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ORIGINAL ARTICLE
Atomoxetine and Methylphenidate Treatment
in Children with ADHD: The Efficacy, Tolerability
and Effects on Executive Functions
Ozlem Yildiz •Sahika G. Sismanlar •Nursu Cakin Memik •
Isik Karakaya •Belma Agaoglu
Published online: 17 December 2010
ÓSpringer Science+Business Media, LLC 2010
Abstract The aim of this study was to compare the safety, efficacy, tolerability, and the
effects of atomoxetine and OROS-MPH on executive functions in children with ADHD.
This study was an open-label study that only included two medication groups. Children
were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary effi-
cacy measures were T-DSM-IV-S, CGI-I and neuropsychological tests battery. Safety
assessments included electrocardiogram, adverse events checklist and laboratory tests.
According to the endpoint improvement scores of CGI and parents T-DSM-IV-S, treatment
responses were not significantly different between the two study groups. OROS-MPH led
to a significantly greater reduction in teacher T-DSM-IV-S scale scores. OROS-MPH was
more effective than atomoxetine on Stroop-5 time and number of corrections. Significant
decrease in the percentage of perseverative errors on WCST in the OROS-MPH group was
seen (p=0.005). The most frequently reported adverse events in the atomoxetine group
were anorexia, nausea, nervousness, weight loss, abdominal pain, and somnolence. In the
OROS-MPH group, patients most frequently reported anorexia, nervousness, insomnia,
headache, nausea, and weight loss. When all these results are considered, although both
drugs can be considered effective in ADHD treatment, more remarkable improvement is
provided by OROS-MPH based on the rates across informant (i.e., teachers, clinicians) and
neuropsychological evaluation.
Keywords Attention deficit/hyperactivity disorder Atomoxetine OROS-MPH
Executive functions Children
Introduction
Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder that occurs
in 3–7% of the school-aged children.The main course of ADHD is a persistent pattern of
inattention and/or hyperactivity-impulsivity that may be seen more frequently and/or
O. Yildiz S. G. Sismanlar N. C. Memik (&)I. Karakaya B. Agaoglu
Department of Child and Adolescent Psychiatry, Kocaeli University, I
˙zmit, Turkey
e-mail: nursucakinmemik@gmail.com
123
Child Psychiatry Hum Dev (2011) 42:257–269
DOI 10.1007/s10578-010-0212-3
severely compared to individuals with the same level of development [1]. Its pathophys-
iology appears to involve different alterations in dopaminergic and noradrenergic pathways
related to the control of attention and impulsivity [2,3]. The psychostimulants (e.g.,
methylphenidate) are considered the first-line of therapy for ADHD, relieving symptoms
by increasing intrasynaptic dopamine, norepinephrine, and serotonin [4]. Nevertheless,
some patients fail to respond to stimulants or are unable to tolerate them, and the stimulants
such as methylphenidate are contraindicated for some children and adolescents including
those with Tourette’s disorder. Nonstimulant agents used in ADHD include tricyclic
antidepressants, bupropion, clonidine, guanfacine, selective serotonin reuptake inhibitors,
and newer atypical antidepressants [4–8]. But their current use is limited, because these
agents do not improve impulsive behavior and cognitive impairments and also they have
serious adverse effects [9]. On the other hand, atomoxetine, a highly selective inhibitor of
the noradrenergic transporter, is the first non-psychostimulant agent approved by the Food
and Drug Administration (FDA) for ADHD.Compared to its effect on the norepinephrine
transporter, atomoxetine has very little affinity for the dopamine or serotonin transpoter. As
a result of the central role of CYP2D6 in metabolism of atomoxetine, the activity of this
enzyme plays a significant role in its pharmachokinetics [10]. The majority of people
([90%), who metabolise atomoxetine and other CYP2D6 substrates relatively rapidly, are
designed as CYP2D6 extensive metaboliser. Its efficacy in children with ADHD has been
demonstrated in three double-blind, placebo-controlled trials [11–13]. However, few data
are available concerning its comparability to stimulants [14–17]. Furthermore, the deficits
due to the behavioral response inhibition, ADHD has been associated with the deficits on a
variety of neuropsychological tasks broadly described as measures of ‘‘executive func-
tioning’’ [18–20]. Thus, these tasks serve as more objective measures for assessing the
efficacy of pharmacotherapy in ADHD. Since cognition may be related to academic per-
formance and functional outcomes of patients, further research is warranted on the impact
of atomoxetine on broader outcome variables such as neuropsychological functioning. In
the current literature, the positive effects of psychostimulants on executive functions in
ADHD have been suggested, however it is still unknown whether atomoxetine has an
effect on neuropsychological functioning in children with ADHD. We therefore have
decided to investigate the efficacy, tolerability of atomoxetine, and sought to determine
whether atomoxetine improves executive functions by using a battery of tests and to
compare it with OROS-methylphenidate (OROS-MPH) in the short-term treatment of
Turkish children and adolescents with ADHD.
