Relationship of ADHD symptoms and global illness severity in adults treated with lisdexamfetamine dimesylate.

C L I N I C A L F O C U S : A D H D, P S Y C H I AT R I C D I S O R D E R S , A N D S T R O K E A N D N E U RO L O G Y

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Relationship of ADHD Symptoms and Global Illness Severity in Adults Treated With Lisdexamfetamine Dimesylate

DOI: 10.3810/pgm.2014.09.2798

Richard H. Weisler, MD 1 Thomas Babcock, DO 2 Ben Adeyi, MS 3 Matthew Brams, MD 4 Adjunct Associate Professor of Psychiatry, Duke University Medical Center, Durham, NC, and Adjunct Professor of Psychiatry, University of North Carolina at Chapel Hill, Raleigh, NC; 2Associate Director of Scientific Publications, Shire Development LLC, Wayne, PA; 3 Director of Global Biostatistics, Shire Development LLC, Wayne, PA; 4Director, Bayou City Research, Houston, TX 1

Abstract: The relationship between attention-deficit/hyperactivity disorder (ADHD) symptoms and global clinical assessment of functionality is complex. This post-hoc analysis explores this relationship and suggests implications for patient assessment in clinical practice. Adults with ADHD on a stable lisdexamfetamine dimesylate (LDX) dose for $ 6 months were enrolled in a double-blind, placebo-controlled, randomized withdrawal study. Participants entered a 3-week open-label phase continuing their prior LDX dose and were then randomized to placebo or the same LDX dose for a 6-week, double-blind, randomized withdrawal phase. ADHD symptom distribution was measured by the ADHD Rating Scale IV (ADHD-RS-IV) with Adult Prompts total score reflecting DSM-IV-TR ADHD symptom criteria and severity by Clinical Global Impressions–Severity (CGI-S) ratings at study entry and at end of study. Of 123 participants enrolled in the open-label phase, 116 were included in the randomized withdrawal phase (placebo, n = 60; LDX, n = 56). As reported in a prior publication, mean (standard deviation) ADHD-RS-IV total score change from baseline (week 3) to end of study (randomized-withdrawal phase) was 16.8 (11.80) for placebo and 1.6 (8.63) for LDX. At end of study, for placebo and LDX, 5.0% and 32.1% of participants, respectively, had a CGI-S = 1, 11.7% and 35.7% had a CGI-S = 2, 11.7% and 17.9% had a CGI-S = 3, 33.3% and 7.1% had a CGI-S = 4, 35.0% and 7.1% had a CGI-S = 5, and 3.3% and 0% had a CGI-S = 6; no participants had a CGI-S = 7 (P , 0.0001). The CGI-S ratings increased (worsened) as ADHD symptom scores worsened. Post-hoc regression analysis between ADHD-RS-IV scores and CGI-S demonstrated shared variance of 47% at week 3 and 69% for both placebo and LDX at end of study. Although ADHD symptom scores demonstrate a linear relationship with global illness severity, the variance suggests that other factors not captured by symptom scales are also important in assessing patient outcomes in clinical practice. (Trial registration: ClinicalTrials.gov NCT00877487.) Keywords: ADHD; ADHD-RS-IV; Clinical Global Impressions–Severity; lisdexamfetamine dimesylate; psychostimulant; adults

Introduction

Correspondence: Richard H. Weisler, MD, University of North Carolina at Chapel Hill, 700 Spring Forest Rd, Suite 125, Raleigh, NC 27609. Tel: 919-872-5900 Fax: 919-878-0942 E-mail: [email protected]

Attention-deficit/hyperactivity disorder (ADHD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria and described in epidemiologic studies, causes serious functional impairments in $ 2 settings (eg, occupational, school, social, and personal/home roles).1–4 Diagnostic criteria specify both ADHD symptoms and functional impairments4 in individuals with ADHD. Although clinicians provide ongoing treatment to address ADHD symptoms and resulting impairments,5 clinical studies generally describe treatment response only in terms of symptom scores.

