JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume XX, Number XX, 2018

ª Mary Ann Liebert, Inc.
Pp. 1–11
DOI: 10.1089/cap.2018.0076

Comparative Efficacy of Methylphenidate and Atomoxetine

on Emotional and Behavioral Problems in Youths
with Attention-Deficit/Hyperactivity Disorder
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Hsien-Hsueh Shih, MD,1,* Chi-Yung Shang, MD, PhD,1,2,* and Susan Shur-Fen Gau, MD, PhD1–3

Abstract
Objective: Methylphenidate and atomoxetine are efficacious in reducing core symptoms of attention-deficit/hyperactivity
disorder (ADHD), but little is known about their efficacy in improving emotional/behavioral problems among youths with
ADHD.
Methods: One hundred sixty drug-naı̈ve youths with DSM-IV-defined ADHD, aged 7–16 years, were recruited and randomly
assigned to osmotic-release oral system methylphenidate (OROS-methylphenidate; n = 80) and atomoxetine (n = 80) in a 24-
week, open-label, head-to-head clinical trial. The primary efficacy measure was parent-reported Child Behavior Checklist
(CBCL), and the secondary efficacy measures included Youth Self Report (YSR) and Strengths and Difficulties Ques-
tionnaire (SDQ), which was based on the ratings of parents, teachers, and subjects.
Results: For CBCL, both methylphenidate and atomoxetine groups showed significant improvement in all scores at weeks 8
and 24 except Somatic Complaints in the atomoxetine group. For SDQ, both treatment groups showed significant im-
provements in the Hyperactive and Conduct subscales for parent ratings, and the Externalizing subscale for teacher ratings at
week 24. Methylphenidate was associated with greater improvements in Aggressive Behavior and Somatic Complaints of
CBCL and in Conduct subscale of self-reported SDQ at week 24 compared with atomoxetine.
Conclusions: Our findings provide evidence to support that both methylphenidate and atomoxetine were effective in im-
proving a wide range of emotional/behavioral problems in youths with ADHD after 24 weeks of treatment, with greater
improvement in aggressive behavior, somatic complaints, and conduct problems in the methylphenidate group.

Keywords: attention-deficit/hyperactivity disorder, atomoxetine, clinical trial, emotional/behavioral problems, methylphenidate

Introduction commonly lead to a negative impact on quality of life, family

function, and interpersonal relationship in individuals with ADHD

A ttention-deficit/hyperactivity disorder (ADHD) is a

common childhood mental disorder affecting 4%–13.3% of
children and adolescents in western countries (Willcutt 2012) and
7%–9% in Taiwan (Gau et al. 2005). Previous studies indicate the
neurological basis for this disorder (Volkow et al. 2005; Shang et al.
2013). ADHD symptoms may last to adolescence and adulthood
with long-term social function impairment (Tseng and Gau 2013;
Lin et al. 2015). In addition to the ADHD core symptoms, youths
with ADHD are at risk of having a wide range of co-occurring
psychopathologies, such as emotional dysregulation, disruptive
behavior, and social problems (Spencer et al. 2011; Biederman
et al. 2012; Steinhausen et al. 2012). These comorbid conditions
(Lin et al. 2015). Furthermore, ADHD patients with emotion-
al/behavioral problems often exhibit a greater number of ADHD
symptoms, which correlates with increased severity of this disorder
(Biederman et al. 2007). Youths with ADHD and emotional/be-
havioral problems display greater levels of psychosocial impair-
ment than youths with either ADHD or emotional/behavioral
problems alone (Blackman et al. 2005). Accordingly, it is essential
to identify these emotional/behavioral profiles of youths with
ADHD in the clinical setting.
Methylphenidate and atomoxetine are the only two medications
approved for treating youth and adults with ADHD in many
countries, and Taiwan as well (Ni et al. 2013). Methylphenidate, a

1
Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan.
2
Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan.
3
Department of Psychology, Graduate Institute of Brain and Mind Sciences, Institute of Clinical Medicine, National Taiwan University, Taipei,
Taiwan.
*These authors contributed equally to this work as the first authors.
Funding: This study was supported by the grant from the National Science Council (NSC 98-2314-B-002-051-MY3, NSC99-2627-B-002-015,
NSC100-2627-B-002-014) and the National Health Research Institute (NHRI-EX100-10008PI, NHRI-EX101-10008PI, NHRI-EX106-10404PI), Taiwan.

1
 2 SHIH ET AL.

dopamine and noradrenaline reuptake inhibitor, promotes the re-
lease of stored dopamine from presynaptic vesicles (Volkow et al.
2005) and is recognized as the first-line treatment for ADHD for
decades worldwide. Atomoxetine is a highly specific inhibitor of
presynaptic norepinephrine transporter, with little affinity for other
neurotransmitter transporters or receptors (Garnock-Jones and
Keating 2009). Clinical trials have shown that both methylpheni-
date and atomoxetine treatments are associated with clinically
meaningful and comparable effectiveness in improving the core
symptoms of ADHD across situations (Kratochvil et al. 2002;
Shang et al. 2015). In contrast, results for the effectiveness of
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(K-SADSE) (Gau et al. 2005). We excluded participants who had
comorbid conditions with bipolar disorders, psychosis, any sub-
stance abuse, autism spectrum disorders, intellectual disability
(Full-Scale Intelligence Quotient score <80), or had serious medi-
cal conditions such as cardiovascular disease, history of seizure, or
prior electroencephalogram abnormalities related to epilepsy, or
had ever used any psychotropic medications before the study. The
details have been reported elsewhere (Shang et al. 2015).
Study design and procedures

