Background
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder that often persists into adulthood. The estimated prevalence of ADHD in adults is 4.4% [
1]. It is well-recognized that ADHD manifests not only as impairments in the core ADHD symptoms (inattention, hyperactivity, impulsivity), but is also correlated with executive function deficits (EFD; impairment in cognitive self-regulatory processes) [
2‐
4] that impact goal-directed behavior and control emotional functioning [
5,
6]. Executive function (EF) domains include verbal and nonverbal working memory, emotional self-regulation, shifting of attention or focus, and planning and problem solving among others [
7,
8]. Deficits in EF remain stable even in adulthood [
9,
10], although presentation of core ADHD symptoms may change with age. EFD affects outcomes in education, work, social relationships, and psychosocial functioning [
11,
12].
Validated rating scales of behaviors thought to be associated with EF include the self-reported Brown Attention-Deficit Disorder Scale (BADDS) [
13], Barkley Deficits in Executive Functioning Scale [
14], and Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) [
15]. The BRIEF-A scoring employs T-scores, where the normative population mean is set at 50, with a SD of 10. A T-score ≥65 indicates clinically significant EF impairments [
15] of complex behavioral tasks in daily real-world settings [
2,
5,
8,
16]. Compared with neuropsychological tests of EF, behavioral assessments may be better predictors of impairment in major life activities [
17]. Such impairments may be reflected in quality of life (QOL), a subjective perception of well-being in various functional life domains including physical, psychological, cognitive, and social [
18]. Since deficits in EF domains may impact QOL across various life domains, concurrent assessments of EF and QOL may more fully quantify patient improvement on ADHD treatment.
Adults with symptoms of ADHD may display impairments in executive functioning and in QOL [
19]. Moreover, improvements in ADHD symptoms may coincide with improvements in both EF and QOL [
20]. Instruments assessing QOL may be disease-specific or nonspecific. In either case, these may enable the physician to assess clinical treatment outcomes that may be perceived as important from a patient perspective and, hence, perceived as an appropriate means to monitor treatment progress [
21].
The self-reported Adult ADHD Impact Module (AIM-A) [
22] multi-item scale is a validated QOL measure that has demonstrated treatment sensitivity in a double-blind, placebo-controlled study of a long-acting psychostimulant [
23]. Another validated QOL measure, the 29-item self-reported Adult ADHD QoL (AAQoL) scale [
24], exhibited responsiveness to ADHD treatment in an 8-week, randomized, placebo-controlled trial of the nonstimulant atomoxetine [
21].
The long-acting prodrug psychostimulant lisdexamfetamine dimesylate (LDX) is indicated in the United States for ADHD in children (6 to 12 years), adolescents (13 to 17 years), and adults [
25]. LDX has demonstrated efficacy in reducing core ADHD symptoms in a randomized, controlled trial in adults [
26], using the ADHD Rating Scale IV (ADHD-RS-IV) [
27,
28]; and was associated with improvements from baseline in EF, using the validated, self-reported BADDS [
13,
29], during the open-label phase of a modified analog classroom study (4-week) of adults with ADHD [
30]. In the modified analog classroom study, LDX treatment demonstrated efficacy in adults with ADHD who had significant impairments in ADHD core symptoms and EF. Moreover, LDX demonstrated efficacy in QOL as assessed by AIM-A [
31].
Further randomized, double-blind, placebo-controlled studies may be useful to confirm the impact of psychostimulant treatment on QOL domains in adults with ADHD and EFD, and provide clinicians with information on the types of assessment tools available as well as their use in making patient-relevant assessments. A randomized, controlled trial using LDX in adult participants with both ADHD and EFD reported improvement in EFD with BRIEF-A Global Executive Composite (GEC) LS mean (SE) change from baseline of -11.1 (1.72) for placebo and -22.3 (1.67) for LDX, respectively (primary efficacy measure,
P<.0001; effect size of 0.74) [
32]. During the course of the study, 2 separate QOL instruments were used as secondary outcomes. With these data, we may be able to explore ADHD treatment effects, not only on core symptoms (inattention, hyperactivity, and impulsivity), but also on EFD and self-reported QOL during the course of that treatment.
Objectives
This report focuses on the secondary study outcomes reported including the effects of LDX treatment on participant-perceived QOL measures, the AIM-A, and the AAQoL. The AAQoL was added to the study as a protocol amendment and was not used on all participants. Also reported in this study is a post hoc subgroup analysis of those participants with both AIM-A and AAQoL scores at baseline. The primary objective of the present study was to demonstrate the efficacy of LDX versus placebo in improving EF in participants with ADHD and coexisting EFD. The primary and other secondary endpoints of this study have been presented in detail elsewhere [
32].
