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Simulated Driving Changes in Young Adults with ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine

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Title: Simulated Driving Changes in Young Adults with ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine
Language: English
Authors: Kay, Gary G., Michaels, M. Alex, Pakull, Barton
Source: Journal of Attention Disorders. 2009 12(4):316-329.
Availability: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: http://sagepub.com
Peer Reviewed: Y
Page Count: 14
Publication Date: 2009
Document Type: Journal Articles
Reports - Evaluative
Descriptors: Hyperactivity, Attention Deficit Disorders, Rating Scales, Young Adults, Drug Therapy, Simulation, Traffic Safety, Motor Vehicles, Statistical Analysis
Geographic Terms: District of Columbia, Maryland
DOI: 10.1177/1087054708322986
ISSN: 1087-0547
Abstract: Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts--extended release (MAS XR) 50 mg/day (Cohort 1) and atomoxetine 80 mg/day (Cohort 2) in young adults with ADHD. Results: Adults aged 19 to 25 years with AD/HD (N = 19) who were administered MAS XR significantly improved overall simulated driving performance versus placebo up to 12 hours after dosing. In contrast, there were no statistically significant differences in simulated-driving-performance scores between atomoxetine and placebo. At endpoint, MAS XR reduced ADHD Rating Scale scores [greater than or equal to] 30% in 80% of subjects, whereas atomoxetine achieved this level of improvement for 40%. Limitations: Small sample size and use of simulated driving may limit generalizability of the findings. Conclusion: MAS XR in young adults with ADHD yields significant improvements in simulated driving performance and ADHD symptoms. (Contains 3 tables and 5 figures.)
Abstractor: As Provided
Number of References: 44
Entry Date: 2009
Accession Number: EJ822489
Database: ERIC
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  Value: <anid>AN0053098537;gs001jan.09;2010Aug27.23:27;v2.2.460</anid> <title id="AN0053098537-1">Simulated Driving Changes in Young Adults With ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine </title> <p>316 Simulated Driving Changes in Young Adults With ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine SAGE Publications, Inc.200910.1177/1087054708322986 Gary G.Kay Cognitive Research Corporation, gkay@cogres.com M. AlexMichaels Astellas Pharma U.S., Inc BartonPakull Washington Neuropsychological Institute Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts—extended release (MAS XR) 50 mg/day (Cohort 1) and atomoxetine 80 mg/day (Cohort 2) in young adults with ADHD. Results: Adults aged 19 to 25 years with AD/HD (N = 19) who were administered MAS XR significantly improved overall simulated driving performance versus placebo up to 12 hours after dosing. In contrast, there were no statistically significant differences in simulated-driving-performance scores between atomoxetine and placebo. At endpoint, MAS XR reduced ADHD Rating Scale scores ≥ 30% in 80% of subjects, whereas atomoxetine achieved this level of improvement for 40%. Limitations: Small sample size and use of simulated driving may limit generalizability of the findings. Conclusion: MAS XR in young adults with ADHD yields significant improvements in simulated driving performance and ADHD symptoms. (J. of Att. Dis. 2009; 12(<reflink idref="bib4" id="ref1">4</reflink>) 316-329) simulated driving performance attention-deficit/hyperactivity disorder adults psychostimulant AD/HD ADHD Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral condition marked by clini- cally significant inattention and impulsivity (American Academy of Pediatrics, 2000) that for many patients per- sists into adolescence and adulthood (Dulcan, 1997; Faraone et al., 2006; Rowland, Lesesne, & Abramowitz, 2002). Current estimates place the prevalence of adult ADHD at approximately 4.4% in the United States (Faraone & Biederman, 2005; Kessler et al., 2006), meaning that 6 to 10 million adults in the United States may meet the diagnostic criteria for ADHD (United States Census Bureau, 2003). The trajectory of ADHD suggests the need for long-term treatment that extends into the adult years (Greenhill, Pliszka, & Dulcan, 2002). Under current guidelines, treatment with psychostimu- lants (e.g., methylphenidate or mixed amphetamine salts [MAS]) is the recommended first-line pharmacologic treatment, with the nonstimulant atomoxetine considered first line for patients with an active substance abuse problem, comorbid anxiety, tics, or severe side effects with stimulants (Pliszka et al., 2007). A number of investigations have described ADHD- related functional and social impairments in adult patients (Barkley, 2002; Biederman, Faraone, Monuteaux, Bober, & Cadogen, 2004; Murphy & Barkley, 1996). These include social and attentional impairments similar to those seen in their pediatric coun- terparts as well as poorer outcomes related specifically to adult activities, such as professional or economic attain- ments, sexual relationships (Barkley, 2002), and driving Authors' Note: Funding provided by Shire Pharmaceuticals Inc. sup- ported the investigation and preparation of this article. The authors wish to thank Craig Ornstein, PhD, for his assistance in the preparation of this article. These data were presented in part at the 158th Annual Meeting of the American Psychiatric Association in Atlanta, GA, on May 24, 2005. Address correspondence to Gary G. Kay, Cognitive Research Corporation, 200 Central Avenue, Suite 1230, St. Petersburg, FL 33701; e-mail: gkay@cogres.com. 317 safety records (Fischer, Barkley, Smallish, & Fletcher, 2007; Fried et al., 2006). Young adults with ADHD receive twice the number of traffic violations, particularly for speeding, and have more license suspensions or revocations than young adults of the same age and education level withoutADHD (Barkley, 2002). Furthermore, adults with ADHD were judged more likely to be involved in automobile collisions for which they were culpable and which resulted in bodily injuries than adults without ADHD (Barkley, Guevremont, Anastopoulos, DuPaul, & Shelton, 1993). The poor dri- ving records seen in adults with ADHD may be at least partially attributed to ADHD symptoms such as attention impairment, distractibility, response inhibition, and slower and more variable reaction time (Barkley, 2004). These data underscore recent research suggesting that ADHD may be due to an impairment of executive function, a self- regulatory system controlled by the lateral prefrontal regions of the brain (Barkley, Murphy, & Fischer, 2007; Owen et al., 1998; Pliszka et al., 2007) that enable flexi- bility and mediate goal-directed behaviors (Castellanos, Sonuga-Barke, Milham, & Tannock, 2006). The great demand on executive function required for driving may also contribute to the increased violations and collisions in subjects with ADHD (T. E. Brown, 2005). Driving performance in test subjects has been objec- tively evaluated during on-the-road observation and in