Clinical Therapeutics/Volume 30, Number 5, 2008
Evolution of the Treatment of Attention-Deficit/Hyperactivity
Disorder in Children: A Review
Robert L. Findling, MD
Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio
ABSTRACT
Background: Efficacious and well-tolerated medi-
cations are available for the treatment of attention-
deficit/hyperactivity disorder (ADHD). Stimulants such
as methylphenidate (MPH) and amphetamines are the
most widely used medications approved by the US Food
and Drug Administration for the treatment of ADHD
in children.
Objective: This article reviews the literature on the
development and use of medications for the treatment
of ADHD in children.
Methods: A search of MEDLINE was conducted to
identify relevant studies and critical reviews on the
treatment of ADHD in children. The main criteria for
inclusion of a study were that it have a controlled design,
enroll >100 subjects if a clinical trial and >20 sub-
jects if a classroom study, assess symptoms with the
most widely used scales and tests, and be published
from 2000 to 2008. A few older pivotal studies were
also included.
Results: Many studies have reported the long-term
efficacy and tolerability of immediate-release formula-
tions of MPH. The disadvantages of such formula-
tions include the need for multiple daily dosing and
a potential for abuse. Various extended-release formu-
lations of MPH have been found effective in con-
trolled studies enrolling large numbers of children with
ADHD. The efficacy and tolerability of dexmethylpheni-
date, the active d-isomer of MPH, in an extended-
release formulation have also been reported. An
extended-release formulation of mixed amphetamine
salts (MAS-XR) that is dosed once daily has been
found to be efficacious and well tolerated. The non-
stimulant atomoxetine has been reported to be well
tolerated and efficacious, although it may not be as
effective as stimulants; this formulation is, however,
less likely than stimulants to be associated with abuse
and diversion. A recently approved prodrug stimulant,
lisdexamfetamine dimesylate (LDX), was developed
to provide a long duration of effect that is consistent
942 Volume 30 Number 5
throughout the day, with a reduced potential for
abuse. In a placebo-controlled study in children with
ADHD, less intersubject variability in Tmax, Cmax, and
AUC from time zero to the last quantifiable concen-
tration was seen in the 8 subjects who received LDX
(percent coefficient of variation, 15.3, 20.3, and 21.6,
respectively) compared with the 9 subjects who re-
ceived MAS-XR (52.8, 44.0, and 42.8). In 2 clinical
trials, significantly greater improvements in teacher
and parent ratings of ADHD symptoms were seen with
LDX compared with placebo (P < 0.001). A study of
the abuse potential of LDX evaluated subjective re-
sponses to the effects of oral LDX and immediate-
release d-amphetamine in adults with a history of
stimulant abuse. LDX was associated with a sig-
nificantly lower abuse-related liking effect than
d-amphetamine (P = 0.039).
Conclusions: Currently available treatments for
ADHD in children are efficacious and well tolerated,
but many of them are limited by the requirement for
multiple daily dosing and abuse potential. LDX, a
long-acting prodrug of d-amphetamine, has been re-
ported to be effective and appears to overcome
some of these limitations. (Clin Ther. 2008;30:942–
957) © 2008 Excerpta Medica Inc.
Key words: attention-deficit/hyperactivity disor-
der, children, stimulants, nonstimulants, prodrugs,
lisdexamfetamine.
INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is
the most prevalent neurobehavioral disorder among
school-aged children in many countries,1 affecting
between 3% and 7% of schoolchildren in the United
Accepted for publication April 16, 2008.
Express Track online publication May 13, 2008.
doi:10.1016/j.clinthera.2008.05.006
0149-2918/$32.00
© 2008 Excerpta Medica Inc. All rights reserved.

States.2 This chronic disorder severely impairs func-
tion both at home and at school, and its symptoms
persist into adolescence and adulthood in 37% to
85% of children, according to the National Comor-
bidity Survey.3
Primary care physicians and pediatricians are in-
creasingly diagnosing and managing ADHD and acting
as the main prescribers of stimulants.4 Effective treat-
ment of ADHD that will achieve an optimal therapeu-
tic response and a suitable duration of effect along with
patient satisfaction and adherence involves many con-
siderations, including the individual characteristics of
stimulant and nonstimulant agents, the available for-
mulations of these agents, and their delivery systems.
Stimulants such as methylphenidate (MPH) and am-
phetamines are currently the most widely prescribed
medications for ADHD, and their efficacy and tolerabili-
ty in children and adults have been reported in numer-
ous studies.5 They represent the first stage of medication
intervention for ADHD.6 However, the need for multiple
daily dosing of short-acting stimulants and concerns
about their abuse potential have led to the development
of alternative agents.7 Other treatment options approved
by the US Food and Drug Administration (FDA) include
extended-release (ER) formulations of MPH and am-
phetamines,8–11 as well as the nonstimulant atomoxe-
tine.5 Lisdexamfetamine dimesylate (LDX), the first
member of a new class of prodrug stimulants, was ap-
proved for the treatment of ADHD in 2007.12–14 FDA-
approved medications for the treatment of ADHD in
children are described in Table I.15–29
This article reviews the literature on the develop-
ment and use of medications for the treatment of
ADHD in children.
METHODS
A search of MEDLINE was conducted to identify rele-
vant studies and critical reviews on the treatment of ADHD
in children. The main criteria for inclusion of a study
were that it have a controlled design, enroll >100 sub-
jects if a clinical trial and >20 subjects if a classroom
study, assess symptoms with the most widely used
scales and tests, and be published from 2000 to 2008.
A few older pivotal studies were also included.
PHARMACOTHERAPIES FOR
ADHD IN CHILDREN
The main results of the studies included in this litera-
ture review are summarized in Table II.9,10,14,30–40
May 2008 943
R.L. Findling
Stimulants
The behavioral effects of stimulants in children
were first reported 70 years ago by Charles Bradley, a
Rhode Island psychiatrist, in 30 children (21 boys,
9 girls; age range, 5–14 years) whose “behavior disor-
ders were severe enough to have warranted hospitali-
zation, but varied considerably.”41 He reported that
after receiving “benzedrine” (d,l-amphetamine, the
racemic form of amphetamine), 14 children responded
“in a spectacular fashion,” with improvements in their
schoolwork that appeared “promptly the first day
benzedrine was given.” Bradley and many others sub-
sequently published clinical reports of children whose
ADHD symptoms improved during treatment with
amphetamines and MPH. These reports led to ran-
domized controlled studies, including the landmark
Multimodal Treatment Study (MTA),42 a 14-month
trial in children that is described in the following sub-
section. Treatment guidelines from the American
Academy of Child and Adolescent Psychiatry11 and
the American Academy of Pediatrics43 stated that
stimulant medications have the most evidence of effi-
cacy and safety in the treatment of ADHD in children
and continue to be recommended as the first stage of
medication intervention. In its clinical practice guide-
line on the diagnosis and evaluation of the child with
ADHD, the American Academy of Pediatrics made
similar recommendations.44
Methylphenidate
The therapeutic effects of MPH are believed to be
elicited primarily through inhibition of the presynap-
tic dopamine transporter, with a lesser effect on the
norepinephrine transporter.8 The immediate-release
(IR) formulation of oral MPH is rapidly and almost
completely absorbed. Cmax occurs in 1 to 3 hours, with
substantial intersubject variation. IR-MPH is rapidly
distributed and has low protein binding. These prop-
erties, combined with a high lipid solubility, result in
rapid uptake of IR-MPH into the central nervous sys-
tem. IR-MPH provides relief from ADHD symptoms
for ~4 hours; thus, multiple daily dosing is necessary
to maintain improvements throughout the day.45
The MTA study evaluated the long-term efficacy
and tolerability of MPH in 579 children with ADHD
(age range, 7–10 years).42 Patients were randomized
to receive 14 months of one of the following: medical
management (MPH plus monthly visits with a phar-
macotherapist who provided support, encouragement,
 Table I. Medications currently approved by the US Food and Drug Administration for the treatment of attention-deficit/

