Pharmacological Treatment of ODD Symptoms in
ADHD Children: A Brief Review
by Daniel
F. Connor, MD
Over the past several years there has
occurred renewed psychiatric interest in
studying the characteristics, validity,
prognosis, and treatment of Oppositional
Defiant Disorder (ODD). Results have
supported the validity of ODD as a meaningful
clinical entity independent of conduct
disorder (Greene et al., 2002). ODD
frequently co–exists with other psychiatric
disorders such as ADHD (Kuhne, Schachar, &
Tannock, 1997). Because of a high association
with ADHD, recent pharmacological research
has begun to examine whether medications
effective for ADHD will also be effective in
diminishing symptoms of ODD when this
disorder co–occurs with ADHD. This report
discusses the characteristics of ODD and then
summarizes recent pediatric
psychopharmacological studies investigating
medication response in ODD with comorbid ADHD.
CHARACTERISTICS OF ODD
ODD is characterized by recurring
negativistic uncooperative, defiant,
disobedient, and hostile behavior toward
authority figures. Symptoms are severe enough
to interfere with the child’s daily
functioning and with quality of life. ODD is
associated with substantial impairment in
social skills, family interaction, and
academic functioning. Problematic behaviors
associated with ODD may include excessive
arguing, defiance of parent or teacher
requests or commands, non–compliance with
rules, displaying frequent temper tantrums,
anger, or resentment, externalizing
responsibility for one’s own actions onto
others, holding grudges and seeking revenge,
and/or deliberately attempting to annoy and
disturb others. Oppositional and defiant
behaviors often trigger negative parent–child
interactions and cause high levels of
parenting stress and family dysfunction
(Loeber, Burke, Lahey, Winters, & Zera,
2000). ODD can usually be distinguished from
childhood temperamental traits by about age 8
years. Once established, ODD can be very
persistent with some
studies reporting up to 57% of children
meeting diagnostic criteria 4 years after
diagnosis (August, Realmuto, Joyce, &
Hektner, 1999), especially when it is
comorbid with another disorder. About
one–third of ODD children may progress to a
diagnosis of conduct disorder and about 10%
eventually progress to a diagnosis of adult
antisocial personality disorder (Burke,
Loeber, & Birmaher, 2002; Loeber et al.,
2000). Thus, the early recognition and
effective treatment of ODD is important in
preventing a developmental progression
towards an antisocial lifestyle for some
children.
PREVALENCE OF ODD WITH/WITHOUT ADHD
The prevalence of ODD in the general
population is about 8.5% (Kessler et al.,
2005). Children and adolescents with ODD have
high rates of comorbid psychiatric disorders.
In non–referred population- based studies of
ODD youths, comorbid ADHD rates ranging
between 14% and 35% are reported (Angold,
Costello,&Erkanli, 1999; Bird et al., 1988).
It is generally agreed that oppositional
defiant disorder is the most common
comorbidity in psychiatric samples of ADHD
children and, in clinically referred
children, the comorbidity rates of ODD and
ADHD are much higher than in non–referred
populations. ADHD and ODD may overlap in up
to 65% of clinically referred ADHD children
(Biederman et al., 1996).
THE RELATIONSHIP BETWEEN ADHD AND ODD
Several studies have examined the
relationship between ADHD and ODD in
clinically referred children and adolescents.
There appears to be a correlation between the
severity of ADHD symptoms and the severity of
ODD symptoms as measured by rating scale
scores. If diagnostic criteria are met for
both ADHD and ODD, as the severity of ADHD
symptoms worsen (based on the number of
symptoms endorsed), ODD symptoms are also
likely to become more severe (Kuhne et al.,
1997). ODD is a significant correlate of
family psychopathology and adverse social
outcomes in ADHD children compared to
children with ADHD alone, even when other
comorbid disorders are controlled (Greene et
al., 2002). In general, ADHD children with
comorbid ODD have higher rates of
psychopathology across a number of domains
compared to youths with ADHD alone, but less
than those with ADHD+ conduct disorder (Burke
et al., 2002; Loeber et al., 2000).
Aggression is a domain of psychopathology
that often causes parents to refer their
child for clinical evaluation and treatment.
Overt aggression is defined as aggression
resulting in a direct confrontation with the
environment. Overt aggression includes such
behaviors as threats towards others,
self–injurious behaviors, explosive acts of
property destruction, and physical fighting
with others. Covert aggression is hidden and
furtive. It may involve behaviors such as
delinquency, lying, shoplifting, and
cheating. In the DSM–IV nosology of
psychiatric disorders, children with high
rates of overt and covert aggression are
generally assigned a diagnosis of conduct
disorder. Despite the absence of overt and/or
covert aggression as a diagnostic criterion
for ODD, recent research has documented
significantly higher rates of overt and
covert aggression in ADHD children with
comorbid ODD compared to children with ADHD
alone (Connor & Doerfler, unpublished). This
is illustrated in Figures 1 and 2.
