Approximately 66% of children and adolescents who have

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1 ORIGINAL CONTRIBUTION Atomoxetine Treatment of Attention-Deficit/Hyperactivity Disorder in Young Adults With Assessment of Functional Outcomes A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Todd M. Durell, MD,* Lenard A. Adler, MD,Þ Dave W. Williams, MS,þ Ahmed Deldar, PhD,* James J. McGough, MD, Paul E. Glaser, MD, PhD, Richard L. Rubin, MD, Teresa A. Pigott, MD,# Elias H. Sarkis, MD,** and Bethany K. Fox, PhD* Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairment in multiple functional domains. This trial evaluated efficacy in ADHD symptoms and functional outcomes in young adults treated with atomoxetine. Methods: Young adults (18Y30 years old) with ADHD were randomized to 12 weeks of double-blind treatment with atomoxetine (n = 220) or placebo (n = 225). The primary efficacy measure of ADHD symptom change was Conners Adult ADHD Rating Scale (CAARS): Investigator-Rated: Screening Version Total ADHD Symptoms score with adult prompts. Secondary outcomes scales included the Adult ADHD Quality of Life-29, Clinical Global Impression-ADHD-Severity, Patient Global Impression-Improvement, CAARS Self-Report, Behavior Rating Inventory of Executive Function-Adult Version Self-Report, and assessments of depression, anxiety, sleepiness, driving behaviors, social adaptation, and substance use. Results: Atomoxetine was superior to placebo on CAARS: Investigator- Rated: Screening Version (atomoxetine [least-squares mean T SE, j13.6 T 0.8] vs placebo [j9.3 T 0.8], 95% confidence interval [j6.35 to j2.37], P G 0.001), Clinical Global Impression-ADHD-Severity (atomoxetine [j1.1 T 0.1] vs placebo [j0.7 T 0.1], 95% confidence interval [j0.63 to j0.24], P G 0.001), and CAARS Self-Report (atomoxetine [j11.9 T 0.8] vs placebo [j7.8 T 0.7], 95% confidence interval [j5.94 to j2.15], P G 0.001) but not on Patient Global Impression-Improvement. In addition, atomoxetine was superior to placebo on Adult ADHD Quality of Life-29 and Behavior Rating Inventory of Executive Function- Adult Version Self-Report. Additional assessments failed to detect significant differences (P Q 0.05) between atomoxetine and placebo. The adverse event profile was similar to that observed in other atomoxetine studies. Nausea, decreased appetite, insomnia, dry mouth, irritability, From *Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN; Department of Psychiatry, NYU School of Medicine; and Psychiatry Service, New York VA Harbor Healthcare System, New York, NY; PharmaNet/i3, Indianapolis, IN; UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA; Department of Psychiatry, University of Kentucky, Lexington, KY; Vermont Clinical Study Center, Burlington, VT; #Department of Psychiatry & Behavioral Sciences, The University of Texas Health Science Center, Houston, TX; and **Sarkis Family Psychiatry, Gainesville, FL. Received September 21, 2010; accepted after revision May 7, Reprints: Todd M. Durell, MD, Lilly Corporate Center, Indianapolis, IN ( durellto@lilly.com). Clinical Trials Registration: ClinicalTrials.gov, Identifier NCT This research was funded by Lilly USA, LLC. This work was presented in poster form at the Society of Biological Psychiatry 65th Annual Convention & Scientific Program, May Copyright * 2013 by Lippincott Williams & Wilkins ISSN: DOI: /JCP.0b013e31827d8a23 dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo. Conclusions: Atomoxetine reduced ADHD symptoms and improved quality of life and executive functioning deficits in young adults compared with placebo. Atomoxetine was also generally well tolerated. Key Words: attention-deficit/hyperactivity disorder, atomoxetine, young adults (J Clin Psychopharmacol 2013;33: 45Y54) Approximately 66% of children and adolescents who have attention-deficit/hyperactivity disorder (ADHD) continue to have symptoms into adulthood, 1 and about 50% continue to meet full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria as adults. 2 Even with considerable syndromatic remission, most adults with ADHD will continue to have high levels of dysfunction. 3 Impairment due to ADHD may have potentially long-lasting negative effects in young adults as they transition into adulthood. Decisions made by young adults as they move away from home, go to college, or start careers affect the trajectories of their lives and can have a serious impact on their future quality of life. Furthermore, as children and adolescents with ADHD transition into adulthood, impairment may increase because of the presence of more comorbid psychopathology and high-risk behaviors than in their non-adhd peers. 4 In a 10-year prospective study that followed male youths with ADHD into young adulthood, subjects reported higher rates of antisocial, addictive, mood, and anxiety disorders compared with control subjects. 4 Attention-deficit/hyperactivity disorder is associated with a range of negative impairments, including lower academic achievement, greater employment disruption, difficulty in initiating and maintaining relationships, and increased severity of gambling problems. 1,5Y8 Young adults with ADHD reported more speeding, increased traffic violation citations, and a tendency for more auto crashes than age-matched counterparts without ADHD. 9,10 Similarly, comorbid alcohol and substance use disorders, including smoking, are more likely to occur in adults with ADHD. 11,12 Despite growing evidence that ADHD is likely to persist into adulthood, there is surprisingly few data specific to treatment response in young adults with ADHD. Stimulant ADHD medications, although highly effective in treating ADHD symptoms, may represent a particularly complex conundrum for some health care providers, because these medications carry a risk for abuse and diversion by college-aged students and young adults. 13Y15 A published post hoc analysis of data from previous Journal of Clinical Psychopharmacology & Volume 33, Number 1, February

