Experimental and Clinical Psychopharmacology © 2010 American Psychological Association

2010, Vol. 18, No. 2, 184 –201 1064-1297/10/$12.00 DOI: 10.1037/a0018059

Psychopharmacology of Aggression in Children and Adolescents With

Primary Neuropsychiatric Disorders: A Review of Current and
Potentially Promising Treatment Options
Robert M. Nevels, Erin E. Dehon, Samuel T. Gontkovsky
and Katrina Alexander Methodist Rehabilitation Center,
Jackson State University Jackson, Mississippi

Research examining the role of pharmacological therapy in the treatment of children and
adolescents with clinical disorders is growing. Clinical disorders that present with comor-
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

bid aggression can add a challenge to treatment. Child and adolescent neuropsychiatric disorders
This document is copyrighted by the American Psychological Association or one of its allied publishers.

associated with aggression include attention-deficit hyperactivity disorder, various mood disorders
and in particular bipolar disorders/pediatric mania, schizophrenia, mental retardation, oppositional
defiant disorder, conduct disorder, and autism spectrum disorders. This review describes the
psychopharmacy to treat these disorders and the aggression that often appears comorbidly.
Existing literature regarding the efficacy and safety of psychotropics for youth with neuropsy-
chiatric disorders also is discussed. In addition, general guidelines for psychopharmacy of
aggression in children and adolescents are presented. Studies reviewed in this article provide
evidence for the use of psychostimulants, alpha-2 agonists, beta blockers, lithium, anticonvulsant
mood-stabilizers, atypical antipsychotics, traditional antipsychotics, and selective serotonin re-
uptake inhibitors in treating pediatric aggression with the choice of medication dependent on
symptomology. Despite increased support for pediatric psychotropic use, there is a need for more
long-term safety and efficacy studies of existing medications and newer, safer, and more effective
agents with fewer side effects for the pharmacological treatment of all childhood disorders in
which aggression is prominent.

Keywords: pediatric psychopharmacology, aggression in children and adolescents, disorders

with comorbid aggression, treatment

Aggression in children and adolescents is a serious and
costly problem that has been vastly examined in the litera-
ture. Research has shown that aggressive children and ad-
olescents tend to exhibit hyperactive and impulsive traits as
well as lower IQs when compared to others their age (Trem-
blay et al., 2004), and that roughly 10 to 20% of individuals
with intellectual disabilities display challenging behavior
such as self-injury and aggression (McClintock, Hall, &
Oliver, 2003). Most children and adolescents who seek
therapeutic intervention present with some type of behavior
problem, and approximately 5 to 14% of preschoolers en-
gage in moderate to severe problem behaviors (Singh et al.,
2006). Although it is expected that many children and
adolescents will display some form of aggression, the out-
ward display of hostility does not necessarily signify the
presence of a psychiatric disorder. Aggressive behavior can
be learned and reinforced in the environment, and through
Robert M. Nevels, Erin E. Dehon, and Katrina Alexander,
Department of Psychology, Jackson State University; Samuel T.
Gontkovsky, Center for Neuroscience and Neurological Recovery,
Methodist Rehabilitation Center, Jackson, Mississippi.
Correspondence concerning this article should be addressed to
Samuel T. Gontkovsky, Center for Neuroscience and Neurological
Recovery, Methodist Rehabilitation Center, 1350 East Woodrow
Wilson, Jackson, MS 39216. E-mail: sgontkovsky@hotmail.com
the processes of socialization children learn what behaviors
are considered socially acceptable. Children whose antago-
nistic behaviors are reinforced and/or those children who
fail to learn appropriate ways of responding in social situ-
ations often will maintain aggressive behaviors throughout
adolescence and adulthood.
The social information processing (SIP) model suggests
that children utilize a three step process when interpreting
information from their environment. They encode social
information, check their schema in efforts to choose an
appropriate behavioral response, and engage in that per-
ceived to be the most appropriate action. This theory posits
that aggressive children and adolescents either may have
difficulty controlling their hostile emotions long enough to
effectively navigate through the information processing
steps or may believe aggression to be an appropriate re-
sponse in social situations more apt to be encoded as pro-
voking and thereby warranting a defensive response
(Werner & Nixon, 2005). Although aggressive children and
adolescents are more likely to harbor feelings of anger,
blame others for social conflicts, and respond to others with
more hostility, this behavior appears to be moderated at
least to some extent by environmental variables. In a study
conducted by Burgess, Rose-Krasnor, Wojslawowicz,
Rubin, and Booth-LaForce (2006), they determined that
friendship and close peer relations tend to alter hostile
behaviors in aggressive children. The researchers found that

184
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION
in emotionally upsetting situations, aggressive children are
less likely to respond antagonistically to their friends.
A large amount of research has focused on the prevention
of and consequences surrounding adolescent aggression. It
is hypothesized by some that hostility in youth manifests
before the age of 5 years and that early problematic parent–
child relationships correlate with aggressive tendencies by
the time the children reach this age. Physical aggression has
been observed in children as young as 17 months, and the
presence of an older sibling in the home increases the
likelihood of hostility in young children below the age of 30
months (Gauthier, 2003). Children who fail to learn socially
acceptable ways of coping with and expressing feelings of
aggression are more receptive to violent and antisocial
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behaviors as adolescents and adults. For example, individ-
This document is copyrighted by the American Psychological Association or one of its allied publishers.
uals reported to be relentlessly hostile as children have been
known to exhibit more alcohol and drug related problems,
demonstrate a predisposition to accidents, and more fre-
quently engage in criminal behavior, attempt suicide, and
perpetrate domestic and family violence (Tremblay et al.,
2004).
Because disruptive behavior problems, characterized by
aggression, noncompliance, and negative emotionality may
persist into adolescence and even adulthood, early diagnosis
and intervention, ideally before school entry, is critical to
obviating later, more serious problems. Assessments across
the four domains of behavioral symptoms, developmental
functioning, parent– child relationships, and broader family
context, for example, stressors, psychopathology, exposure
to violence, and risk factors, are needed (Breitenstein, Hill,
& Gross, 2009). These authors concluded that the most
effective treatment strategies include addressing problems
as they occur, and are structured, goal-oriented, and devel-
opmentally attainable.
Furthermore, neurobiological perspectives of aggression
operate on the premise that certain physiological processes
within the organism contribute to the overt manifestation of
aggression. The precise means by which these internal vari-
ables function independently and collectively as well as in
conjunction with environmental factors to elicit violent re-
sponses remains unclear, but several mechanisms have been
demonstrated by which brain dysfunction can be linked to
aggressive behavior (see Golden, Jackson, Peterson-Rohne,
& Gontkovsky, 1996; Gontkovsky, 2005). Although aggres-
sion may present in many forms, children and adolescents
having a psychiatric disorder oftentimes display proactive
aggression, reactive aggression, or both. Proactive aggres-
sion is that in which the aggressor acts out in hopes of
receiving some type of compensation. Reactive aggression,
on the other hand, is more impulsive, out of control, and
overt in nature (Washburn, McMahon, King, Reinecke, &
Silver, 2004). Several clinical disorders occur comorbidly
with aggression and with one another during childhood and
adolescence. Attention-deficit hyperactivity disorder (ADHD),
mood disorders, and in particular bipolar disorders/pediatric
mania, schizophrenia, mental retardation (MR), opposi-
tional defiant disorder (ODD), conduct disorder (CD), and
autism spectrum disorders (ASD) most notably are charac-
terized by aggressive behaviors (Barkley, 2003; Barkley &
185
Benton, 1998; Conner et al., 2003; Goldman, Genel, Bez-
man, & Slanetz, 1998; Mick, Biederman, Pandina, & Fara-
one, 2003). Disruptive behavior also often is associated with
Tourette’s syndrome in adolescents and has been signifi-
cantly reduced by treatment with anger control training
(Sukhodolsky et al., 2009). The aggression and behavioral
acting-out symptomatology associated with these serious
childhood and adolescent psychiatric disorders has been
subjected to numerous therapeutic efforts at ameliorating or
eliminating such behaviors; primary among these are phar-
macological or medication therapies and psychotherapeutic
or psychosocial/behavioral therapies. Other approaches
with little, some, or no research support have included
megavitamin and orthomolecular supplement therapies, di-
etary therapies, herbal therapies, chelation therapies, and
possibly effective biofeedback (Haber, 2003; Stahl, 2008).
The focus of this review will be on psychopharmacy used to
treat these disorders and the aggression and other acting-out
behaviors that often appear comorbidly.
ADHD and Aggression
The most well-known disorder of childhood and adoles-
cence, ADHD is highly comorbid with mood disorders
(especially pediatric mania), learning disabilities, ASD,
ODD, and CD. Aggression can be manifested by a child or
adolescent with ADHD absent comorbid diagnoses simply
through the phenomenon of behavioral disinhibition or im-
pulsivity in which he or she finds it difficult to inhibit, delay,
or extinguish responses to the environment or to “think
through” behavior to its likely consequences (Barkley &
Benton, 1998). It seems certain now that the prefrontal
cortex (PFC) is essential for the regulation of behavior,
cognition, and attention (Arsten, 2006), and underlying ge-
netic polymorphisms of the dopamine system have been
identified in children with ADHD. In particular the 7-repeat
allele of the dopamine D4 receptor gene, which produces
less efficient receptors and less ability to inhibit PFC cog-
nitions, leads to more externalized behaviors, including
aggression (DeYoung et al., 2006). Furthermore, there is a
continuum of behaviors that are characteristic of such PFC-
mediated behavioral disinhibition and that are not unique to
any one specific disorder, including mania, ODD, substance
abuse, and CD. Indeed, it is difficult to imagine aggression,
disobedience, resistance to societal norms, substance abuse,
or criminal acts on the part of children and adolescents
without reference to behavioral disinhibition. Differentially
diagnosing these disorders is difficult, and the best clini-
cians can fail to determine comorbidity (Preston, O’Neal, &
Talaga, 2008).
The primary psychopharmacological intervention for
children and adolescents with ADHD is psychostimulant
medications, which are approved by the Food and Drug
Administration (FDA) for treating individuals 6 years of age
and older. How well do these medications work to treat
ADHD and, subsequently, any aggressive behaviors that
result from behavioral disinhibition?
There is good news on part of this front. ADHD is the
most successfully treated psychiatric disorder in the history
 186 NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY
of psychopharmacology (Findling, 2008; Haber, 2003;
Julien, Advokat, & Comaty, 2008; Preston et al., 2008;
Stahl, 2008). Up to 78% of patients have an efficacious
response to one or several of the medications used to treat
ADHD and related problems (Haber, 2003; Preston,
O’Neal, & Talaga, 2006). Among these medications are
psychostimulants, such as the methylphenidate derivatives
Ritalin, Focalin, and Focalin XR (dexmethylphenidate, the
twice-as-potent active isomer of methylphenidate), Con-
certa, Ritalin LA, Metadate CD, Methylin ER, and the
Daytrona transdermal patch. The amphetamine-related
drugs Dexedrine, Adderall, Adderall XR, and Vyvanse are
considered stimulants, as well. The latter, lisdexfetamine
(Vyvanse), is the first psychostimulant prodrug (dependent
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on first pass metabolism to become active) and has received
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support in randomly assigned, controlled, double-blind tri-
als for being effective in the treatment of ADHD (Bieder-
man, Krishnan, Zhang, McGough, & Findling, 2007).
Certain antidepressants also are used to treat this disorder,
such as Strattera (marketed to treat ADHD but actually a
NARI antidepressant), Tofranil (imipramine), nortryptiline,
Wellbutrin (buproprion), Wellbutrin SR (buproprion SR),
and Wellbutrin XL. A newer class of alertness drugs used to
treat narcolepsy and sleep–wake schedule disorders, such as
Provigil and Nuvigil, also have been tried with varying
degrees of success (Biederman et al., 2005; see Table 1).
Treatment with the stimulant medications used at appropri-
ate dosing levels results in increased alertness, decreased
activity levels, and decreased impulsivity in 70 to 80% of
those treated (Haber, 2003). Responses to the antidepres-
sants and the newer alertness drugs appear to be signifi-
cantly less robust, occurring in about 37 to 48% of treated
subjects (Preston et al., 2006). The tricyclic antidepressants
(TCAs), such as imipramine and nortryptiline, have fallen
out of favor because of their potential for overdose, cardio-
toxicity, and other detrimental side effects. However, imip-
ramine recently has been remarketed as Tofranil-PM for the
treatment of depression. There is no FDA approval for the
pediatric use of imipramine, but some advertisements seem
to depict a depressed female adolescent. It would not be a
surprise in an era of rising health care costs to see the
remarketing of TCAs, with off-label use increasing for the
treatment of ADHD.
Despite the superior success rate of the psychostimulants,
however, many prescribers now appear to be “defaulting” to
the newer antidepressants and alertness drugs as first-line
treatments because they are not scheduled, or in the case of
Provigil and Nuvigil, are schedule IV and thus are consid-
ered less likely to be abused or to have associated deleteri-
ous or life-threatening adverse events. Liability issues al-
most certainly are playing a role in this prescribing pattern.
Indeed, all stimulant medications, including the nonstimu-
lant drug atomoxetine, received a FDA black box warning
in February 2007 regarding increased risk of cardiovascular
events, exacerbation of preexisting symptoms including in-
creased aggression and hostility, and treatment-emergent
mania and psychosis. It had long been known that all
psychostimulants have abuse potential, could cause central
nervous system and/or cardiovascular problems, and could
be associated with compulsive behaviors, movement disor-
ders, and hallucinations. Furthermore, TCAs were noted to
potentially cause cardiac arrhythmias and buproprion to
potentially lead to seizures (Stahl, 2005).
In addition to treating comorbid depression, the antide-
pressants may afford the advantages of once-a-day dosing,
no need for a triplicate prescription, and longer half lives
thereby providing coverage during the evening hours
(Kelsey et al., 2004; Preston et al., 2006). A meta-analysis
(Polzer et al., 2007) of 14 randomized controlled clinical
trials examining the effects of atomoxetine for treating
aggression or hostile events, however, suggested a possible
increased risk for aggression in children and adolescents
with ADHD treated with atomoxetine (Strattera). Although
not statistically significant, the trend in this meta-analytical
study is worrisome (See Table 1).
Another meta-analysis (Connor, Glatt, Lopez, Jackson, &
Melloni, 2002) identified 28 studies from 1970 to 2001
examining the effect of stimulants on aggressive behavior in
children age 7 to 15 years. Findings of this study revealed a
large reduction in overt and covert aggression in individuals
with ADHD independent of the effects on attention, hyper-
activity, and impulsivity. Stimulants were effective in re-
ducing aggression in CD and ADHD, but not as effective for
comorbid ADHD and CD (see Table 1).
The various psychostimulant medications, however, do
appear at least minimally to be moderately effective in
treating aggression and related problems in social function-
ing that may be associated with ADHD (Haber, 2003; Julien
et al., 2008; Stahl, 2008). Furthermore, the use of stimulants
in the successful treatment of ADHD is associated with a
significantly decreased, as opposed to increased, risk
of substance abuse. This finding is of particular import
because substance abuse itself is associated with increased
aggression and acting out (Barkley, 1998; Julien et al.,
2008). A recent naturalistic controlled 10-year study with
112 participants with ADHD found no significant associa-
tions between stimulant treatment and alcohol, drug, or
nicotine use disorders (Biederman et al., 2008). It is un-
treated ADHD that most often presents with comorbid sub-
stance abuse (Biederman, Wilens, Mick, Spencer, & Fara-
one, 1999; Hechtman & Greenfield, 2003).
The amphetamine and methylphenidate derivatives are
similar in efficacy, response rate, side effects, and cost (see
Table 2). Currently, there exist no clear guidelines to indi-
cate which to initiate treatment of children and adolescents
with ADHD. A cross-over study found many symptoms
commonly attributed to stimulant medication are actually
preexisting characteristics of children with ADHD and im-
prove with stimulant treatment. At the doses investigated,
both dextroamphetamine and methylphenidate caused appe-
tite suppression, and dextroamphetamine caused insomnia.
Negative emotional symptoms were more severe with dex-
troamphetamine than methylphenidate (Efron, Jarman, &
Barker, 1997). A 2002 meta-analysis (Faraone, Biederman,
& Roe, 2002) of four available studies suggested that
Adderall has a small but statistically significant advantage
over the standard-release form of methylphenidate, an ad-
vantage observed for both symptom measures and global

