Escitalopram reduces attentional performance in anxious older adults with high-expression genetic

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Open Access Publications
2013
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Eric J. Lenze
Washington University School of Medicine in St. Louis
David Dixon
Washington University School of Medicine in St. Louis
Petra Nowotny
Washington University School of Medicine in St. Louis
Francis E. Lotrich
University of Pittsburgh - Main Campus
Peter M. Doré
Washington University School of Medicine in St. Louis
See next page for additional authors
Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs
RReeccoommmmeennddeedd CCiittaattiioonn
Lenze, Eric J.; Dixon, David; Nowotny, Petra; Lotrich, Francis E.; Doré, Peter M.; Pollock, Bruce G.; Hinrichs,
Anthony L.; and Butters, Meryl A., ,"Escitalopram reduces attentional performance in anxious older adults
with high-expression genetic variants at serotonin 2A and 1B receptors." International journal of
neuropsychopharmacology. 16,2. 279-288. (2013).
https://digitalcommons.wustl.edu/open_access_pubs/3505
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Eric J. Lenze, David Dixon, Petra Nowotny, Francis E. Lotrich, Peter M. Doré, Bruce G. Pollock, Anthony L.
Hinrichs, and Meryl A. Butters
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CNS Spectrums
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Lisdexamfetamine Dimesylate: A Prodrug Stimulant for the
Treatment of ADHD in Children and Adults
Gregory Mattingly
CNS Spectrums / Volume 15 / Issue 05 / May 2010, pp 315 - 325
DOI: 10.1017/S1092852900027541, Published online: 07 November 2014
Link to this article: http://journals.cambridge.org/abstract_S1092852900027541
How to cite this article:
Gregory Mattingly (2010). Lisdexamfetamine Dimesylate: A Prodrug Stimulant for the Treatment of ADHD in
Children and Adults. CNS Spectrums, 15, pp 315-325 doi:10.1017/S1092852900027541
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Review Article
Lisdexamfetamine Dimesylate:
A Pro drug Stimulant for
the Treatment of ADHD in
Children and Adults
Gregory Mattingly, MD
ABSTRACT
FOCUS POINTS
Attention-deficit/hyperactivity disorder
Once-daily stimulant medications continue to
(ADHD) is a highly genetic neuropsychiatric be the first-line treatment for attention-deficit/
hyperactivity disorder (ADHD).
disorder that can cause impairment at school,
Lisdexamfetamine dimesylate (LDX) is the first
work, home, and in social relationships. Once long-acting prodrug stimulant indicated for
considered a childhood disorder, as many as the treatment of ADHD. Clinical evidence sup-
ports the safety and efficacy of LDX for the
65% of children with ADHD continue to exhibit
treatment of ADHD in children 6-12 years of
symptoms into adulthood. While a mainstay age and adults.
No significant cardiovascular effects or effects
of ADHD patient care, immediate-release stim-
on sleep quality have been observed in stud-
ulant use has been constrained by concerns ies of adults taking LDX. Clinical data suggest
that LDX is generally well tolerated in children
about safety, tolerability, and issues related to
and adults, with a safety profile consistent
nonmedical use and abuse. These concerns
with long-acting stimulant use.
have prompted interest in developing modified
versions or new delivery systems for stimu- dimesylate (LDX) is an inactive, water-soluble
lants. Prodrugs have been used in pharmaceu- prodrug in which d-amphetamine is bonded to
tical development to optimize delivery of an l-lysine, a naturally occurring amino acid. After
active drug or to minimize toxicity. Prodrugs oral ingestion, LDX is metabolized into l-lysine
are pharmacologically inactive compounds that and active d-amphetamine. This review of LDX
require in vivo conversion to release therapeu- presents the efficacy, safety, and pharmacoki-
tically active medications. Lisdexamfetamine netic profile of this novel stimulant medication,
Dr. Maltingly is Associate Clinical Professor in the Department of Psychiatry at Washington University in St. Louis, MO.
Faculty Disclosures: Dr. Mattingly is a consultant to Eli Lilly, Forest, Ortho-McNeil, Pfizer, Shire, and Vanda; is on the speaker's bureau of Abbott, Eli Lilly,
Forest, GlaxoSmithKline, Janssen, OrthoMcNeil, and Shire; has received grant/research support from AstraZeneca, Dainippon-Sumitomo, Eli Lilly, Forest,
GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Orthc-McNeil, Pfizer, Sanofi-Synthelabo, Sepracor, Shire, Solvay, Takeda,
Vanda, and Wyeth; and has received honoraria from Abbott, Eli Lilly, Forest, GlaxoSmithKline, Janssen, OrthcnMcNeil, Pfizer, and Shire.
