Atomoxetine in Adults with ADHD: Two Randomized, Placebo-Controlled Studies

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1 in Adults with ADHD: Two Randomized, -Controlled Studies David Michelson, Lenard Adler, Thomas Spencer, Frederick W. Reimherr, Scott A. West, Albert J. Allen, Douglas Kelsey, Joachim Wernicke, Anthony Dietrich, and Denái Milton Background: Attention-deficit/hyperactivity disorder (ADHD) has been less studied in adults than in children, and the treatment studies reported to date have been small, single-center trials. To assess the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, we conducted two large, multicenter treatment trials. Methods: Two identical studies using randomized, double-blind, placebo-controlled designs and a 10-week treatment period were conducted in adults with DSM-IVdefined ADHD as assessed by clinical history and confirmed by a structured interview (study I, n 280; study II, n 256). The primary outcome measure was a comparison of atomoxetine and placebo using repeated measures mixed model analysis of postbaseline values of the Conners Adult ADHD Rating Scale. Results: In each study, atomoxetine was statistically superior to placebo in reducing both inattentive and hyperactive and impulsive symptoms as assessed by primary and secondary measures. Discontinuations for adverse events among atomoxetine patients were under 10% in both studies. Conclusions: appears to be an efficacious treatment for adult ADHD. Its lack of abuse potential may be an advantage for many patients. Biol Psychiatry 2003; 53: Society of Biological Psychiatry Key Words:, ADHD, adults, nonstimulant Introduction Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by difficulties sustaining attention and difficulties with impulse control. Evidence suggests that genetic factors are important in its From Lilly Research Laboratories (DM, AJA, DK, JW, DM) and Indiana University School of Medicine (DM), Indianapolis, Indiana; New York University (LA), New York, New York; Massachusetts General Hospital (TS), Boston, Massachusetts; University of Utah (FWR), Salt Lake City, Utah; Psychiatric Institute of Florida (SAW), Orlando, Florida; Neuropsychiatric Associates (AD), Woodstock, Vermont. Address reprint requests to David Michelson, M.D., Lilly Research Laboratories, DC 6026, Indianapolis Indiana Received April 26, 2002; revised August 12, 2002; accepted August 26, pathogenesis (Hudziak 1997) and that its pathophysiology involves alterations in central dopaminergic and noradrenergic tone (Biederman et al 1999a; Safer 2000). The disorder begins early in life and has been studied primarily in children, among whom its prevalence is 3 7% (American Psychiatric Association 2000). As children mature, symptoms can become less problematic, most likely through developmental changes in the brain, by learning to compensate for deficits with adaptive behaviors, or by gravitating toward environments that make fewer demands in areas of impairment; however, the disorder often persists into adulthood (Biederman et al 2000; Weiss 1985) and is associated with significant morbidity and undesirable outcomes (Brown et al 1986; Hechtman 1996; Klein and Mannuzza, 1989, 1991; Murphy and Barkley 1996; Seidman et al 1998; Thorley 1984; Weiss 1996; Weiss and Hechtman 1993). Pharmacotherapies effective in children appear to be valuable in adults (Spencer et al 1995; Wender and Reimherr, 1990; Wender et al 1985; Wilens et al 1996); however, the literature on treatment of adult ADHD is limited. Published studies have been small and have differed in the methodologies used for diagnostic ascertainment and symptom assessment. No large, paralleldesign, placebo-controlled trial using rigorous diagnostic and assessment procedures has been reported to date for any agent. The most widely used medications for ADHD are the psychostimulants methylphenidate and amphetamine (Popper 2000). There is, however, considerable interest in alternative, nonstimulant therapies, because some patients respond poorly to stimulants or are unable to tolerate them. In addition, some physicians are reluctant to use stimulants because of concerns about misuse in a population at increased risk for substance abuse (Wilens and Biederman 1992), although whether treatment with psychostimulants increases risk for substance abuse in adult ADHD is controversial (Biederman et al 1999b; Wilens 2000). The current alternatives to stimulants are primarily the antidepressants desipramine and bupropion. These are efficacious in children (Biederman et al 1989; Conners et al 2003 Society of Biological Psychiatry /03/$30.00 doi: /s (02)