This study had been approved by the Research Ethics Committee

methylphenidate and atomoxetine in improving emotional/behav-
of the National Taiwan University Hospital, Taiwan (IRB ID,
ioral problems in patients with ADHD are mixed. For example,
200812153M; ClinicalTrials.gov number, NCT00916786) before
although several studies observed no significant effects on emo-
implementation. The potential subjects who met the recruitment
tional control after treatment with methylphenidate (Biederman
criteria received a comprehensive explanation of the purpose and
et al. 2011), others documented the effectiveness of methylpheni-
procedure of this study, as well as the reassurance of confidenti-
date in improving emotional dysregulation (Kutlu et al. 2017).
ality. All the participants provided their written informed consent.
Some trials showed a significant reduction in anxiety and depres-
During the 24-week, open-label, head-to-head randomized clinical
sion after treatment with methylphenidate in patients with ADHD
trial, participants were assigned to either the osmotic-release oral
(Bouffard et al. 2003); others found no change (Kuperman et al.
system (OROS)-methylphenidate or atomoxetine group at a 1:1 ratio
2001), and still others demonstrated an increase in anxiety and
according to computer-generated random sequence. Participants were
depressive symptoms (Spencer et al. 2005). A clinical trial dem-
assessed seven times at baseline (visit 1), week 2 (visit 2), week 4 (visit
onstrated that atomoxetine is not superior to placebo in reducing
3), week 8 (visit 4), week 12 (visit 5), week 16 (visit 6), and week 24
oppositional problems (Bangs et al. 2008), whereas other studies
(visit 7). At visit 1, participants started taking medication with OROS-
showed positive findings for the efficacy of atomoxetine in im-
methylphenidate (an initial dosage of 18 mg per day, administered as a
proving oppositional behaviors (Dittmann et al. 2011). Given the
single morning dose) or atomoxetine (an initial dosage of 0.5 mg/kg
remarkable variability in methods across pharmacological studies
per day, administered as once-daily dose). Drug dosage would be
on ADHD (Faraone et al. 2006), further clinical trials are required
titrated based on treatment response and adverse effects at visits 2–7
to examine the efficacy of methylphenidate and atomoxetine in the
(weeks 2–24) depending upon clinical response and adverse effects.
treatment of emotional/behavioral problems in youths with ADHD.
The maximal dose was 54 mg daily for OROS-methylphenidate or
Numerous rating scales are available for measuring the emotion-
1.2 mg/kg daily for atomoxetine.
al/behavioral symptoms associated with ADHD in different settings.
Parent-reported CBCL and Youth Self Report (YSR) were
Compared with narrowband scales, broadband scales such as Children
gathered at baseline (visit 1), week 8 (visit 4), week 16 (visit 6), and
Behavior Checklist (CBCL) and Strength and Difficulties Ques-
week 24 (visit 7). Parent-, teacher-, and self-reported SDQ were
tionnaire (SDQ) are better for a comprehensive assessment of the
gathered at each visit, from visit 1 through visit 7.
emotional/behavioral symptoms associated with ADHD. However,
only a few studies have used the CBCL (Wang et al. 2013) and SDQ
Efficacy measure
(Gelade et al. 2016) as outcome measures for treatment studies. For
example, a previous report showed no improvement in emotion- Our primary efficacy measure was parent-reported CBCL, and
al/behavioral symptoms measured by CBCL after treatment with the secondary outcomes were YSR and SDQ.
methylphenidate in youths with ADHD (Wang et al. 2013). A clinical
trial demonstrated that methylphenidate is associated with significant CBCL and YSR
improvement in the total score of teacher-rated SDQ, but no im-
The CBCL is a parental questionnaire used to measure the
provement on parent-rated SDQ (Gelade et al. 2016).
emotional/behavioral problems in youths aged 4–18, and the YSR
Given that the emotional/behavioral symptoms influence the
is administered to adolescents aged 11–18 to obtain self-reports
psychosocial functions and disease course of ADHD, a direct
about their emotional/behavioral problems (Achenbach and Du-
comparative trial is required to identify the therapeutic effect of
menci 2001). Each item is scored 0 if not true, 1 if somewhat or
methylphenidate and atomoxetine on the emotional/behavioral
sometimes true, and 2 if very true or often true. Eight emotion-
problems in youths with ADHD. The present study aimed to di-
al/behavioral scales were created for both the CBCL and YSR,
rectly compare the effectiveness of methylphenidate and atomox-
including Anxious/Depressed symptoms, Attention Problems,
etine in improving a wide range of emotional/behavioral problems
Aggressive Behaviors, Delinquent Behaviors, Social Problems,
in drug-naı̈ve youths with ADHD in a head-to-head, open-label, 24-
Thought Problems, Somatic Complaints, and Withdrawn.
week randomized clinical trial.
The Chinese versions of CBCL and YSR have been shown to
have good validity and reliability (Yang et al. 2001; Shang et al.
Methods
2006), and these two scales have been widely used to measure
Participants emotional/behavioral problems in Taiwanese youth populations
(Chen et al. 2017).
We recruited drug-naı̈ve youths, aged between 7 and 16 years,
who met the DSM-IV diagnostic criteria for ADHD, as assessed by
Strengths and Difficulties Questionnaire
the investigator’s clinical evaluation and confirmed using the
Chinese version of the Schedule for Affective Disorders and The SDQ, a 25-item screening questionnaire, has been designed
Schizophrenia for School-Age Children–Epidemiological Version to assess a broad area of emotions and behaviors of youths
 MEDICATIONS FOR EMOTIONAL/BEHAVIORAL PROBLEMS 3

(Goodman 1999). Each item is rated on a three-point Likert scale
(0 = not true, 1 = somewhat true, and 2 = certainly true). There are
three versions of the SDQ for ratings by self, parents, and teachers.
Our previous work on the Chinese version of SDQ identified four
subscales in the parent version (prosocial, conduct, internalizing,
and hyperactive), four subscales in the teacher version (peer/pro-
social, externalizing, internalizing, and inattention), and five sub-
scales in the self-report (prosocial, conduct, hyperactive, peer
problems, and emotion) (Liu et al. 2013).
Statistical analyses
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tween week 24 (last observation) and baseline, with the small,
medium, and large effect sizes being d = 0.2 to <0.5, >0.5 to <0.8,
and >0.8, respectively. In particular, both intercepts and slope
(time) effects in the linear mixed model with time-dependent var-
iables were treated as random effects, to account for variations
among subjects in baseline values, and slopes for individual tra-
jectories of changes in emotional/behavioral problems over visits,
in addition to the main treatment and fixed time effects of the two
treatment groups. To test the difference in the slope of change
between the two treatment groups, the interaction terms between
visits · drugs were tested. The alpha value was preselected at the

level of p < 0.05.

Baseline demographic characteristics and assessment of emo-
tional/behavioral problems were presented in mean scores and SD
for continuous variables, and number and corresponding percent-
age for categorical variables. The t-scores of CBCL, YSR, and SDQ
were used to present the severity of emotional/behavioral problems.
The t-score was defined as multiplying the z-scores by 10 and
adding 50, with a mean of 50 and a SD of 10. We used the intent-to-
treat principle for missing data in the statistical analysis, and the
last-observation-carried-forward method was applied to missing
data or patient dropout. Hierarchical linear mixed-effects models
were employed to address the lack of statistical independence of
repeated measurements of the same participants over time. Cohen’s
d was used to compute the effect size for the comparisons of scores
of CBCL, YSR, and SDQ between week 8 and baseline and be-
Results
Sample description and medication
Of the 174 patients screened, 160 were enrolled and randomly
assigned to atomoxetine (n = 80) or methylphenidate (n = 80)
groups. Among them, 80 patients with atomoxetine and 76 patients
with methylphenidate had complete data on CBCL. Given that
YSR was only applied to patients aged 11 years or more, 54 patients
treated with atomoxetine and 51 patients treated with methylphe-
nidate had complete data on YSR (Fig. 1). There were no statisti-
cally significant group differences in demographic characteristics
and baseline severity of emotional/behavioral problems except that