Funding/Support: Funding was provided by Shire Development, Inc., Wayne, Pennsylvania.
Acknowledgments: Editorial assistance was provided by Jill Shuman, Robert Gregory, William Perlman, and Rosa Real, Excerpla Medica, Bridgewater, New Jersey.
Submitted for publication: December 4, 2009; Accepted for publication: January 13, 2010.
Please direct all correspondence to: Dr. Gregory Mattingly, MD, Washington University School of Medicine, Department of Psychiatry and Behavioral
Neurosciences, 330 First Capitol Drive, #390, St. Charles, MO, 63301; Tel: [phone], Fax: [phone]; e-mail: [email protected].
CNS Spectr 15:5 315 May 2010
Review Article
and is intended to help clinicians understand its The estimated prevalence of ADHD in adults
throughout the US is ~4.4%, or 9 million adults.9
role in treating children and adults with ADHD.
ADHD in adults is highly comorbid with mood
CNSSpectr. 2010;15(5):315-325 disorders, anxiety disorders, and substance-use
disorders (SUDs). In the National Comorbidity
Survey Replication,9 only 10.9% of adults with
INTRODUCTION
ADHD were currently receiving treatment for
Attention-deficit/hyperactivity disorder (ADHD)
ADHD, although as many as 53.1% of women
is a highly heritable neuropsychiatric disorder
and 36.5% of men were being treated for other
associated with significant impairments in occu-
comorbid mental health or substance-related
pational, academic, neuropsychological, and
social functioning.1 ADHD is commonly diag- disorders. Adults with ADHD frequently present
in crisis and are often initially diagnosed with
nosed in children and adolescents, and affects 3%
to 7% of children in the United States.23 Children mood and anxiety disorders, temper problems,
or substance abuse. Clinicians frequently treat
with ADHD may experience significant social,
the presenting crisis and miss the underlying
emotional, and academic problems, including
problems from ADHD. Untreated ADHD then
low self-esteem, poor peer relationships, delin-
creates a pervasive pattern of repeated diffi-
quency, and substance abuse. Evidence shows
culties or impairment. Continuing impairment
that ADHD often runs in families, with a herita-
bility of 76%.2A Children and adolescents with from ADHD may cause individuals to struggle
with academic, career, and personal goals, or
ADHD often present with comorbid psychiatric
may cause significant difficulty within interper-
disorders, including major depression, anxiety
sonal relationships.
disorders, conduct disorder, and oppositional
defiant disorder.5 ADHD in adolescents is also Functional imaging studies and cognitive neu-
associated with suboptimal academic achieve- roscience have focused on disruptions in brain
ment and a greater use of illicit drugs.5 regions normally involved in attention/cognition,
executive function, working memory, response
While once thought of as a childhood disor-
inhibition, and/or reward/motivation. Structural
der, ADHD symptoms persist into adulthood in
up to 65% of children with ADHD.6 Diagnostic imaging studies have identified smaller volumes
in the frontal cortex, cerebellum, and subcortical
criteria for ADHD in adults are still based on the
structures in adults and children with ADHD com-
18 symptoms that were originally identified in
pared with those without ADHD.1 Additionally,
children with ADHD. These diagnostic symp-
neuroanatomic studies in children with ADHD
toms are centered around disruptions in atten-
have shown delayed maturation in the prefrontal
tion and/or hyperactivity-impulsivity that are
prevalent in children with ADHD.3 Inattention cortex, an area known to be involved with execu-
tive function and working memory.10
is a key component of the behaviors associ-
ated with ADHD in both children and adults.
