Morning and evening behavior in children and adolescents treated with atomoxetine once daily for Attention-Deficit/Hyperactivity Disorder (ADHD): Findings from two 24-week, open-label studies

Study design and procedures

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 by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [1] were eligible for one of the two studies. The diagnosis was confirmed using the "Diagnose-Checkliste Hyperkinetische Störungen" (DCL-HKS) (Diagnostic Checklist for Hyperkinetic Disorders) assessment tool, a structured instrument which is routinely used for diagnostic assessment of ADHD in Germany [42]. The items of this instrument correspond to those of the ADHD-RS [30, 31]. 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. The protocol was approved by an ethics committee and the study was conducted in accordance with the principles of the Declaration of Helsinki and international standards of Good Clinical Practice (GCP).

Following a wash-out period, baseline assessments were carried out with all instruments used. During the first week of treatment, 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. This dose 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 together 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. Again, this dose 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: at 12, 16, and 24 weeks after baseline.

The following instruments were used: Weekly Rating of Evening and Morning Behavior – Revised (WREMB-R), Global Impression of Perceived Difficulties (GIPD), Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS), and the Clinical Global Impression-Severity (CGI-S) scale. The data from both studies were combined and analyzed together.

The Global Impression of Perceived Difficulties (GIPD) instrument is a five-item rating of ADHD-related difficulties that assesses difficulties in the morning, during school, during homework, in the evening, and overall difficulties over the entire day and the night [26, 40]. Each item is rated on a seven point scale (1 = not at all difficult, 7 = extremely difficult) and reflects the situation during the past week. This instrument was devised and validated to capture the patient's ADHD-related difficulties from a patient, parent (or primary caregiver), and physician perspective [39]. For the patient rating, an independent person (e. g. a study nurse) was allowed to provide assistance if the child was unable to fill in the scale on his/her own. The GIPD was designed to reflect any kind of difficulty perceived as such by the rater (patient, parent, physician). Thus, the scale captures ADHD-related difficulties in a very general and inclusive way, potentially including symptom-related difficulties, dysfunction, impairment, and subjective dissatisfaction.

The GIPD total score was calculated for each rater as the mean of the item scores ranging from 1 to 7. If one item was missing, the total score was also considered to be missing. The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored (ADHD-RS) is an 18-item scale, with one item for each of the 18 ADHD symptoms listed in DSM-IV-TR [30, 31]. There are two subscales: the "hyperactivity/impulsivity" subscale is the sum of the even items, and the "inattention" subscale is the sum of the odd items. This scale is scored by an investigator while interviewing the parent (or primary caregiver). Reliability and validity of this scale has been demonstrated in several European samples, including Germany [44].

The Clinical Global Impression-Severity-Attention-Deficit/Hyperactivity Disorder (CGI-S ADHD) scale is a seven point single-item rating scale of the clinician's assessment of the severity of ADHD symptoms [32, 33].

Sample size and statistical analysis

Details on the sample size calculation for the two studies first using the GIPD have been published elsewhere in detail [26, 40]. In summary, the sample sizes were sufficient to estimate the intraclass kappa of the GIPD for the different perspectives in sufficient precision using a 95% confidence interval. The data of all patients were evaluated (Full Analysis Set, FAS) using SAS version 8.0. The dataset for all analyses of changes from baseline to endpoint comprised the data of all patients with a baseline measurement and at least one post-baseline measurement during the 8 week treatment phase.

Evaluation was largely descriptive. To present WREMB-R and GIPD scores over time, a last observation carried forward (LOCF) approach was used. Two-sided confidence intervals (CI) were computed using a 95% confidence level. All inferences regarding statistical significance were based on comparisons of the 95% CI. This is equivalent to significance tests with p-values and a two-sided α-level of 5%.

The WREMB-R morning and evening subscores were compared with the corresponding GIPD items for morning and evening behavior by calculating Pearson's correlation coefficients with 95% CIs for each perspective, at each time point, and for all time points pooled. To avoid correlations of imputed values, only observed cases (OC) were used for these correlation analyses. There was no imputation of missing values. 95% confidence intervals for the correlation coefficients were computed based on Fisher's z-transformation.