Subjects screened (n=174)

Excluded from random assignment (n=14)

Entry criteria not met (n=11)
Personal reasons (n=3)

Subjects provided consent and randomized (n=160)

Assigned to OROS-methylphenidate (n=80) Assigned to atomoxetine (n=80)

Completed CBCL (n=76) and YSR (n=51) at baseline Completed CBCL (n=80) and YSR (n=54) at

Completed CBCL (n=60) and YSR (n=38) at week 8 Completed CBCL (n=68) and YSR (n=45) at week

Completed CBCL (n=37) and YSR (n=22) at week 24 Completed CBCL (n=36) and YSR (n=25) at week 24

FIG. 1. Flowchart of the randomization procedure. CBCL, Child Behavior Checklist; YSR, Youth Self Report.
 4 SHIH ET AL.

the methylphenidate group had higher Peer/Prosocial scores of
teacher-reported SDQ compared with the atomoxetine group
(Table 1).
For the OROS-methylphenidate group, the mean administered
dose was 20.45 (SD = 6.76) mg/day or 0.64 (SD = 0.19) mg/kg per
day at week 2 (visit 2), 24.91 (SD = 9.65) mg/day or 0.75
(SD = 0.24) mg/kg per day at week 4 (visit 3), 26.38 (SD = 11.32)
mg/day or 0.79 (SD = 0.28) mg/kg per day at week 8 (visit 4), 27.98
(SD = 11.77) mg/day or 0.84 (SD = 0.3) mg/kg per day at week 12
(visit 5), 27.02 (SD = 11.83) mg/day or 0.81 (SD = 0.32) mg/kg per
day at week 16 (visit 6), and 27.83 (SD = 12.44) mg/day or 0.82
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day at week 8 (visit 4), 31.39 (SD = 9.12) mg/day or 0.93
(SD = 0.31) mg/kg per day at week 12 (visit 5), 31.68 (SD = 8.76)
mg/day or 0.95 (SD = 0.31) mg/kg per day at week 16 (visit 6), and
31.74 (SD = 10.34) mg/day or 0.98 (SD = 0.28) mg/kg per day at
week 24 (visit 7). Regarding adverse events, vomiting ( p = 0.017),
somnolence ( p < 0.001), and dizziness ( p = 0.009) were reported
more often for atomoxetine, while insomnia ( p = 0.035) was re-
ported more often for OROS-methylphenidate. The details have
been reported elsewhere (Shang et al. 2015).

(SD = 0.34) mg/kg per day at week 24 (visit 7). For the atomoxetine
group, the mean administered dose was 26.09 (SD = 9.07) mg/day
or 0.78 (SD = 0.28) mg/kg per day at week 2 (visit 2), 27.94
(SD = 9.74) mg/day or 0.84 (SD = 0.33) mg/kg per day at week 4
(visit 3), 29.37 (SD = 8.23) mg/day or 0.89 (SD = 0.31) mg/kg per
Efficacy on CBCL
Both treatment groups showed significant improvements in all
the eight scales of CBCL from baseline to week 8 and from baseline
to week 24 except Somatic Complaints in the atomoxetine group
(Table 2). Compared with the atomoxetine group (Table 2), the

Table 1. Demographics and Baseline Emotional/Behavioral (t-Score) Between the Two Treatment Groups

Methylphenidate
Mean (SD) or n (%) Atomoxetine (n = 80) (n = 76) F/v2 p value

Age 9.90 (2.78) 9.70 (2.42) F = 0.24 0.628

Male 70 (87.50) 66 (86.84) v2 = 0.02 0.902
Intelligence quotient (IQ)
Full-scale IQ 102.92 (11.50) 105.93 (11.94) F = 2.31 0.131
Performance IQ 103.04 (13.07) 104.99 (14.02) F = 0.72 0.397
Verbal IQ 103.01 (11.33) 106.09 (9.92) F = 2.91 0.091
CBCL
Aggressive behavior 62.75 (12.50) 64.98 (13.50) F = 1.09 0.297
Anxious/depressed 60.69 (14.06) 58.31 (14.82) F = 1.07 0.303
Attention problems 68.10 (10.92) 67.07 (11.90) F = 0.32 0.572
Delinquent behavior 59.20 (10.07) 61.83 (14.06) F = 1.78 0.185
Social problems 63.13 (12.25) 62.18 (11.91) F = 0.24 0.621
Somatic complaints 53.39 (12.36) 55.50 (15.04) F = 0.93 0.336
Thought problems 60.88 (11.84) 60.52 (15.66) F = 0.03 0.869
Withdrawn 58.35 (11.02) 57.45 (11.54) F = 0.25 0.621
YSR n = 54 n = 51
Aggressive behavior 61.10 (13.81) 63.56 (16.93) F = 0.67 0.415
Anxious/depressed 61.38 (18.08) 64.14 (19.86) F = 0.55 0.459
Attention problems 65.88 (13.73) 66.29 (13.97) F = 0.02 0.879
Delinquent behavior 60.49 (16.16) 61.51 (17.89) F = 0.09 0.761
Social problems 60.67 (12.93) 61.68 (13.96) F = 0.15 0.701
Somatic complaints 60.01 (18.51) 60.92 (17.46) F = 0.07 0.795
Thought problems 62.43 (16.65) 65.83 (19.09) F = 0.95 0.333
Withdrawn 60.74 (14.97) 59.40 (14.85) F = 0.21 0.646
SDQ—parent report n = 78 n = 76
Internalizing 53.89 (11.66) 53.63 (11.01) F = 0.02 0.883
Prosocial 47.10 (10.42) 48.33 (10.01) F = 0.56 0.456
Hyperactive 51.05 (6.33) 49.55 (6.90) F = 1.98 0.161
Conduct 59.84 (10.95) 61.10 (12.10) F = 0.46 0.497
SDQ—self-report n = 54 n = 51
Emotion 51.96 (10.04) 53.40 (11.01) F = 0.49 0.486
Prosocial 51.10 (12.45) 51.73 (11.89) F = 0.07 0.790
Hyperactive 53.07 (6.53) 51.85 (8.60) F = 0.68 0.412
Conduct 51.30 (10.25) 54.22 (13.97) F = 1.50 0.223
Peer problem 60.82 (10.02) 58.95 (8.23) F = 1.08 0.301
SDQ—teacher report n = 73 n = 68
Peer/prosocial 45.51 (8.91) 49.00 (9.53) F = 5.05 0.026*
Externalizing 56.50 (10.18) 58.19 (10.25) F = 0.96 0.328
Internalizing 53.17 (9.45) 55.05 (10.63) F = 1.24 0.268
Inattention 45.37 (8.14) 46.43 (7.96) F = 0.62 0.434