Patients and Methods
Study Design and Patients
This prospective, randomized, open-label study compared the efficacy, safety and effects
on executive functions of atomoxetine and OROS-MPH in children and adolescents with
ADHD. The study duration was 14 weeks. All subjects underwent a 1–2 week screening
phase to determine the persistence and severity of entry diagnostic and eligibility criteria.
The patients were randomly assigned to 12 weeks of treatment with either atomoxetine or
OROS-MPH. All measurements were performed by the first two authors.
Patients in this study were 8–14 years old at their initial visit and met diagnostic criteria
for ADHD and other comorbid psychiatric disorders as defined by DSM-IV-TR. They were
assessed by clinical interviews based on DSM-IV-TR and the Kiddie Schedule for
258 Child Psychiatry Hum Dev (2011) 42:257–269
123
Affective Disorders and Schizophrenia (K-SADS) [21]. Symptom severity at entry was
required to be at least 4 points or above as assessed by the Clinical Global Impression-
Severity Scale (CGI-S) [22]. Patients who had seizures, bipolar disorder, psychotic illness,
mental retardation, pervasive developmental disorder or who were taking concomitant
psychoactive medications were excluded from the study. Because anxiety and tic disorders
are relative contraindications for the use of OROS- methylphenidate, patients with these
conditions were also excluded. Patients in this study met diagnostic criteria for co-morbid
oppositional defiant disorder (n =7) and learning disorder (n =6).
Baseline measures including medical history, vital signs (weight, height, pulse, systolic
and diastolic blood pressure), physical examination, complete blood count, Aspartate
Amino Transferase (AST), Alenine Amino Transferase (ALT), electroencephalogram
(EEG), and electrocardiogram (ECG), Clinical Global Impression Scales (CGI-S, CGI-I)
Severity and Improvement [22], Turgay DSM-IV based Child and Adolescent Behavior
Disorders Screening and Rating Scale (parent and teacher forms) (T-DSM-IV-S) [23],
Wechsler Intelligence Scale for Children–Revised (WISC-R) [24], neuropsychological
tests battery (Wisconsin Card Sorting Test, Visual Memory Span Test, Stroop test), and
adverse events checklist were performed before randomization to treatments. Vital signs
were recorded at weeks 0 and 12. Physical examination, laboratory assessments, EEG,
Turgay DSM-IV-S and neuropsychological tests battery were repeated at week 12; other
assessments were repeated at weeks 4, 8, and 12. Neither the investigators nor the subjects
were blind to the study in both of the medication groups.
This study was conducted in accordance with the ethical principles of the Declaration of
Helsinki and the Good Clinical Practice guidelines established at the International Con-
ference on Harmonization. The study protocol was approved by the Local Independent
Ethics Committee.
Study Drugs
A total of 30 patients were randomized to receive atomoxetine or OROS-MPH. Treatment
was initiated at a standard specified dose (atomoxetine: 0.5 mg/kg/day; OROS-MPH:
18 mg/day administered as a single morning dose) for all patients and increased to 1.2 mg/
kg/day and 36–54 mg/day respectively based on parent and clinicians’ reports at the 4th
and 8th week. Of the 30 subjects randomized, 26 completed the study. Three subjects who
were administered atomoxetine, and one subject who was administered OROS-MPH dis-
continued the study. Nausea and vomiting in the atomoxetine group and chest pain and
palpitations in the OROS-MPH group were reported as reasons for discontinuation.
