Study design and procedures

This is a secondary analysis of data from two almost identical multi-center, single-arm, open-label studies in two different age groups (children and adolescents) that were designed to investigate the quality of life in patients with ADHD treated with atomoxetine as reflected by the degree of difficulties perceived by patients, parents and physicians [28, 29]. Patients were recruited from child and adolescent psychiatric and pediatric practices and outpatient clinics throughout Germany. Patients aged 6–17 years with ADHD as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [1] were eligible for the studies. The diagnosis was confirmed using the "Diagnose-Checkliste Hyperkinetische Störungen" (Diagnostic Checklist for Hyperkinetic Disorders), a structured instrument which is routinely used for the diagnostic assessment of ADHD in Germany [35]. The items of this instrument correspond to those of the ADHD-RS [21, 22]. Patients had to have an IQ of ≥70 based on the clinical judgment of the investigator. The exclusion criteria included clinically significant abnormal laboratory findings, acute or unstable medical conditions, cardiovascular disorder, history of seizures, pervasive developmental disorder, psychosis, bipolar disorder, suicidal ideation, any medical condition that might increase sympathetic nervous system activity, or the need for psychotropic medication other than study drug. Patients already being treated with atomoxetine were also excluded. Other previous treatments were allowed, provided they were discontinued prior to enrolment in the study. The protocol was approved by an ethics committee, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Following a wash-out period, baseline assessments were carried out with all the instruments used. During the first week of treatment, the patients received atomoxetine at a dose of approximately 0.5 mg/kg body weight (BW) per day. During the following 7 weeks, the recommended target dose was 1.2 mg/kg BW per day, but could be adjusted within a range of 0.5–1.4 mg/kg BW per day, depending on effectiveness and tolerability. Medication was given once a day in the morning. Assessments were carried out weekly during the first two weeks of treatment, and every two weeks thereafter. After the 8 week treatment period, the physicians decided in accordance with the patients and their parents whether the patient was to continue treatment for additional 16 weeks. Those who participated in this extension period continued on the same atomoxetine dose which again could be adjusted within a range of 0.5–1.4 mg/kg BW per day as considered appropriate by the physician. During the extension period, three assessments were carried out, after 12, 16, and 24 weeks after baseline. The following instruments were used to assess efficacy: Global Impression of Perceived Difficulties (GIPD), Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS), Clinical Global Impression-Severity (CGI-S), and the Weekly Rating of Evening and Morning Behavior – Revised (WREMB-R). The results from these scales have been published elsewhere [28, 29].

In order to assess the tolerability of atomoxetine in more detail than is possible using spontaneous adverse event reports, the Pediatric Adverse Event Rating Scale (PAERS) [30] was used in the two studies reported here. The data from both studies were combined and analyzed together. Tolerability assessments included monitoring vital signs at every visit and recording all spontaneously reported adverse events, followed by a systematic elicitation of any further adverse events using the PAERS. First, the physician asked an open question as to any adverse events. Then, the patient and the parent (or other primary caregiver) filled out the PAERS independently and without any interference by the physician. Both the patient and the parent had to rate each adverse event in terms of how bothersome or how much of a problem it was during the past week on a scale from 0 (= not present) to 4 (= a lot). If the patient was unable to fill out the scale all by him or her self, an independent person (e. g. a study nurse, but not the parent or physician) was allowed to provide assistance. As the spontaneous adverse event reports captured by the physician preceded the elicitation of any further adverse events using the PAERS, the number of adverse events captured by these two methods potentially differed.

Although the PAERS was designed to measure adverse events, some items are reflecting ADHD symptoms and difficulties associated with ADHD rather than adverse events. These items can be expected to improve but not worsen during ADHD treatment. Of these, all ten items of the PAERS that were thought to reflect emotional well-being by face validity were selected for this post-hoc analysis to measure changes over time.

Noncompliance was defined as missing intake of study drug on more than five consecutive days, failure to take at least 70% of study medication for at least two weeks, or repeated intentional intake of more than the prescribed dose.

Sample size and statistical analysis

Details on the sample size calculation for the two studies have been published elsewhere [28, 29]. The data of all patients were evaluated (Full Analysis Set, FAS) using SAS version 8. The dataset for all analyses of changes from baseline to endpoint consisted of all patients with a baseline measurement and at least one post-baseline measurement during the 8-week treatment phase.

Evaluation was largely descriptive. All tests of statistical significance were carried out at a nominal level of 5% using two-tailed test procedures. Two-sided confidence intervals (CIs) were computed using a 95% confidence level. All inferences regarding statistical significance were based on comparisons of the 95% confidence intervals (CI). This is equivalent to significance tests with p-values and a two-sided α-level of 5%. To avoid correlations of imputed values, only observed cases (OC) analysis were performed. No imputation of missing values like last observation carried forward (LOCF) was applied as the intention was to describe the patterns for patients still on medication.

Spearman's correlation coefficients were computed between all items within each perspective in order to identify patterns of interdependency among items. This analysis was based on all visits. A sensitivity analysis was done using the baseline visit only. 95% confidence intervals for the correlation coefficients were computed based on Fisher's z-transformation.

Patient population and disposition

Of the 425 patients screened, 421 patients (100%) were enrolled in the two studies and treated with atomoxetine [28, 29]. All patients were diagnosed with ADHD according to DSM-IV criteria. The mean age of the patients was 11.1 years, 338 (80.3%) were boys, 83 (19.7%) were girls. The 8-week treatment period was completed by 355 (84.3%) patients. 27 (6.4%) of these did not continue into the extension period because of physician decision. 68 (16.1%) patients discontinued the study between week 8 and week 24. The extension period was completed at week 24 by 260 (61.8%) patients. The reasons for discontinuation at any time during the 24-month observation period were lack of efficacy (12.4%), parent decision (6.9%), adverse event (4.8%), protocol violation 3.6%, patient decision (2.4%), entry criteria exclusion (0.7%), physician decision (0.7%), and patient lost to follow-up (0.5%). The patient disposition is shown in Figure 1.