CBCL, Child Behavior Checklist; YSR, Youth Self Report; SDQ, Strengths and Difficulties Questionnaire.
*p < 0.05.
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Table 2. Change in Child Behavior Checklist and Youth Self Report from Baseline to Weeks 8 and 24 (Endpoint) in the Two Treatment Groups

Atomoxetine Methylphenidate Group differences

(p values)
Week 8-baseline Endpoint-baseline Week 8-baseline Endpoint-baseline
Week 8- Endpoint-
Mean (SD) Cohen’s d p Mean (SD) Cohen’s d p Mean (SD) Cohen’s d p Mean (SD) Cohen’s d p baseline baseline

CBCL
Aggressive -2.66 (10.42) -0.24 0.033* -4.46 (11.36) -0.37 0.002** -8.31 (10.28) -0.60 <0.001*** -8.48 (9.86) -0.68 <0.001*** 0.003** 0.032*
behavior
Anxious/ -4.04 (12.72) -0.31 0.011* -5.33 (11.85) -0.44 <0.001*** -5.02 (11.25) -0.36 0.001** -5.71 (12.57) -0.44 <0.001*** 0.647 0.857
depressed
Attention -5.33 (10.02) -0.54 <0.001*** -6.80 (10.61) -0.66 <0.001*** -8.37 (9.84) -0.70 <0.001*** -8.59 (10.30) -0.80 <0.001*** 0.087 0.326
problems
Delinquent -4.01 (8.52) -0.43 <0.001*** -4.93 (8.87) -0.52 <0.001*** -8.74 (11.55) -0.63 <0.001*** -7.98 (11.17) -0.64 <0.001*** 0.009** 0.083
behavior
Social problems -5.72 (10.90) -0.50 <0.001*** -6.39 (9.81) -0.55 <0.001*** -7.11 (9.33) -0.58 <0.001*** -7.57 (10.30) -0.68 <0.001*** 0.443 0.502
Somatic 0.14 (12.99) 0.02 0.898 -0.14 (13.10) -0.01 0.931 -4.20 (11.75) -0.30 0.009** -6.18 (12.95) -0.48 <0.001*** 0.051 0.008**
complaints
Thought -5.22 (12.18) -0.50 <0.001*** -4.51 (12.53) -0.40 0.004** -5.80 (12.85) -0.38 0.001** -6.84 (12.59) -0.52 <0.001*** 0.793 0.287

5
problems
Withdrawn -2.54 (10.21) -0.24 0.039* -2.79 (10.98) -0.25 0.038* -5.78 (10.09) -0.54 <0.001*** -5.81 (11.34) -0.53 <0.001*** 0.073 0.122
YSR
Aggressive -5.60 (14.38) -0.44 0.009** -6.60 (14.42) -0.50 0.003** -7.19 (11.87) -0.40 <0.001*** -9.55 (13.31) -0.55 <0.001*** 0.597 0.338
behavior
Anxious/ -3.55 (15.69) -0.22 0.121 -3.86 (13.57) -0.20 0.066 -6.52 (18.73) -0.34 0.041* -9.59 (17.14) -0.51 0.002** 0.440 0.093
depressed
Attention -6.62 (12.54) -0.51 <0.001*** -9.87 (12.00) -0.74 <0.001*** -9.57 (14.04) -0.74 <0.001*** -13.91 (15.03) -1.00 <0.001*** 0.322 0.177
problems
Delinquent -6.40 (15.67) -0.42 0.009** -6.72 (16.18) -0.41 0.008** -5.23 (17.64) -0.25 0.088 -6.97 (14.19) -0.39 0.005** 0.753 0.941
behavior
Social -5.82 (9.32) -0.48 <0.001*** -6.85 (8.64) -0.55 <0.001*** -4.77 (14.54) -0.38 0.043* -9.43 (12.98) -0.74 <0.001*** 0.694 0.282
problems
Somatic -6.23 (16.55) -0.35 0.016* -7.39 (19.40) -0.42 0.015* -2.31 (19.67) -0.20 0.350 -6.37 (22.25) -0.39 0.061 0.332 0.824
complaints
Thought -2.68 (17.24) -0.20 0.252 -5.41 (16.60) -0.32 0.035* -5.12 (19.85) -0.31 0.093 -8.31 (17.47) -0.46 0.005** 0.555 0.442
problems
Withdrawn 5.58 (14.02) -0.42 0.009** -7.52 (14.05) -0.53 <0.001*** -5.51 (16.75) -0.42 0.039* -6.84 (14.79) -0.50 0.008** 0.985 0.831

*p < 0.05.
**p < 0.01.
***p < 0.001.
 A B
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C D

FIG. 2. Improvements in the emotional/behavioral scores of CBCL in youths with ADHD randomly assigned to treatment with either
methylphenidate or atomoxetine. (A) Aggressive Behavior; (B) Attention Problems; (C) Delinquent Behavior; (D) Social Problems;
(E) Somatic Complaints. For the OROS-methylphenidate group, the mean administered dose was 26.38 (SD = 11.32) mg/day or 0.79
(SD = 0.28) mg/kg per day at visit 4, 27.02 (SD = 11.83) mg/day or 0.81 (SD = 0.32) mg/kg per day at visit 6, and 27.83 (SD = 12.44)
mg/day or 0.82 (SD = 0.34) mg/kg per day at visit 7. For the atomoxetine group, the mean administered dose was 29.37 (SD = 8.23)
mg/day or 0.89 (SD = 0.31) mg/kg per day at visit 4, 31.68 (SD = 8.76) mg/day or 0.95 (SD = 0.31) mg/kg per day at visit 6, and 31.74
(SD = 10.34) mg/day or 0.98 (SD = 0.28) mg/kg per day at visit 7. Error bars indicate 1 SD in both directions. *p < 0.05; d, Cohen’s d.