944
hyperactivity disorder in children.

Formulation Brand Name* Dosing Frequency Tmax, h

Immediate-release stimulants
   Dexmethylphenidate HCl Focalin®15 Twice daily (≥4 h) 1.5
Clinical Therapeutics

   Methylphenidate HCl Ritalin®16 Twice daily 1.9

   Dextroamphetamine sulfate Dexedrine®17 1–3 Times daily (4–6 h) 3
DextroStat®18 1–3 Times daily (4–6 h) 2
   Mixed amphetamine salts Adderall®19 1–3 Times daily (4–6 h) 3
Extended-release stimulants
   Dexmethylphenidate HCl Focalin® XR 20 Once daily 1.5†
   Dextroamphetamine sulfate Dexedrine® Spansule®17 Once daily 8
   Methylphenidate HCl Metadate ER®21 Twice daily 4.7
Metadate CD®22 Once daily 1.5†
Methylin® ER 23 Twice daily 4.7
Ritalin LA®24 Once daily 1–3†
Ritalin SR®16 Twice daily 4.7
   Methylphenidate HCl OROS Concerta®25 Once daily 6.8
   Methylphenidate
    transdermal system Daytrana™ 26 Once daily (9-h wear time) 7.5–10.5
   Mixed amphetamine salts,
    extended release Adderall XR®27 Once daily 7
Nonstimulant
   Atomoxetine HCl Strattera®28 1–2 Times daily 1–2
Long-acting prodrug stimulant
   Lisdexamfetamine dimesylate Vyvanse™ 29 Once daily 3.5‡

XR = extended release; ER = extended release; CD = controlled delivery; LA = long acting; SR = sustained release; OROS = osmotic controlled-
release system.
* Focalin® and Focalin® XR are trademarks of Novartis Pharmaceuticals Corporation; Ritalin®, Ritalin LA®, and Ritalin SR® are registered
trademarks of Novartis Pharmaceuticals Corporation; Dexedrine® and Dexedrine® Spansule® are registered trademarks of GlaxoSmithKline;
DextroStat ® is a registered trademark of Shire US Inc.; Adderall® is a registered trademark of Shire LLC, under license to Duramed
Pharmaceuticals, Inc.; Metadate ER® and Metadate CD® are registered trademarks of UCB Inc.; Methylin® is a registered trademark of
Mallinckrodt Inc.; Concerta® is a registered trademark of ALZA Corporation; Daytrana™ is a trademark of Shire Pharmaceuticals Ireland
Ltd.; Adderall XR® is a registered trademark of Shire LLC; Strattera® is a registered trademark of Eli Lilly and Company; and Vyvanse™
is a trademark of Shire LLC.
† First peak.
‡ T
max of d -amphetamine.

Volume 30 Number 5
May 2008
Table II.  Selected studies of pharmacotherapies for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents.

Formulation/ No. of Duration of Study

Authors Subjects (Age) Regimens Treatment Measures Results
Stimulants
MPH
   Biederman et al30 136 (6–14 y) ER-MPH (n = 65) 2 wk CADS teacher scale ER-MPH > placebo
Placebo (n = 71)    (P < 0.001)
   Findling et al31 282 (6–12 y) MTS (n = 100) 7 wk ADHD Rating Scale MTS and
OROS-MPH (n = 94)    OROS-MPH > placebo
Placebo (n = 88)    (P < 0.001)
   Greenhill et al32 321 (6–16 y) ER-MPH (n = 158) 3 wk Conners Global Index ER-MPH > placebo
Placebo (n = 163)    teacher scale    (P < 0.001)
   Greenhill et al33 103 (6–17 y) d -MPH-ER (n = 53) 7 wk CADS teacher scale d -MPH-ER > placebo
Placebo (n = 50)    (P < 0.001)
   McGough et al9 80 (6–12 y) MTS 1-wk crossover SKAMP deportment scale MTS > placebo
Placebo    (P < 0.001)
   Wolraich et al34 282 (6–12 y) OROS-MPH (n = 95) 3 wk IOWA teacher rating OROS-MPH and
IR-MPH (n = 97)    IR-MPH > placebo
Placebo (n = 90)    (P < 0.05);
   OROS-MPH = IR-MPH
Amphetamine
   Biederman et al10 563 (6–12 y) MAS-XR 10 mg (n = 128) 3 wk Conners Global Index All MAS-XR doses >
MAS-XR 20 mg (n = 112)    teacher scale    placebo (P < 0.001)
MAS-XR 30 mg (n = 120)
Placebo (n = 203)

