Neuropsychol Rev (2007) 17:61–72
DOI 10.1007/s11065-006-9017-3
ORIGINAL PAPER
Pharmacologic Treatment of Attention-Deficit/Hyperactivity
Disorder: Efficacy, Safety and Mechanisms of Action
Steven R. Pliszka
Received: 30 November 2006 / Accepted: 30 November 2006 / Published online: 23 January 2007


C Springer Science+Business Media, LLC 2007
Abstract Studies examining the efficacy, safety and mech-
anisms of action of agents for the treatment of attention-
deficit/hyperactivity disorder (ADHD) are reviewed, with an
emphasis on newer agents such as the long acting stimulants
and atomoxetine. Recent studies of medications are charac-
terized by large, rigorously diagnosed samples of children,
adolescents and adults with ADHD, use of standardized rat-
ing scales and extensive safety data. These studies confirm
a robust treatment effect for the Food and Drug Adminis-
tration approved agents ranging from 0.7 to 1.5. The most
common short term side effects to the most commonly used
agents include insomnia, loss of appetite, and headaches.
Despite public controversy and labeling changes to warn of
extremely rare cardiovascular and psychiatric side effects,
the evidence does not support the hypothesis that medication
for ADHD increases risk for sudden death, mania or psy-
chosis. A wide variety of neuroimaging techniques including
electrocephalogram (EEG) power, event related potentials
(ERP), functional magnetic resonance imaging (fMRI), and
positron emission tomography (PET) are beginning to exam-
ine the mechanisms of action of medications for ADHD, and
implicating the catecholamines and prefrontal and anterior
cingulate cortices as prime sites of actions for these agents.
Keywords ADHD . Psychopharmacology . Magnetic
resonance imaging . PET
S. R. Pliszka (
)
Division of Child and Adolescent Psychiatry,
Department of Psychiatry,
7703 Floyd Curl Drive MC 7792,
San Antonio, TX 78229-3900, USA
e-mail: pliszka@uthscsa.edu
Introduction
The pharmacological treatment of attention-deficit/hyper-
activity disorder (ADHD) is one of the most thoroughly
researched topics in the mental health arena. The use of
amphetamine in children with disruptive behavior disorders
was first described by Bradley (1937) seven decades ago,
thus the treatment of ADHD (albeit referred to by many dif-
ferent names) predates the use of antibiotics. The negative
impact of symptoms of ADHD on many different aspects of
patient and family life is well established (Barkley, 2006);
fortunately, a wide array of pharmacological agents is now
available for the treatment of ADHD. Advances in functional
magnetic resonance imaging (fMRI), electroencephalogram
(EEG) techniques, event related potentials (ERP), and ra-
dionucleotide imaging have begun to examine the mecha-
nisms of action of these agents, particularly the stimulants.
This article will examine the efficacy and safety of phar-
macological agents for ADHD, with an emphasis on the
more recently developed medications. Recent neuroimaging
studies examining the action of methylphenidate in normal
volunteers and patients with ADHD will then be reviewed.
Stimulants
Stimulants have consistently shown robust behavioral ef-
ficacy in hundreds of randomized controlled trials (RCT)
conducted since the 1960’s. By 1993, Swanson’s “Review
of reviews” reported over 3,000 citations and 250 reviews
of stimulant treatment (Swanson et al., 1993). Robust short-
term stimulant-related improvements in ADHD symptoms
were found in 161 studies encompassing 5 preschool, 140
school age, 7 adolescent and 9 adult RCTs (Spencer et al.,
1996). Improvement was noted for 65–75% of the 5,899
patients assigned to stimulant treatment versus only 4–30%
Springer
62
of those assigned to placebo for methylphenidate (MPH)
(n = 133 trials), dextroamphetamine (DEX) (n = 22 tri-
als), and pemoline (n = 6 trials). This body of data has
continued to grow since then with the introduction of the
short acting mixed salts of amphetamine (MSA) (Pliszka,
Browne, Olvera, & Wynne, 2000). MPH has both a dextro
(d) and levo (l) isomer; the d-MPH isomer alone shows effi-
cacy equal to that of the d, 1-MPH form, with some evidence
that the d-isomer administered alone has a slightly longer
duration of action than d,l.-MPH (Weiss, Wasdell, & Patin,
2004). Short acting stimulants rarely have a duration of ac-
tion longer than six hours, requiring multiple doses per day.
In recent years, long acting forms have been developed for
d,l MPH (Concerta, Daytrana Transdermal System, Metadate
CD, Ritalin LA), MSA (Adderall XR) and d-MPH (Focalin
XR). Studies documenting the efficacy of these agents rela-
tive to placebo are listed in Table 1. All of these studies are
characterized by large samples, rigorous diagnostic criteria
for ADHD, use of standardized rating scales for assessing
symptoms of ADHD, and double blind, controlled designs.
Results showed long acting agents to have a response rate
similar to that shown by short acting stimulants in the earlier
studies.
Side effects of stimulants
As noted in Table 1, the most common stimulant side ef-
fects are headache, insomnia and loss of appetite. Despite
many years of use, there continues to be some controversy
regarding stimulant safety. Many of the short term studies in
Table 1 were followed by longer term open label studies
lasting 1–2 years (Wilens et al., 2005; McGough et al.,
2005). No serious adverse events were reported and lab-
oratory and electrocardiogram (ECG) findings were unre-
markable (Findling et al., 2005). In 2005, Health Canada
briefly suspended the sale of Adderall XR due to concerns
regarding a small number of cases of sudden death in both
children and adolescents. A review by the U.S. Food and
Drug Administration (FDA) Villalaba (2006) estimated the
rate of sudden death in stimulant-treated ADHD children for
the exposure period January 1, 1992 to December 31, 2004
to be 0.2/100,000 patient years for MPH, and 0.3/100,000
patient-years for amphetamine (the differences between the
agents not clinically meaningful). Thus the sudden death
rate for children on ADHD medications does not exceed
the base rate of sudden death in the general population. No
evidence currently indicates a need for routine cardiac eval-
uation (i.e., ECG) before starting stimulant treatment in oth-
erwise healthy individuals. However, these findings suggest
that ADHD medications should be used cautiously in chil-
dren and adolescents with pre-existing heart disease. These
cases should be referred for a pediatric cardiology consul-
tation for possible EKG and/or echocardiogram. The FDA
Springer
Neuropsychol Rev (2007) 17:61–72
also reviewed post-marketing safety data for stimulants for
reports of mania/psychotic symptoms, aggression, and suici-
dality (Gelperin, 2006). Such reports have many limitations,
as information about dosage, comorbid diagnoses, and con-
comitant medications is often not available. Nonetheless, for
each of the stimulants, there occurred very rare events of
psychotic symptoms, specifically involving visual and tac-
tile hallucinations of insects. Symptoms of aggression and
suicidality (but no completed suicides) were also reported.
The FDA ordered changes to stimulant medication labeling
to more prominently discuss these risks. While such labeling
changes encourage families and clinicians to more closely
monitor patients for these rare events, the new label does not
require a change in the clinical use of stimulant medications.
Whether stimulants affect the growth of children with
ADHD has been controversial for many years. Recently, two
major reviews (Poulton, 2005; Faraone, Biederman, Morley,
& Spencer, 2006) examined all of the available data and con-
cluded that stimulant treatment may be associated with a re-
duction in expected height gain, at least in the first 1–3 years
of treatment. The Multi-modality Treatment of ADHD study
showed reduced growth in ADHD patients after 2 years of
stimulant treatment compared with those patients who re-
ceived no medication (MTA Cooperative Group, 2004) and
these differences persisted at 36 months (MTA Coopera-
tive Group, 2006). Interestingly, the children with ADHD in
the MTA study were taller and heavier than average at the
start of the study; those treated continuously with medication
tended to approach the mean of the population for height and
weight by year three of follow up. Charach et al. (2006) found
higher doses of stimulant correlated with reduced gains in
height and weight. The effect did not become significant until
the dose in MPH equivalents was >2.5 mg/kg/day for four
years. In a review by Poulton (2005) concern was raised that
children with ADHD treated with stimulants might show a
reduced height gain of about 1 cm/year and more long term
studies were recommended. However, two recent 1–3 years
follow up studies did not show an impact on growth (Pliszka,
Matthews, Braslow, & Watson, 2006c; Spencer et al., 2006a).
Children with ADHD treated with stimulants should have
height and weight measured at least semi-annually. Children
whose height or weight percentile drops across two major
lines (5th, 10th, 25th, 50th, 75th, 90th, and 95th) should be
considered for treatment with a non stimulant. Drug holidays
appear to eliminate any growth effects of stimulants (Pliszka
et al., 2006c) and should be considered if the child’s ADHD
symptoms do not cause severe impairment on weekends and
during the summer.
Atomoxetine
Atomoxetine is a noradrenergic reuptake inhibitor that is
superior to placebo in the treatment of ADHD in children,
 Table 1 Summary of recent studies of the use of stimulants in the treatment of ADHD