Table 1presents the patient characteristics. Dosages in the atomoxetine group (n =14)
ranged from 18 to 60 mg/day (mean =1.28 mg/kg/day), and those in the OROS-MPH
group (n =11) ranged from 18 to 54 mg/day (mean =1.07 mg/kg/day).
Measurement
Efficacy
Clinical Global Impression Scales (CGI-S, CGI-I) Severity and Improvement [22]
These scales are 7-point, single-item scales that are used by investigators in order to record
either illness severity or the response to an intervention. The CGI-S is used to measure
Child Psychiatry Hum Dev (2011) 42:257–269 259
123
illness severity, and the CGI-I is employed as a measure of improvement associated with
treatment.
Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating
Scale (T-DSM-IV-S)
This scale was developed by Turgay [25] and translated and adapted by Ercan et al. [23].
The T-DSM-IV-S is based on the DSM-IV diagnostic criteria and assesses hyperactivity-
impulsivity (9 items), inattention (9 items), opposition-defiance (8 items), and conduct
disorder (15 items). The symptoms are scored by assigning a severity estimate for each
symptom on a 4-point Likert-type scale (namely, 0 =not at all; 1 =just a little; 2 =quite
a bit; and 3 =very much). Subscale scores on the T-DSM-IV-S are calculated by summing
the scores on the items of each subscale.
Table 1 Description of the sample
Atomoxetine (n =14) OROS-MPH (n =11) pvalue
Age
Mean (SD) 9.78 ±1.36 10.16 ±1.7 0.539
a
Range 8–12 8–13
Gender
(Male/female) 13/1 9/2 0.208
b
Weight (kg)
At week 0 (mean ±SD) range 33.9 ±8.9 (25–59) 34.0 ±5.9 (25–43) 0.661
a
At week 12 (mean ±SD) range 32.7 ±7.6 (26–54) 32.8 ±6.4 (24–45) 0.052
a
Height (cm)
At week 0 (mean ±SD) range 135.6 ±4.6 (129–143) 138.6 ±7.5 (125–149) 0.536
a
At week 12 (mean ±SD) range 136.7 ±4.2 (131–145) 139.6 ±7.6 (126–151) 0.395
a
ADHD subtype (n; %)
Combined 13 (92.9) 8 (66.7) 0.091
b
Inattentive 1 (7.1) 3 (33.3)
Vital signs
Systolic BP
c
(mmHg) at week 0
(mean ±SD)
101.5 ±9.4 97.0 ±10.8 0.246
a
Systolic BP (mmHg) at week 12
(mean ±SD)
105.0 ±9.2 92.7 ±10.1 0.054
a
Diastolic BP (mmHg) at week 0
(mean ±SD)
63.5 ±4.7 63.5 ±12.0 0.285
a
Diastolic BP (mmHg) at week 12
(mean ±SD)
68.1 ±7.9 62.5 ±9.7 0.286
a
Pulse (beat/min) at week 0 (mean ±SD) 82.3 ±13.6 80.8 ±9.8 0.486
a
Pulse (beat/min) at week 12 (mean ±SD) 84.2 ±7.6 84.5 ±13.5 0.766
a
a
Mann–whitney U non-parametric test
b
Frequencies analyzed with fisher exact test
c
BP blood pressure
260 Child Psychiatry Hum Dev (2011) 42:257–269
123
Wisconsin Card Sorting Test (WCST)
The Turkish version of the WCST [26] was adapted by Karakas [27]. Each card carries a
set of red, blue, green or yellow symbols, e.g. from one to four stars, triangles, crosses or
circles that can be matched according to color, number or shape. The subject is instructed
to sort the cards beneath four reference cards with feedback as to whether the sort is correct
or not. Once the correct rule has been discovered and 10 consecutive correct sorts are
made, the rule is changed without warning. The subject must then discover the new sorting
rule and so forth, until six correct sorting categories are achieved or 128 cards are given.
Standard WCST variables include number of categories completed (up to six maximum),
total errors, perseverative errors, perseverative responses (includes nonerrors) and failures
to maintain set. Perseverative errors and perseverative responses are sorts according to a
previous operating principle rather than the current one, and are thought to represent either
the failure to inhibit a response or the failure to switch set according to external feedback.