(continued)

945
R.L. Findling
946
Table II.  (Continued)

Formulation/ No. of Duration of Study

Authors Subjects (Age) Regimens Treatment Measures Results
Clinical Therapeutics

Amphetamine and
MPH
   Efron et al35 125 (5–15 y) DEX 2-wk crossover CTRS IR-MPH > DEX
IR-MPH    (P < 0.01)
   Findling et al36 4–7.9 y: 69 IR-MAS 1-wk crossover ASQ parent and teacher IR-MAS and
8–10.9 y: 56 IR-MPH    ratings    IR-MPH > placebo
11–18 y: 52 Placebo    (P < 0.001)
   Pelham et al37 22 (8–13 y) SR-DEX 3–6-d crossover Continuous performance All active
IR-MPH    task    treatments > placebo
ER-MPH    (P < 0.01)
Pemoline
Placebo
   Pliszka et al38 58 (mean [SD] IR-MAS (n = 20) 3 wk CTRS IR-MAS > IR-MPH >
age, 8.1 [1.4] y) IR-MPH (n = 20)    placebo (P < 0.05)
Placebo (n = 18)
LDX
   Biederman et al14 52 (6–12 y) LDX 1-wk crossover SKAMP deportment scale LDX and MAS-XR >
MAS-XR    placebo (P < 0.001)
Placebo
Nonstimulant
   Kelsey et al39 197 (6–12 y) Atomoxetine (n = 133) 8 wk ADHD Rating Scale Atomoxetine >
Placebo (n = 64)    placebo (P < 0.05)
   Michelson et al40 297 (8–18 y) Atomoxetine 0.5 mg/kg (n = 44) 8 wk ADHD Rating Scale Atomoxetine 1.2 and
Atomoxetine 1.2 mg/kg (n = 84)    1.8 mg > placebo
Atomoxetine 1.8 mg/kg (n = 85)    (P < 0.05)
Placebo (n = 84)

MPH = methylphenidate; ER = extended release; CADS = Conners ADHD/DSM-IV Scale; MTS = MPH transdermal system; OROS = osmotic controlled-release
system; d -MPH = dexmethylphenidate; SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale; IR = immediate release; IOWA = Inattention/
Overactivity with Aggression Conners Rating Scale; MAS-XR = mixed amphetamine salts extended release; DEX = dextroamphetamine; CTRS = Conners Teacher
Rating Scale; ASQ = Abbreviated Symptom Questionnaire; SR = sustained release; LDX = lisdexamfetamine.