6
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Table 3. Change in Strengths and Difficulties Questionnaire from Baseline to Weeks 8 and 24 (Endpoint) in the Two Treatment Groups
Atomoxetine Methylphenidate
Group differences
Week 8-baseline Endpoint-baseline Week 8-baseline Endpoint-baseline
Week 8- Endpoint-
Mean (SD) Cohen’s d p Mean (SD) Cohen’s d p Mean (SD) Cohen’s d p Mean (SD) Cohen’s d p baseline baseline

Parent report
Internalizing -2.19 (9.86) -0.19 0.076 -2.19 (11.63) -0.21 0.122 -3.32 (9.71) -0.32 0.011* -3.23 (9.62) -0.33 0.009** 0.513 0.576
Prosocial 0.49 (9.19) 0.07 0.604 -0.63 (9.66) -0.06 0.593 -0.58 (10.32) -0.07 0.629 0.63 (10.95) 0.06 0.644 0.535 0.482
Hyperactive -1.74 (7.36) -0.28 0.056 -2.42 (6.49) -0.42 0.003** -1.79 (8.33) -0.21 0.179 -1.96 (7.79) -0.32 0.046* 0.968 0.714
Conduct -5.06 (11.96) -0.52 <0.001*** -3.95 (10.56) -0.37 0.003** -8.16 (11.51) -0.71 <0.001*** -7.22 (12.22) -0.67 <0.001*** 0.139 0.099
Self-report

7
Emotion -3.54 (9.26) -0.36 0.015* -3.03 (10.88) -0.30 0.061 -3.99 (9.52) -0.32 0.024* -4.74 (10.08) -0.46 0.004** 0.830 0.446
Prosocial -3.12 (15.55) -0.23 0.184 -3.23 (15.75) -0.24 0.165 0.98 (11.64) 0.06 0.654 0.11 (11.57) 0.01 0.951 0.192 0.262
Hyperactive -2.94 (9.26) -0.43 0.032* -3.22 (9.87) -0.43 0.026* -2.44 (7.54) -0.18 0.156 -2.43 (9.92) -0.28 0.120 0.794 0.707
Conduct -4.30 (10.60) -0.45 0.009** -2.21 (11.09) -0.21 0.174 -4.79 (8.50) -0.34 0.002** -6.95 (10.35) -0.61 <0.001*** 0.821 0.041*
Peer problem -3.38 (9.79) -0.44 0.021* -2.24 (11.84) -0.25 0.201 -1.15 (9.69) -0.09 0.617 -2.42 (10.06) -0.33 0.127 0.307 0.941
Teacher report
Peer/prosocial 3.19 (5.85) 0.30 <0.001*** 2.17 (8.25) 0.25 0.046* 1.62 (6.95) 0.13 0.237 1.37(9.24) 0.15 0.278 0.217 0.623
Externalizing -5.49 (9.49) -0.65 <0.001*** -5.66 (10.64) -0.64 <0.001*** -6.46 (10.53) -0.66 <0.001*** -6.29 (10.41) -0.71 <0.001*** 0.624 0.746
Internalizing -1.38 (9.12) -0.10 0.325 -1.61 (8.69) -0.17 0.157 -1.45 (11.73) -0.11 0.459 -0.17 (10.53) -0.02 0.905 0.970 0.425
Inattention 1.84 (10.58) 0.20 0.235 0.39 (9.52) 0.05 0.754 0.39 (9.21) -0.01 0.672 1.16 (10.81) 0.13 0.432 0.466 0.687