2 Durell et al Journal of Clinical Psychopharmacology & Volume 33, Number 1, February 2013 atomoxetine trials showed that younger and older adults had similar improvements at the study end point, although the effect size was higher in younger adults. 16 With these issues in mind, the current study is the first multicenter, double-blind, placebo-controlled medication trial conducted in young adults (18Y30 years old) with ADHD. This study examined the efficacy and tolerability of atomoxetine in treating ADHD symptoms, as well as atomoxetine s effects on functional outcomes in this age group. METHODS Participant Population Adults, aged 18 to 30 years, met DSM-IV, Text Revision (DSM-IV-TR) criteria for ADHD as determined by a clinical interview and assessed by the Adult ADHD Clinician Diagnostic Scale version 1.2. All participants also must have had a Clinical Global Impression-ADHD-Severity (CGI-S) score of 4 (moderate symptoms) or greater to be eligible for study participation. Participants with concomitant current or lifetime diagnoses of specific phobias, generalized anxiety disorder, or social anxiety disorder were allowed in the trial, as were participants with a history of dysthymia within 2 years of study screening. Potential participants were excluded from the trial if they had current major depression, panic disorder, posttraumatic stress disorder, an eating disorder, or substance abuse or dependence, as well as current or lifetime obsessive-compulsive disorder, bipolar disorder, or psychosis. In addition, any participant who had more than a 25% reduction in their ADHD symptoms as measured by the Conners Adult ADHD Rating Scale: Investigator-Rated: Screening Version (CAARS-Inv:SV) Total ADHD Symptoms scores between visits 1 and 2 (screening period) was excluded from the study. Before initiation of any study procedures, site investigators provided participants with thorough verbal and written descriptions of protocol requirements, and participants gave written consent under procedures approved by each participating site s institutional review board. The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and consistent with Good Clinical Practices. Study Design This study was a multicenter, 12-week, randomized, placebocontrolled, double-blind trial conducted at 32 sites in the United States and Puerto Rico between August 2007 and February Participants completing the double-blind portion of the trial were eligible to enter an optional 12-week, open-label, extension period. This article reports the results of the 12-week double-blind period of the randomized clinical trial. Study Period I (5- to 28-Day Screening Period, Visits 1 2) This study utilized a 2-step screening process: a Web screening followed by a site screening. After providing privacy statement consent, potential participants completed an Internetbased, nonidentifiable Adult ADHD Self-Report Scale-V1.1 Screener to determine their likelihood of meeting ADHD diagnostic criteria. Those with an Adult ADHD Self-Report Scale- V1.1 Screener raw score of 14 or greater were given the option to electronically sign an additional online informed consent. 17 Participants opting in then answered additional inclusion/ exclusion criteria questions via the study Web site, and those who met inclusion/exclusion criteria for the trial and who lived near an available investigative site were eligible to enter the study and were provided with contact information for the site. In addition, eligible participants could give permission for their contact information to be provided to the site. The site would then contact eligible participants to schedule a live screening visit to confirm that the participant fully met all study inclusion/ exclusion criteria. Site personnel obtained informed consent for the study from participants before conducting any study procedures and before participants discontinued any excluded medications. Participants underwent laboratory tests, an electrocardiogram (ECG) evaluation, a psychiatric evaluation, and a physical examination. Participants underwent a washout period if they had been taking medications excluded by the study protocol. At visit 2, participants were further evaluated for inclusion/exclusion criteria to ensure that they could continue in the study. Study Period II (12-Week Double-Blind Treatment Phase, Visits 2 6) Participants were assessed 2 weeks after visit 2 (randomization), then every 3 weeks until visit 5 (8 weeks on active treatment or placebo) and then after 4 weeks (visit 6, the end of the 12-week double-blind phase of the study). This study used a double-blind, sham placebo lead-in period, which blinded investigators and participants to the initiation of active therapy. The sham placebo lead-in period was used because of the particular challenges of detecting a true drug effect in the face of the typically sizable placebo response in this clinical population and to gain an accurate evaluation of the treatment effect. Participants were randomized 1:1 to either atomoxetine or placebo in a double-blind manner (neither participant nor investigator knew treatment assignment). Investigators were informed that all participants might receive placebo during a lead-in period