Original article 1
High pretreatment cognitive impulsivity predicts response of
oppositional symptoms to methylphenidate in patients with
attention-deficit hyperactivity disorder/oppositional defiant
disorder
Pavel Golubchika,d,f, Lilach Shaleve, Dina Tsamire, Iris Manora,d
and Abraham Weizmanb,c,d
The aim of this study was to compare impulsivity levels, as
assessed by a continuous performance test (CPT), and the
correlations between baseline CPT performance and
response to methylphenidate (MPH), as assessed by the
conjunctive CPT (CCPT), in children with only Diagnostic
and Statistical Manual of Mental Disorders, 5th ed. attention-
deficit hyperactivity disorder with no oppositional defiant
disorder (ADHD/noODD) or with comorbid ODD (ADHD/
ODD). Fifty-three children and adolescents were included in
the study (ADHD/noODD group, n = 25, 12 women/13 men
and ADHD/ODD group, n = 28, eight females/20 males).
Attention was assessed at baseline using CCPT. ADHD and
ODD severities were assessed at baseline and following a
12-week MPH treatment using the ADHD-rating scale
(ADHD-RS) completed by the parent and by a teacher and
the Kiddie-Schedule for Affective Disorders and
Schizophrenia for School-Age Children-ODD (K-SADS-
ODD) completed by the treating psychiatrist. Higher
baseline commission-errors rates (P = 0.0031) in ADHD-
RS/parent–child, ADHD-RS/teacher, and K-SADS-ODD
scores were detected in ADHD/ODD compared with the
ADHD/noODD. Significant improvements in ADHD-RS/
parent–child, ADHD-RS/teacher, and K-SADS-ODD scores
were achieved following MPH treatment in both groups.
Introduction
Attention-deficit/hyperactivity disorder (ADHD) has been
associated with aggressive behavior and comorbid oppositional
defiant disorder (ODD). Comorbidity between ADHD and
ODD is substantial: one-third to one-half of children with one
of these disorders also fulfill criteria for the other (Waschbusch,
2002; Harvey et al., 2016). Although the consequences and
correlates of comorbid ADHD/ODD have been well docu-
mented (Larson et al., 2002; Waschbusch, 2002), the over-
lapping mechanisms for the two disorders are as yet unclear.
Deficits in executive functioning and reward sensitivity in
ADHD patients and in particular the unfavorable balance of
effort to reward in ADHD that is frequently exacerbated in
ODD may explain the high co-occurrence and overlap
between ADHD and ODD (Poulton and Nanan, 2014).
Several studies linking ADHD and ODD symptoms provide
evidence of the relationship in both disorders, between
0268-1315 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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Significant correlations were found between baseline CCPT
commission-error rates and improvement in ADHD-RS-
teacher in ADHD/noODD, but not in ADHD/ODD. Among
the ADHD/ODD, but not the ADHD/noODD, a significant
correlation was found between baseline CCPT commission-
error rates and improvement in K-SADS-ODD. Baseline
cognitive impulsivity (as measured by the CCPT) can predict
response of ODD to MPH treatment in ADHD/ODD
patients. Int Clin Psychopharmacol 00:000–000 Copyright ©
2019 Wolters Kluwer Health, Inc. All rights reserved.
International Clinical Psychopharmacology 2019, 00:000–000
Keywords: attention-deficit/hyperactivity disorder,
attention-deficit/hyperactivity disorder rating scale,
conjunctive continuous performance test, impulsivity,
Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age
Children, methylphenidate, oppositional defiant disorder
a
Child and Adolescent Outpatient Clinic, bResearch Unit, Geha Mental Health
Center, cFelsenstein Medical Research Center, Sackler Faculty of Medicine,
Tel Aviv University, Petah Tikva, dSackler Faculty of Medicine, eConstantiner
School of Education and Sagol School of Neuroscience, Tel Aviv University,
Tel Aviv and fMaccabi Health Services, Jerusalem, Israel
Correspondence to Pavel Golubchik, MD, Child and Adolescent Outpatient
Clinic, Geha Mental Health Center, PO Box 102, Petah Tikva 4910002, Israel
Tel: + 972 39 258 270; fax: + 972 39 523 598; e-mail: pavelgo@gmail.com
Received 11 November 2018 Accepted 19 December 2018
impulsivity and externalizing behaviors in childhood.