dri- ving simulators, which are commonly employed as a safe and effective method for evaluating driving performance and the effects of medications on driving. Current driving simulators are capable of characterizing numerous driving components, including operational habits (e.g., turn signal use, obeying traffic signals and signs), skills for maneu- vering in traffic, responses to imminent crash situations, risk taking, and resistance to distractions. They provide a wider range of scenarios in a safer setting than can be achieved during over-the-road evaluation. They also allow for standardization of driving scenarios that incorporate relevant driving challenges. A number of studies have used driving simulators to assess changes in driving per- formance with psychostimulants (Barkley, Murphy, & Kwasnik, 1996; Cox et al., 2006; Cox, Humphrey, Merkel, Penberthy, & Kovatchev, 2004; Cox, Merkel, Kovatchev, & Seward, 2000; Cox, Merkel, Penberthy, Kovatchev, & Hankin, 2004) or nonstimulants (Barkley, Anderson, & Kruesi, 2007) used in ADHD treatment. Data obtained from an on-the-road study with individ- uals with ADHD showed that open-label, extended- release methylphenidate, compared with placebo, reduced the number of inattentive-type errors among adults with ADHD (Cox, Humphrey, et al., 2004). Studies using dri- ving simulators have demonstrated significant improvements in simulated driving performance with short-acting (Cox et al., 2000) and long-acting (Cox, Merkel, et al., 2004) stimulant medications. Moreover, these investigations show that simulated driving improvements appear to be sensitive to stimulant dose and pharmacokinetics, with the most robust improvements seen at higher stimulant doses (Barkley, Murphy, O'Connell, & Connor, 2005) and at times of peak (Cox, Merkel, et al., 2004) or waning (Cox et al., 2006) serum drug concentrations. Recent results from a virtual reality driving simulator study showed that driving scores worsened after prolonged use in subjects receiving immediate-release methylphenidate but remained stable in those receiving long-acting methylphenidate. Mixed results were observed because of apparent practice effects and short-duration scenarios (Cox, Merkel, et al., 2004). The improvements seen in simulated driving performance with stimulants may also be due to improvements in executive function observed with these medications (Kempton et al., 1999). Treatment with a nonstimulant (atomoxetine) was shown by Barkley and colleagues (2007) to have mixed effects on (virtual reality) simulated driving performance in adults with ADHD. The current investigation is a pilot study (i.e., con- ducted without sufficient data to perform a formal power analysis). The purpose of the study is to assess the effect of an extended-release formulation of MAS, MAS XR (Cohort 1), and atomoxetine (Cohort 2) on simulated dri- ving performance in young adults with ADHD. The pri- mary efficacy outcome is the overall assessment of driving safety and performance, based on seven com- puter-generated scores from the STISIM™ driving simu- lator and one objective behavioral rating of the subjects' responses to crash-likely events. Method This Phase 3b pilot study was conducted in accor- dance with the Declaration of Helsinki (2000), the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice, and applicable local regulations. Before study participation, subjects received written information explaining the study pur- pose and procedures and were required to sign an informed consent form, reviewed and approved by the Institutional Review Board (IRB). Subjects were reim- bursed for travel costs and were compensated for study participation with $100 toward ADHD treatment expenses. Subjects also were informed at the beginning of the test day that they would be rewarded with a $50 gift card at the end of testing for good performance on 318 the driving simulator; all subjects received the gift card irrespective of their driving performance. Study Design and Procedures This was a 6-week, randomized, single-center, crossover study with two double-blind, placebo-controlled cohorts (Cohort 1: MAS XR and placebo; Cohort 2: atom- oxetine and placebo; see Figures 1a and 1b). There were four study visits, which included screening (Visit 1), base- line/simulator familiarization (Visit 2), and Testing Days 1 and 2 (Visits 3 and 4). The initial screening visit was fol- lowed by a washout and clinical stabilization period of 7 to 35 days to eliminate presence of any restricted medications and to manage clinical issues related to the washout. Prior medications for ADHD, as well as agents with central ner- vous system effects that could influence assessments dur- ing baseline and active treatment, were also washed out. Following the washout period, assessments were con- ducted at the baseline/simulator familiarization visit, and subjects were provided with a standardized orientation and introduction to the STISIM™ driving simulator at Visit 2. At that visit, subjects were then randomized to receive either study drug or placebo for 3 weeks. On Testing Day 1 (Visit 3), subjects were examined on all of the outcome measures and were then immediately switched over to the other arm of the assigned cohort for 3 weeks (no washout period occurred). After 3 weeks of dosing on the second study drug, they returned to the study site for Testing Day 2 (Visit 4), during which they were reexamined on the entire set of outcome measures. A follow-up telephone call was conducted 30 days after the last dose of study drug to inquire about any new-onset, serious adverse events and to follow up ongoing adverse events related to study drug exposure. Study Population Subjects were referred for study participation by treat- ing clinicians in the local study area (Washington, DC and suburban Maryland). They were also recruited from responses to newspaper advertisements and flyers and through local college and university resource centers for special education and learning disabled students in the area. Eligible subjects were men or women, aged 19 to 25 years, who satisfied Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition, Text Revision (DSM-IV-TR; American Psychiatric Association, 2000) criteria for a primary diagnosis of ADHD, any subtype, confirmed by a psychiatric evaluation and the Structured Clinical Interview for DSM-IV, conducted by a qualified clinician. Women of childbearing potential Figure 1a Study Design Flow Chart—Cohort 1 Figure 1b Study Design Flow Chart—Cohort 2 were included only if they had a negative serum beta human chorionic gonadotropin pregnancy test and abstained from sexual activity that could result in preg- nancy or used acceptable contraceptives from time of informed consent throughout the study duration. Additional inclusion criteria included a valid driver's license and ≥ 3 years of driving experience, abstinence from illegal drug use during the study, and willingness and ability to comply with all study requirements defined in the protocol. A score ≥ 24 (severity worse than mild to moderate range) on the ADHD Rating Scale (ADHD-RS; DuPaul, Power, Anastopoulos, & Reid, 1998; Wilens & Dodson, 2004)—with adult prompts based on the ADHD-RS- Version IV—was required. The ADHD-RS was com- pleted by the clinician with the subject as the informant. Normal intellectual functioning was confirmed by a score ≥ 89 on the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). To evaluate the impact of treatment on executive function, subjects were eligible for inclusion in the study if they demonstrated no greater than average performance on at least one of two stan- dardized measures of executive function: a score ≤ 50th percentile on either the Stroop Color and Word Test (interference trial; Golden & Freshwater, 2002) or the 319 Halstead–Reitan Category Test (total errors; Reitan & Wolfson, 1993). Women who were pregnant or lactating were excluded from study participation. Additional exclusion criteria included a recent history (past 6 months) of drug depen- dence or substance abuse (excluding nicotine); a positive urine drug screen; alcohol use 24 hours before any test day; any cardiac condition that, in the opinion of the investigator, would require exclusion; a current comor- bid psychiatric diagnosis (controlled or uncontrolled) with significant symptoms that, in the opinion of the investigator, would confound efficacy or safety assess- ments; documented allergic or adverse reactions to MAS XR or atomoxetine; documented history of failure to respond clinically to amphetamines or atomoxetine; history of at least one seizure within the past 2 years, a tic disorder, or family history of Tourette's syndrome; inadequately treated thyroid dysfunction; history of glaucoma; any concurrent chronic or acute illness (including severe allergic rhinitis or severe cold) that might interfere with assessments; and use of any med- ication that is contraindicated with MAS XR or atomox- etine or that might have confounded results of the safety assessment. In addition, subjects who were naïve to pharmacologic treatment for ADHD were excluded from study participation. Study Drugs and Dosing Each subject was enrolled in one of two double-blind, placebo-controlled cohorts—either Cohort 1 (MAS XR versus placebo) or Cohort 2 (atomoxetine versus placebo). To avoid potential bias, on completion of enrollment in Cohort 1, subjects were then recruited for participation in Cohort 2. Subjects in each cohort were randomized to begin with either study drug or placebo using sequentially allocated four-digit randomization numbers. During each 3-week treatment period, subjects ran- domized to receive MAS XR were given 20 mg for the first week, 40 mg for the second week, and 50 mg for the third week in a forced–dose-titration schedule. In contrast to previous studies in which MAS XR 60 mg was used (Goodman, Ginsberg, Weisler, Cutler, & Hodgkins, 2005) 50 mg was selected as the maximum MAS XR dose in this study to achieve approximate dose equivalency with atom- oxetine. Atomoxetine treatment began with an initial dose of 40 mg for 1 week, followed by 80 mg for weeks 2 and 3. Atomoxetine dosing was based on product labeling instruc- tions (Eli Lilly and Company, 2006) and is consistent with the dosing employed in the study by Barkley and colleagues (2007). Study drugs (e.g., MAS XR and atomoxetine) and identical matching placebos were administered orally, once daily, in capsule form. Subjects were instructed to take the study medication after eating a light breakfast at approxi- mately 7:30 a.m. (except for study visits) and were also instructed to bring all unused study drug with them to each clinic visit. Study drug was administered in the clinic on testing days. Compliance was based on counts of unused capsules; subjects who took ≥ 80% of study drug were con- sidered compliant. Prohibited Medications Subjects were prohibited from taking any medications (including over-the-counter products) that have central nervous system effects, could affect performance, or could interfere with assessments. Antibiotics and over- the-counter medications that do not affect blood pres- sure, heart rate, or the central nervous system, and that were necessary for the subject's welfare, were permitted. Washout period for other medications was a minimum of five half-lives and no fewer than 7 days prior to the base- line familiarization visit for stimulant medication and up to 28 days for selective serotonin reuptake inhibitors. Use of any other investigational drug within the past 30 days was prohibited. Simulated Driving Performance (STISIM™) The driving simulator used in this study is a commer- cially available PC-based system (STISIM™ Model 100W [Three-Screen]) that includes a steering wheel and pedal. Subjects are placed in various driving scenarios using realistic graphics projected on three large (25-in diagonal) video monitors to provide a 160° visual field (see Figure 2). To reduce practice effects, three parallel 20-minute ver- sions of the three driving scenarios of comparable diffi- culty (A, B, C) were used on each of the testing days to minimize predictability and practice effects. The three different versions of the scenarios contained the same number of obstacles, but they varied in the timing and location of events. By including three 20-minute driving scenarios, a 1-hour sample of driving behavior was provided. The scenarios were developed specifically for this study and were designed to replicate the known dri- ving challenges faced by young adult ADHD patients under a variety of driving conditions. The three scenarios were (a) a boring, monotonous scenario with two-lane dri- ving with minimal stimulation and an embedded sec- ondary vigilance task (Vigilance); (b) a high-workload scenario with an embedded secondary psychomotor task (Urban); and (c) a frustrating scenario with heavy traffic and stop lights with a time challenge designed to create a 320 Figure 2 STISIM Model 100W Driving Simulator risk-taking environment (Challenge). The scenarios con- sisted of realistic visual and auditory displays of highway and city driving as well as changes in traffic and terrain. There were four simulators used simultaneously, and they were all located at the investigator's site. The driving sim- ulators were identical with respect to hardware and soft- ware. Data equivalence was established for the four driving simulators prior to conducting subject testing. The driving simulator digitally captured the following driving parameters: total citations (e.g., traffic tickets) and collisions (collisions with pedestrians + collisions with other vehicles + nonvehicle collisions), time to collision (TTC, a complex variable that provides a measure of awareness and avoidance of potential crash situations), dri- ving out-of-lane incidents, percentage of time spent above excessive speed threshold, number of times overcornering (i.e., excessive speed in corners), and number of times tail- gating. Note that for the TTC measure, higher scores are preferred, indicating an earlier awareness and response to potential crashes. To provide consistent directionality of data, the TTC results were reversed. In