Figure 1 (not included, see original
article) illustrates findings using the
parent–report Modified Overt Aggression Scale
(MOAS) (Yudofsky, Silver, Jackson, Endicott,
& Williams, 1986) in ADHD children
with/without comorbid ODD. The MOAS provides
an overt aggression total score, and has
subscales for self–injurious behavior, verbal
threats of violence directed towards others,
property destruction, and physical fighting.
In a clinic-referred population of male ADHD
children and adolescents, those with ADHD
alone (N = 61) were compared to those with
ADHD and ODD (N= 83). As Figure 1
illustrates, significantly higher rates of
overt aggression were found for the comorbid
ADHD + ODD group.
Figure 2 (not included, see original
article) illustrates findings from the
parent–completed Child Behavior Checklist
(CBCL) narrowband Aggression and Delinquency
subscales. Similar to findings from the MOAS,
significantly elevated rates of overt
aggression and delinquency were found in the
ADHD + ODD group compared to the ADHD alone
group. These data suggest that both overt and
covert aggression may be significant clinical
problems in referred ADHD + ODD children and
adolescents (who are without conduct
disorder) despite the absence of criteria for
aggression in the DSM–IV diagnostic symptom
set for ODD.
TREATMENT OF ADHD AND COMORBID ODD
Because of high rates of overlap between ODD
and ADHD in clinical samples and because
comorbid ADHD and ODD often results in higher
rates of psychopathology resulting in
clinical referral, clinicians who evaluate
and treat children with ADHD are often faced
with assessing and managing comorbid ODD.
Behavioral therapy is the mainstay of
treatment for ODD. Parent management training
(PMT) programs have been extensively studied
and found effective, especially for younger
ODD patients (Barkley, 1997). However, there
are several problems with this form of
behavioral therapy for
ODD. Effectiveness of PMT programs appears to
diminish as children age into
pre–adolescence. Thus, PMT programs are best
suited for younger ODD children. The
effectiveness of PMT appears to diminish as
the severity of ADHD and ODD increases. Since
the severity of ODD covaries with the
severity of ADHD, and comorbidity is
associated with higher rates of aggressive
behavior, PMT might be less effective in
comorbid children than IN those with mild
ADHD or just ODD alone. Finally, community
practitioners may be untrained in the use of
empirical interventions such as PMT and thus,
effective PMT may be difficult to access in
the community.
MEDICATION TREATMENT OF ODD
Although no medication is currently approved
for treatment of ODD, several randomized
controlled efficacy and open effectiveness
trials have examined the effects of various
stimulants and atomoxetine in the treatment
of ODD, usually in the context of
co–occurring ADHD. These studies are
presented in Table 1 (not included, see
original article) .
Three recent studies investigated
stimulants for ODD symptoms in ADHD children
and adolescents, many of whom also had a
comorbid diagnosis of ODD (MTA Group, 1999;
Spencer et al., 2006; Steele et al., 2006).
In the landmark Multimodal Treatment Study of
Children with ADHD (MTA Study), 40% of ADHD
children also met baseline diagnostic
criteria for ODD (MTA Group, 1999). With an
average methylphenidate immediate release (IR
MPH) dose range between 30.2 mg/day and 41.3
mg/day (depending on treatment arm) given in
three divided daily doses, children receiving
medication management or medication
management and behavioral therapy experienced
a significantly greater improvement in ODD
symptoms than did children assigned to
behavior therapy alone. Another study
investigated mixed amphetamine salts extended
release (MAS XR) in children and adolescents
with either ODD alone (21%) or ADHD and ODD
(79%) (Spencer et al., 2006). Parent ODD
ratings significantly improved on daily doses
of 30 mg or 40 mg compared with placebo in
the comorbid ADHD + ODD group. In the
comorbid ADHD + ODD group, lower MAS XR doses
of 10 mg/day or 20 mg/day were not
significantly different from placebo on ODD
measures. The “pure” ODD group did not
improve on MAS XR at any dose relative to
placebo (Spencer et al., 2006). This study
suggests that “pure” ODD in the absence of
comorbid ADHD might not be medication
responsive, although more studies are needed
because of the small sample size of the ODD
alone group in this study. Additionally,
results suggest that higher MAS XR doses
might be necessary when treating comorbid ODD
than when treating ADHD alone. Finally, a
randomized, open–label effectiveness study
compared a long–acting stimulant OROS–MPH
with MPH immediate release given three times
daily on ADHD and ODD outcomes (Steele et
al., 2006). In this study 41% of subjects had
comorbid ADHD + ODD. Results showed that the
longer-acting OROS preparation improved ADHD
and ODD symptoms to a significantly greater
degree on parent report measures than did IR
MPH given in three divided daily doses. These
studies suggest that ODD symptoms may be
responsive to a variety of stimulant
preparations, that higher doses may be
necessary to diminish comorbid ODD symptoms
when they occur in the context of ADHD, and
that longer–acting stimulant preparations may
have better effectiveness on parent–report
ODD measures than IR MPH even when given in
multiple daily doses. Although further
research is needed, these studies also raise
a question as to whether ODD in the absence
of comorbid ADHD is medication responsive.
