Download Advances in the Treatment of Attention-Deficit

Advances in the Treatment of
Attention-Deficit/Hyperactivity
Disorder: A Guide for Pediatric Neurologists
Sharon B. Wigal, PhD, Stephanie Chae, Avni Patel, and Robin Steinberg-Epstein, MD
The purpose of this article is to assist pediatric neurologists in practice and in training to better
understand and distinguish between several of the most commonly prescribed treatments for
attention-deficit/hyperactivity disorder (ADHD) in school-aged children. Among the various
pharmacotherapies available for ADHD, 4 specific medications will be reviewed: oral release
osmotic system methylphenidate hydrochloride (CON; Concerta, McNeil Pharmaceuticals),
lisdexamfetamine dimesylate (LDX; Vyvanse, Shire Pharmaceuticals), atomoxetine (ATX; Strattera, Eli Lilly), and guanfacine extended-release (GXR; Intuniv, Shire Pharmaceuticals). This
article contains information including medication-release pattern, administration including
available dosing, adverse reactions, and case studies to serve as a guide to help determine
when a particular treatment might be more appropriate than another. Although ADHD is
apparent across the lifespan, this article will focus on children with ADHD from ages 6 to 12
years old. Importantly, although a number of stimulant and nonstimulant treatment options are
available for school-aged children diagnosed with ADHD, choosing the best treatment options
is highly dependent on obtaining thorough family and medical histories.
Semin Pediatr Neurol 17:230-236 © 2010 Elsevier Inc. All rights reserved.
A
ttention-deficit/hyperactivity disorder (ADHD) is the
most common child psychiatric disorder of hyperactivity, impulsivity and/or inattention. It is a chronic condition
that affects people of all ages from young children through
adulthood. Symptoms of ADHD are noticeable and diagnosed at various stages of life although more commonly in
children before age 7 years. In children with ADHD, symptoms may be apparent socially, emotionally, and academically. ADHD may lead to low self-esteem, poor peer relationships, delinquencies, and substance abuse. Approximately
From the Department of Pediatrics, Child Development Center, University
of California, Irvine, CA.
Dr Sharon B. Wigal is a consultant for Abbott, McNeil, NuTec, Shire, Taisho,
and the NIMH; has received grant/research support from Addrenex, Eli
Lilly, McNeil, Next Wave Pharmaceuticals, Otsuka, Psychogenics, Quintiles, Shionogi Pharm, Shionogi Pharm, Shire, and the NIMH; and is on
the speaker or advisory boards for McNeil, the NIMH, Shire, and UCB.
Dr Robin Steinberg-Epstein is a consultant for McNeil and Shire; has
received grant/research support from Addrenex, Eli Lilly, McNeil, Next
Wave Pharmaceuticals, Otsuka, Psychogenics, Quintiles, Shionogi
Pharm, Shire, and the NIMH; and is on the speaker or advisory boards
for Eli Lilly, McNeil, and Shire.
Address reprint requests to Sharon B. Wigal, PhD, Department of Pediatrics,
Child Development Center, University of California, Irvine, CA 92612.
E-mail: [email protected]
230
1071-9091/10/$-see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.spen.2010.10.005
65% of children identified with ADHD since childhood will
continue to exhibit symptoms as adults.1
To diagnose ADHD, the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) is
used.1 Approximately 3% to 7% of children from ages 8 to 15
years old meet criteria for ADHD. The diagnosis of ADHD can
be divided into 3 categories: predominantly inattentive, predominantly hyperactive-impulsive, and combined type,
which is both inattentive and hyperactive. The DSM-IV-TR
lists 9 different symptoms for both categories of inattentiveness and hyperactivity-impulsivity (Table 1). To be diagnosed with one of the categories of ADHD, a child must
present with 6 of the 9 symptoms of impairment in at least 2
different settings, such as classroom and home. These symptoms must be present for at least 6 months and must not be
explained by other psychiatric diagnoses.