Volume 30 Number 5

and practical advice); behavioral treatment (intensive
behavioral treatment, including parent, school, and
child components); combined medication manage-
ment and behavioral treatment; or community care
(standard treatment by community providers that in-
cluded ADHD medications in most cases). Children in
all 4 groups had reductions in symptoms during the
14 months of treatment. Both medication manage-
ment and combined treatment were clinically and
statistically better at reducing ADHD symptoms than
behavioral treatment and community care (P < 0.05).
There was no significant difference between medica-
tion management and combined treatment in reducing
core ADHD symptoms. This study extended the find-
ings of previous studies, indicating that the benefits of
medication management persisted through 14 months
of treatment.
Extended-Release Methylphenidate Formulations
IR-MPH formulations have the disadvantages of a
short duration of action (3–5 hours) that makes multi-
ple daily dosing necessary and a potential for abuse.9,46
Early ER formulations of MPH employed a wax ma-
trix or a similar vehicle to provide slow continual re-
lease of d,l-MPH. However, these formulations were
not well accepted in clinical practice because of their
slower onset of action, reduced efficacy, and greater
variability in response relative to the IR formulations.47
The reduction in efficacy was putatively the result of
a nonascending (ie, flat or descending) drug-delivery
profile and the development of acute tolerance to
MPH.48
An ER formulation in which MPH is delivered via
an osmotic controlled-release system (OROS) was in-
troduced in 2000. The efficacy and tolerability of
OROS-MPH were evaluated in 2 controlled studies in
children with ADHD of any subtype.34,49 The larger
of these trials, reported by Wolraich et al,34 was a
double-blind study in which 282 children with ADHD
(age range, 6–12 years) were randomized to receive
OROS-MPH once daily (n = 95), IR-MPH 3 times
daily (n = 97), or placebo (n = 90) for 28 days. The
mean daily doses of IR-MPH and OROS-MPH were
29.5 and 34.3 mg, respectively. Both at week 1 and the
end of the study, children receiving IR-MPH 3 times
daily or OROS-MPH once daily had significantly
greater improvements on both the teacher rating (pri-
mary efficacy measure) and parent rating components
of the Inattention/Overactivity with Aggression Con-
May 2008 947
R.L. Findling
ners Rating Scale50 compared with those who received
placebo (P < 0.001). Teachers’ mean (SD) inattention/
overactivity scores at baseline and end point were
9.94 (3.70) and 6.35 (4.31), respectively, for IR-MPH;
9.74 (4.10) and 5.98 (3.91) for OROS-MPH; and
10.28 (3.80) and 9.77 (4.02) for placebo (P < 0.05,
IR-MPH and OROS-MPH vs placebo). Differences
between IR-MPH and OROS-MPH were not signifi-
cant. On the Clinical Global Impressions Improve-
ment (CGI-I) scale,51 47% of subjects receiving IR-
MPH or OROS-MPH and 17% of those receiving
placebo were rated as much improved or very much
improved. Overall, the treatments were well tolerated,
and most adverse events were mild. Two adverse
events were considered related to study medication:
headache, reported in 6%, 14%, and 10% of the IR-
MPH, OROS-MPH, and placebo groups, respectively;
and abdominal pain, reported in 6%, 7%, and 1%,
respectively. Two children discontinued treatment be-
cause of an adverse event: emotional lability in 1 child
in the IR-MPH group and depression in 1 child in the
OROS-MPH group.
Two other ER formulations of MPH are available.
One formulation contains both short- and long-acting
beads of MPH that deliver 30% of the dose immedi-
ately, with Cmax occurring at 1.5 hours, and the re-
mainder reaching Cmax at 4.5 hours. The first random-
ized placebo-controlled study of this formulation was
a 32-site, 3-week, double-blind, placebo-controlled
trial in 321 children with ADHD (age range, 6–
16 years).32 Treatment was started at a dose of 20 mg
and could be increased to a maximum of 60 mg once
daily. Efficacy was assessed using the teacher (primary
efficacy measure) and parent scales of the Conners
Global Index52 and the CGI-I. Significantly greater
improvements on all 3 scales were seen in patients
receiving the ER formulation compared with placebo
(P < 0.001). Mean (SD) scores on the teacher scale
were reduced from 12.7 (7.2) at baseline to 4.9 (4.7)
at week 3 in the ER-formulation group and from 11.5
(7.4) to 10.3 (6.9) in the placebo group (P < 0.001).
Treatment was well tolerated, the most frequent ad-
verse events being headache (15% ER formulation,
11% placebo), anorexia (10% and 3%, respectively),
abdominal pain (10% and 5%), and insomnia (7%
and 3%).
The other ER formulation of MPH contains short-
and long-acting beads that deliver 50% of the dose
immediately and 50% approximately 4 hours later.
 Clinical Therapeutics
In a double-blind, placebo-controlled, parallel-group
study,30 136 children with ADHD (age range, 6–
14 years) were randomized to receive 10 to 40 mg of
this formulation or placebo for 2 weeks. Efficacy was
assessed in terms of the change in scores on the Con-
ners ADHD/DSM-IV Scale (CADS) (Multi-Health
Systems, Tonawanda, New York) and the CGI-I. Sig-
nificantly greater improvements on the CADS teacher
and parent scales were seen in children receiving the
ER formulation compared with those receiving pla-
cebo (P < 0.05). At the end of the study, the total
subscale score on the CADS teacher scale (primary
efficacy variable) was reduced from a mean (SD) of
27.2 (15.5) at baseline to 16.3 (12.1) in children re-
ceiving the ER formulation and was increased from
28.3 (15.8) to 31.3 (15.4) in the placebo group (P <
0.001). On the CGI-I, 70% of children receiving the
ER formulation were rated as much or very much
improved, compared with 40% of the placebo group
(P = 0.001). Adverse events were generally mild or
moderate. The most frequently reported adverse events
in the group that received the ER formulation were
anorexia (3%), insomnia (3%), and headache (2%);
in the placebo group, the most frequently reported
adverse events were sore throat (4%), headache (3%),
and vomiting (3%).
Methylphenidate Transdermal System
A transdermal formulation has been developed that
contains MPH in a multipolymeric adhesive platform
from which drug is released continuously over a wear
time of 9 hours when applied to intact skin. McGough
et al9 conducted a double-blind, placebo-controlled,
crossover laboratory classroom study of the MPH
transdermal system (MTS) in 80 children with ADHD
(age range, 6–12 years). The optimal daily dose deliv-
ered over the 9-hour patch wear time for each child
was determined during a 5-week period. The children
were then randomly assigned to receive 1 week of MTS
or placebo, followed by 1 week of the alternative
treatment. Measures of efficacy included assessments
of deportment and attention (Swanson, Kotkin, Agler,
M-Flynn, and Pelham Rating Scale [SKAMP]53) and
age-adjusted mathematical problems (Permanent
Product Measure of Performance [PERMP] Derived
Measures54). Children performed significantly better
on both the SKAMP and PERMP Derived Measures
when receiving each dose of MTS than when receiving
placebo (P < 0.001). The least squares mean (SE)
948 Volume 30 Number 5
SKAMP deportment score (primary efficacy measure)
was 3.2 (0.6) for MTS and 8.0 (0.6) for placebo (P <
0.001). MTS was well tolerated, with headache being
the most frequently reported adverse event (4% in
each group). Based on the results, MTS appeared to
offer a useful strategy for once-daily administration of
MPH in children with ADHD. MTS can be adapted to
individual duration-of-action needs by changing the
patch wear time within the recommended 9 hours.
The efficacy and tolerability of MTS and OROS-
MPH were compared in a placebo-controlled study in
282 children (age range, 6–12 years).31 After 5 weeks
of dose optimization, subjects entered a 2-week double-
blind assessment period. At the end of this period,
improvements in scores on the ADHD Rating Scale55
(primary efficacy measure), the CGI-I, and the Con-
ners Parent Rating Scale56 (CPRS) were significantly
greater in children receiving MTS or OROS-MPH
than in those receiving placebo (P < 0.001). The mean
changes in scores on the ADHD Rating Scale at end
point were –24.2 in the MTS group, –21.6 in the
OROS-MPH group, and –10.3 in the placebo group
(P < 0.001, MTS and OROS-MPH vs placebo). The
study was not designed or powered to compare MTS
and OROS-MPH. The most frequently reported ad-
verse events in both treatment groups were reduced
appetite (26% MTS, 19% OROS-MPH, and 5% pla-
cebo), insomnia (13%, 8%, and 5%, respectively), and
nausea (12%, 8%, and 2%).
Dexmethylphenidate
Dexmethylphenidate, the active d-isomer of MPH,
has been reported to be as efficacious and well toler-
ated as MPH in the treatment of ADHD in children.57
An ER formulation of dexmethylphenidate (d-MPH-
ER) is also available.58
Greenhill et al33 conducted a double-blind, placebo-
controlled study of d-MPH-ER in 103 children with
ADHD (age range, 6–17 years; median age, 10 years).
After a 2-week evaluation phase, patients were ran-
domly assigned to receive d-MPH-ER (5–30 mg) or
placebo once daily for 7 weeks. Flexible dosing of
d-MPH-ER was employed during the first 5 weeks to
establish optimal doses for each child, which were
then given for the remaining 2 weeks. The CADS
teacher (primary efficacy measure) and parent scales
and the CGI-I were used to assess patients at baseline
and at the end of each week. The mean final dose of
d-MPH-ER was 24 mg/d. Significantly greater im-