© Postgraduate Medicine, Volume 126, Issue 5, September 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 31 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


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Clinical response to treatment has been defined as symptom improvement that is recognizable to clinicians and patients, although symptoms of the disorder may still be present.6,7 Symptomatic remission can be considered as sufficient improvement in symptoms so that a patient is only minimally symptomatic and does not meet diagnostic criteria of the disorder.7 In ADHD studies, as reviewed by Steele et al,6 clinical response has been operationalized as improvement from baseline of 25% to 40% on rating scales such as the ADHD Rating Scale IV (ADHD-RS-IV),8 the Swanson, Nolan, and Pelham Scale–Version IV,9 or the Conners’ Adult ADHD Rating Scale–Investigator Rated: Screening Version.10,11 Excellent response and symptomatic remission have been assessed as mean per-item score # 1 on the Swanson, Nolan, and Pelham Scale (from a composite of parent and teacher ratings), indicating a severity level below symptomatic ADHD12 or an ADHD-RS-IV total score of # 18.13 However, in a disorder such as ADHD, each of 18 individual symptoms can cause difficulty in daily life. As such, a patient can show improvements of 25% to 30% or meet arbitrary cutoff scores and still exhibit symptoms or display evidence of impairment. However, more rigid criteria for symptomatic remission (such as “no item score . 1” or “total score # 10”) may exclude individuals with excellent symptom control.14 Clinicians who treat patients with ADHD may need to look beyond ADHD symptom scales.15,16 Recent efforts have focused on developing patient-reported outcomes (PROs).17 According to Willke and colleagues,18 “There is growing appreciation beyond the health outcomes field per se that well-designed PRO measures may provide useful and important perspectives on the impact and value of treatments.” However, the lack of available validated PROs for functional impairment in ADHD limits the ability to quantify clinical response. Other outcome measures have been used as secondary end points in ADHD clinical trials. A few studies have assessed relationships among these measures and ADHD symptom control.14,19,20 Assessments of ADHD core symptoms and executive function showed a shared variance of approximately 20%.14 Another study demonstrated that an ADHD symptom scale and a quality-of-life measure generally showed low correlations, with only a few subdomains indicating moderate correlations.19 Clinical Global Impressions (CGI) rating scales measure illness severity and response to treatment according to the clinician’s judgment of the patient’s condition compared with normal individuals.21 A study that used post-hoc data from pharmacotherapy trials 32

using the ADHD-RS-IV and CGI-Severity (CGI-S) ratings in children and adults suggested that an 8- to 10-point difference on the ADHD-RS-IV was consistent with a 1-point difference on the CGI-S.20 Moreover, the CGI may emphasize the importance of measuring treatment success based not only on symptom control, but also on the impact of the disorder and its treatment on issues that are meaningful to the patient. Psychostimulants have been considered a mainstay of ADHD treatment for adults.22,23 However, randomized controlled psychostimulant trials have generally been short term (4–6 weeks) for currently used long-acting agents of this class.24–28 To our knowledge, there has been only 1 published long-term (24 weeks) controlled clinical trial in adults with ADHD.29 To add perspective to the available data, we examined data from a study that used an “enrichment strategy” recognized by the US Food and Drug Administration. In this double-blind withdrawal study, participants who had been receiving active treatment for a specified time are randomly assigned to continue on treatment until they no longer show response or to be switched to placebo until their symptoms return. The between-group difference reveals the persistence of treatment effects without need for the ethically questionable long-term use of placebo.30,31 In a randomized, double-blind, multicenter, placebocontrolled withdrawal study of the long-acting prodrug psychostimulant lisdexamfetamine dimesylate (LDX), relapse of clinical response in adults was defined as a $ 50% increase in ADHD-RS-IV with Adult Prompts total score and a $ 2-point increase in CGI-S rating versus baseline prior to withdrawal.32 Based on this definition of relapse, LDX discontinuation after $ 6 months of stable treatment was associated with symptom relapse in 75% of participants randomized to placebo and in 8.9% of participants who continued on LDX.32 The safety and tolerability profile of LDX in this study was generally consistent with previous LDX studies conducted in adults with ADHD28,33,34 and with other long-acting psychostimulant studies for ADHD.24,26,27 Here, we present post-hoc analyses of data from this randomized withdrawal study to examine the relationship of ADHD symptoms and global illness severity assessments to (1) the value of symptom scores in defining clinical response in ADHD management and (2) the persistence of treatment effects with continued LDX versus switch to placebo.