Based on current research, including the Multimodality
Treatment Study of Children with ADHD (MTA), there is
overwhelming consensus that the primary treatment of
ADHD is medication and that accessory symptoms are benefited by multimodal treatment (a combination of medication
and alternative treatments).2 This is further supported by the
guidelines set forth by 3 major academies (the American
Academy of Neurology, the American Academy of Child &
Adolescent Psychiatry, and the American Academy of Pedi-
ADHD treatment update
Table 1 DSM-IV-TR Criteria of Symptomatology in AttentionDeficit Disorder
Inattention: must include at least 6 of the following
symptoms of inattention that must have persisted for
at least 6 months to a degree that is maladaptive and
inconsistent with developmental level:
Often fails to give close attention to details or makes
careless mistakes in schoolwork, work, or other
activities
Often has difficulty sustaining attention in tasks or play
activities
Often does not seem to listen to what is being said
Often does not follow through on instructions and fails
to finish schoolwork, chores, or duties in the
workplace (not due to oppositional behavior or failure
to understand instructions)
Often has difficulties organizing tasks and activities
Often avoids or strongly dislikes tasks (such as
schoolwork or homework) that require sustained
mental effort
Often loses things necessary for tasks or activities
(school assignments, pencils, books, tools, or toys)
Often is easily distracted by extraneous stimuli
Often forgetful in daily activities
Hyperactivity/impulsivity: must include at least 6 of the
following symptoms of hyperactivity-impulsivity that
must have persisted for at least 6 months to a degree
that is maladaptive and inconsistent with
developmental level:
Hyperactivity evidenced by fidgeting with hands or feet,
squirming in seat
Hyperactivity evidenced by leaving seat in classroom or
in other situations in which remaining seated is
expected
Hyperactivity evidenced by running about or climbing
excessively in situations where this behavior is
inappropriate (in adolescents or adults, this may be
limited to subjective feelings of restlessness)
Hyperactivity evidenced by difficulty playing or engaging
in leisure activities quietly
Hyperactivity evidenced by often on the go or acting as
if driven by a motor
Hyperactivity evidenced by talking excessively
Impulsivity evidenced by blurting out answers to
questions before the questions have been completed
Impulsivity evidenced by showing difficulty waiting in
lines or awaiting turn in games or group situations
Impulsivity evidenced by interrupting or intruding on
others
Data from DSM-IV-TR. Copyright 2000 American Psychiatric Association.
atrics) as well as by international consensus.3 Although some
alternative treatments (eg, nutrition and exercise) have been
shown to improve psychiatric comorbidities, there is limited
evidence to suggest their direct benefit for ADHD.4
Treatment Algorithm
The Texas Children’s Medication Algorithm Project5 was designed to be used in community mental health centers, pro-
231
viding suggestions for drug choice as it applies to ADHD
treatment. As a guide that serves as the basis for the American
Academy of Child & Adolescent Psychiatry practice parameter on the treatment of children and adolescents with
ADHD,6 it offers opportunities to determine pharmacotherapy with maximal benefits while taking into consideration
the unique attributes of any given case. Overall, this consensus-driven algorithm establishes the use of a stimulant for the
first stage of treatment followed by a second stage of stimulant, progressing to nonstimulant use. Although some aspects of this algorithm are no longer relevant, such as the use
of pemoline (mostly because of concerns regarding fatal hepatotoxicity), the general rationale still can be used and applied to presently available agents.
Stimulants
Stimulants have been used to treat symptoms of ADHD for
more than 50 years. As mentioned earlier, the Texas Consensus Conference Panel on Pharmacotherapy of Childhood
ADHD developed the use of stimulant medications as firstline options for the medical management of children and
adolescents with classic ADHD without other complicating
features.5,6 The expectation is that 70% of patients will respond to the first stimulant that is tried with the recommendation that a second be tried to yield up to an 80% benefit.7
Case Study 1
This child has been diagnosed with ADHD, inattentive subtype and comorbid oppositional defiant disorder (ODD; see
Figure 1 below for Case Study 1). Following the treatment
algorithm,5 this would suggest starting with a stimulant medication. One must first consider whether there are contraindications to a stimulant. We know that there is no known
cardiac history in this patient to suggest a need for a pretreatment echocardiogram. No laboratory studies are necessary.
