Comparative Efficacy of Methylphenidate and Atomoxetine on Emotional and Behavioral Problems in Youths with Attention-Deficit/Hyperactivity Disorder

1. Comparative Efficacy of Methylphenidate and Atomoxetine
on Emotional and Behavioral Problems in Youths
with Attention-Deficit/Hyperactivity Disorder
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-naı¨ve 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
Attention-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
commonly lead to a negative impact on quality of life, family
function, and interpersonal relationship in individuals with ADHD
(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.
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
1
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2. 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
methylphenidate and atomoxetine in improving emotional/behav-
ioral problems in patients with ADHD are mixed. For example,
although several studies observed no significant effects on emo-
tional control after treatment with methylphenidate (Biederman
et al. 2011), others documented the effectiveness of methylpheni-
date in improving emotional dysregulation (Kutlu et al. 2017).
Some trials showed a significant reduction in anxiety and depres-
sion after treatment with methylphenidate in patients with ADHD
(Bouffard et al. 2003); others found no change (Kuperman et al.
2001), and still others demonstrated an increase in anxiety and
depressive symptoms (Spencer et al. 2005). A clinical trial dem-
onstrated that atomoxetine is not superior to placebo in reducing
oppositional problems (Bangs et al. 2008), whereas other studies
showed positive findings for the efficacy of atomoxetine in im-
proving oppositional behaviors (Dittmann et al. 2011). Given the
remarkable variability in methods across pharmacological studies
on ADHD (Faraone et al. 2006), further clinical trials are required
to examine the efficacy of methylphenidate and atomoxetine in the
treatment of emotional/behavioral problems in youths with ADHD.
Numerous rating scales are available for measuring the emotion-
al/behavioral symptoms associated with ADHD in different settings.
Compared with narrowband scales, broadband scales such as Children
Behavior Checklist (CBCL) and Strength and Difficulties Ques-
tionnaire (SDQ) are better for a comprehensive assessment of the
emotional/behavioral symptoms associated with ADHD. However,
only a few studies have used the CBCL (Wang et al. 2013) and SDQ
(Gelade et al. 2016) as outcome measures for treatment studies. For
example, a previous report showed no improvement in emotion-
al/behavioral symptoms measured by CBCL after treatment with
methylphenidate in youths with ADHD (Wang et al. 2013). A clinical
trial demonstrated that methylphenidate is associated with significant
improvement in the total score of teacher-rated SDQ, but no im-
provement on parent-rated SDQ (Gelade et al. 2016).
Given that the emotional/behavioral symptoms influence the
psychosocial functions and disease course of ADHD, a direct
comparative trial is required to identify the therapeutic effect of
methylphenidate and atomoxetine on the emotional/behavioral
problems in youths with ADHD. The present study aimed to di-
rectly compare the effectiveness of methylphenidate and atomox-
etine in improving a wide range of emotional/behavioral problems
in drug-naı¨ve youths with ADHD in a head-to-head, open-label, 24-
week randomized clinical trial.
Methods
Participants
We recruited drug-naı¨ve youths, aged between 7 and 16 years,
who met the DSM-IV diagnostic criteria for ADHD, as assessed by
the investigator’s clinical evaluation and confirmed using the
Chinese version of the Schedule for Affective Disorders and
Schizophrenia for School-Age Children–Epidemiological Version
(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
of the National Taiwan University Hospital, Taiwan (IRB ID,
200812153M; ClinicalTrials.gov number, NCT00916786) before
implementation. The potential subjects who met the recruitment
criteria received a comprehensive explanation of the purpose and
procedure of this study, as well as the reassurance of confidenti-
ality. All the participants provided their written informed consent.
During the 24-week, open-label, head-to-head randomized clinical
trial, participants were assigned to either the osmotic-release oral
system (OROS)-methylphenidate or atomoxetine group at a 1:1 ratio
according to computer-generated random sequence. Participants were
assessed seven times at baseline (visit 1), week 2 (visit 2), week 4 (visit
3), week 8 (visit 4), week 12 (visit 5), week 16 (visit 6), and week 24
(visit 7). At visit 1, participants started taking medication with OROS-
methylphenidate (an initial dosage of 18mg per day, administered as a
single morning dose) or atomoxetine (an initial dosage of 0.5mg/kg
per day, administered as once-daily dose). Drug dosage would be
titrated based on treatment response and adverse effects at visits 2–7
(weeks 2–24) depending upon clinical response and adverse effects.