provements in CADS scores from baseline to end
point were seen on both the CADS teacher and parent
scales in patients receiving d-MPH-ER compared with
those receiving placebo (P < 0.05). Adjusted mean
changes in total scores on the CADS teacher scale
from baseline to the final visit were 16.3 in the d-MPH-
ER group and 5.7 in the placebo group (P < 0.001).
On the CGI-I, 67% of patients receiving d-MPH-ER
were rated as much improved or very much improved,
compared with 13% of the placebo group (P < 0.001).
The most frequently reported adverse events were re-
duced appetite (30% of the d-MPH-ER group, 9% of
the placebo group) and headache (25% vs 11%, re-
spectively). No serious adverse events were reported
and no patient receiving d-MPH-ER discontinued
treatment because of an adverse event. Based on the
results, d-MPH-ER once daily appeared to be a well-
tolerated and effective alternative treatment for reduc-
ing ADHD symptoms in children.
Amphetamines
By 1999, ~80% of all children diagnosed with
ADHD were reported to be receiving MPH,59 suggest-
ing that this stimulant was well tolerated and effec-
tive. However, MPH had certain limitations, including
a short half-life resulting in a need for multiple daily
doses and a 30% to 40% nonresponse rate.59
Mixed Amphetamine Salts
A formulation of mixed amphetamine salts (MAS),
a combination of dextroamphetamine and racemic
amphetamine salts, was introduced in 1994.60 There
are few published controlled comparative trials of MAS
and MPH. In a randomized, double-blind, parallel-
group trial,38 58 children (mean age, 8.1 years) re-
ceived IR-MAS (n = 20), IR-MPH (n = 20), or placebo
(n = 18) for 3 weeks. Study measures included the
Conners Teacher Rating Scale,50 the CGI-I, and the
Conners Global Index (parents’ evening evaluation).
On the teacher ratings, patients receiving MAS had sig-
nificantly greater improvements in both the inattention/
overactivity and aggression/defiance factors compared
with those receiving MPH or placebo (analysis of
variance, P < 0.05); differences between MPH and
placebo were also significant (P < 0.05). A treatment
response, defined as a score of 1 or 2 on the CGI-I
(very much or much improved), was seen in 90% of
MAS recipients, 65% of MPH recipients, and 27% of
placebo recipients (P < 0.05, both active treatments vs
May 2008 949
R.L. Findling
placebo). Parents’ evening evaluations indicated im-
provements in all 3 patient groups; between-group
differences were not statistically significant. Adverse
events were generally similar in the MAS and MPH
treatment groups; however, those receiving MAS had
a significantly higher frequency of sadness and stom-
achache compared with those receiving MPH (both
adverse events, 25% vs 5%, respectively; P < 0.05).
IR-MAS and IR-MPH were compared in 3 age
groups of children and adolescents with ADHD: 69
aged 4 to 7.9 years (mean, 6.4 years); 56 aged 8 to
10.9 years (mean, 9.5 years); and 52 aged 11 to 18 years
(mean, 13.6 years).36 Sixty-six patients received MAS
5, 10, or 15 mg or placebo once daily for 1 week, and
111 patients received MAS 5, 10, or 15 mg or placebo
twice daily for 1 week. The mean (SD) best dose for
each subject, determined from parent interviews, pa-
tient reports, teacher ratings, and clinical observations,
was 9.1 (3.7) mg for subjects aged 4 to 7.9 years, 10.4
(4.0) mg for those aged 8 to 10.9 years, and 9.8 (4.9) mg
for those aged 11 to 18 years. According to parent and
teacher ratings (Abbreviated Symptom Questionnaire61),
treatment at the best dose resulted in significantly
greater symptom improvements compared with the
placebo week in each age group (P < 0.001). Teacher
ratings in the 3 groups ranged from 50.4 to 54.5 dur-
ing treatment at the best dose and from 60.1 to 65.6
during the placebo week (P < 0.001). The study medi-
cations were generally well tolerated. The most frequent-
ly reported adverse events were irritability (16%),
anorexia (15%), tearfulness (11%), and onychophagia
(10%) during treatment at the best dose, and irritabili-
ty (23%), tearfulness (16%), repetitive behavior (15%),
and onychophagia (12%) during the placebo week.
In this study, MAS and MPH had similar effectiveness
in children and adolescents with ADHD.
Faraone et al62 conducted a meta-analysis of 4 con-
trolled comparative studies of IR-MAS and IR-MPH
in children and adolescents with ADHD. The stan-
dardized mean differences were positive for MAS rela-
tive to MPH in 16 of 19 evaluations made by teachers,
parents, and clinicians in these studies. However, the
standardized mean difference was statistically signifi-
cant in only one of these comparisons (P < 0.05).
Extended-Release Mixed Amphetamine Salts
A 2-component ER capsule formulation of MAS
(MAS-XR) was developed to allow once-daily dosing
of amphetamine, with 1 morning dose of MAS-XR
 Clinical Therapeutics
designed to produce similar pharmacokinetic and
pharmacodynamic effects to those of IR-MAS given
twice daily.10 The efficacy and tolerability of MAS-XR
have been evaluated in children, adolescents, and
adults with ADHD.
The pharmacokinetic properties of MAS-XR were
compared with those of IR-MAS in 51 children with
ADHD (age range, 6–12 years).63 The study was con-
ducted over 7 consecutive analogue classroom ses-
sions held 1 day per week. At visit 1, administration
of a single 20-mg dose of MAS-XR was followed by
repeated plasma sampling to assess the drug’s acute
pharmacokinetic profile and tolerability. All subjects
who tolerated the drug were randomized to partici-
pate in a 5-week, double-blind, crossover pharmaco-
dynamic study in which they received 1 week each of
IR-MAS 10 mg once daily; MAS-XR 10, 20, or 30 mg
once daily; or placebo. Week 6 served as a make-up
week for subjects who were absent during one of the
5 core treatment weeks. Both drugs were well toler-
ated. Pharmacokinetic analyses indicated a high de-
gree of correlation between d- and l-isomer con-
centrations. Tmax values for MAS-XR compared with
IR-MAS indicated a mean delay of 3.0 hours for
d-amphetamine and 3.2 hours for l-amphetamine.
There was substantial intersubject variation in plasma
concentrations of both IR-MAS and MAS-XR (per-
cent coefficient of variation [%CV], 28–56), under-
scoring the need for individualized dose adjustment.
In a double-blind, placebo-controlled, parallel-group
study conducted at 47 sites in the United States,10
children aged between 6 and 12 years were randomly
assigned to receive MAS-XR 10 mg (n = 128), 20 mg
(n = 112), or 30 mg (n = 120) once daily or placebo
(n = 203). Over 3 weeks, the Conners Global Index
was used for teachers’ assessments twice daily on
3 school days per week and for parents’ assessments
3 times daily on Saturday or Sunday. Beginning at
week 1, significantly greater improvements on both
scales were seen in children receiving all 3 doses of
MAS-XR compared with those receiving placebo.
Mean change scores at treatment end point on the
teacher scale were –5.3, –6.0, and –6.4 in children
receiving MAS-XR 10, 20, or 30 mg, respectively, and
–0.9 in children receiving placebo (P < 0.001, each
comparison vs placebo). Similar improvements were
seen on the parent scale (P < 0.001). Adverse events
reported more frequently in children receiving MAS-
XR than in those receiving placebo (>5% between-
950 Volume 30 Number 5
group difference) were anorexia (22% vs 2%, respec-
tively), insomnia (17% vs 2%), and emotional lability
(9% vs 2%). The authors concluded that once-daily
dosing with MAS-XR was well tolerated overall and
was associated with adequate control of the signs and
symptoms of ADHD.
Dextroamphetamine
Dextroamphetamine (DEX) is the dextro isomer of
d,l-amphetamine sulfate, a sympathomimetic amine
of the amphetamine group. In a 4-week, double-
blind crossover study of DEX and MPH taken twice
daily in 125 children with ADHD (age range, 5–
15 years),35 scores on the Conners Parent and Teacher
Rating Scales61 were significantly improved in both
groups (P < 0.001). Nonsignificant between-group
differences were noted on the parent scale. Improve-
ments on the teacher scale, however, were significant-
ly greater with MPH than with DEX: the differences
in improvement between MPH and DEX were 3.31
on the conduct problems factor (P < 0.01), 2.78 on
the hyperactivity factor (P < 0.01), and 1.61 on the
inattentive-passive factor (P = 0.02). The severity of
adverse events (in particular, “negative emotional side
effects” such as irritability, tearfulness, and anxiety)
was greater in patients receiving DEX than MPH
(P values not reported).
Sustained-Release Dextroamphetamine
A sustained-release (SR) formulation of DEX has
been developed that releases active drug more gradu-
ally than from the standard formulation.17 In a study
of this formulation in 9 hyperactive children,64 peak
plasma d-amphetamine levels occurred 3 to 8 hours
after administration of SR-DEX 0.5 mg/kg (mean [SD]:
65.7 [7.1] ng/mL at 3 hours; 64.1 [9.5] ng/mL at 8 hours).
Substantial between-subject variation in plasma levels
were noted (%CV during the 8 hours, 31–42).
The efficacy of SR-DEX, IR-MPH, ER-MPH, and
pemoline was compared in a double-blind, placebo-
controlled crossover study in 22 boys with ADHD
(age range, 8–13 years).37 Social behavior, classroom
performance, and results on a continuous perfor-
mance task were evaluated. All 3 long-acting medica-
tions were associated with significant improvements
in performance, starting at 1 hour after ingestion and
continuing for 9 hours (P < 0.05). On the continuous
performance task, all 4 medications were associated
with a significant effect within 2 hours of ingestion,