Table 1
Representative Studies of Psychopharmacology of Child and Adolescent Aggression in Primary Neuropsychiatric
Disorders
Reference
Biederman, Krishnan, Zhang,
McGough, & Findling
(2007)
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This document is copyrighted by the American Psychological Association or one of its allied publishers.
Biederman et al. (2005)
Polzer et al. (2007)
Connor, Glatt, Lopez,
Jackson, & Melloni (2002)
Faraone, Biederman, & Roe
(2002)
PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION 187
N Diagnosis Age range Duration Findings and conclusions
230 ADHD 6–12 4 weeks Compared with placebo, treatment with LDX
significantly improved symptoms of
ADHD as shown by improvements in
ADHD–RS–IV and CPRS scores; common
adverse effects were decreased appetite
(39%), insomnia (19%), abdominal pain
(12%), headache (12%), irritability (10%),
vomiting (9%), weight decrease (9%), and
nausea; at treatment end points, ADHD–
RS–IV scores yielded the following ESs:
30 mg LDX (ES ⫽ 1.21), 50 mg LDX
(ES ⫽ 1.34), 70 mg LDX (ES ⫽ 1.60).
LDX (30–70 mg/day) is generally well
tolerated and an effective treatment for
ADHD
246 ADHD 6–17 9 weeks Compared with placebo, treatment with
modafinil significantly improved the core
symptoms of ADHD as shown by
reductions in ADHD–RS–IV School
Version (ES ⫽ 0.69) and Home Version
scores (ES ⫽ 0.61); at the final visit, 48%
of modafinil-treated patients were rated as
much or very much improved in overall
clinical condition compared with 17% of
placebo-treated patients (CGI–I).
Improvements were observed at Week 1
and maintained; common adverse effects
were insomnia (29%), headache (20%),
and decreased appetite (16%); treatment
with modafinil (170–425 mg/day)
improves ADHD symptoms at home and
school and is generally well tolerated
3,152 ADHD 6–17 6–18 weeks In this meta-analysis of 14 randomized
ADHD ⫹ CD controlled clinical trials, aggression or
ADHD ⫹ Dep hostility events occurred more often in
children treated with atomoxetine
compared with placebo; compared to
placebo, adults in a comparator database
treated with atomoxetine were no more
likely to display aggressive behavior;
though not significant, this trend in
children treated with atomoxetine is
worrisome
683 ADHD 7–15 1 day to 7 In this meta-analysis of 28 studies from
CD weeks 1970–2001, treatment with stimulants was
effective in reducing overt (ES ⫽ 0.84)
and covert (ES ⫽ 0.69) aggression in
children with ADHD, but not as effective
if CD was comorbid
188 ADHD 5–17 3–10 weeks In this meta-analysis of four studies,
Adderall had a small but significant
advantage over standard-release
methylphenidate; the advantage was
observed for symptom and global
measures; the effect was significant for
clinician and parent ratings, but not teacher
ratings
(table continues)
 188
Table 1 (continued)
Reference N Diagnosis
Molina et al. (2009) 436
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This document is copyrighted by the American Psychological Association or one of its allied publishers.
Manuzza et al. (2008) 176
Connor, Fletcher, & 150
Swanson (1999)
Ipser & Stein (2007) 823
NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY
Age range Duration Findings and conclusions
ADHD 7–9 8 years After 14 months, children receiving
medication management improved more
than those receiving behavioral
interventions alone or community care; the
methylphenidate ⫹ behavioral interventions
group experienced the best outcomes on
social skills and parent–child relationships;
advantages of medication management and
combination treatment diminished after
interventions stopped; no significant
differences were noted between any of the
initial randomized groups 22 months after
initial treatment phase ended; after 8 years,
the types of treatments received 8 years
before did not predict social functioning,
academic performance, or ADHD
symptoms; medication use within the
previous year was not associated with
significantly better functioning at the 8 year
evaluation; children do not outgrow their
symptoms when they reach adolescence and
treatment in childhood does not make a
difference in the long term compared with
less intense treatment for ADHD
ADHD w/out CD 6–12 Childhood to Analysis revealed a relationship between early
adulthood age initiation of methylphenidate and
nonalcohol substance use disorder;
antisocial personality disorder explained the
relationship between age at first treatment
and later substance use disorder; early age
at initiation of methylphenidate treatment
does not increase the risk for negative
outcomes and may have beneficial long-
term effects
ADHD ⬍18 3–51 weeks In this meta-analysis of 11 studies from
ADHD ⫹ CD 1980–1999, treatment with clonidine
ADHD ⫹ DD revealed a moderate effect size (ES ⫽ 0.42–
ADHD ⫹ TD 0.74) on symptoms of ADHD and ADHD
with comorbid CD, DD, and TD; common
adverse effects were sedation, irritability,
sleep disturbance, low blood pressure drop,
dizziness, and dry mouth; treatment with
clonidine (0.1–0.3 mg/day) demonstrates
moderate treatment effects for ADHD
symptoms, but is not as effective as
stimulants in treating ADHD and is
associated with many side effects
CD 5–19 2–12 weeks In this meta-analysis of 14 studies from
ODD 1985–2006, lithium was the most effective
CD ⫹ ADHD agent in treating disruptive behavior
disorders; psychostimulant therapy showed
a positive trend but not statistical
significance; bupropion and reboxetine
demonstrated efficacy, and anticonvulsants
exhibited marginal effectiveness;
risperidone treatment was associated with
fewer relapses; most subjects in this review
did not have comorbid ADHD; common
adverse effects were sedation, dizziness, and
nausea; treatments were generally well
tolerated and drop out rates were not
significant; targeted psychopharmacy was
often twice as effective as placebo
suggesting efficacy in treating disruptive
behavior disorders
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION 189

Table 1 (continued)
Reference
Biederman, Mick, et al.
(2007)
Ruginvo & Janvier (2005)
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N Diagnosis Age range Duration Findings and conclusions
19 Bipolar 10–17 8 weeks In this prospective open-label trial, aripiprazole
was associated with significant
improvements in YMRS scores; aripiprazole
was not associated with significant weight
gain, but two youths experienced
extrapyramidal symptoms; aripiprazole (5.2–
13.6 mg/day) was generally well tolerated
and may be an effective treatment for mania
in youth; larger, placebo-controlled, double-
blind studies are needed to further this claim
17 Bipolar autism 8.6–18 2–12 weeks Aripiprazole was associated with
psychosis improvements in aggressive symptoms
without adverse effects in four of 16 bipolar/
autism subjects and improvements in two of

four psychotic subjects; adverse effects, such

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as aggression and lability, were common in

smaller children and those taking sedatives;
the efficacy of aripiprazole in treating mood
instability, aggression, and psychosis in
children and adolescents has not been
established; larger, placebo-controlled,
double-blind studies are needed
Pavuluri et al. (2004) 37 Bipolar 5–18 6 months In this prospective open-label study, both Li ⫹
Risp (ES ⫽ 2.82) and DVPX ⫹ Risp
(ES ⫽ 4.36) were associated with significant
improvements on YMRS, CGI–BP, and
CDRS–R; neither Li ⫹ Risp nor DVPX ⫹
Risp were associated with serious adverse
effects; both Li ⫹ Risp or DVPX ⫹ Risp are
promising treatment options for mania and
mixed episodes in children with bipolar I
Schneck et al. (2008) 1,742 Bipolar ⬎15 yrs Up to 1 year In this naturalistic follow-up study, only 5% of
patients who previously had rapid cycling
bipolar met criteria for rapid cycling 1 year
later; antidepressant use was the major
predictor of worse outcome; antidepressant
use is associated with worsened course of
illness in patients with bipolar
Pappadopulos et al. (2006) 3,458 ADHD ⬍19 yrs 7 to 70 days In this meta-analysis of 45 randomized
ODD placebo-controlled trials from 1980–2005,
CD treatment with psychotropic agents revealed
autism or PDD MR/ a moderate effect size (ES ⫽ 0.56) on
subaverage IQ symptoms of aggression: the largest effects
were found with MPH for ADHD with
comorbid disruptive behavior problems
(ES ⫽ 0.90) and risperidone for CD and
subaverage IQ (ES ⫽ 0.90); treatment with
mood stabilizers, SNRIs, antidepressants,
alpha-2 agonists revealed low to moderate
effect sizes (ES ⫽ 0.3–0.5); several
medications can be quite effective in treating
pediatric aggression
Note. ADHD ⫽ attention deficit hyperactivity disorder; LDX ⫽ Lisdexamfetamme dimesylate; ADHD–RS–IV ⫽ ADHD–Rating
Scale–IV; CPRS ⫽ Connors’ Parent Rating Scale; ES ⫽ effect size; CGI–I ⫽ Clinical Global Impression–Improvement; CD ⫽ conduct
disorder; Dep ⫽ depression; DD ⫽ developmental delay; TD ⫽ tic disorders; ODD ⫽ oppositional defiant disorder; YMRS ⫽ Young
Mania Rating Scale; Li ⫹ Risp ⫽ lithium plus risperidone; DVPX ⫹ Risp ⫽ divalproex sodium plus risperidone; CGI–BP ⫽ Clinical
Global Impression Scale for Bipolar Disorder; CDRS–R ⫽ Child Depression Rating Scale; PDD ⫽ pervasive developmental disorder;
MR ⫽ mental retardation; MPH ⫽ methylphenidate; SNRI ⫽ selective-norepinephrine reuptake inhibitors.