Impulsivity is frequently identified as the core underlying
neurobehavioral component of ADHD and often co-occurs
with ODD (Gadow and Nolan, 2002). Children with ADHD
combined presentation (hyperactivity–impulsivity and inat-
tentive symptoms) are more likely to fulfill the diagnostic
criteria for ODD than children without ADHD or children
diagnosed with ADHD, predominantly inattentive presenta-
tion (Eiraldi et al., 1997; Martel et al., 2017), suggesting that
impulsivity is more likely to coexist with ODD symptoms.
In addition, children with impulsive behaviors are at greater
risk of showing externalizing behaviors such as opposition-
ality, aggression, and conduct disorder than are children
without these behaviors (Lanza and Drabick, 2011; Harvey
et al., 2016).
Despite the fact that ADHD and ODD often co-occur, data
on the pharmacological management of this comorbidity are
DOI: 10.1097/YIC.0000000000000252
 2 International Clinical Psychopharmacology 2019, Vol 00 No 00
relatively scarce, especially when impulsive aggression is
prominent. Treatment with stimulants improves impulse
control and aggressive behavior among children with
ADHD (Blader et al., 2013). In a 5-week clinical trial of
administering methylphenidate (MPH), correlations were
found between ODD and conduct disorder (CD) symptoms
and the ADHD hyperactivity/impulsivity subscale. Further-
more, long-acting MPH treatment was found to be effective
in the treatment of ODD with aggressive behavior (Sinzig
et al., 2007).
In the present study, we compared the baseline para-
meters of a continuous performance test (CPT) in chil-
dren with only ADHD (ADHD/noODD) and children
with ADHD with comorbid ODD (ADHD/ODD). In
addition, we assessed the correlations between the
baseline performance on the CPT and the response of
both groups to a 3-month MPH treatment, as assessed by
the ADHD-rating scale (ADHD-RS) (DuPaul et al.,
1994). We hypothesized that the level of impulsivity, as
measured by the baseline magnitude of commission
errors, would predict the efficiency of MPH in reducing
ADHD symptoms.
Participants and methods
Participants
All participants were recruited from a pediatric psychia-
tric outpatient clinic, at Maccabi Health Services,
Jerusalem, Israel. Children were referred for psychiatric
assessment by a pediatrician or a school consultant or
brought in by the parents. Inclusion criteria consisted of
fulfillment of the Diagnostic and Statistical Manual of
Mental Disorders, 5th ed. (DSM-5) criteria for ADHD
alone or with comorbid ODD and no history of previous
treatment with stimulants. Exclusion criteria were as
follows: treatment with psychotropic agents, history
of organic brain syndrome, substance use, intellectual
disability, bipolar disorder, schizophrenia, autistic
spectrum disorder, delusional disorder, and suicidal
ideations.
Fifty-three children and adolescents (33 boys and
20 girls, age: 12.2 ± 1.9 years) were included in the study.
All fulfilled the DSM-5 criteria for ADHD and 28 of
them also for ODD. The ADHD/noODD group (n = 25)
did not differ significantly from the ADHD/ODD group
(n = 28) in age (12.4 ± 1.8 vs. 12.1 ± 2.0 years, t = 0.58,
P = 0.55, d.f. = 51) and sex distribution (12 females/13
males vs. eight females/20 males, χ2 = 2.12, P = 0.15).
All participants attended regular school at the time of the
study and came from the same geographical area and
from similar socioeconomic status.
The study was approved by the Maccabi Health Services
Review Board for Human Clinical Studies. All partici-
pants and their parents provided written informed con-
sent for participation in the study.
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Procedure
Diagnosis
The diagnoses of DSM-5 ADHD and ODD were
established by a semistructured interview (conducted by
a board-certified senior child and adolescent psychiatrist)
that followed the guidelines of the Schedule for Affective
Disorders and Schizophrenia for School-Age Children
(K-SADS-ODD) – Present and Lifetime Version (K-SADS-
PL; Kaufman et al. 2000).