with the effect lasting for 9 hours (P < 0.05). At
9 hours, the percentage of errors of omission on the con-
tinuous performance task was 29.3 with SR-DEX, 32.3
with IR-MPH, 30.4 with ER-MPH, 30.9 with pemoline,
and 46.9 with placebo (P < 0.01, each active treatment
vs placebo). The most frequently reported adverse events
in all groups were loss of appetite and stomachache/
nausea, which were reported in 23% of the SR-DEX
group and 9% to 14% of the other 3 groups.
Nonstimulant—Atomoxetine
Atomoxetine is a potent inhibitor of the presynap-
tic norepinephrine transporter, with minimal affinity
for other noradrenergic receptors or for other neuro-
transmitter transporters or receptors. It is indicated
for the treatment of ADHD in children, adolescents,
and adults. Rappley5 noted that in randomized trials
of atomoxetine that included >1000 children and adults,
58% to 64% of children treated for 6 to 12 weeks
achieved 25% to 30% or greater improvement in
symptoms. In a multicenter study by Michelson et
al,40 297 children and adolescents (age range, 8–
18 years; median, 10.8 years) were randomly assigned
to receive atomoxetine 0.5, 1.2, or 1.8 mg/kg per day,
dosed twice daily, or placebo for 8 weeks (the maxi-
mum FDA-approved daily dose for children and ado-
lescents is 1.4 mg/kg). Most patients had ADHD of
the combined (67%) or inattentive (31%) subtype.
The primary outcome measure was the ADHD Rating
Scale. Overall, significantly greater improvements in
symptoms were seen in those receiving the 2 higher
doses of atomoxetine compared with those receiving
placebo. Mean (SD) changes in total scores from base-
line to end point were –9.9 (14.6) with atomoxetine
0.5 mg/kg daily, –13.6 (14.0) with atomoxetine 1.2 mg/
kg daily, –13.5 (14.5) with atomoxetine 1.8 mg/kg
daily, and –5.8 (10.9) with placebo (P < 0.05, atomoxe-
tine 1.2 and 1.8 mg/kg daily vs placebo). Similar symp-
tom improvements were seen in younger children and
in older children and adolescents (those below and
above the median age). However, among older chil-
dren and adolescents, significant improvements were
also seen in those receiving the lowest atomoxetine
dose (0.5 mg/kg daily) compared with placebo (–14.1
[14.5] vs –5.6 [11.3], respectively; P < 0.05). All doses
of atomoxetine were well tolerated. The 2 higher
doses of atomoxetine (1.2 and 1.8 mg/kg daily) tended
to be associated with anorexia (12% with both doses)
and somnolence (7% and 11%, respectively).
May 2008 951
R.L. Findling
Kelsey et al39 conducted a multicenter, randomized
study in 197 children (age range, 6–12 years) who
received atomoxetine once daily for 8 weeks. The final
mean dose of atomoxetine was 1.3 mg/kg daily. Atom-
oxetine was significantly more effective than placebo
in treating the core symptoms of ADHD. The mean
(SD) changes in total scores on the ADHD Rating
Scale at end point were –16.7 (14.5) in the atomoxe-
tine group and –7.0 (10.8) in the placebo group (P <
0.05). Atomoxetine was reported to be well tolerated.
Gibson et al65 analyzed the outcomes of 5 studies
that compared atomoxetine and stimulants in the
treatment of ADHD in children and adolescents. The
duration of treatment in these trials ranged from
18 days to 10 weeks. No significant differences in
outcome (ADHD Rating Scale total scores) were
found in the 2 studies comparing IR-MPH and atom-
oxetine. However, in the study comparing MAS-XR
with atomoxetine and the 2 studies comparing OROS-
MPH and atomoxetine, significantly greater improve-
ments on measures including the ADHD Rating Scale
and SKAMP were seen in patients receiving the 2 ER
stimulant formulations compared with those receiving
atomoxetine (P < 0.001).
Atomoxetine and other nonstimulants that are pre-
scribed off-label in ADHD (eg, bupropion66) are less
likely to be associated with abuse and diversion than
stimulants.65,67 In a placebo-controlled comparative
study of atomoxetine and MPH in “light drug users,”68
atomoxetine was associated with no positive subjec-
tive effects of the sort associated with MPH.
The 2007 treatment guidelines from the American
Academy of Child and Adolescent Psychiatry11 sug-
gest consideration of atomoxetine as the first medica-
tion for ADHD in persons with an active substance
abuse problem, comorbid anxiety, or tics, or in pa-
tients who experience severe adverse effects when re-
ceiving stimulants.
Prodrug Stimulants
The prodrug concept was introduced in 1958 to
describe pharmacologically inactive chemical deriva-
tives that might be used to alter the physiochemical
properties of drugs to increase their usefulness or re-
duce their toxicity.69 The International Union of Pure
and Applied Chemistry defines a prodrug as “any
compound that undergoes biotransformation before
exhibiting its pharmacological effects.”70 Because of
its chemical composition, a prodrug is pharmacologi-
 Clinical Therapeutics