addition, a trained observer completed a crash-likely event rating for each test session. A crash-likely event is a situation in which a colli- sion will occur if the driver fails to respond, is delayed in responding, or makes an inappropriate response. There were five crash-likely events during each session (one dur- ing the Vigilance and Urban scenarios; and two during the Challenge scenario). To qualify as an observer, trained individuals were required to achieve a ≥ 90% level of inter- observer agreement on 20 blinded, crash-likely events. Observers recorded reactions to all driving challenges, including the type and time of the challenge, and how the subject handled each challenge, rating subject response on a 5-point scale (Table 1) for each of the five crash-likely sit- uations that occurred during each session. Efficacy Assessments Primary Efficacy Assessment At the baseline/simulator familiarization visit (Visit 2), subjects were introduced to the STISIM driving simula- tor and practiced each of the three scenario types. On each of the testing days (Visits 3 and 4), subjects com- pleted a 10-minute, unscored practice session before the first test session of each day to become refamiliarized with the system and controls. On test days, the 1-hour test sessions were conducted at 2 hours, 7 hours, and 12 hours after the administration of study drug. The primary efficacy variable was the simulated dri- ving safety and performance of young adults with ADHD as measured by the overall Driving Safety Score (DSS). Seven simulator-derived variables contribute to the DSS: total citations (e.g., traffic tickets), total colli- sions, time to collision, driving out-of-lane incidents, percentage of time above excessive speed threshold, number of times overcornering, and number of times tailgating. The eighth DSS variable is the rating of the driver's response to crash-likely events. Before being entered into the DSS calculation, these eight variables were first standardized, using population-based z scores. In addition, the sign was reversed for the TTC variable. Lower numerical DSS scores indicate better driving per- formance. The mean of the eight z-scores for the three test sessions completed at Visits 3 and 4 is the DSS score. Secondary Efficacy Assessments Secondary efficacy assessments included the eight standardized driving safety and performance scores as well as the DSS scores obtained at test sessions conducted 2 hours, 7 hours, and 12 hours post dose. ADHD symptom severity was assessed using the ADHD-RS with adult prompts and the CGI scale. The adult ADHD-RS is an 18- item assessment tool designed to evaluate current symp- toms of ADHD in adults and reflects the respondent's experience of symptoms during the previous 7 days (Conners, Erhardt, & Sparrow, 1999). The ADHD-RS was completed by the investigator at the screening (Visit 1), the familiarization/practice (Visit 2), and Test Days 1 and 2 (Visits 3 and 4). The CGI scale provides a clinician's assessment of baseline condition severity (CGI–Severity [CGI-S]) and change or improvement in the subject's con- dition over time (CGI–Improvement [CGI-I]) based on a 7-point scale (Guy, 1976). The CGI-S was assessed at the baseline/simulator familiarization visit (Visit 2), and the CGI-I was subsequently assessed by the same clinician on the two testing days (Visits 3 and 4). 321 Table 1 Crash-Likely Event Response Ratings Source: Cognitive Research Corporation (2007). Permission received to reprint scale. Following each 1-hour driving simulation session on Test Days 1 and 2 (Visits 3 and 4), subjects were asked two questions regarding their performance on the driving simulator to provide insight into whether an adult with ADHD recognizes his or her own driving impairment. Question 1 was “How well do you think you drove for the last 60 minutes?” Question 2 was “How motivated did you feel to drive at your best during your last 60 min- utes of driving?” Answers to Question 1 were dichotomized into satisfactory and not satisfactory. Answers to Question 2 were dichotomized into moti- vated and not motivated. Safety Assessments Safety and tolerability were assessed based on sponta- neously reported and elicited adverse events and reasons for early discontinuation. At each study visit and during a follow-up phone interview 30 days after completion, subjects could volunteer information about adverse events and were asked nonleading questions to inquire about adverse events. Vital sign measurements were obtained at all four study visits. At Visits 3 and 4, vital signs were obtained after the subject was seated for 4 to 5 minutes and prior to dosing. A full physical examina- tion conducted by a licensed physician and clinical labo- ratory assessments were made during screening (Visit 1) and Test Day 2 (Visit 4). A 12-lead electrocardiogram and pregnancy test (for females) were conducted at screening (Visit 1), baseline/simulator familiarization (Visit 2), and Test Day 2 (Visit 4), and a urine drug screen was conducted at Visit 1 and Visit 2. All safety measures were monitored for any clinically significant abnormalities or changes. Statistical Analyses For analysis of drug treatment effects, data were derived from subjects in the intent-to-treat (ITT) popula- tion, defined as all subjects who were randomized to treatment, who received at least one dose of study drug, and who completed at least one test session. The primary efficacy outcome was the simulated driving safety and performance of young adults with ADHD, as measured by the mean overall DSS for the entire test day (the mean of the three test sessions). Secondary outcomes included DSS scores obtained at 2 hours, 7 hours, and 12 hours post dose, in addition to ADHD-RS and CGI-I scores. Standardized scores (i.e., a cohort-based z score) were calculated for the eight driving safety and performance variables. Treatment effects on the primary and sec- ondary efficacy variables were assessed by analysis of variance models using a two-sided alpha level set at 5%. Models included effects for subject within sequence, period, treatment sequence, and drug. Continuous vari- ables were summarized by descriptive statistics. Categorical data were described in terms of number of responses and percentages for each category. The CGI-I ratings were described for the standard response cate- gories and also dichotomized as improved (very much improved/much improved) and not improved (all other categories). With regard to ADHD-RS scores, subjects were categorized as improved if ADHD-RS scores decreased from baseline ≥ 30% and not improved if scores decreased from baseline < 30%. For analysis of safety and tolerability, relevant data were derived from the entire enrolled population. All statistical analyses were performed using SAS for Windows, Version 6.12 or higher (SAS Institute, 1997). 