Background
Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and hyperactivity and affects 3–7% of school-aged children in the United States
Beyond the improvement of core symptoms during ADHD treatment, there is growing appreciation of possible additional patient and family benefits, including QoL and functional outcome parameters
Atomoxetine is a non-stimulant treatment option for ADHD
However, when assessing QoL in adolescents with ADHD, both, symptom severity and ADHD-related difficulties, may be perceived and rated differently by patients, parents, and physicians
Thus, the primary objective of this study was to investigate the severity of ADHD-related difficulties perceived by patients, parents, and physicians during atomoxetine treatment, and to compare these three perspectives over the course of the study, using the Global Impression of Perceived Difficulties (GIPD) instrument. The psychometric properties of this brief scale have recently been reported
As German ethic committees tend to be rather reluctant towards placebo-controlled studies in juvenile patients, and efficacy was not a main objective in this post-launch study, we decided on a single-arm, open-label design for reasons of feasibility.
Secondary objectives were to evaluate the effectiveness and tolerability of atomoxetine in adolescents with ADHD. Results from a parallel study performed in children with ADHD (6 – 11 years of age) have been published
Methods
Study design and procedures
This multicenter, open-label, single-arm study was designed to investigate the degree of ADHD-related difficulties in adolescents with ADHD treated with atomoxetine as perceived by patients, parents, and physicians. Patients were recruited at 35 child and adolescent psychiatry and pediatric practices and outpatient clinics throughout Germany. Boys and girls aged 12–17 years with ADHD as defined in DSM-IV-TR were eligible for the study. The diagnosis was confirmed using the "Diagnose-Checkliste Hyperkinetische Störungen" (Diagnostic Checklist for Hyperkinetic Disorders), a structured standard instrument based on the respective DSM-IV-TR and ICD-10 criteria
Patients were to have an IQ of ≥70 based on the clinical judgment of the investigator. The exclusion criteria comprised significantly 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 the ethics committee of the University of Cologne, Germany, 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, the patients were treated with atomoxetine at a dose of approximately 0.5 mg/kg per day. During the following 7 weeks, the recommended atomoxetine dose was 1.2 mg/kg per day, which could be adjusted within a range of 0.5 – 1.4 mg/kg 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 going to continue treatment for further 16 weeks, considering both effectiveness and tolerability/safety of the compound for the respective patient. Patients 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 per day if necessary. During the extension period, three assessments were carried out at 12, 16, and 24 weeks after baseline.
The Global Impression of Perceived Difficulties (GIPD) instrument was used as the primary outcome measure. The GIPD is a validated instrument
The Clinical Global Impression-Severity-Attention-Deficit/Hyperactivity Disorder Scale (CGI-S-ADHD) is a seven point single-item rating scale of the physician's assessment of the severity of ADHD symptoms
Following the clinical interview with patients and parents, and the completion of ADHD-RS-IV and CGI-S-ADHD scales by the investigator, GIPD ratings were done independently by patients and parents during each office visit. The investigator would then score the GIPD physician version taking into account the patient and parent GIPD scorings from the respective visit plus all additional information about the patient provided to him. Adverse event assessment concluded the session. Thus, GIPD ratings from patients and parents were not used to inform ADHD-RS or CGI-S ratings by the investigator or to guide treatment decisions, e.g., dose-adjustments. Given the open-label design of the study, this sequence was also chosen to resemble the routine (naturalistic) course of an office visit.
Sample size and statistical analysis
For calculating an appropriate sample size, we assumed that the true value of Kappa
The data of all patients were evaluated (Full Analysis Set, FAS). 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 period.
In addition to Last Observation Carried Forward (LOCF) analyses and Observed Cases (OC) analyses, LOCF-BR (LOCF – baseline rater) and OC-BR (OC – baseline rater) analyses were applied: Values not rated by the same individual both at baseline and later on (e. g., father rated at baseline, mother rated later) were replaced by the last value from the baseline rater (if present), otherwise the value was deleted. Obviously, this applied only to the parent rating scales.