ratings but strongest for global ratings. Most of the newer
formulations of methylphenidate, however, are time-re-
lease, and some, like Concerta, have the newer OROS
osmotic-pressure time-release system. Many studies have
found a sizable proportion of patients do well on either
amphetamines or methylphenidate (Preston et al., 2006).
Aside from stimulant medications, alpha-2 agonists like
Catapres (clonidine) and Tenex (guanfacine) also have been
used to treat aggressiveness and irritability associated with
ADHD. FDA approval of INTUNIV, a time-release version of
guanfacine, for the treatment of ADHD in children and ado-
lescents was received on September 6, 2009. In a randomized,
 190 NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY

Table 2
Costs of Selected Brand/Generic Medications Used for Treatment of Aggression
Medication & Dose Quantity Average retail cost Average discount cost
Adderall XR 25 mg 30 $237.78 $134.54
Amph/Salts XR 25 mg 30 $179.98 $107.98
Concerta 18 mg 30 $129.12 $115.30
Ritalin LA 20 mg 30 $127.54 $106.28
Focalin XR 20 mg 30 $151.25 $126.74
Methylphenidate 5 mg 90 $34.09 $10.00
Dextroamphetamine 10 mg 90 $127.94 $34.26
Risperdal 2 mg 60 $537.65 $475.53
Risperidone 2 mg 60 $403.90 $183.82
Seroquel XR 400 mg 30 $418.00 $53.38
Abilify 15 mg 30 $483.00 $431.38
Zyprexa 15 mg 30 $691.00 $623.56
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

Geodon 60 mg 60 $528.00 $483.02

This document is copyrighted by the American Psychological Association or one of its allied publishers.

Perphenazine 4 mg 30/90 $29.00/37.50 $4.00/10.00

Thioridazine 50 mg 30/90 $19.78 $4.00/10.00
Lithium carbonate 300 mg 90/270 $17.99/48.66 $4.00/10.00
Lithium ER 300 mg 90 $52.79 $18.00
Depakote 500 mg 90 $339.68 $291.75
Depakote ER 500 mg 30/90 $108.99/308.99 $98.59
Divalproex 500 mg 90 $240.78 $118.24
Divalproex EC 250 mg 60/120 $103.68/$169.84 $61.99/$111.89
Carbamazepine 200 mg 60 $17.99; XR $69 $4.00; XR $29
Atenolol 25 mg 30/90 $7.48/$21.98 $4.00/10.00
Clonidine patches 1.5 mg 10 $198.39 $93.43
Clonidine 0.2 mg 30/90 $10.99/$26.39 $4.00/10.00
Guanfacine 1 mg 30/90 $15.99/49.29 $4.00/10.00
Prozac 20 mg 30/90 $204.89/614.25 $185.34/$534.22
Prozac 40 mg 30/90 $389.82/$1,161.99 $352.59/$1,007.69
Fluoxetine 40 mg 30/90 $47.69/$142.99 $4.00/10.00
Lexapro 20 mg 30/90 $113.84/$323.51 $95.99/$265.98
Citalopram 40 mg 30/90 $24.99/$29.99 $4.00/10.00
Paroxetine 20 mg 30/90 $31.99/95.99 $4.00/10.00
Setraline 100 mg 90 $87.99 $29.00
Effexor-XR 75 mg 30/90 $278.89/$463.71 $158.36/$323.68
Venlafaxine IR 75 mg 90 $169.49 $40.15
Zolpidem tartrate 10 mg 90 $157.78 $45.97
Note. Prices are averages of multiple regional and national pharmacies. Canadian or other foreign discount pharmacies were not
included. Prices are prior to insurance coverage.

