Background
Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral condition that is estimated to affect 5% to 10% of youths worldwide and approximately 4.4% of adults in the United States [
1,
2]. Clinical trials of stimulant pharmacotherapy in adults with ADHD indicate high levels of efficacy. Significantly improved ADHD symptom scores (versus placebo) based on randomized, placebo-controlled trials using long-acting formulations of either methylphenidate (MPH) [
3,
4] or amphetamines have been reported [
5,
6].
Despite the overall high degree of treatment response, there are very limited guidelines for how to judge clinical response or how to define optimal treatment/remission when treating adults with ADHD [
7]. Meta-analyses indicate effect sizes (relative to placebo) of approximately 0.7 with long-acting psychostimulant medications in adults with ADHD [
8]. ADHD symptom scores, based on the ADHD Rating Scale IV (ADHD-RS-IV) [
9] and other similar scales, as well as effect size estimates have value but do not indicate what percentage of participants may be expected to improve, when improvement may become apparent, and whether improvements persist. Neither do they address whether participants continue to meet diagnostic criteria, particularly criteria related to functional impairments associated with ADHD symptoms.
Few clinical trials have assessed ADHD treatment efficacy in terms of clinical response, and, to date, no trials in adults (to our knowledge) have described rates of symptomatic remission. Throughout the broad field of psychiatry, numerous definitions of “response” have been proposed, all generally aimed at defining individuals who show clinically apparent improvement to a definitive intervention but who still experience some degree of symptoms [
10,
11]. As reviewed by Steele et al. [
12] and based on various clinical trials of participants with ADHD, response to treatment has been operationally defined as improvement from baseline of 25% to 30% in rating scales such as the ADHD-RS-IV or Swanson, Nolan, and Pelham, Version IV (SNAP)-IV. Inherent to this definition of treatment response is that individuals may continue to have symptoms of the disorder because percent reductions do not account for baseline severity levels. For that reason, a definition of clinical response that is both a composite of a percent reduction in symptoms (eg, a 30% improvement in symptom levels from baseline), as well as a second measure of clinical improvement (eg, Clinical Global Impressions-Improvement [CGI-I] [
13] of 1 [very much improved] or 2 [much improved]) may be considered a more meaningful measure. Moreover, it has been reported that an approximate 10- to 15-point change or a percent change of approximately 25% to 30% in ADHD-RS-IV scores corresponded to a 1-level change on the CGI-I [
14].
Three types of remission have also been proposed for ADHD: syndromatic, symptomatic, and functional [
15]. Syndromatic remission is defined as “failing to meet the full diagnostic criteria for ADHD” [
15] and was originally described for bipolar disorder by Keck et al. [
16] as syndromatic recovery. Symptomatic remission is defined as having fewer than 5 symptoms, the number of symptoms required for a subthreshold ADHD diagnosis [
15]. Functional remission is defined as “the loss of partial diagnostic status plus functional recovery” [
15]. In clinical practice, this is likely to be thought of as successful treatment, where the participant no longer exhibits the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) behavioral diagnostic criteria for ADHD [
17,
18]. As reviewed by Keck and colleagues, functional recovery indicates that a patient has attained premorbid levels of functioning (eg, work and psychosocial) for a defined extended period of time [
16]. Although not assessed in this study, functional outcome measures in conjunction with those of clinical response and symptomatic remission used to evaluate ADHD symptoms may be clinically relevant assessments for managing and treating ADHD.
Researchers have attempted to objectively define clinical response and symptomatic remission using scale-based cutoff thresholds [
18,
19]. In the Multimodal Treatment Study of Children With ADHD, success or “excellent response” was defined as a SNAP-IV mean per-item score ≤1, indicating symptom ratings of “not at all” to “just a little” and a severity level below the ADHD diagnostic threshold [
18]. Similarly, a total score of ≤18 on the ADHD-RS-IV, which scores each of the 18-item
DSM-IV-TR criteria, defines an ADHD population that is rated on average by the clinician as mildly symptomatic. To define symptoms, each item was rated on a 4-point scale: 0 (never or rarely); 1 (sometimes); 2 (often); and 3 (very often) [
9]. On average, a score of 1 (ie, “sometimes”) across the 18-item scale has been proposed as defining symptomatic remission for participants with combined-type ADHD [
12]. This cut off score of ≤18 indicates loss of ADHD symptom status such that the clinician considers the individual with ADHD as no longer exhibiting
DSM-IV-TR symptom criteria [
12]. The cut off for symptomatic remission is having clinically minimal (eg, “sometimes ill” on the ADHD-RS-IV and “just a little ill” on SNAP-IV) or no symptoms (eg, “never or rarely” on the ADHD-RS-IV and “not at all” on SNAP-IV), which is considered in the range of a matched control group without ADHD [
12].