Given that her weight is greater than the 95th percentile,
there is no concern that weight loss will be a problem for her,
and, in fact, stimulants may at first be helpful. Although there
may be some initial weight loss, we would not expect ongoing weight loss.
In general, over two thirds of the Multimodality Treatment
Study of Children with ADHD sample exhibited concurrent
psychiatric disorders.2 As for ODD, the literature supports
the use of stimulants in patients with ODD and ADHD.8
Controlling ADHD with a stimulant may offer benefits for
ODD symptoms. There is certainly evidence that in the face
of ODD, stimulants still work to improve ADHD symptoms
and do not worsen the ODD.3
How does one know which stimulant to choose? Stimulants generally belong to either the methylphenidate family
or the amphetamine family. The first consideration is one of
duration. Given that this is a 9 year old with homework that
is taking an inordinate amount of time to complete and her
problems exist throughout the school day, a long-acting
medication would be the most appropriate. Table 2 provides
S.B. Wigal et al
232
Case Study #1
Identification and Presenting Complaints: A 9-year-old girl was brought into the clinic
for diagnosis and treatment of possible ADHD. Her mother was concerned because for
the last 3 years teachers had mentioned that her daughter was seated up front due to
problems staying on task during schoolwork. Her grades are mostly “C’s” with a
sprinkling of “B’s” and “D’s”. She has difficulty finishing books and likes to skip to the
end to see what happens. Mom often finds her completed, ungraded homework at the
bottom of her backpack. Her mom also mentions that she does not listen when spoken
to and is quite a daydreamer. She misplaces or loses things that are not important to
her; always forgetting things at school. She can takes hours to complete a simple
homework assignment.
In addition, her mother reports that the teachers also mentioned that she has a hard
time making friends. She also has a lot of trouble getting along with her mom; she picks
fights and demands things her way. She gets along with her dad and is a tomboy when
it comes to her relationship with her brother. She initiates fights with her brother.
Physical Exam: She is moderately obese (weight 47 kg (>95th percentile)) but
otherwise has a normal general and neurologic exam.
Family History: There is a maternal history of ADHD, including the patient’s mother
and grandmother having ADHD diagnoses. The girl’s father does not have any history of
behavior or mental health problems. No family history exists for sudden, unexpected
death or structural cardiac defects.
Supporting Data: ADHD rating scales submitted by both parent and teacher showed
significant elevations in inattentive and oppositional symptoms.
Diagnosis: ADHD, predominantly inattentive subtype with a comorbid problem of ODD
Treatment considerations and diagnostic formulation:
- Child’s weight is > 95th percentile
- Oppositional Defiant Disorder (ODD) diagnosed.
- No other psychiatric condition identified (i.e., anxiety or autism spectrum
disorders)
Key questions for differential treatment:
- Is the child’s weight within the normal range, high or low?
- Is ODD or some other comorbid disorder present with ADHD symptoms?
- Are there any contraindications to treatment?
Figure 1 A case study of a child treated with stimulant pharmacotherapy.
key details of a few research studies regarding the development of 2 of these products.
For the purpose of our discussion, we have chosen to
compare 2 long-acting medications: lisdexamfetamine (LDX;
Shire Pharmaceutical, Wayne, PA) and Concerta (CON;
McNeil Pharmaceuticals, Fort Washington, PA) (See Table 3
for summary information about these 2 stimulants). Although they have similar duration of action and side effect
profiles, there are subtle differences that may lead to a choice
of one over the other. For example, studies suggest that the
severity of appetite suppression may be more significant for
LDX and other amphetamines than for other methylphenidate products with the same average duration of action. Such
an “adverse effect” might actually be of benefit for this particular patient. By contrast, if this child could not be taught to
swallow a pill, LDX can be combined with a liquid to make a
solution. Overall, either of these medications serves as an
excellent option for her. However, should she respond with
significant sleep-onset problems, one might choose a shorteracting (ie, not a sustained- or extended-release) stimulant
medication.