cally inactive until metabolized by enzymes into an
active pharmacologic moiety.71 Prodrugs are designed
to overcome pharmaceutical and pharmacokinetic
barriers to the clinical application of drugs, such as
low oral absorption, lack of site specificity, chemical
instability, toxicity, and poor patient acceptability.70
In addition, prodrugs can be designed to target spe-
cific enzymes or carriers to overcome undesirable drug
effects. Some prodrugs are designed to be slowly con-
verted to the active drug to prolong drug activity.70
Lisdexamfetamine Dimesylate
LDX is the first prodrug stimulant to be developed
and is indicated for the treatment of ADHD. It is a
therapeutically inactive molecule. After oral ingestion,
LDX is converted to l-lysine, a naturally occurring
essential amino acid, and active d-amphetamine, which
is responsible for its activity. The conversion of LDX
to d-amphetamine is not affected by gastrointestinal
pH and is unlikely to be affected by alterations in
normal gastrointestinal transit times.72 LDX was de-
signed to provide a long duration of effect that is
consistent throughout the day and to have a reduced
potential for abuse.13
The pharmacokinetics of LDX were analyzed in a
placebo-controlled crossover study in 52 children
with ADHD (age range, 6–12 years; mean [SD], 9.1
[1.7] years).14,73 Subjects received LDX 30, 50, or
70 mg and MAS-XR 10, 20, or 30 mg. In subjects
receiving the highest dose of each treatment (8 receiv-
ing LDX 70 mg and 9 receiving MAS-XR 30 mg), the
median Tmax for d-amphetamine was 4.5 hours
(range, 4.5–6.0 hours) after administration of LDX
and 6.0 hours (range, 3.0–12.0 hours) after adminis-
tration of MAS-XR (Table III). The %CV for Tmax,
Cmax, and AUC from time zero to the last quantifiable
concentration was 15.3%, 20.3%, and 21.6%, re-
spectively, after administration of LDX and 52.8%,
44.0%, and 42.8% after administration of MAS-XR.
The same study evaluated efficacy in an analogue
classroom environment.14 After an open-label dose-
adjustment period to determine the optimal dose of
MAS-XR, 3 groups of subjects entered the double-
blind study: group A received MAS-XR 10 mg/d,
LDX 30 mg/d, or placebo for 1 week each; group B
received MAS-XR 20 mg/d, LDX 50 mg/d, or placebo
for 1 week each; and group C received MAS-XR
30 mg/d, LDX 70 mg/d, or placebo for 1 week each.
Efficacy was assessed using the SKAMP, PERMP, and
952 Volume 30 Number 5
CGI-I scales. Significantly greater improvements on
all efficacy measures were seen in children receiving
all doses of MAS-XR and LDX compared with those
receiving placebo (P < 0.001). Least squares mean
scores at end point on the SKAMP deportment scale
(primary efficacy measure) were 0.8 (0.1) in both the
MAS-XR and LDX groups and 1.7 (0.1) in the pla-
cebo group (P < 0.001, both active treatments vs pla-
cebo). CGI-I ratings of much improved or very much
improved were seen in 72% of patients receiving
MAS-XR, 74% receiving LDX, and 18% receiving
placebo. Ratings of very much improved were seen in
16% of children receiving MAS-XR, 32% receiving
LDX, and 2% receiving placebo. Adverse events re-
ported during the double-blind period in the MAS-XR
group were upper abdominal pain and decreased ap-
petite (4% each) and upper respiratory infection, in-
somnia, and vomiting (2% each). Adverse events in
the LDX group were insomnia (8%), decreased ap-
petite (6%), anorexia (4%), and upper respiratory
infection (2%).
Biederman et al13 conducted a Phase III multicenter,
double-blind, placebo-controlled, parallel-group study
of LDX in 201 boys and 89 girls (age range, 6–
12 years; mean [SD], 9.0 [1.8] years) with a primary
diagnosis of ADHD. The children were randomly as-
signed to receive placebo or LDX at the following oral
doses for 4 weeks: 30 mg, 50 mg (30 mg/d in week 1,
with forced dose escalation to 50 mg/d for the remain-
der of the study), or 70 mg (30 mg/d in week 1, with
forced dose escalation to 50 mg/d in week 2 and to
70 mg/d in weeks 3 and 4). Efficacy was assessed us-
ing the ADHD Rating Scale (primary efficacy mea-
sure), the CPRS, and the CGI-I. Of 290 patients ran-
domized to treatment, 230 (79.3%) completed the
study (56 receiving LDX 30 mg, 60 receiving LDX
50 mg, 60 receiving LDX 70 mg, and 54 receiving
placebo). Improvements on the ADHD Rating Scale
were significantly greater with LDX compared with
placebo by the first week of treatment (P < 0.001).
Improvements in scores on the ADHD Rating Scale,
CPRS, and CGI-I were significantly greater with all
3 doses of LDX than with placebo (P < 0.001). Reduc-
tions in total ADHD Rating Scale scores were 4- to
5-fold greater for each dose of LDX compared with
placebo (P < 0.001); the greatest change was seen in
the LDX 70-mg group relative to the placebo group
(–26.7 [1.5] vs –6.2 [1.6], respectively; P < 0.001).
CGI-I ratings of much improved or very much im-
 R.L. Findling