2 in Adults with ADHD BIOL PSYCHIATRY ) and have been superior to placebo in small studies in adults (Wilens et al 1996, 2001), but neither drug is approved for the treatment of ADHD, and desipramine has a low therapeutic index and can adversely affect cardiac conduction. The investigational drug atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter (Ki 4.5nM) with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters. It is efficacious in children and adolescents with ADHD (Michelson et al 2001), and preliminary data suggest efficacy in adults (Spencer et al 1998). does not appear to have abuse potential (Heil et al 2002), and unlike desipramine, atomoxetine is not associated with adverse effects on cardiac conduction (Michelson et al 2001). To assess the efficacy of atomoxetine for adult ADHD, we conducted two large, prospective, doubleblind, placebo-controlled, randomized studies. We report the results of these studies here. Methods and Materials Two identical randomized, double-blind, placebo-controlled studies were conducted concurrently at 17 (study I) and 14 (study II) outpatient sites in North America. Adults who met DSM-IV (American Psychiatric Association 2000) criteria for ADHD as assessed by clinical interview and confirmed by the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAAR-D; Conners et al 1999) were recruited from clinics and by advertisement. Patients were required to have at least moderate symptom severity, and the diagnosis had to be corroborated by a second reporter for either current symptoms (by a significant other) or childhood symptoms (by a parent or older sibling). If the second reporter s rating did not corroborate the patient s report, the patient was ineligible to participate in the study. Comorbid psychiatric diagnoses were assessed by clinical interview and by the Structured Clinical Interview for DSM-IV (SCID; First et al 2000). Patients who met diagnostic criteria for current major depression or anxiety disorder or for current or past bipolar or psychotic disorders were excluded, as were patients with serious medical illness and patients who met DSM-IV criteria for alcohol dependence. A history of episodic recreational drug use did not exclude patients, but patients actively using drugs of abuse at the time of study entry were excluded. Urine screening for drugs of abuse was performed at the initial visit and could be repeated at any time during the trial at the investigator s discretion. Following an initial 1-week medication washout and evaluation period, patients entered a 2-week placebo lead-in phase (modified double blind, because efficacy raters were blind to the protocol, but others at the investigative sites were not). Patients who maintained the initial severity criteria required for study entry were randomized to receive atomoxetine or placebo for a 10-week period, during which visits were biweekly. Patients were randomized according to computer-generated treatment codes obtained from an interactive voice-response system. Study drug materials for both treatment groups were identical in appearance. Adherence was assessed by pill counts and history. Each site s institutional review board evaluated and approved the study protocol. After description of the procedures and purpose of the study and before the administration of any study procedure or dispensing of study medication, written informed consent was obtained from each patient. The study was conducted in accordance with the ethical standards of each of the investigative sites institutional review boards and with the Declaration of Helsinki 1975, as revised in The primary outcome measure was the sum of the Inattention and Hyperactivity/Impulsivity subscales of the investigator-rated CAARS, for which psychometric data have been reported (Conners et al 1999). Each of the 18 items of these subscales corresponds to one of the 18 DSM-IV symptoms for ADHD and is rated on a 4-point scale. At each visit clinicians also rated a Clinician Global Impression of Severity Scale (CGI-S; Guy 1976). Before starting the study, efficacy raters were required to attend a training session using observed interviews and group discussion to standardize rating practices for the CAARS. Efficacy raters for the primary outcome measure were blind to all details of the study design, including severity criteria for entry, dose titration, and timing of the initiation of therapy, and were not allowed to evaluate or ask about adverse events. At baseline and end point, patients completed a self-rated version of the CAARS and the Wender Reimherr Adult Attention Deficit Disorder Scale (WRAADDS; Wender et al 1985). Anxiety and depressive symptoms