Nonstimulants
Although stimulant drug treatments have proved to be
highly effective and safe in treating symptoms of ADHD,
approximately 20% of children with ADHD fail to respond
or have significant side effects to one of the first 2 stimulants that are tried. Following the treatment algorithm,5
practitioners are encouraged to consider nonstimulant
drugs as second-line treatments, with the exception of
individuals with ADHD having an active substance abuse
problem, comorbid anxiety, or tics, for which nonstimulants would be the first-line treatment.9 Thus, nonstimulants are used when ADHD patients fail to respond to
stimulants or have increased side effects. Furthermore,
there are subgroups of children whose comorbid conditions (eg, anxiety, tics) may be exacerbated by stimulant
treatment. Thus, alternate pharmacotherapy may yield
beneficial effects on accessory symptoms while also treating primary ADHD symptoms. Table 4 summarizes several
key studies regarding development of 2 specific nonstimulant medications.
ADHD treatment update
233
Table 2 Representative Studies of 2 Stimulant Treatments for ADHD
OROS Methylphenidate Hydrochloride
Citation
200211
Swanson et al,
Swanson et al, 200412
Wolraich et al, 200113
Emphasis
Conclusion
Laboratory school study comparing objective activity
levels during structured classroom activities and
outside recess activities
Comparative trial of 2 long-acting MPH products in
the laboratory school setting
Randomized study comparing placebo, immediate
release MPH tid and CON
CON treatment improved attention and behavior during
classroom seatwork but generally showed no
difference from placebo in the playground
The specific time-course profiles are demonstrated,
which show differences in onset and duration
Demonstrated significance of both MPH treatments
over placebo with equivalent efficacy to each other
Lisdexamfetamine
Citation
Emphasis
Biederman, et al,
200714
Pennick, 2010
Conclusion
Laboratory school study of LDX demonstrating its
long acting effects
15
Absorption and metabolic conversion of LDX to
d-amphetamine
Wigal, et al, 200916
Laboratory school study evaluating the onset and
offset effects of LDX
Significant improvements were noted from the first
time point measured until 12 h. However, no
predose baseline was measured
Blood vs liver tissue as responsible for the conversion
of the inactive prodrug to active amphetamine
treatment
Placebo controlled study of LDX with efficacy extended
in both directions from Biederman et al, 200714
OROS, Oral release osmotic system; CON, Concerta (OROS methylphenidate hydrochloride); MPH, Methylphenidate; tid, 3 times per day.
Table 3 Summary Information for 2 Commonly Prescribed Stimulants to Treat ADHD
Stimulants
Product
Delivery System
Approval by FDA
Doses
Initial dose
Onset of activity
Duration of activity
Administration
Common side effects
OROS Methylphenidate Hydrochloride (Concerta)
LDX Dimesylate (Vyvanse)
Methylphenidate Oral Release Osmotic System
August 2000
18, 27, 36, 54, and 72 mg; (2 ⴛ 36 mg)
18 mg
1h
Up to 12 h postdose, extended
Once daily in the morning with or without food; Swallow
whole; do not crush or chew
Decreased appetite, dry mouth, trouble sleeping, dizziness,
stomach ache, increased sweating, headache, nausea,
anxiety, weight loss, irritability
d-amphetamine prodrug
February 2007
Twenty, 30, 40, 50, 60, and 70 mg
30 mg
1.5 h
Up to 13 h postdose, extended
Daily in the morning with or without food;
May dissolve it in water.