The maximal dose was 54 mg daily for OROS-methylphenidate or
1.2mg/kg daily for atomoxetine.
Parent-reported CBCL and Youth Self Report (YSR) were
gathered at baseline (visit 1), week 8 (visit 4), week 16 (visit 6), and
week 24 (visit 7). Parent-, teacher-, and self-reported SDQ were
gathered at each visit, from visit 1 through visit 7.
Efficacy measure
Our primary efficacy measure was parent-reported CBCL, and
the secondary outcomes were YSR and SDQ.
CBCL and YSR
The CBCL is a parental questionnaire used to measure the
emotional/behavioral problems in youths aged 4–18, and the YSR
is administered to adolescents aged 11–18 to obtain self-reports
about their emotional/behavioral problems (Achenbach and Du-
menci 2001). Each item is scored 0 if not true, 1 if somewhat or
sometimes true, and 2 if very true or often true. Eight emotion-
al/behavioral scales were created for both the CBCL and YSR,
including Anxious/Depressed symptoms, Attention Problems,
Aggressive Behaviors, Delinquent Behaviors, Social Problems,
Thought Problems, Somatic Complaints, and Withdrawn.
The Chinese versions of CBCL and YSR have been shown to
have good validity and reliability (Yang et al. 2001; Shang et al.
2006), and these two scales have been widely used to measure
emotional/behavioral problems in Taiwanese youth populations
(Chen et al. 2017).
Strengths and Difficulties Questionnaire
The SDQ, a 25-item screening questionnaire, has been designed
to assess a broad area of emotions and behaviors of youths
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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
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-
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.
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.
MEDICATIONS FOR EMOTIONAL/BEHAVIORAL PROBLEMS 3
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4. 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
(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
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).
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
Mean (SD) or n (%) Atomoxetine (n = 80)
Methylphenidate
(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.
4 SHIH ET AL.
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5. Table2.ChangeinChildBehaviorChecklistandYouthSelfReportfromBaselinetoWeeks8and24(Endpoint)intheTwoTreatmentGroups
AtomoxetineMethylphenidateGroupdifferences
(pvalues)
Week8-baselineEndpoint-baselineWeek8-baselineEndpoint-baseline
Week8-
baseline
Endpoint-
baselineMean(SD)Cohen’sdpMean(SD)Cohen’sdpMean(SD)Cohen’sdpMean(SD)Cohen’sdp
CBCL
Aggressive
behavior
-2.66(10.42)-0.240.033*-4.46(11.36)-0.370.002**-8.31(10.28)-0.60<0.001***-8.48(9.86)-0.68<0.001***0.003**0.032*
Anxious/
depressed
-4.04(12.72)-0.310.011*-5.33(11.85)-0.44<0.001***-5.02(11.25)-0.360.001**-5.71(12.57)-0.44<0.001***0.6470.857
Attention
problems
-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***0.0870.326
Delinquent
behavior
-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
Socialproblems-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***0.4430.502
Somatic
complaints
0.14(12.99)0.020.898-0.14(13.10)-0.010.931-4.20(11.75)-0.300.009**-6.18(12.95)-0.48<0.001***0.0510.008**
Thought
problems
-5.22(12.18)-0.50<0.001***-4.51(12.53)-0.400.004**-5.80(12.85)-0.380.001**-6.84(12.59)-0.52<0.001***0.7930.287
Withdrawn-2.54(10.21)-0.240.039*-2.79(10.98)-0.250.038*-5.78(10.09)-0.54<0.001***-5.81(11.34)-0.53<0.001***0.0730.122
YSR
Aggressive
behavior
-5.60(14.38)-0.440.009**-6.60(14.42)-0.500.003**-7.19(11.87)-0.40<0.001***-9.55(13.31)-0.55<0.001***0.5970.338
Anxious/
depressed
-3.55(15.69)-0.220.121-3.86(13.57)-0.200.066-6.52(18.73)-0.340.041*-9.59(17.14)-0.510.002**0.4400.093
Attention
problems
-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***0.3220.177
Delinquent
behavior
-6.40(15.67)-0.420.009**-6.72(16.18)-0.410.008**-5.23(17.64)-0.250.088-6.97(14.19)-0.390.005**0.7530.941
Social
problems
-5.82(9.32)-0.48<0.001***-6.85(8.64)-0.55<0.001***-4.77(14.54)-0.380.043*-9.43(12.98)-0.74<0.001***0.6940.282
Somatic
complaints
-6.23(16.55)-0.350.016*-7.39(19.40)-0.420.015*-2.31(19.67)-0.200.350-6.37(22.25)-0.390.0610.3320.824
Thought
problems
-2.68(17.24)-0.200.252-5.41(16.60)-0.320.035*-5.12(19.85)-0.310.093-8.31(17.47)-0.460.005**0.5550.442
Withdrawn5.58(14.02)-0.420.009**-7.52(14.05)-0.53<0.001***-5.51(16.75)-0.420.039*-6.84(14.79)-0.500.008**0.9850.831
*p<0.05.