Adults with ADHD may present with poor time UNMET NEEDS IN THE TREATMENT
management or a lack of attention to detail. OF ADHD
Patients are easily distracted, find it difficult Pharmacotherapy continues to be the main-
to concentrate, and are forgetful when faced stay of treatment for ADHD.2 All US Food and
with tasks that they find monotonous or bor- Drug Administration-approved medications for
ing.78 Hyperactivity, while a common feature the treatment of ADHD enhance the physiologi-
among children with ADHD, is likely to be less cal effects of either norepinephrine, dopamine,
overt in adults. Rather than the constant activity or both. ADHD stimulants are all derived from
seen in children, adults are more likely to report various preparations of either methylphenidate
restlessness, difficulty sitting through meet- (MPH) or amphetamines. MPH is felt to exert
ings, and a feeling of being chronically "on the its clinical effect by blocking the reuptake of
go."38 They may have a sloppy workspace and dopamine and norepinephrine, while amphet-
may avoid work that is challenging or requires amines are felt to work by both blocking reup-
a maintained focus. Patients with impulsive ten- take and enhancing release of dopamine and
dencies have great difficulty waiting in line, will norepinephrine. Immediate-release (IR) and
interrupt conversations, may act without think- extended-release (ER) formulations of MPH,
ing, or experience emotional volatility.3-7'8 mixed amphetamine salts (MAS-XR), and dex-
CNS Spectr 15:5 316 May 2010
Review Article
troamphetamine are available as pharmaco- may help explain the consistent pharmacokinetic
logic treatment options. parameters, the sustained duration of action, and
Despite the efficacy of short-acting stimu- the decreased abuse likeability scores, which will
lants, they can "wear off" during the day, which be detailed in the remainder of this review.
may increase symptoms of inattention during
late morning or afternoon activities." Therefore, Pharmacokinetic and Formulation Studies
multiple doses during the day may be required Nonclinical in vivo and in vitro studies have
to achieve continuous symptom management. been conducted to investigate the absorption16
Generally, longer-acting ER formulations may and hydrolysis1516 of LDX using rodent and
eliminate the need for in-school medication human tissues. Results of these studies suggest
administration and provide ongoing clinical effect that absorption of LDX occurs primarily in the
during the school day.12 Long-acting stimulants small intestine and that conversion of LDX into
have traditionally been created utilizing mechani- active d-amphetamine occurs primarily in the
cal delivery systems or beaded preparations. blood. Intact LDX was readily absorbed through
Although these improved treatment options exist, duodenal, jejunal, and ileal intestinal segments,
unmet therapeutic needs remain, including con- and underwent presystemic enzymatic conver-
sistent delivery of medication, adequate duration sion to active d-amphetamine in rodents.16 LDX
of action, and reduced potential for abuse. was converted to amphetamine in the presence
of rat and human whole blood, but conversion
did not occur in plasma or human white blood
PRODRUG STIMULANT
cells or platelets.1516 In vitro studies of enzymatic
LISDEXAMFETAMINE DIMESYLATE
conversion by human blood cell fractions dem-
Lisdexamfetamine dimesylate (LDX), the first
onstrated that LDX was converted into active d-
long-acting prodrug stimulant, is indicated for the
amphetamine by red blood cells.1516
treatment of ADHD in children (approved in 2007)
and adults (approved in 2008).13 LDX is a therapeu- In an open-label study,17 six healthy adult vol-
tically inactive, water-soluble molecule. After oral unteers 22-52 years of age were administered
ingestion, LDX is converted to l-lysine and active a single oral 70 mg dose of 14C-radiolabelled
d-amphetamine (Figure 1),14 which is responsi- LDX in solution following a fast of at least 10
ble for the therapeutic effect. LDX is thought to be hours. Blood samples were drawn predose
primarily absorbed intact in the small intestines and at time points up to 120 hours postdose.
and into the portal circulation, where hydrolysis Plasma pharmacokinetic analysis was conducted
is thought to occur by enzymatic cleavage medi- for active d-amphetamine and the intact par-
ated by enzymes primarily found on the red blood ent compound, LDX. Analysis showed LDX to
cells.1516 Hydrophilic drugs, such as the prodrug be quickly absorbed and extensively converted
LDX, are thought to be unable to permeate the to d-amphetamine. Systemic exposure to d-
blood-brain barrier. While this specific hypothesis amphetamine was ~20-fold higher than systemic
has not been tested with LDX, the requirement for exposure to intact LDX, which exhibited rapid
enzymatic cleavage to free the d-amphetamine elimination with a mean apparent terminal elimi-
nation half-life of 0.47 hours.17 Urinary excre-
tion was the predominant route of elimination of
radioactivity, with -96% of the oral dose radio-
FIGURE 1.
activity recovered in the urine over a period of
Chemical structure of lisdexamfet- 120 hours. Of the radioactivity recovered in the
amine dimesylate14 urine, 41.5% of the dose was related to amphet-
amine, 24.8% to hippuric acid, and 2.2% to intact
H3C-S-OH H,N ,0 LDX. Plasma concentrations of unconverted LDX
were low and transient, generally becoming non-
quantifiable by 8 hours after administration.17
Shojaei and colleagues18 reported that the
l-lysine d-amphetamine
absorption of LDX to d-amphetamine was not
Reprinted from Krishnan et al, 2008, with permission of SAGE affected by pH in an in vitro study. Krishnan and
Publications.