Table III. Pharmacokinetic data from children receiving lisdexamfetamine (LDX) 70 mg and extended-release
mixed amphetamine salts (MAS-XR) 30 mg.

d -Amphetamine

Tmax, h Cmax, ng/mL AUC0–last, h • ng/mL

LDX (n = 8)
   Mean (SD) 5.1 (0.8) 155.0 (31.4) 1326.0 (285.8)
   Median 4.5 – –
   Range 4.5–6.0 99.9–187.0 851.8–1618.0
   %CV 15.3 20.3 21.6
MAS-XR (n = 9)
   Mean (SD) 6.6 (3.5) 119.0 (52.5) 1019.0 (436.2)
   Median 6.0 – –
   Range 3.0–12.0 49.8–218.0 492.7–1899.0
   %CV 52.8 44.0 42.8

AUC0–last = AUC from time zero to the last quantifiable concentration; %CV = percent coefficient of variation.
Adapted with permission of Elsevier from Biederman et al. Biol Psychiatry. 2007;62:970–976.14

proved were seen in ≥70% of patients in the active-
treatment groups, compared with 18% of patients
receiving placebo (P < 0.001). According to the parent
evaluations, reductions in ADHD symptoms were ob-
served at approximately 10 am, 2 pm, and 6 pm with
all LDX doses (P < 0.01). Adverse events reported in
≥10% of patients receiving LDX were reduced appe-
tite (39.0%), insomnia (18.8%), upper abdominal
pain (11.9%), and headache (11.9%).
Abuse Potential in Adults
A double-blind crossover study was conducted in
9 adults with a history of stimulant abuse to assess
the abuse potential of intravenously administered
LDX.74 Subjects received d-amphetamine sulfate
20 mg IV, LDX 50 mg IV, and placebo at 48-hour in-
tervals. Doses of IR d-amphetamine sulfate and LDX
contained equivalent amounts of d-amphetamine
base. The subjective response to treatment was
rated using the liking score of the Drug Rating
Questionnaire–Subject (DRQS).75 Subjects receiving
d-amphetamine 20 mg had significantly higher liking
scores than those receiving placebo (P = 0.01). The
liking effects for LDX 50 mg and placebo did not dif-
fer significantly.
The abuse potential of orally administered LDX
and IR d-amphetamine sulfate was assessed in a
double-blind crossover study in 36 adults with a his-
tory of stimulant abuse within the past 28 days.76 The
primary measure of the subjective response to treatment
was the DRQS liking score. The mean maximum post-
dose increase from baseline in the liking score was sig-
nificantly greater in subjects receiving d-amphetamine
40 mg compared with those receiving LDX 100 mg
(mean [SD]: 4.9 [7.7] vs 2.6 [35], respectively; P =
0.039). However, the difference in mean maximum
liking scores between subjects receiving d-amphetamine
40 mg and LDX 150 mg (4.9 [7.7] and 6.5 [8.2], re-
spectively) was not statistically significant.
CONCLUSIONS
Treatment goals for patients with ADHD are symp-
tom improvement, a duration of effect that is consis-
tent throughout the day, and an acceptable risk pro-
file. Stimulant medications such as amphetamine and
MPH have been used successfully for decades as first-
line treatments for ADHD in children, and the efficacy
and safety profiles of these agents are extensively
documented in the literature. However, the short-
acting formulations of MPH and amphetamines re-

May 2008 953

 Clinical Therapeutics
quire multiple daily dosing to achieve the desired thera-
peutic response and are associated with abuse potential.
Nonstimulants such as atomoxetine are recommended
when patients are unresponsive to or unable to toler-
ate treatment with stimulants. Once-daily dosing of
ER formulations of stimulants has been reported to be
effective for the treatment of ADHD, although these
formulations may be associated with high pharma-
cokinetic variability due to their dependence on pH
and gastrointestinal transit time for drug delivery.
LDX, a long-acting prodrug of d-amphetamine, has
been developed to address the potential limitations of
currently available short- and long-acting stimulants.
The evidence supports the effectiveness of LDX as the
first member of a new class of stimulants for the treat-
ment of ADHD in children, with a potential for reduced
pharmacokinetic variability and a tolerability profile
similar to that of currently available ER stimulants.
ACKNOWLEDGMENTS
Funding for this article was provided by Shire Develop-
ment Inc., Wayne, Pennsylvania. Editorial assistance
was provided by Timothy Coffey, Robert Gregory, and
Rosa Real, MD, of Excerpta Medica Inc., Bridgewater,
New Jersey. Dr. Findling receives or has received re-
search support, acted as a consultant, and/or served on
a speakers’ bureau for Abbott, Astra-Zeneca, Bristol-
Myers Squibb, Cypress Bioscience, Forest, GlaxoSmith-
Kline, Johnson & Johnson, Eli Lilly, Neuropharm,
New River, Novartis, Organon, Otsuka, Pfizer, sanofi-
aventis, Sepracore, Shire, Solvay, Supernus, and Wyeth.
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over study to evaluate the likability,

safety, and abuse potential of lis-
dexamfetamine dimesylate (LDX) in
adult stimulant abusers. Poster pre-
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Health Congress; November 16–19,
2006; New Orleans, La.

Address correspondence to: Robert L. Findling, MD, Director, Child &

Adolescent Psychiatry, University Hospitals Case Medical Center, 11100
Euclid Avenue, Cleveland, OH 44106–5080. E-mail: robert.findling@
UHhospitals.org

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