placebo-controlled, flexible-dose study, INTUNIV demon-
strated significant ADHD symptom improvement in pa-
tients with oppositional symptoms and also overall clin-
ical improvement and reduction of symptoms including
anger, defiance, arguing with adults, and loss of temper
(Sallee et al., 2009).
To counterbalance the good news, usually there is some
discouraging news. Although intensive medication manage-
ment with or without behavioral intervention helps with
symptoms and impairments, children with ADHD have a
hard time catching up with their non-ADHD peers as they
leave intensive treatment and become adolescents. Intensive
short-term treatments for children with ADHD, whether
pharmacological management or behavioral interventions or
the combination, may have immediate clinical benefits, but
these disappear over time as these patients return to usual
community care according to results from the Collaborative
Multisite Multimodal Treatment Study of Children With
ADHD (Molina et al., 2009). Known as the MTA study and
begun in the late 1990s, it enrolled 579 children aged 7 to 9
diagnosed with combined type ADHD (see Table 1). Re-
searchers concluded that many children do not outgrow
their symptoms when they reach adolescence, and that a
1-year intensive treatment in childhood does not make much
difference in the long term compared with less intense
treatment for a chronic disorder like ADHD. However, this
study needs cautious interpretation because randomization
was lost after 14 months and the dropout rate at 8 years
should be taken into consideration (Fassler as cited in Yan,
2009).
A comment concerning the use of psychostimulants in the
treatment of ADHD should be noted. On April 22, 2008, a
new American Heart Association statement recommended
that children with ADHD receive a careful cardiac evalua-
tion, including an electrocardiogram (EKG), before starting
treatment with stimulant drugs (Vetter et al., 2008).
In summary, psychostimulants are effective for ADHD
with comorbid aggression and reduce both overt and covert
aggression independently of effects on attention, hyperac-
tivity, and impulsiveness. Methylphenidate and amphet-
amine derivatives have equivalent efficacy. Time-release
versions are preferable. Antidepressants (atomoxetine, bu-
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION
propion, and some older TCAs) can be effective, especially
when there is comorbid depression. Newer alertness drugs,
for example, modafinil, may be useful but, along with
antidepressants, appear to be less effective than stimulants.
Alpha-2 agonists like clonidine and guanfacine also have
been used successfully to treat aggressiveness and irritabil-
ity associated with ADHD. The possibility of cardiotoxicity,
including fatal heart attacks, warrants complete cardiac
workups prior to treatment with psychostimulants.
Comorbid ODD, CD, ADHD, and Aggression
Although both CD and ODD are highly prevalent in
clinical practice, no specific medications have received ap-
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
proval from the FDA for their treatment (Julien et al., 2008).
This document is copyrighted by the American Psychological Association or one of its allied publishers.
Comorbid ODD is reportedly present in 40 to 60% of
children and adolescents with ADHD, whereas rates of
comorbidity with CD range from 21 to 45%. Approximately
50% of all children with ADHD will have a significant
behavioral disturbance (Abikoff et al., 2002). Perhaps the
most important point to made in regard to the psychophar-
macy of CD within this context is that the outward signs of
aggression, antisocial behavior, and disregard for rules are
often seen in the context of other Axis I disorders. These
disorders, although generally treatable, are often undiag-
nosed and may include bipolar disorders, depressive disor-
ders, adjustment disorders associated with significant
situational stress (e.g., divorce of parents), emotional dys-
control secondary to neurological pathology (e.g., closed
head trauma), substance abuse, and/or ADHD. According to
Preston et al. (2006), the only pharmacological treatments for
“pure” CD target aggression, irritability, and impulsivity.
These medications include atypical antipsychotics (e.g., ris-
peridone), selective serotonin reuptake inhibitors (SSRIs), and
clonidine. If ADHD is a comorbid diagnosis, however, stim-
ulants may prove useful. Of interest in this regard is a recent
perspective longitudinal study of 176 White male children
ages 6 to12 years with ADHD but without CD, which
concluded that early age at initiation of methylphenidate
treatment does not increase the risk for negative outcomes
and may have beneficial long-term effects. A relationship
between early initiation of methylphenidate and nonalcohol
substance use disorder was noted, however. Post hoc anal-
yses of this finding revealed that the development of anti-
social personality disorder explained the relationship be-
tween age at first treatment and later substance use disorder
(Manuzza et al., 2008). This is a somewhat puzzling finding,
as many diagnosticians consider CD to be a precursor to
antisocial personality disorder. More research is required to
shed additional light on this issue.
ODD and CD may be conceptualized as representing a
continuum of disturbance rather than isolated constellations
of symptoms. Thus, children with ADHD and ODD have a
high risk of developing CD and almost all youth with CD
will have a prior history of ODD (Barkley, 1998; Pliszka,
Carlson, & Swanson, 2001). At the present time, there is no
specific recommended psychopharmacy for ODD other than
the medications previously mentioned for addressing ag-
gression and other symptoms in CD (e.g., SSRIs, atypical
191
antipsychotics, alpha-2 agonists, beta blockers, and occa-
sionally psychostimulants). Though they generally have
fallen into disfavor, it is worth mentioning that typical
antipsychotics like haloperidol, chlorpromazine, and thio-
ridazine as well as the mood-stabilizer lithium have been
used successfully to treat aggression in CD and pervasive
developmental disorders (Findling, 2003).
When stimulant treatment is deemed ineffective for the
treatment of aggressive symptoms in a child with a dual
diagnosis of ADHD/CD or ADHD/ODD, adjunctive treatment
of clonidine (Catapres) could be considered. Clonidine, al-
though not FDA approved for psychiatric uses, is often used
to help manage the possible side effects (e.g., tics, insom-
nia) of psychostimulants as well as aggression in individuals
with ADHD/CD or ADHD/ODD (Althoff, Rettew, & Hud-
ziak, 2003; Hazell & Stuart, 2003). A meta-analysis re-
vealed that although clonidine is not as effective as stimu-
lants for treatment of ADHD symptoms, it demonstrates
positive treatment effects on symptoms of ADHD. Com-
monly reported side effects of clonidine include sedation,
irritability, sleep disturbance, low blood pressure drop, diz-
ziness, and dry mouth (Connor, Fletcher, & Swanson,
1999). Ipser and Stein (2007) performed a meta-analytical
review of 14 studies involving the pharmacotherapy of
disruptive behavioral disorders in 823 children and adoles-
cents and found that targeted psychopharmacy was effective
and well-tolerated (see Table 1). Investigation of the treat-
ment of a small number of very young (ages 4 to 5 years)
highly aggressive children through a chart review revealed
that psychotropics were used successfully in over three-
quarters of cases (Staller, 2007). Agents included stimulants
and atypical antipsychotics. The severity of the children’s
conduct in conjunction with diagnostic uncertainty seemed
to explain the use of these medications as a generic ap-
proach to treating these severe aggressive behaviors. It was
concluded, however, that there was no clear guidance for
this kind of treatment.
Although results are inconsistent, studies provide support
for lithium, mood stabilizers (anticonvulsants), alpha-2 ago-
nists, stimulants, typical, and atypical antipsychotics for the
treatment of aggression in children and adolescents with
comorbid ADHD, CD, and ODD. Julien et al. (2008) sug-
gested that antipsychotics are more efficacious for treating
agitation than aggression. These authors also viewed stim-
ulants and benzodiazepines as being the least useful agents
for treating pathological aggressiveness alone in young peo-
ple, a conclusion, in our opinion, justified for benzodiaz-
epines but not psychostimulants.
Pediatric Bipolar Disorder, ADHD, and Aggression
The association between early onset bipolar disorder and
ADHD remains controversial. Various researchers and di-
agnosticians have concluded that they are entirely separate
disease entities, that in some children ADHD is a prodrome
of bipolar disorder, that pediatric bipolar is related to but
different from adult bipolar disorder, or that pediatric bipo-
lar together with ADHD constitutes its own serious disease
syndrome. Small sample sizes and retrospective designs in
 192 NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY
many studies limit firm conclusions, and results should be
interpreted with caution (Sachs, Baldassano, Truman, &
Guille, 2000). It should be noted, however, that although
there is symptom overlap, most children with ADHD do not
go on to develop bipolar disorder (Preston et al., 2008;
Stahl, 2005).
Psychopharmacotherapy is the essential treatment of bi-
polar disorder. Lithium and other mood stabilizers, includ-
ing Depakote and Tegretol, as well as newer anticonvul-
sants, such as Lamictal and Trileptal, are the mainstay of
bipolar treatment in children and adolescents. Lithium has
been approved by the FDA for use in children 12 to 18 years
of age. Lithium treats not only mania but also bipolar
depression and may well prevent relapse (Stahl, 2008).
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
There are multiple-hypothesized mechanisms of lithium’s
This document is copyrighted by the American Psychological Association or one of its allied publishers.
mood-stabilizing action, including its inhibition of GSK-3
and its glutamate antagonism at NMDA receptors, both of
which potentially make lithium neuroprotective (Wada,
Yokoo, Yanagita, & Kobayashi, 2005). Response effective-
ness ranges from 50 to 80% in nonrapid cycling bipolar
disorder. Lithium-level-monitoring requirements in con-
junction with doses and dosing schedules, side effects, and
serum chemistry unfortunately often limit its use in pediat-
ric patients. Indeed, lithium has a narrow therapeutic index,
can easily become toxic, and has side effects ranging from
increased thirst, weight gain, and a worsening of acne to
changes in kidney functioning, cardiac conduction abnor-
malities, and leukocytosis (Preston et al., 2006; Stahl, 2005,
2008). Nevertheless, lithium has aggressolytic properties
and generally ameliorates aggressiveness, irritability, and
acting out associated with both the manic and depressive
phases of pediatric bipolar illness (Stahl, 2008).
The anticonvulsants divalproex and carbamazepine both
have shown efficacy in the treatment of bipolar disorder in
adults and are approved for the acute and maintenance
phases of treatment. These and other anticonvulsants appear
to be effective in treating both bipolar and seizure disorders
through the stabilization of cell membrane ion channels,
acting on second messengers intracellularly, potentiating
GABA inhibitory neurotransmission, and inhibiting excita-
tory glutamate transmission (Preston et al., 2006). These
agents also appear to be neuroprotective. Lamictal (lam-
otrigine) is approved for treating bipolar depression in
adults and may even be a better antidepressant than a mood
stabilizer. Its use in treating pediatric bipolar disorder is
complicated by one of its side effects, Stevens–Johnson
Syndrome, a potentially life-threatening rash that occurs
more frequently in children than adults treated with Lam-
ictal. It is, at best, a second- or third-line agent and generally
utilized as augmentation to another mood-stabilizer or an
atypical antipsychotic. Any rash should immediately be
reported to the child’s health care provider, as even indis-
tinguishable benign rashes are more common with Lamic-
tal.
Carbamazepine has been shown to be clinically and sta-
tistically effective in treating children hospitalized for ag-
gression in some small open-label trials; concordant results
have not consistently been found, however, in double-blind,
placebo-controlled studies targeted at reducing aggression
in similar participants. Lithium repeatedly has shown effi-
cacy in treating aggressive behavior in adolescents and
children as has the typical antipsychotic haloperidol. Its
efficacy has not only been demonstrated in pediatric bipolar
disorder but also in many other conditions presenting with
aggressive features (e.g., pervasive developmental disorders
and CD). A reported difference between lithium and Haldol
is that the latter results in children being more manageable
while the former may evoke positive behaviors in children
(Campbell et al., 1984). Haldol also is associated with more
serious side effects (Findling, 2003).
Haloperidol and other typical antipsychotics, including
chlorpromazine, thioridazine, and even molindone have
been found effective in reducing pediatric aggression, in-
cluding that associated with intermittent explosive disorder
(Jensen, Vitiello, Leonard, & Laughren, 1994). These med-
ications, other than haloperidol (usually in psychiatric emer-
gencies), are rarely used anymore due to the revolution in
the use of the atypical antipsychotics.
Only recently have pediatric bipolar disorder treatment
guidelines been issued by pharmacotherapy researchers
(Kowatch et al., 2005). Based on the emerging literature,
Preston et al. (2006) offered treatment guidelines for both
the manic and depressive phases of pediatric bipolar dis-
ease, its associated symptoms (e.g., agitation, aggression,
and psychosis), and its comorbidities (e.g., ADHD and
anxiety).
In mania, according to these experts (Findling et al.,
2003; Geller & Debello, 2003; Kowatch et al., 2000), lith-
ium and divalproex are first-line agents, and therapy with a