322 Table 2 Subject Demographics and Baseline Characteristics of All Randomized Subjects Results Subjects Demographic and baseline characteristics of all subjects enrolled in the 6-week study are presented in Table 2. The most common medications used by subjects in both cohorts to treat ADHD during the 12 months before study participation were MAS (Cohort 1: 6 subjects, or 31.6%; Cohort 2: 5 subjects, or 31.3%); and methylphenidate hydrochloride (Cohort 1: 6 subjects, or 31.6%; Cohort 2: 4 subjects, or 25.0%). Other medica- tions used during this time period were MAS XR, dex- troamfetamine, and dextroamfetamine sulfate. In Cohort 1 (n = 19), 9 subjects were randomized to receive MAS XR first, and 10 were assigned to receive placebo first; 15 subjects were included in the ITT popula- tion. In the MAS XR/placebo sequence, 1 subject discon- tinued prematurely because of an adverse event while receiving MAS XR. In the placebo/MAS XR sequence, 1 subject withdrew from the study because of an adverse event while receiving placebo, and 2 subjects were with- drawn from analysis because of protocol violations while receiving placebo (see Figure 3); all of these subjects failed to complete at least one test session. In Cohort 2 (n = 16), 8 subjects were assigned to receive atomoxetine first, and 8 were assigned to receive placebo first; 16 subjects were included in the ITT population. In the placebo/atomoxetine sequence, 1 subject withdrew from the study because of an adverse event while receiving atomoxetine, and 1 was withdrawn because of a protocol violation while receiving atomoxetine; however, all subjects were included in the analysis, because they all completed at least one test session. No subjects from the atomoxetine/placebo sequence were withdrawn from the study (see Figure 3). Treatment Compliance Treatment compliance was similar between cohorts. The mean treatment compliance in Cohort 1 was 97.9% among subjects receiving MAS XR and 96.1% among those receiving placebo. Most subjects in Cohort 1 had treatment compliance rates ranging between 80% and 100%, with 16 (84.2%) subjects receiving MAS XR and 17 (89.5%) receiving placebo who were compliant in that range. There were no obvious signs of MAS XR diversion during the study; however, 1 subject tampered with the drug and unblinded himself (which was recorded as a protocol deviation) and the subject was withdrawn from the study. The mean treatment compli- ance in Cohort 2 was 97.0% among subjects receiving atomoxetine and 97.3% among those receiving placebo. Similar to Cohort 1, most subjects in Cohort 2 had treatment compliance rates ranging between 80% and 100%, with 15 (93.8%) subjects receiving atomoxetine and 16 (100%) subjects receiving placebo who were compliant in that range. One subject in Cohort 2 had five unexplained miss- ing pills (which was recorded as a protocol deviation). Driving Simulator Safety and Performance Scores Mean overall and individual time point DSS scores for MAS XR and placebo in Cohort 1 are shown in Figure 4a, with negative scores indicating improvement in sim- ulated driving performance. The mean score across all time points examined (the primary endpoint of the study) was significantly lower with MAS XR compared with placebo (p = .014). Analysis of secondary endpoints revealed that significant improvements in overall simulated driving performance with MAS XR were evident at 7 hours (p = .013) and 12 hours (p = .005) post dose com- pared with placebo; results approached significance at 2 hours (p = .052). In contrast, in Cohort 2, mean overall (p = .293) DSS scores at 2 hours, 7 hours, and 12 hours post dose for atomoxetine did not differ significantly from placebo (see Figure 4b). For Cohort 1, statistically significant improvements with MAS XR versus placebo in simulated driving perfor- mance were evident at 2 hours post dose (the first time point measured) on number of times driving out-of-lane and number of times tailgating; at 7 hours post dose, on number of citations, number of times driving out-of-lane, number of times overcornering, and time to collision; and at 12 hours post dose (the last time point measured), on number of collisions, number of times driving out-of-lane, 323 Figure 3 Disposition of Subjects number of times tailgating, time to collision, and the crash-likely event rating (see Figure 5a). None of the Cohort 2 comparisons for atomoxetine versus placebo were statistically significant (see Figure 5b). Regardless of whether they were receiving active treat- ment or placebo, however, the majority of subjects in both cohorts rated themselves as being both motivated and per- forming satisfactorily on the driving simulator. The only statistically significant treatment difference was observed in Cohort 1 for Question 1 at 7 hours post dose, in which more subjects who were receiving MAS XR described them- selves as having performed satisfactorily (93.3%) compared with subjects receiving placebo (42.9%; p = .002). ADHD-RS and CGI-I Scores In Cohort 1, significantly more subjects showed ADHD-RS score improvement from baseline (≥ 30% decrease from baseline ADHD-RS total scores) with MAS XR (80.0%) compared with placebo (13.3%, p = .0004); similarly, more subjects were rated as very much improved/much improved on the CGI-I with MAS XR (66.7%) compared with placebo (0.0%, p = NE). In con- trast, there was no significant difference between treat- ment groups in the number of subjects who showed improvement from baseline in Cohort 2 on the ADHD- RS (atomoxetine 40.0%; placebo 25.0% [p = .408]) or CGI-I (atomoxetine 13.3%; placebo 6.3% [p = .533]). Safety and Tolerability Treatment-emergent adverse events reported by ≥ 1 subject and considered possibly or probably related to active treatment are summarized in Table 3. Most adverse events reported in this study were mild or moderate in intensity; no serious adverse events were reported in either cohort. In Cohort 1, the overall incidence of treatment-emergent adverse events (TEAE's) considered to be related to the study drug was higher in subjects receiving MAS XR (75%) compared with subjects receiving placebo (16.7%). The most commonly reported TEAE's consid- ered possibly or probably related to study drug in subjects receiving MAS XR were anorexia (50.0%), weight decreases (25.0%), and dry mouth, insomnia, and bruxism (18.8% each). Adverse events leading to study termination in Cohort 1 included flu-like symptoms in 1 male subject who received placebo and agitation, anxi- ety, and insomnia in 1 male subject receiving MAS XR (judged probably related to MAS XR). In Cohort 2, the overall incidence of TEAE's was also higher in subjects receiving atomoxetine (68.8%) compared with subjects receiving placebo (56.3%). The most commonly reported TEAE's considered possibly or probably related to study drug in subjects receiving atomoxetine were nausea, upper abdominal pain (18.8% each), dry mouth, thirst, anorexia, headache, and somnolence (12.5% 324 Figure 4a Mean Driving Safety Scores for the ITT Population in Cohort 1 (N = 29) Figure 4b Mean Driving Safety Scores for the ITT Population in Cohort 2 (N = 30) Figure 5a Overall Summary of Driving Safety Component Scores for the ITT Sample in Cohort 1 each). Adverse events leading to study termination in Cohort 2 included insomnia, anger, and irritability in 1 male subject receiving