Zhang14 reported the results of a randomized,
Mattingly G. CNS Spectr. Vol 15, No 5. 2010.
open-label, three-period crossover study of 18
CNS Spectr 15:5 317 May 20,10
Review Article
healthy adult volunteers. A single LDX dose of administration of LDX (30, 50, or 70 mg/day) and
70 mg was administered to each subject under MAS-XR (10, 20, or 30 mg/day) in children with a
three conditions: fasting, a solution containing primary diagnosis of ADHD. LDX demonstrated
the capsule contents, and an intact capsule after considerably lower interpatient variability of phar-
a high-fat meal. The results demonstrated that macokinetic measures compared with MAS-XR,
systemic exposure to d-amphetamine was bio- indicating consistent d-amphetamine pharmaco-
equivalent when administered with or without kinetics between patients. For example, the mean
food or in solution. This finding suggests that maximum observed drug concentration (Cmax)
LDX is not likely to be affected by changes in values for d-amphetamine following MAS-XR (30
gastrointestinal transit times.14 mg) or LDX (70 mg) administration were 119±52.5
LDX, unlike other currently approved long- ng/mL and 155±31.4 ng/mL, respectively (Figure
acting stimulant formulations, does not rely on 2)23,24 AS measured by coefficient of variance,
encapsulated matrix or beaded formulations the interpatient variability of Cmax following LDX
to prolong the absorption period of the active administration was lower than that observed fol-
drug.19 MAS-XR is an example of a mechanically lowing MAS-XR administration (20.34 ng/mL and
formulated capsule that contains two types of 43.96 ng/mL, respectively), indicating that LDX
drug-containing beads; one bead designed to may provide more consistent drug delivery.23 A
be released immediately and the other to be further pharmacokinetic study of healthy adults
released in the lower intestine, where pH lev- confirmed low interpatient variability in pharma-
els are higher.20 This formulation creates a pH- cokinetic values and also demonstrated low intra-
dependent delivery system designed to give a patient variability in values when measured over
double-pulsed delivery of amphetamine, which all doses within individual subjects.26
prolongs the release of the medication.20 Using
this technology, consistent drug delivery may be Efficacy Studies
compromised by alterations in gastric pH due to The efficacy of LDX for the treatment of ADHD
coadministration with proton pump inhibitors.21 has been demonstrated in three controlled clinical
When compared with MAS-XR, LDX pharma- trials232627 and two open-label trials2829 in children,
cokinetics were significantly more consistent as well as two randomized, controlled trials3031
when coadministered with the proton pump and one open-label trial32 in adults (Table).
inhibitor omeprazole.21 Regarding other drug- Studies in Children
drug interactions, d-amphetamine, the active Biederman and colleagues23 conducted a mul-
ingredient in LDX, is known to inhibit monoamine ticenter, randomized, double-blind, placebo-con-
oxidase.13 The ability of d-amphetamine and its trolled, analog classroom crossover study of 52
metabolites to inhibit varjous cytochrome P450 children 6-12 years of age with ADHD. After 3
(CYP) isozymes and other enzymes has not been
adequately elucidated. In vitro experiments with
FIGURE 2.
human microsomes indicate minor inhibition
Time to peak plasma d-amphetamine
of CYP2D6 by amphetamine and minor inhibi-
concentration in individual patients
tion of CYP1A2, 2D6, and 3A4 by one or more
following LDX (70 mg) and MAS-XR
metabolites, but there are no in vivo studies of
CYP enzyme inhibition.13 In a study22 conducted to (30 mg) 24 •••-,•
analyze potential inhibitory drug-drug interactions I"
with the seven major CYP isoforms using pooled
g1 250 LDX (70 mg) (n=8)
human liver microsomes, neither concentration- .2 200- MAS-XR (30 mg)(n=9l
dependent nor mechanism-based inhibition of
I 150-1
human CYP isoforms was demonstrated for LDX
o ,00- • i
during in vitro testing.