Generic name Brand N, age group Design Efficacy data Safety Author

MSA Adderall XR 509 children, aged 6–12 4 week, DBPC parallel AM and PM teacher and behavior Decreased appetite-22% (Biederman, Lopez,
years groups rating scales improved relative to Headache-14% Boellner, & Chandler, 2002)
placebo Insomina-16%
Abdominal pain-14%
Moodiness-9%
OROS-MPH Concerta 282 children aged 6–12 MPH responders Response rates: OROS MPH: 47% Decreased appetite, headache and (Wolraich et al., 2001)
years randomized to placebo MPH-47% insomnia
Neuropsychol Rev (2007) 17:61–72

MPH or OPOS MPH Placebo-17%

MPH Metadate 321 children aged 6–16 3 week DBPC parallel Response rates: MPH-64% Headache-15% (Greenhill, Findling, &
CD years groups Placebo-27% Decreased appetite-10% Swanson, 2002)
Abdominal pain-10%
Insomnia-7%
MPH Ritalin LA 134 children aged 6–12 2 week DBPC parallel Teacher ratings significantly Decreased appetite and insomnia Package Insert
groups improved over placebo
d-MPH Focalin XR 97 children aged 6–17 7 week, DBPC parallel Response rates: d-MPH-67% (Greenhill et al., 2006b)
years groups Placebo-13%
OROS-MPH Concerta 141 adults 6 weeks, DBPC parallel 66% response to MPH, 39% to Small but clinically insignificant (Biederman et al., 2006)
groups placebo effects on blood pressure
MSA Adderall XR 278 adolescents aged 4 weeks, DBPC parallel Response rates: Placebo- 27% Decreased appetite- 36% (Spencer et al., 2006b)
10–17 years groups 10 mg-52% Headache-16%
20 mg 66% Weight loss-9%
30 mg 71% Insomnia-12;
40 mg 64%
MSA Adderall XR 223 adults 4 week, DBPC parallel Significant improvement of ADHD Insomnia-33% (Biederman et al., 2005;
group, placebo vs 4 symptoms relative to baseline Decreased appetite-32% Weisler et al., 2006)
doses of MSA Headache-30%
Nervousness-26%
ORPS MPH Concerta 220 adolescents Open titration to Response rates: OROS MPH-52% Headache-7% (Wilens et al., 2006)
efficacious dose of Placebo-31% Decreased appetite-2%
OROS MPH, then 37% of subjects required 72 mg of Insomnia-4% (Only MPH
randomized for two OROS MPH a day responders in study)
weeks to OROS MPH or
placebo
MPH Daytrana 270 children aged 6–12 5-week DBPC parallel Response rate: MPH MTS-72% Decreased appetite-25% (Findling & Lopez, 2005)
transdermal groups, 4 dose levels of Placebo-24% Insomnia 10%
system MTS Nausea-10%
(MTS) Decreased weight-10%
Tic-5%
Moodiness-5%

Springer
63
64
adolescents, and adults (Michelson et al., 2003; Michelson
et al., 2001; Michelson et al., 2002; Swensen, Michelsen,
Buesching, & Faries, 2001). Given its pharmacokinetic half-
life of 5 hours, it is generally dosed twice a day. Atomoxetine
may also reduce tics (Allen et al., 2005) and be effective in
children with ADHD who have comorbid anxiety (Sumner
et al., 2005). The FDA has issued warnings regarding rare
side effects of hepatotoxicity and suicidal ideation (Food and
Drug Administration, 2005).
Modafinil
Modafinil showed efficacy in the treatment of ADHD in
two double-blind, placebo-controlled trials (Greenhill et al.,
2006a; Swanson et al., 2006) but the FDA declined to ap-
prove it for clinical use. There was one case of suspected
Stevens Johnson syndrome among the hundreds of children
who participated in the clinical trials, so the sponsor declined
to pursue further development of modafinil as a treatment for
ADHD.
Other agents
A number of agents have historically been used off-label for
the treatment of ADHD. Controlled studies have shown that
tricyclic antidepressants are superior to placebo in ADHD
treatment, although the effect size is less than that of stimu-
lants (Daly & Wilens, 1998). Bupropion is an antidepressant
with effects primarily on the norepinephrine and dopamine
systems that also shows modest efficacy in the treatment of
ADHD (Conners et al., 1996). These antidepressant med-
ications are used much less frequently today because of
the availability of atomoxetine and multiple stimulant for-
mulations. Nonetheless, they remain reasonable second-line
agents. The alpha-agonist clonidine has long been used for
treating ADHD. Connor, Fletcher, & Swanson (1999) per-
formed a meta-analysis of 11 studies which suggested cloni-
dine possessed efficacy in the treatment of ADHD, although
no definitive studies have been performed. The closely re-
lated alpha-2A agonist guanfacine was superior to placebo
in reducing ADHD symptoms in children with comorbid
ADHD and tics (Scahill et al., 2001), although it did not
improve executive functioning in healthy adult volunteers
(Muller et al., 2005). The most common current use for the
alpha-agonists is in combination with stimulants to optimally
treat ADHD symptoms and tics, in those with this comor-
bidity (Tourette’s Syndrome Study Group, 2002).
Medication algorithm for ADHD
The Texas Children’s Medication Algorithm Project
(CMAP) has recently updated its guidelines for ADHD
treatment (Pliszka et al., 2006a). Fig. 1 lays out the rec-
Springer
Neuropsychol Rev (2007) 17:61–72
ommended stages of pharmacologic treatment for ADHD.
The algorithm recommends stimulants as the first stage of
ADHD treatment due to their large effect size and superiority
to non-stimulants in comparative trials (Biederman, Wigal,
Spencer, McGough, & Mays, 2006; Wigal et al., 2005). It is
also recommended that if one stimulant class (MPH or am-
phetamine) fails, then the alternative class should be tried.
Atomoxetine may also be combined in low doses with a
stimulant. Clinical experience suggests this is helpful for
symptoms late in the day or at bedtime when administering a
stimulant may induce insomnia. Buproprion or a tricyclic an-
tidepressant should be tried if the FDA-approved agents are
unsatisfactory, and alpha-agonists should be used for ADHD
alone only as medication of last resort.
Treatment of comorbidity
The Texas CMAP algorithm discusses the pharmacologic
treatment of ADHD with major depressive disorder (MDD),
anxiety disorder, tics disorder, and severe aggression (Pliszka
et al., 2006a). Treatment of comorbid MDD is complicated
by the association of antidepressant treatment with increased
suicidal ideation (4% on antidepressant vs. 2% on placebo)
in children and adolescents with depression (Hammad,
Laughren, & Racoosin, 2006). CMAP recommends that the
patient with both ADHD and MDD be assessed for the sever-
ity of the two disorders, and that the most severe disorder be
treated first. Thus, a child whose ADHD is causing greater
impairment should be treated via the ADHD CMAP algo-
rithm. If the ADHD and MDD symptoms simultaneously
resolve with ADHD treatment, no further pharmacologic
intervention is needed. If the MDD symptoms persist
despite resolution of the ADHD symptoms, then treatment
of depression should be added; either an antidepressant or
a psychosocial intervention. In contrast, if the MDD symp-
toms are more severe (pervasive depression, weight loss,
loss of functioning) than the ADHD symptoms, treatment
for MDD should be initiated (usually a serotonin reuptake
inhibitor). If the ADHD symptoms persist after remission
of the depression, than an ADHD treatment should be
added.
Since atomoxetine has been shown to be effective in the
treatment of both anxiety and ADHD (Sumner et al., 2005), it
may be considered for first line use for children with ADHD
and comorbid anxiety. Serotonin reuptake inhibitors are com-
monly added to stimulants for this subgroup of patients, al-
though data showing the efficacy of this approach are lacking
(Abikoff et al., 2005).
Children with tic disorders can be treated safely with
stimulants without increasing tics (Gadow, Sverd, Sprafkin,
Nolan, & Grossman, 1999) and the CMAP algorithm sug-
gests beginning at Stage 1 with stimulant medications for
this subgroup. If stimulants worsen tics, then the clinician
Neuropsychol Rev (2007) 17:61–72 65