*p < 0.05.
**p < 0.01.
***p < 0.001.
 8 SHIH ET AL.
methylphenidate group had greater improvements in Aggressive
Behavior ( p = 0.003) and Delinquent Behavior ( p = 0.009) from
baseline to week 8, and in Aggressive Behavior ( p = 0.032) and
Somatic Complaints ( p = 0.008) from baseline to week 24. In ad-
dition, the methylphenidate group had lower scores in Attention
Problems (Fig. 2B) at week 8 (Cohen’s d = 0.35) and week 16
(Cohen’s d = 0.55), and Social Problems (Fig. 2D) at week 16
(Cohen’s d = 0.57) compared with the atomoxetine group. There
were significant effects of the drug · visit interactions on the Ag-
gressive Behavior ( p = 0.013), Delinquent Behavior ( p = 0.041),
and Somatic Complaints ( p = 0.003) (Fig. 2A, C, E). There were no
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effects noted for the interactions of drug · visit on the Anxious/-
Depressed, Attention Problems, Social Problems, Thought Pro-
blems, and Withdrawn.
Efficacy on YSR
Both treatment groups showed significant improvements in the
YSR scores from baseline to week 8 and from baseline to week 24
except Anxious/Depressed (weeks 8 and 24) and Thought Problems
(week 8) in the atomoxetine group, and Delinquent Behavior (week
8), Somatic Complaints (weeks 8 and 24), and Thought Problems
(week 8) in the methylphenidate group (Table 2). The analysis of
mean changes in the YSR scores (Table 2) revealed no significant
differences between the two treatment groups from baseline to
week 8 and from baseline to week 24.
Efficacy on SDQ
From baseline to week 24, both treatment groups showed sig-
nificant improvements in the Hyperactive and Conduct subscales
for parent ratings and the Externalizing subscale for teacher ratings
(Table 3). For the self-report, the Emotion and Conduct problems
improved with methylphenidate treatment at week 24, and the
Hyperactive problems improved with atomoxetine treatment at
week 24. Compared with the atomoxetine group, the methylphe-
nidate group had greater improvements in the self-reported Con-
duct subscale ( p = 0.041) at week 24.
Discussion
To our best knowledge, this is the first head-to-head, random-
ized, long-term treatment study to prospectively compare the ef-
fects of methylphenidate and atomoxetine on a wide range of
emotional/behavioral problems in drug-naı̈ve youths with ADHD.
We found that both treatments are efficacious in reducing the se-
verity of emotional/behavioral problems measured by CBCL, YSR,
and SDQ. Compared with atomoxetine, methylphenidate is asso-
ciated with greater improvements in Aggressive Behavior and
Somatic Complaints of CBCL and in the Conduct subscale of self-
reported SDQ from baseline to week 24. In contrast to an obser-
vational study showing no effect of short-acting methylphenidate
on the behavioral problems measured by CBCL in youths with
ADHD (Wang et al. 2013), our randomized clinical trial using
OROS-methylphenidate once daily provided strong evidence to
support that emotional/behavioral problems are reduced by treat-
ment not only with methylphenidate but also with atomoxetine.
Our results showed the large effect of treatment with methylphe-
nidate in the realm of attention problems (Cohen’s d = 0.7 at week 8
and 0.8 at week 24), consistent with an average effect size of 0.8 in
prior reports (Conners 2002). Previous studies have demonstrated the
effects of methylphenidate (Conners 2002; Sinzig et al. 2007) and
atomoxetine (Schwartz and Correll 2014) on externalizing symptoms
associated with ADHD, including aggressive, oppositional, and
conduct problems. Meta-analytic reviews in assessing the impact of
methylphenidate (Connor et al. 2002) reported a weighted mean ef-
fect size of 0.84 for overt and 0.69 for covert aggression-related
behaviors in ADHD, consistent with our findings in the Aggressive
Behavior subscale of CBCL for methylphenidate (Cohen’s d = 0.6 at
week 8 and 0.68 at week 24). In contrast, although atomoxetine is
effective in reducing the core symptoms of ADHD, a relatively small
effect size of 0.33 was found for disruptive problems (Schwartz and
Correll 2014), consistent with our findings in the Aggressive Beha-
vior subscale of CBCL for atomoxetine (Cohen’s d = 0.24 at week 8
and 0.37 at week 24). A systemic review reported a moderate-to-large
effect for methylphenidate and a small effect for atomoxetine on
oppositional behavior, conduct problems, and aggression in youths
with ADHD (Pringsheim et al. 2015). Animal studies have shown that
aggressive behaviors in mice are associated with the altered function
of dopamine transporter (Yu et al. 2014). Taken together, converging
evidence supports that methylphenidate demonstrates a greater
magnitude of treatment effect for aggressive spectrum symptoms in
youths with ADHD compared with atomoxetine. Future studies are
needed to explore the factors associated with the differential effects of
methylphenidate and atomoxetine on aggression.
Similarly, our findings demonstrated the effectiveness of both
methylphenidate and atomoxetine in improving the externalizing
problems assessed by a parent- and teacher-rated SDQ at week 24,
including Hyperactive, Conduct, and Externalizing subscales. No
significant improvement in parent- and self-rated Prosocial subscale
was observed after 24-week treatment with methylphenidate or
atomoxetine, whereas atomoxetine is associated with improvement
in teacher-rated Peer/Prosocial subscale at weeks 8 and 24. Our
previous work has shown the effectiveness of atomoxetine in chil-
dren with ADHD in improving interactions with peers and teachers
(Shang and Gau 2012). The literature documents the importance of
teacher ratings on treatment response in youths with ADHD (La-
vigne et al. 2012), and a lack of reports from teachers may result in
the inadequate assessment of treatment effects (Miller 1999).
For internalizing symptoms, our findings showed a similar ef-
ficacy of methylphenidate and atomoxetine in reducing Anxious/-
Depressed symptoms measured by CBCL in youths with ADHD,
with effect sizes ranging from 0.31 to 0.44. Previous studies
demonstrated the efficacy of atomoxetine on anxiety symptoms
associated with ADHD, with an effect size of 0.4 (Geller et al.
2007). In addition, clinical trials showed that symptoms of anxiety
and depression in patients with ADHD improved after treatment
with methylphenidate (Mattos et al. 2013).
The Somatic Complaints subscale of CBCL, one of the inter-
nalizing problems, is intended to assess the physical symptoms with
no medical basis, and psychiatric disability may accentuate the
incidence of somatic complaints in children with ADHD (Egger
et al. 1999). Previous studies showed that parent-rated somatic
complaints improved after treatment with methylphenidate (Rap-
port et al. 2002) in youths with ADHD, consistent with our findings.
Youths with ADHD experience significant distress at home and in
school, owing to inherent difficulties with this disorder, and may
internalize this distress as physical complaint (Rapport et al. 2002).
Further studies are needed to examine whether improved perfor-
mance at home and in school associated with methylphenidate
treatment corresponds with reductions in parent-rated somatic
complaints in youths with ADHD.
In our present study, changes in YSR scores also showed sig-
nificant improvements in emotional/behavioral problems from
baseline to week 24 for both methylphenidate and atomoxetine,
 MEDICATIONS FOR EMOTIONAL/BEHAVIORAL PROBLEMS
except the Anxious/Depressed subscale for atomoxetine and the
Somatic Complaints subscale for methylphenidate, inconsistent
with parent ratings of treatment response measured by CBCL.
Although youths are valuable informants about their own emo-
tional/behavioral problems (Klimkeit et al. 2006), previous studies
analyzing ratings on CBCL and YSR showed better parent–youth
agreement for externalizing problems than internalizing problems
(Rescorla et al. 2017). For example, youths may report more anx-
ious symptoms with higher degrees of intensity than their parents
(Weitkamp et al. 2010). Parent–youth discrepancies may arise due
to not only contextual variations in emotional/behavioral problems
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(De Los Reyes et al. 2013) but also parents’ inability to observe
youths’ emotional/behavioral problems where they are not present
(Achenbach 2011). Further research is needed to identify the spe-
cific factors associated with the inconsistent ratings of treatment
response for Anxious/Depressed symptoms and Somatic Com-
plaints between parents and youths with ADHD.
There are several methodological limitations in our study. First, due
to a lack of a placebo group, we could not determine whether the
improvements in emotional/behavioral problems may be partially at-
tributed to the placebo or maturity effect. In addition, we were unable to
contrast both baseline and placebo with active drug conditions to dif-
ferentiate the drug-unrelated somatic complaints from those due to
drug-related side effects. Second, methylphenidate is a controlled
drug in Taiwan, which prevents us from conducting a double-
blinded, placebo-controlled trial as an investigator-initiated clin-
ical trial. The bias derived by an open trial design could be reduced
since in Taiwan neither a teacher nor a school nurse distributed
medication to students, and thus the teachers were blinded to which
medication the subjects were taking. Third, given that the stimu-
lant comparator in the present study was OROS-methylphenidate,
our findings may not be generalized to other formulations of
methylphenidate or Dextro-amphetamine. Fourth, we included the
study sample from only one medical center in Taipei. Thus, the
study results may not be generalized to broader ethnic Chinese
populations with ADHD. Fifth, allowing investigators to adjust
dose without using a systematic titration schedule could have led to
underdosing in one group or the other; however, doses in the
current study were consistent with those in the package informa-
tion. Sixth, missing data in the long-term follow-up period may
result in insufficient power to detect the differences in efficacy
between the two drugs.
Conclusions
Our findings suggest that information about the emotional/be-
havioral profiles, collected from direct caregivers, school teachers,
and self-reports, is valuable in monitoring the response to phar-
macological treatment in youths with ADHD.
Clinical Significance
Our findings demonstrate that both methylphenidate and ato-
moxetine produce significant reductions in emotional/behavioral
problems measured by CBCL, YSR, and SDQ, suggesting that
obtaining assessments from multiple informants is crucial in es-
tablishing a comprehensive understanding of the pharmacological
effects in youths with ADHD.
Author Contributions
