHD with Anxiety:
1.
2.
3.

Atomoxetine or Stimulant for ADHD

If ADHD symptoms improve but not
anxiety, add an SSRI
If ADHD symptoms dont improve or
anxiety persists, change to alternate ADHD
agent (atomoxetine or stimulant)

Texas Medication Algorithm

Revised

(JAACAP, June 2006)

ADHD with Tics:
1.
2.
3.
4.
5.

Begin ADHD algorithm

If nonresponse to ADHD treatment,
continue with algorithm
If ADHD improves but tics persist or
worsen, add alpha-2 agonist
If tics do not respond, try an atypical
antipsychotic
If tics do not respond, try haloperidol or
pimozide

Texas Medication Algorithm

Revised

(JAACAP, June 2006)

ADHD with Aggression:
1.
2.
3.
4.
5.

Begin ADHD algorithm

Add behavioral intervention
Add atypical antipsychotic to stimulant
Add LiCO3 or VPA to stimulant
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

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

4752

Strattera: Pharmacokinetics/
Pharmacodynamics
Rapidly

absorbed following oral administration

Maximal plasma concentrations reached 12 hrs p dose
Metabolized via hepatic CYP P450 2D6
Half-life (t) ~ 5 hours
(~ 20+ hours in poor metabolizers)
Observed

duration of action with once-daily dosing

suggests:
Therapeutic effects may persist after drug is cleared and/or
Brain concentration may differ from plasma concentration

Strattera: Pharmacodynamics Contd

Brain Concentration 10X Plasma Concentration*
Strattera Concentration (ng/mL or ng/g)

3000
Brain
Plasma

2500
2000
1500
1000
500
0

10

15
Hours**

*AUC.
**Mouse half-life ~1 hour; (human half-life 5 hours).
Data on file, Eli Lilly and Company.

20

25

30

Strattera: Efficacy in Children

& Adolescents
24-hour

duration of action with once-daily

dosing
Incidence of insomnia comparable with placebo
(for children/adolescents)
Not contraindicated in patients with tics and
anxiety
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
3

(Swanson et al,
2001)

Effect Size

Effect size:
a statistical
measurement
of the
magnitude of
effect of a
treatment.
Large = 0.8

Large (0.8)
Moderate (0.5)
Small (0.2)

Nonstimulant

Stimulant

Long-acting
Stimulant

Faraone SV et al. Poster presented at APA; May 1722, 2003; San Francisco, CA.
Swanson JM et al. J Am Acad Child Adolesc Psychiatry. 2001;40:168179.

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 metaanalysis 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%
-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
BP/HR

Adults:
Anticholinergic side effects (dry mouth, constipation, urinary

retention)
Sexual SEfx (decreased libido, erectile disrurbance, anorgasmia)
Insomnia
Nausea and decrease in appetite
BP/HR

Liver

Toxicity?...Suicide?

Published Studies in Adult ADHD

Study
Mattes et al
Wender et al
Gualtieri et al
Shekim et al (open label)
Spencer et al
Iaboni et al
Wilens et al
Wilens et al
Paterson et al
Taylor et al
Horrigan et al (open label)
Spencer et al
Taylor et al
Michelson et al

Year
1984
1985
1985
1990
1995
1996
1996
1999
1999
2000
2000
2001
2001
2001

N
26
37
8
33
23
30
42
35
68
21
24
27
17
536

Medication
Duration*
Methylphenidate
3 weeks
Methylphenidate
2 weeks
Methylphenidate
5 days
Methylphenidate
8 weeks
Methylphenidate
3 weeks
Methylphenidate
2 weeks
Pemoline
4 weeks
Pemoline
4 weeks
Dextroamphetamine
4 weeks
Amphetamine
2 weeks
Amphetamine
16 weeks
Amphetamine
3 weeks
Amphetamine
2 weeks
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 Tourettes
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
Organization

of Settings
Materials Management
Collection
Storage
Transfer

Time

Management
Time Estimation
Scheduling
Planning
Single Time Period
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
ADHD