Diagnostic Assessment and

Stage 0 Family Consultation Regarding
Treatment Alternatives
Any stage(s) can be skipped Non-Medication
depending on the clinical picture. Treatment Alternatives

Stage 1 Methylphenidate or Amphetamine

Response

Partial Stage 1A
Response (Optional)
(if MSA or AMP formulation Response
Continuation
DEX used not used in Stage 1
in Stage 1)
Partial Response
or Nonresponse Partial Response
or Nonresponse
Stage 2 Stimulant not used in Stage 1

Response

Partial Stage 2A
Response (Optional)
(if MSA or Response
AMP formulation
Continuation
DEX used not used in Stage 2
in Stage 2)
Partial Response
or Nonresponse Partial Response
or Nonresponse
Stage 3 Atomoxetine

Response

Stage 3A
Partial (Optional)
Response Response
Combine stimulant
Continuation
to stimulant and atomoxetine
or atomoxetine
Partial Response
or Nonresponse Partial Response
or Nonresponse
Stage 4 Bupropion or TCA

Response
Continuation
Partial Response
or Nonresponse

Stage 5 Agent not used in Stage 4

Response
Continuation
Partial Response
or Nonresponse

Stage 6 Alpha Agonist

AMP = Amphetamine
DEX = Dextroamphetamine
Clinical MSA = Mixed salts amphetamine Maintenance
Consultation TCA = Tricyclic antidepressant
Fig. 1 Algorithm for the psychopharmacological treatment of ADHD

should utilize a non-stimulant medication such as atomox-
etine (Allen et al., 2005). Some children with ADHD and
comorbid tics respond only to stimulants in terms of their
ADHD, yet the stimulant worsens their tics. In such cases,
alpha-agonist medication should be added to the stimulant
to reduce both classes of symptoms (Tourette’s Syndrome
Study Group, 2002).
Severe aggressive behavior occurs in substantial num-
bers of children with ADHD, particularly in those with co-
morbid oppositional defiant, conduct disorder, or bipolar