Measures
(1) Severity of ADHD was assessed using the ADHD-
RS (DuPaul et al. 1994), a clinician-rated scale with
one item for each of the 18 DSM-4 symptom criteria
for ADHD each with a score ranging from 0 (not
present) to 3 (severe). Total scores ranged from a
minimal score of 0 to a maximal score of 54. It was
used as a parent-administered (ADHD-RS-parent)
and teacher (ADHD-RS-teacher)-administered scale
completed at baseline and following 3 months of
treatment.
(2) Severity of ODD was assessed through a semistruc-
tured clinical interview of the child and his parent(s)
by the treating psychiatrist according to the guide-
lines of K-SADS (Kaufman et al. 2000). The scale
includes nine items with a score for each item ranging
from 0 (not more than others), 1 (somewhat more
than others), and 2 (much more than others), with a
maximal total score of 18. The K-SADS-ODD scale
was completed at baseline and following 3 months of
treatment.
(3) Baseline impulsivity level of all participants was
assessed using the conjunctive continuous performance
task (CCPT), which measures commission errors,
omission errors, reaction time, and SD of reaction
time. This task provides a valid measure of sustained
attention as it minimizes the involvement of working
memory and perceptual abilities while maximizing the
requirement to focus attention on a monotonous task
for a long period of time (Shalev et al., 2011). In
previous studies, this task produced significant differ-
ences between children and adolescents with ADHD
compared with typically developing children and
adolescents with strong effect sizes (Tsal et al., 2005;
Stern and Shalev, 2013; Shalev et al., 2016).
Methylphenidate administration and assessment
The trial was conducted for 12 weeks. All participating
patients received daily doses of 0.8–1.2 mg/kg of MPH –
doses in the range recommended by the British
Association for Psychopharmacology (Bolea-Alamanac
et al., 2014). Daily doses did not exceed 90 mg/day (fol-
lowing the recommendation of the Israeli Ministry of
Health). Daily MPH doses were adjusted for all partici-
pants according to their condition at the end of week 2

and at the end of week 4. Throughout the study period,
the patients were kept off all other medications.
The patients were assessed by ADHD-RS and the
K-SADS before initiation of MPH treatment and after
3 months of treatment. The CCPT was administered
only during the first visit before starting MPH treatment.
Safety
Adverse effects of MPH treatment were evaluated at
baseline and endpoint by spontaneous self-report. The
participants were able to report side effects by telephone
any time during the study period. Monitoring of adverse
events was performed by a psychiatric researcher.
Statistical analysis
Two-tailed, paired, and unpaired Student’s t-tests and
Spearman’s correlation test were used as appropriate. All
results are expressed as mean ± SD.
Results
Baseline severity levels
CCPT commission error rates were significantly higher in
the ADHD/ODD group compared with the ADHD/
noODD group (t = 3.1, d.f. = 51, P = 0.0031; Table 1).
This comparison yielded a large effect size (Cohen’s
d = 0.89). The two groups did not differ in any of the
other four CCPT’s measures that reflect sustained
attention.
As expected, significantly higher scores in both ADHD-
RS-parent (n = 28) and ADHD-RS-teacher (n = 20) were
observed in the ADHD/ODD group in comparison with
the ADHD/noODD group (16.7 ± 10.8 vs.26.6 ± 9.9,
t = 3.67, P < 0.0005 and 16.8 ± 12.3 vs. 24.7 ± 10.9, t = 2.14,
P = 0.038, respectively). The degree of improvement in
the parent scores indicated a large effect size (Cohen’s
d = 0.96), whereas the change in the teachers’ scores
yielded medium effect size (Cohen’s d = 0.68).
Similarly, significantly higher baseline levels of K-SADS-
ODD scores were detected in the ADHD/ODD group
(n = 28) compared with the ADHD/noODD group
(n = 25) (6.6 ± 1.4 vs. 3.1 ± 0.4, t = 13.7, P < 0001), yielding
very strong effect size (Cohen’s d = 3.40).
Table 1Baseline CCPT differences between the ADHD/noODD
and ADHD/ODD groups
ADHD/noODD ADHD/ODD
CCPT (N = 25) (N = 28) t (P value)
Mean RT (ms) 518 ± 78.0 493 ± 70.7 1.01 (0.314)
SD of RT (ms) 110 ± 44 111 ± 37 0.007 (0.99)
Omission error 0.020 ± 0.0 0.032 ± 0.0 0.94 (0.35)
rate
Commission 0.019 ± 0.017 0.050 ± 0.046 3.1 (0.0031)
error rate
ADHD, attention-deficit/hyperactivity disorder; CCPT, conjunctive continuous
performance task; ODD, oppositional defiant disorder; RT, reaction time.