In the current investigation, rates of clinical response and symptomatic remission were examined based on post hoc analysis of efficacy data from 2 adult clinical trials of lisdexamfetamine dimesylate (LDX) [
5,
20]. In a short-term (4-week), randomized, placebo-controlled forced-dose escalation trial, ADHD-RS-IV clinician-rated symptom scores were significantly reduced (
P≤.001) in all LDX groups (30, 50, and 70 mg/day [mg/d]) compared with placebo at weeks 1 to 4 and endpoint, and CGI-I ratings were significantly reduced at endpoint (
P≤.001) [
5]. A 12-month, open-label extension study enrolled eligible participants from the preceding short-term LDX trial. Results of the extension study demonstrated that ongoing LDX treatment was associated with a significant reduction in ADHD symptom scores from baseline of the prior study at all postbaseline visits and at endpoint (
P<.001) [
20]. In the current post hoc analysis, maintenance of clinical response and symptomatic remission during the 12-month open-label treatment was evaluated. The main goal of examining these post hoc analyses was to assess how useful these criteria are in providing additional clinically relevant information to evaluate the use of LDX in short- and long-term ADHD treatment.
Discussion
Limited data exist on how to monitor and optimize treatment in adults with ADHD. We propose that a 30% reduction on the ADHD-RS-IV along with a 1- to 2-point improvement in CGI is a useful measure of initial clinical response. Even more importantly, a score of 18 or less on the ADHD-RS-IV (the 18 symptoms of ADHD are mild or less on average) appears to be a realistic goal for ADHD treatment in adults. These post hoc analyses of data from a short-term study [
5] and a long-term study [
20] have shown that LDX in adults with ADHD is associated with clinical response and symptomatic remission that persist over time for many participants. In the 4-week study, the majority of participants met post hoc criteria for clinical response and nearly half met criteria for symptomatic remission. In the 12-month study, nearly all dose-optimized participants (95.7%) met criteria for clinical response and many participants (85.0%) met criteria for symptomatic remission at least once during the trial. Of the participants who met clinical response criteria, 75.2% continued to meet criteria at every subsequent visit, and of those who met symptomatic remission criteria, nearly two-thirds (65.7%) continued to meet symptomatic remission criteria at all subsequent visits.
In adults with ADHD, there are not many recognized and clinically relevant measures that have been established. Similar to treatment guidelines for major depression that have emphasized the importance of treating to levels of symptomatic remission, describing criteria for clinical response and symptomatic remission in adults with ADHD may provide a useful, clinically relevant measure. This may be more meaningful to clinicians than are assessments of group average scores and population norms on symptom rating scales, most of which may not be applied in a clinical setting [
18]. Describing clinical response and symptomatic remission provides clinicians with outcome measures that resemble clinical approaches to patient assessment and treatment [
18]. Applying these criteria in clinical practice will offer a useful assessment measure with benchmarks for optimal treatment. Time to median clinical response and symptomatic remission informs both the participant and the clinician about when noticeable therapeutic effects could be expected to emerge for most patients, setting the stage for more timely recognition of a need for dose optimization or medication switching. In the short-term study, time to median clinical response with LDX was achieved by most participants in approximately 2 weeks. Due to the forced-dose escalation design of the 4-week study, however, it is not possible to differentiate the relative contributions of dose level versus time on treatment for achieving clinical response criteria.