Failure to maintain set occurs when a subject makes five correct sorts and then abandons
that strategy in favor of another (incorrect) principle.
Stroop Test
The Turkish version of the Stroop test [28] was adapted by Kilic et al. [29]. This test
measures the capability of an individual to maintain attention on 1 of 2 competing stimuli
by suppressing the other. It measures whether patients can change their existing perception
of changing desires. The Stroop test is used to evaluate the suppression of stimuli that
distract attention (interference resistance) and the strength to keep the response waiting for
the inappropriate stimuli. The test consist of 5 sections in which 4 cards are presented in a
fixed order. In the first 2 sections, the words on the cards are to be read. In the other 3
sections, the colors of the words or forms are to be named. The duration of reading rate and
the number of mistakes and corrections made are recorded for each section on the Stroop
standard registration form. Therfore, 5 different completion durations and mistake and
correction scores are obtained.
Visual Memory Span (VMS)
The visual memory span is one of the subtests of Weschler Memory Scale-Revised (WMS-R).
The Turkish version was adapted by Karakas [27]. Among the forward and backward visual
memory span parts, the first part is for the understanding of attention and visual memory span;
the second part is for the working memory functions.
Safety Measures
Clinical safety was assessed by means of the patients’ and parents’ reports of adverse events
checklist and collection of electrocardiogram, electroencephalography and laboratory data
including liver function tests and complete blood counts. Children and their parents were
asked whether any new development in the child’s health had occurred. At weeks 4, 8, and
12, investigators asked children and their parents about the adverse events using an 18-item
list of medication-related adverse events symptoms lists which was composed by the
authors. It included 2 general, 4 gastrointestinal, 3 central nervous system, 1 cardiovascular,
1 metabolic and nutritional, and 7 psychiatric inquiries. The gathered advers events were
rated according to the severity (mild, moderate, severe, or life-threatening). The following
Child Psychiatry Hum Dev (2011) 42:257–269 261
123
information was recorded for all adverse events: date of onset, date of disappearance,
severity, frequency.
Statistical Analysis
All data analyses were performed using SPSS 13.0 for Windows. For the comparison of
continuous variables such as age, weight, height, vital signs, T-DSM-IV-S, neuropsy-
chological tests between 2 medication groups Mann–Whitney Utest was used. And con-
tinuous variables before and after the treatment was compared by using Wilcoxon signed
rank test. For the categorical variables (treatment response) chi- square test was performed,
and results of Fisher exact test was taken as a basis at appropriate. Significance value was
p\0.005.
Results
Measures
Efficacy
CGI-S and CGI-I According to the CGI-S scores at baseline, of the 14 atomoxetine
patients who completed the study, 11 (75%) were markedly ill and 3 (21.6%) were severely
ill. Of the 12 patients on OROS-MPH, 9 (75%) were markedly ill and 3 (25%) were
severely ill.
At endpoint, according to the CGI-I scores, 2 (18.2%) of the atomoxetine patients were
markedly improved, 5 (45.5%) were moderately improved, 3 (27.3%) were slightly
improved and 1 (9.1%) showed no change. In the OROS-MPH group, 5 (45.5%) patients
were markedly improved, 5 (45.5%) were moderately improved, and 1 (8.3%) were
slightly improved. Since three patients in the atomoxetine group, and one patient in the
OROS-MPH group discontinued treatment due to side effects at week 8 the endpoint CGI-I
scores could not be evaluated. The CGI improvement scores were not significantly dif-
ferent between the two study groups at the endpoint. Based on the endpoint CGI-I, 7
(63.6%) patients in the atomoxetine group and 10 (83.3%) patients in the OROS-MPH
group were treatment responders. According to the CGI endpoint improvement scores,
responses to treatment were not significantly different between the two study groups
(p=0.076, v
2
=3.292). Table 2presents scale scores at the endpoint versus baseline for
each group.
T-DSM-IV-S The OROS-MPH group showed changes from baseline to endpoint on all
parent T-DSM-IV-S subscale scores. The atomoxetine group improved significantly only
on the total score (p=0.033). The atomoxetine group did not show significant
improvements on other subscale scores of parent T-DSM-IV-S (Table 2).