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. Cohen's weighted Kappa (Kappa) with 95% confidence intervals
Results
Patient population and disposition
Of the 160 patients screened, 159 patients (100%) were enrolled in the study and treated with atomoxetine, 137 (86.2%) patients completed the treatment period and continued into the extension period. 20 (12.6%) patients discontinued early over the course of the 8 week treatment period, two more (1.3%) completed the treatment period, but did not continue into the extension period based on the decision of the physician. 26 (16.4%) patients discontinued between weeks 8 and 24. 111 (69.8%) patients completed the study at week 24. Discontinuations were mostly due to lack of efficacy. All reasons for discontinuation are shown in Figure
Patient disposition
Patient disposition.
Table
Patient characteristics
N
%
Age (years)
Height (cm)
Weight (kg)
Age at start of symptoms (years)
Age at ADHD diagnosis (years)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
All patients
159
100
14.1
1.53
163
10.96
54.4
13.40
4.3
2.21
9.8
2.77
Girls
34
21.4
14.4
1.70
162
8.27
55.3
12.96
4.9
2.50
10.7
2.91
Boys
125
78.6
14.0
1.48
163
11.60
54.2
13.56
4.2
2.11
9.6
2.69
ADHD, combined type*
81
50.9
13.9
1.50
161
11.09
53.8
14.41
4.1
2.13
9.5
2.68
ADHD, predominantly inattentive type*
73
45.9
14.2
1.53
165
10.85
54.3
11.90
4.5
2.03
10.1
2.87
ADHD, NOS*
5
3.1
15.0
1.80
167
4.51
67.2
13.19
6.3
4.58
11.2
2.51
* According to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition™.
SD = Standard Deviation, NOS = not otherwise specified
Consisting of only 5 subjects, the subgroup of patients with ADHD, not otherwise specified (NOS) was too small for further detailed subgroup analyses. There were no patients meeting criteria for the predominantly hyperactive-impulsive subtype. For the entire patient sample, the mean time span between first occurrence of symptoms (parent report) and first professional diagnosis amounted to approximately 5.5 years.
137 (86.2%) of the 159 adolescents had previously been treated for ADHD. The percentages of pretreated patients differed slightly with respect to sex (boys: N = 109, 87.2%, girls: N = 28, 82.4%) or ADHD-subtype (combined subtype N = 67, 82.7%, predominantly inattentive subtype N = 65, 89.0%). Most frequently used compounds had been short-acting methylphenidate (N = 119, 74.8%), long-acting methylphenidate (N = 92, 57.9%), amphetamines (N = 17, 10.7%), and antidepressants (N = 7, 4.4%). Commonly reported non-drug therapies prior to study start were: structured psychotherapy (N = 22, 13.8%), occupational therapy (N = 11, 6.9%), and other forms of psychotherapy (N = 10, 6.3%). The most frequent reason for discontinuation of any previous therapy was inadequate response (N = 88, 64.2%).
At baseline, patients (N = 155–158) were rated with the following mean scores (± SD): GIPD Total: patient 12.5 (± 5.8), parent 17.2 (± 6.3), physician 18.8 (± 6.0); ADHD-RS-IV: 28.4 (± 10.1), and CGI-S-ADHD: 4.8 (± 0.9).
The mean atomoxetine dose (± SD) given during the first week of treatment was 0.51 (± 0.06) mg/kg per day (minimum 0.40, maximum 0.60 mg/kg per day). Thereafter, the mean dose ranged between 1.17 and 1.19 mg/kg per day (minimum 0.40, maximum 1.40 mg/kg per day). With respect to ADHD-subtype or sex, mean doses were largely within the same range. Overall compliance was at least 96.5% over the entire course of the study according to investigator assessment.