A number of investigators have described clinical response and symptomatic remission rates for stimulant and nonstimulant pharmacotherapy in adults with ADHD. In previous trials of adults with ADHD, clinical response has been defined either as at least a 30% decline from baseline in symptom scores on a validated rating scale of adult ADHD symptom severity [
6,
23,
24] or as very much improved or much improved on ratings of global improvement at endpoint [
3,
4,
25]. Studies using variable dosing designs have been conducted with other long-acting psychostimulants (besides LDX) in adults with ADHD. Clinical response rates ranged from 48.5% to 95.1% [
3,
4,
6,
23‐
25]. No previous reports have explicitly described symptomatic remission in adults with ADHD. Adler et al. [
25] described the proportions of “normal to mildly ill” adults with ADHD based on endpoint CGI-S ratings; 64.6% met those criteria in the 5-week, short-term double-blind treatment phase (fixed dose of d-MPH extended release). In the open-label extension phase, 90.0% who switched from placebo and 92.7% who continued on active treatment met those criteria. Jain and colleagues [
4] described participants with “normalization rates…[of] 73.7%” based on Conners’ Adult ADHD Rating Scales–Self Report Index T-scores of <65, which indicates that the severity of impairment is below clinical threshold levels. In the current analysis, 85.0% of participants in the long-term trial met the criteria for symptomatic remission; in 65.7% of these participants, symptomatic remission persisted with continued treatment. Study design differences may account for the broad variability seen among these trial outcomes. Importantly, definitions of clinical response and symptomatic remission varied widely, which is understood to lead to different outcomes [
12,
15,
18]. Neither the current trial nor prior investigations have conducted head-to-head treatment comparisons, precluding meaningful comparisons of clinical response and symptomatic remission rates between treatments.
The criteria for clinical response used in this post hoc analysis were more stringent than most existing reports because they required improvement as assessed by 2 separate measures: ADHD-RS-IV with adult prompts and the CGI-I. This double-measure criterion is not without precedent. It has been used previously in adults with ADHD in a trial of osmotic-release oral system MPH [
3]. Most trials, however, have defined clinical response based on a single measure, such as Medori and colleagues [
24]. Several factors argue against a single cutoff criterion. For example, recent research has shown that, in adults, a 25% to 30% change from baseline to endpoint in ADHD-RS-IV score or an absolute change of approximately 10 to 15 points corresponds to a change of one level in CGI-I rating in both adults and children, [
14] and this may not be clinically meaningful. A percent reduction in ADHD-RS-IV total score alone is not sufficient because participants who are severely ill at baseline may still exhibit significant symptoms [
12]. Addition of the CGI-I criterion of 1 or 2, as applied in the current study, prevents such participants from being defined as clinical responders. The criteria for symptomatic remission applied in the current study are consistent with some definitions previously proposed for symptomatic remission [
18,
19] and represent a substantial treatment-associated decrease of symptoms, but they do not preclude the ongoing presence of mild residual symptoms that are not disabling. Further studies are required to validate this concept of symptomatic remission and its relationship to daily functioning and ADHD diagnostic threshold.
The application of different criteria for clinical response and symptomatic remission could lead to different results [
15]. These classifications of clinical response and symptomatic remission are based on a current symptom scale and do not purport to reflect functional outcomes or other measures that may be used to characterize clinical improvement or recovery in a disease state. Recent studies [
26,
27] have focused on looking beyond symptom assessment to a more comprehensive understanding of functional outcomes and the real-world impact of symptom severity and treatment-related improvements [
27]. For example, a combined analysis of randomized participants from 4 different studies that pooled participants across treatment groups suggested that a reduction of approximately 20 points on the ADHD-RS was associated with pronounced functional outcome improvement (social and behavioral) on the Life Participation Scale [
28]. This result corresponded to a 50% to 65% improvement in symptom severity levels and demonstrated improvement in functional outcome status. The analysis also indicated that a threshold of 40% to 45% improvement in symptom severity was needed to achieve clinically apparent functional improvement [
28]. Diagnostic criteria for ADHD in adult patients and the criteria for clinical response and symptomatic remission in these post hoc analyses were based on those listed in the
DSM-IV-TR. Although changes in symptom thresholds of the diagnostic criteria may occur with the expected adoption of the revised version,
DSM 5 in 2013, current considerations maintain the requirement for 6 symptoms of either subtype to diagnose ADHD in adults [
29]. Pending implementation of potential changes, it may be interesting for future analyses to examine the impact of revised criteria for symptom presentation on clinically relevant assessments of clinical response and symptomatic remission.
Limitations
There were several limitations of the current studies and analyses. This publication is derived from post hoc analyses rather than predefined study endpoints. Both the short- and the long-term investigations excluded adult participants with common medical and psychiatric comorbidities; hence, current findings may not generalize to a broader clinical population. The use of a forced-dose escalation design in the short-term study may have led to nonrandom participant discontinuation (eg, possible poor tolerability in higher dose groups and lack of efficacy in lower dose groups). As in other trials that use open-ended questioning and spontaneous report to collect data on AEs, incidence may be underreported. In interpreting the findings on maintenance of response and remission in the long-term study, one should keep in mind that dose changes were possible for each individual during the maintenance phase of the study and, as such, may have contributed to maintenance of response and remission. The long-term study was open label, introducing the potential for investigator and participant bias toward reporting clinical improvement and, as with other long-term studies, participants leave over the course of the study for various reasons.