were assessed with the Hamilton Anxiety and 17-item Hamilton Depression Rating scales (Hamilton 1960), respectively, whereas changes in social and occupational functioning were assessed using the Sheehan Disability scale (a self-report scale that assesses work, family, and social functioning). was administered in evenly divided doses in the morning and late afternoon early evening beginning at a total daily dosage of 60 mg. Patients with residual symptoms had their dosage increased to 90 mg/day after 2 weeks and to 120 mg/day after 4 weeks. If tolerability problems developed, dosage could be decreased to the last tolerated dosage or an increase omitted. Safety and tolerability were assessed at each visit by openended questioning for adverse events and by monitoring of vital signs and laboratory data. Statistical Methods Results were analyzed on an intent-to-treat basis. The primary analysis was a comparison between treatment groups using a repeated measures mixed model with the MIXED procedure in SAS (SAS Institute 1997) that contained fixed class effect terms for treatment, investigative site, visit, and interaction between treatment and visit. The model included postbaseline values of the investigator-rated CAARS Total ADHD Symptom Score as the dependent variable with a random patient effect and baseline investigator-rated CAARS Total ADHD Symptom Score as a covariate and used an unstructured covariance. In addition to the sum of the 18-item score, investigator-rated CAARS Inattentive and Hyperactive/Impulsive subscales were also computed. If more than one item of a subscale was missing, the score for the

3 114 BIOL PSYCHIATRY D. Michelson et al Figure 1. Patient flow diagram: Study I. LOE, loss of efficacy. subscale (and the total score) was also considered missing. If only a single item was missing, the mean score for all other items in the subscale was imputed as the score for the missing item. For the self-reported CAARS, outcomes are presented as t scores to allow comparison of symptom severity in the study population relative to healthy adults; t scores are transformations of raw scores based on normative data adjusted for age and gender, such that the normative mean is assigned a t score of 50, and a change of 1 SD is represented by a change in t score of 10 points. Thus, for example, a patient with a raw score 3.2 SD above the population mean would have a T score of 82. Secondary efficacy analyses of primary and secondary outcomes included all patients with at least 1 postbaseline measurement. Safety analysis included all patients who took at least 1 dose of study drug. Secondary efficacy analyses and safety analysis of continuous measures were performed using a last observation carried forward (LOCF) approach to compare mean change values from baseline to end point using an analysis of variance (ANOVA). Treatment differences in binary measures were assessed using Fisher s Exact Test. All tests used a two-sided significance level of.05. Results Of 448 patients initially assessed in study I, 280 met entry criteria and were randomized to atomoxetine (n 141) or placebo (n 139). In study II, 388 patients were assessed, and 256 met entry criteria and were randomized to atomoxetine (n 129) or placebo (n 127). Details of reasons for failure to be randomized (including all patients who signed consent but discontinued before the placebo lead-in as well as those who entered the placebo lead-in) are provided in Figures 1 and 2. Among patients who met initial screening criteria and entered the placebo lead-in phase, 19 of 318 (6.0%) in study I and 12 of 287 (4.2%) in study II were not randomized because their symptoms improved in response to placebo. Patient characteristics Figure 2. Patient flow diagram: Study II. LOE, loss of efficacy.

4 in Adults with ADHD BIOL PSYCHIATRY 115 Table 1. Patient Characteristics and Baseline Symptom Severity by Study (n 139) Study I (n 141) p Value (n 127) Study II (n 129) p Value Gender Male 87 (62.6) 91 (64.5).804 a 87 (68.5) 83 (64.3).510 a Female 52 (37.4) 50 (35.5) 40 (31.5) 46 (35.7) Age Mean (SD) 40.3 (11.6) 40.2 (11.7).976 b 41.2 (11.2) 43.0 (10.3).186 b ADHD Subtype Combined 100 (71.9) 101 (71.6) 1.00 a 75 (59.1) 80 (62.0).326 a Inattention 38 (27.3) 39 (27.7) 44 (34.6) 46 (35.7) Hyperactive/Impulsive 1 (.7) 1 (.7) 8 (6.3) 3 (2.3) Previous Stimulant Exposure 68 (48.9) 62 (44.0).472 a 55 (43.3) 65 (50.4).263 a CAARS-INV Mean (SD) Total ADHD Symptom Score 33.2 (7.8) 33.6 (7.2).603 b 34.2 (7.5) 34.9 (6.9).597 b Inattentive 18.6 (4.4) 18.4 (4.2).736 b 19.3 (4.3) 20.0 (4.1).223 b Hyperactive/Impulsive 14.5 (5.4) 15.2 (5.0).309 b 14.9 (5.2) 14.8 (4.8).785 b