Materials and Methods Study Design

The methodology for this double-blind, multicenter, placebocontrolled randomized withdrawal study of the efficacy

© Postgraduate Medicine, Volume 126, Issue 5, September 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


ADHD Symptoms and Global Illness Severity

and safety of LDX (clinicaltrials.gov: NCT00877487) was previously reported in detail.32 Eligible adults with documented LDX treatment in a community setting who were on a stable LDX dose were enrolled for baseline assessments (week 0) and an open-label LDX treatment lead-in phase (weeks 0–3). During the open-label phase, participants were maintained on their stable LDX dose (30, 50, or 70 mg/d) for 3 weeks and assessed at weekly intervals. Participants were then randomized to 6 weeks of double-blind treatment with either placebo or the same LDX dose. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice in agreement with the International Conference on Harmonisation guidelines; the protocol was approved by each center’s institutional review board. After a complete explanation of the study and prior to conducting any study procedures, a voluntary, signed, written informed consent was obtained from each participant.

Participants

Key Inclusion Criteria Adults (aged 18–55 years) with ADHD who met DSM-IVTR criteria35 and had baseline ADHD-RS-IV with Adult Prompts8,36 total scores , 22 and CGI-S21 ratings of 1, 2, or 3 were enrolled. Participants were required to have received LDX (30, 50, or 70 mg/d) for $ 6 months, to have had an acceptable safety and tolerability profile, and to have a body mass index of . 18.5 kg/m2 and , 40 kg/m2.

Key Exclusion Criteria Participants were excluded if they had a current Axis I/II comorbid psychiatric disorder, as assessed by the Structured Clinical Interview for DSM-IV-TR disorders, that was uncontrolled with significant symptoms or controlled with a prohibited medication. Participants with a current risk/history of suicide attempts; history of seizures; a family history of sudden cardiac death or ventricular arrhythmias; history of symptomatic cardiovascular disease, stroke, or structural cardiac abnormalities; or moderate-severe hypertension were not eligible. Participants with a history (within the last 6 months) of suspected substance abuse or dependence disorder and participants with amphetamine hypersensitivity, allergy, or intolerance were also ineligible.

Efficacy Assessments

Efficacy was assessed using the ADHD-RS-IV with Adult Prompts and the CGI-S scale at open-label baseline (week 0) and randomized withdrawal phase baseline (week 3) and weekly during the open-label (weeks 1–3) and randomized

withdrawal (weeks 4–9) treatment phases. The ADHD-RS-IV with Adult Prompts consists of 18 items grouped into 2 subscales (inattention and hyperactivity/impulsivity), reflecting DSM-IV-TR ADHD symptom criteria, and is scored from 0 (no symptoms) to 3 (severe symptoms); total scores range from 0 to 54. The CGI-S is a clinician assessment of symptom severity in the context of their general clinical experience with the disorder; it uses a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill).

Efficacy Outcomes Efficacy Endpoints

The primary efficacy end point was the percentage of participants who met ADHD symptom relapse criteria during the randomized withdrawal phase. The ADHD-RS-IV with Adult Prompts total scores and CGI-S ratings at each week of both trial phases and at the end of study (last withdrawal phase week with a valid score) were prespecified secondary end points. The findings associated with these prespecified end points have previously been reported in detail.32

Post-Hoc Analyses For the current post-hoc analyses, ADHD-RS-IV with Adult Prompts total scores and CGI-S categories were examined for all participants (n = 116) entering the double-blind randomized withdrawal phase. Randomized withdrawal baseline values were those at week 3 for all participants in the fullanalysis set (FAS; all randomized participants who received $ 1 dose of LDX with $ 1 ADHD-RS-IV with Adult Prompts and CGI-S assessment during the randomized withdrawal phase); the FAS was the prespecified analysis set used in the assessment of efficacy end points in the primary publication from this study.32 End-of-study values (last post-baseline visit of the double-blind randomized withdrawal phase for which an assessment was available) were examined separately in participants randomized to placebo (n = 60) or LDX (n = 56); these values represented the final study assessment for all study completers at week 9 (placebo, n = 13; LDX, n = 50), from the early termination visit of those participants who lost clinical response (placebo, n = 45; LDX, n = 5), and for the final visit of any participants who discontinued but did not meet study criteria for termination (placebo, n = 2; LDX, n = 1). Additional post-hoc analysis examined CGI-S scores at baseline of the randomized withdrawal phase and at end of study with placebo and LDX by relapse status. A key component of the current post-hoc analysis was assessment of correlations between ADHD symptoms and disease severity



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at specific time points in a randomized withdrawal study. As such, the use of an intent-to-treat analysis set with last observation carried forward was not used because it could skew the end-of-study values.