combination of mood stabilizers often is necessary to
achieve a good outcome in the majority of children with
mania. Several of the atypical antipsychotics that were FDA
approved as monotherapy in adults for acute and mixed
episodes (both manic and depressed symptoms), olanzapine,
risperidone, quetiapine, and aripiprazole, now have received
either FDA approval or panel recommendation for approval.
Aripiprazole specifically was approved in July 2009 for
maintenance treatment of manic or mixed episodes, and as
augmentation to lithium or valproate, for children/adoles-
cents ages 10 to 17 years with bipolar disorder. It also is
approved for the acute treatment of manic and mixed epi-
sodes associated with bipolar disorder with or without psy-
chotic features in pediatric patients age 10 to 17 years. The
FDA approved Risperdal in July 2009 to treat schizophrenia
in adolescents aged 13 to 17 years and for the short-term
treatment of manic or mixed episodes in bipolar disorder in
children and adolescents aged 10 to 17 years. Risperdal is
the first FDA-approved atypical antipsychotic to treat either
disorder in these age groups. Also in June 2009, Seroquel,
Geodon, and Zyprexa were voted to be “acceptably safe”
and effective for the treatment of teenagers and children
with schizophrenia and bipolar disorder by the FDA Psy-
chopharmacologic Drugs Advisory Committee. These
pending approvals were for Seroquel (quietiapine) for the
acute treatment of schizophrenia in adolescents 13 to 17
years, and acute treatment of pediatric bipolar mania for
ages 10 to 17 years; Geodon (ziprasidone) for acute treat-
ment of manic or mixed episodes associated with bipolar
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION
disorder, with or without psychotic features in children and
adolescents ages 10 to 17 years; and Zyprexa (olanzapine)
for the acute treatment of manic or mixed episodes associ-
ated with bipolar disorder in adolescents 13 to 17 years, and
acute treatment in schizophrenia in adolescents 13 to 17
years. The studies resulting in all of these approvals were
only 4 and 6 weeks in duration. The FDA usually follows
such panel recommendations with an approval for the stated
indications. It is likely that both the atypical antipsychotic,
Invega (palideridone), with the OROS time-release system,
and Fanapt (iloperidone), both approved for the treatment of
schizophrenia in adults, will receive similar adult and pedi-
atric approval in the near future. Saphris (asenapine), an-
other atypical antipsychotic, approved for the treatment of
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
both schizophrenia and bipolar I disorder in adults in Au-
This document is copyrighted by the American Psychological Association or one of its allied publishers.
gust 2009, likely also will receive future pediatric approval.
Aripiprazole, as noted above, is approved for treatment of
bipolar disorder in children and adolescents aged 10 to 17
years, but the efficacy of aripiprazole in treating children
and adolescents with bipolar disorder is not entirely consis-
tent in the literature. Aripiprazole was associated with rapid
improvements of manic symptoms in 19 youth with bipolar
disorder, and adverse effects were well tolerated for most
subjects with few overall adverse effects (Biederman, Mick,
et al., 2007).
Another study using aripiprazole in the treatment of chil-
dren with autism, bipolar disorder, and psychosis reported
that only four of 16 patients demonstrated improvement in
aggressive behavior without significant adverse effects. The
most common side effect was increased aggression and
lability (Ruginvo & Janvier, 2005). The heterogeneity of
disorders in this study limits the conclusiveness of its find-
ings.
Investigations also have looked at combination therapies.
One study (Pavuluri et al., 2004) compared the combina-
tions divalproex sodium plus risperidone (DVPX ⫹ Risp)
and lithium plus risperidone (Li ⫹ Risp). Results revealed
that both are equally effective and safe for treatment of
mania and mixed episodes in children with bipolar I disor-
der.
In the depressed phase, antidepressants should be used
cautiously because of the high risk of bipolar switching.
Adequate time for mood stabilization from a mood stabi-
lizer or atypical antipsychotic should be allowed before an
antidepressant is initiated. Indeed, recent research has
shown that many patients fare better on a mood stabilizer as
monotherapy without the addition of an antidepressant.
Schneck and colleagues (2008) reported new data from the
NIMH-sponsored Systematic Treatment Enhancement Pro-
gram for Bipolar Disorder (STEP–BD) study, in which
about one third of the patients had rapid cycling bipolar
disorder (defined as four or more episodes in a year). These
patients also had more recurrences in the 1-year follow up.
Only 5% of these rapid-cycling patients continued to meet
that definition at the 1-year follow up, either because of
appropriate treatment in STEP–BD or because of natural
disease course. The major predictor of worse outcome was
antidepressant use, which about 60% of the patients re-
ceived, most often accompanied by mood stabilizers. This
193
study was far larger (N ⫽ 1,742) than any prior investiga-
tion of its kind. It also was prospective, unlike all but one
prior observational study (Coryell et al., 2003). Moreover,
unlike that investigation, this STEP–BD study showed that
antidepressants are associated with worsened course of ill-
ness even after adjustment for severity of baseline depres-
sion. Others, such as Preston et al. (2006), previously had
recommended that antidepressant therapy generally should
be considered time limited, if used at all. It should be noted
that Symbyax, a combination of olanzapine and fluoxetine,
also is available for bipolar depression.
For severe agitation and sleep disturbance, the short-term
use of a benzodiazepine such as lorazepam or clonazepam,
can be considered. Atypical antipsychotics should be pre-
ferred, however, because of the possibility of behavioral
disinhibition with the benzodiazepines (Julien et al., 2008;
Preston et al., 2006). In our view, zolpidem (Ambien),
eszopiclone (Lunesta), or other sedative-hypnotics could be
considered on a strictly short-term basis for insomnia. Of
course, if psychosis is present, atypical antipsychotics are
preferred. These agents likely would decrease aggression
whether or not associated with psychosis.
If ADHD is comorbid with bipolar disorder, mood stabi-
lizers should be the initial treatment. Once the child is
stable, psychostimulants may be added gradually. If anxiety
is present, SSRIs can be used with careful titration and
monitoring. Although not stated by Preston et al. (2006),
benzodiazepines may be used with caution in the short term,
as the SSRIs and SNRIs (Effexor, Effexor XR, Cymbalta,
and now Pristiq [desvenlafaxine, the active, completely
renally excreted metabolite of venlafaxine in the OROS
time-release formulation]), most of which have been ap-
proved to treat various anxiety disorders in adults, all ini-
tially may increase anxiety. Buspar (buspirone) also might
be a long-term option because of its low abuse potential.
Prescribers must remain aware of the possibility for abuse
of the benzodiazepines, although the risk appears to be
lower than previously thought so long as these drugs are
prescribed appropriately, with careful patient monitoring.
Overdose precautions are in order for both Effexor and
Cymbalta, as some recent anecdotal reports have suggested
the therapeutic indexes of these agents may be lower than
previously believed.
All of the mood stabilizing medications and many of the
other psychotropic medications are typically dosed on an
mg/kg/day basis. Thus, prescribers must remain aware of
and carefully follow these specified parameters. This infor-
mation is found in virtually all prescribing guides.
Although anticonvulsants and atypical antipsychotics
have been shown effective in treating adult bipolar disorder,
the treatment of this disorder in children is complicated by
side effects. Lithium has both antimanic and depressolytic
properties in the treatment of pediatric bipolar disorder but
has a narrow therapeutic index, cardiotoxicity, and other
short- and long-term side effects. For the treatment of ma-
nia, divalproex or lithium still appear to be neck and neck
for the treatment of choice, and atypical antipsychotics are
preferred for severe agitation and sleep disturbance. Lith-
ium ⫹ risperidone or divalproex ⫹ risperidone are promis-
 194 NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY
ing treatments for mania and mixed episodes in children
with bipolar I. The cost of these medicines is increasingly a
concern (see Table 2). These medications, as well as others
previously discussed, should be accompanied by psycho-
therapy to maximize outcomes.
Autism/MR and Aggression
There presently exists no medication treatment that is
specific to any of the ASDs or any other pervasive devel-
opmental disorder. Certain medications have been shown to
be beneficial, however, in the treatment and/or control of
associated symptoms of these disorders, including aggres-
sive behaviors (Preston et al., 2006). In particular, atypical
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
antipsychotics (e.g., risperidone, ziprasidone, olanzapine,
This document is copyrighted by the American Psychological Association or one of its allied publishers.
etc.) have become indispensable in the treatment of a variety
of symptoms in autism. They are frequently used to treat
irritability and associated behaviors including aggression
and self-injury. Risperdal (risperidone) orally disintegrating
tablets now have FDA approval for treatment of the irrita-
bility associated with ASDs. These agents also may be
efficacious for hyperactivity and stereotyped behavior, but
they can give rise to significant adverse events, including
weight gain, insulin resistance, hyperlpidemia, prolonged
cardiac conduction times (QTc prolongation), and possibly
extrapyramidal side effects (EPS), and neuroleptic malig-
nant syndrome (Posey, Stigler, Erickson & McDougle,
2008). The reported high comorbidity (up to 85% in some
studies) of ASDs with MR and other pervasive develop-
mental disorders (PDDs) necessitates conceptualizing the
psychopharmacy of these conjointly.
Medications most frequently used for children with ASDs
include SSRIs, typical antipsychotics like Haldol (haloper-
idol), older mood-stabilizers like Depakote (sodium val-
proate) and Tegretol (carbamazepine) or newer mood-sta-
bilizers like Trileptal (oxcarbazepine) and psychostimulants
like Ritalin (methylphenidate) or Adderall (mixed amphet-
amine salts). The atypical antipsychotics, in particular
Risperdal (risperidone), may be used as well. Abilify also is
being frequently prescribed for children with ASDs because
of its more benign appearing side effects profile. There still
may be some role for lithium in the treatment of agitation
and aggression in ASD and other PDDs, but its use is
complicated by its narrow therapeutic index and potential
adverse events profile (e.g., becoming lithium toxic due to
dehydration, cardiotoxicity, decreased renal functioning,
weight gain, polyuria, polydipsia, intentional tremors, hy-
pothyroidism, etc.). Sedative-hypnotics, like Ambien (zol-
pidem) and Rozerem (ramelteon), sometimes are used in
rare situations for occasional sleep problems (Exkorn,
2005).
Research shows that SSRIs can decrease obsessive pre-
occupations, stereotypy, self-injury and aggression as well
as anxiety and depressed mood seen in ASDs (Fukuda,
Sugie, Ito, & Sugie, 2001; McDougle et al., 1996). How-
ever, citalopram was found to have no effect on stereotypy
in subjects with autism and with severe repetitive move-
ments (King et al., 2009). A small, largely imperfect liter-
ature suggested that beta blockers, such as atenolol and
alpha-2 agonists, including clonidine and guanfacine, also
may have some role for treating such symptoms (Cohen,
Tsiouris, & Pfadt, 1991; Preston et al., 2008). Opioid an-
tagonists like naltrexone and naloxone also have been tried
in this population and have shown some ability to reduce
restlessness and improve attention, but results have been
inconsistent (Campbell et al., 1993; Kolmen, Feldman,
Handen, & Janosky, 1995). More research is needed on the
management of all of these target symptoms, both for newer
agents (e.g., atomoxetine) and for established psychoactive
medicines (Aman, 2004).
Stimulants have demonstrated positive effects on atten-
tion, concentration, and decreased hyperactivity in ASDs
and MR as they do with patients with ADHD. Recently, a
number of small trials suggested that methyphenidate does
have a role in the management of hyperactivity in children
with ASDs. Santosh, Baird, Pityaratstian, Tavare and Grin-
gras (2006) retrospectively and prospectively studied chil-
dren with comorbid ASD and ADHD as well as children
with ADHD but without ASDs who received standard treat-
ment with methyphenidate from a specialist center. A com-
bination of standardized and novel outcome tools was used
to allow both an exploratory retrospective study of 174
children followed by a prospective study of an additional 52
children. After treatment with methylphenidate, the subjects
in both groups showed statistically significant improve-
ments in target symptoms of hyperactivity, impulsivity,
inattention, oppositionality, aggression, and intermittent ex-
plosive rage. The Clinical Global Impression-Improvement
and Efficacy index (Guy, 1976) measures also improved in
each group. In both the retrospective and the prospective
components, there was no statistically significant difference
in the degree of improvements between each group. More
important, neither tics nor repetitive behaviors worsened in
either group. Children in the ADHD-only group who were
prescribed stimulants experienced significant nausea, giddi-
ness, headaches, and sleep difficulties, whereas sleep diffi-
culties were the only side effect that emerged in children in
the comorbid ASD/ADHD group. Results supported find-
ings from smaller studies demonstrating that children with
autism and ADHD can respond as well to stimulants as