= 50-
LDX has predictable pharmacokinetic char-
acteristics. Three published studies23 26 have ^ 0 1 2 3 4 5 6 7 89 10 11 12
Time (hours)
examined the pharmacokinetic variability and
dose proportionality of LDX. Biederman and LDX=lisdexamfetamine dimesylate; MAS-XR=mixed amphetamine salts
colleagues23 compared the interpatient phar- extended-release.
macokinetic variability of d-amphetamine after Mattingly G. CNS Spectr. Vol 15, No 5. 2010.
CNS Spectr 15:5 318 May 2010
Review Article
weeks of open-label dose adjustment and opti- LDX produced significantly greater improve-
mization with 10, 20, or 30 mg/day of MAS-XR, ment compared with MAS-XR on both PERMP-
the children received, in randomized order, 1 Attempted and PERMP-Correct measures (P<.05;
week each of their optimized dose of MAS-XR, Figure 3).2336 On the CGI scale, ratings of very
an approximately equivalent dose of 30, 50, or much improved or improved were noted in 74%
70 mg of LDX, and placebo.23 The primary effi- of children who received LDX and 72% of chil-
cacy measure was the Swanson, Kotkin, Agler, dren who received MAS-XR versus .18% of those
M-Flynn, and Pelham (SKAMP)-Deportment33 rat- who received placebo.23 Additionally, CGI ratings
ing scale. Secondary efficacy measures included of very much improved were noted in 32% of
the Permanent Product Measure of Performance children who received LDX and 16% of children
(PERMP)34 derived measures and the Clinical who received MAS-XR versus 2% of those who
Global Impressions (CGI) scale.35 Treatment with received placebo.37
LDX and MAS-XR significantly improved mea- Biederman and colleagues26 also conducted
sures of efficacy on the SKAMP-Deportment and a double-blind, multicenter, placebo-controlled,
PERMP-Attempted (both P<.0001) scales. A post- parallel-group study in 290 children (6-12 years
hoc analysis36 showed that at 12 hours postdose, of age) with a primary diagnosis of ADHD.
TABLE.
Trials of 1LDX Efficacy
Primary Outcome
Study Trial Type Duration Interventions Measure Efficacy Outcome
Children
Biederman RCT 4 weeks Open-label MAS-XR 10/20/30 mg SKAMP- P<.0001 vs placebo
et al, 200723 n=52 LDX 30/50/70 mg Deportment33 PcOOOl vs placebo
Placebo
Biederman RCT 4 weeks LDX 30/50/70 mg, forced titration ADHD-RS-IV38 P<.001 vs placebo
et al, 200726 n=290 Placebo -ifoaHft
Wigal et al, RCT 6 weeks LDX 30/50/70 mg SKAMP33 P<.005 vs placebo
200827 n=129 Placebo
(4 week, open-label, dose-optimi-
zation phase followed by 2 week
crossover phase)
Findling etal, Open-label 1 year LDX 30/50/70 mg ADHD-RS-IV38 Overall: >60% reduction from
200828 n=272 baseline
ft
P<.0001
Findling etal, Open-label, dose- 7 weeks Open-label LDX ADHD-RS-IV38 Mean change in ADHD-RS-IV
200829 optimization 20/30/40/50/60/70 mg total scores38 from baseline
was significant (P<.0001)
n=318
Adults
Adler etal, RCT 4 weeks LDX 30/50/70 mg ADHD-RS-IV38 Overall: 40%-45% reduction
200830 n=420 Placebo from baseline
P<.0001 vs placebo
Brams, 13 weeks LDX 30/50/70 mg PERMP34 P<.0001 vs placebo
200931 n=142 Placebo
Weisler et al, Open-label, single- 1 year LDX 30/50/70 mg ADHD-RS-IV38 Mean change in ADHD-RS-IV
200932 arm extension total scores38 from baseline
was significant (P<.0001)
n=345
••'••.". -..-.•,-. -.-•'
LDX=lisdexamfetamine dimesylate; RCT=randomized clinical trial; MAS-XR=extended-release mixed amphetamine salts; SKAMP=Swanson, Kotkin, Agler, M-Flynn, and
Pelham rating scale; ADHD-RS-IV=Attention-Defich/Hyperactivity Disorder Rating Scale Version IV; PERMP=Permanent Product Measure of Performance. . .