Pre-existing comorbid conditions were reported for 310 (73.6%) patients, the most frequent being psychiatric comorbidities, specifically conduct disorder (19.7%), oppositional defiant disorder (17.6%), enuresis (4.3%), tic disorder (2.4%), emotional disorder of childhood (2.6%), and depression (1.4%). Physical comorbidities that were reported at a rate of >2% were headache (5.7%), seasonal allergy (4.3%), asthma (3.3%), neurodermatitis (2.6%), acne (2.4%), upper respiratory tract infection (2.1%), and rhinitis (2.1%).

349 (82.9%) of the 421 patients had previously been treated for ADHD. The percentage was similar for the predominantly inattentive subtype (N = 101, 81.5%) and the combined subtype (N = 231, 83.1%). Medications most frequently used before study entry were short-acting methylphenidate (N = 290, 68.9%), long-acting methylphenidate (N = 196, 46.6%), amphetamines (N = 56, 13.3%), antipsychotic drugs (N = 12, 2.9%) and herbal/complementary therapies (N = 10, 2.4%). Commonly reported non-drug therapies prior to study were: occupational therapy (N = 48, 11.4%), "other" psychotherapy (N = 31, 7.4%), structured psychotherapy (N = 42, 10.0%), and remedial education (N = 10, 2.4%). The most frequent reason for discontinuation of previous therapy in patients with pre-treatment was inadequate response (N = 216, 61.9%). N = 68 patients (16.2%) discontinued previous therapy because of adverse events.

The mean atomoxetine dose given during the first week of treatment was 0.50 mg/kg per BW day (SD 0.07, range 0.40 – 0.80 mg/kg BW per day). Thereafter, the mean dose for the respective visit intervals ranged between 1.17 and 1.18 mg/kg per day (min. 0.40, max. 1.50 mg/kg per day). Compliance as defined above was present in 91.2% of all patients over the course of the entire study.

Concomitant medication was taken by 272 (64.6%) of the patients. Cough and cold remedies, analgesics, antibiotics and herbal/complementary medicines were given most frequently. Whilst continuous medication with any psychotropic compound other than the study medication led to discontinuation of the patient in the study, 3.8% (N = 16) of patients did receive a psychotropic medication at least once over the entire course of the 24-week study. The medication included compounds such as St. John's Wort, imipramine or a benzodiazepine. Concomitant behavioral therapy was given to 27 (6.4%) patients, and 20 (4.8%) patients received additional occupational therapy.

Results from ten items of the PAERS

The following ten items of the Pediatric Adverse Event Rating Scale (PAERS) were selected to investigate emotional well-being: "feeling withdrawn or numb" (item 8), "nervous, tense, or uptight" (item 16), "trying to hurt him or her self" (item 20), "feeling restless or keyed up" (item 26), "sad or low mood/unhappy" (item 32), "drowsy or 'out of it"' (item 37), "unusually good mood/super happy" (item 38), "not interested/no enthusiasm" (item 39), "angry or irritable/in a bad mood" (item 42), and "thinking about or wanting to hurt self" (item 43). Each of these items was rated from three perspectives (patient, parent, and physician) like all PAERS items. If present, the severity of the respective behavior or emotional state was rated on a 5 point Likert scale (0 = not present, 1 = mild, 2 = moderate, 3 = severe, and 4 = extreme).

In general, the correlations were moderate to high only for parent and physician ratings, but not for patient ratings. The pattern of moderate to high correlations was similar between parent and physician ratings. In the sensitivity analyses using baseline ratings only (rather than all ratings), the correlations were generally lower, but confirmed the overall pattern of correlations based on the other points in time. A total score of all the items was not calculated as correlations were low between items that belonged to different groups (Table 2). These correlations are not reported here.

Items relating to depressed mood

Items relating to self-harm

The scores for the items relating to self-harm were extremely low at baseline and stayed low over time (Table 4). The scores were comparable in terms of the three perspectives. No significant changes were observed compared to baseline.

Items relating to irritability/agitation

At baseline, a similar pattern was observed for items "nervous, tense, or uptight" (item 16), "feeling restless or keyed up" (item 26), and "angry or irritable/in a bad mood" (item 42). Based on the confidence intervals, the parent rating was significantly higher than the physician rating, which was again significantly higher than the patient rating for all three items. The scores for the items relating to irritability/agitation decreased over time (Table 4). The decreases from baseline were largest for parents, followed by physicians and patients: the mean changes from baseline were statistically significant for all perspectives, all three items, and both at week 8 and week 24, as shown by non-overlapping confidence intervals.

Item relating to drowsiness

Based on the confidence intervals at baseline, the item "drowsy or 'out of it"' (item 37) was scored similarly by parents and patients, and significantly higher than by physicians. The scores for the item relating to drowsiness decreased over time (Table 4). Also the changes from baseline were more pronounced in parent and patient ratings than in physician ratings. The mean changes from baseline were statistically significant for all perspectives and both at week 8 and week 24, as shown by non-overlapping confidence intervals.

Item relating to euphoria

Based on the confidence intervals at baseline, the item "unusually good mood/super happy" (item 38) was scored significantly higher by patients than by parents, and significantly higher than by physicians. The scores for the item relating to euphoria decreased over time (Table 4). The changes from baseline were scored similarly by patients and physicians, but the decreases were smaller in the physician rating. The mean changes from baseline were statistically significant in terms of all three perspectives and were significant both at week 8 and week 24, as shown by non-overlapping confidence intervals.