Upper abdominal pain, decreased appetite,
dry mouth, dizziness, irritability,
insomnia, weight loss
Table 4 Representative Studies of 2 Nonstimulant Treatments for ADHD
Atomoxetine
Citation
Faraone et al,
Study Description
200717
Statistical extension of Wigal, et al, laboratory
school study (see below)
Wigal et al, 200518
Laboratory school study measuring time course
effects of ATX and MAS-XR
Michelson et al, 200219
Clinic study of ATX with quality of life
measurements
Comparison of two different methods for initiating
ATX to reduce incidence of adverse events
Greenhill et al, 200720
Conclusion
Forecasting to 8-wk treatment period showed continued
greater efficacy for mixed amphetamine salts,
extended-release MAS-XR compared with ATX
Short-term study replicating significant ATX within 1-wk
of initial dosing and time course effects in
comparison with amphetamine treatment
Demonstrated treatment effects within 1 wk of usage
Lower risk of adverse events if over the first few weeks
of treatment, patients receive doses divided into 2 per
day and titrated to full dose (1.2 mg/kg/d) more
slowly
Guanfacine Extended Release
Citation
Biederman et al,
Study Description
200821
Connor & Rubin,
201022
Spencer et al, 200923
Forced dose escalation study of GXR vs placebo for
8 wks
Review paper on GXR
Coadministration of GXR and stimulant medication
Conclusion
Improvements with GXR similar to other nonstimulants
Mild slowing of heart rate and some lowering of systolic
blood pressure and diastolic blood pressure occurs
and requires vital sign monitoring during treatment
Increased ADHD symptom improvement with no new
adverse events
S.B. Wigal et al
234
Case Study #2
Identification and Presenting Complaints: This 10 ½-year-old boy presents with
concerns regarding inconsistent grades and several behavioral complaints. His mother
reports that he will get “A’s” on tests but will not turn in projects and will end up with
“C’s” as final grades. At a parent-teacher conference, his teacher mentioned that he
disrupts other students when they are speaking, blurts out answers, and is very
talkative. He has trouble listening and following directions, and often daydreams in
class. He feels as if his teacher “hates” him and favors other students in the class.
He says he does not understand why others don’t see things the way he does including
his older brother, with whom he is continually arguing. The only thing he will sit still for
is video games. His mother also notices that his backpack and his room are extremely
messy and disorganized. Mom is also concerned because he is still so afraid of the dark
that he sleeps with the light on. He will not spend the night at a friend's house and is
extremely afraid of dogs, even the neighbor's puppy.
th
Physical Exam: The patient weighs 26.4 kg (just below 5 percentile) and otherwise
has normal general and neurologic exams, with the exception of blood pressure being
130/85.
Family History: There is no maternal or paternal history of mental health disorders;
however the father had an alcohol problem prior to marriage. In addition, the patient’s
older brother is diagnosed and in treatment for a chronic tic disorder. No family history
exists for sudden, unexpected death or structural cardiac defects.
Diagnosis: ADHD, combined subtype
Treatment considerations:
- Sibling with chronic tic disorder
- Blood pressure
- Co-morbid symptoms of anxiety
Key questions for differential treatment:
- Is there a family history of tics or Tourette’s Disorder?
- Is the child’s blood pressure within normal limits, high or low?
Figure 2 A case study of a child treated with nonstimulant pharmacotherapy.
Case Study 2
This child was diagnosed with ADHD, combined subtype
(see Figure 2). However, there are some distinct concerns
that may alter the choice of medication. Although it would
not be incorrect to choose a stimulant as the treatment of
choice, one must consider how this child presents (eg, high
blood pressure, a family history of a tic disorder, low weight,
and a potential comorbid anxiety issue). Each of these issues
are explored more closely later.
Although studies of stimulant medication typically show a
statistically significant increase in blood pressure, they do not
show a clinically relevant increase. However, one of the medication options, guanfacine extended-release (GXR) (a recently available extended-release form of guanfacine), is a
known antihypertensive agent and thus can cause decreases
in blood pressure. Therefore, one might opt to consider this
nonstimulant as a strong possibility because, in this case,
such blood pressure effects are an advantage. It is important
to become familiar with the side effect profile of each medication because they can sometimes be used to the patient’s
advantage (Table 5). In addition, instructions to families
should be clear about discontinuation practices. For instance, GXR should be tapered off with decreases in incre-
ments of 1 mg every 3 to 7 days as directed on the product
label. This would even be important for a child with hypertension because it would be very important for this child’s
family to be aware of potential rebound hypertension if the
medication were to be suddenly withdrawn. Of course, any
child with elevated blood pressure also requires further medical investigation to determine the etiology. In a child with
known hypertension being managed by a cardiologist, nephrologist, or pediatrician, that physician should be consulted
regarding possible medication choices.