Discussion
This population of adults with ADHD and significant EF impairment at baseline demonstrated significantly improved QOL versus placebo as assessed by the self-reported AIM-A in the subscales of Performance and Daily Functioning, Impact of Symptoms: Daily Interference, Impact of Symptoms: Bother/Concern, and Relationships/Communications. Moreover, self-reported responses to AIM-A questions 1 to 4 suggested that participants perceived better overall improvement in QOL with LDX treatment versus placebo. These data indicate that with LDX treatment, adults who have ADHD and EFD showed significant improvement on the self-reported AIM-A QOL. Numerical improvements over placebo were also seen with LDX treatment on the self-reported AAQoL total and subscale scores, although the prespecified testing hierarchy precludes inferential statistical analysis of the AAQoL. The self-reported QOL data in this analysis suggest comparable findings using either QOL measure (AIM-A or AAQoL).
The ability to be productive in the workplace is an important issue for adults with ADHD in an increasingly competitive work environment [
36‐
38]. The study by Kupper et al. [
38], which reviewed published literature reporting on the impact of ADHD on work productivity and occupational health, suggested that adults with ADHD exhibited decreased work performance and productivity, increased behavioral issues (irritability and frustration), absenteeism, increased workplace accidents or injury, as well as increased indirect effects (eg, substance use and criminality) on occupational health. Real-life outcomes, such as productivity, can be assessed using these validated QOL scales and can be important for clinicians to determine ADHD treatment response. Adults with ADHD in this study reported significantly improved QOL with LDX treatment compared to placebo on the AIM-A Performance and Daily Functioning subscale and numerical improvement on the AAQoL Life Productivity domain.
The AIM-A QOL data from the present study were consistent with a 7-week, randomized controlled ADHD study of an extended-release mixed amphetamine salts formulation that also demonstrated significantly improved QOL at study endpoint relative to placebo [
39]. These study data suggest that significant improvement in QOL in those with ADHD may become apparent in as early as 7 weeks after initiating psychostimulant treatment.
Another 14-week randomized controlled study [
40] demonstrated that the AAQoL total score was significantly improved from baseline versus placebo with atomoxetine (a nonstimulant), with an effect size of 0.24. In that study, however, significant improvement with atomoxetine versus placebo was only demonstrated on 1 of the 4 subscales, Psychological Health. Another 6-month, double-blind study, using the AAQoL scale, showed greater numerical improvement with atomoxetine than placebo in adult participants with ADHD of at least moderate severity, with the Life Outlook subscale score showing significant improvement versus placebo [
19].
In the current study, QOL measures improved along with improvements in self-reported EF, using the BRIEF-A, and investigator-reported symptom improvement, using the ADHD-RS-IV with adult prompts. As described in the primary study [
32], LDX treatment versus placebo significantly improved deficits in EF (BRIEF-A GEC T-scores of ≥65) bringing scores well within the normative range. Likewise, significant improvements in ADHD symptoms with LDX treatment compared to placebo were also demonstrated with ADHD-RS-IV and CGI-I scores. Overall, these findings suggest that LDX treatment might result in improvements in multiple functional areas affected by ADHD, and that researchers as well as clinicians have available tools and resources to monitor such improvements [
41].
Limitations
Since adults with comorbid psychiatric disease and significant cardiovascular disease were excluded from the current study population, caution should be taken when generalizing results to the overall population. In addition, study participants were required to meet a prespecified level of EFD, and this further limits generalization. The subjective, participant-reporting nature of such rating scales should also be considered because it is not possible to account for variability in rating scores among individual participants. Also, the short duration of the trial limits the ability to specify the long-term effects of LDX on assessments of QOL. The predefined hierarchical statistical testing program precludes statistical inferences on some of the measures, and no statistical inferences were made based on the post hoc analyses.