The criteria for response and remission were based on assessment of global and individual symptom level and severity. The impact of treatment on other important facets of ADHD, such as quality of life, or functional recovery/remission cannot be addressed. Although analyses evaluating participants who did not respond to treatment or who failed to maintain clinical response to treatment would be quite interesting and informative, it is beyond the scope of the current analysis. Also, not all participants respond to psychostimulant treatments, including LDX. Future work could examine characteristics and/or predictors of clinical nonresponse.
A limitation in interpreting time to occurrence of a specific event (in this study the event is defined as either loss of response or remission status) using the Kaplan-Meier survival analysis approach involves the process of censoring (removing) participants from the analysis. Participants are censored (removed) from the analysis if they have not had the event (eg, achieved response or remission status), and are no longer available to observe for the event. This occurred at the end of the study period, and when participants discontinued or were lost to follow-up while still a responders/remitters at their last visit. Therefore when we report that of 278 participants experiencing a clinical response on entering the maintenance phase of the study; 209 did not lose that response during their participation, not all had completed the study.
Competing interests
Dr Mattingly serves/d as a consultant for GlaxoSmithKline, Johnson & Johnson, Novartis, Sepracor, Shionogi, and Shire; receives/d research support from Sepracor; receives/d honoraria from Forest, GlaxoSmithKline, Johnson & Johnson, Lilly, Novartis, and Shire; serves/d as speaker or advisory board member for Sepracor.
Dr Richard Weisler, 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 of 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, 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, 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.
Dr Young receives/d grant/research support from Cyberonics, Lilly, Novartis, Pfizer, Otsuka, and Shire; is/has been a speaker for AstraZeneca, Bristol-Myers, Cephalon, Forest, GSK, Lilly, McNeil, Novartis, Pfizer, Sepracor, Schering Plough, Shionogi, and Shire.
Mr Adeyi is an employee of Shire and holds stock and/or stock options in Shire.
Dr Dirks is an employee of Shire and holds stock and/or stock options in Shire.
Dr Babcock is an employee of Shire and holds stock and/or stock options in Shire.
Dr Lasser was an employee of Shire with stocks and stock options from 2008 to July 2012. From July 2012 to the present, he is an employee of Pharmanet/i3, an inVentiv Health company (no stock or options in Shire or any other company).
Dr Scheckner is an employee of Shire and holds stock and/or stock options in Shire.
Dr Goodman receives/d research support from Lilly and Company, McNeil, and Shire Inc.; receives/has received honoraria from McNeil, Shire Inc.; is/has been a speaker for American Professional Society of ADHD and Related Disorders, Audio-Digest Foundation, CME Inc, Medscape, SynerMed Communications, Temple University, Veritas Institute, WebMD; is/has been a consultant for Avacat, Clinical Global Advisors, McNeil, New River Pharmaceuticals, Novartis, Schering-Plough, Shire Inc., Major League Baseball, and Thompson Reuters; receives royalties from MBL Communications, Inc.
Authors’ contributions
GM was an investigator on the parent study and participated in data acquisition, analysis, interpretation, and presentation. GM was fully involved in drafting the manuscript and revising the intellectual content of this manuscript. He has given final approval of this version. 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. He has given final approval of this version. JY was an investigator on the parent study and participated in data acquisition, analysis, interpretation, and presentation. JY was fully involved in drafting the manuscript and revising the intellectual content of this manuscript. He has given final approval of this version. BA was a statistician involved in all post hoc data analysis, interpretation, and presentation. He was fully involved in drafting and revising the intellectual content of this manuscript. He has given final approval to this version. BD was the Director, Clinical Development and 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. He has given final approval of this version. TB was the Associate Director Scientific Publications, Clinical Development and 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. He has given final approval of this version. RL was the Senior Director, Clinical Development and 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. He has given final approval of this version. BS was the Director-Scientific Publications, Clinical Development and 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. He has given final approval of this version. DG was an investigator on the parent study and participated in data acquisition, analysis, interpretation, and presentation. JY was fully involved in drafting the manuscript and revising the intellectual content of this manuscript. He has given final approval of this version. All authors read and approved the final manuscript.
Presented at the 162nd Annual Meeting of the American Psychiatric Association; May 16–21, 2009; San Francisco, CA
Presented at the US Psychiatric and Mental Health Congress Conference and Exhibition; November 2–5, 2009; Las Vegas, NV