As for the history of a tic disorder, there is evidence that
stimulant treatment, at least temporarily, may increase tics in
some individuals.10 Longer-term studies show, however, that
there is no overall increase in tics in most individuals.10 As for
ATX, there is no evidence of an effect on tics in either direction. GXR, in contrast, may decrease tics because guanfacine
has commonly been prescribed as a primary treatment for
motor tics in the non– extended-release form.
Stimulants and ATX may lead to decreased appetite and
weight loss, but GXR does not appear to have an effect in that
regard. Finally, anxiety seems to be a presenting problem for
this child. The stimulants may worsen anxiety. GXR generally
has no effect on anxiety, whereas ATX has mild anxiolytic
ADHD treatment update
235
Table 5 Summary Information for 2 Commonly Prescribed
Nonstimulants to Treat ADHD
Nonstimulants
Product
Guanfacine
Extended-Release
(Intuniv)
FDA approval
Doses
September 2009
1, 2, 3, and 4 mg
Initial dose
Onset of
activity
Duration of
activity
Administration
1 mg
Some effects in 1 wk
6-8 h extended
Atomoxetine
(Strattera)
November 2002
10,18,25,40, 60,
80, and 100 mg
0.5 mg/kg
Some effects in
1 wk
7-9 h and up to 24 h
Once or twice daily
Once daily in the
by mouth with or
morning. Swallow
without food
whole; do not crush
or chew
Common Side Sleepiness, dry mouth Abdominal pain,
decreased
effects
drowsiness,
appetite, nausea
dizziness low blood
or vomiting,
pressure, irritability,
dizziness, mood
headache,
swings,
constipation, nausea,
somnolence
not hungry
(decreased appetite),
stomach pain
benefits. Therefore, if one had the sense that anxiety were an
overriding issue, ATX might be the medication of choice. Of
course, one might alternatively consider medical therapies
specifically focused on anxiety, but these options will not be
further considered in this review.
As mentioned earlier, stimulants produce an overall more
robust response, with over 70% of subjects responding to the
first stimulant tried and up to 80% to the second one. The
response to the nonstimulant medications (both GXR and
ATX) is closer to 50%. Prolonged sedation may be seen with
GXR in the first several weeks of use and with ATX in the first
few days of use.
For this patient, it seems likely that starting either GXR or
ATX may provide some unique benefits or protections. See
Table 5 for summary information for each of these 2 nonstimulant medications.
Conclusions
Each of the reviewed stimulant and nonstimulant medications has its own set of benefits and drawbacks. Thus, it is
imperative for individual practitioners to gain familiarity
with the nuances of treatment options. By reviewing research
findings and medication properties of each, following the suggested practical algorithm, and carefully choosing the best option for a particular patient profile, neurologists can gain clinical
experience in the optimal treatment of ADHD in children while
helping them reach their true potential.
References
1. American Psychiatric Association, DSM: IV TR: Diagnostic and Statistical Manual of Mental Disorders (ed 4). Washington, DC, American
Psychiatric Publishing, Inc, 2000, pp 78-85
2. MTA Cooperative Group: A 14-month Randomized Clinical Trial of
Treatment strategies for attention deficit hyperactivity disorder. Arch
Gen Psychiatry 56:1073-1086, 1999
3. Kutcher S, Aman M, Brooks SJ, et al: International consensus statement
on attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBDs): clinical implications and treatment practice
suggestions. Eur Neuropsychopharmacol 14:11-28, 2004
4. Larzelere MM, Campbell JS, Robertson M: Complementary and alternative medicine usage for behavioral health indications. Prim Care
37:213-236, 2010
5. Pliszka SR, Crismon ML, Hughes CW, et al: Texas Consensus Conference
Panel on pharmacotherapy of childhood attention deficit hyperactivity
disorder. Revision of the algorithm for pharmacotherapy of attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 45:642657, 2006