C.Y.S. and S.S.G. contributed to concept and design of the study.
H.H.S., C.Y.S., and S.S.G. contributed to data acquisition/analy-
9
sis/interpretation. H.H.S. and C.Y.S. contributed to drafting the
article, tables, and figures, which were critically reviewed by S.S.G.
All authors read and approved the final version of the article.
Acknowledgment
The authors express thanks to Ming-Fang Chen, M.S., for as-
sistance in data analysis.
Disclosures
C.Y.S. has conducted clinical trials on behalf of and was on the
speakers’ bureau for Janssen-Cilag and Eli Lilly & Co., Taiwan.
S.S.G. has conducted clinical trials on behalf of and was on the
speakers’ bureau for Janssen-Cilag, Eli Lilly & Co., and Astellas
Pharma, Inc., Taiwan.
References
Achenbach TM: Commentary: Definitely more than measurement
error: But how should we understand and deal with informant
discrepancies? J Clin Child Adolesc Psychol 40:80–86, 2011.
Achenbach TM, Dumenci L: Advances in empirically based assess-
ment: Revised cross-informant syndromes and new DSM-oriented
scales for the CBCL, YSR, and TRF: Comment on Lengua, Sa-
dowksi, Friedrich, and Fischer (2001). J Consult Clin Psychol 69:
699–702, 2001.
Bangs ME, Hazell P, Danckaerts M, Hoare P, Coghill DR, Wehmeier PM,
Williams DW, Moore RJ, Levine L, Atomoxetine AODDSG: Ato-
moxetine for the treatment of attention-deficit/hyperactivity disorder
and oppositional defiant disorder. Pediatrics 121:e314–e320, 2008.
Biederman J, Spencer TJ, Newcorn JH, Gao H, Milton DR, Feldman
PD, Witte MM: Effect of comorbid symptoms of oppositional de-
fiant disorder on responses to atomoxetine in children with ADHD:
A meta-analysis of controlled clinical trial data. Psychopharma-
cology (Berl) 190:31–41, 2007.
Biederman J, Mick E, Fried R, Wilner N, Spencer TJ, Faraone SV:
Are stimulants effective in the treatment of executive function
deficits? Results from a randomized double blind study of OROS-
methylphenidate in adults with ADHD. Eur Neuropsychopharmacol
21:508–515, 2011.
Biederman J, Petty CR, Day H, Goldin RL, Spencer T, Faraone SV,
Surman CBH: Severity of the Aggression/Anxiety-Depression/
Attention (A-A-A) CBCL profile discriminates between different
levels of deficits in emotional regulation in youth with ADHD.
J Dev Behav Pediatr 33:236–243, 2012.
Blackman GL, Ostrander R, Herman KC: Children with ADHD and
depression: A multisource, multimethod assessment of clinical,
social, and academic functioning. J Atten Disord 8:195–207, 2005.
Bouffard R, Hechtman L, Minde K, Iaboni-Kassab F: The efficacy of 2
different dosages of methylphenidate in treating adults with attention-
deficit hyperactivity disorder. Can J Psychiatry 48:546–554, 2003.
Chen YY, Ho SY, Lee PC, Wu CK, Gau SS: Parent-child dis-
crepancies in the report of adolescent emotional and behavioral
problems in Taiwan. PLoS One 12:e0178863, 2017.
Conners CK: Forty years of methylphenidate treatment in attention-
deficit/hyperactivity disorder. J Atten Disord 6 Suppl 1:S17–S30,
2002.
Connor DF, Glatt SJ, Lopez ID, Jackson D, Melloni RH, Jr.: Psy-
chopharmacology and aggression. I: A meta-analysis of stimulant
effects on overt/covert aggression-related behaviors in ADHD.
J Am Acad Child Adolesc Psychiatry 41:253–261, 2002.
De Los Reyes A, Thomas SA, Goodman KL, Kundey SM: Principles
underlying the use of multiple informants’ reports. Annu Rev Clin
Psychol 9:123–149, 2013.
 10
Dittmann RW, Schacht A, Helsberg K, Schneider-Fresenius C, Leh-
mann M, Lehmkuhl G, Wehmeier PM: Atomoxetine versus placebo
in children and adolescents with attention-deficit/hyperactivity
disorder and comorbid oppositional defiant disorder: A double-
blind, randomized, multicenter trial in Germany. J Child Adolesc
Psychopharmacol 21:97–110, 2011.
Egger HL, Costello EJ, Erkanli A, Angold A: Somatic complaints and
psychopathology in children and adolescents: Stomach aches,
musculoskeletal pains, and headaches. J Am Acad Child Adolesc
Psychiatry 38:852–860, 1999.
Faraone SV, Biederman J, Spencer TJ, Aleardi M: Comparing the
Downloaded by Wegner Health Science Information Center/ University of South Dakota multisite from www.liebertpub.com at 11/21/18. For personal use only.
efficacy of medications for ADHD using meta-analysis. Med-
GenMed 8:4, 2006.
Garnock-Jones KP, Keating GM: Atomoxetine: A review of its use in
attention-deficit hyperactivity disorder in children and adolescents.
Paediatr Drugs 11:203–226, 2009.
Gau SS, Chong MY, Chen TH, Cheng AT: A 3-year panel study of
mental disorders among adolescents in Taiwan. Am J Psychiatry
162:1344–1350, 2005.
Gelade K, Janssen TW, Bink M, van Mourik R, Maras A, Oosterlaan
J: Behavioral effects of neurofeedback compared to stimulants and
physical activity in attention-deficit/hyperactivity disorder: A ran-
domized controlled trial. J Clin Psychiatry 77:e1270–e1277, 2016.
Geller D, Donnelly C, Lopez F, Rubin R, Newcorn J, Sutton V,
Bakken R, Paczkowski M, Kelsey D, Sumner C: Atomoxetine
treatment for pediatric patients with attention-deficit/hyperactivity
disorder with comorbid anxiety disorder. J Am Acad Child Adolesc
Psychiatry 46:1119–1127, 2007.
Goodman R: The extended version of the Strengths and Difficulties
Questionnaire as a guide to child psychiatric caseness and conse-
quent burden. J Child Psychol Psychiatry 40:791–799, 1999.
Klimkeit E, Graham C, Lee P, Morling M, Russo D, Tonge B:
Children should be seen and heard: Self-report of feelings and
behaviors in primary-school-age children with ADHD. J Atten
Disord 10:181–191, 2006.
Kratochvil CJ, Heiligenstein JH, Dittmann R, Spencer TJ, Biederman
J, Wernicke J, Newcorn JH, Casat C, Milton D, Michelson D:
Atomoxetine and methylphenidate treatment in children with
ADHD: A prospective, randomized, open-label trial. J Am Acad
Child Adolesc Psychiatry 41:776–784, 2002.
Kuperman S, Perry PJ, Gaffney GR, Lund BC, Bever-Stille KA, Arndt
S, Holman TL, Moser DJ, Paulsen JS: Bupropion SR vs. methyl-
phenidate vs. placebo for attention deficit hyperactivity disorder in
adults. Ann Clin Psychiatry 13:129–134, 2001.
Kutlu A, Akyol Ardic U, Ercan ES: Effect of methylphenidate on
emotional dysregulation in children with attention-deficit/
hyperactivity disorder + oppositional defiant disorder/conduct dis-
order. J Clin Psychopharmacol 37:220–225, 2017.
Lavigne JV, Dulcan MK, LeBailly SA, Binns HJ: Can parent reports
serve as a proxy for teacher ratings in medication management of
attention-deficit hyperactivity disorder? J Dev Behav Pediatr 33:
336–342, 2012.
Lin YJ, Lo KW, Yang LK, Gau SS: Validation of DSM-5 age-of-onset
criterion of attention deficit/hyperactivity disorder (ADHD) in
adults: Comparison of life quality, functional impairment, and
family function. Res Dev Disabil 47:48–60, 2015.
Liu SK, Chien YL, Shang CY, Lin CH, Liu YC, Gau SSF: Psycho-
metric properties of the Chinese version of Strength and Difficulties
Questionnaire. Compr Psychiatry 54:720–730, 2013.
Mattos P, Louza MR, Palmini AL, de Oliveira IR, Rocha FL: A
multicenter, open-label trial to evaluate the quality of life in adults
with ADHD treated with long-acting methylphenidate (OROS
MPH): Concerta Quality of Life (CONQoL) study. J Atten Disord
17:444–448, 2013.
SHIH ET AL.
Miller A: Appropriateness of psychostimulant prescription to chil-
dren: Theoretical and empirical perspectives. Can J Psychiatry 44:
1017–1024, 1999.
Ni HC, Shang CY, Gau SS, Lin YJ, Huang HC, Yang LK: A head-to-
head randomized clinical trial of methylphenidate and atomoxetine
treatment for executive function in adults with attention-deficit
hyperactivity disorder. Int J Neuropsychopharmacol 16:1959–1973,
2013.
Pringsheim T, Hirsch L, Gardner D, Gorman DA: The pharmaco-
logical management of oppositional behaviour, conduct problems,
and aggression in children and adolescents with attention-deficit
hyperactivity disorder, oppositional defiant disorder, and conduct
disorder: A systematic review and meta-analysis. Part 1: psychos-
timulants, alpha-2 agonists, and atomoxetine. Can J Psychiatry 60:
42–51, 2015.
Rapport MD, Randall R, Moffitt C: Attention-Deficit/Hyperactivity
Disorder and methylphenidate: A dose-response analysis and
parent-child comparison of somatic complaints. J Atten Disord 6:
15–24, 2002.
Rescorla LA, Ewing G, Ivanova MY, Aebi M, Bilenberg N, Dieleman
GC, Dopfner M, Kajokiene I, Leung PW, Pluck J, Steinhausen HC,
Winkler Metzke C, Zukauskiene R, Verhulst FC: Parent-adolescent
cross-informant agreement in clinically referred samples: Find-
ings from seven societies. J Clin Child Adolesc Psychol 46:74–87,
2017.
Schwartz S, Correll CU: Efficacy and safety of atomoxetine in chil-
dren and adolescents with attention-deficit/hyperactivity disorder:
Results from a comprehensive meta-analysis and metaregression.
J Am Acad Child Adolesc Psychiatry 53:174–187, 2014.
Shang CY, Gau SS, Soong WT: Association between childhood sleep
problems and perinatal factors, parental mental distress and be-
havioral problems. J Sleep Res 15:63–73, 2006.
Shang CY, Gau SS: Improving visual memory, attention, and school
function with atomoxetine in boys with attention-deficit/hyperactivity
disorder. J Child Adolesc Psychopharmacol 22:353–363, 2012.
Shang CY, Wu YH, Gau SS, Tseng WY: Disturbed microstructural
integrity of the frontostriatal fiber pathways and executive dys-
function in children with attention deficit hyperactivity disorder.
Psychol Med 43:1093–1107, 2013.
Shang CY, Pan YL, Lin HY, Huang LW, Gau SS: An open-label,
randomized trial of methylphenidate and atomoxetine treatment in
children with attention-deficit/hyperactivity disorder. J Child Ado-
lesc Psychopharmacol 25:566–573, 2015.
Sinzig J, Döpfner M, Lehmkuhl G: Long-acting methylphenidate has
an effect on aggressive behavior in children with attention-deficit/
hyperactivity disorder. J Child Adolesc Psychopharmacol 17:421–
432, 2007.
Spencer T, Biederman J, Wilens T, Doyle R, Surman C, Prince J,
Mick E, Aleardi M, Herzig K, Faraone S: A large, double-blind,
randomized clinical trial of methylphenidate in the treatment of
adults with attention-deficit/hyperactivity disorder. Biol Psychiatry
57:456–463, 2005.
Spencer TJ, Faraone SV, Surman CB, Petty C, Clarke A, Batchelder
H, Wozniak J, Biederman J: Toward defining deficient emotional
self-regulation in children with attention-deficit/hyperactivity dis-
order using the Child Behavior Checklist: A controlled study.
Postgrad Med 123:50–59, 2011.
Steinhausen HC, Zulli-Weilenmann N, Brandeis D, Muller UC, Valko
L, Drechsler R: The behavioural profile of children with attention-
deficit/hyperactivity disorder and of their siblings. Eur Child
Adolesc Psychiatry 21:157–164, 2012.
Tseng WL, Gau SS: Executive function as a mediator in the link
between attention-deficit/hyperactivity disorder and social prob-
lems. J Child Psychol Psychiatry 54:996–1004, 2013.
 MEDICATIONS FOR EMOTIONAL/BEHAVIORAL PROBLEMS 11