(11.80) with placebo and 1.6 (8.63) with LDX (P , 0.0001 based on a t test). Mean (SD) CGI-S scores were 2.2 (0.78) with placebo, 2.1 (0.80) with LDX, and 2.1 (0.79) overall at randomization baseline.32

Data Presentation and Statistical Analysis

Post-Hoc Analyses

Histogram distributions of ADHD-RS-IV with Adult Prompts total scores for each CGI-S category were generated using 5-point spans on the symptom scale (arbitrarily chosen, for convenience). The histograms illustrate the percentage represented by each span of symptom scores (sum of 100%) for each CGI-S category. Box plots illustrating the mean, median, 25th, and 75th percentiles, 1.5 times the interquartile range, and actual symptom score values were also created. The histograms and box plots were generated for the FAS at baseline, and for LDX and placebo at the end of study. The distribution of CGI-S scores was assessed using Cochran-Mantel-Haenszel tests. A generalized linear regression analysis of variance model was used to explore the extent to which ADHD-RS-IV with Adult Prompts total scores (symptom scores) predicted CGI-S (severity of illness). The observed variance of the ADHD-RS-IV with Adult Prompts (dependent variable) can be explained with the CGI-S (explanatory variable), which is the covariate at baseline or end of study. Regressions were modeled separately for all participants at baseline and for all participants treated with either placebo or LDX at end of study.

Results Baseline Demographics, Participant Disposition, and Clinical Characteristics

Baseline demographics, participant disposition, and clinical characteristics were previously reported in detail.32 In summary, 6 of 122 participants in the open-label treatment phase discontinued. Of 116 participants entering the doubleblind randomized withdrawal phase, 60 were randomized to placebo; 56 continued their prior LDX dose (30 mg/d, n = 6; 50 mg/d, n = 23; 70 mg/d, n = 27). During the randomized withdrawal phase, 53 (45.7%) participants discontinued, of whom 50 (43.1%) met protocol-defined relapse criteria.

Efficacy

Prespecified Efficacy Analyses As previously reported,32 mean (standard deviation [SD]) ADHD-RS-IV with Adult Prompts total scores at baseline of randomized withdrawal phase were 10.6 (4.82) with placebo (n = 60), 10.6 (4.96) with LDX (n = 56), and 10.6 (4.87) overall; at end of study, changes from baseline were 16.8 34

The CGI-S score distributions were generally comparable in the placebo and LDX groups. For the placebo and LDX groups, 20.0% and 28.6% of participants, respectively, had a CGI-S = 1, 41.7% and 37.5% had a CGI-S = 2, 36.7% and 33.9% had a CGI-S = 3, and 1.7% and 0% had a CGI-S = 4; there were no participants with CGI-S = 5 to 7 (Figure 1). At end of study for placebo and LDX, 5.0% and 32.1% of participants had a CGI-S = 1, 11.7% and 35.7% had a CGI-S = 2, 11.7% and 17.9% had a CGI-S = 3, 33.3% and 7.1% had a CGI-S = 4, 35.0% and 7.1% had a CGI-S = 5, and 3.3% and 0% had a CGI-S = 6; there were no participants with CGI-S = 7 (P , 0.0001; Figure 1). In all study participants, the distribution of participants with specific CGI-S ratings as a function of ADHD-RS-IV total scores was similar at open-label baseline (Figure 2A) and randomization baseline (Figure 2B). For the histograms, rectangular widths represent class intervals, whereas their areas are proportional to the corresponding frequencies. Intervals are placed together to indicate that the data were exclusive and continuous; empty intervals are represented as empty and not skipped. Box plots illustrate mean (star within box), median (line through the center of box), 75th percentile (top line of box), 25th percentile (bottom line of box), 1.5 times the interquartile range (bars projecting up and down from the box), and actual symptom score values (small dots throughout the range of the box plot). The histogram data demonstrate that as CGI-S ratings increase (worsen), there is a corresponding worsening of ADHD symptom scores. At randomization baseline, mean CGI-S ratings ranged from 2.0 to 2.4 for participants who did or did not meet relapse criteria in the placebo and LDX groups (Table 1). At end of study, mean CGI-S ratings were approximately 2 points higher for participants who met relapse criteria compared with those who did not. At end of study, the distribution of participants with higher ADHD-RS-IV with Adult Prompts total scores with increasing CGI-S severity rating differed between placebo (Figure 3A) and LDX (Figure 3B), with scores being higher (worse) with placebo than with LDX. (The histograms in Figure 3 are displayed similarly to the histograms in Figure 2, as explained previously.) Overall, there was considerable overlap of symptom severity scores across CGI-S categories.