children with ADHD alone. Research is still sparse in this
area, however, and it should be noted that, in addition to
their other well-noted side effects, these agents can increase
anxiety and agitation in children with ASDs and those with
MR (Jepson, 2007; Preston et al., 2006).
Children with ASDs and MR have a wider variation of
responses to medications than normally developing children
(Exhorn, 2005). Thus, any treatment plan requires regular
monitoring to assess for a medication’s effectiveness and
toxicity. Furthermore, as children and adolescents with
these disorders often present with other medical comorbidi-
ties (e.g., asthma, diabetes, hyperlipidemia, etc.) all physi-
cians/prescribers involved in the care of these individuals
must be informed of any modifications to their medication
regimens. Parents should keep written records of all of their
children’s medications as well as their reactions to these
agents. In addition, objective records of their children’s
behaviors (e.g., frequency of self-injuries, temper tantrums
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION
per day, aggressive acts toward others, sleep patterns, ability
to focus/concentrate, etc.) are extraordinarily useful in fa-
cilitating successful intervention. Properly monitored and
flexible prescribing of medications improve the success of
behavioral/psychosocial interventions (Haber, 2003; Julien
et al., 2008).
Aggression in children with MR, when uncontrolled,
frequently results in admission to highly restrictive environ-
ments, such as units of state psychiatric facilities (Benson &
Aman, 1999). The medications most frequently used in
addressing the aggression of children and adolescents with
MR are the atypical antipsychotics, especially risperidone,
which was approved by the FDA in October 2006 for the
treatment of irritability in children with autism. One long-
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
term open-label study of risperidone in children with severe
This document is copyrighted by the American Psychological Association or one of its allied publishers.
disruptive behaviors and below-average IQ found favorable
results (Findling et al., 2004). An investigation by Croonen-
berghs and colleagues (2005) strengthened previous find-
ings by means of a 1-year open-label study of risperidone in
children with disruptive behavior disorders and subaverage
IQ. Risperidone was found to substantially reduce severity
of disruptive behaviors. Intervention generally was well
tolerated; only 9% of participants discontinued treatment
due to adverse effects and a high-completion rate (73%) was
noted. Risperidone treatment also was associated with im-
proved social skills and cognitive functioning. The most
frequently experienced adverse effects were somnolence,
rhinitis, and headache. Weight gain was most common in
the first few months of treatment, but little change in weight
was observed after 6 months. More important, this investi-
gation provided evidence for the long-term efficacy and
safety of risperidone in the treatment of children.
Several randomized, double-blind, placebo-controlled tri-
als have demonstrated that risperidone is modestly effica-
cious in reducing aggressive behaviors, hyperactivity, and
self-stimulatory behaviors (Pandina, Aman, & Findling,
2006; Pandina, Bossie, Youssef, Zhu, & Dunbar, 2007). A
high rate of adverse reactions, including somnolence (52%),
headache (38%), weight gain (36%), anxiety, sad mood,
dystonias, gynecomastia, and gastrointestinal side effects,
also was noted. These detrimental effects are in addition to
those reported above for the atypical antipsychotics, in
general.
We find it interesting that there has been one small (N ⫽
18) open-label study (Erickson et al., 2007) examining the
use of Namenda, an NMDA glutamate receptor antagonist
prescribed in the treatment of Alzheimer’s disease, in chil-
dren with autism. Results revealed modest improvements in
the areas of social withdrawal and hyperactivity, including
aggressiveness. There were multiple-side effects, including
seizures, in over a third of the patients. With the absence of
larger trials, no firm conclusions can be drawn concerning
either the safety or efficacy of Namenda in the treatment of
children with ASDs.
Several medications have been found to be effective in
the treatment of ASDs. SSRIs are used most frequently
because of their effect on stereotypy, self-injury, depression,
and aggression. Moreover, SSRIs are effective treatments
for aggression in children with MR. The atypical antipsy-
195
chotics, especially risperidone, have become indispensable
in the treatment of irritability and aggression associated
with autism. Stimulants, such as methyphenidate, yield im-
provement in ASD symptoms, specifically reducing both
hyperactivity and impulsivity.
Schizophrenia and Aggression
Recent research has indicated that early onset schizophre-
nia is more severe than adult onset schizophrenia and that
25% of children and adolescents with early onset schizo-
phrenia spectrum disorders have a history of aggression or
legal problems. In addition, 45% of youth with schizophre-
nia and 54% of those with schizoaffective disorder have
been hospitalized (Frazier et al., 2007). The early onset
schizophrenia spectrum disorders also share features with
other disorders, leading to children with early onset schizo-
phrenia often having received previous diagnoses, such as
ADHD, MDD, and bipolar disorder. In many cases, these
children have been prescribed multiple medications and
therefore require a comprehensive evaluation by a clinician
well-versed in early onset schizophrenia. In an investigation
of 119 children and adolescents with schizophrenia, schizo-
phreniform, or schizoaffective disorder, Frazier and col-
leagues (2007) found that schizophrenia onset prior to the
age of 18 years occurs in approximately 0.5% of cases and
very early onset prior to the age of 13 years occurs in
approximately 0.002% of cases.
Evidence concerning the efficacy and safety of the atyp-
ical antipsychotics in children and adolescents with schizo-
phrenia is limited. A recent review by Toren, Ratner, Laor
and Weizman (2004) assessed the published data on the use
of atypical antipsychotics in children and adolescents with
schizophrenia alone and with comorbid disorders to estab-
lish formal benefit-risk guidelines for clinicians. Of note,
risperidone, olanzapine, and clozapine were found to be
effective in the treatment of aggression and mania. Findings
suggest that risperidone, and possibly also olanzapine, may
be the drugs of choice in children with comorbid tic disor-
ders. Ziprasidone was noted to possess some monoamine
reuptake inhibition properties and may be administered as
an augmenting agent in children and adolescents with
schizophrenia and comorbid anxiety and mood disorders.
Compared with the typical antipsychotics, the atypical
drugs were found to be more effective as well as better
tolerated and lead to better patient adherence. More impor-
tant, the atypical antipsychotics were found to have a lower
propensity to induce extrapyramidal symptoms and a poten-
tial (shown so far only in adults) to improve cognitive
function and inhibit suicidal behavior, in particular cloza-
pine. Yet, the adverse effects associated with these agents,
especially weight gain, may lead to noncompliance in the
young population. In children and adolescents receiving
clozapine, olanzapine, and quetiapine (but not ziprasidone,
which does not have a pro-appetite effect), particularly
those with obesity or a family history of diabetes mellitus,
fasting blood glucose and lipid levels must be monitored
frequently. Weight gain might be better controlled when the
children and their parents are properly informed about this
 196 NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY
adverse effect and diet is regulated. Another major disad-
vantage of the atypical antipsychotics, especially risperi-
done, is their association with hyperprolactinemia, which
can lead to hypogonadism-induced osteoporosis, galactor-
rhea, gynecomastia, irregular menstruation, and sexual dys-
function, all seen also with typical antipsychotics. Other
atypical antipsychotics, namely olanzapine and ziprasidone,
have been reported to be prolactin-sparing in adults but may
not be completely devoid of hyperprolactinemic effects in
children and adolescents. Thus, prolactin levels should be
assessed routinely in young patients treated with atypical
antipsychotics. Furthermore, children and adolescents with
hyperprolactinemia-related effects should be switched to a
prolactin-sparing agent, such as quetiapine. All atypical
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
antipsychotics may induce sedation, and they are not devoid
This document is copyrighted by the American Psychological Association or one of its allied publishers.
of extrapyramidal symptoms (especially risperidone). Clo-
zapine now is rarely used except in the most refractory of
cases because of the possibility of agranulocytosis and the
frequent blood monitoring requirement. In addition, this
agent causes extreme metabolic syndrome.
In an open-label study examining the effects of clozapine
on aggressive behavior in 20 children and adolescents
(ages 8 to 15 years) with treatment-refractory schizophrenia,
a clinically significant improvement in aggressive behaviors
was noted following 6 months of treatment, and all partic-
ipants were rated as much improved on the Clinical Global
Improvement Scale. Although patients were receiving psy-
chotropic medications other than clozapine and conclusions
are limited secondary to the lack of a control group, it is
relevant that decreases in aggression allowed patients to be
discharged to a less restrictive setting (Kranzler et al.,
2005).
The use of typical antipsychotics has been limited to
patients who are resistant to atypical antipsychotics, intol-
erant to their adverse effects, or require injections or depot
preparations. (One of the newer agents now is available in
depot form, Risperdal Consta, and all of the atypicals are
available in fast-acting IM formulations, which may further
obviate the use of typical agents.) Additional double-blind,
placebo-controlled trials and long-term safety assessments
are needed before definitive conclusions can be reached
about the place of atypical antipsychotics in the therapeutic
armamentarium of childhood-onset schizophrenia and espe-
cially the treatment of associated aggression. One wonders
if the results of the recently completed CATIE (Clinical
Antipsychotic Trials of Intervention Effectiveness) and
CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study) studies, which found the older typical
antipsychotics, especially perphenazine, dosed at lower than
usual levels to be just as effective at treating adult schizo-
phrenia as the newer atypical agents, will affect clinicians’
prescribing patterns for children and adolescents (Tandon,
Carpenter, & Davis, 2007). Newly published findings from
the CATIE investigation indicate that atypical antipsychot-
ics were no more effective in reducing violent behavior in
schizophrenia patients than was perphenazine. Perphena-
zine, a first generation antipsychotic, was superior to quiet-
iapine, one of the second-generation atypical antipsychotics,
in reducing violence in patients who completed 6 months of
treatment on their assigned medications. The authors of this
study suggested that quietiapine’s anticholinergic and sedat-
ing properties might be disinhibiting, especially when com-
bined with mood-altering substances that also are disinhibi-
tory (e.g., alcohol, benzodiazepines, opioid analgesics, etc.).
Especially relevant to children and adolescents is that treat-
ment was not effective for adults who had histories of CD
and antisocial behavior as children, suggesting that their
violence was not caused by psychosis and therefore was not
responsive to antipsychotic medication (Swanson et al.,
2008).
Childhood onset schizophrenia can be treated with atyp-
ical and typical agents; however, patient safety is of concern
and adverse side effects of atypical drugs are numerous. The
atypical antipsychotics have a lower propensity to induce
extrapyramidal symptoms but are associated with hyperp-
rolactinemia, prolonged QTc intervals, and metabolic syn-
drome. Typical antipsychotics are used in patients who are
resistant to atypical antipsychotics, intolerant to their ad-
verse effects, or require injections or depot preparations.
This is likely to change with recent evidence for equal
effectiveness and similar side-effect profiles for typical ver-
sus atypical antipsychotics. Moreover, cost is a major con-
cern for many patients (see Table 2).
General Guidelines for Psychopharmacy of
Aggression in Children and Adolescents
There is no established algorithm for the pharmacological
treatment of aggression in children and adolescents; the
choice of medication generally depends on the underlying
symptoms (Preston et al., 2006; Stahl, 2008). For instance,
if the child or adolescent has ADHD and the aggression
stems from impulsivity, the use of psychostimulants (e.g.,
amphetamines or their mixed salts, Adderall, Adderall XR;
methylphenidate in its various formulations, preferably
time-released; e.g., Ritalin LA, Metadate CD, Focalin, Con-
certa; or the newer prodrug, lisdexfetamine [Vyvanse]) can
be helpful. If the aggression is marked by hyperarousal to
environmental stimuli, treatment with alpha-2 agonists (e.g.,
clonidine [Catapres] or guanfacine [Tenex or INTUNIV,
time-release version]) or beta blockers (e.g., atenolol or
propranolol, which decrease norepinephrine levels or block
norepinephrine, lower blood pressure and have an overall
calming effect) could be useful. Clonidine comes in a trans-
dermal patch that can be changed every 3 to 5 days for
maintenance of steady serum levels. Initially, sedation oc-
curs in the majority of children treated with alpha-2 agonists
and beta blockers. An EKG also should be done in fol-
low-up treatment, because these medications may prolong
cardiac conduction (Hagerman, 1996; Hagerman, 1999;
Hagerman et al., 1994).