between visits 2 and 4, before randomization (week 0 through week 5). Investigators did not know that the randomization of all participants actually occurred at visit 2 (week 0), and all participants randomized to atomoxetine began treatment at the end of visit 2. Assignment to treatment groups was determined by a computer-generated random sequence using an interactive voice response system, which assigned packages of doubleblind study drug to each participant. To achieve between-group comparability for site factors, participants were randomized at the site level. Dosing In study period II, participants randomized to atomoxetine began treatment with 40 mg/d (dosed 20 mg twice daily [BID]) for a minimum of 7 days. Following the last dose of 20 mg BID, the participants received 80 mg/d (dosed 40 mg BID) for a minimum of 7 days. At or after visit 5 (week 8), the dose could be increased to the maximum of 100 mg/d (dosed 50 mg BID), if the participant had residual symptoms in the judgment of the investigator. One unscheduled dose change was allowed during study period II if needed for tolerability or safety. Unscheduled dose decreases and dose increases were allowed only 1 dose level at a time, and participants unable to tolerate 40 mg/d were discontinued. The 40- to 100-mg/d dose of atomoxetine was chosen for this study because of results obtained in previous studies 18,19 and is consistent with dosing recommendations in the US label. 20 Assessments All efficacy and outcome measures were prespecified in the study protocol * 2013 Lippincott Williams & Wilkins

3 Journal of Clinical Psychopharmacology & Volume 33, Number 1, February 2013 Atomoxetine Treatment of ADHD in Young Adults Primary Efficacy Measure The primary objective was to compare the efficacy of atomoxetine at 40 to 100 mg/d dosed BID and placebo on reducing ADHD symptoms after 12 weeks of double-blind treatment as measured by the mean change in the CAARS-Inv:SV Total ADHD Symptoms score using a repeated-measures analysis. The CAARS-Inv:SV was investigator-administered with adult ADHD prompts used in previous adult atomoxetine trials and prompts developed by Massachusetts General Hospital and New York University School of Medicine. 21 Each investigator received scale training for the CAARS-Inv:SV following standard guidelines. 22 The 18-item Total ADHD Symptoms score is the sum of the Inattention and the Hyperactivity-Impulsivity subscales. Each individual symptom is scored on a 0- to 3-point scale (0 = not at all, never; 1 = just a little, once in a while; 2 = pretty much, often; 3 = very much, very frequently), resulting in a total score ranging from 0 to 54. The rating scale assessed symptom severity over the past week. 23 Gated Secondary Measure The Adult ADHD Quality of Life-29 (AAQOL-29) is a participant-reported outcome measure used to examine diseasespecific functional impairments and quality of life for adults with ADHD. The AAQOL-29 includes Life Productivity, Psychological Health, Quality of Relationships, and Life Outlook subscales. Higher scores on the AAQOL-29 indicate better functioning. Using a Gatekeeper strategy, 24 the following 2 secondary objectives were tested: (1) the effect of atomoxetine compared with placebo on the AAQOL-29 total score and (2) the effect of atomoxetine compared with placebo in a stepwise fashion on AAQOL-29 subscales in the following order: Relationship, Life Productivity, Psychological Health, and Life Outlook. Testing stopped when a measure failed to show statistical significance favoring atomoxetine (P e 0.05) based on a 2-sided test of significance. Additional Assessments The CAARS Self-Report (CAARS-S:SV) was completed by the participant. The individual items, subscales, and scoring are the same as described for the CAARS-Inv:SV. 23 The CGI-S is a single-item clinician rating of the patient s illness severity, in this case ADHD, in relation to the clinician s total experience with the particular population. 25 The CGI-S is rated on a 7-point scale (1 = normal, not at all ill; 7 = among the most extremely ill patients). The Patient Global Impression- Improvement (PGI-I) is a 7-point scale modeled after the CGI in which patients rate any change in their overall status since beginning the study medication (1 = very much improved, 7 = very much worse). The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item investigator-rated scale for severity of depressive mood symptoms. The MADRS total score ranges from 0 to 60, and higher scores denote more severe depressive symptoms. 26 The Beck Anxiety Inventory (BAI) is a 21-item, selfreported tool for measuring severity of anxiety. The total score ranges from 0 (not at all) to 63 (severe), and each item is descriptive of subjective, somatic, or panic-related symptoms of anxiety. The Habits Timeline Followback (TLFB) is a variation of the Alcohol Timeline Followback, a method for assessing the quantity of alcohol consumption on a daily basis. 27,28 In addition to assessing alcohol use, the TLFB assessed nicotine, caffeine, marijuana, and drug habits. With a calendar as a guide, the participant provided a retrospective estimate of daily habits. Consumption is measured as the number of alcoholic drinks; cigarettes, pipes, or pinches of snuff; caffeinated drinks; or amount of marijuana consumed per day. For other drugs, consumption was measured as the number of days on which the drugs were used. The Fagerström Test for Nicotine Dependence (FTND) was designed to provide an ordinal measure of nicotine dependence. It contains self-reported items that evaluate the quantity of cigarette consumption, the compulsion to use, and dependence. 