Mattingly G. CMS Spectr. Vol 15, No 5. 2010
CNS Spectr 15:5 319 May 2010
Review Article
Children were randomly assigned to receive cebo (P<.005) beginning at 1.5 hours postdose
LDX (30, 50, or 70 mg/day) with forced dose and persisting up to and including 13 hours.27
titration or placebo for 4 weeks. Efficacy was Findling and colleagues28 conducted a 12
assessed using the ADHD Rating Scale Version month, open-label study to determine the long-
IV (ADHD-RS-IV),38 the Conners' Parent Rating term efficacy of LDX in children. The intent-to-
Scale (CPRS),39 and the CGI; tolerability was also treat (ITT) population included 272 children 6-12
assessed throughout the study. Significantly years of age with previously diagnosed ADHD,
greater improvements in ADHD-RS-IV scores some of whom may have received LDX dur-
were seen with each of the three LDX doses ing a prior study.23-2628 After a 1 week screening
throughout the day compared with placebo period and a 1 week washout period, subjects
(P<.001 for all comparisons).26 The effect sizes of were titrated to 30, 50, or 70 mg/day of LDX over
treatment with LDX were 1.39, 1.42, and 1.73 for 4 weeks and then placed on a maintenance dose
30, 50, and 70 mg/day of LDX, respectively.40 LDX for 11 months. Week 4 reductions in the ADHD-RS-
showed similar significant improvements in both IV total score were maintained throughout the 12
the inattention and hyperactivity subscales of the month treatment period (Figure 4).28 At endpoint,
ADHD-RS-IV. Using the CPRS at home, parents the ADHD-RS-IV total score change from baseline
of patients in each LDX dose group reported sig- was -27.2 points (>60% reduction; P<.0001).28
nificantly greater improvements in symptom Findling and colleagues29 also conducted an
control throughout the day (morning, ~10 AM; open-label, 7 week, dose-optimization study of
afternoon, ~2 PM; evening, ~6 PM). Compared daily LDX doses up to 70 mg in 318 children 6-12
with placebo (18%), CGI-lmprovement (CGI-I) rat- years of age with ADHD. Subjects were dosed
ings of very much improved or much improved to optimal symptom response and tolerability.
were seen in 2=70% of children receiving LDX.26 The primary efficacy assessment was the ADHD-
Wigal and colleagues27 evaluated the efficacy RS-IV, and secondary assessments included the
of LDX in 129 school-aged children with ADHD CGI-I and the Parent Global Assessment (PGA).
in a 6 week, randomized, double-blind, placebo- Because symptoms of ADHD in children are
controlled, analog classroom crossover study. often accompanied by deficits in executive func-
Significant improvements on SKAMP-Deportment tioning and abnormalities in emotional expres-
scores, the primary efficacy measure, were noted sion,4142 additional secondary measures included
in the active treatment group compared with pla- the Expression and Emotion Scale for Children
(EESC)43 and the Behavior Rating Inventory of
Executive Function (BRIEF)-Parent Form.44 At
FIGURE 3.
Change in children's PERMP scores
over 12 hours2336 FIGURE 4.
Children's ADHD-RS-IV average by
-•-LDX -•-MAS-XR -e- Placebo
each month of treatment28*
t • , t
E 1 2 3 45 6 8 10 12 1 2 3 4.5 6 8 10 12
Postdose (hours)
N=270 270 263 259 251 243 222 204 193 190 172 165 158 156 150 146 270
* P<.0001 vs placebo; N=50. y Month of Treatment
t P<.0001 vs placebo and P<.05 LDX vs MAS-XR.
* Results at each time point are reported for all subjects participating at
Study was not designed to compare LDX and MAS-XR groups. that time point (n). Results at endpoint are last-observation-carried-for-
Adapted from Biederman et al, 2007,23 with permission from Elsevier, and ward results for the intent-to-treat population.
Lopez et al, 2008.3B t P<.0001; paired t-test.
PERMP^Permanent Product Measure of Performance; LS=least squares; Used with permission from Findling et al, 2008.28
LDX=lisdexamfetamine dimesylate; MAS-XR=mixed amphetamine salts
extended-release. ADHD-RS-IV=Attention-DeficitfHyperactivity Disorder Rating Scale Version IV.
Mattingly G. CNS Spectr. Vol 15, No 5. 2010. Mattingly G. CNS Spectr. Vol 15, No 5. 2010.