Volkow ND, Wang GJ, Fowler JS, Ding YS: Imaging the effects of
methylphenidate on brain dopamine: New model on its therapeutic
actions for attention-deficit/hyperactivity disorder. Biol Psychiatry
57:1410–1415, 2005.
Wang LJ, Chen CK, Huang YS: Changes in behaviour symptoms of
patients with attention deficit/hyperactivity disorder during treat-
ment: Observation from different informants. Psychiatry Invest 10:
1–7, 2013.
Weitkamp K, Romer G, Rosenthal S, Wiegand-Grefe S, Daniels J:
German Screen for Child Anxiety Related Emotional Disorders
(SCARED): Reliability, validity, and cross-informant agreement in
Downloaded by Wegner Health Science Information Center/ University of South Dakota multisite from www.liebertpub.com at 11/21/18. For personal use only.
teachers in a Taiwanese nonreferred sample. J Am Acad Child
Adolesc Psychiatry 40:1045–1052, 2001.
Yu Q, Teixeira CM, Mahadevia D, Huang Y, Balsam D, Mann JJ,
Gingrich JA, Ansorge MS: Dopamine and serotonin signaling
during two sensitive developmental periods differentially impact
adult aggressive and affective behaviors in mice. Mol Psychiatry
19:688–698, 2014.
Address correspondence to:
Chi-Yung Shang, MD, PhD

a clinical sample. Child Adolesc Psychiatry Ment Health 4:19, Department of Psychiatry
2010. National Taiwan University Hospital
Willcutt EG: The prevalence of DSM-IV attention-deficit/hyperactivity No. 7, Chung-Shan South Road
disorder: A meta-analytic review. Neurotherapeutics 9:490–499, Taipei 10002
2012. Taiwan
Yang HJ, Chen WJ, Soong WT: Rates and patterns of comorbidity of
adolescent behavioral syndromes as reported by parents and E-mail: cyshang@ntu.edu.tw