29 The items on the FTND are summed to yield a total score of 0 (very low dependence) to 10 (very high dependence). The Social Adaptation Self-Evaluation Scale (SASS) is a 21-item, participant-completed scale that examines behaviors and subjective perception of relationships with family and friends, satisfaction in work, home and leisure activities, and intellectual interests. Higher scores correspond with better social functioning, with a total score range from 0 to The Driving Behavior Survey Self-Report (DBS-Self ) is a 26-item, self-rated driving survey. Examples of driving behaviors included in the survey are putting on seat belt, driving within speed limits, and yielding the right of way to other drivers. The total score is the sum of the 26 items, and higher scores indicate better driving habits. The Driving Behavior Survey Other-Report (DBS-Other) includes the same 26 items but is completed by someone other than the participant/driver. The Behavior Rating Inventory of Executive Function- Adult Version Self-Report (BRIEF-A) is a standardized measure consisting of 75 items that assesses adult executive functioning and self-regulation in his/her everyday environment. 31 The Global Executive Composite is a summary score that incorporates all of the clinical scales of the BRIEF-A, and higher scores indicate greater impairment. The Epworth Sleepiness Scale (ESS) is an 8-item questionnaire used to determine the level of daytime sleepiness. 32 Participants rated the likelihood of dozing off or falling sleep in each of 8 normative daily situations, and each item score is summed to produce a total score (range of 0Y24). Scores greater than 10 (95th percentile) are considered to be suggestive of significant daytime sleepiness. Scores greater than 15 have been associated with pathological sleepiness that may be due to specific conditions, such as obstructive sleep apnea or narcolepsy. Safety Spontaneously reported treatment-emergent adverse events, weight, and vital signs were recorded at every visit. Laboratory and ECG measures were collected during the first study visit and the final visit of the double-blind phase (visit 6). Safety analyses were performed for all randomized participants who took at least 1 dose of study drug. Statistical Analyses The study planned to randomize 440 participants in a 1:1 ratio between atomoxetine and placebo (220 participants per group). This sample size was selected to allow for more than 80% power to detect a difference between atomoxetine and placebo on the CAARS-Inv:SV Total ADHD Symptom score and AAQOL-29 Total score. These estimates were based on the results of previous trials. 19,33 All statistical analysis plans were described in the study protocol. The planned statistical methods were to use an intentto-treat population (all participants randomized to a treatment group, even if the participant did not take the assigned treatment, did not receive the correct treatment, or did not otherwise follow the protocol) for all efficacy analyses. All enrolled participants who had both a baseline and at least 1 postbaseline * 2013 Lippincott Williams & Wilkins 47

4 Durell et al Journal of Clinical Psychopharmacology & Volume 33, Number 1, February 2013 score were included in the analysis of the efficacy data, because both observations are necessary to measure their change. All participants who took at least 1 dose of study medication were included in the analysis of safety data. Investigative sites with less than 2 participants per treatment arm were pooled with the next smallest investigative site until that pooled site had at least 2 participants per treatment arm. Treatment effects for all efficacy and safety variables were evaluated based on a 2-sided significance level of 0.05 and the interaction effects at The prespecified primary outcome measure, the CAARS- Inv:SV Total ADHD Symptoms score, as well as the Inattention and the Hyperactivity-Impulsivity subscale scores, were analyzed using a restricted maximum likelihoodybased, mixedmodel repeated measures (MMRM) technique. The model included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline (last of scores at visits 1 and 2) score and baseline score-by-visit interaction. The unstructured covariance was used as the primary analysis. The Kenward- Roger approximation was used to estimate denominator degrees of freedom. Significance tests were based on least-squares means and type III sum-of-squares. Analyses were implemented using SAS PROC MIXED (SAS Institute, Cary, NC). The primary comparison was the contrast between treatments at visit 6 (12 weeks postbaseline). Secondary evidence of efficacy from the primary analysis was based on the main effect of treatment and the treatment-by-visit interaction terms from the MMRM analysis. In addition, CAARS-Inv:SV Total ADHD Symptoms score and Inattention and Hyperactivity-Impulsivity subscale scores were analyzed using last-observation-carried-forward (LOCF) analysis. Patients who discontinued before visit 6 were also included in the LOCF analysis as long as they had at least 1 nonmissing score at visits 3 to 5. Change from baseline to LOCF end point was compared across treatments using an analysis of covariance (ANCOVA) model with terms for baseline, treatment, and investigator. The gated secondary efficacy measures were assessed with an MMRM at the final postbaseline visit, including the same terms as those used for the primary efficacy measure. A post hoc analysis was conducted to show arithmetic mean changes in the CAARS-Inv:SV Total ADHD Symptoms score over