If the aggression is the result of pediatric bipolar mania,
it is appropriate to use either mood-stabilizers, such as
divalproex sodium (Depakote, Depakote ER), carbamaz-
epine (Tegretol, Carbatrol), or oxcarbazepine (Trileptal).
Topiramate (Topamax) may be suitable if weight gain
would be of significant concern, as Topamax may result in
weight loss. Atypical antipsychotics, such as risperidone
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION
(Risperdal), ziprasidone (Geodon), aripiprazole (Abilify), or
olanzapine (Zyprexa), which are mood-stabilizing, may be
most appropriate if psychosis has emerged. Both of these
classes of agents require initial medication workups and
careful follow up of electrolytes, complete blood counts,
liver function studies, glucose levels, and lipid panels. Al-
most all of the atypicals are associated with metabolic
syndrome, which involves weight gain, insulin resistance,
hyperlipidemia, and the onset of diabetes mellitus. Most
also can result in QTc prolongation. Thus, pretreatment
cardiac workups are justified. One exception to many of
these side effects may be aripiprazole, but akathisia and
other EPS phenomena can occur with Abilify.
In the case of certain mood-stabilizers, including lithium,
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
Tegretol, and Depakote, serum drug levels require frequent
This document is copyrighted by the American Psychological Association or one of its allied publishers.
evaluation on their initiation and periodic monitoring over
time. Weight, blood pressure, and EKG should be assessed
routinely with prescription of most of the atypical antipsy-
chotics and also with many of the mood-stabilizers. Cogni-
tive functioning, including memory and perception, and
motor skills also should to be evaluated periodically (Pres-
ton et al., 2006; Stahl, 2005).
If anxiety is the primary presenting problem and aggres-
sion occurs in situations that escalate anxiety, treatment
with SSRIs, such as fluoxetine (Prozac), sertraline (Zoloft),
paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Cel-
exa), or escitalopram (Lexapro) should be considered. In
many cases, SSRIs will function to decrease anxiety, ag-
gression, and obsessive/compulsive behaviors and will reg-
ulate irritability or minor mood fluctuations (Hagerman,
1999).
Another consideration in any psychopharmacy of chil-
dren is that they have different metabolic responses to
medications than adults. Preadolescent children also may
have either faster or slower metabolism of certain medica-
tions than adults and even adolescents (Preston et al., 2006).
Prescribers must consider these metabolic differences when
determining appropriates dosages and schedules. Again,
dosing usually is provided in mg/kg. Furthermore, changes
in weight and height along with other previously mentioned
parameters should be carefully measured and monitored
with psychostimulant therapy.
A review of the literature from 1980 to November of
2005 (Pappadopulos et al., 2006) yielded 45 randomized,
placebo-controlled trials that addressed the treatment of
aggression as either a primary or secondary outcome
variable. Effect sizes, as assessed by Cohen’s d, were
calculated for studies that met inclusion criteria (see
Table 1). These authors concluded that a growing liter-
ature supports the use of certain medications for manag-
ing pediatric aggression and that future studies should
distinguish between impulsive and predatory aggression
as well as examine the efficacy of agents over longer
treatment periods.
No review of psychopharmacy in children and adoles-
cents would be complete without recognizing that there still
is not enough supportive data for most pediatric psycho-
tropic use. The above review of 45 studies by Pappadopulos
and colleagues (2006) is encouraging, but more research
197
clearly is needed. Especially alarming and most critical are
the lack of efficacy and safety studies. There virtually is no
evidence for the long-term effectiveness and safety of the
use of most of these medications in this population (Preston
et al., 2006). Paradoxically, despite recent bad press, the use
of stimulants in the treatment of ADHD is the sole excep-
tion (Preston et al., 2008; Stahl, 2008). There is solid
support for treatment effectiveness of pediatric obsessive-
compulsive disorder (OCD) with SSRIs, and several SSRIs
(i.e., Luvox, Prozac, and Zoloft) have received FDA ap-
proval for this indication. Prozac remains the only antide-
pressant approved for treatment of depression in children 6
years of age and older (Julien et al., 2008; Preston et al.,
2006). However, Lexapro (escitalopram) received FDA ap-
proval on March 20, 2009 for treating depression in ado-
lescents 12 to 17.
Antidepressant Black Box Warning
Pertinent to a review of pediatric aggression and its
treatments, the FDA review of combined studies indicated
that antidepressant interventions double the risk of suicid-
ality and aggression in children and adolescents. On
March 22, 2004, the FDA issued a public health advisory
asking manufacturers to include a warning statement that
recommends close observation of adult and child patients
(U.S. Food and Drug Administration, 2004b, para. 1). This
FDA action followed a hearing in February 2004, which
heard testimony from parents, researchers, and others on
suicide and antidepressant medication (U.S. Food and Drug
Administration, 2004, February). Reviewing 24 clinical tri-
als dating back to 1983, five different conditions (i.e., MDD,
16; OCD, 4; generalized anxiety disorder, 2; seasonal af-
fective disorder, 1; and ADHD, 1), and nine different anti-
depressants (i.e., Prozac, Zoloft, Remeron, Paxil, Effexor,
Celexa, Wellbutrin, Luvox, and Serzone), Matthew Rudor-
fer of the National Institute of Mental Health (NIMH)
concluded that most of the trials were flawed and not
designed to capture a signal for suicidality or aggression.
Although there was concern about a 2 to 3% increase in
suicidality and aggressive impulses with these treatments,
depression itself carries a 15% risk of completed suicide if
left untreated. Dr. Rudorfer was concerned the black box
warning would impede access to treatments, and hypothe-
sized that children on antidepressants may have been more
honest about their feelings (Vedantam, 2004). In October
2004 the FDA required manufacturers of all antidepressants
to add black box warnings to their product labeling (U.S.
Food and Drug Administration, 2004a, para. 1).
Conclusions: Multimodal Treatment and Future
Pharmacotherapy
The current treatment of aggression in children and ado-
lescents with primary neuropsychiatric disorders leaves
thoughtful clinicians in three places. First, psychopharmacy
should never be considered monotherapy for any child or
adolescent with aggression and comorbid neuropsychiatric
disorders. Treatment should be multimodal. Psychosocial
 198 NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY
interventions, including environmental restructuring, behav-
ioral and family therapies are indispensable elements of
successful treatment with this population. And, if possible,
these interventions should be tried first and evaluated care-
fully before initiation of psychopharmacology. Second, the
prevention of aggression developing and becoming life
changing in its consequences calls for early diagnosis and
intervention, ideally before school entry. Assessments in-
cluding developmental functioning, parent– child relation-
ships, family context issues like stressors, psychopathology,
exposure to violence, and other risk factors, are needed.
Finally, in addition to the need for more long-term safety
and efficacy studies of existing medications, it is obvious
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
that we need newer, safer, and more effective agents with
This document is copyrighted by the American Psychological Association or one of its allied publishers.
fewer detrimental side effects for the pharmacological treat-
ment of all childhood disorders in which aggression and
hostility are prominent features. The pharmaceutical indus-
try is responding to this need, with prompting from the
FDA, NIMH, and the public. A number of new treatment
trials currently are underway, and there are novel and po-
tentially more effective and adverse-free agents in clinical
phase I, II, and III trials of many pharmaceutical companies.
These investigations include GSK-3 inhibitors, “super” tri-
ple reuptake inhibitors, glutamate antagonist/agonist anxio-
lytics and antipsychotics, agents with specific glutamate
receptor (AMPA [ampakines], NMDA, aspartate, mGlu,
and kainate) and GABA receptor (GABA-A; GABA-B;
GAT) targets in the treatment of mood disorders with ag-
gression, nicotinergic antipsychotics, CRF inhibitors, M1
receptor agonists, new monoamine partial agonists, inverse
and partial inverse agonists, combinations of existing med-
ications with different pharmacodynamics, agents that more
directly increase brain-derived neurotrophic factor, even the
antimanic, aggressolytic effects of tamoxifen and other on-
cology drugs due to their inhibition of PKC. Many of these
mechanisms of action are multiply co-occurring (Julien et
al., 2008; Preston et al., 2008; Stahl, 2008). Alternate routes
of administration, including intravenous, also are demon-
strating rapid and potentially lasting effects on depression,
mania, and associated irritability and aggression. Newer
time-release versions of every class will soon receive ap-
proval. The future psychopharmacological treatment of ag-
gression and disorders with which it frequently is comorbid
in children and adolescents holds the promise of agents and
combinations of agents with increased efficacy and safety.
References
Abikoff, H. B., Jensen, P. S., Arnold, L. E., Hoza, B., Hechtman,
L., Pollack, S., . . . Wigal, T. (2002). Observed classroom be-
havior of children with ADHD: Relationship to gender and
comorbidity. Journal of Abnormal Psychology, 30, 349 –359.
Althoff, R. R., Rettew, D. C., & Hudziak, J. J. (2003). Attention-
deficit/hyperactivity disorder, oppositional defiant disorder, and
conduct disorder. Psychiatric Annals, 33, 245–252.
Aman, M. G. (2004). Management of hyperactivity and other
acting-out problems in patients with autism spectrum disorder.
Seminars in Pediatric Neurology, 11, 225–228.
Arsten, A. F. (2006). Fundamentals of attention-deficit/hyperac-
tivity disorder: Circuits and pathways. Journal of Clinical Psy-
chiatry, 67(Suppl. 8), 7–12.
Barkley, R. A. (1998). Attention deficit hyperactivity disorders: A
handbook for diagnosis and treatment. New York: Guilford
Press.
Barkley, R. A. (2003). Issues in the diagnosis of attention-deficit/
hyperactivity disorder in children. Brain and Development, 25,
77– 83.
Barkley, R. A., & Benton, C. M. (1998). Your defiant child: 8 steps
to better behavior. New York, NY: Guilford Press.
Benson, B. A., & Aman, M. G. (1999). Disruptive behavior
disorders in children with mental retardation. In H. C. Quay &
A. E. Hogan (Eds.), Handbook of disruptive behavior disorders
(pp. 559 –578). New York, NY: Plenum Press.
Biederman, J., Krishnan, S., Zhang, Y., McGough, J. J., & Find-
ling, R. L. (2007). Efficacy and tolerability of lisdexamfetamine
dimesylate (NRP-104) in children with attention-deficit/hyper-
activity disorder: A phase III, multicenter, randomized, double-
blind, forced-dose, parallel-group study. Clinical Therapeu-
tics, 29, 450 – 463.
Biederman, J., Mick, E., Spencer, T., Doyle, R., Joshi, G., Ham-
merness, P., . . . Wozniak, J. (2007). An open-label trial of
aripiprazole monotherapy in children and adolescents with bi-
polar disorder. CNS Spectrums, 12, 683– 689.
Biederman, J., Monuteaux, M. C., Spencer, T., Wilens, T. E.,
MacPhearson, H. A., & Faraone, S. V. (2008). Stimulant ther-
apy and risk for subsequent substance use disorders in male
adults with ADHD: A naturalistic controlled 10-year follow-up
study. American Journal of Psychiatry, 165, 597– 603.
Biederman, J., Swanson, J. M., Wigal, S. B., Kratochvil, C. J.,
Boellner, S. W., Earl, C. Q., . . . Greenhill, J. (2005). Efficacy
and safety of modafinil film-coated tablets in children and
adolescents with attention-deficit/hyperactivity disorder: Results
of a randomized, double-blind, placebo-controlled, flexible-dose
study. Pediatrics, 116, 777–784.
Biederman, J., Wilens, T., Mick, E., Spencer, T., & Faraone, S. V.
(1999). Pharmacotherapy of attention-deficit/hyperactivity dis-
order reduces risk for substance use disorder. Pediatrics, 104.
doi:10.1542/peds.104.2.e20
Breitenstein, S. M., Hill, C., & Gross, D. (2009). Understanding
disruptive behavior problems in preschool children. Journal of
Pediatric Nursing, 24, 3–12.
Burgess, K. B., Rose-Krasnor, L., Wojslawowicz, J. C., Rubin,
K. H., & Booth-LaForce, C. (2006). Social information process-
ing and coping strategies of shy/withdrawn and aggressive chil-
dren: Does friendship matter? Child Development, 77, 371–383.
Campbell, M., Anderson, L. T., Small, A. M., Adams, P., Gonza-
lez, N. M., & Ernst, M. (1993). Naltrexone in autistic children:
Behavioral symptoms and attentional learning. Journal of the
American Academy of Child and Adolescent Psychiatry, 32,
1283–1291.
Campbell, M., Small, A. M., Green, W. H., Jennings, S. J., Perry,
R., Bennett, W. G., . . . Anderson, L. (1984). Behavioral efficacy
of haloperidol and lithium carbonate. A comparison in hospi-
talized aggressive children with conduct disorder. Archives of
General Psychiatry, 41, 650 – 656.
Cohen, I., Tsiouris, J. A., & Pfadt, A. (1991). Effects of long-
acting propranolol on agonistic and stereotyped behaviors in a
man with pervasive developmental disorder and fragile-X syn-
drome: A double-blind, placebo controlled study. Journal of
Clinical Psychopharmacology, 11, 398 –399.
Conner, D. E., Edwards, G., Fletcher, K. E., Baird, J., Barkley,
R. A., & Steingard, R. J. (2003). Correlates of comorbid psy-
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION
chopathology in children with ADHD. Journal of the American
Academy of Child and Adolescent Psychiatry, 42, 193–200.
Connor, D. F., Fletcher, K. E., & Swanson, J. M. (1999). A
meta-analysis of clonidine for symptoms of attention-deficit