The change from baseline to endpoint in teacher T-DSM-IV-S inattention subscale
score was significant for both groups (p=0.05 for atomoxetine; p=0.023 for OROS-
MPH). The OROS-MPH group also showed changes from baseline to endpoint on other
teacher T-DSM-IV-S subscale scores: opposition-defiance score (p=0.016), conduct
disorder score (p=0.027) and total score (p=0.041). The atomoxetine group did not
show significant improvements on other subscale scores of teacher T-DSM-IV-S (Table 2).
262 Child Psychiatry Hum Dev (2011) 42:257–269
123
Table 2 Scale scores at the endpoint versus baseline for each group
Atomoxetine group (n =14) OROS-MPH group (n =11)
Baseline Endpoint *Statistical test (t; p) Baseline Endpoint *Statistical test (t; p)
Parents T-DSM-IV scores
Inattention scores 16.72 ±4.02 13.90 ±4.34 -1.42; 0.153 17.72 ±4.56 9.81 ±4.53 -2.80; 0.005
Hyperactivity/impulsivity scores 16.97 ±4.41 11.18 ±5.28 -1.91; 0.056 13.81 ±5.65 6.72 ±5.27 -2.39; 0.017
Opposition-defiance scores 9.09 ±4.54 8.36 ±4.45 -0.71; 0.474 12.90 ±5.65 6.00 ±2.82 -2.55; 0.011
Conduct disorder scores 2.00 ±3.06 2.00 ±3.16 -0.21; 0.833 2.81 ±2.22 0.72 ±0.90 -2.45; 0.015
Total scores 44.18 ±7.48 34.27 ±13.58 -2.13; 0.033 47.27 ±16.70 23.27 ±11.88 -2.58; 0.010
Teacher T-DSM-IV-S
Inattention scores 14.45 ±5.76 11.90 ±5.16 -2.00; 0.04 13.90 ±6.20 7.63 ±6.00 -2.27; 0.023
Hyperactivity/impulsivity scores 10.63 ±7.1 8.18 ±4.62 -1.49; 0.136 9.45 ±6.54 5.09 ±5.08 -1.55; 0.119
Opposition-defiance scores 4.63 ±4.10 4.54 ±3.77 -0.07; 0.944 9.27 ±4.71 3.72 ±3.00 -2.40; 0.016
Conduct disorder scores 1.72 ±1.73 2.36 ±4.24 -0.36; 0.715 3.18 ±2.60 0.81 ±1.25 -2.20; 0.027
Total scores 33.27 ±12.67 27.00 ±12.57 -1.95; 0.050 35.63 ±17.65 17.27 ±13.52 -2.04; 0.041
Stroop test
Stroop-1 time (/sec) 16.04 ±7.35 12.59 ±3.84 -0.59; 0.009 11.86 ±2.21 11.19 ±1.82 -0.35; 0.721
Stroop-2 time (/sec) 16.83 ±10.62 13.30 ±3.01 -1.47; 0.139 12.92 ±2.48 12.33 ±2.79 -0.66; 0.507
Stroop-3 time (/sec) 23.35 ±8.50 17.39 ±4.02 -2.49; 0.013 20.04 ±7.19 16.56 ±2.79 -2.04; 0.041
Stroop-4 time (/sec) 31.96 ±6.97 28.20 ±11.09 -1.98; 0.047 35.22 ±14.11 23.14 ±6.47 -2.70; 0.007
Stroop-5 time (/sec) 48.41 ±23.44 40.27 ±23.51 -1.88; 0.059 55.13 ±25.03 34.35 ±9.34 -2.59; 0.009
Stroop-5 error 0.90 ±1.59 0.63 ±0.92 -0.96; 0.334 0.60 ±1.26 0.27 ±0.46 -0.81; 0.414
Stroop-5 correction 0.90 ±0.73 1.36 ±1.74 -0.17; 0.863 1.90 ±1.28 0.81 ±1.53 -1.99; 0.046
VMS
VMS-forward 7.63 ±2.33 8.18 ±1.77 -0.88; 0.379 6.80 ±1.39 7.63 ±1.50 -0.566; 0.572
VMS-backward 5.30 ±2.75 6.54 ±2.94 -1.89; 0.058 5.90 ±2.18 5.45 ±2.46 -1.61; 0.107
VMS-total scores 13.50 ±4.06 14.72 ±3.95 -1.55; 0.120 12.80 ±2.57 13.27 ±3.43 -0.17; 0.864
Child Psychiatry Hum Dev (2011) 42:257–269 263
123
Table 2 continued
Atomoxetine group (n =14) OROS-MPH group (n =11)
Baseline Endpoint *Statistical test (t; p) Baseline Endpoint *Statistical test (t; p)
Wisconsin test
Perservative error (%) 23.46 ±10.82 20.56 ±9.21 -1.78; 0.074 33.62 ±18.19 13.47 ±9.12 -2.80; 0.005
Conceptual level responses (%) 39.33 ±23.59 51.99 ±23.01 -2.19; 0.028 38.29 ±19.70 62.66 ±17.20 -2.39; 0.017
Failure to maintain set 0.60 ±0.84 0.81 ±1.25 -0.27; 0.078 1.00 ±1.15 1.18 ±1.07 -0.35; 0.726