time. Significance tests for the post hoc analyses were from 2-sample t tests. Mean changes from baseline to 12-week end point on the CGI-S, the CAARS-S:SV, the PGI-I, the MADRS, the BAI, the TLFB (Alcohol, Nicotine, Caffeine, Marijuana, and Drugs), the FTND, the SASS, the DBS-Self, the DBS-Other, BRIEF-A, and the ESS were analyzed using an ANCOVA model with terms for baseline score, treatment, and investigator. A Fishers exact test was used to assess baseline smoking status as a predictor of response, and correlation between the improvements on the AAQOL-29 Total score, with symptom reduction as measured by improvement on the CAARS-Inv:SV Total ADHD Symptoms score, was computed using Pearson correlation coefficient. Effect sizes were calculated by dividing the differences in the least-squares mean changes by the pooled SD of the changes. RESULTS Disposition of Participants Of the 584 participants screened for the study, 445 were randomized to treatment, and 385 received at least 1 dose of study drug. Of the 11 patients who had more than a 25% reduction in their ADHD symptoms as measured by the CAARS-Inv:SV Total ADHD Symptoms scores between visits 1 and 2, 8 patients were randomized, and 5 patients completed the study in violation of the study protocol. Overall, 115 (52.3%) of the 220 participants randomized to atomoxetine and 130 (57.8%) of the 225 participants randomized to placebo completed the study, and the difference in completion rate between treatment groups was not statistically significant (P = 0.25). The most common reasons for early discontinuation were lost to follow-up (n = 97), participant decision (n = 54), and adverse events (n = 27). Adverse event as reason for discontinuation was statistically significantly more common in the atomoxetine group (n = 21, 9.5%) compared with the placebo group (n = 6, 2.7%; P = 0.003). Other reasons for discontinuation were not statistically significant. Demographics and Baseline Characteristics Age and sex were similar across treatment groups, and there were more males than females in both groups (Table 1). The majority of participants were white, with 83% having at least some college or vocational training. Nearly all participants met the criteria for combined or inattentive ADHD subtypes. In addition, slightly more than one third of all participants had previously used stimulants. No statistically significant differences between treatment groups were observed for any of the TABLE 1. Demographics Atomoxetine Placebo P No. participants Age, mean (SD) 24.7 (3.4) 24.7 (3.5) 0.92* Gender, n (%) 0.77 Female 92 (41.8) 98 (43.6) Male 128 (58.2) 127 (56.4) Height, mean (SD), cm* (9.6) (9.9) 0.51* Weight, mean (SD), kg* 79.6 (22.6) 81.6 (21.5) 0.35* Ethnicity, n (%) African descent 12 (5.5) 26 (11.6) Caucasian 169 (76.8) 166 (73.8) East Asian 8 (3.6) 7 (3.1) Hispanic 27 (12.3) 25 (11.1) Native American 0 (0.0) 1 (0.4) West Asian 4 (1.8) 0 (0.0) DSM-IV ADHD subtype, n (%) 0.91 Combined 173 (78.6) 174 (77.3) Hyperactive/impulsive 1 (0.5) 1 (0.4) Inattentive 46 (20.9) 50 (22.2) Prior stimulant use, n (%) 83 (37.7) 79 (35.1) 0.62 Highest education attainment 0.38 No. participants Elementary school 2 (0.9) 0 (0.0) Middle school 1 (0.5) 0 (0.0) High school 29 (13.3) 41 (18.3) College, some or all 153 (70.2) 147 (65.6) Postgraduate, some or all 26 (11.9) 30 (13.4) Vocational training 7 (3.2) 6 (2.7) *Analysis of variance model: baseline = treatment (type III sums of squares). Treatment comparison was analyzed using Fisher exact test. n indicates number of participants in the specified category * 2013 Lippincott Williams & Wilkins

5 Journal of Clinical Psychopharmacology & Volume 33, Number 1, February 2013 Atomoxetine Treatment of ADHD in Young Adults measured baseline parameters. The median baseline ESS score for all randomized participants was 10.0, although daytime sleepiness did not exclude patients from the study. Atomoxetine Doses The median and mean final atomoxetine doses for all randomized participants who took at least 1 dose were 80 and 87.1 mg/d, respectively. These doses are consistent with the atomoxetine label 20 and previous adult ADHD trials. 18,19 Efficacy Primary Efficacy Measure Atomoxetine was associated with statistically significantly greater improvements than placebo on the primary outcome measure, the CAARS-Inv:SV Total ADHD Symptoms score, overall and at every postbaseline visit during the study using either the pre hoc statistical analysis method (least-squares mean T SE; week 2 atomoxetine j7.7 T 0.6 vs placebo j5.0 T 0.6, P G 0.001; week 5 atomoxetine j11.4 T 0.7 vs placebo j7.9 T 0.7, P G 0.001; week 8 atomoxetine j13.6 T 0.8 vs placebo j8.9 T 0.7, P G 0.001; week 12 atomoxetine j14.9 T 0.9 vs placebo j9.8 T 0.9, P G 0.001) or the post hoc statistical method (arithmetic mean, Fig. 1). Similar results were demonstrated for the Inattention and the Hyperactivity-Impulsivity subscales, with significant effects at every postbaseline visit (Inattention least-squares mean T SE;week2atomoxetinej4.3 T 0.3 vs placebo j2.7 T 0.3, P G 0.001; week 5 atomoxetine j6.5 T 0.4 vs placebo j4.3 T 0.4, P G 0.001; week 8 atomoxetine j7.7 T 0.4 vs placebo j5.0 T 0.4, P G 0.001; week 12 atomoxetine j8.4 T 0.5 vs placebo j5.5 T 0.5, P G 0.001; and Hyperactivity-Impulsivity least-squares mean T SE; week 2 atomoxetine j3.4 T 0.3 vs placebo j2.30 T 0.3, P = 0.008; week 5 atomoxetine j4.9 T 0.4 vs placebo j3.6 T 0.4, P = 0.016; week 8 atomoxetine j5.9 T 0.4 vs placebo j3.8 T 0.4, P G 0.001; week 12 atomoxetine j6.6 T 0.5 vs placebo j4.3 T 0.4, P G 0.001). The LOCF analysis (baseline to end point) also demonstrated