Figure 1. Proportion of participants categorized by CGI-S ratings at randomization baseline (week 3) and end of study.

Abbreviations: CGI-S, Clinical Global Impressions–Severity; LDX, lisdexamfetamine dimesylate.

This overlap was observable both with the baseline CGI-S and ADHD symptom scores and the end-of-study CGI-S and ADHD symptom scores. For each CGI-S rating category, at baseline and end of study, these box plots with individual data points illustrate the wide distribution of ADHD symptom scores within each CGI-S category. Post-hoc regression analyses of ADHD-RS-IV with Adult Prompts total score (dependent variable) and the CGI-S (independent variable) are summarized in Table 2. The covariance between these 2 variables was statistically significant (P , 0.0001 for each regression; the coefficient of variation of the estimate equal to zero was tested). The r2 values describe the proportion of total variability in ADHDRS-IV with Adult Prompts total scores that can be explained by the CGI-S. At baseline, 47% of the variability in ADHD symptoms could be explained by the CGI-S. At the end of the study, 69% of the variability in ADHD symptoms could be explained by the CGI-S in both treatment arms.

Discussion

This was the first study that used a randomized withdrawal design as a surrogate for long-term maintenance of LDX efficacy in adults with ADHD,32 with the primary findings indicating that participants who previously responded well to their medication exhibited a return in ADHD symptomatology after being switched from LDX to placebo. This effect was demonstrated by higher ADHD-RS-IV with Adult

Prompts total scores and higher CGI-S ratings compared with those participants who were maintained on LDX during the randomized withdrawal phase. Additionally, CGI-S ratings were approximately 2 points higher in participants meeting relapse criteria regardless of receiving placebo or LDX treatment. Their initial symptom scores and global illness severity ratings were consistent with previous adult ADHD data of clinical response to LDX treatment. For example, in a 12-month open-label study of long-term safety of LDX, mean (SD) ADHD-RS-IV with Adult Prompts total score for study completers was 13.0 (9.1).34 The post-hoc analyses described in this report demonstrate that ADHD symptom scores are generally aligned with CGI-S categories in adults with ADHD at baseline and end of study, and they are consistent with the positive linear relationship between ADHD symptoms and global illness ratings previously shown in a linkage analysis.20 Swanson and colleagues12 suggested that most patients with an ADHD-RS-IV total symptom score of # 18 (mean item score # 1) may be defined as symptomatic remitters (excellent responders), as they may exhibit global ratings of “not at all” or “just a little” symptomatic. The current histograms and box plots illustrate the ranges or variance in symptom scores for each severityof-illness category and show substantial but not complete overlap. The overlapping pattern of ADHD symptom scores across adjacent CGI-S ratings suggests that overreliance on symptom scores alone may erroneously characterize patients


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Figure 2. Distribution of ADHD-RS-IV with Adult Prompts total score for CGI-S ratings for both treatments combined. A) Open-label baseline (week 0). B) Randomization baseline (week 3).

Abbreviations: ADHD-RS-IV, ADHD Rating Scale–Version IV; CGI-S, Clinical Global Impressions–Severity.