Atomoxetine is a nonstimulant agent
approved by the U.S. Food and Drug
Administration (FDA) for the treatment of
ADHD in children, adolescents, and adults. A
number of recent studies suggest that
atomoxetine may improve ODD symptoms when
they are comorbid with ADHD (see Table 1). A
study examined the effects of atomoxetine on
ODD symptoms in a sample of children and
adolescents ages 8 to 18 with ADHD and ODD
(Newcorn, Spencer, Biederman, Milton, &
Michelson, 2005). These investigators found
that youths with ADHD and comorbid ODD showed
statistically significant improvement in
ADHD, ODD, and quality–of–life measures. The
study authors concluded that atomoxetine
treatment improves ADHD and ODD symptoms in
youths with ADHD and ODD, although the
comorbid group may require higher atomoxetine
doses of up to 1.8 mg/kg/day. A randomized
controlled discontinuation study examined the
time to relapse in children with ADHD and ODD
who were previous responders to open–label
atomoxetine. Responders were randomly
assigned atomoxetine continuation or placebo
(Hazell et al., 2006). Time to ADHD relapse
was not influenced by the presence or absence
of comorbid ODD. A negative randomized
controlled trial was reported in which
atomoxetine in doses up to 1.6 mg/kg/day did
not separate from placebo on parent-report
ODD measures in comorbid ADHD + ODD children
(Kaplan et al., 2004). Finally, a post–hoc
meta–analysis was performed to determine the
effect of the presence of comorbid ODD
symptoms on clinical outcomes in ADHD
outpatients aged 6–16 from three previously
completed randomized controlled atomoxetine
trials (Biederman et al., 2007). Of the 512
ADHD subjects studied, 158 (31%) were
diagnosed with comorbid ODD. Relative to
placebo, atomoxetine treatment significantly
reduced ADHD symptoms in both ODD–comorbid
and noncomorbid subjects irrespective of the
comorbidity with ODD. This meta–analysis also
showed that reduction in ODD symptoms was
highly correlated (0.78) to the magnitude of
ADHD response to atomoxetine.
SUMMARY
Comorbid ODD is highly prevalent among
children and adolescents clinically referred
for ADHD. Comorbid youngsters have greater
ADHD symptom severity, more psychopathology,
and greater impairment than children with
either ADHD or ODD alone. There appears to be
a linear relationship between the severity of
ADHD and ODD symptom severity in clinically
referred children. Despite the absence of
criteria for overt/covert aggression in the
DSM–IVsymptom set for ODD, clinicians should
be aware that higher rates of overt and
covert aggression may be found in
non-conduct- disordered clinically referred
comorbid ADHD + ODD children than in referred
children withADHDalone.
An emerging literature suggests that ODD
symptoms may be responsive to the same
medications used to treat ADHD when both
disorders are comorbid in the same patient.
However, it is presently unclear whether ODD
in the absence of comorbid ADHD is responsive
to medication. Pure ODD without concomitant
ADHD remains a target for behavioral therapy
intervention and parent management training.
When using medication for comorbid ADHD +
ODD, the practicing clinician should be aware
of the following points:
- Higher doses of medication may be
necessary to treat comorbid ODD symptoms in
ADHD patients than are needed for ADHD
symptoms alone.
- Longer–acting stimulant preparations may
have greater effectiveness on parent-report
ODD symptoms than immediate release stimulant
preparations given multiple times daily.
- Comorbid ODD does not seem to influence
the response of ADHD to medications.
- Response of ODD symptoms to medication
in comorbid patients appears highly
correlated with medication effectiveness for
ADHD symptoms.
Dr. Connor is a member of the Editorial
Board of The ADHD Report. He is also Director
of the Division of Child and Adolescent
Psychiatry and Professor in the Department of
Psychiatry (MC 1410), University of
Connecticut Health Care,
263 Farmington Avenue, Farmington, CT
06030–1410. He can be reached at:
connor@psychiatry.uchc.edu
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Reprinted with permission from ADHD Report,
Guilford Publications, Inc.,
February 2007, Volume 15 No. 1