statistically significant improvements on the CAARS- Inv:SV Total ADHD Symptoms score, between atomoxetine and placebo treatment groups (Table 2). The effect size for the CAARS-Inv:SV Total ADHD Symptoms score was 0.4, indicating a moderate effect. Gated Secondary Efficacy Measure Patients treated with atomoxetine experienced statistically significantly greater score reduction on the AAQOL-29 Total score compared with placebo at every postbaseline visit (P G 0.05) throughout the double-blind phase (least-squares mean T SE; week 2 atomoxetine 10.2 T 1.0 vs placebo 7.5 T 0.9, P = 0.026; week 5 atomoxetine 11.6 T 1.1 vs placebo 8.2 T 1.1, P = 0.021; week 8 atomoxetine 15.0 T 1.2 vs placebo 10.3 T 1.1, P = 0.003; week 12 atomoxetine 15.8 T 1.3 vs placebo 11.0 T 1.2, P = 0.005). Score decreases from baseline to the 12-week end point were also statistically significantly (P G 0.05) greater in the atomoxetine treatment group compared with placebo for the AAQOL-29 Total score and all the subscale scores, except for the Life Outlook subscale score (P = 0.08,Table 2).A negative Pearson correlation coefficient was observed between improvements on the AAQOL-29 Total score and symptom reduction as measured by improvement on the CAARS-Inv:SV Total ADHD Symptoms score after 12 weeks of treatment, suggesting that participants whose scores improved on one measure also showed improvement on the other. Additional Assessments Several other measures of ADHD symptoms also demonstrated greater improvements following 12 weeks of atomoxetine treatment compared with placebo including the CAARS-S:SV Total ADHD Symptoms scores as well as the Inattention and the Hyperactivity-Impulsivity subscales. Thus, the results on both the investigator-rated and self-rated versions of the CAARS were consistent. The atomoxetine treatment group also had statistically significantly greater improvement compared with the placebo treatment group on the following functional outcome measures: the CGI-S and the BRIEF-A Global Executive Composite (Table 2). Although both the atomoxetine-treated and FIGURE 1. Post hoc analysis of the primary efficacy measure. Arithmetic mean changes from baseline and SEs for the CAARS-Inv:SV Total ADHD Symptoms score over time. * 2013 Lippincott Williams & Wilkins 49

6 Durell et al Journal of Clinical Psychopharmacology & Volume 33, Number 1, February 2013 TABLE 2. Efficacy and Functional Outcome Measures (Mean Score and P Values, LOCF ANCOVA Analyses) Atomoxetine Placebo Baseline End Point Change Baseline End Point Change Efficacy Variable n Mean (SD) Mean (SD) LS Mean T SE n Mean (SD) Mean (SD) LS Mean T SE 95% CI P CAARS-Inv:SV Total ADHD Symptoms score (7.4) 26.1 (11.4) j13.6 T (7.8) 30.2 (11.1) j9.3 T 0.8 j6.35 to 2.37 G CAARS-Inv:SV Hyperactivity/Impulsivity subscale (5.7) 11.5 (6.3) j6.1 T (5.7) 13.3 (6.3) j4.1 T 0.4 j3.04 to j0.99 G0.001 V CAARS-Inv:SV Inattention subscale (3.4) 14.6 (6.4) j7.6 T (3.6) 16.8 (6.3) j5.2 T 0.5 j3.51 to 1.19 G0.001 V AAQOL-29 Total score (13.6) 59.7 (17.2) 14.8 T (13.4) 55.3 (15.6) 10.6 T to AAQOL-29 Quality of Relationships Domain (19.1) 65.9 (20.3) 14.0 T (19.5) 61.6 (20.0) 9.6 T to V AAQOL-29 Life Productivity Domain (17.5) 53.8 (22.5) 20.1 T (17.8) 48.6 (20.9) 14.5 T to V AAQOL-29 Psychological Health Domain (18.3) 63.1 (20.6) 13.9 T (18.1) 59.7 (18.9) 9.8 T to V AAQOL-29 Life Outlook Domain (15.4) 61.8 (17.3) 8.3 T (15.1) 57.7 (16.6) 5.6 T 1.1 j0.33 to V CAARS-S:SV Total (9.1) 24.3 (11.8) j11.9 T (8.6) 28.5 (10.6) j7.8 T 0.7 j5.94 to 2.15 G CAARS-S:SV Hyperactivity/Impulsivity subscale (6.0) 11.1 (6.2) j5.5 T (5.6) 12.8 (5.8) j3.4 T 0.4 j2.97 to 1.09 G0.001 V CAARS-S:SV Inattention subscale (4.7) 13.3 (6.7) j6.4 T (4.6) 15.7 (6.1) j4.4 T 0.4 j3.11 to 0.90 G0.001 V CGI-S (0.7) 3.7 (1.2) j1.1 T (0.6) 4.1 (1.0) j0.7 T 0.1 j0.63 to j0.24 G PGI-I 189 NA 3.2 (0.08) NA 197 NA 3.4 (0.08) NA j0.45 to j NA BRIEF-A Global Executive Composite (21.5) (28.4) j22.4 T (21.5) (26.6) j14.8 T 1.9 j12.37 to j V MADRS Total Score (4.2) 5.9 (4.1) j0.7 T (4.1) 6.1 (4.2) j0.3 T 0.3 j1.19 to V BAI Total Score (9.5) 7.9 (9.4) j2.6 T (8.2) 7.3 (8.0) j2.1 T 0.7 j2.21 to V TLFB-Alcohol (1.1) 1.3 (2.3) j0.2 T (1.5) 1.6 (3.2) j0.1 T 0.1 j0.39 to V TLFB-Caffeine (1.7) 1.7 (1.8) j0.2 T (1.7) 1.6 (1.8) j0.2 T 0.1 j0.33 to V TLFB-Drugs (0.0) 0.5 (0.7) NA (0.4) 1.0 (0.0) NA NA NA V TLFB-Marijuana (0.7) 0.7 (0.9) 0.1 T (0.3) 0.3 (0.5) 0.0 T 0.1 j0.24 to V TLFB-Nicotine (7.3) 6.3 (7.0) 0.0 T (7.7) 6.4 (7.8) j0.8 T 0.5 j0.53 to V FTND Total Score (2.0) 1.9 (1.9) 0.1 T (2.1) 2.4 (2.5) 0.4 T 0.3 j1.00 to V SASS Total Score (6.4) 38.1 (6.7) 1.2 T (5.9) 38.7 (6.5) 1.5 T 0.4 j1.24 to V DBS-Self (12.5) 82.0 (13.0) 1.9 T (12.0) 82.2 (13.9) 3.5 T 1.0 j4.08 to V DBS-Observer (12.0) 74.1 (10.4) 3.2 T (8.1) 74.7 (13.8) 2.6 T 4.0 j16.41 to V ESS Total Score (4.7) 8.2 (4.7) j1.8 T (4.8) 8.8 (4.8) j1.1 T 0.3 j1.42 to V 95% CI indicates 95% confidence interval of the treatment difference (atomoxetine-placebo); LS, least-squares; n, number of participants with a baseline and at least 1 postbaseline result within each treatment group; NA, not available. Effect Size 50 * 2013 Lippincott Williams & Wilkins