Patient population and disposition

Overall, 421 patients (100%) diagnosed with ADHD according to DSM-IV-TR criteria were enrolled in the two studies and treated with atomoxetine [26, 40]. Of these patients, 355 (84.3%) completed the initial 8-week treatment period, and 260 (61.8%) patients completed the extension period until week 24. Reasons for discontinuation 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 detail in Figure 1.

The baseline characteristics of the patients are shown in Table 2. At baseline, 78% of patients were rated as being at least "markedly ill" on the CGI-S scale for ADHD. Their mean ADHD-RS total score was 32.6 (± 10.9). On the GIPD-scale, patients perceived ADHD-related difficulties as being significantly less severe than parents and physicians did (see Table 2), as shown by the non-overlapping 95% confidence intervals (as shown in Figure 2).

Demographics
Boys, N (%)	338 (80.3)
Girls, N (%)	83 (19.7)
Age [years], mean (± SD)	11.1 (2.7)
ADHD subtype, N (%)
Combined	278 (66.0)
predominantly inattentive	124 (29.5)
predominantly hyperactive-impulsive	6 (1.4)
ADHD, not otherwise specified	13 (3.1)
Most frequent psychiatric comorbidities, N (%)
Conduct disorder	83 (19.7)
Oppositional defiant disorder	74 (17.6)
Enuresis	18 (4.3)
Emotional disorder of childhood	11 (2.6)
Tic disorder	10 (2.4)
Depression	6 (1.4)
Depressed mood	5 (1.2)
Baseline disease characteristics, mean (± SD)
ADHD-RS, total score	32.6 (10.9)
CGI-Severity (of ADHD)	5.0 (0.8)
WREMB-R, total score	18.0 (7.0)
GIPD, total score patient-rated	13.1 (5.8)
GIPD, total score parent-rated	18.6 (6.1)
GIPD, total score physician-rated	20.3 (5.9)

Abbreviations: ADHD = Attention deficit/hyperactivity disorder, ADHD-RS = ADHD Rating Scale (parent-rated, investigator-administered and scored), CGI-Severity = Clinical Global Impression, Severity, GIPD = Global Impression of perceived difficulties, SD = standard deviation, WREMB-R = Weekly Ratings of Evening and Morning Behavior-Revised

In boys, a combined subtype of ADHD according to DSM-IV criteria was diagnosed most frequently (N = 239, 70.7%) followed by the predominantly inattentive subtype (N = 86, 25.4%). The combined subtype of ADHD according to DSM-IV criteria was diagnosed in 39 girls (47.0%) and the predominantly inattentive subtype in 38 girls (45.8%). The subgroups of patients with "predominantly hyperactive-impulsive subtype" and "ADHD, not otherwise specified" were small (6 and 13 individuals, respectively).

The most frequent pre-existing comorbid conditions in the two study populations were psychiatric comorbidities (Table 2). 349 (82.9%) of patients had previously received a medication for ADHD. Medications most frequently used prior to entering the study 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%). The most frequent reason for discontinuation of previous treatment prior to entering the study was inadequate response (N = 216, 51.3%). N = 68 patients (16.2%) discontinued the previous treatment because of adverse events.

The mean atomoxetine dose given during the first week of treatment was 0.5 mg/kg body weight (BW) per day (SD 0.07, range 0.4 – 0.8 mg/kg BW per day). Thereafter, the mean dose for the respective visit intervals ranged between 1.17 and 1.18 mg/kg BW per day (range 0.4 – 1.5 mg/kg BW per day).

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. Concomitant behavioral therapy was given to 27 (6.4%) patients, and 20 (4.8%) patients received additional occupational therapy.

