Pharmacological Treatment Of ODD Symptoms In ADHD ... - PsyBC

the
R E P O R T
Edited by Russell A. Barkley
• Volume Fifteen • Number One • ISSN 1065-8025 • February 2007 •
Pharmacological Treatment of ODD
Symptoms in ADHD Children: A Brief Review
Daniel F. Connor, M.D.
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.
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
Contents
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.
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,
Pharmacological Treatment of ODD Symptoms in ADHD
Children: A Brief Review, 1 Occupational Functioning in
Adults with ADHD, 6 Understanding the Pharmacogenetics
of ADHD, 10 Research Findings, 12
NOTICE TO NON-PROFESSIONALS The information contained in this newsletter is not intended as a
substitute for consultation with health care professionals.
© 2007 The Guilford Press The ADHD Report • 1

Russell A. Barkley, Ph.D.
Department of Psychiatry
SUNY Upstate Medical University
Send correspondence to:
1752 Greenspoint Ct.
Mount Pleasant, SC 29466
E-mail: russellbarkley@earthlink.net
www.russellbarkley.org
EDITORIAL BOARD
Arthur Anastopoulos, Ph.D., University of
North Carolina at Greensboro • José J.
Bauermeister, Ph.D., University of Puerto
Rico, San Juan • Joseph Biederman, M.D.,
Massachusetts General Hospital • Caryn
Carlson, Ph.D., University of Texas, Austin •
Andrea M. Chronis, Ph.D., University of
Maryland, College Park • Daniel F. Connor,
M.D., University of Connecticut Health Center
• Charles E. Cunningham, Ph.D.,
McMaster University Medical Center •
George J. DuPaul, Ph.D., Lehigh University,
PA • Mariellen Fischer, Ph.D., Medical College
of Wisconsin, Milwaukee • Sam
Goldstein, Ph.D., University of Utah, Salt
Lake City • Michael Gordon, Ph.D., State
University of New York Upstate Medical University
• Lily Hechtman, M.D., Montreal
Children’s Hospital, Montreal • Stephen
Hinshaw, Ph.D., UC, Berkeley • Betsy Hoza,
Ph.D., University of Vermont • James
Hudziak, M.D., University of Vermont Medical
Center • Charlotte Johnston, Ph.D., University
of British Columbia, Vancouver •
Laura Knouse, M.A., University of North
Carolina, Greensboro • Rafael Klorman,
Ph.D., University of Rochester, NY • Florence
Levy, M.D., The Prince of Wales Children’s
Hospital, Australia • Larry
Lewandowski, Ph.D., Syracuse University,
NY • Sandra Loo, Ph.D., Neuropsychiatric
Institute, UCLA • Richard Milich, Ph.D.,
University of Kentucky, Lexington • Kevin
Murphy, Ph.D., Adult ADHD Clinic of Central
Massachusetts • Joel Nigg, Ph.D., Michigan
State University, East Lansing • William
Pelham, Ph.D., SUNY, Buffalo • Linda
Pfiffner, Ph.D., University of Chicago • Stephen
Pliszka, M.D., University of Texas
Medical School, San Antonio • Mark Rapport,
Ph.D., University of Central Florida •
Russell Schachar, M.D., The Hospital for Sick
Children, Toronto • Bradley Smith, Ph.D.,
University of South Carolina, Columbia •
Thomas Spencer, M.D., Massachusetts General
Hospital • Mark Stein, Ph.D., University
of Illinois, Chicago • Rosemary Tannock,
Ph.D., Hospital for Sick Children, Toronto •
Lisa Weyandt, Ph.D., Central Washington
University • Thomas E. Wilens, M.D., Massachusetts
General Hospital • Alan Zametkin,
M.D., National Institute of Mental Health,
Bethesda
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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 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 illustrates findings from the
parent–completed Child Behavior
Checklist (CBCL) narrow band 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
2 • The ADHD Report © 2007 The Guilford Press

35
30
25
20
15
10
5
0
Total MOAS
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
SIB
ADHD
ADHD + ODD
VERBAL THREATS
PROPERTY DEST
AGGRESSION
FIGURE 1. Overt Aggression Scale raw scores in clinically referred ADHD children and
adolescents with/without comorbid ODD. MOAS (modified overt aggression scale)
total score, SIB (self-injurious behavior), verbal threats of harm directed towards others,
explosive acts of property destruction, and physical aggression (fighting).
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.
T-Score
68
66
64
62
60
58
56
54
52
CBCL Aggression
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.
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 (MTAGroup, 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
ADHD + ODD
CBCL Delinquency
FIGURE 2. Parent report Child Behavior Checklist Aggression and Delinquency
T-scores in clinically referred ADHD children and adolescents with/without comorbid
ODD. *p 0.01.
© 2007 The Guilford Press The ADHD Report • 3