Number of categories 2.60 ±2.41 4.18 ±2.31 -2.04; 0.041 3.00 ±1.94 4.81 ±1.53 -1.99; 0.046
The statistically significant results were written in bold
* Wilcoxon signed rank test
264 Child Psychiatry Hum Dev (2011) 42:257–269
123
If the endpoint scores (12th week points) of T-DSM-IV-S were less than 40% of baseline
scores, it is considered as ‘‘response’’ to the treatment. According to parent T-DSM-IV
total endpoint improvement scores, treatment responses were not significantly different
between the two study groups (p=0.076, v
2
=3.292). Based on the endpoint parent
T-DSM-IV total scores, 4 (36.4%) patients in the atomoxetine group and 7 (63.6%)
patients in the OROS-MPH group were treatment responders.
Stroop Test The post-treatment versus pretreatment improvements in Stroop-1, Stroop-3
and Stroop-4 times in the atomoxetine group were statistically significant. In the OROS-
MPH group Stroop-3, Stroop-4, Stroop-5 times and Stroop-5 number of corrections were
improved significantly (Table 2).
VMS There were no statistically significant changes after treatment in VMS-forward,
VMS-backward and VMS-total scores for both groups (Table 2).
Wisconsin Test At the end of 12 weeks of treatment, there were statistically significant
improvements in % conceptual level responses and number of categories in the ato-
moxetine group, where as there were statistically significant improvements in % persev-
erative errors, % conceptual level responses and number of categories in the OROS-MPH
group (Table 2).
Vital Signs and Laboratory Evaluations
Both atomoxetine and OROS-MPH were well tolerated, with no statically significant
difference in discontinuations due to adverse events (atomoxetine 3/14, OROS-MPH 1/11).
Analysis of electrocardiogram results showed no statistically or clinically significant
changes in corrected QT intervals, nor was there any evidence of a pattern of change in
laboratory values associated with either atomoxetine or OROS-MPH. The atomoxetine
group experienced significant differences in diastolic blood pressure (p=0.039). A stat-
ically significant decrease in weight was seen with both atomoxetine and OROS-MPH. The
most frequently reported adverse events in the atomoxetine group were anorexia (85.7%),
nausea (71.4%), nervousness (71.4%), weight loss (57.1%), abdominal pain (57.1%), and
somnolence (35.7%). In the OROS-MPH group, patients most frequently reported anorexia
(75.0%), nervousness (75.0%), insomnia (58.3%), headache (50.0%), nausea (41.7%), and
weight loss (41.7%) (Table 3). All the adverse events indicated in the table were at weak or
moderate level and did not led to discontinuation. The patients continued the treatment
despite the adverse events.
Discussion
Atomoxetine is a new compound that has been proposed as a potential treatment for
ADHD on the basis of its pharmacologic property of blocking the presynaptic norepi-
nephrine transporter. The efficacy and safety of atomoxetine have been demonstrated in
multiple double-blind, placebo-controlled studies [12,13,30]. Also, most trials indicated
that atomoxetine is safe and well tolerated in children and adolescents with ADHD.