Concomitant medication was taken by 99 (62.3%) of the patients. Analgesics (N = 37, 23.3%), cough and cold remedies (N = 22, 13.8%), antibiotics (N = 18, 11.3%), phytotherapeutics (N = 14, 8.8%; herbal remedies to treat common colds and upper respiratory tract infections), and medications for gastrointestinal diseases (N = 7, 4.4%) were reported most frequently. Continuous behaviour therapy (ongoing before study start) was applied in 10 (N = 6.3%) patients, and 2 (1.3%) patients received occupational therapy. Pre-existing concomitant conditions were reported for 105 (66.0%) patients, the most frequent being psychiatric comorbidities, i.e., conduct disorder (N = 29, 18.2%), oppositional defiant disorder (N = 21, 13.2%), emotional disorder of childhood (N = 4, 2.5%). Two patients had depressed mood (N = 2, 1.3%), none had concomitant anxiety disorder. Physical comorbidities reported at a rate of >2% were headache (N = 10, 6.3%), seasonal allergy (N = 9, 5.7%), acne (N = 8, 5.0%), and asthma and atopic dermatitis (N = 7, 4.4% each).
GIPD: course over time and agreement between perspectives
The mean GIPD total scores for the three rater groups (patients, parents and physicians) took parallel courses over time (Figure
Global Impression of Perceived Difficulties (GIPD) total scores, rated by patients, parents and physicians, by ADHD subtype
GIPD total score
Patient rated
Parent rated
Physician rated
ADHD subtype
N
Mean
95% CI
N
Mean
95% CI
N
Mean
95% CI
All
Week 0
156
12.5
11.6 – 13.5
155
17.2
16.2 – 18.2
155
18.8
17.8 – 19.8
Week 2
157
10.5
9.6 – 11.4
148
12.6
11.7 – 13.6
158
12.6
11.8 – 13.5
Week 8
158
9.6
8.7 – 10.5
150
11.4
10.5 – 12.4
158
11.0
10.2 – 11.9
Week 24
158
9.9
8.9 – 10.9
153
11.7
10.7 – 12.7
158
12.1
11.0 – 13.1
Combined type
Week 0
79
12.6
11.4 – 13.8
79
17.8
16.4 – 19.2
79
19.6
18.3 – 21.0
Week 2
80
10.7
9.4 – 11.9
76
13.4
12.0 – 14.8
81
13.8
12.5 – 15.0
Week 8
81
10.1
8.9 – 11.3
77
11.9
10.7 – 13.2
81
12.4
11.1 – 13.7
Week 24
81
10.0
8.7 – 11.3
77
11.9
10.6 – 13.2
81
12.9
11.4 – 14.3
Predominantly inattentive type
Week 0
72
12.5
11.0 – 14.0
71
16.4
14.9 – 17.9
71
17.9
16.5 – 19.3
Week 2
72
10.1
8.8 – 11.5
67
11.7
10.4 – 13.0
72
11.3
10.3 – 12.3
Week 8
72
9.0
7.7 – 10.3
68
10.7
9.4 – 12.1
72
9.6
8.5 – 10.7
Week 24
72
9.6
8.1 – 11.1
71
11.4
9.9 – 12.8
72
11.2
9.7 – 12.6
Patient and physician ratings based on LOCF (Last Observation Carried Forward), parient ratings are for LOCF-BR (LOCF, Baseline Rater:
Values not rated by the same individual both at baseline and later on (e. g., father rated at baseline, mother rated later) were replaced
by the last value from the baseline rater (if present), otherwise the value was deleted.
CI = Confidence Interval
GIPD total (a), morning (b) and evening (c) scores, as rated by patients, parents and physicians (OC analysis)
GIPD total (a), morning (b) and evening (c) scores, as rated by patients, parents and physicians (OC analysis).