Springer
66
disorder (Jensen et al., 2005). Stimulant or atomoxetine
treatment of children with ADHD often reduces comorbid
oppositional or aggressive behavior (Connor, Glatt, Lopez,
Jackson, & Melloni, 2002; Newcorn, Spencer, Biederman,
Milton, & Michelson, 2005). Thus, aggressive and conduct
disorders symptoms will resolve in the comorbid child when
the ADHD is robustly treated (Klein et al., 1997). If treat-
ment of ADHD is not sufficient to eliminate the aggressive
behavior, then a behavioral treatment should be added to the
ADHD treatment. It is prudent to address any psychosocial
or parent management problems contributing to the aggres-
sion (Pappadopulos et al., 2003; Schur et al., 2003). If the
aggressive behavior is not resolved with such an approach,
and the aggressive behavior is dangerous to the patient or
others, than a second generation antipsychotic should be
added to the stimulant (Pliszka et al., 2006a). The efficacy of
second generation antipsychotic monotherapy in treating ag-
gression is increasingly well established by controlled trials
(Snyder et al., 2002). A recent study by Aman et al. (2004)
randomized a group of aggressive children with ADHD to
risperidone or placebo; one-half of these children were also
already being treated with a stimulant for their ADHD and
remained on it during the double-blind trial testing risperi-
done or placebo. No significant increases in side effects were
seen in the combined risperidone-stimulant group, although
both groups had similar reductions in aggression. Second
generation antipsychotics should be used with caution, how-
ever, as children exposed to them chronically are at long
term risk of weight gain, diabetes, and metabolic syndrome
(Correll & Carlson, 2006).
Neurobiological mechanisms of action of ADHD treatments
Radio-labeled ligands can be used to study cerebral blood
flow, or they can be designed to bind to areas of interest
in the brain, particularly the dopamine transporter (Spencer
et al., 2005) or dopamine receptors (Volkow, Wang, Fowler,
& Ding, 2005). Methylphenidate itself can be labeled with
carbon-11 to determine its distribution in the brain (Volkow
et al., 2005). A typical therapeutic dose of 0.5 mg/kg of
MPH will lead to the blockade of about 60% of the dopamine
transporters in the striatum (Volkow et al., 1998). Another
approach to examine the effects of MPH in the brain is to
image subjects with positron emission tomography (PET)
using 11C-raclopride, which binds to dopamine-2 receptors.
Volkow et al. (2001) performed PET using this ligand in
healthy men on both placebo and 60 mg of MPH. On MPH,
more dopamine was released, leading to a decline in raclo-
pride binding relative to placebo. MPH (and amphetamine)
also have affinity for the norepinephrine transporter as well,
but since the raclopride does not bind to it, studies of this
sort cannot elucidate the effect of MPH on norepinephrine.
Nonetheless, Volkow et al. (2001) established that MPH
Springer
Neuropsychol Rev (2007) 17:61–72
acutely increases the amount of dopamine in the synap-
tic cleft. Next, Volkow et al. (2004) examined the effect
of MPH on dopamine release in two different situations:
while subjects passively viewed pictures and again while
performing a difficult mathematics task. Relative to placebo,
MPH produced much greater reduction in raclopride bind-
ing (dopamine release was increased) during the mathemat-
ics tasks than in the passive condition. Thus it appears that
the dopamine release is associated with tasks requiring ex-
ecutive functions or response to a stimuli signaling reward.
MPH can block reuptake of dopamine only when it is being
released in significant amounts. This may explain why the ef-
fects of MPH (and other stimulants) are most pronounced in
the classroom or other structured settings where cognitively
stressful activities occur. Recently, Rosa-Neto et al. (2005)
performed a PET raclopride study with nine adolescents with
ADHD; the subjects were scanned both on placebo and again
on a therapeutic dose of MPH. MPH induced a decrease in
raclopride binding relative to placebo. The magnitude of the
decrease in raclopride binding correlated well with MPH-
induced improvements on cognitive testing.
Another approach that is becoming more fruitful in as-
sessing stimulant action in the brain is the direct study of the
binding of ligands to the dopamine transporter (Spencer et al.,
2005). Several ligands, including 123I-Altropane, 123I-IPT
and 99Tc-TRODAT-1, and 123I-citalopram are available
which bind to the dopamine transporter and give a measure
of its binding potential. Typically, Single Positron Emission
Tomography (SPECT) is used to assess the amount of lig-
and binding to the receptor, although Altropane can be use
with PET (Spencer et al., 2005). The PET ligand PE2I can
also be used to image the dopamine transporter (Jucaite,
Fernell, Halldin, Forssberg, & Farde, 2005). In seven studies
reviewed by Spencer et al. (2005), five showed the dopamine
transporter binding to be increased in subjects with ADHD
relative to controls, while two studies showed no difference
between the ADHD and control groups. Some early stud-
ies have begun to examine the effect of MPH on dopamine
transporter binding.
Krause et al. (2003) obtained SPECT using TRPDAT-1 in
a small number of adults with ADHD both at baseline and
again after a dose of MPH. They found the dopamine trans-
porter binding potential to be reduced with treatment, but
the SPECT was done 90 minutes after the MPH dose when
the medication is expected to be binding to the transporter.
Thus it cannot be concluded that MPH down regulated the
transporter (Spencer et al., 2005). Vles et al. (2003) also
found that dopamine transporter binding potential was re-
duced after three months of MPH treatment in six boys with
ADHD, but the timing of SPECT in relation to the last MPH
dose was not reported. When MPH treatment was withdrawn
from five children with ADHD, dopamine transporter bind-
ing potential immediately increased to pretreatment values,
Neuropsychol Rev (2007) 17:61–72
suggesting that MPH does not induce any long term down
regulation of the transporter (Feron et al., 2005).
Cerebral blow flood can be assessed by either SPECT
(2001) or PET (Matochik et al., 1993; Matochik et al.,
1994) but this technique has not been as fruitful as might be
expected, either as a diagnostic tool or to assess stimulant
effects in the brain. In the largest study to date, Kim et al.
(2001) assessed 32 boys with ADHD using 99 Tc HMPAO
SPECT at baseline and after a trial of MPH. The subjects
were rigorously screened to insure the absence of psychiatric
comorbidity or learning disabilities. Significant cerebral
blow flow increases after MPH were found in bilateral
prefrontal cortex, caudate, and thalamus of subjects who
were MPH responders. Unfortunately, studies performed
since then have not had the power to allow firm conclusions
to be made about the effects of MPH on cerebral blood
flow. Ten adult subjects had cerebral blood flow assessed by
PET before and after a three week MPH trial. MPH induced
increases in blood flow in cerebellar vermis, but decreases
in precentral gyri, left caudate nucleus, and right claustrum
(Schweitzer et al., 2003). In contrast, Szobot et al. (2003)
found decreased left parietal blood flow on MPH relative to
placebo in a relatively large (n = 36) study of children and
adolescents with ADHD; the same group also found that
MPH withdrawal led to increases in blood flow as assessed
by SPECT in the motor, premotor, and anterior cingulate
cortex (Langleben et al., 2002). Reviewing these data,
Castellanos (2002) questioned the utility of SPECT/PET
cerebral blood flow studies, suggesting that fMRI and
assessment of catecholamine transporter would be more
likely to lead to further understanding of the mechanisms
of pharmacological treatments for ADHD. In view of
this, the American Psychiatric Association recommended
against the use of SPECT for the diagnosis or monitoring
of treatment for ADHD or other psychiatric disorders
(http://www.psych.org/psych pract/clin issues/populations/
children/SPECT.pdf).
EEG and ERP measures have also been used to study
the response of children with ADHD to medication. In
this line of work, EEG activity is examined within specific
frequency bands. The complex EEG waveform is decom-
posed via Fournier analysis into component frequency bands:
delta (<4 Hz), theta (4–7 Hz), alpha (8–12 Hz) and beta
(>13 Hz). The beta band is associated with mental alert-
ness; most studies have shown that children with ADHD
show decreased beta and increased amounts of the other fre-
quencies, particularly in the frontal area (Barry, Clarke, &
Johnstone, 2003; Loo & Barkley, 2005). While there is a
subgroup of children who show an excess of beta (Clarke,
Barry, McCarthy, & Selikowitz, 2001), they do not appear
to be clinically distinguishable from those with decreased
beta. Children with ADHD also show decreased theta/beta
and theta/alpha ratios relative to controls; stimulant
67
treatment of ADHD can increase these ratios, “normaliz-
ing” the EEG (Clarke, Barry, Bond, McCarthy, & Selikowitz,
2002). This would also suggest that stimulants might act by
increasing cortical arousal, consistent with the blood flow
studies of Kim et al. (2001) noted above. Clarke et al. (2002)
compared 20 children with ADHD who responded well to
MPH to 20 children who had responded well to dextroam-
phetamine using EEG power. Theta/beta ratios in the frontal,
central, and posterior leads were higher for the MPH respon-
ders than the dextroamphetamine responders, MPH respon-
ders had greater theta/alpha ratios in the frontal leads. Loo
et al. (2004), found similar results, adding that MPH non
responders tended to show decreased beta while on medi-
cation. Increased beta also correlated with improvements in
ADHD symptoms on parent behavior rating scales. It is im-
portant to note, however, that these results represent group
averages. At the level of the individual patient, EEG does
not predict stimulant response above the rate predicted by
the clinical diagnostic information (Loo and Barkley, 2005).
Nonetheless, while not yet appropriate for standard clinical
practice, examination of EEG power may help elucidate pat-
terns of medication response that are not yet distinguishable
on clinical measures. Loo et al. (2003) compared the MPH
response of children with ADHD who were homozygous for
the 10-repeat allele of the dopamine transporter with those
who were heterozygous for the 9-repeat allele. The 10-R
homozygotes showed increased beta power and increased
beta/theta ratios on MPH relative to placebo, while children
with ADHD who were 9-repeat allele carriers showed the
opposite pattern. In the future, use of EEG in conjunction
with genetic and functional MRI may allow a more compre-
hensive picture of the neurophysiology of stimulant effects.
In ERP, the subject performs a repetitive cognitive task and
EEG is obtained during each trial. The EEG is then averaged
over many trials, canceling out random brain activity and
producing a waveform which represents the brain’s response
to each class of stimuli in the task. In studies of ADHD,
oddball auditory ERP tasks and inhibitory tasks such as the
continuous performance test (CPT) have been most utilized
(Barry, Johnstone, & Clarke, 2003). In the auditory oddball
task, the subject must detect rare tones among a long string
of common tones. Healthy controls produce a larger P300
wave to the oddball tones than to the common tones, but
this difference is markedly reduced in children with ADHD
(Barry et al., 2003). The meaning of this difference in the
P300 is debated. The P300, which in these tasks is most
prominent over the parietal areas, possibly reflects activity
related to evaluation of the stimuli but may also represent
the amount of mental capacity that is invested in the task
(Kok, 1997). In most treatment studies of oddball tasks using
ERP, MPH enhances the P300 response to the rare stimuli
(Klorman, 1991). Thus it is tempting to conclude that MPH
increases the allocation of mental resources to a task, but
Springer
68
further studies have not borne this out. Jonkman et al. (2000)
obtained ERP on healthy controls and children with ADHD
while they performed a decision task, which was presented
in both easy and hard conditions. Irrelevant probes appeared
at various times in the task. Consistent with other studies,
children with ADHD had a reduced P300, particularly in the
hard condition. In the easy condition, the P300 to the probe
was higher in both groups relative to the hard condition.
This is because in the hard condition, attentional capacity
must be reallocated from the probes to the main task. Since
the groups did not differ on the P300 to the probe, this
indicated that the groups were not different in total attentional
capacity. Since the P300 was smaller to the difficult task
stimuli in the ADHD children, it was concluded that they
did not allocate those attentional resources as efficiently as
controls. ADHD subjects then performed the task on placebo
and again on MPH. Relative to placebo, MPH increased P300
to task stimuli in both the easy and hard conditions, and did
not affect P300 to the probe stimuli. The lack of an effect on
the probe means that MPH did not increase overall attentional
capacity, but the equal effect of MPH on P300 in both the
easy and hard tasks also means that the stimulant was not
excreting its effect by changing the allocation of resources.
Thus the effect of MPH on P300 in this type of task is unclear.
Since ADHD (particularly the combined type) has been
conceptualized as a disorder of inhibitory control (Barkley,
1997), more clear results have emerged from studies us-
ing tasks assessing this cognitive domain. On the CPT, the
child must respond to target stimuli and avoid responding
to other stimuli, in the Go/No Go task the child responds
to a Go stimuli the majority of the time but must refrain
from responding when the No Go stimuli are presented.
No-Go or stop signals on an inhibitory task are associated
with a right lateralized N200 which may signal the trig-
gering of the prefrontal inhibitory processes (Kok, 1986);
this N200 has been shown to be reduced in children with
ADHD (Pliszka, Liotti, & Woldorff, 2000). When on MPH,
the N200 to No Go stimuli of children with ADHD no longer
showed any differences from controls (Broyd et al., 2005).
No Go stimuli of inhibitory tasks also elicit a frontocentral
P300 (to be distinguished from the parietal P300 discussed
above) which is thought to be generated by the anterior cin-
gulate (Schmajuk, Liotti, Busse, & Woldorff, 2006). Seven-
teen boys with ADHD performed the CPT while ERP was
obtained at baseline and then one week later after a 10 mg
dose of MPH (Seifert, Scheuerpflug, Zillessen, Fallgatter, &
Warnke, 2003). A group of healthy controls was also stud-
ied. P300 to the No Go stimuli was greater than that to
the Go stimuli, the No Go P300 of children with ADHD
was significantly increased after treatment with MPH. Thus
there is some evidence that MPH improves the functioning
of prefrontal and anterior cingulate mechanisms involved in
inhibition.
Springer
Neuropsychol Rev (2007) 17:61–72
Functional MRI (fMRI), which is non invasive and
involves no nuclear radiation, is an expanding research tool.
Using primarily measures of inhibitory control, comparisons
of ADHD children to controls during fMRI have shown
differences in fronto-striatal activity (Bush, Valera, &
Seidman, 2005), particularly in the right prefrontal cortex
(Rubia, Smith, Brammer, Toone, & Taylor, 2005) and
anterior cingulate (Bush et al., 1999; Pliszka et al., 2006b).
Studies of stimulant effects on the brain using fMRI have
been limited to date, but are increasing. Initially, Vaidya
et al. (1998) showed that MPH, relative to placebo, increased
frontal activation in both children with ADHD and controls.
Striatal activation was increased on MPH relative to placebo
in children with ADHD but controls showed the opposite
pattern, even though both groups improved in cognitive task
performance. In a small heterogeneous group of adolescents
with ADHD and reading disorders, MPH increased activity
in the left ventral basal ganglia relative to placebo, but had
no effect on task performance (Shafritz, Marchione, Gore,
Shaywitz, & Shaywitz, 2004). Adults with ADHD showed
increased activation of the anterior cingulate on MPH
relative to placebo while performing a difficult interference
task (Bush, 2005). Larger scales treatment studies with
children, adolescents, and adults remain to be done.
Future directions
Today there is a wide array of effective agents for the treat-
ment of ADHD. Stimulants are the most effective agents
available, but atomoxetine is a valuable agent, particularly
for those who do not respond to stimulants or who have co-