CAARS-Self (t Score) Mean (SD) Total ADHD Symptom Score 80.8 (12.3) 82.6 (12.7).291 b 80.0 (13.8) 82.6 (12.2).179 b Inattentive 85.6 (12.7) 87.5 (12.5).249 b 84.4 (15.4) 87.4 (12.7).161 b Hyperactive/Impulsive 68.4 (13.0) 69.7 (13.6).517 b 68.3 (14.1) 69.7 (11.7).511 b CGI-ADHD-S Mean (SD) 4.7 (.7) 4.7 (.8).886 b 4.6 (.7) 4.6 (.6).769 b WRAADDS Mean (SD) 17.6 (4.2) 18.3 (4.7).109 b 15.5 (5.7) 16.5 (5.0).275 b HAMD-17 Mean (SD) 5.9 (3.9) 5.1 (3.6).073 b 4.6 (3.3) 4.7 (3.7).918 b HAMA Mean (SD) 8.2 (4.8) 7.4 (5.2).169 b 5.9 (4.5) 6.5 (5.1).333 b ADHD, attention-defict/hyperactivity disorder; CAARS, Conners Adult Attention Rating Scale; INV, Investigator rated; CGI-ADHD-S, Clinical Global Impressions of Severity of ADHD Symptoms; WRAADDS, Wender Reimherr Adult Attention Deficit Disorder Scale; HAMD-17, 17 Item Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale. a Treatment comparisons conducted using Fisher s Exact Test. b Treatment comparisons conducted using analysis of variance. and baseline symptom severity for each study are provided in Table 1. A majority of patients were men, and most patients met criteria for the combined subtype of ADHD. Overall symptom severity in all groups was approximately 3 SD above mean normative total CAARS self-report scores, with inattentive symptoms more prominent than hyperactive symptoms (Table 1). There were no statistically significant differences in demographics and baseline severity between treatment groups in either study. Efficacy results are summarized in Table 2. In both studies, atomoxetine was superior to placebo in reduction of ADHD symptoms as assessed by the primary outcome measure. No treatment-by-site interaction was observed in either study. Both the Attention and Hyperactive/Impulsive subscales improved significantly in the atomoxetine groups compared with placebo groups in each study, and outcomes were similar among patients with the combined ADHD subtype and the inattentive subtype. No statistically significant interactions between treatment and gender or treatment and age (dichotomized in each study by median age) were observed in either study. The treatment effect size (defined as the difference between treatment groups in least squares means divided by the square root of the mean square error for the entire sample) for the primary outcome measure was 0.35 in study I and 0.40 in study II. Statistically significant change favoring atomoxetine was also observed in both studies on secondary assessments including the CAARS self-reports, the WRAADS, and the CGI-S. In both studies atomoxetine was statistically significantly superior to placebo at the first postrandomization visit; from the third postrandomization visit it was superior to placebo at every visit in each study. There was no difference between groups in change in Hamilton Anxiety rating scale scores for either study. In study II but not study I a small but statistically significant reduction favoring placebo was observed in the 17-Item Hamilton Depression Rating Scale score. At end point, the most frequently prescribed dose was 90 mg (study I: 40.4%; study II: 38.8%), followed by 120 mg (study I: 39.7%; study II: 34.9%) and 60 mg (study I: 19.9%; study II: 26.4%). Patient disposition by study is summarized in Table 3. Compared with placebo, a greater proportion of patients taking atomoxetine discontinued from study II but not study I due to adverse events (Table 3). No serious safety concerns were observed in either study. was associated with modest increases in blood pressure (all values expressed as mean [SD] change from baseline to end point in mm Hg: diastolic: study I: placebo 0.5 [7.8], atomoxetine 2.3 [8.1], p.063; study II: placebo 0.6 [7.7], atomoxetine 1.2 [9.0], p.556; systolic: study I:

5 116 BIOL PSYCHIATRY D. Michelson et al Table 2. Efficacy Outcomes by Study, Mean (SD) Change from Baseline to End-Point (n 134) Study I (n 133) (95% CI) p Value a (n 124) Study II (n 124) (95% CI) CAARS-INV Total ADHD Symptom 6.0 (9.3) 9.5 (10.1) ( 5.61,.99) (9.3) 10.5 (10.9) ( 6.40, 1.49).002 Score Inattentive 3.1 (5.8) 5.0 (5.7) ( 3.21,.45) (5.3) 5.8 (6.5) ( 3.84,.94).001 Hyperactive/Impulsive 2.9 (4.9) 4.5 (5.1) ( 2.67,.27) (4.7) 4.7 (5.3) ( 2.78,.33).013 CAARS-Self (T Scores) Total ADHD Symptom 9.3 (14.0) 16.0 (16.2) ( 10.53, 2.47) (16.1) 17.3 (17.6) ( 10.83, 1.61).008 Score Inattentive 8.6 (13.8) 15.9 (16.3) ( 11.00, 2.94) (16.6) 17.1 (17.9) ( 10.81, 1.34).012 Hyperactive/Impulsive 7.5 (12.1) 11.9 (13.5) ( 7.75,.94) (13.4) 12.5 (14.1) ( 8.05,.54).025 CGI-ADHD-S.4 (1.0).8 (1.2) (.61,.08) (1.0).9 (1.2) (.67,.15).002 WRAADDS 2.9 (4.8) 5.3 (6.6) ( 3.80,.91) (5.7) 4.5 (5.9) ( 