However, few data are available concerning its comparability to stimulants [14–17]. There
are no studies available in the literature that compare the effects of atomoxetine and OROS
Child Psychiatry Hum Dev (2011) 42:257–269 265
123
methylphenidate on executive functions. The results of our study demonstrated that ato-
moxetine, a nonstimulant norepinephrine-specific reuptake inhibitor, was effective and safe
at a mean dose of 1.2 mg/day in Turkish children with ADHD, and that both atomoxetine
and OROS methylphenidate produced significant improvements on symptom severity and
executive functions.
In the present study, there was no statistically significant difference in response rates
between the drug groups according to clinician rated CGI-I, and parent and teacher rated
T-DSM-IV-S scores. However, according to CGI-I endpoint scores, the response rates
were 83.3% in the OROS-MPH group and 63.6% in the atomoxetine group, indicating a
more pronounced response was achieved in the OROS-MPH group. Similarly, although the
response rates according to parent rated T-DSM-IV were not statistically significantly
different between the two groups, the response rate was 63.4% in the OROS-MPH group
and 36.4% in the atomoxetine group. In the teacher T-DSM-IV-S subscales, it is
remarkable that while all subscale and total scores in the OROS-MPH group were
improved significantly, only inattention subscale score was improved significantly in the
atomoxetine group. When all these results are considered, while both drugs can be con-
sidered effective in ADHD treatment, more remarkable improvement is provided by
OROS-MPH based on the rates across informant (i.e., teachers, clinicians). In the first
study comparing atomoxetine and OROS-MPH in terms of efficacy, Kemner et al. reported
that the response rates were significantly superior in the OROS-MPH group according to
CGI and parent-rated ADHD-RS [14]. The study by Newcorn et al. also reported signif-
icantly higher response rates with OROS-MPH treatment compared to atomoxetine. Yet in
another study comparing the efficacy of the two drugs, response rates were found to be
similar [15]. As the result of our study, which included feedback from teachers in addition
to clinician and parent ratings unlike the other studies, it can be concluded that while both
drugs were effective in ADHD treatment, OROS-MPH provided a more marked
improvement on the symptoms.
An important aspect of our study is that treatment efficacy was assessed with neuro-
psychological tests battery. As the result of neuropsychological tests assessing frontal lobe
functions, significant post-treatment improvements were seen in both drug groups. A low
Table 3 Treatment-emergent
advers events of either group
Treatment-emergent adverse
events are events that first
occurred or worsened in severity
after the initiation of study drug
administration
a
Frequencies analyzed with
fisher exact test
Event Atomoxetine
(n =14)
OROS-MPH
(n =11)
pvalue
a
n% n%
Anorexia 12 85.7 9 75.0 0.635
Nausea 10 71.4 5 41.7 0.431
Nervousness 10 71.4 9 75.0 0.695
Weight loss 8 57.1 5 41.7 1.00
Abdominal pain 8 57.1 3 25.0 0.683
Somnolence 5 35.7 1 8.3 0.635
Headache 5 35.7 3 25.0 0.203
Insomnia 5 35.7 7 58.3 1.00
Vertigo 5 35.7 3 25.0 0.130
Tics 0 0.0 2 16.7 0.233
Vomiting 2 14.3 1 8.3 0.170
Depression 2 14.3 3 25.0 1.00
266 Child Psychiatry Hum Dev (2011) 42:257–269
123
Stroop interference score means that children demonstrate a high-interference tendency.
Altogether, the Stroop color-word interference task is useful to determine the ability to
process information despite interference of information and to test sustained attention.
While there are studies that report improvements achieved in Stroop test interference
scores and speed of reading, no studies were encountered in the literature that evaluated
effects of atomoxetine. Our results showed that both drugs improved Stroop-1 and Stroop-2
times which assess the speed of reading, but OROS-MPH was more effective than ato-
moxetine particularly on Stroop-5 time evaluating interference and even on number of
corrections.
When WCST was evaluated, while there were significant improvements in both groups
in the percentage of conceptual level responses and number of categories completed,
additionally a significant decrease in the percentage of perseverative error in the OROS-
MPH group was seen. Perseverative errors, decreased conceptual responses and failure in
completing categories on WCST are among the most important indicators of neuropsy-
chiatric deficits in ADHD [19]. The results of these two tests used in the present study are
significant both in terms of showing impaired executive functions in ADHD and the
improvements achieved with treatment.