the placebo. No clinically mean- ingful changes were observed on physical examination results, vital signs, or electrocardiographic data in either cohort. Discussion In a sample of young adults with ADHD, treatment with MAS XR, but not atomoxetine, yielded statistically signif- icant improvements in simulated driving performance compared to the same subjects who were given placebo up 325 Figure 5b Overall Summary of Driving Safety Component Scores for the ITT Sample in Cohort 2 to 12 hours post dose. The time course of improvements on most of the component scores comprising the overall DSS coincides with the known time course of therapeutic effi- cacy with MAS XR and is consistent with the beneficial effects on simulated and on-the-road driving performance seen in previous studies with other stimulant medications (Barkley et al., 2005; Cox et al., 2000; Cox, Humphrey, et al., 2004; Cox, Merkel, et al., 2004). Following 3 weeks of treatment with MAS XR at a final dose of 50 mg/day, there was significant improve- ment compared with placebo on a number of measures of driving safety and performance, including total number of collisions, driving out-of-lane incidents, tailgating incidents, time to collision, and ratings of response to crash-likely events. These changes are similar in nature to those described by Cox and colleagues in adolescents with ADHD who were treated with long-acting formula- tions of methylphenidate (Cox et al., 2006; Cox, Humphrey, et al., 2004; Cox, Merkel, et al., 2004). Improvements in simulated driving performance in these studies were marked by decreases in the incidence of inattentive-type errors, such as failing to see or react to a traffic signal or sign, and braking. In one of the prior driving simulation studies conducted in patients with ADHD, the investigators compared long- acting methylphenidate (72 mg/day) with MAS XR (30 mg/day) and placebo using a crossover design (Cox et al., 2006) In that study, the overall simulated driving perfor- mance with MAS XR was not significantly different from that seen with placebo. In contrast, at the higher dose of MAS XR given in the present study (50 mg/day), robust improvements in simulated driving performance were seen at all time points examined, including 12 hours post dose. In a similar investigation with controlled-release methylphenidate (Cox, Humphrey, et al., 2004), the investigators observed improvements in the same driving parameters in over-the-road driving test conditions. This finding supports the view that simulated driving assess- ments provide a valid prediction of real-world driving habits and that the improvements seen in simulated dri- ving performance following treatment with psychostim- ulant medication are likely to translate into improved over-the-road driving performance in patients with ADHD receiving psychostimulant medication. In the present study, the improvement observed on measures of driving safety and performance coincided with clinical improvement in ADHD symptoms. There was a significant reduction in ADHD-RS scores in Cohort 1 when comparing MAS XR and placebo. In con- trast, the differences in ADHD-RS scores between atom- oxetine and placebo were not significant, and there was no improvement in driving safety and performance scores. The findings that simulated driving performance improved in concert with enhanced ADHD symptom control builds on published reports that demonstrate sig- nificant driving improvements were more stable and per- sisted into the evening hours with long-acting stimulant treatment (Cox, Merkel, et al., 2004). 326 Table 3 Treatment-Emergent Adverse Events Reported by More Than 1 Subject in Any Treatment Group and Considered Possibly or Probably Related to Study Drug Note: Treatment-emergent adverse events (TEAE's) for Treatment Period 1 were defined as all adverse events occurring on and after the first dose date of Treatment Period 1 and before the first dose date of Treatment Period 2. TEAE's for Treatment Period 2 were defined as all adverse events occurring on and after the first dose date of Treatment Period 2 and on and before the last dose date. MAS XR = mixed amphetamine salts–extended release. The results observed with atomoxetine on simulated driving performance in this study are consistent with the mixed pattern of results observed by Barkley and col- leagues (2007). Importantly, subjects receiving placebo generally failed to recognize how poorly that they per- formed in the driving simulation, underscoring an impaired self-awareness of patients with ADHD. These results correspond with the findings observed by Knouse and colleagues (Knouse, Bagwell, & Barkley, 2005), who also found that adults with ADHD overestimated their simulated driving performance on a self-rating questionnaire, despite objectively poor performance on a driving simulator. Individuals who lack awareness of their driving difficulties are not likely to take precautions to compensate for these performance deficits. Safety and tolerability outcomes observed in this study are commensurate with the known adverse event profile for both active treatment arms. The most fre- quently reported TEAE's with MAS XR were anorexia and weight decreases; however, only 1 subject discontin- ued the study because of adverse events considered related to MAS XR. The most frequently reported TEAE's with atomoxetine were upper abdominal pain and nausea, and no subject on active treatment in Cohort 2 discontinued the study because of adverse events con- sidered related to atomoxetine. No serious adverse events were reported in either cohort. In theory, improvements in simulated driving perfor- mance with appropriate stimulant treatment, such as observed here, if applied to real-world situations might help to reduce the recognized negative consequences of ADHD on motor vehicle safety. This investigation and prior reports indicate that the time course of simulated driving performance improvements coincides with the known time course of clinical benefits seen with the given stimulant medications. Extended-release formula- tions appear to exert continued benefit on both ADHD symptoms and simulated driving performance up to 12 hours after morning dosing. It seems reasonable to infer that the improvements in simulated driving performance observed here would be associated with reductions in driving-related collisions, injuries, and medical and vehi- cle repair costs when placed in the context of real-world driving situations. As a greater number of adults obtain 327 stimulant treatment for ADHD symptoms, future analy- ses conducted on driving records of these individuals over time, as well as subjects not receiving treatment, may provide insight into the long-term impact of ongo- ing stimulant treatment on real-world driving behavior. Limitations Because the sample of adults with ADHD who partic- ipated in this study was limited to those between the ages of 19 and 25 years—an age group associated with the highest incidence of traffic collisions in the general pop- ulation (R. C. Brown, Sanders, & Schonberg, 1986)— the magnitude of