3.27,.07).041 HAMD-17.6 (4.2).3 (3.8) (.72, 1.34) (3.5).2 (3.6) (.26, 2.21).013 HAMA 1.2 (4.8) 1.0 (5.3) ( 1.16, 1.38) (5.4).7 (4.3) ( 1.12, 1.57).738 Sheehan Disability Total 2.9 (7.7) 4.5 (8.3) ( 5.14,.41) (6.9) 4.4 (7.9) ( 3.21, 1.83).589 Work Life 1.0 (3.3) 1.6 (3.1) ( 2.22,.36) (2.9) 1.8 (3.0) ( 1.76,.20).118 Family Life 1.0 (2.8) 1.5 (3.2) ( 1.64,.12) (2.7) 1.4 (2.8) ( 1.08,.80).773 Social Life.9 (3.0) 1.3 (3.1) ( 1.65,.20) (2.8) 1.2 (2.9) (.77, 1.22).654 p Value a WRAADDS, Wender Reimherr Adult Attention Deficit Disorder Scale; HAMD-17, 17 Item Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale; CAARS, Conners Adult Attention Rating Scale; INV, Investigator rated; CGI-ADHD-S, Clinical Global Impressions of Severity of ADHD Symptoms; 95% CI, 95% confidence interval of the treatment difference (atomoxetine-placebo). a Treatment comparisons conducted using analysis of variance. placebo 0.8 [9.8], atomoxetine 2.3 [11.1], p.015; study II: placebo 0.9 [11.1], atomoxetine 3.5 [10.6], p.059) as well as heart rate (mean [SD] change in beats/min: study I: placebo 0.5 [9.3], atomoxetine 6.7 [11.6], p.001; study II: placebo 0.1[9.6], atomoxetine 3.8 [10.2], p.002). Pooled adverse event data are presented in Table 4. No meaningful differences between groups in laboratory results were observed. Discussion In two large, identical studies conducted concurrently, atomoxetine was superior to placebo in reduction of ADHD symptoms in adults. Outcomes were similar for most measures across the two studies, and both attention and hyperactive/impulsive symptoms improved with drug treatment. Psychostimulants (methylphenidate and amphetamine), desipramine, and bupropion have been reported to be effective in adults with ADHD (Wilens et al 2001); however, all studies reported to date have been small, several used crossover rather than parallel designs, and most did not exclude patients with comorbid psychiatric disorders that could have confounded efficacy assessments. No study has been large enough to provide reliable estimates of treatment effect sizes or evidence that adult ADHD can be reliably identified and studied in large populations by different investigators. We are aware of only one study Table 3. Patient Disposition by Study Reason (N 139) Study I (N 141) p Value a (N 127) Study II (N 129) Completed Acute Treatment Phase 107 (77.0) 103 (73.1) (81.9) 94 (72.9).101 Adverse Event 6 (4.3) 11 (7.8) (2.4) 12 (9.3).030 Lack of Efficacy 3 (2.2) 3 (2.1) (4.7) 5 (3.9).768 Physician Decision 0 1 (.7) (.8) 1 (.8) 1.00 Protocol Violation/Entry Criteria Not Met 4 (2.9) 1 (.7) (2.4) 1 (.8).368 Other b 19 (13.7) 22 (15.6) (7.9) 16 (12.4).301 a Treatment comparisons conducted using Fisher s Exact Test. b Includes personal conflict, patient moved, lost to follow-up, and sponsor s decision. p Value a

6 in Adults with ADHD BIOL PSYCHIATRY 117 Table 4. Treatment-Emergent Adverse Events Reported by at Least 5% of Patients and Statistically Significantly More Frequent Than Event (N 263) (N 269) p Value a Dry Mouth 18 (6.8) 57 (21.2).001 Insomnia 23 (8.7) 56 (20.8).001 Nausea 13 (4.9) 33 (12.3).003 Decreased Appetite 9 (3.4) 31 (11.5).001 Constipation 10 (3.8) 29 (10.8).002 Libido Decreased 5 (1.9) 19 (7.1).006 Dizziness 5 (1.9) 17 (6.3).015 Difficulty Attaining or 2 (1.2) 17 (9.8).001 Maintaining Erection b Sweating 2 (.8) 14 (5.2).004 Numbers represent all patients who took at least one dose of study medication from studies I and II. a Treatment comparisons conducted using Fisher s Exact Test. b Percentage based on men only (placebo n 172; atomoxetine n 174). with more than 41 patients (a five-arm, 279 patient assessment of the experimental compound GW presented in abstract form), and its results provided mixed evidence for efficacy (DeVeaugh-Geiss et al 2001). The results of our studies are consistent with previous reports but go beyond them in size, methodologic rigor, and in providing an initial test of efficacy as well as a replication. Several factors may limit the interpretation of our results. The DSM-IV diagnosis of ADHD requires the onset of symptoms before age 7. This can only be assessed historically, because many adults with ADHD may not have come to medical attention as children and because diagnostic criteria have evolved greatly over the past 20 years. Therefore, recall bias could affect the reliability of the diagnosis. We also note that patients who participated in these studies may not be representative of the broader universe of adults with ADHD, because patients with common comorbid psychiatric disorders, including depression and anxiety, were excluded. Also, we cannot rule out the possibility that investigators