Altough rates of adverse effects are high for both drug groups, most of the patients
continued to use the medications. So it is considered that both atomoxetine and OROS-
MPH were generally well tolerated, with few discontinuations due to adverse events. Three
patients in the atomoxetine group, and one patient in the OROS-MPH group discontinued
treatment due to side effects at week 4 of the study. Nausea and vomiting in the ato-
moxetine group and chest pain and palpitations in the OROS-MPH group were reported as
reasons for discontinuation. Among patients who completed the study, the most frequently
reported adverse events in the atomoxetine group were anorexia, nausea, abdominal pain,
weight loss and somnolence. In the OROS-MPH group, patients most frequently reported
anorexia, nervousness, weight loss and insomnia. In two previous studies [11,16],
insomnia was more frequently reported among patients randomized to methylphenidate
than among those to atomoxetine. In another study vomiting and somnolence were reported
to occur most frequently among patients in atomoxetine group than among those in
methylphenidate [15]. In general, the pattern of adverse events and effects on vital signs
observed for atomoxetine was consistent with that expected of a drug associated with
increased noradrenergic tone. This could also be the reason for the statistically significant
increase in diastolic blood pressure in the atomoxetine group. Furthermore, in the present
study no genetic study was performed in patients on atomoxetine in terms of being
extensive and poor metabolizers. For this reason more adverse effects may have occurred
and greater number of patients may have discontinued in the atomoxetine group.
The interpretation of the results of this study is limited by several factors. Open label
design of our study and inclusion of a small number of patients is an important limitation.
Although limited number of patients were evaluated in the present study, it may be con-
sidered important as this is the first study where OROS-MPH was compared to ato-
moxetine both in terms of efficacy and tolerability and executive functions. In addition, the
age for cohort in this investigation ranged from 8 to 14 years. The heterogeneity of age in
this investigation is also a problem. One other major limitation of the study is basing
assessment of the symptom severity on T-DSM-IV-S which is not a frequently used
measurement in the literature such as Child and Adolescent Behavior Disorders Screening
and Rating Scales. Another major limitation of this study is that it does not include a
comparison group of children who were not receiving any medication. Inclusion of a
placebo control group which enables comparison of other psychotropics can be an issue of
Child Psychiatry Hum Dev (2011) 42:257–269 267
123
future studies.It is also an important limitation that CYP2D6 metabolism of atomoxetine
could not been studied. This makes it difficult to generalize the side effects occurred during
the present study.
As the result of the present study, despite its limitations, atomoxetine and OROS-MPH
were effective and safe in Turkish children with ADHD. Both drugs produced marked
improvement on executive functions. Long-term, double-blind, placebo-controlled follow-
up studies with a larger sample size are needed for generalizability of the findings.
Summary
In the current, open-label, 12 weeks trial, the efficacy, adverse events and effects on
executive functions atomoxetine in the treatment of children with ADHD were compared
with those of OROS-MPH. A total 25 children with ADHD were recruited to the study.
The principal outcome measures were parents and teachers T-DSM-IV-S, CGI, and neu-
ropsychological tests battery. The results indicated that there was no significant difference
were observed between the two medication groups in terms of the CGI and parents
T-DSM-IV-S scores. However, in the teacher T-DSM-IV-S, all subscale and total scores in
the OROS-MPH group were improved significantly. Both drugs improved Stroop 1 and
Stroop 2 times, but OROS-MPH was more effective than atomoxetine particularly on
Stroop 5 time evaluating interference and even on number of corrections. When WCST
was evaluated, a significant decrease in the percentage of perseverative error in the OROS-
MPH group was seen. Although rates of adverse events are high, both drug groups were
generally well tolerated. When all these results are considered, while both drugs can be
considered effective in ADHD treatment, more remarkable improvement is provided by
OROS-MPH based on the rates across informant (i.e. teachers, clinicians), and neuro-
psychological tests.
Preliminary data were presented as posters at the following meetings: 20th National
Congress on Child and Adolescent Psychiatry, Bodrum—Turkey, April 2010.
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