**p<0.01.
***p<0.001.
5
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6. A B
C D
E
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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7. Table3.ChangeinStrengthsandDifficultiesQuestionnairefromBaselinetoWeeks8and24(Endpoint)intheTwoTreatmentGroups
AtomoxetineMethylphenidate
Groupdifferences
Week8-baselineEndpoint-baselineWeek8-baselineEndpoint-baseline
Week8-
baseline
Endpoint-
baselineMean(SD)Cohen’sdpMean(SD)Cohen’sdpMean(SD)Cohen’sdpMean(SD)Cohen’sdp
Parentreport
Internalizing-2.19(9.86)-0.190.076-2.19(11.63)-0.210.122-3.32(9.71)-0.320.011*-3.23(9.62)-0.330.009**0.5130.576
Prosocial0.49(9.19)0.070.604-0.63(9.66)-0.060.593-0.58(10.32)-0.070.6290.63(10.95)0.060.6440.5350.482
Hyperactive-1.74(7.36)-0.280.056-2.42(6.49)-0.420.003**-1.79(8.33)-0.210.179-1.96(7.79)-0.320.046*0.9680.714
Conduct-5.06(11.96)-0.52<0.001***-3.95(10.56)-0.370.003**-8.16(11.51)-0.71<0.001***-7.22(12.22)-0.67<0.001***0.1390.099
Self-report
Emotion-3.54(9.26)-0.360.015*-3.03(10.88)-0.300.061-3.99(9.52)-0.320.024*-4.74(10.08)-0.460.004**0.8300.446
Prosocial-3.12(15.55)-0.230.184-3.23(15.75)-0.240.1650.98(11.64)0.060.6540.11(11.57)0.010.9510.1920.262
Hyperactive-2.94(9.26)-0.430.032*-3.22(9.87)-0.430.026*-2.44(7.54)-0.180.156-2.43(9.92)-0.280.1200.7940.707
Conduct-4.30(10.60)-0.450.009**-2.21(11.09)-0.210.174-4.79(8.50)-0.340.002**-6.95(10.35)-0.61<0.001***0.8210.041*
Peerproblem-3.38(9.79)-0.440.021*-2.24(11.84)-0.250.201-1.15(9.69)-0.090.617-2.42(10.06)-0.330.1270.3070.941
Teacherreport
Peer/prosocial3.19(5.85)0.30<0.001***2.17(8.25)0.250.046*1.62(6.95)0.130.2371.37(9.24)0.150.2780.2170.623
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***0.6240.746
Internalizing-1.38(9.12)-0.100.325-1.61(8.69)-0.170.157-1.45(11.73)-0.110.459-0.17(10.53)-0.020.9050.9700.425
Inattention1.84(10.58)0.200.2350.39(9.52)0.050.7540.39(9.21)-0.010.6721.16(10.81)0.130.4320.4660.687
*p<0.05.
**p<0.01.
***p<0.001.
7
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8. 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
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-naı¨ve 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 atweek24). A systemic review reporteda moderate-to-large
effect for methylphenidate and a small effect for atomoxetine on
oppositional behavior, conduct problems, and aggression in youths
withADHD(Pringsheimetal.2015).Animalstudies haveshownthat
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
neededtoexplorethe factorsassociatedwiththedifferentialeffects 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,
8 SHIH ET AL.
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9. 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
(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-
tributedtotheplaceboormaturityeffect.Inaddition,wewereunableto
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-
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.
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Address correspondence to:
Chi-Yung Shang, MD, PhD
Department of Psychiatry
National Taiwan University Hospital
No. 7, Chung-Shan South Road
Taipei 10002
Taiwan
E-mail: cyshang@ntu.edu.tw
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