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Cognitive impulsivity, MPH, and ADHD/ODD Golubchik et al. 3
No significant correlation was found between the base-
line CPT commission errors and the baseline ADHD-
RS-teacher scores either in the ADHD/noODD group
[Spearman’s r = 0.07, 95% confidence interval (CI):
− 0.20 to 0.63, n = 20, P = 0.26] or in the ADHD/ODD
group (Spearman’s r = 0.13, 95% CI: − 0.32 to 0.54,
P = 0.56). No significant correlations were found between
the baseline CPT commission errors and the baseline
ADHD-RS-parent scores in either ADHD/noODD
(r = 0.06, 95% CI: − 0.31 to − 0.40, P = 0.74) or ADHD/
ODD (r = 0.015, 95% CI: − 0.30 to 0.38, P = 0.93).
No significant correlation was found between the base-
line CPT commission error rates and the K-SADS-ODD
scores at baseline in either ADHD/noODD (Spearman’s
r = 0.28, 95% CI: − 0.13 to 0.60, n = 25, P = 0.17) or
ADHD/ODD (Spearman’s r = − 0.29, 95% CI: − 0.59 to
0.09, n = 28, P = 0.13).
The effects of 3 months of methylphenidate treatment
Significant improvements in ADHD-RS-parent and
ADHD-RS-teacher scores were found following a 3-month
MPH treatment in both ADHD/noODD (before:
16.7 ± 10.8, after: 12.6 ± 7, paired t = 4.7, P = 0.0001: and
before: 16.8 ± 12.3, after: 12.5 ± 7.4, paired t = 3.7, P = 0.0015,
respectively) and ADHD/ODD (before: 26.6 ± 9.9, after
18.8 ± 6.2, paired t = 6.7, P < 0.0001, and before: 24.7 ± 10.9,
after: 18.9 ± 8, paired t = 5.5, P = 0.0001, respectively).
Significant improvements were also found in the severity
of K-SADS-ODD in both the ADHD/ODD group (before:
6.6 ± 1.4, after: 5.1 ± 1.1, paired t = 6.4, P = 0.0001) and the
ADHD/noODD group (before: 3.1 ± 0.4, after: 2.9 ± 0.4,
paired t = 2.9, P = 0.006).
Correlations between the baseline continuous
performance test impulsivity and clinical improvements
following methylphenidate treatment
A significant correlation was found between the baseline
CPT commission errors and the improvements in total
ADHD-RS-teacher scores in the ADHD/noODD group
(Spearman’s r = 0.45, 95% CI: 0.011–0.74, P = 0.045), but
not in the ADHD/ODD group (Spearman’s r = 0.38, 95%
CI: − 0.078 to 0.70, P = 0.10).
In contrast, no significant correlations were found
between the baseline CPT commission errors and the
improvements in total ADHD-RS-parent–child scores in
either the ADHD/noODD (r = 0.29, 95% CI: − 0.82 to
− 0.59, P = 0.12) or the ADHD/ODD group (r = 0.032,
95% CI: − 0.39 to 0.33, P = 0.87).
A significant correlation was found between the baseline
CPT commission error rates and the improvements in
ODD K-SADS scores in the ADHD/ODD group
(Spearman’s r = 0.42, 95% CI: 0.079–0.68, n = 28,
P = 0.019), but not in the ADHD/noODD group
(Spearman’s r = 0.042, 95% CI: − 0.34 to 0.41, n = 25,
P = 0.83).
 4 International Clinical Psychopharmacology 2019, Vol 00 No 00
Discussion
As expected, on the pharmacological level, significant
improvements in the ADHD-RS scores were detected in
both the ADHD/noODD and the ADHD/ODD groups
following a 12-week MPH treatment. The major inno-
vations in the findings of the present study were the
higher baseline cognitive impulsivity scores (as reflected
by a higher rate of commission errors) in the CCPT of
the ADHD/ODD children compared with those of
the ADHD/noODD (P = 0.0031) and the correlation
between the baseline CCPT impulsivity levels and the
improvement in K-SADS-ODD scores following a
12-week MPH treatment in the ADHD/ODD patients.