Competing interests
Lenard A. Adler, MD, has been a consultant to AstraZeneca, Eli Lilly, Epi-Q, i3 Research, INC Research, Mindsite, Organon/Schering-Plough/Merck, Ortho-McNeil/Janssen/Johnson & Johnson, Otsuka, Shire, United Biosource, Major League Baseball, Major League Baseball Players Association, the National Football League, Alcobra Pharmaceuticals and Theravance; he has received research support from Bristol-Myers Squibb, Chelsea Therapeutics, Eli Lilly, Organon/Schering-Plough/Merck, Ortho-McNeil/Janssen/Johnson & Johnson and the National Institute of Drug Abuse (NIDA); he has been on the advisory boards of Eli Lilly, i3 Research, INC Research, Mindsite, Organon/Schering-Plough/Merck, Ortho-McNeil/Janssen/Johnson & Johnson, Theravance and Alcobra Pharmaceuticals. He has previously been (and has not been for the last three years) on the Speaker’s Board for Ortho-McNeil/Janssen/Johnson & Johnson, Shire and Eli Lilly. He has received an options grant from Alcobra Pharmaceuticals and has received royalty payments (as inventor) from New York University for license of adult ADHD scales and training materials. Bryan Dirks, MD, is an employee of Shire and holds stocks and/or stock options in Johnson & Johnson and Shire. Patrick Deas, BS, is an employee of Shire and holds stocks and/or stock options in Shire. Aparna Raychaudhuri, PhD, is an employee of Shire and holds stocks and/or stock options in Shire. Matthew Dauphin, MS, is an employee of Shire and holds stocks and/or stock options in Shire. Keith Saylor, PhD, has received research support from Shire, Eli Lilly, Otsuka, Supernus, Bristol-Myers Squibb, Novartis, Merck; is/has been a consultant or on an advisory board of Supernus Pharmaceuticals, Eli Lilly and Company, Shire. Richard Weisler, MD, in his career, has been a consultant to, on the Speaker’s Bureaus of, and/or received research support from the following: Abbott - Speaker’s Bureau, Consultant, Received Research Support, Agency for Toxic Substances and Disease Registry- Consultant, AstraZeneca - Speaker’s Bureau, Consultant, Received Research Support, Biovail - Speaker’s Bureau, Consultant, Received Research Support, Bristol-Myers Squibb - Speaker’s Bureau, Consultant, Received Research Support, Stockholder has held or holds stock, Burroughs Wellcome - Speaker’s Bureau, Received Research Support, Cenerx - Received Research Support, Centers for Disease Control and Prevention - Consultant, Cephalon - Speaker’s Bureau, Consultant, Received Research Support, Ciba Geigy - Speaker’s Bureau, Received Research Support, CoMentis - Received Research Support, Corcept - Consultant, Cortex - Stockholder has held or holds stock, Dainippon Sumitomo Pharma America - Received Research Support, Eisai - Received Research Support, Elan - Received Research Support, Eli Lilly - Speaker’s Bureau, Consultant, Received Research Support, Forest - Speaker’s Bureau, Consultant, Received Research Support, GlaxoSmithKline - Speaker’s Bureau, Consultant, Received Research Support, Janssen - Speaker’s Bureau, Received Research Support, Johnson & Johnson - Speaker’s Bureau, Consultant, Received Research Support, Lundbeck - Received Research Support, McNeil Pharmaceuticals - Received Research Support, Medicinova - Received Research Support, Medscape Advisory Board - Consultant, Merck - Received Research Support, Stockholder has held or holds stock, National Institute of Mental Health - Consultant, Received Research Support, Neurochem - Received Research Support, New River Pharmaceuticals - Received Research Support, Novartis - Speaker’s Bureau, Received Research Support, Organon - Speaker’s Bureau, Consultant, Received Research Support, Otsuka America Pharma - Consultant, Pfizer - Speaker’s Bureau, Consultant, Received Research Support, Stockholder has held or holds stock, Pharmacia - Consultant, Received Research Support, Repligen - Received Research Support, Saegis - Received Research Support, Sandoz - Received Research Support, Sanofi - Speaker’s Bureau, Consultant, Received Research Support, Sanofi-Synthelabo - Speaker’s Bureau, Consultant, Received Research Support, Schwabe/Ingenix - Received Research Support, Sepracor - Received Research Support, Shire - Speaker’s Bureau, Consultant, Received Research Support, Solvay - Speaker’s Bureau, Consultant, Sunovion - Speaker’s Bureau, Consultant, Received Research Support, Synaptic - Received Research Support, Takeda - Received Research Support, TAP - Received Research Support, Theravance - Received Research Support, Transcept Pharma - Consultant, Received Research Support, TransTech - Consultant, UCB Pharma - Received Research Support, Validus - Speaker’s Bureau, Consultant, Vela - Received Research Support, and Wyeth - Speaker’s Bureau, Consultant, Received Research Support.
Authors’ contributions
LA was the principal investigator on the parent study and participated in data acquisition, analysis, interpretation, and presentation. LA was fully involved in drafting the manuscript and revising the intellectual content of this manuscript. BD was the Director, Clinical Development/Medical Affairs for this study and made substantial contributions to the analysis and interpretation of the data. He was deeply involved in drafting the manuscript and revising the intellectual content. PD was the Senior Clinical Scientist for this study and made substantial contributions to the analysis and interpretation of the data. He was deeply involved in drafting the manuscript and revising the intellectual content. AR was the statistician involved in all analysis, interpretation and presentation. She was fully involved in drafting and revising the intellectual content of this manuscript. MD was the Associate Clinical Programs Director for this study and made substantial contributions to the analysis and interpretation of the data. He was deeply involved in drafting the manuscript and revising the intellectual content. KS was an investigator on the parent study and participated in data acquisition, analysis, interpretation, and presentation. KS was fully involved in drafting the manuscript and revising the intellectual content of this manuscript. RW was an investigator on the parent study and participated in data acquisition, analysis, interpretation, and presentation. RW was fully involved in drafting the manuscript and revising the intellectual content of this manuscript. All authors read and approved the final manuscript.