6. Pliszka S: Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder.
J Am Acad Child Adolesc Psychiatry 7:894-921, 2007
7. Elia J, Ambrosini PJ, Rapoport JL: Treatment of attention-deficit-hyperactivity disorder. N Engl J Med 340:780-788, 1999
8. Connor DF, Doerflor LA: Attention-deficit/hyperactivity disorder and
comorbid oppositional defiant disorder or conduct disorder. Curr Attention Dis Rep 1:5-11, 2009
9. American Academy of Child and Adolescent Psychiatry (AACAP): Official action: Practice parameter for the assessment and treatment of
children and adolescents with attention-deficit/hyperactivity disorder.
J Am Acad Child Adolesc Psychiatry 46:894-921, 2007
10. Poncin Y, Sukhodolsky DG, McGuire J, et al: Drug and non-drug treatments of children with ADHD and tic disorders. Eur Child Adolesc
Psychiatry 7 16:78-88, 2007 (suppl 1)
11. Swanson J, Gupta S, Williams L, et al: Efficacy of a new pattern of
delivery of methylphenidate for the treatment of ADHD: Effects on
activity level in the classroom and on the playground. J Am Acad Child
Adolesc Psychiatry 41:1306-1314, 2002
12. Swanson JM, Wigal SB, Wigal T, et al: A comparison of once-daily
extended release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (The Comacs Study). Pediatrics 113:206-216, 2004
13. Wolraich ML, Greenhill LL, Pelham W, et al: Randomized, controlled
trial of OROS methylphenidate once a day in children with attentiondeficit/hyperactivity disorder. Pediatrics 108:883-892, 2000
14. Biederman J, Boellner SW, Childress AC, et al: Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with
ADHD: A double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry 62:970-976, 2007
15. Pennick M: Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat 6:317327, 2010
16. Wigal SB, Kollins SH, Childress AC, et al: A 13-hour laboratory school
study of lisdexamfetamine dimesylate in school-aged children with
attention-deficit/hyperactivity disorder. Child Adolesc Psychiatry Ment
Health 3:17, 2009
17. Faraone SV, Wigal SB, Hodgkins P: Forecasting three-month outcomes
in a laboratory school comparison of mixed amphetamine salts extended release (Adderall XR) and atomoxetine (Strattera) in schoolaged children with ADHD. J Atten Disord 11:74-82, 2007
18. Wigal SB, McGough JJ, McCracken JT, et al: A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR)
and atomoxetine (Strattera) in school-aged children with attention deficit/hyperactivity disorder. J Atten Disord 9:275-289, 2005
19. Michelson D, Allen AJ, Busner J, et al: Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity
disorder: A randomized, placebo-controlled study. Am J Psychiatry
159:1896-1901, 2002
236
20. Greenhill LL, Newcorn JH, Gao H, et al: Effect of two different methods
of initiating atomoxetine on the adverse event profile of atomoxetine.
J Am Acad Child Adolesc Psychiatry 46:566-572, 2007
21. Biederman J, Melmed RD, Patel A, et al: A randomized, double-blind,
placebo-controlled study of guanfacine extended release in children and
adolescents with attention-deficit/hyperactivity disorder. Pediatrics 121:
e73-e84, 2008
S.B. Wigal et al
22. Connor DF, Rubin J: Guanfacine extended release in the treatment of
attention deficit hyperactivity disorder in children and adolescents.
Drugs Today 46:299-314, 2010
23. Spencer TJ, Greenbaum M, Ginsberg LD, et al: Safety and effectiveness
of coadministration of guanfacine extended release and psychostimulants in children and adolescents with attention-deficit/hyperactivity
disorder. J Child Adolesc Psychopharmacol 19:501-510, 2009