Received: 1 June 2016 Revised: 22 August 2016 Accepted: 10 October 2016

DOI 10.1002/hup.2559

RESEARCH ARTICLE

Effectiveness of atomoxetine and methylphenidate for

problematic online gaming in adolescents with attention deficit
hyperactivity disorder
Jeong Ha Park | Young Sik Lee | Ji Hyun Sohn | Doug Hyun Han

Department of Psychiatry, Chung Ang

University Hospital, Seoul, Korea
Correspondence
Doug Hyun Han, MD, PhD, Department of
Psychiatry, Chung Ang University Hospital,
Heuk Seok Ro 224‐1, Seoul 135‐755, Korea.
Email: hduk70@gmail.com
Abstract
Objective There is a high prevalence of problematic online gaming in adolescents with atten-
tion deficit hyperactivity disorder (ADHD). In the current study, we compared the effectiveness
of atomoxetine (ATM) and methylphenidate (MPH) on problematic online gaming in adolescents
with ADHD.

Funding information
Korea Healthcare Technology Research and
Development Project, Ministry for Health and
Welfare Affairs, Republic of Korea, Grant/
Award Number: A120013.
Methods We recruited 86 adolescents diagnosed with ADHD together with Internet gaming
disorder. These participants were divided into two treatment groups: 44 participants were
treated with MPH for 12 weeks, and 42 participants were treated with ATM for 12 weeks.
Results During the 3‐month study period, the MPH group showed greater improvement in
Korean ADHD rating scale scores than the ATM group. The ATM group showed greater improve-
ment in Child Depression Inventory scores than the MPH group. However, Young Internet Addic-
tion Scale and Behavioral Inhibition & Activation Scales score changes did not differ significantly
between the MPH and ATM groups. In both groups, changes in Young Internet Addiction Scale
scores were positively correlated with the changes in Behavioral Inhibition & Activation Scales
scores.

Conclusions Both MPH and ATM reduced the severity of Internet gaming disorder symp-
toms, and this reduction was correlated with impulsivity reduction, which also resulted from both
ADHD medications. These findings suggest impulsivity plays a critical role in the development of
problematic online gaming.

KEY W ORDS

atomoxetine, attention deficit hyperactivity disorder, methylphenidate, online gaming

1 | I N T RO D U CT I O N studies have sought to clarify its underlying mechanisms, progression,

Frequent exposure to the Internet via computers, mobile devices, and
other electronic devices is widespread in daily life, with online gaming
representing a large portion of online entertainment activities
(KOCCA, 2012). Concurrently, concerns have arisen about problematic
online gaming that disturbs daily life (Kuss, Griffiths, Karila, & Billieux,
2014; Schou Andreassen, Billieux, Griffiths, et al., 2016). Internet gam-
ing disorder (IGD), defined as a loss of control over online gaming, was
proposed as a new psychiatric disorder requiring further research and
experience in the fifth edition of the Diagnostic and Statistical Manual
of Mental Disorders (DSM‐5), Section III (American Psychiatric Associ-
ation, 2003). Considering IGD as a psychiatric disorder, a number of
and characteristics, but further research is needed.
Several studies have suggested that IGD has high comorbidity
with other psychiatric disorders, including major depressive disorder,
attention deficit hyperactivity disorder (ADHD), and obsessive com-
pulsive disorder (Dalbudak, Evren, Aldemir, et al., 2013; Han, Kim,
Bae, Renshaw, & Anderson, 2015; Ko, Yen, Chen, Yeh, & Yen,
2009b; Yen, Ko, Yen, Wu, & Yang, 2007). In particular, children with
ADHD appear to be vulnerable to developing IGD symptoms (Bioulac,
Arfi, & Bouvard, 2008; Chan & Rabinowitz, 2006; Weinstein &
Weizman, 2012; Yoo, Cho, Ha, et al., 2004). In a survey of 2,114
Taiwanese high school students, Yen et al. (2007) reported that
17.9% of students were classified as Internet addicts and that Internet