With respect to GIPD total scores for different ADHD subtypes (Table
Table
GIPD morning scores, rated by patients, parents and physicians, by ADHD subtype
GIPD morning score
Patient rated
Parent rated
Physician rated
ADHD subtype
N
Mean
95% CI
N
Mean
95% CI
N
Mean
95% CI
All
Week 0
158
2.5
2.3 – 2.8
157
3.1
2.8 – 3.4
158
3.3
3.1 – 3.5
Week 2
157
2.1
1.9 – 2.3
148
2.2
2.0 – 2.5
158
2.3
2.1 – 2.5
Week 8
158
2.0
1.8 – 2.2
150
2.1
1.9 – 2.3
158
1.9
1.7 – 2.1
Week 24
158
1.9
1.7 – 2.2
153
2.1
1.9 – 2.4
158
2.2
2.0 – 2.4
Combined type
Week 0
80
2.6
2.2 – 2.9
80
3.2
2.8 – 3.6
80
3.4
3.1 – 3.7
Week 2
80
2.2
1.8 – 2.6
76
2.4
2.1 – 2.7
81
2.5
2.2 – 2.7
Week 8
81
2.1
1.8 – 2.4
77
2.2
1.9 – 2.5
81
2.2
1.9 – 2.5
Week 24
81
2.0
1.7 – 2.4
77
2.2
1.9 – 2.5
81
2.4
2.1 – 2.7
Predominantly inattentive type
Week 0
73
2.5
2.1 – 2.8
72
3.0
2.6 – 3.4
73
3.2
2.9 – 3.6
Week 2
72
2.0
1.7 – 2.3
67
2.1
1.8 – 2.3
72
2.1
1.8 – 2.3
Week 8
72
1.8
1.5 – 2.1
68
2.0
1.7 – 2.3
72
1.7
1.4 – 1.9
Week 24
72
1.8
1.5 – 2.1
71
2.1
1.7 – 2.4
72
2.0
1.7 – 2.3
Patient and physician ratings based on LOCF (Last Observation Carried Forward), parent ratings are for LOCF-BR (LOCF, Baseline Rater:
Values not rated by the same individual both at baseline and later on (e. g., father rated at baseline, mother rated later) were replaced by the last value from the baseline rater (if present), otherwise the value was deleted.
CI = Confidence Interval
GIPD evening scores, rated by patients, parents and physicians, by ADHD subtype
GIPD evening score
Patient rated
Parent rated
Physician-rated
ADHD subtype
N
Mean
95% CI
N
Mean
95% CI
N
Mean
95% CI
All
Week 0
158
2.2
2.0 – 2.4
158
3.5
3.3 – 3.7
158
3.9
3.6 – 4.1
Week 2
158
1.9
1.7 – 2.1
149
2.6
2.3 – 2.8
158
2.5
2.3 – 2.7
Week 8
158
1.8
1.6 – 2.0
150
2.2
2.0 – 2.4
158
2.2
2.0 – 2.4
Week 24
158
1.9
1.7 – 2.1
153
2.3
2.1 – 2.6
158
2.4
2.2 – 2.7
Combined type
Week 0
80
2.4
2.0 – 2.7
80
3.7
3.4 – 4.1
80
4.2
3.8 – 4.5
Week 2
81
2.1
1.8 – 2.4
77
2.9
2.5 – 3.2
81
2.8
2.5 – 3.1
Week 8
81
1.9
1.7 – 2.2
77
2.4
2.1 – 2.7
81
2.5
2.2 – 2.9
Week 24
81
1.9
1.6 – 2.2
77
2.4
2.0 – 2.7
81
2.6
2.3 – 3.0
Predominantly inattentive type
Week 0
73
2.1
1.7 – 2.4
73
3.3
2.9 – 3.6
73
3.5
3.2 – 3.9
Week 2
72
1.8
1.5 – 2.0
67
2.3
1.9 – 2.6
72
2.1
1.9 – 2.4
Week 8
72
1.7
1.4 – 2.0
68
2.1
1.8 – 2.4
72
1.9
1.6 – 2.1
Week 24
72
1.8
1.5 – 2.1
71
2.4
2.1 – 2.7
72
2.2
1.9 – 2.6
Patient and physician ratings based on LOCF (Last Observation Carried Forward), parent ratings are for LOCF-BR (LOCF, Baseline Rater:
Values not rated by the same individual both at baseline and later on (e. g., father rated at baseline, mother rated later) were replaced by the last value from the baseline rater (if present), otherwise the value was deleted.