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Table 1. CGI-S Ratings at Randomization Baseline and End of Study by Relapse Status

Randomization baseline, mean (SD) End of study, mean (SD)

Non-Relapse

Relapse

Placebo (n = 15)

LDX (n = 51)

Placebo (n = 45)

LDX (n = 5)

2.2 (0.68)

2.0 (0.79)

2.2 (0.81)

2.4 (0.89)

2.4 (1.06)

2.0 (0.89)

4.4 (0.81)

4.8 (0.45)


Abbreviations: CGI-S, Clinical Global Impressions–Severity; LDX, lisdexamfetamine dimesylate.

with residual functional deficits despite excellent symptom scores, or those with restored excellent function despite persistent borderline or elevated symptom scores. This would suggest that, in clinical practice, assessment of treatment response should not rely on ADHD symptom scores alone. The DSM-IV-TR requires not only demonstration of ADHD symptoms for the diagnosis of ADHD, but also significant impairments in relevant life activities; symptom scales do not address these latter aspects of ADHD. Post-hoc correlation analyses of the relationship of ADHD symptom assessment (ADHD-RS-IV) to global symptom severity assessment (CGI-S) at randomization baseline and end of study suggest that these outcomes may be dependent on each other. Our analyses also suggest that the level of agreement between these outcomes improves after treatment and that a clinically predictive relationship may exist between these assessments. This relationship is illustrated by the r2 values (0.47 at baseline for all participants; 0.69 for both placebo and LDX at end of study), which describe the proportion of total variability in ADHD symptom scores that can be explained by CGI-S ratings. These findings suggest that monitoring of ADHD treatment and evaluation of clinical response should include assessment not only of ADHD symptoms but also of functional or quality-of-life outcomes that reflect how ADHD impacts daily life activities. The CGI-S is a nonspecific surrogate for these other outcomes, as may be the Global Assessment of Functioning Scale.37 Treating physicians should assess not only the presence of ADHD symptoms but also the effect that ADHD has on their patients either through the use of a clinical measuring instrument or through a clinical interview. This may help guide appropriate pharmacologic and nonpharmacologic treatment. In a meta-analysis examining symptomatic versus functional changes reported in randomized double-blind treatment trials in children and adolescents with ADHD, functional outcomes reported on the Life Participation Scale for ADHD showed moderate correlation with symptomatic improvement

reported on the investigator-administered ADHD-RS-IV Parent Version.38 However, it was not possible to determine with certainty whether there is a point beyond which there is no further functional improvement despite continued symptomatic improvement, or whether a worsening in function is necessarily associated with a worsening in symptom severity.38 Thus, this meta-analysis of pediatric studies would seem to be consistent with our conclusion that functionality in adults shows some correlation with symptoms, but the fact that the correlation is not absolute suggests that other factors can also affect functional outcomes. It should be noted that the exclusion of participants with a history of poor medication adherence or unstable medical, psychiatric, or cardiovascular conditions from enrollment may limit drawing a conclusion about the general clinical population of adults with ADHD from these data. Also, the study population comprised mainly white young adults, potentially limiting the ability to generalize these results to other racial or ethnic groups or to older adults. The enrolled participants were mostly female, which may hinder broad generalization to males. Because only participants who were responders to long-term LDX treatment were enrolled, the incidence of treatment-emergent adverse events as well as other safety assessments was generally lower versus other LDX studies, whereas the extent of therapeutic response maintenance may have been heightened. The study was not powered to detect statistically significant differences among CGI-S rating categories. The CGI-S used in this study was an ADHD-specific global impression; however, in clinical practice, patients may present with a range of functional impairments or problems in life domains across differing aspects of their lives. Moreover, results from the post-hoc analyses were exploratory in nature; hence, findings may not be generalizable to clinical settings and need to be confirmed in a prospective randomized placebo-controlled study.

Conclusion

Although ADHD symptom scores demonstrate a linear relationship with global illness severity, variance levels suggest other factors not captured by symptom scales are important in assessing patient outcomes in clinical practice. Scale ranges or variance show substantial overlap, suggesting that careful symptom assessment and global severity may be relevant in clinical practice. This would suggest that, in clinical practice, assessment of ADHD symptom scores should be considered in relation to global illness severity. Clinicians should assess not only ADHD symptom severity, but also how the patient is responding; many useful options


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Figure 3. Distribution of ADHD-RS-IV with Adult Prompts total score for CGI-S ratings at end of study. A) Placebo group (n = 60). B) LDX group (n = 65).