Hum Psychopharmacol Clin Exp 2016; 31: 427–432 wileyonlinelibrary.com/journal/hup Copyright © 2016 John Wiley & Sons, Ltd. 427
428
addiction was strongly associated with ADHD symptoms. Ha et al.
(2006) similarly reported high psychiatric comorbidity of Internet
addiction and ADHD in Korean children. Ko et al. (2009b) conducted
a single prospective study following more than 2,000 adolescents for
2 years and identified ADHD as the strongest predictor of the devel-
opment of Internet addiction. Han, Lee, Na, et al. (2009) suggested that
online video gaming might be a means of self‐treatment for ADHD
children.
Given the high prevalence of comorbid IGD with ADHD, appro-
priate guidelines to treat these conditions together are needed.
Methylphenidate and atomoxetine are effective in treating ADHD,
with underlying distinct pharmacological mechanisms (Golmirzaei,
Mahboobi, Yazdanparast, et al., 2016), and we should consider
whether these medications could be effective for comorbid IGD
symptoms (Han et al., 2009). In ADHD, stimulant medications like
methylphenidate (MPH) are the most widely used pharmacological
treatment, and atomoxetine (ATM), a non‐stimulant medication, is
also a commonly used and effective pharmacological therapy. The
effects of MPH on ADHD symptoms are related to their effects on
dopaminergic and noradrenergic neurotransmission within the central
nervous system (Engert & Pruessner, 2008). MPH acts by inhibiting
catecholamine reuptake, primarily as a dopamine–norepinephrine
reuptake inhibitor, modulating levels of dopamine and to a lesser
extent levels of norepinephrine. MPH binds to and blocks dopamine
and norepinephrine transporters and increased concentrations of
dopamine and norepinephrine in the synaptic cleft lead to escalated
neurotransmission (Heal & Pierce, 2006). ATM, a selective norepi-
nephrine reuptake inhibitor, received US Food and Drug Administra-
tion approval in 2002 as the first non‐stimulant medicine used for
the treatment of ADHD in children ≥6 years of age and adults
(Childress, 2016). Although the effect size of ATM is generally lower
than that of stimulants, numerous trials have found that ATM
improves emotional labiality in addition to treating core ADHD symp-
toms (Childress, 2016).
1.1 | Hypothesis
Based on the previous studies and the comprehensive considerations
above, we hypothesized that MPH and ATM would both be effective
for reducing symptoms of IGD in adolescents with ADHD. In addition,
we hypothesized that MPH and ATM would induce different treatment
responses with regard to attention, impulsivity, and mood. Specifically,
we expected that MPH would have a stronger effect on attention and
that ATM would show better outcomes for mood. We also examined
whether there were differences in their effects on impulsivity.
2 | METHODS
2.1 | Participants
Study participants were recruited from Chung‐Ang University Hospital
through advertisements posted at the hospital; 106 adolescents with
problematic online gaming who were diagnosed with ADHD agreed
to participate in this study. Our criteria for IGD were those given in
Section III of DSM‐5. All the participants (13–18 years old) were
PARK ET AL.
screened using the Structured Clinical Interview for DSM‐5 (American
Psychiatric Association, 2003) and diagnosed with ADHD by a psychi-
atrist. Exclusion criteria were (a) history or current episodes of psychi-
atric diseases other than ADHD, (b) lifetime diagnosis of substance
abuse other than tobacco or alcohol, (c) neurological or medical disor-
der, and (d) a low IQ (Korean Wechsler Intelligence Scale for Children
(IV) score < 70). Written informed consent was provided by all partic-
ipants and their parents.
Finally, 84 adolescents met the study criteria, and we classified
them into two study groups: 44 participants were treated with the
Osmotic Release Oral System (Concerta®, MPH) for 3 months, and
40 participants were treated with atomoxetine hydrochloride
(Strattera®, ATM) for 3 months.
2.2 | Estimated scales
This study was designed as a 3‐month prospective trial. At baseline, all
participants were tested using the Young Internet Addiction Scale
(YIAS; Ha et al., 2006; Young, 1998), Beck Depression Inventory
(BDI; Beck et al., 1961), ADHD Rating Scale (ARS; DuPaul, 1991; So,
Noh, Kim, Ko, & Koh, 2002), and Behavioral Inhibition & Activation
Scales (BIS/BAS; Carver & White, 1994).
The YIAS is a self‐report scale for addictive use of the Internet
(Young, 1998). It was proposed by Young in 1998. The Korean version
of the YIAS was verified by Lee et al. The internal consistency of the
YIAS has been reported to range from 0.90 to 0.91 (Lee et al., 2013).
The Children's Depression Inventory (CDI) was developed in 1977
by Maria Kovacs (Kovacs, 1985). It was based on the BDI, which is a
self‐report measure of depression in adults. The CDI was designed to
assess depression in children and adolescents from the ages of 7 to
17 years. The Korean version of the CDI was verified by Cho and
Lee and is composed of 27 items (Cho & Lee, 1990). Each question is
scored on a scale from 0 to 3, so the total scores of the CDI range from
0 to 81 points.
The ARS is an ADHD symptom severity scale composed of 18
items (9 items for assessing inattention and 9 items for assessing
hyperactivity) and designed by Dupaul (DuPaul, 1991). The Korean
version of the ARS was validated by So et al., and the internal consis-
tency has been reported to range from 0.77 to 0.89 (2002).
The BIS/BAS is a self‐report scale assessing impulsiveness
(Carver & White, 1994). Carver and White created the BIS/BAS
scale to estimate stable individual differences in BIS and BAS sensi-
tivities. Specifically, the BAS measures reward responsiveness, drive,
and fun seeking. The Korean version of the BIS/BAS was verified
by Kim et al. (Kim & Kim, 2001). The BIS/BAS uses a 4‐point Likert
scale ranging from 1 = not at all to 4 = strongly agree, and the total
score of the BIS/BAS ranges from 0 to 80 points. The BIS/BAS
internal consistency (Cronbach's α) has been reported to range from
0.78 to 0.79 (Kim & Kim, 2001).
2.3 | Study procedure
We designed a single‐blind, randomized, and controlled trial. All partic-
ipants were randomly assigned to either the MPH group or the ATM
group at a 1:1 ratio. In order to preserve the allocation concealment,
PARK ET AL. 429