CI = Confidence Interval
The calculation of Cohen's Kappa coefficients for the GIPD total score (all patients) revealed an overall increase of agreement between the three rater groups over the course of the study. This improvement was statistically significant for the agreement between patients and physicians (cf. 95% CIs, Table
Agreement (Cohen's Kappa coefficients) between patient-, parent- and physician rated GIPD total scores, by ADHD subtype
Agreement between
Physician and parent
Patient and parent
Patient and physician
ADHD subtype
N
Kappa
95% CI
N
Kappa
95% CI
N
Kappa
95% CI
All
Week 0
153
0.533
0.451 – 0.615
153
0.221
0.132 – 0.310
154
0.186
0.112 – 0.259
Week 2
128
0.550
0.460 – 0.641
127
0.359
0.257 – 0.461
147
0.391
0.294 – 0.489
Week 8
112
0.538
0.443 – 0.633
111
0.318
0.205 – 0.432
126
0.385
0.284 – 0.485
Week 24
104
0.639
0.552 – 0.725
103
0.363
0.255 – 0.471
111
0.425
0.319 – 0.532
Combined type
Week 0
79
0.504
0.382 – 0.626
78
0.155
0.041 – 0.270
78
0.131
0.045 – 0.216
Week 2
68
0.509
0.375 – 0.644
67
0.313
0.184 – 0.442
74
0.411
0.287 – 0.534
Week 8
61
0.454
0.306 – 0.602
62
0.222
0.081 – 0.362
66
0.347
0.209 – 0.484
Week 24
55
0.662
0.529 – 0.795
55
0.382
0.237 – 0.527
57
0.402
0.267 – 0.536
Predom. inattentive type
Week 0
69
0.551
0.439 – 0.663
70
0.280
0.142 – 0.419
71
0.237
0.113 – 0.360
Week 2
55
0.556
0.437 – 0.674
55
0.399
0.235 – 0.562
68
0.339
0.190 – 0.489
Week 8
48
0.631
0.511 – 0.751
46
0.434
0.250 – 0.619
56
0.419
0.270 – 0.568
Week 24
45
0.609
0.499 – 0.720
44
0.320
0.159 – 0.481
50
0.438
0.263 – 0.613
Patient and physician ratings based on LOCF (Last Observation Carried Forward), parent ratings are for LOCF-BR (LOCF, Baseline Rater: Values not rated by the same individual both at baseline and later on (e. g., father rated at baseline, mother rated later) were replaced by the last value from the baseline rater (if present), otherwise the value was deleted.
CI = Confidence Interval
The highest degree of agreement was found between physicians and parents. Agreement between patients and parents as well as agreement between patients and physicians were both markedly below the agreement between physicians and parents, with differences in Kappa coefficients reaching statistical significance at various points in time throughout the study (cf. 95% CIs).
Largely the same pattern as for the entire sample was observed in patients with the ADHD combined type, while patients with the predominantly inattentive ADHD-subtype displayed a slightly higher degree of agreement with their parents and physicians (n. s.).
ADHD Rating Scale (ADHD-RS)
During the first two weeks of atomoxetine treatment, mean total scores for the investigator-rated ADHD-RS (ADHD-RS-IV-Parent:Inv) significantly decreased from 28.4 [26.8 to 29.9] at baseline to 16.7 [15.0 to 18.3] at week 2 (mean [95% CI]; LOCF). Total scores were at 12.9 [11.4 to 14.4] by week 8, and at 13.3 [11.7 to 15.0] by the end of week 24. The course was largely parallel for both ADHD subtypes (Figure
ADHD Rating Scale (ADHD-RS-Par:Inv), a) total score, b) hyperactivity-impulsivity subscore, c) inattention subscore (for all patients and by ADHD subtype, OC analysis)
ADHD Rating Scale (ADHD-RS-Par:Inv), a) total score, b) hyperactivity-impulsivity subscore, c) inattention subscore (for all patients and by ADHD subtype, OC analysis).