may have tended to exclude the most severely affected patients out of concern for their ability to cope with the structure and organization demanded by a clinical trial. This study was not designed to assess the efficacy of atomoxetine relative to other compounds used to treat adult ADHD and therefore did not include an active comparator. Among children, the efficacy of atomoxetine compared with stimulants has not been established, although preliminary studies suggest the magnitude of response is within a comparable range (Kratochvil et al 2002). Comparisons of the data presented here to previous adult ADHD studies are difficult to interpret because of their small sample size and methodologic limitations. Further complicating comparisons, ours were multicenter studies that incorporated design elements intended to reduce nonspecific effects, including blinded efficacy raters, separate safety and efficacy raters, and double-blind placebo lead-ins. These probably reduced observed response rates in both treatment arms and have not been used in other studies of adult ADHD. We cannot definitively assess dose response and time course of response because these studies employed a dose-titration design that confounds time and dose effects; however, the most common final dose, 90 mg/day, is approximately 1.3 mg/kg/day in a 70 kg adult. This is consistent with the results of a dose-finding study in children (Michelson et al 2001) that demonstrated a maximal effect at approximately 1.2 mg/kg/day, suggesting that dose response in adults is likely to be similar to that in children. With respect to onset of response, statistically significant separation from placebo in both studies was noted as early as the first postrandomization visit (week 2); however, scores on the investigator-rated CAARS continued to decline in the atomoxetine-treated group through most of the study, well after patients could have attained the highest dose. Thus, although onset of a drug-specific effect is rapid, longer periods of time appear to be required to attain a maximal response. As noted earlier, no comparably large sample of adults with ADHD has previously been as systematically or rigorously characterized with respect to diagnosis, symptoms, or treatment response. In this regard, the findings are also important for what they reveal about the disorder in adults and, at least with respect to atomoxetine, its response to treatment. In particular, comparisons with pediatric atomoxetine studies (Heiligenstein et al 2000; Kratochvil et al 2002; Michelson et al 2001) conducted by many of the same investigators using similar designs, dose ranges, and a primary symptom assessment that mirrored exactly that used in the adult studies in number, scoring, and content of the items, are of interest. Perhaps most striking is the differential severity of symptoms between children and adults at baseline. ADHD symptoms are generally divided in two major clusters, inattentive and hyperactive/impulsive. Approximately one third of patients met criteria for the inattentive subtype without prominent hyperactive/impulsive symptoms in both of the adult studies; however, mean symptom severity relative to healthy subjects was considerably greater for the inattentive cluster (more than 3.5 SD above age and gender norms in both studies) than for the hyperactive/ impulsive cluster (less than 2 SD above norms for both studies). In four acute placebo-controlled pediatric atomoxetine studies (Heiligenstein et al 2000; Michelson et al 2001, in press), the proportion of pediatric patients who met criteria for the inattentive subtype was similar (typically about 30%); however, mean overall scores at base-

7 118 BIOL PSYCHIATRY D. Michelson et al line on the primary outcome measure were typically 10 15% higher than those in adults and more evenly distributed across symptom clusters. These data suggest a tendency for children to have more hyperactive signs and symptoms than adults. This finding is consistent with a previous report that with maturation, inattentive symptoms become more prominent and hyperactive symptoms recede (Biederman et al 2000). Alternatively, this difference could reflect a selection bias in that children who are inattentive but not particularly hyperactive may tend to go unnoticed, whereas adults bothered by inattention can seek help. Both inattentive and hyperactive/impulsive symptom clusters responded to atomoxetine in adults and children. Among adults, the magnitude of change for the inattentive cluster was greater than that observed in the hyperactive/ impulsive cluster, with reductions of approximately SD relative to inattentive