sequential numbered containers with tamper‐proof, equal in weight,
and similar appearance were used. After the baseline test, the MPH
group was treated with MPH, and the ATM group was treated with
ATM. At a 3‐month follow‐up visit, all participants underwent
reexamination with the YIAS, BDI, ARS, and BIS/BAS. The participants
in the MPH group were started on MPH 10 mg/day and increased to
40 mg/day during the first 2 weeks of treatment, according to individ-
ual symptoms. The participants in the ATM group were started on
ATM 10 mg/day and increased to 60 mg/day during the first 2 weeks
of treatment, according to individual symptoms.
2.4 | Statistics
The demographic data and clinical symptoms of the two groups were
analyzed using independent t tests. To assess the changes in the respec-
tive scales between the two groups, we performed repetitive measures
ANOVA. We analyzed the Pearson correlations between the changes in
YIAS scores and the changes in each of the other scale scores.
3 | RESULTS
3.1 | Demographic characteristics
There were no significant differences in age, education level, IQ, YIAS,
Korean ARS (K‐ARS), CDI, or BIS/BAS scores between the MPH group
and the ATM group (Table 1).
3.2 | Comparison of changes in online gaming
pattern between MTX and ATM
Over the 3‐month study period, there were no significantly different
changes in YIAS or BIS/BAS scores between the MPH group and the
ATM group. The K‐ARS scores in the MPH group improved (baseline
(B): 33.3 ± 9.1, follow‐up (F): 15.1 ± 9.4) much more than those in
the ATM group (B: 34.3 ± 9.6, F: 22.1 ± 8.3; F(1.81) = 8.0., df = 1,
p < 0.01; Table 1; Figure 1). The CDI scores in the ATM group
improved (B: 13.7 ± 3.7, F: 8.9 ± 4.4) much more than those in the
MPH group (B: 13.0 ± 4.4, F: 10.8 ± 5.4; F(1.81) = 5.86, df = 1, p = 0.02;
Table 1; Figure 1).
3.3 | Correlations
In all participants, the change in YIAS scores was positively correlated
with the change in BIS/BAS scores (r = 0.35, p < 0.01). In the MPH
group (r = 0.38, p = 0.01) and the ATM group (r = 0.35, p = 0.03), the
changes in YIAS scores were positively correlated with the changes
in BIS/BAS scores. However, there were no significant correlations
between changes in YIAS and CDI scores, or between changes in YIAS
and K‐ARS scores in any of the participants.
4 | DISCUSSION
In the current study, both MPH and ATM treatments improved the
clinical symptoms of IGD, showing decreased impulsivity in adoles-
cents with ADHD. There were no significant differences between the
MPH and ATM groups in changes in the severity of IGD; however,
MPH improved ADHD symptoms more than ATM did.
The current findings contribute to the growing body of evidence
of an association between IGD and ADHD, suggesting that ADHD
increases vulnerability to IGD. MPH and ATM have become the first‐
line treatment options for ADHD patients, according to the American
Academy of Child and Adolescents Psychiatry guidelines (2014).
MPH may mediate dopamine neurotransmitter processes whereby
increased dopamine causes a blockade of dopamine transporters,
which strengthens the dopamine signals and reduces core ADHD
symptoms, such as inattention, impulsivity, and hyperactivity (Volkow,