morbid anxiety or depressive disorders. Older agents such
as bupropion and tricyclic antidepressants now have a lesser
role, although alpha agonists have a valuable role in treat-
ing comorbid tics. Neuroimaging studies will soon begin
to unlock the mechanisms of actions of these agents and
genetic studies may identify subtypes that are clinically in-
distinguishable but respond preferentially to certain agents.
In general, understanding of the pathophysiology of ADHD
will hopefully lead to the development of new and more
effective agents.
References
Abikoff, H., McGough, J., Vitiello, B., McCracken, J., Davies, M.,
Walkup, J., et al. (2005). Sequential pharmacotherapy for children
with comorbid attention-deficit/hyperactivity and anxiety disor-
ders. Journal of the American Academy of Child and Adolescent
Psychiatry, 44, 418–427.
Allen, A. J., Kurlan, R. M., Gilbert, D. L., Coffey, B. J., Linder, S. L.,
Lewis, D. W., et al. (2005). Atomoxetine treatment in children and
adolescents with ADHD and comorbid tic disorders. Neurology,
65, 1941–1949.
Neuropsychol Rev (2007) 17:61–72
Aman, M. G., Binder, C., & Turgay, A. (2004). Risperidone effects
in the presence/absence of psychostimulant medicine in children
with ADHD, other disruptive behavior disorders, and subaverage
IQ. Journal of Child and Adolescent Psychopharmacology, 14,
243–254.
Barkley, R. A. (1997). ADHD and the nature of self control. New York:
Guildford Press.
Barkley, R. A. (2006). Comorbid disorders, social and family adjust-
ment, and subtyping. In R. A. Barkley (Ed.), Attention Deficit
Hyperactivity Disorder (pp. 184–218). New York: Guilford Press.
Barry, R. J., Clarke, A. R., & Johnstone, S. J. (2003). A review of elec-
trophysiology in attention-deficit/hyperactivity disorder: I. Qual-
itative and quantitative electroencephalography. Clinical Neuro-
physiology, 114, 171–183.
Barry, R. J., Johnstone, S. J., & Clarke, A. R. (2003). A review of elec-
trophysiology in attention-deficit/hyperactivity disorder: II. Event-
related potentials. Clinical Neurophysiology, 114, 184–198.
Biederman, J., Lopez, F. A., Boellner, S. W., & Chandler, M. C.
(2002). A randomized, double-blind, placebo-controlled, parallel-
group study of SLI381 (Adderall XR) in children with attention-
deficit/hyperactivity disorder. Pediatrics, 110, 258–266.
Biederman, J., Mick, E., Surman, C., Doyle, R., Hammerness, P.,
Harpold, T., et al. (2006). A randomized, placebo-controlled
trial of OROS methylphenidate in adults with attention-
deficit/hyperactivity disorder. Biological Psychiatry, 59, 829–835.
Biederman, J., Spencer, T. J., Wilens, T. E., Weisler, R. H., Read, S. C.,
& Tulloch, S. J. (2005). Long-term safety and effectiveness of
mixed amphetamine salts extended release in adults with ADHD.
CNS Spectrum, 10, 16–25.
Biederman, J., Wigal, S. B., Spencer, T. J., McGough, J. J., & Mays,
D. A. (2006). A post hoc subgroup analysis of an 18-day ran-
domized controlled trial comparing the tolerability and efficacy
of mixed amphetamine salts extended release and atomoxetine
in school-age girls with attention-deficit/hyperactivity disorder.
Clinical Therapeutics, 28, 280–293.
Bradley, C. (1937). The behavior of children receiving benzedrine.
American Journal of Psychiatry, 94, 577–585.
Broyd, S. J., Johnstone, S. J., Barry, R. J., Clarke, A. R., McCarthy,
R., Selikowitz, M., et al. (2005). The effect of methylphenidate
on response inhibition and the event-related potential of children
with attention deficit/hyperactivity disorder. International Journal
of Psychophysiology, 58, 47–58.
Bush, G. (2005). Funcitional MRI: Recent advances in studying ADHD
pathophysiology and treatment. Presented at the 52nd Annual
Meeting of the American Academy of Child and Adolescent Psy-
chiatry. Toronto, CA (Oct. 18–23).
Bush, G., Frazier, J. A., Rauch, S. L., Seidman, L. J., Whalen, P. J.,
Jenike, M. A., et al. (1999). Anterior cingulate cortex dysfunction
in attention-deficit/hyperactivity disorder revealed by fMRI and
the Counting Stroop. Biological Psychiatry, 45, 1542–1552.
Bush, G., Valera, E. M., & Seidman, L. J. (2005). Functional neu-
roimaging of attention-deficit/hyperactivity disorder: A review
and suggested future directions. Biological Psychiatry, 57, 1273–
1284.
Castellanos, F. X. (2002). Proceed, with caution: SPECT cerebral blood
flow studies of children and adolescents with attention deficit
hyperactivity disorder. Journal of Nuclear Medicine, 43, 1630–
1633.
Charach, A., Figueroa, M., Chen, S., Ickowicz, A., & Schachar, R.
(2006). Stimulant treatment over 5 years: Effects on growth. Jour-
nal of the American Academy of Child and Adolescent Psychiatry,
45, 415–421.
Clarke, A. R., Barry, R. J., Bond, D., McCarthy, R., & Selikowitz,
M. (2002). Effects of stimulant medications on the EEG of chil-
dren with attention-deficit/hyperactivity disorder. Psychopharma-
cology (Berl.), 164, 277–284.
69
Clarke, A. R., Barry, R. J., McCarthy, R., & Selikowitz, M. (2001).
Electroencephalogram differences in two subtypes of attention-
deficit/hyperactivity disorder. Psychophysiology, 38, 212–221.
Clarke, A. R., Barry, R. J., McCarthy, R., & Selikowitz, M.
(2002). EEG differences between good and poor responders to
methylphenidate and dexamphetamine in children with attention-
deficit/hyperactivity disorder. Clinical Neurophysiology, 113,
194–205.
Conners, C. K., Casat, C. D., Gualtieri, C. T., Weller, E., Reader,
M., Reiss, A., et al. (1996). Bupropion hydrochloride in atten-
tion deficit disorder with hyperactivity. Journal of the American
Academy of Child and Adolescent Psychiatry, 35, 1314–1321.
Connor, D. F., Fletcher, K. E., & Swanson, J. M. (1999). A meta-analysis
of clonidine for symptoms of attention-deficit hyperactivity dis-
order. Journal of the American Academy of Child and Adolescent
Psychiatry, 38, 1551–1559.
Connor, D. F., Glatt, S. J., Lopez, I. D., Jackson, D., & Melloni,
R. H., Jr. (2002). Psychopharmacology and aggression. I: A meta-
analysis of stimulant effects on overt/covert aggression-related
behaviors in ADHD. Journal of the American Academy of Child
and Adolescent Psychiatry, 41, 253–261.
Correll, C. U. & Carlson, H. E. (2006). Endocrine and metabolic ad-
verse effects of psychotropic medications in children and adoles-
cents. Journal of the American Academy of Child and Adolescent
Psychiatry, 45, 771–791.
Daly, J. M., & Wilens, T. (1998). The use of tricyclics antidepressants
in children and adolescents. Pediatric Clinics of North America,
45, 1123–1135.
Faraone, S. V., Biederman, J., Morley, C. P., & Spencer, T. J. (2006).
The effect of stimulants on height and weight: a review of the
literature (manuscript in preparation).
Feron, F. J., Hendriksen, J. G., van Kroonenburgh, M. J.,
Blom-Coenjaerts, C., Kessels, A. G., Jolles, J., et al. (2005).
Dopamine transporter in attention-deficit hyperactivity disorder
normalizes after cessation of methylphenidate. Pediatric Neurol-
ogy, 33, 179–183.
Findling, R. L., & Lopez, F. A. (2005). Efficacy of transdermal
methylphenidate with reference to Concerta in ADHD. Presented
at the 25th Annual Meeting of the American Academy of Child
and Adolescent Psychiatry, Toronto, CA, (Oct 18–23).
Findling, R. L., Biederman, J., Wilens, T. E., Spencer, T. J., McGough, J.
J., Lopez, F. A., et al. (2005). Short- and long-term cardiovascular
effects of mixed amphetamine salts extended release in children.
The Journal of Pediatrics, 147, 348–354.
Food and Drug Administration (2005). FDA Alert [09/05]: Sui-
cidal thinking in children and adolescents. Available at.
Food and Drug Administration Website [On-line]. Available:
http://www.fda.gov/cder/drug/infopage/atomoxetine/default.htm
Gadow, K. D., Sverd, J., Sprafkin, J., Nolan, E. E., & Grossman, S.
(1999). Long-term methylphenidate therapy in children with co-
morbid attention-deficit hyperactivity disorder and chronic multi-
ple tic disorder [see comments]. Archives of General Psychiatry,
56, 330–336.
Gelperin, K. (2006). Psychiatric adverse events associated with drug
treatment of ADHD: Review of post marketing safety data. Avail-
able at. Food and Drug Administration Website [On-line]. Avail-
able: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-
4210B-Index.htm
Greenhill, L. L., Biederman, J., Boellner, S. W., Rugino, T. A.,
Sangal, R. B., Earl, C. Q., et al. (2006a). A randomized, double-
blind, placebo-controlled study of modafinil film-coated tablets in