symptom norms versus approximately 1.2 SD relative to hyperactive/impulsive symptom norms (note that not all this reduction can be attributed to drug specific effects in light of the observed changes in the placebo group). At end point, however, inattentive symptoms remained more prominent than hyperactive symptoms. By contrast, in the four placebocontrolled pediatric studies noted earlier, the pattern of change was more uniform across symptom clusters. These differences in response seem most likely to be accounted for by the greater initial severity of the inattentive symptoms relative to hyperactive symptoms in adults, although we cannot definitively rule out the possibility that this finding reflects true differences in symptom response between adults and children. It is also of interest that the treatment effect sizes for the primary outcome measure in the adult studies (0.35 and 0.40) are consistent with those seen in large efficacy studies in adult psychiatric disorders such as depression (Bech et al 2000) and were somewhat smaller than those previously observed in the atomoxetine studies in children and adolescents, which ranged from in the four placebo-controlled studies. This discrepancy is most likely related to the greater placebo response among adults compared with children, which reduced the observed difference between treatment arms in the adult studies, as well as to the lower absolute total scale scores at baseline among adults compared with children. It is possible that the apparent differences in response between adults and children are artifacts of cross-study comparisons or idiosyncrasies of different study populations. Alternatively, they could be related to differences in symptom assessment and expression. In children, diagnosis and symptom ratings are largely based on observable behaviors; however, as adaptive mechanisms and greater self-control develop with maturation, the symptoms expressed as hyperactivity in a child may evolve to become feelings rather than actions (e.g., feeling like jumping up or blurting out). As a result, the problems that symptoms cause for many adults may be more related to the internal tension and discomfort related to suppressing and controlling these feelings than to hyperactive behavior as such, making assessment more reliant on subjective descriptions of feeling states. Similarly, the translations of child behaviors into adult equivalents may not be optimal in currently available instruments, potentially leading to inaccurate estimates of treatment effects because of insensitivity of the assessment tool. Finally, although reliance on self-report for evaluation is necessarily greater in adults than in children, the hallmark of the disorder inattention suggests that patients with ADHD may not be optimal self-observers. Therefore, it is possible that an end point observer-rated scale might have captured aspects of change not reported by patients and that some of the differences between children and adults are attributable to the fact that symptom ratings in children with ADHD are typically provided by their parents, whereas symptom ratings in adults are typically provided by the patients themselves. Little controlled data about the effects of treatment of adult ADHD on occupational and social functioning is available for any drug. In children we have observed a marked improvement in overall psychosocial and role functioning that coincided with core ADHD symptom improvements (Michelson et al 2001). Impairments associated with ADHD in adults are probably related not only to core symptoms, but also the developmental consequences of growing up with those symptoms. This probably affects the degree of reasonably expectable improvement, particularly during acute treatment, as well as the time course of response. Our studies were primarily designed to test for evidence of drug-specific effects on reducing symptoms of ADHD. Both studies, however, included the Sheehan Disability scale at baseline and end point in an effort to provide some information about changes in social and occupational functioning during treatment. In study I, atomoxetine was superior to placebo on the overall Sheehan Disability score as well as the work-life subscale, and differences between atomoxetine and placebo approached statistical significance for the family life scale. These results suggest that improvements in core ADHD symptoms related to atomoxetine also led to some drug-specific improvements in functional status. These differences were not replicated in study II, however, and more definitive conclusions regarding the effects of atomoxetine treatment on social and occupational functioning will require further studies. It is of interest to speculate about the mechanism by which atomoxetine improved ADHD symptoms. The psychostimulants, which have been the most widely used treatments for ADHD, are generally thought to act primar-