Looking at the ADHD-RS sub-scores, courses of the Hyperactivity-Impulsivity and Inattention sub-scores followed the general pattern shown for the total score. Combined subtype of ADHD was again associated with statistically significantly higher mean scores than the predominantly inattentive subtype, this held for the Hyperactivity-Impulsivity subscore but not the Inattention subscore (Figures
Clinical Global Impression (CGI-S)
The mean CGI-S-ADHD score (LOCF) for the overall sample significantly decreased from 4.8 [95%CI 4.7 to 5.0] at baseline to 3.4 [3.2 to 3.6] at week 8 and stayed stable thereafter until week 24 (3.3 [3.1 to 3.5]). Regarding the ADHD-subtypes, a comparable decrease was observed. The mean CGI-S-ADHD scores of the predominantly inattentive subtype tended to be slightly lower than the scores of the combined type over the entire course of the study, but the differences did not reach statistical significance (Figure
Clinical Global Impression – Severity (CGI-S-ADHD), for all patients and by ADHD subtype (OC analysis)
Clinical Global Impression – Severity (CGI-S-ADHD), for all patients and by ADHD subtype (OC analysis).
Tolerability
Investigators reported treatment emergent adverse events in 124 (78.0%) patients over the entire study period. Adverse events reported in more than 5% of all patients (N = 159) were: fatigue 45 (28.3%), headache 38 (23.9%), nausea 30 (18.9%), nasopharyngitis 21 (13.2%), vomiting 21 (13.2%), upper abdominal pain 12 (7.5%), decreased appetite 12 (7.5%), dizziness 12 (7.5%), diarrhea 9 (5.7%). In 82 (51.6%) patients the investigators considered the adverse event as possibly related to atomoxetine. Adverse events reported in more than 5% of the patients and rated as possibly related to atomoxetine were: fatigue (N = 42, 26.2%), nausea (N = 22, 13.8%), headache (N = 15, 9.4%), upper abdominal pain (N = 11, 6.9%), decreased appetite (N = 11, 6.9%), dizziness 9 (5.7%) and vomiting 9 (5.7%). There were 8 patients with serious adverse events, which were considered related to atomoxetine in two patients (1 patient with severe vomiting; 1 patient with abdominal pain, dissociation, disturbance in attention, dizziness, fatigue and peripheral vasoconstriction with dark, marbled skin).
Treatment-emergent adverse events led to discontinuation in 7 (4.4%) patients: alopecia, decreased appetite, drug abuse (acute intoxication with unknown medication plus alcohol, hospitalized at emergency unit, then at inpatient adolescent psychiatry ward) fatigue, vasoconstriction (patient above, with additional symptoms/events, hospitalized for diagnostic process), vertigo and vomiting in 1 (0.6%) patient each. Except for fatigue and drug abuse, all these adverse events were rated as possibly related to treatment.
Mean laboratory parameters, including liver function tests, were found within normal ranges with only minor fluctuations over the course of the study (observed cases; ALT: BL 19 ± 8 U/L; wk 8, 18 ± 9; wk 24, 17 ± 7. AST: BL 28.0 ± 6 U/L; wk 8, 28 ± 9, week 24, 26 ± 5). For vital signs, increases in systolic and diastolic blood pressure (SBP, DBP) and heart rate were observed as: SBP: BL, 112.6 ± 13.9 mmHg; wk 8, 115.4 ± 12.9, wk 24, 117.5 ± 12.1. DBP: BL, 70.3 ± 10.0 mmHg; wk 8, 72.8 ± 8.8; wk 24, 73.8 ± 9.2. Heart rate: BL, 77.9 ± 10.7 bpm; wk 8, 87.1 ± 13.6; week 24, 84.8 ± 12.0.
Discussion
To our knowledge, this is the largest single study focusing on adolescent ADHD patients treated with atomoxetine
As the primary objective, we investigated possible differences in perceptions of ADHD-related difficulties by patients, parents, and physicians using the recently devised GIPD instrument
In this study with adolescent ADHD patients, the degree of the ADHD-related difficulties was rated statistically significantly lower by the patients than by their parents or their physicians. In contrast, the difference between the parent and physician GIPD ratings was small. With reference to the methodological approach chosen in this trial, it appeared that these patients subjectively perceived the degree of their ADHD-related difficulties as lower than their parents or physicians did. These findings were consistent with the parallel open-label study in children with ADHD
Interestingly, the baseline self-reports of adolescent ADHD patients with the combined subtype vs. the predominantly inattentive subtype did not differ as to the severity of perceived ADHD-related difficulties. In contrast, parents and physicians rated the difficulties of the patients with the combined type as slightly more severe (n. s.) than those of the patients with the predominantly inattentive type, potentially corresponding to the clinical observation of third-party raters' assessing the impact of inattention as less burdensome.