Abbreviations: ADHD-RS-IV, ADHD Rating Scale–Version IV; CGI-S, Clinical Global Impressions–Severity; LDX, lisdexamfetamine dimesylate.

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Table 2. Regression Analysis: ADHD-RS-IV With Adult Prompts Versus CGI-S at Randomization Baseline and End of Study Treatment/Visit

Variables

Estimate

t Statistic

P Value

All participants at randomization baseline (week 3), n = 116

Intercept Coefficient r2 Intercept Coefficient r2 Intercept Coefficient r2

1.67 4.46 0.47 –5.23 8.32 0.69 –3.30 6.96 0.69

1.68 10.05 –1.75 11.42 –2.06 10.89

0.0947 , 0.0001 0.0858 , 0.0001 0.0442 , 0.0001

Placebo group at end of study, n = 60

LDX group at end of study, n = 56


Abbreviations: ADHD-RS-IV, ADHD Rating Scale–Version IV; CGI-S, Clinical Global Impressions–Severity; LDX, lisdexamfetamine dimesylate.

exist for such an assessment, including the CGI, the Global Assessment of Functioning Scale, patient self-ratings, or a clinical interview focused on functional outcomes. Gathering clinical information and ratings of patients from family and/or significant others about functioning in home and/or work settings could potentially inform CGI and other ratings, and result in improved clinical care. It may be that several clinical approaches to the management of ADHD would be advantageous to provide a comprehensive assessment that is also patient-specific.

Acknowledgments

The authors thank Lenard A. Adler, MD, for his valuable insights and for discussions of the data and manuscript. Clinical research was funded by Shire Development LLC, Wayne, PA. Under the direction of the authors, Huda Ismail Abdullah, PhD, a former employee of SCI Scientific Communications and Information (SCI), and Michael Pucci, PhD, an employee of SCI, provided writing assistance for this publication. Editorial assistance in the form of proofreading, copy editing, and fact checking was also provided by SCI. Editorial assistance in revising the manuscript as directed by the authors and formatting the manuscript for submission to Postgraduate Medicine was provided by Complete Healthcare Communications, Inc. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in Postgraduate Medicine were made by the authors independently.

Conflict of Interest Statement

Richard H. Weisler, MD, in his career has been a consultant to, on the speakers bureaus of, or received research support from the following: Abbott—speakers bureau, consultant, received research support; Alcobra—consultant, received

research support; Research Agency for Toxic Substances and Disease Registry—consultant; AstraZeneca—speakers bureau, consultant, received research support; Biovail— speakers bureau, consultant, received research support; Bristol-Myers Squibb—speakers bureau, consultant, received research support, stockholder (has held or holds stock); Burroughs Wellcome—speakers bureau, received research support; CeNerX—consultant, received research support; Centers for Disease Control and Prevention—consultant; Cephalon—speakers bureau, consultant, received research support; Ciba-Geigy—speakers 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—speakers bureau, consultant, received research support; Forest—speakers bureau, consultant, received research support; GlaxoSmithKline—speakers bureau, consultant, received research support; Janssen— speakers bureau, received research support; Johnson & Johnson—speakers 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, speakers bureau, 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—speakers bureau, received research support; Organon—speakers bureau, consultant, received research support; Otsuka America Pharma—consultant; Pfizer—speakers bureau, consultant, received research support, stockholder (has held or holds stock); Pharmacia—consultant, received research support; ProPhase—consultant; Repligen—received research support; Saegis—received research support; Sandoz—received



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research support; Sanofi—speakers bureau, consultant, received research support; Sanofi-Synthelabo—speakers bureau, consultant, received research support; Schwabe/ Ingenix—received research support; Sepracor—received research support; Shire—speakers bureau, consultant, received research support; Solvay—speakers bureau, consultant; Sunovion—speakers 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, speakers bureau; TransTech—consultant; UCB Pharma—received research support; Validus—speakers bureau, consultant; Vela—received research support; and Wyeth—speakers bureau, consultant, received research support. Thomas Babcock, DO, and Ben Adeyi, MS, are employees of Shire and hold stock and/or stock options in Shire. Matthew Brams, MD, serves as a speaker for Cephalon, Eli Lilly, McNeil, Novartis, Pfizer, and Shire and has served as a speaker for Wyeth.

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