8 in Adults with ADHD BIOL PSYCHIATRY 119 ily via effects on dopaminergic systems. is very specific for the norepinephrine transporter and does not appear to be pharmacologically active at dopaminergic receptors, suggesting that its effects are likely mediated by norepinephrine; however, in vitro studies suggest that in the prefrontal cortex, norepinephrine and dopamine are coreleased by noradrenergic neurons (Devoto et al 2001). This is consistent with preclinical studies demonstrating that atomoxetine increases dopamine in the rat prefrontal cortex but not the nucleus accumbens or striatum (Bymaster et al, in press), potentially accounting for its efficacy in ADHD as well as its lack of abuse potential (Heil et al 2002). Alternatively, the improvements observed in this study could have been secondary to improvements in mood or anxiety because drugs that inhibit norepinephrine reuptake are associated with antidepressant effects (Versiani et al 2000). This seems unlikely to account for atomoxetine s effects on ADHD symptoms in the studies reported here, however. Patients with comorbid depressive or anxiety disorders were excluded, baseline scores on both Hamilton depression and anxiety scales were low, and no clinically meaningful change in anxiety or depression scores occurred in either study. No serious safety concerns were observed during the 10-week treatment period. The tolerability profile in adults differed somewhat from that seen in children, with more adverse events consistent with increased noradrenergic tone, including insomnia, gastrointestinal, and genitourinary symptoms, but overall tolerability appears to have been satisfactory, evidenced by discontinuation rates for adverse events under 10% over 10 weeks of treatment in both studies. Modest mean increases in blood pressure and heart rate were not associated with tolerability problems for most patients and appear to be comparable in magnitude to those associated with stimulants (Kratochvil et al 2002) but suggest that atomoxetine should be used cautiously in patients with hypertension or other risk factors. In summary, these studies represent the largest, most rigorous demonstrations of the efficacy of pharmacotherapy in adults with ADHD. In both studies, atomoxetine was efficacious and without serious safety concerns. appears to provide a promising therapy for adults with ADHD, and its lack of abuse potential may be an advantage for many patients. was originally called tomoxetine. The name was changed to avoid confusion with tamoxifen which might lead to errors in dispensing drug. This research was funded by Eli Lilly and Company. The authors thank Nancy J. Trapp for her contributions to this manuscript. The following were study investigators for these studies: Lenard Adler, M.D., Hospital for Joint Disease, New York, NY; Richard J Burch, M.D., University of Missouri Columbia, Columbia, MO; Edward Cherlin, M.D., Valley Clinical Research, El Centro, CA; Anthony P. Dietrich, M.D., Neuropsychiatric Associates, Woodstock, VT; David Feifel, M.D., Ph.D., UCSD Medical Center-Hillcrest, San Diego, CA; Carlos Figueroa, M.D., Research Stratreties, Inc., Torrance, CA; Samuel Kuperman, M.D., University of Iowa Hospitals and Clinics, Iowa City, IA; Peter Londborg, M.D., Cabrini Medical Tower, Seattle, WA; Frederick Reimherr, M.D., University of Utah Medical Center, Salt Lake City, UT; Michael J. Rieser, M.D., Psychiatry and Neurobehavioral Medicine, Lexington, KY; Robert Riesenberg, M.D., Atlanta Center for Medical Research, Atlanta, GA; Leon I. Rosenberg, M.D., Center for Emotional Fitness, Moorestown, NJ; Betty Jo Salmeron, M.D., Milwaukee, WI; Paul Winner, D.O., Premier Research Institute, West Palm Beach, FL; Neil Allen, M.D., Consultants in Neurology, Ltd., Wilmette, IL; Henry F. Crabbe, M.D., Ph.D., Psychiatric Medicine Center, PC, New London, CT; Howard A. Hassman, D.O., Comprehensive Clinical Research, Clemontone, NJ; Stephen R. Luber, M.D., Rockwood Clinic, PS, Spokane, WA; James J. McGough, M.D., Los Angeles, CA; Matthew A. Menza, M.D., UMDNJ Robert Wood Johnson Medical School, Piscataway, NJ; Randall Ricardi, D.O., Arizona Family Resource Counseling Center, Phoenix, AZ; Murray Rosenthal, D.O., Behavioral and Medical Research, San Diego, CA; R. Bart Sangal, M.D., Director Clinical Neurobiology Services, PC, Troy, MI; Keith E. 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