TABLE 1 Demographic data

Methylphenidate OROS Atomoxetine Statistics

Age (years) 16.9 ± 1.6 17.1 ± 1.0 t = 0.28, p = 0.77

Education (years) 9.8 ± 1.4 9.9 ± 1.5 t = 0.43, p = 0.67
IQ 96.7 ± 12.7 98.7 ± 10.0 t = 0.79, p = 0.43
Dose (mg/day) 26.6 ± 9.5 34.6 ± 12.9 —
YIASa B 62.7 ± 11.6 63.4 ± 9.9 t = 0.31, p = 0.76
F 46.6 ± 16.9 51.8 ± 15.7 t = 1.47, p = 0.15
K‐ARSb B 33.3 ± 9.1 34.3 ± 9.6 t = 0.51, p = 0.61
F 15.1 ± 9.4 22.1 ± 8.3 t = 3.60, p < 0.01
CDIc B 13.0 ± 4.4 13.7 ± 3.7 t = 0.75, p = 0.46
F 10.8 ± 5.4 8.9 ± 4.4 t = 0.49, p = 0.62
BIS/BASd B 56.2 ± 7.8 54.5 ± 7.9 t = 0.98, p = 0.33
F 42.6 ± 8.1 43.2 ± 9.5 t = 0.30, p = 0.76

Note. Repeated measures ANOVA.