improvement with active treatments may be larger than might be seen for older individuals with more driving experience, because older drivers may perform better under baseline or placebo conditions and thus may exhibit a smaller degree of improvement fol- lowing administration of active stimulant treatment. Conversely, because the study sample excluded adults with ADHD who have lost their driver's license—a sub- population who may have more severe symptoms (Barkley et al., 1993)—the magnitude of improvement with the study drug may be smaller compared with that which would be seen in a more diverse study population. Furthermore, with respect to MAS XR, in this study only the effects of a 50-mg/day dose of MAS XR were assessed, a dose chosen to approximate dose equivalency with atomoxetine (Eli Lilly and Company, 2006). Future research on simulated driving performance should explore the effects of other doses of MAS XR and their effects on patients with a range of ADHD severity. Only one third of the subjects in the current study had taken medication for ADHD in the prior 12 months, sug- gesting that this group may have had ADHD of low to mod- erate severity. The results observed with atomoxetine in this study may be attributed to lower doses than may be neces- sary to demonstrate improvements on the driving simulator; the maximum suggested dosage is 100 mg. In addition, a period of dosing longer than 3 weeks may be required to evaluate the full treatment effect of atomoxetine (Virani, 2005). We had also hoped to enroll more subjects in the ato- moxetine treatment arm. Future research on simulated dri- ving performance with atomoxetine should take into consideration employing a higher dose, perhaps for a longer dosing period, and including a larger number of subjects. The relationship between simulated driving perfor- mance and actual (on-the-road) driving is still being explored. Obviously, the consequences of collisions and citations are markedly different for the simulated and actual driving conditions. Further investigations of stimu- lant treatment should attempt to assess simulated driving performance of adults with ADHD in a variety of stimu- lant dosing and driving conditions and might include esti- mates of the costs and consequences of collisions and citations. This might be researched by including various schedules of reinforcement and costs associated with the driving simulator performance. Conclusion The findings of this study indicated that MAS XR, but not atomoxetine, yielded significant improvements in simulated driving performance that persisted for up to 12 hours post dose in young adults with ADHD. These improvements coincided with enhanced ADHD symp- tom control. In contrast, there was a lack of correspon- dence between self-reported driving quality and simulated driving performance, suggesting a lack of awareness of driving problems in adults with ADHD. Further research on the impact of ADHD treatment on driving outcomes in adult patients is warranted. References American Academy of Pediatrics. (2000). Clinical practice guideline: Diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics, 105, 1158-1170. American Psychiatric Association. (2000). Diagnostic and statistical manual for mental disorders-fourth edition text revision (DSM-IV-TR). Washington, DC: Author. Barkley, R.A. (2002). Major life activity and health outcomes associated with attention-deficit/hyperactivity disorder. Journal of Clinical Psychiatry, 63(Suppl. 12), 10-15. Barkley, R.A. (2004). Driving impairments in teens and adults with attention-deficit/hyperactivity disorder. Psychiatric Clinics of North America, 27, 233-260. Barkley, R.A., Anderson, D.L., & Kruesi, M. (2007). A pilot study of the effects of atomoxetine on driving performance in adults with ADHD. Journal of Attention Disorders, 10, 306-316. Barkley, R.A., Guevremont, D.C., Anastopoulos, A.D., DuPaul, G.J., & Shelton, T.L. (1993). Driving-related risks and outcomes of attention-deficit/hyperactivity disorder in adolescents and young adults: A 3- to 5-year follow-up survey . Pediatrics, 92, 212-218. Barkley, R.A., Murphy, K.R., & Fischer, M. (2007). The science of ADHD in adults: Clinic-referred adults vs. children grown up. New York: Guilford. Barkley, R.A., Murphy, K.R., & Kwasnik, D. (1996). Motor vehicle driving competencies and risks in teens and young adults with attention-deficit/hyperactivity disorder. Pediatrics, 98(<reflink idref="bib6" id="ref2">6</reflink>,Pt.1), 1089-1095. Barkley, R.A., Murphy, K.R., O'Connell, T., & Connor, D.F. (2005). Effects of two doses of methylphenidate on simulator driving performance in adults with attention-deficit/hyperactivity disorder . Journal of Safety Research, 36, 121-131. Biederman, J., Faraone, S.V., Monuteaux, M.C., Bober, M., & Cadogen, E. (2004). Gender effects on attention-deficit/ hyperactivity disorder in adults, revisited. Biological Psychiatry, 55, 692-700. 328 Brown, R.C., Sanders, J.M., Jr., & Schonberg, S.K. (1986). Driving safety and adolescent behavior. Pediatrics, 77, 603-607. Brown, T.E. (2005). Attention deficit disorder: The unfocused mind in children and adults. New Haven, CT: Yale University Press. Castellanos, F.X., Sonuga-Barke, E.J., Milham, M.P., & Tannock, R. (2006). Characterizing cognition in ADHD: Beyond executive dysfunction. Trends in Cognitive Science, 10, 117-123. Cognitive Research Corporation. (2007). Crash Likely Event Rating Scale. St. Petersburg, FL: Author. Conners, C.K., Erhardt, D., & Sparrow, E.P. (1999). Conners'Adult ADHD Rating Scales (CAARS) technical manual. New York: Multi-Health Systems . Cox, D.J., Humphrey, J.W., Merkel, R.L., Penberthy, J.K., & Kovatchev, B. (2004). Controlled-release methylphenidate improves attention during on-road driving by adolescents with attention-deficit/hyperactivity disorder. Journal of the American Board of Family Practice , 17, 235-239. Cox, D.J., Merkel, R.L., Kovatchev, B., & Seward, R. (2000). Effect of stimulant medication on driving performance of young adults with attention-deficit/hyperactivity disorder: A preliminary, double-blind, placebo-controlled trial. Journal of Nervous and Mental Disease, 188, 230-234. Cox, D.J., Merkel, R.L., Moore, M., Thorndike, F., Muller, C., & Kovatchev, B. (2006). Relative benefits of stimulant therapy with OROS methylphenidate versus mixed amphetamine salts extended release in improving the driving performance of adolescent drivers with attention-deficit/hyperactivity disorder. Pediatrics, 118, e704-e710. Cox, D.J., Merkel, R.L., Penberthy, J.K., Kovatchev, B., & Hankin, C.S. (2004). Impact of methylphenidate delivery profiles on driving performance of adolescents with attention-deficit/hyperactivity disorder: A pilot study. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 269-275. Dulcan, M. (1997). Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 36(10 Suppl.), 85S-121S. DuPaul, G.J., Power, T., Anastopoulos, A., & Reid, R. (1998). In G. J. DuPaul (Ed.), ADHD rating scale IV: Checklist, norms, and clinical interpretation . New York: Guilford. Eli Lilly and Company. (2006). Strattera (atomoxetine HCl) prescribing information. Indianapolis, IN: Author. Faraone, S.V., Biederman, J. (2005). What is the prevalence of adult ADHD? Results of a population screen of 966 adults. Journal of Attention Disorders, 9, 384-391. Faraone, S.V., Biederman, J., Doyle, A., Murray, K., Petty, C., Adamson, J.J., et al. (2006). Neuropsychological studies of late onset and subthreshold diagnoses of adult attention-deficit/hyperactivity disorder . Biological Psychiatry, 60, 1081-1087. Fischer, M., Barkley, R.A., Smallish, K., & Fletcher, K. (2007). Hyperactive children as adults: Driving behavior, safe driving abilities, and adverse driving outcomes. Accident Analysis and Prevention, 39, 94-105. Fried, R., Petty, C.R., Surman, C.B., Reimer, B., Aleardi, M., Martin, J.M., et al. (2006). Characterizing impaired driving in adults with attention-deficit/hyperactivity disorder: A controlled study. Journal of Clinical Psychiatry, 67, 567-574. Golden, C.J., & Freshwater, S.M. (2002). A manual for the Adult Stroop Color and Word Test. Chicago: Stoelting. Goodman, D.W., Ginsberg, L.D., Weisler, R.H., Cutler, A.J., & Hodgkins, P. (2005). 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Executive function and attention-deficit/hyperactivity disorder: Stimulant medication and better executive function performance in children. Psychological Medicine, 29, 527-538. Kessler, R.C., Adler, L., Barkley, R., Biederman, J., Conners, C.K., Demler, O., et al. (2006). The prevalence and correlates of adult ADHD in the United States: Results from the National Comorbidity Survey Replication . American Journal of Psychiatry, 163, 716-723. Knouse, L.E., Bagwell, C.L., & Barkley, R.A. (2005). Accuracy of self-evaluation in adults with ADHD: Evidence from a driving study. Journal of Attention Disorders , 8, 221-234. Murphy, K., & Barkley, R.A. (1996). Attention-deficit/hyperactivity disorder adults: Comorbidities and adaptive impairments. Comprehensive Psychiatry , 37, 393-401. National Highway Traffic Safety Association (NHTSA). Objective 3, determine the differences in demographic data, test battery results, and performance-based measures between inattentive and attentive drivers (chapter 4). Retrieved August 29, 2007, from <ulink href="http://www-nrd.nhtsa.dot.gov/departments/nrd-13/810594/">http://www-nrd.nhtsa.dot.gov/departments/nrd-13/810594/</ulink> pages/4aObjective3.htm Owen, A.M., Stern, C.E., Look, R.B., Tracey, I., Rosen, B.R., & Petrides, M. (1998). Functional organization of spatial and non-spatial working memory processing within the human lateral frontal cortex. Proceedings of the National Academy of Sciences, USA, pp. 7721-7726. Pliszka, S., Bernet, W., Bukstein, O., et al., and the AACAP Work Group on Quality Issues. (2007). Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 894-921. Reitan, R.M., & Wolfson, D. (1993). The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation (2nd ed.). South Tucson, AZ: Neuropsychology Press. Rowland, A.S., Lesesne, C.A., & Abramowitz, A.J. (2002). The epidemiology of attention-deficit/hyperactivity disorder (ADHD): A public health view. Mental Retardation and Developmental Disabilities Research Reviews, 8, 162-170. SAS Institute. (1997). SAS/STAT software: Changes and enhancements through release 6.12. Cary, NC: SAS Institute. U.S. Census Bureau. (2003). Census 2000 Summary File 4. Retrieved August 16, 2004, from <ulink href="http://factfinder.census.gov">http://factfinder.census.gov</ulink> Virani, A. (2005). Perspectives in psychopharmacology: Spotlight on atomoxetine. The Canadian Child and Adolescent Psychiatry Review, 14, 96-98. Wechsler, D. (1999). Wechsler Abbreviated Scale of Intelligence. San Antonio, TX: The Psychological Corporation. Wilens, T.C., & Dodson, W. (2004). A clinical perspective of attention-deficit/hyperactivity disorder into adulthood. Journal of Clinical Psychiatry, 65, 1301-1313. 329 Gary G. Kay, PhD, is the president of Cognitive Research Corporation, where he is involved in the design, conduct, and analysis of CNS clinical research trials. Much of his work is focused on computer-based cognitive testing and driving sim- ulation. In his recent publications he has compared the effect of antimuscarinic agents on memory functioning of older adults, presented results of studies evaluating the efficacy of treatments for dementia, and reviewed developments in com- puter-based cognitive testing systems. M. Alex Michaels, MD, is Senior Medical Director at Astellas Pharma U.S., Inc. based in Deerfield, IL. He was formerly employed by Shire Development Inc. He has held senior U.S. and international pharmaceutical industry positions, where his clinical research activities have focused on aspects of safety and efficacy of marketed drugs. A recent publication examined cardiovascular effects of mixed amphetamine salts in school- aged children with ADHD. He received his BS degree in bio- chemistry and his medical degree from the University of Toronto. Barton Pakull, MD, is a consulting psychiatrist in Aviation Medicine and was formerly the chief psychiatrist in the Office of Aviation Medicine, Federal Aviation Administration. In that role, he frequently dealt with issues related to ADHD. He cur- rently serves as a consultant in occupational psychiatry.</p> <aug> <p>By Gary G. Kay; M. Alex Michaels and Barton Pakull</p> </aug> <nolink nlid="nl1" bibid="bib4" firstref="ref1"></nolink> <nolink nlid="nl2" bibid="bib6" firstref="ref2"></nolink> <nolink nlid="nl3" bibid="bib12" firstref="ref3"></nolink>
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  Data: Simulated Driving Changes in Young Adults with ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine
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  Data: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: http://sagepub.com
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  Data: 10.1177/1087054708322986
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  Data: Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts--extended release (MAS XR) 50 mg/day (Cohort 1) and atomoxetine 80 mg/day (Cohort 2) in young adults with ADHD. Results: Adults aged 19 to 25 years with AD/HD (N = 19) who were administered MAS XR significantly improved overall simulated driving performance versus placebo up to 12 hours after dosing. In contrast, there were no statistically significant differences in simulated-driving-performance scores between atomoxetine and placebo. At endpoint, MAS XR reduced ADHD Rating Scale scores [greater than or equal to] 30% in 80% of subjects, whereas atomoxetine achieved this level of improvement for 40%. Limitations: Small sample size and use of simulated driving may limit generalizability of the findings. Conclusion: MAS XR in young adults with ADHD yields significant improvements in simulated driving performance and ADHD symptoms. (Contains 3 tables and 5 figures.)
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      – TitleFull: Simulated Driving Changes in Young Adults with ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine
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