CNS Spectr 15:5 320 May 2010
Review Article
endpoint, the mean change in ADHD-RS-IV total ADHD-RS-IV scores, were 0.73, 0.89, and 0.99 for
scores from baseline was significant (P<.0001),29 the 30, 50, and 70 mg groups, respectively.30 The
By weeks 2-3 of the study, most subjects showed investigators also measured the efficacy of LDX
improvement by clinician-rated CGI-I and par- using the CGI-I scale. On this scale, the percent-
ent-rated PGA. Also at endpoint, the mean EESC ages of adults taking LDX rated by investigators
total and subscale scores and the BRIEF Global as improved or very much improved at endpoint
Executive Composite scores were significantly were 57% (30 mg), 62% (50 mg), and 61% (70 mg),
improved. Overall, LDX was effective as rated by significantly more (P<.01) than with placebo.30
both investigator and parental assessment.29 In a separate presentation of the short-term
Studies in Adults adult data,30 Adler and colleagues45 analyzed the
Adler and colleagues30 evaluated the efficacy effect of LDX on sleep quality using the Pittsburgh
of LDX in 420 adults with moderate-to-severe Sleep Quality Index (PSQI). At baseline, patients
ADHD. The study was a randomized, double- with ADHD generally had global PSQI scores >5,
blind, placebo-controlled, parallel-group, 4 week suggesting that they were poor sleepers. LDX
study with forced dose escalations. After a 7-28 was not associated with statistically significant
day washout period, patients received 30, 50, changes in overall sleep quality.45
or 70 mg/day of LDX or placebo for 4 weeks. Additional post hoc subpopulation analyses46
Baseline symptom severity as measured by of these adult data30 revealed that LDX treatment
ADHD-RS-IV with adult prompts ranged from
was effective and generally well tolerated in 36
39.4 (placebo) to 41.1 (LDX groups).30 Treatment
patients with a history of depression or mood
with LDX at all three doses was significantly
disorders not currently requiring treatment with
more effective than placebo, with a mean reduc-
antidepressants. LDX produced similar improve-
tion in ADHD-RS-IV scores of 16.2-18.6 points in
ments in ADHD-RS-IV and CGI-I scores in those
the active treatment groups compared with 8.2
with and without a history of depressive disor-
after placebo (P<.0001 versus placebo). ders.46 In another exploratory post hoc analy-
Significant changes in ADHD-RS-IV scores sis,47 LDX produced similar improvements in
(P<.001) were observed after the first week of ADHD-RS-IV and CGI-I scores in subjects with
LDX treatment and continued at each postbase- and without a history of SUD. Lastly, when the
line visit (Figure 5).30 Each week during the dose data were assessed as a function of gender,48
titration period, a significantly greater proportion LDX treatment produced significant improve-
of subjects in each active treatment group had ments in ADHD-RS-IV scores for both male and
a reduction in ADHD-RS-IV total score of s30% female subjects when compared with same-sex
(P<.01). Treatment effect sizes at endpoint ver- subjects treated with placebo.
sus placebo, calculated using mean changes in
The efficacy and duration of effect of LDX in
adults with ADHD have also been assessed in a
randomized, double-blind, placebo-controlled
FIGURE 5.
crossover study31 in a simulated workplace envi-
Change from baseline in adult ADHD-
ronment. Three doses of LDX (30, 50, and 70 mg)
RS-IV scores in the intent-to-treat
were compared with placebo in 142 adults with
population30
ADHD. When compared with those given placebo,
Endpoint patients treated with LDX demonstrated significant
improvement in average total PERMP scores (289.5
and 312.9, respectively; P<.0001) and significantly
better mean PERMP total scores at each postdose
assessment from 2-14 hours (P<.01 for all).31
Long-term LDX treatment efficacy in adults
was evaluated in a 12 month, open-label, sin-
gle-arm, long-term extension study32 of LDX
* P<.0001 vs placebo; t P<001 vs placebo.
30, 50, or 70 mg/day for 4 weeks, and then con-
Reprinted by permission from Adler et al, 2008.30 Copyright 2008, Physicians
Postgraduate Press. tinued for 11 months with dose adjustments
made as necessary. Patients treated with LDX
ADHD-RS-IV=Attention-Deficit/Hyperactivity Disorder Rating Scale
Version IV; LS=least squares; LDX=lisdexamfetamine dimesylate. showed significant improvements in ADHD-
Mattingly G. CNS Spectr. Vol 15, No 5. 2010. RS-IV total scores relative to baseline at all vis-
CNS Spectr 15:5 321 May 2010