A study by Newcorn et al. (2001) found that compared
with healthy controls, CPT inattention, impulsivity, and
dyscontrol errors were high in ADHD with comorbid
conditions as well as in ADHD without comorbid con-
ditions. However, similar to our observation, children
with ADHD/ODD or ADHD/CD were rated as more
impulsive than inattentive. It is noteworthy that in our
sample, baseline CCPT measures were shown to con-
stitute a discriminating factor between children with
ADHD/ODD and ADHD/noODD. Namely, the two
groups differ only in the commission error rates that
represent the level of impulsivity, but not in the other
three parameters that reflect sustained attention. This
specificity suggests that the commission error rate in the
CCPT can differentiate between ADHD/ODD versus
ADHD/noODD.
Another study (Munkvold et al., 2014) assessed the ability
of Conners’ Continuous Performance Test-II to differ-
entiate between children with ADHD, children with
ODD, children with both, and normal controls. In con-
trast to our study, significant group differences in the
Conners’ Continuous Performance Test-II scores were
restricted to omissions (but not commissions) for the
ADHD-only group, but not for the ODD group.
In another study of children with ADHD, baseline
executive functioning task performance correlated with
the teacher-rated ADHD scores, but not with the parent-
rated ones (Oosterlaan et al., 2005). Yet, in our study,
using a CPT task, a mirror pattern was obtained, namely,
a significant correlation was found between the baseline
CPT commission error rates and the ADHD-RS-parent-
–child scores (P = 0.045). Thus, it seems that there is an
association between baseline ADHD severity and
attentional functioning.
These positive correlations indicate the important role of
the impulsivity component in ADHD and support the
notion of a possible progression of ADHD to developing
ODD symptoms that aggravate the severity of the
disorder and may interfere with the efficacy of MPH
treatment. Despite the possibility of comorbid ODD
impacting the response to MPH treatment negatively, in
a recent study by Masi et al. (2017), MPH as monotherapy
Copyright r 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
for ADHD/ODD patients with aggression was found to
be as effective on the aggressive behavior as risperidone.
Wehmeier et al. (2015) compared the response of ADHD
symptoms with atomoxetine treatment in patients with
and without comorbid ODD or CD using a CPT com-
bined with an infrared motion tracking device. The
results showed that atomoxetine reduced ADHD sever-
ity as measured by CPT and motion tracking parameters
irrespective of whether comorbid ODD or CD were
present. The treatment effect of atomoxetine on hyper-
activity appears to be more pronounced in the subgroup
of patients with comorbid ODD/CD than in the sub-
group without this comorbidity (Wehmeier et al., 2015).
In the present study, a significant improvement in
K-SADS severity was found following MPH treatment in
the ADHD/ODD group. Moreover, the baseline and the
change in K-SADS-ODD scores were correlated sig-
nificantly with the baseline CCPT commission error rate
in the ADHD/ODD group, but not in the ADHD/
noODD group (Spearman’s r = 0.42, n = 28, P = 0.019).
The main limitations of this study were the open-label
design, the small sample size, the relatively short treat-
ment duration (12 weeks), and the lack of long-term
follow-up.
An additional limitation was the lack of an ODD-only
group (i.e. without comorbid ADHD). Although mono-
therapy with MPH is strength of the study, it did not
allow for comparison with other anti-ADHD treatments
such as amphetamine, clonidine, guanfacine, or atomox-
etine. No data on additional comorbidity or subdimen-
sions of ODD were collected in the present study.
Moreover, unfortunately, the CCPT was not adminis-
tered after the MPH treatment period; thus, clinical
treatment effects were limited only to clinical rating
scales.
Conclusion
It appears that baseline cognitive impulsivity levels, as
reflected by the commission error rate in the CCPT
(Shalev et al., 2011), can predict the impact of MPH
treatment on K-SADS-ODD scores in ADHD/ODD
patients. Future studies on the putative effectiveness of
the CCPT in distinguishing children with ADHD/
noODD or ADHD/ODD from normal controls should be
monitored before and following MPH treatment as well
as any other intervention.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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