TABLE 1. Recent Randomized Efficacy and Effectiveness Trials Targeting ODD in ADHD Children and Adolescents
Study ADHD Subjects ODD Drug Dose Duration ODD Measures Outcome
Hazell, Zhang,
Wolanczyk, et al.,
2006
Kaplan, Heiligenstein,
West, et al., 2004
MTA Cooperative
Group, 1999
Newcorn, Spencer,
Biederman, et al.,
2005
Spencer, Abikoff,
Connor, et al., 2006
Steele, Weiss,
Swanson, et al., 2006
n = 416; 6–15 years 43% ADHD + ODD Atomoxetine 0.5–1.8 mg/kg/d Time to
relapse
KSADS–PL
diagnosis of
ODD
n = 98; 7–13 years 100% ADHD + ODD Atomoxetine 1.6 mg/kg/d 9 weeks CPRS–R:S (ODD
subscale)
n = 256; 7–9.9 years 40% ADHD + ODD IR MPH tid Average dose at
endpoint = 30.2 –
41.3 mg/d
14 months SNAP ODD
parent and
teacher rating
scales
n = 297; 8–18 years 39% ADHD + ODD Atomoxetine 0.5, 1.2, 1.8 mg/kg/d 8 weeks CPRS–R:S (ODD
subscale)
n = 308; 6–17 years 21% pure ODD; 79%
ADHD + ODD
n = 147; 6–12 years 41% ADHD + ODD OROS–MPH
versus IR
MPH tid
MAS XR 10, 20, 30, 40 mg/d 4 weeks SNAP–IV ODD
parent rating
scale
Average Dose:
OROS–MPH = 37.8
mg/d; IR MPH tid =
33.3 mg/d
8 weeks SNAP–IV parent
rating scale
Comorbid ODD does
not influence rate of
relapse of pts with
ADHD given
atomoxetine
No significant
difference
Combination med
mgt and behav =
med mgt alone >
behav alone
ADHD + ODD
improved 1.8 > 1.2 =
0.5 mg/kg/d
MAS XR 30mg and 40
mg arms > placebo
on parent ODD
ratings
ADHD + ODD
improved
OROS–MPH > IR
MPH tid
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 con-
4 • The ADHD Report © 2007 The Guilford Press

trolled 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–IV symptom 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 with ADHD alone.
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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Occupational Functioning in
Adults with ADHD
Kevin R. Murphy, Ph.D. and Russell A. Barkley, Ph.D.
Results from past studies suggest that as
adolescents, ADHD individuals are no
different in terms of functioning in their
jobs than are normal adolescents (Weiss
& Hechtman, 1993). However, these
findings need to be qualified by the fact
that most jobs taken by adolescents are
unskilled or only semiskilled, are usually
part time, and typically are of a limited
duration (summer months). As children
with ADHD enter adulthood and take on
full–time jobs that require skilled labor,
independence of supervision, acceptance
of responsibility, and periodic
training in new knowledge or skills, their
deficits in attention, impulse control, and
regulating activity level, as well as their
poor organizational and self–control
skills, could begin to handicap them on
the job. The findings from the few outcome
studies that have examined job
functioning suggest this may be the case.
Two prior studies examined occupational
status by adulthood and reported
that their hyperactive groups ranked significantly
lower than control groups
(Mannuzza, Gittelman–Klein, Bessler,
Malloy, & LaPadula, 1993, 1998; Weiss &
Hechtman, 1993). Employer ratings revealed
significantly worse job performance
in the hyperactive than the control
group (Weiss & Hechtman, 1993).
More of the hyperactive group also reported
having been fired or laid off from
employment than had members of the
control group. The Milwaukee follow–up
study (Barkley, Fischer, Smallish,
& Fletcher., 2006) obtained employer ratings
of work performance at the young
adult assessment and found that hyperactive
participants were rated as
performing significantly more poorly at
work than were control subjects.
Adults who grew up with ADHD are
likely to have lower socioeconomic status
than their brothers or control subjects
in these studies and to move and
change jobs more often. But they also
have more part–time jobs outside their
full–time employment. Employers
have been found to rate these adults as
less adequate in fulfilling work demands,
less likely to be working independently
and to complete tasks, and
less likely to be getting along well with
supervisors. They also do more poorly
at job interviews than do normal individuals
(Weiss & Hechtman, 1993).
And these adults report that they find
certain tasks at work too difficult for
them. Finally, children with ADHD followed
to adulthood are more likely to
have been fired from jobs as well as to
be laid off from work relative to control
participants. In general, adults who
grew up with hyperactivity/ADHD
appear to have a poorer work record
and lower job status than normal adults
(Weiss & Hechtman, 1993). These findings
were recently corroborated in the
Milwaukee follow–up study as well
(Barkley, Fischer et al., 2006).
The above findings pertain to hyperactive/ADHD
children followed into
adulthood, some of whom no longer
have the disorder. In contrast, all
clinic–referred adults diagnosed with
ADHD by definition have the disorder.
For these and other reasons the results
of children with ADHD followed to
adulthood may not be necessarily representative
of clinic–referred adults diagnosed
with the disorder. Though
opinions abound on the topic in trade
books on ADHD in adults (Hallowell &
Ratey, 1994; Triolo, 1999; Wender, 1995),
there is very little research on the occupational
functioning of clinic–referred
adults with ADHD. In one such study
of 172 adults with ADHD, we (Murphy
6 • The ADHD Report © 2007 The Guilford Press