children and adolescents with attention-deficit/hyperactivity dis-
order. Journal of the American Academy of Child and Adolescent
Psychiatry, 45, 503–511.
Greenhill, L. L., Findling, R. L., & Swanson, J. M. (2002).
A double-blind, placebo-controlled study of modified-release
Springer
70
methylphenidate in children with attention-deficit/hyperactivity
disorder. Pediatrics, 109, E39.
Greenhill, L. L., Muniz, R., Ball, R. R., Levine, A., Pestreich,
L., & Jiang, H. (2006b). Efficacy and safety of dexmethylphenidate
extended-release capsules in children with attention-
deficit/hyperactivity disorder. Journal of the American Academy
of Child and Adolescent Psychiatry, 45, 817–823.
Hammad, T. A., Laughren, T., & Racoosin, J. (2006). Suicidality in
pediatric patients treated with antidepressant drugs. Archives of
General Psychiatry, 63, 332–339.
Jensen, P. S., Youngstrom, Y., Steiner, H., Findling, R. L., Meyer, R. E.,
Malone, R., et al. (in press) Consensus report: Impulsive aggres-
sion as a symptom across diagnostic categories in child psychi-
atry. Journal of the American Academy of Child and Adolescent
Psychiatry.
Jonkman, L. M., Kemner, C., Verbaten, M. N., van Engeland, H.,
Camfferman, G., Buitelaar, J. K., et al. (2000). Attentional ca-
pacity, a probe ERP study: Differences between children with
attention-deficit hyperactivity disorder and normal control chil-
dren and effects of methylphenidate. Psychophysiology, 37, 334–
346.
Jucaite, A., Fernell, E., Halldin, C., Forssberg, H., & Farde, L. (2005).
Reduced midbrain dopamine transporter binding in male adoles-
cents with attention-deficit/hyperactivity disorder: Association be-
tween striatal dopamine markers and motor hyperactivity. Biolog-
ical Psychiatry, 57, 229–238.
Kim, B. N., Lee, J. S., Cho, S. C., & Lee, D. S. (2001). Methylphenidate
increased regional cerebral blood flow in subjects with attention
deficit/hyperactivity disorder. Yonsei Medical Journal, 42, 19–29.
Klein, R. G., Abikoff, H., Klass, E., Ganeles, D., Seese, L. M., &
Pollack, S. (1997). Clinical efficacy of methylphenidate in conduct
disorder with and without attention deficit hyperactivity disorder.
Archives of General Psychiatry, 54, 1073–1080.
Klorman, R. (1991). Cognitive event-related potentials in attention
deficit disorder. Journal of Learning Disabilities, 24, 130–140.
Kok, A. (1986). Effects of degradation of visual stimuli on components
of the event-related potential (ERP) in go/nogo reaction tasks.
Biological Psychology, 23, 21–38.
Kok, A. (1997). Event-related-potential (ERP) reflections of mental
resources: A review and synthesis. Biological Psychology, 45,
19–56.
Krause, K. H., Dresel, S. H., Krause, J., la Fougere, C., &
Ackenheil, M. (2003). The dopamine transporter and neuroimag-
ing in attention deficit hyperactivity disorder. Neuroscience and
Biobehavioral Reviews, 27, 605–613.
Langleben, D. D., Acton, P. D., Austin, G., Elman, I., Krikorian, G.,
Monterosso, J. R., et al. (2002). Effects of methylphenidate discon-
tinuation on cerebral blood flow in prepubescent boys with atten-
tion deficit hyperactivity disorder. Journal of Nuclear Medicine,
43, 1624–1629.
Loo, S. K. & Barkley, R. A. (2005). Clinical utility of EEG in attention
deficit hyperactivity disorder. Applied Neuropsychology, 12, 64–
76.
Loo, S. K., Hopfer, C., Teale, P. D., & Reite, M. L. (2004). EEG cor-
relates of methylphenidate response in ADHD: Association with
cognitive and behavioral measures. Journal of Clinical Neuro-
physiology, 21, 457–464.
Loo, S. K., Specter, E., Smolen, A., Hopfer, C., Teale, P. D., & Reite,
M. L. (2003). Functional effects of the DAT1 polymorphism on
EEG measures in ADHD. Journal of the American Academy of
Child and Adolescent Psychiatry, 42, 986–993.
Matochik, J. A., Liebenauer, L. L., King, A. C., Szymanski, H. V.,
Cohen, R. M., & Zametkin, A. J. (1994). Cerebral glucose
metabolism in adults with attention deficit hyperactivity disorder
after chronic stimulant treatment. American Journal of Psychiatry,
151, 658–664.
Springer
Neuropsychol Rev (2007) 17:61–72
Matochik, J. A., Nordahl, T. E., Gross, M., Semple, W. E., King, A. C.,
Cohen, R. M., et al. (1993). Effects of acute stimulant medication
on cerebral metabolism in adults with hyperactivity. Neuropsy-
chopharmacology, 8, 377–386.
McGough, J. J., Biederman, J., Wigal, S. B., Lopez, F. A., McCracken,
J. T., Spencer, T., et al. (2005). Long-term tolerability and effec-
tiveness of once-daily mixed amphetamine salts (Adderall XR) in
children with ADHD. Journal of the American Academy of Child
and Adolescent Psychiatry, 44, 530–538.
Michelson, D., Adler, L., Spencer, T., Reimherr, F. W., West, S. A.,
Allen, A. J., et al. (2003). Atomoxetine in adults with ADHD:
Two randomized, placebo-controlled studies. Biological Psychia-
try, 53, 112–120.
Michelson, D., Allen, A. J., Busner, J., Casat, C., Dunn, D., Kratochvil,
C., et al. (2002). Once-daily atomoxetine treatment for children
and adolescents with attention deficit hyperactivity disorder: A
randomized, placebo-controlled study. American Journal of Psy-
chiatry, 159, 1896–1901.
Michelson, D., Faries, D., Wernicke, J., Kelsey, D., Kendrick, K., Sallee,
R., et al. (2001). Atomoxetine in the treatment of children and ado-
lescents with attention-deficit/hyperactivity disorder: a random-
ized, placebo-controlled, dose-response study. Pediatrics, 108, 1–
9.
MTA Cooperative Group (2004). National institute of mental health
multimodal treatment study of ADHD follow-up: Changes in ef-
fectiveness and growth after the end of treatment. Pediatrics, 113,
762–769.
MTA Cooperative Group (2006). Effects of stimulant medication on
growth rates across three years in the MTA follow up. (in submis-
sion).
Muller, U., Clark, L., Lam, M. L., Moore, R. M., Murphy, C. L.,
Richmond, N. K., et al. (2005). Lack of effects of guanfacine
on executive and memory functions in healthy male volunteers.
Psychopharmacology (Berl.), 182, 205–213.
Newcorn, J. H., Spencer, T. J., Biederman, J., Milton, D. R., &
Michelson, D. (2005). Atomoxetine treatment in children and ado-
lescents with attention-deficit/hyperactivity disorder and comorbid
oppositional defiant disorder. Journal of the American Academy
of Child and Adolescent Psychiatry, 44, 240–248.
Pappadopulos, E., Macintyre Ii, J. C., Crismon, M. L., Findling, R. L.,
Malone, R. P., Derivan, A., et al. (2003). Treatment recommenda-
tions for the use of antipsychotics for aggressive youth (TRAAY).
Part II. Journal of the American Academy of Child and Adolescent
Psychiatry, 42, 145–161.
Pliszka, S. R., Browne, R., Olvera, R. L., & Wynne, S. K. (2000). A
double-blind placebo controlled trial of Adderall and methylphen-
diate in the treatment of Attention deficit hyperactivity disorder.
Journal of the American Academy of Child and Adolescent Psy-
chiatry, 39, 619–626.
Pliszka, S. R., Crismon, M. L., Hughes, C. W., Corners, C. K., Emslie,
G. J., Jensen, P. S., et al. (2006a). The Texas Children’s Medication
Algorithm Project: Revision of the algorithm for pharmacotherapy
of attention-deficit/hyperactivity disorder. Journal of the American
Academy of Child and Adolescent Psychiatry, 45, 642–657.
Pliszka, S. R., Glahn, D. C., Semrud-Clikeman, M., Franklin, C., Perez,
R., Xiong, J., et al. (2006b). Neuroimaging of inhibitory control
areas in children with attention defict hyperactivity disorder who
were treatment naive or in long term treatment. American Journal
of Psychiatry, 163, 1052–1060.
Pliszka, S. R., Liotti, M., & Woldorff, M. G. (2000). Inhibitory control in
children with attention deficit/hyperactivity disorder: Event related
potentials identify the processing component and timing of an
impaired right-frontal response-inhibition mechanism. Biological
Psychiatry, 48, 238–246.
Pliszka, S. R., Matthews, T. L., Braslow, K. J., & Watson, M. A.
(2006c). Comparative effects of methylphenidate and mixed salts
Neuropsychol Rev (2007) 17:61–72
amphetamine on height and weight in children with attention-
deficit/hyperactivity disorder (ADHD). Journal of the American
Academy of Child and Adolescent Psychiatry, 45, 520–526.
Poulton, A. (2005). Growth on stimulant medication; clarifying the
confusion: A review. Archives of Diseases of Childhood, 90, 801–
806.
Rosa-Neto, P., Lou, H. C., Cumming, P., Pryds, O., Karrebaek, H.,
Lunding, J., et al. (2005). Methylphenidate-evoked changes in
striatal dopamine correlate with inattention and impulsivity in ado-