WREMB-R evening and morning subscores

Evening and morning behavioral symptoms, as reflected by the WREMB-R evening and morning subscores, both decreased significantly over time, as shown by non-overlapping confidence intervals (see Table 3 and Figure 3). The greatest change occurred within the first two weeks, after which the scores remained relatively stable until the end of study (24 weeks). The mean evening subscore (95% CI) decreased significantly from 13.7 (13.2 to 14.2) at baseline down to 8.0 (7.4 to 8.5) at week 2 and remained at 8.0 (7.4 to 8.6) until week 24. Mean morning subscores decreased significantly from 4.3 (4.0 to 4.5) down to 2.4 (2.2 to 2.6) at week 2 and remained at 2.3 (2.1 to 2.6) until week 24. Figure 3 shows the two WREMB-R subscores over time, scaling was adjusted to reflect the different number of items, 8 items for the evening subscore and 3 items for the morning subscore. Nevertheless, the WREMB-R evening subscores were higher than the respective morning subscores at each point in time from baseline until Week 24 (Figure 3).

	Baseline (BL)		Week 2			Week 8			Week 24
	N	Score	N	Score	Change	N	Score	Change	N	Score	Change
WREMB-R
Evening subscore (8 items)	418	13.7 ± 5.24	419	8.0 ± 5.57	-5.7 ± 5.43	419	7.1 ± 5.78	-6.6 ± 6.14	419	8.0 ± 6.16	-5.7 ± 6.30
Morning subscore (3 items)	419	4.3 ± 2.49	418	2.4 ± 2.23	-1.8 ± 2.53	419	2.1 ± 2.22	-2.2 ± 2.84	419	2.3 ± 2.37	-1.9 ± 2.83
GIPD
Difficulties in the morning
patient-rated	418	2.5 ± 1.60	418	2.0 ± 1.40	-0.5 ± 1.74	419	1.9 ± 1.35	-0.6 ± 1.80	419	1.9 ± 1.40	-0.6 ± 1.68
parent-rateda	418	3.4 ± 1.69	393	2.5 ± 1.44	-0.9 ± 1.77	404	2.4 ± 1.55	-1.0 ± 1.97	409	2.5 ± 1.62	-0.9 ± 1.97
physician-rated	419	3.6 ± 1.58	419	2.5 ± 1.33	-1.1 ± 1.71	419	2.3 ± 1.45	-1.3 ± 1.84	419	2.6 ± 1.57	-1.1 ± 1.82
Difficulties during school
patient-rated	417	2.7 ± 1.65	417	2.1 ± 1.34	-0.6 ± 1.66	418	2.1 ± 1.52	-0.6 ± 1.93	418	2.2 ± 1.60	-0.5 ± 2.04
parent-rateda	415	3.6 ± 1.58	389	2.9 ± 1.48	-0.8 ± 1.75	403	2.8 ± 1.61	-0.9 ± 1.96	408	3.0 ± 1.73	-0.7 ± 2.11
physician-rated	416	4.0 ± 1.51	419	2.9 ± 1.40	-1.1 ± 1.77	419	2.7 ± 1.60	-1.3 ± 2.00	419	3.0 ± 1.75	-1.0 ± 2.12
Difficulties during homework
patient-rated	416	2.7 ± 1.67	417	2.2 ± 1.51	-0.5 ± 1.81	418	2.1 ± 1.50	-0.6 ± 1.91	418	2.2 ± 1.59	-0.5 ± 1.93
parent-rateda	417	4.0 ± 1.65	390	3.1 ± 1.51	-1.0 ± 1.67	403	3.0 ± 1.63	-1.0 ± 1.97	408	3.0 ± 1.69	-1.0 ± 2.03
physician-rated	415	4.2 ± 1.56	418	3.0 ± 1.46	-1.2 ± 1.72	419	2.9 ± 1.62	-1.4 ± 1.91	419	3.0 ± 1.68	-1.2 ± 1.99
Difficulties in the evening
patient-rated	418	2.5 ± 1.72	419	1.9 ± 1.26	-0.6 ± 1.67	419	1.9 ± 1.32	-0.6 ± 1.86	419	1.9 ± 1.34	-0.6 ± 1.84
parent-rateda	419	3.8 ± 1.60	394	2.8 ± 1.50	-1.0 ± 1.66	404	2.6 ± 1.52	-1.2 ± 1.79	409	2.7 ± 1.60	-1.1 ± 1.87
physician-rated	419	4.2 ± 1.47	419	2.8 ± 1.43	-1.4 ± 1.56	419	2.6 ± 1.54	-1.5 ± 1.82	419	2.9 ± 1.72	-1.3 ± 1.85

Change is shown relative to baseline.