The differences between the three perspectives persisted over the entire observation period. At the end of the acute treatment period (week 8), GIPD Total scores were statistically significantly reduced for all three rater groups (mean change from baseline: patients -2.9, -23.2%, parents -5.9, -34.3%, physicians -7.8, -41.5%), This level of improvement persisted until week 24. In general, these findings also held for the single-item GIPD evening and morning assessments. This statistically significant and consistent decline in ADHD-related difficulties during atomoxetine treatment may cautiously be interpreted to reflect an improvement in patient overall impairment, social functioning, and QoL in this adolescent patient population. Again, findings were highly consistent with the parallel study in children
Previous studies that used more specific instruments to assess QoL in children and adolescents with ADHD
As summarized by Steele et al.
Cohen's Kappa coefficients varied considerably across the three rater groups and the course of the study, with strongest (moderate) agreements between physician and parent assessments, and significant improvements of patient/physician agreements over time. Study design features, with choosing a nearly naturalistic sequence of applying instruments and using information as in an office-setting, may have impacted on this outcome.
With respect to the secondary objectives of this study, mean ADHD-RS Total scores decreased statistically significantly over time, with -15.6 (-54.9%) mean change, from a relatively low baseline (28.4) to week 8 (12.9) in this adolescent population. Wilens et al.
The percentage of ADHD-RS mean change for adolescents reported here was generally in line with several placebo-controlled trials – involving both children and adolescents – which showed efficacy with atomoxetine treatment
Based on ADHD-RS assessments, effectiveness was shown both for the combined type and the predominantly inattentive type of ADHD. This finding could be anticipated since atomoxetine has been known to improve both hyperactive/impulsive and inattentive symptoms of ADHD
Mean CGI-S scores also significantly improved over time [cf.
In general, the pattern of treatment-emergent adverse events in this study appeared to be in line with that reported in randomized, placebo-controlled trials in children
The reported data from this study should be interpreted cautiously in the context of its methodological limitations: The open-label study design in general is prone to rater bias, although symptom improvements over time were corresponding to results from double-blind placebo-controlled trials. And, as often observed when using several instruments, there will be overlap in constructs measured by the various scales
In summary, adolescent patients rated their ADHD-related difficulties, which can be considered to reflect overall impairment, social functioning, and QoL, as lower than either parents or physicians did. All three rater groups reported clear reductions in severity of these perceived difficulties over time, for total, evening, and morning assessments. The different views, the patient perspective on daily difficulties in particular, may provide important additional information when evaluating effectiveness of a treatment [cf
The reported differences in overall GIPD ratings and their statistical relevance may guide clinicians and researchers to collect more detailed differential data on actual impairment and quality of life from both adolescent ADHD patients and their parents, if applying more elaborate techniques and measures, both in clinical work and in future studies focussing on HRQoL. Additionally, comparative research is needed on the impact of various ADHD medications, focusing not only on the core symptoms of ADHD but as well on the health-related quality of life and functional outcomes of both patients and families, considering age and gender effects across the life-span.
Competing interests
RWD is a former employee of Lilly Deutschland and now holds an Eli Lilly Endowed Chair of Pediatric Psychopharmacology. PMW, AS, AM, and ML are full-time employees of Lilly Deutschland, RWD and PMW own Eli Lilly & Co. stock. GL has received research grants and speaker honoraria from Eli Lilly & Co. and is member of a Lilly Advisory Board.
Authors' contributions
RWD, PMW, ML and AS developed the clinical trial. AS developed the analyses reported in this manuscript. All authors participated in development of the GIPD scale and the interpretation of data. RWD, AS and AM drafted the manuscript, PMW, ML, KS and GL revised it critically for important intellectual content. All authors read and approved the final manuscript.