OROS = Osmotic Release Oral System.
a
F(1.81) = 1.92, df = 1, p = 0.17.
b
F(1.81) = 8.0., df = 1, p < 0.01.
c
F(1.81) = 5.86, df = 1, p = 0.02.
d
F(1.81) = 2.83, df = 1, p = 0.09.
430
FIGURE 1 Changes in psychological scales in response to 3 months of medication for problematic online gaming in adolescents with attention
deficit hyperactivity disorder. Repeated measures ANOVA; YIAS: F(1.81) = 1.92, df = 1, p = 0.17; K‐ARS: F(1.81) = 8.0, df = 1, p < 0.01; CDI: F
(1.81) = 5.86, df = 1, p = 0.02; and BIS/BAS: F(1.81) = 2.83, df = 1, p = 0.09
Wang, Fowler, et al., 2001). The mechanism of action of ATM is
thought to be related to inhibition of the presynaptic norepinephrine
transporter (Golmirzaei et al., 2016). Previous comparisons between
MPH and ATM have found MPH to be more effective for reducing
attention symptoms in ADHD children (Kemner, Starr, Ciccone,
Hooper‐Wood, & Crockett, 2005), and this result is consistent with
our finding that the MPH group showed greater improvement in K‐
ARS scores than the ATM group. In addition, ATM showed greater
improvement in emotional lability compared to controls in a study
examining temper, affective lability, and emotional overreactivity
(Reimherr, Marchant, Strong, et al., 2005). Our finding that the ATM
group showed a greater improvement in depressive symptom than
the MPH group is in line with past findings that ATM at clinically rele-
vant doses occupied both norepinephrine transporters and selective
serotonin transporters, which has implications for treatments of not
only ADHD, but also depression (Ding, Naganawa, Gallezot, et al.,
2014). These investigations contribute to our understanding of the
different drug mechanisms for MPH, acting on norepinephrine and
dopamine transporters and release, as well as for ATM, a selective
norepinephrine uptake inhibitor, and this also suggests the possibility
of action on serotonin transporter (Golmirzaei et al., 2016).
Interestingly, among the three personal psychiatric factors (atten-
tion, impulsivity, and mood) examined in the current study, impulsivity
appeared to be the most crucial factor for improvement of problematic
Internet gaming behavior. Patients with ADHD are thought to have a
reward deficiency syndrome including functional vulnerability of the
prefrontal cortex and deficiency of dopamine neurotransmission (Han
et al., 2007; Ko et al., 2010; Ko, Liu, Hsiao, et al., 2009a; Shaw, Gornick,
PARK ET AL.
Lerch, et al., 2007; Thalemann, Wolfling, & SM, 2007; Volkow, Wang,
Newcorn, et al., 2007; Weinstein and Weizman; Weinstein, Yaacov,
Manning, Danon, & Weizman, 2015). Han suggested that Internet
video games activate the brain's dopamine reward system, resulting
in significant dopamine release during exposure to Internet video
gaming, which indicates the possibility that Internet video gaming
may be a form of self‐treatment in ADHD children (Han et al., 2009).
This finding is similar to the mechanisms of substance addiction that
explain the high level of substance addiction comorbidity in ADHD
(Thalemann et al., 2007). Additionally, reward and sensitization mech-
anisms involve effects on not only dopamine but also norepinephrine,
serotonin, gamma‐aminobutyric acid, and other neurotransmitters
involved in ADHD (Comings, Gade‐Andavolu, Gonzalez, et al., 2000).
In particular, both norepinephrine and dopamine, which can be related
to reward pathways, have been implicated in the pathophysiology of
ADHD (Arnsten, 2011).
When reward and sensitization mechanisms break down, it may
predispose individuals to addictive, impulsive, and compulsive
behaviors, which are known to involve several neurotransmitters,
including not only dopamine but also norepinephrine, serotonin,
gamma‐aminobutyric acid, and other neurotransmitters (Weinstein
& Weizman, 2012). MPH and ATM showed similar responses for
improvement in impulsivity and IGD symptoms, despite their differ-
ent drug mechanisms. That is, MPH and ATM showed no signifi-
cant differences in drug efficacy for improving IGD symptoms in
ADHD adolescents. This remarkable finding indicates that comorbid
IGD symptoms in ADHD could be managed by either the main
ADHD pharmacological stimulant or non‐stimulant treatment, both
PARK ET AL.
via regulating impulsivity. At this point, we considered the common
pharmacological mechanisms of both MPH and ATM associated
with impulsive IGD symptoms that might also be associated with
impulsivity. Recent evidence suggests an involvement of glutamate
neurotransmission in the pathology and treatment of ADHD, via
mechanisms to be clarified (Chang, Lane, & Tsai, 2014; Dorval,
Wigg, Crosbie, et al., 2007). Extending these study results, one
study suggested that MPH and ATM may alter the electrophysio-
logical activity of prefrontal cortex neurons, a region that plays a
major role in control of attention and impulsivity, through interac-
tion with catecholamine and glutamate NMDA receptors (Di Miceli
& Gronier, 2015). Therefore, we suggest that MPH and ATM may
reduce the severity of ADHD symptoms through reducing impulsiv-
ity, unrelated to mood and attention.
5 | L I M I T A T I O NS
The limitations of this study include the relatively small sample size and
male‐only participation. Additionally, a double‐blind element was not
carried out in the current study due to the parents' concerns about
the side effects of medication. Experimental artifacts can be intro-
duced through the interpretation of the researchers. To reduce such
bias, the measurement of clinical symptoms was based on parent or
participant reports. The maximum doses of MPH and ATM used in
the current study are lower than the maximum recommended doses
(60 mg/day for MPH and 1.4 > mg/kg for ATM). Thus, caution is
recommended when interpreting the effects of the two drugs on
problematic online gaming in adolescents with ADHD. Future research
should address these limitations.
6 | C O N CL U S I O N S
Both MPH and ATM reduced the severity of IGD symptoms, and this
reduction was correlated with impulsivity reduction, which also
resulted from both MPH and ATM ADHD medications. Thus, in
ADHD, impulsivity may play a critical role in the development of
problematic online gaming. Managing the individual's impulsivity is a
key therapeutic goal for reducing IGD symptoms, and both stimulant
and non‐stimulant medications are effective primary options.
ACKNOWLEDGMENTS
The authors would like to acknowledge financial support from the
Korea Healthcare Technology Research and Development Project,
Ministry for Health and Welfare Affairs, Republic of Korea (grant
number A120013) and the Korean Creative Content Agency
(R2014040055).
CONF LICT OF INTE R ES T
No conflicts of interest have been declared.
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How to cite this article: Park, J. H., Lee, Y. S., Sohn, J. H., and
Han, D. H. (2016), Effectiveness of atomoxetine and methyl-
phenidate for problematic online gaming in adolescents with
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