lescents with attention deficit hyperactivity disorder. Neuroimage,
25, 868–876.
Rubia, K., Smith, A. B., Brammer, M. J., Toone, B., & Taylor, E. (2005).
Abnormal brain activation during inhibition and error detection in
medication-naive adolescents with ADHD. American Journal of
Psychiatry, 162, 1067–1075.
Scahill, L., Chappell, P. B., Kim, Y. S., Schultz, R. T., Katsovich, L.,
Shepherd, E., et al. (2001). A placebo-controlled study of guan-
facine in the treatment of children with tic disorders and attention
deficit hyperactivity disorder. American Journal of Psychiatry,
158, 1067–1074.
Schmajuk, M., Liotti, M., Busse, L., & Woldorff, M. G. (2006). Elec-
trophysiological activity underlying inhibitory control processes
in normal adults. Neuropsychologia., 44, 384–395.
Schur, S. B., Sikich, L., Findling, R. L., Malone, R. P., Crismon, M.
L., Derivan, A., et al. (2003). Treatment recommendations for
the use of antipsychotics for aggressive youth (TRAAY). Part I: A
review. Journal of the American Academy of Child and Adolescent
Psychiatry, 42, 132–144.
Schweitzer, J. B., Lee, D. O., Hanford, R. B., Tagamets, M. A., Hoff-
man, J. M., Grafton, S. T., et al. (2003). A positron emission
tomography study of methylphenidate in adults with ADHD: Al-
terations in resting blood flow and predicting treatment response.
Neuropsychopharmacology, 28, 967–973.
Seifert, J., Scheuerpflug, P., Zillessen, K. E., Fallgatter, A., & Warnke,
A. (2003). Electrophysiological investigation of the effectiveness
of methylphenidate in children with and without ADHD. Journal
of Neural Transmission, 110, 821–829.
Shafritz, K. M., Marchione, K. E., Gore, J. C., Shaywitz, S. E., &
Shaywitz, B. A. (2004). The effects of methylphenidate on neural
systems of attention in attention deficit hyperactivity disorder.
American Journal of Psychiatry, 161, 1990–1997.
Snyder, R., Turgay, A., Aman, M., Binder, C., Fisman, S., & Carroll, A.
(2002). Effects of risperidone on conduct and disruptive behavior
disorders in children with subaverage IQs. Journal of the American
Academy of Child and Adolescent Psychiatry, 41, 1026–1036.
Spencer, T., Biederman, J., Wilens, T., Harding, M., O’Donnell, D.,
& Griffin, S. (1996). Pharmacotherapy of attention-deficit hyper-
activity disorder across the life cycle. Journal of the American
Academy of Child and Adolescent Psychiatry, 35, 409–432.
Spencer, T. J., Biederman, J., Madras, B. K., Faraone, S. V., Dougherty,
D. D., Bonab, A. A., et al. (2005). In vivo neuroreceptor imaging in
attention-deficit/hyperactivity disorder: A focus on the dopamine
transporter. Biological Psychiatry, 57, 1293–1300.
Spencer, T. J., Faraone, S. V., Biederman, J., Lerner, M., Cooper, K. M.,
& Zimmerman, B. (2006a). Does prolonged therapy with a long-
acting stimulant suppress growth in children with ADHD? Journal
of the American Academy of Child and Adolescent Psychiatry, 45,
527–537.
Spencer, T. J., Wilens, T. E., Biederman, J., Weisler, R. H., Read,
S. C., & Pratt, R. (2006b). Efficacy and safety of mixed am-
phetamine salts extended release (Adderall XR) in the manage-
ment of attention-deficit/hyperactivity disorder in adolescent pa-
tients: A 4-week, randomized, double-blind, placebo-controlled,
parallel-group study. Clinical Therapeutics, 28, 266–279.
Sumner, C. S., Donnelly, C., Lopez, F. A., Sutton, V., Bakken, R.,
Paczkowski, M., et al. (2005). Atomoxetine treatment for pediatric
71
patients with ADHD and comorbid anxiety. Presented at the annual
meeting of the American Psychiatric Association, Altanta, GA
(May).
Swanson, J. M., Greenhill, L. L., Lopez, F. A., Sedillo, A., Earl, C. Q.,
Jiang, J. G., et al. (2006). Modafinil film-coated tablets in chil-
dren and adolescents with attention-deficit/hyperactivity disorder:
Results of a randomized, double-blind, placebo-controlled, fixed-
dose study followed by abrupt discontinuation. Journal of Clinical
Psychiatry, 67, 137–147.
Swanson, J. M., McBurnett, K., Wigal, T., Pfiffner, L. J., Lerner,
M. A., Williams, L., et al. (1993). Effect of stimulant medica-
tion on children with attention deficit disorder: A “review of re-
views.”Exceptional Children, 60, 154–162.
Swensen, A., Michelsen, D., Buesching, D., & Faries, D. E. (2001).
Effects of atomoxetine on social and family functioning of ADHD
children and adolescents. Presented at the 48th Annual Meeting
of the American Academy of Child and Adolescent Psychiatry,
Honolulu,HI, (Oct 23–28).
Szobot, C. M., Ketzer, C., Cunha, R. D., Parente, M. A., Langleben, D.
D., Acton, P. D., et al. (2003). The acute effect of methylphenidate
on cerebral blood flow in boys with attention-deficit/hyperactivity
disorder. European Journal of Nuclear Medicine and Molecular
Imaging, 30, 423–426.
Tourette’s Syndrome Study Group (2002). Treatment of ADHD in chil-
dren with tics: A randomized controlled trial. Neurology, 58, 527–
536.
Vaidya, C. J., Austin, G., Kirkorian, G., Ridlehuber, H. W., Desmond,
J. E., Glover, G. H., et al. (1998). Selective effects of
methylphenidate in attention deficit hyperactivity disorder: A
functional magnetic resonance study. Proceedings of the National
Academy of Science, 95, 14494–14499.
Villalaba, L. (2006). Follow up review of AERS search identifying
cases of sudden death occuring with drugs used for the treatment
of attention deficit hyperactivity disorder (ADHD). Available
at. Food and Drug Administration Website [On-line]. Available:
http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-
Index.htm
Vles, J. S., Feron, F. J., Hendriksen, J. G., Jolles, J., van Kroonenburgh,
M. J., & Weber, W. E. (2003). Methylphenidate down-regulates
the dopamine receptor and transporter system in children with
attention deficit hyperkinetic disorder (ADHD). Neuropediatrics.,
34, 77–80.
Volkow, N. D., Wang, G., Fowler, J. S., Logan, J., Gerasimov, M.,
Maynard, L., et al. (2001). Therapeutic doses of oral
methylphenidate significantly increase extracellular dopamine in
the human brain. Journal of Neuroscience, 21, RC121.
Volkow, N. D., Wang, G. J., Fowler, J. S., & Ding, Y. S. (2005). Imaging
the effects of methylphenidate on brain dopamine: New model on
its therapeutic actions for attention-deficit/hyperactivity disorder.
Biological Psychiatry, 57, 1410–1415.
Volkow, N. D., Wang, G. J., Fowler, J. S., Gatley, S. J., Logan, J.,
Ding, Y. S., et al. (1998). Dopamine transporter occupancies in the
human brain induced by therapeutic doses of oral methylphenidate.
American Journal of Psychiatry, 155, 1325–1331.
Volkow, N. D., Wang, G. J., Fowler, J. S., Telang, F., Maynard, L.,
Logan, J., et al. (2004). Evidence that methylphenidate enhances
the saliency of a mathematical task by increasing dopamine in
the human brain. American Journal of Psychiatry, 161, 1173–
1180.
Weisler, R. H., Biederman, J., Spencer, T. J., Wilens, T. E., Faraone,
S. V., Chrisman, A. K., et al. (2006). Mixed amphetamine salts
extended-release in the treatment of adult ADHD: A randomized,
controlled trial. CNS Spectrum, 11, 625–639.
Weiss, M., Wasdell, M., & Patin, J. (2004). A post hoc analy-
sis of d-threo-methylphenidate hydrochloride (focalin) versus
d,l-threo-methylphenidate hydrochloride (ritalin). Journal of the
Springer
72
American Academy of Child and Adolescent Psychiatry, 43, 1415–
1421.
Wigal, S. B., McGough, J. J., McCracken, J. T., Biederman, J., Spencer,
T. J., Posner, K. L., et al. (2005). A laboratory school compari-
son of mixed amphetamine salts extended release (Adderall XR)
and atomoxetine (Strattera) in school-aged children with attention
deficit/hyperactivity disorder. Journal of Attention Disorders, 9,
275–289.
Wilens, T., McBurnett, K., Stein, M., Lerner, M., Spencer, T., &
Wolraich, M. (2005). ADHD treatment with once daily OROS
methylphendiate treatment: Final results from a long term open-
Springer
Neuropsychol Rev (2007) 17:61–72
label study. Journal of the American Academy of Child and Ado-
lescent Psychiatry, 44, 1015–1023.
Wilens, T. E., McBurnett, K., Bukstein, O., McGough, J., Greenhill,
L., Lerner, M., et al. (2006). Multisite controlled study of OROS
methylphenidate in the treatment of adolescents with attention-
deficit/hyperactivity disorder. Archives of Pediatrics and Adoles-
cent Medicine, 160, 82–90.
Wolraich, M. L., Greenhill, L. L., Pelham, W., Swanson, J., Wilens,
T., Palumbo, D., et al. (2001). Randomized, controlled trial of
oros methylphenidate once a day in children with attention-
deficit/hyperactivity disorder. Pediatrics, 108, 883–892.