7 Journal of Clinical Psychopharmacology & Volume 33, Number 1, February 2013 Atomoxetine Treatment of ADHD in Young Adults FIGURE 2. Attention-deficit/hyperactivity disorder categorical analysis of prespecified CAARS-Inv:SV and CGI-S response rates for all randomized participants. placebo-treated participants had statistically significant withingroup improvement on the PGI-I, the placebo group had statistically significantly greater improvement than the atomoxetine group (P = 0.02). After 12 weeks of treatment, there was no statistically significant difference between atomoxetine-treated and placebo-treated participants on the TLFB, the FTND, the SASS, the DBS-Self, the DBS-Other, or the ESS (Table 2). There were no statistically significant differences between treatment groups in improvements on the MADRS or the BAI; however, baseline scores were considered subthreshold for depression and anxiety, respectively. Treatment Response Rates Atomoxetine showed superiority over placebo on all 4 predefined response criteria (Fig. 2). No statistically significant differences between atomoxetine and placebo treatment groups were observed for baseline smoking status as a predictor for response or strong response to treatment. Safety Of the treatment-emergent adverse events reported by at least 5% of the participants in either treatment group, nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo during this study (Table 3). Erectile dysfunction was reported in 4.6% of male participants (n = 5) receiving atomoxetine treatment in comparison to none in the placebo group (P = 0.03). Other adverse events were not statistically significantly different between the treatment groups. Effects on vital signs and ECG parameters were consistent with previous observations. 18,19,33,34 Statistically significantly more participants in the atomoxetine treatment group (23.9%) than the placebo group (8.7%) experienced a 3.5% weight decrease or greater (P G 0.001). More participants receiving atomoxetine than placebo experienced an increase of 5 mm Hg or greater to a value above the 95th percentile on either diastolic (atomoxetine 5.9%, placebo 0.5%, P = 0.003) or systolic blood pressure (atomoxetine 5.9%, placebo 1.5%, P = 0.029). DISCUSSION This is the first large, prospective, placebo-controlled trial examining the effect of a medication to treat ADHD in a cohort of young adults. Results from this study provide evidence that atomoxetine 40 to 100 mg/d is superior to placebo in treating young adults (aged 18Y30 years) with ADHD. The improvement of ADHD symptoms with atomoxetine treatment (j13.6 on the CAARS Total ADHD Symptoms score) in this trial was consistent with reductions (j7.7 to j13.8 on the CAARS Total ADHD Symptoms score) shown in previous adult ADHD trials 18,19,33,34 and represents not only a statistically significant, but also a clinically meaningful improvement in symptoms. In this prospective trial, atomoxetine s effect size on ADHD symptom reduction (.40) was moderate and similar to previously reported adult ADHD trials. 18,33 This finding does not lend support to the hypothesis generated by a previously published post hoc analysis of data comparing the effect size of TABLE 3. Summary of Treatment-Emergent Adverse Events Occurring in at Least 5% of All Randomized Participants Who Took at Least 1 Dose Treatment-Emergent Adverse Events Participants with at least 1 event Atomoxetine (n = 188), n (%) Placebo (n = 197), n (%) Between-Group P* 145 (77.1) 122 (61.9) Nausea 30 (16.0) 11 (5.6) Decreased appetite 27 (14.4) 5 (2.5) G0.001 Insomnia 23 (12.2) 10 (5.1) Dry mouth 19 (10.1) 5 (2.5) Fatigue 13 (6.9) 13 (6.6) 1.0 Irritability 12 (6.4) 4 (2.0) Dizziness 11 (5.9) 3 (1.5) Dyspepsia 11 (5.9) 2 (1.0) Headache 11 (5.9) 18 (9.1) 0.25 Somnolence 10 (5.3) 4 (2.0) 0.11 Upper respiratory 10 (5.3) 13 (6.6) 0.67 tract infection Nasopharyngitis 6 (3.2) 10 (5.1) 0.45 *Treatment comparison was analyzed using Fisher exact test. n indicates number of participants with at least 1 adverse event. * 2013 Lippincott Williams & Wilkins 51

8 Durell et al Journal of Clinical Psychopharmacology & Volume 33, Number 1, February 2013 atomoxetine treatment in young adults (mean age = 21.6, effect size = 0.8) with older adults (mean age = 43.4, effect size = 0.3) that suggested that younger adults might experience a more consistent response to the medication. 16 The larger effect size for the younger adults in this post hoc analysis was driven by smaller variability and was not confirmed in the current trial. This trial found that atomoxetine improved not only ADHD symptoms but also quality-of-life outcomes in young adults as measured by the AAQOL-29. These results are similar to those from previous atomoxetine trials, which also showed improvement in quality of life. 18,19 Given the well-documented dysfunction across many domains of life experienced by young adults with ADHD, this finding of improvement of participants quality of life may be of particular value to clinicians. Also of interest is the finding in this trial of positive effects of atomoxetine on executive functioning in young adults with ADHD, in addition to ADHD DSM-IV core symptoms. The adverse event profile in this study was comparable to that observed in other atomoxetine trials in adults. 18,21,33,34 The discontinuation rate due to an adverse event for patients receiving atomoxetine was 9.5% and was fairly consistent with the 7.8% to 10.5% discontinuation rates from previous adult atomoxetine trials of similar duration. 18,33 In a previously published post hoc analysis, erectile dysfunction did not occur in adults 18 to 25 years old but was reported in 10.9% of adults older than 25 years in the atomoxetine treatment group. 16 In the current study of adults aged 18 to 30 years, 4.6% of the male participants (n = 5) receiving atomoxetine treatment reported erectile dysfunction. The changes noted in weight, ECG, and blood pressure in this study were not unexpected, given what has been observed in other adult atomoxetine trials. 