BL = baseline, GIPD = Global Impression of Perceived Difficulties, LOCF = last patient carried forward analysis, N = Number of patients, SD = standard deviation, WREMB-R = Weekly Ratings of Evening and Morning Behavior-Revised.

^a Post-baseline parent-rated GIPD scores were considered only if rated by the baseline rater.

GIPD scores at different times of the day, as perceived by patients, parents and physicians

All four GIPD items reflecting ADHD-related difficulties in the morning, during school, during homework and in the evening improved over time (Table 3). For each item, the majority of change occurred within the first 2 weeks. Scores then remained stable until week 24. Figure 2 shows the ADHD-related difficulties at various times of the day as perceived from a patient, parent and physician perspective. At each time of the day and at all time points up to 24 weeks, patients rated the ADHD-related difficulties as being less severe than parents and physicians did. Parents and physicians tended to perceive the ADHD-related difficulties as being similar in the morning and the evening. Until week 8, parents and physicians rated the perceived difficulties as being most pronounced during homework. For example, mean parent ratings at baseline (95% CI) were 3.4 (3.2 to 3.6) for difficulties in the morning, 3.6 (3.5 to 3.8) for difficulties during school, 4.0 (3.8 to 4.1) for difficulties during homework, and 3.8 (3.6 to 4.0) in the evening. At week 2, all parent ratings had decreased significantly to 2.5 (2.4 to 2.7) for difficulties in the morning, 2.9 (2.8 to 3.1) for difficulties during school, 3.1 (2.9 to 3.2) for difficulties during homework, and 2.8 (2.6 to 2.9) for difficulties in the evening. Ratings then generally remained stable until week 24.

Patients did not only perceive their ADHD-related difficulties as being less severe than parents and physician, but also differed slightly in their perception of difficulties at various times of the day. As compared to parents and physicians, patients perceived their morning and evening difficulties as being similarly severe. At baseline, mean patient ratings (95% CI) were 2.5 (2.4 to 2.7) for difficulties in the morning and 2.5 (2.3 to 2.6) for difficulties in the evening. At week 2, both ratings had decreased significantly to 2.0 (1.9 to 2.2) for difficulties in the morning and 1.9 (1.8 to 2.0) for difficulties in the evening. Again, ratings then remained stable until week 24.

Correlation of WREMB-R evening and morning subscores and the respective GIPD scores for the evening and morning items

Tolerability

Treatment emergent adverse events were reported in 331 (78.6%) patients over the entire study period. Adverse events reported in more than 5% of all patients (N = 421, 100%) were: fatigue 106 (25.2%), headache 86 (20.4%), nausea 77 (18.3%), vomiting 52 (12.4%), upper abdominal pain 42 (10.0%), nasopharyngitis 41 (9.7%), decreased appetite 30 (7.1%), diarrhea 27 (6.4%), abdominal pain 24 (5.7%), upper respiratory tract infection 23 (5.5%), cough 21 (5.0%), dizziness 21 (5.0%). In 207 (49.2%) patients the investigator considered the adverse event possibly related to atomoxetine. Adverse events reported in more than 5% of the patients and rated as possibly related to atomoxetine were: fatigue (N = 94, 22.3%), nausea (N = 57, 13.5%), headache (N = 36, 8.6%), upper abdominal pain (N = 30, 7.1%), reduced appetite (N = 26, 6.2%), and vomiting (N = 21, 5.0%). There were 11 (2.6%) patients with serious adverse events: dissociation, fall, fatigue and forearm fracture were reported twice, abdominal injury, abdominal pain, alcohol poisoning, appendicitis, circulatory collapse, depression, disturbance in attention, dizziness, drug abuse, head injury, hypothermia, injury, somnolence, tendon rupture, vasoconstriction, and vomiting were reported once (several patients experienced more than one serious adverse event). In two of these 11 patients, the adverse events were considered related to atomoxetine by the physician (one patient with vomiting and one patient with peripheral vasoconstriction, attention disturbance, fatigue, dizziness, abdominal pain and feeling of absence). Overall, no clinically relevant changes in vital signs were observed for the entire sample.