18,19,33,34 Overall, atomoxetine was well tolerated in this population of 18- to 30-year-olds. The median baseline ESS score for all randomized participants was 10.0, indicating clinically significant dysfunction in sleep. 32 Therefore, half the participants in the trial had scores indicating that they should be further evaluated for sleep disorders. This finding is consistent with previous reports in the literature of sleep impairment co-occurring with ADHD 35,36 and serves as a reminder to clinicians who treat young adults with ADHD to be aware of the potential for comorbid sleep problems in their patients. Treatment with atomoxetine did not worsen daytime sleepiness as measured by the ESS. Although atomoxetine was superior to placebo on the investigator-rated CGI-S, participants who received placebo had greater improvements on the participant-rated PGI-I compared with atomoxetine-treated participants. This point is interesting, considering that participants treated with atomoxetine experienced statistically significantly greater symptom reduction on the participant-rated CAARS-S:SV Total ADHD Symptoms score compared with placebo. In addition, participants rated their driving behaviors more positively than did others. At both baseline and end point, self-ratings on the CAARS were lower than the investigator-rated scores. These findings underscore how this population may be generally less self-aware of their impairments than those around them. 37 In fact, in a longitudinal study in the literature that used self-report information, at age 21 years only 5% of participants thought that they had ADHD, even though they were significantly impaired, but by age 27 years, 30% of the same group thought that they did indeed have ADHD. 1 One limitation that should be considered when evaluating these data is that there were no adjustments for multiple comparisons except for the Gatekeeper analysis. Another potential limitation in this trial is the overrepresentation of white participants relative to African Americans and Hispanics compared with overall demographic trends in the US in this age group. 38 Previous analyses of atomoxetine treatment in children across racial/ethnic categories found no significant differences in efficacy or tolerability. 39,40 Nonetheless, the underrepresentation of minorities in this trial is consistent with a broader problem of the difficulties in minority recruitment in clinical trials in the United States. 41 The completion rate for this trial was lower than for other adult atomoxetine trials. 18,19,33,34 The higher-than-expected dropout rate could have contributed in not seeing a statistically significant difference between treatment groups for several of the secondary outcomes by reducing the statistical power. The fact that ADHD symptom improvement did not lead to significantly lower substance use is not surprising, because the study duration may not have been long enough to measure such a change. Also, the overall rates of substance use were low, which may have caused a floor effect, leaving the average rate of substance use very little room to decrease. Although the study design used a sham placebo lead-in period, there was still a substantial number of responders in the placebo group. Atomoxetine still separated from placebo in all 4 prespecified response criteria despite the presence of placebo responders. Placebo response is not unique to ADHD and varies among psychiatric disorders. 42 This trial and others point to the need to develop innovative study designs and to study placebo response across disease states. CONCLUSIONS This is the first prospective, placebo-controlled study demonstrating the efficacy of atomoxetine in ADHD focusing solely on the treatment of young adults (aged 18Y30 years). Statistically significant and clinically relevant differences in the improvements of ADHD symptoms, as well as quality-of-life outcomes, were observed between the atomoxetine and placebo groups. Overall, the efficacy and clinical response to atomoxetine were consistent with previous adult studies, as was the safety and tolerability profile. The results provide support for the use of atomoxetine for the treatment of ADHD in young adults. ACKNOWLEDGMENTS The authors thank the principal investigators and their research staffs, as well as the many participants who generously agreed to participate in this clinical trial. AUTHOR DISCLOSURE INFORMATION Dr Adler has received research funding from Bristol-Myers Squibb, Chelsea Therapeutics, Eli Lilly, National Institute of Drug Abuse, Pfizer, Shire; served on advisory boards or as a consultant for AstraZeneca Pharmaceuticals, Eli Lilly, i3 Research, Major League Baseball, Mindsite, Shire; served as a consultant for Epi-Q, INC Research, Otsuka Pharmaceuticals, and United Biosource; and has received royalty payments (as inventor) from NYU for license of adult ADHD scales and training materials. Dr McGough has received consulting honoraria and research support from Eli Lilly and consulting honoraria from Shire Pharmaceuticals. Dr Glaser has received research funding from Eli Lilly; consulting fees from Shire; and speaking honoraria from Bristol-Myers Squibb, Eli Lilly, and Shire. Dr Rubin has received research funding from Abbott, Eli Lilly, Johnson and Johnson, and Shire; consulting fees from Eli Lilly, Novartis, Shionogi, and Shire; and speaking honoraria from Eli Lilly and Shire pharmaceuticals. Dr Sarkis has received clinical research support from AstraZeneca, Boehringer- Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, 52 * 2013 Lippincott Williams & Wilkins

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