hyperactivity disorder. Journal of the American Academy of
Child and Adolescent Psychiatry, 38, 1551–1559.
Connor, D. F., Glatt, S. J., Lopez, I. D., Jackson, D., & Melloni,
R. H. (2002). Psychopharmacology and aggression. I: A meta-
analysis of stimulant effects on overt/covert aggression—Re-
lated behaviors in ADHD. Journal of the American Academy of
Child and Adolescent Psychiatry, 41, 253–260.
Coryell, W., Solomon, D., Turvey, C., Keller, M., Leon, A. C.,
Endicott, J., . . . Mueller, T. (2003). The long-term course of
rapid-cycling bipolar disorder. Archives of General Psychia-
try, 60, 914 –920.
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
This document is copyrighted by the American Psychological Association or one of its allied publishers.
Croonenberghs, J., Fegert, J. M., Findling, R. L., Smedt, G., Van
Dongen, S., & the Risperidone Disruptive Behavior Study
Group. (2005). Risperidone in children with disruptive behavior
disorders and subaverage intelligence: A 1-year, open-label
study of 504 patients. Journal of the American Academy of
Child and Adolescent Psychiatry, 44, 64 –72.
DeYoung, C. G., Peterson, J. B., Séguin, J. R., Mejia, J. M., Pihl,
R. O., Beitchman, J. H., . . . Palmour, R. M. (2006). The dopa-
mine D4 receptor gene and moderation of the association be-
tween externalizing behavior and IQ. Archives of General Psy-
chiatry, 63, 1410 –1416.
Efron, D., Jarman, F., & Barker, M. (1997). Methylphenidate
versus dexamphetamine in children with attention deficit hyper-
activity disorder: A double-blind, crossover trial. Pediatrics.
doi:10.1542/peds.100.6.e6
Erickson, C. A., Posey, D. J., Stigler, K. A., Mullet, J., Katsche,
A. R., & McDougle, C. J. (2007). A retrospective study of
memantine in children and adolescents with pervasive develop-
mental disorders. Psychopharmacology, 191, 141–147.
Exkorn, K. S. (2005). The autism sourcebook: Everything you
need to know about diagnosis, treatment, coping, and healing.
New York, NY: HarperCollins.
Faraone, S. V., Biederman, J., & Roe, C. M. (2002). Comparative
efficacy of adderall and methylphenidate in attention-deficit/
hyperactivity disorder: A meta-analysis. Journal of Clinical
Psychopharmacology, 22, 468 – 473.
Findling, R. L. (2003). Treatment of aggression in children. Pri-
mary care companion. Journal of Clinical Psychiatry, 5(Suppl.
6), 5–9.
Findling, R. L. (2008). Evolution of the treatment of attention-
deficit/hyperactivity disorder in children: A review. Clinical
Therapeutics, 30, 942–957.
Findling, R. L., Aman, M. G., Eerdekens, M., Derivan, A., Lyons,
B., & the Risperidone Disruptive Behavior Study Group.
(2004). Long-term, open-label study of risperidone in children
with severe disruptive behaviors and below-average IQ. Amer-
ican Journal of Psychiatry, 161, 677– 684.
Findling, R. L., McNamara, N. K., Gracious, B. L., Youngstrom,
E. A., Stansbrey, R. J., Reed, M. D., . . . Calabrese, J. R. (2003).
Combination of lithium and divalproex sodium in pediatric
bipolarity. Journal of the American Academy of Child and
Adolescent Psychiatry, 42, 895–901.
Frazier, J. A., McClellan, J., Findling, R. L., Vitiello, B., Ander-
son, R., Zablotsky, B., . . . Sikich, L. (2007). Treatment of
early-onset schizophrenia spectrum disorders (TEOSS): Demo-
graphic and clinical characteristics. Journal of the American
Academy of Child and Adolescent Psychiatry, 46, 979 –988.
199
Fukuda, T., Sugie, H., Ito, M., & Sugie, Y. (2001). Clinical
evaluation of treatment with fluvoxamine, a selective serotonin
reuptake inhibitor in children with autistic disorder. No To
Hattatsu, 33, 314 –318.
Gauthier, Y. (2003). Infant mental health as we enter the third
millennium: Can we prevent aggression? Infant Mental Health
Journal, 24, 296 –308.
Geller, B., & Debello, M. P. (Eds.). (2003). Bipolar disorder in
childhood and early adolescence. New York, NY: Guilford
Press.
Golden, C. J., Jackson, M. L., Peterson-Rohne, A., & Gontkovsky,
S. T. (1996). Neuropsychological correlates of violence and
aggression: A review of the clinical literature. Aggression and
Violent Behavior, 1, 3–25.
Goldman, L. S., Genel, M., Bezman, R. J., & Slanetz, P. J. (1998).
Diagnosis and treatment of attention-deficit/hyperactivity disor-
der in children and adolescents. Journal of the American Med-
ical Association, 279, 1100 –1107.
Gontkovsky, S. T. (2005). Neurobiological bases and neuropsy-
chological correlates of aggression and violence. In J. P. Morgan
(Ed.), Psychology of aggression (pp. 101–116). Hauppauge,
NY: Nova Science.
Guy, W. (1976). Assessment manual for psychopharmacology–
revised (DHEW Publ No ADM 76-338, pp. 218-222). Rock-
ville, MD: U.S. Department of Health, Education, and Welfare.
Haber, J. S. (2003). ADHD: The great misdiagnosis. Lanham, MD:
Taylor Trade.
Hagerman, R. J. (1996). Medical follow-up and pharmacotherapy.
In R. J. Hagerman & A. Cronister (Eds.), Fragile X syndrome:
Diagnosis, treatment, and research (2nd ed., pp. 283–331).
Baltimore, MD: Johns Hopkins University Press.
Hagerman, R. J. (1999). Fragile X syndrome. New York, NY:
Oxford University Press.
Hagerman, R. J., Fulton, M. J., Leaman, A., Riddle, J., Hagerman,
K., & Sobesky, W. (1994). A survey of fluoxetine therapy in
fragile X syndrome. Developmental Brain Dysfunction, 7, 155–
164.
Hazell, P. L., & Stuart, J. E. (2003). A randomized controlled trial
of clonidine added to psychostimulant medication for hyperac-
tive and aggressive children. Journal of the American Academy
of Child and Adolescent Psychiatry, 42, 886 – 894.
Hechtman, L., & Greenfield, B. (2003). Long-term use of stimu-
lants in children with attention hyperactivity disorder: Safety,
efficacy and long-term outcome. Paediatric Drugs, 5, 787–794.
Ipser, J., & Stein, D. (2007). Systematic review of pharmacother-
apy of disruptive behavioral disorders in children and adoles-
cents. Psychopharmacology, 191, 127–140.
Jensen, P. S., Vitiello, B., Leonard, H., & Laughren, T. P. (1994).
Design and methodology issues for clinical treatment trials in
children and adolescents. Child and adolescent psychopharma-
cology: Expanding the research base. Psychopharmacology Bul-
letin, 30, 3– 8.
Jepson, B. (2007). Changing the course of autism: A scientific
course for parents and physicians. Boulder, CO: Sentient.
Julien, R. M., Advokat, C. D., & Comaty, J. E. (2008). A primer
of drug action: A comprehensive guide to the actions, uses, and
side effects of psychoactive drugs (11th ed.). New York, NY:
Worth.
Kelsey, D. K., Sumner, C. R., Casat, C. D., Coury, D. L., Quintana,
H., Saylor, K. E., . . . Allen, A. J. (2004). Once-daily atomox-
etine treatment for children with attention-deficit/hyperactivity
disorder, including an assessment of evening and morning be-
havior: A double-blind, placebo-controlled trial. Pediatrics,
114, e1– 8.
 200 NEVELS, DEHON, ALEXANDER, AND GONTKOVSKY
King, B. H., Hollander, E., Sikich, L., McCracken, J. T., Scahill,
L., Bregman, J. D., . . . Ritz, L. (2009). Lack of efficacy of
citalopram in children with autism spectrum disorders and high
levels of repetitive behavior: Citalopram ineffective in children
with autism. Archives of General Psychiatry, 66, 583–590.
Kolmen, B. K., Feldman, H. M., Handen, B. L., & Janosky, J. E.
(1995). Naltrexone in young autistic children: A double-blind,
placebo-controlled crossover study. Journal of the American
Academy of Child and Adolescent Psychiatry, 34, 223–231.
Kowatch, R. A., Fristad, M., Birmaher, B., Wagner, K., Findling,
R., & Hellander, M. (2005). Treatment guidelines for children
and adolescents with bipolar disorder: Child psychiatric work-
group on bipolar disorder. Journal of the American Academy of
Child and Adolescent Psychiatry, 44, 213–235.
Kowatch, R. A., Suppes, T., Carmody, T. J., Bucci, J. P., Hume,
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
This document is copyrighted by the American Psychological Association or one of its allied publishers.
J. H., Kromelis, M., . . . Rush, A. J. (2000). Effect size of
lithium, divalproex sodium, and carbamazepine in children and
adolescents with bipolar disorder. Journal of the American
Academy of Child and Adolescent Psychiatry, 39, 713–720.
Kranzler, H., Roofeh, D., Gerbino-Rosen, G., Dombrowski, C.,
McMeniman, M., DeThomas, C., . . . Kumra, S. (2005). Cloza-
pine: Its impact on aggressive behavior among children and
adolescents with schizophrenia. Journal of the American Acad-
emy of Child and Adolescent Psychiatry, 44, 55– 63.
Manuzza, S., Klein, R. G., Truong, N. L., Moulton, J. L., III,
Roizen, E. R., Howell, K. H., . . . Castellanos, F. X. (2008). Age
of methylphenidate treatment initiation in children with ADHD
and later substance abuse: Prospective follow-up into adulthood.
American Journal of Psychiatry, 165, 604 – 609.
McClintock, K., Hall, S., & Oliver, C. (2003). Risk markers
associated with challenging behaviours in people with intellec-
tual disabilities: A meta-analytic study. Journal of Intellectual
Disability Research, 47, 405– 416.
McDougle, C. J., Naylor, S. T., Cohen, D. J., Volkmar, F. R.,
Heninger, G. R., & Price, L. H. (1996). A double-blind, placebo-
controlled study of fluvoxamine in adults with autistic disorder.
Archives of General Psychiatry, 53, 1001–1008.
Mick, E., Biederman, J., Pandina, G., & Faraone, S. V. (2003). A
preliminary meta analysis of the Child Behavior Checklist in
pediatric bipolar disorder. Biological Psychiatry, 53, 1021–
1027.
Molina, B. S. G., Hinshaw, S. P., Swanson, J. M., Arnold, L. E.,
Vitiello, B., Jensen, P. S., . . . the MTA Cooperative Group. (2009).
The MTA at 8 years: Prospective follow-up of children treated for
combined type ADHD in the multisite study. Journal of the Amer-
ican Academy of Child and Adolescent Psychiatry. Advance online
publication. doi:10.1097/CHI.0b013e31819c23d0
Pandina, G. J., Aman, M. G., & Findling, R. L. (2006). Risperi-
done in the management of disruptive behavioral disorders.
Journal of Child and Adolescent Psychopharmacology, 16,
379 –392.
Pandina, G. J., Bossie, C. A., Youssef, E., Zhu, Y., & Dunbar, F.
(2007). Risperidone improves behavioral symptoms in children
with autism in a randomized, double-blind, placebo-controlled
trial. Journal of Autism and Developmental Disorders, 37, 367–
373.
Pappadopulos, E., Woolston, S., Chait, A., Perkins, M., Connor,
D. F., & Jensen, P. S. (2006). Pharmacotherapy of aggression in
children and adolescents: Efficacy and effect size. Journal of the
Canadian Academy of Child and Adolescent Psychiatry, 15,
27–39.
Pavuluri, M. N., Henry, D. B., Carbray, J. A., Sampson, G.,
Naylor, M. W., & Janicak, P. G. (2004). Open-label prospective
trial of risperidone in combination with lithium and divalproex
sodium in pediatric mania. Journal of Affective Disorders, 82,
103–111.
Pliszka, S. R., Carlson, C. L., & Swanson, J. M. (2001). ADHD
with comorbid disorders: Clinical assessment and management.
New York, NY: Guilford Press.
Polzer, J., Bangs, M. E., Zhang, S. Y., Dellva, M. A., Tauscher-
Wisniewski, S., Acharya, N., . . . Wilens, T. E. (2007). Meta-
analysis of aggression or hostility events in randomized, con-
trolled clinical trials of atomoxetine for ADHD. Biological
Psychiatry, 61, 713–719.
Posey, D. J., Stigler, K. A., Erickson, C. A., & McDougle, C. J.
(2008). Antipsychotics in the treatment of autism. Journal of
Clinical Investigations, 118, 6 –14.
Preston, J., O’Neal, J. H., & Talaga, M. C. (2006). Child and
adolescent clinical psychopharmacology made simple. Oakland,
CA: New Harbinger.
Preston, J., O’Neal, J. H., & Talaga, M. C. (2008). Handbook of
clinical psychopharmacology for therapists (5th ed.). Oakland,
CA: New Harbinger.
Psychopharmacological Drugs Advisory Committee and the Pedi-
atric Subcommittee of the Anti-Infective Drugs Advisory Com-
mittee. February 2, 2004. Retrieved from http://www.fda.gov/
Drugs/DrugSafety/PublicHealthAdvisories/ucm161696.htm
Ruginvo, T. A., & Janvier, Y. M. (2005). Aripiprazole in children
and adolescents: Clinical experience. Journal of Child Neurol-
ogy, 20, 603– 610.
Sachs, G. S., Baldassano, C. F., Truman, C. J., & Guille, C. (2000).
Comorbidity of attention deficit hyperactivity disorder with
early- and late-onset bipolar disorder. American Journal of
Psychiatry, 157, 466 – 468.
Sallee, F., McGough, J., Wigal, T., Donahue, J., Lyne, A., &
Biederman, J. (2009). Guanfacine extended release in children
and adolescents with ADHD: A placebo-controlled trial. Jour-
nal of the American Academy of Child and Adolescent Psychi-
atry, 48, 1–11.
Santosh, P. J., Baird, G., Pityaratstian, N., Tavare, E., & Gringras,
P. (2006). Impact of comorbid autism spectrum disorders on
stimulant response in children with attention deficit hyperactiv-
ity disorder: A retrospective and prospective effectiveness
study. Child Care Health Development, 32, 575–583.
Schneck, C. D., Miklowitz, D. J., Miyahara, S., Araga, M.,
Wisniewski, S., Gyulai, L., . . . Sachs, G. S. (2008). The pro-
spective course of rapid-cycling bipolar disorder: Findings from
the STEP-BD. American Journal of Psychiatry, 165, 370 –377.
Singh, N. N., Lancioni, G. E., Winton, A. S. W., Fisher, B. C.,
Wahler, R. G., McAleavey, K., . . . Sabaawi, M. (2006). Mindful
parenting decreases aggression, noncompliance, and self-injury
in children with autism. Journal of Emotional and Behavioral
Disorders, 14, 169 –177.
Stahl, S. M. (2005). Essential psychopharmacology: The prescriber’s
guide. Cambridge, England: Cambridge University Press.
Stahl, S. M. (2008). Stahl’s essential psychopharmacology: Neu-
roscientific basis and practical applications (3rd ed.). Cam-
bridge, England: Cambridge University Press.
Staller, J. A. (2007). Psychopharmacologic treatment of aggressive
preschoolers: A chart review. Progress in Neuro-Psychophar-
macology and Biological Psychiatry, 31, 131–135.
Sukhodolsky, D. G., Vitulano, L. A., Carroll, D. H., McGuire, J.,
Leckman, J. F., & Schahill, L. (2009). Randomized trial of anger
control training for adolescents with Tourette’s syndrome and
disruptive behavior. Journal of the American Academy of Child
and Adolescent Psychiatry, 48, 413– 420.
 PSYCHOPHARMACOLOGY OF PEDIATRIC AGGRESSION
Swanson, J. W., Swartz, M. S., Van Dorn, R. A., Volavka, J.,
Monahan, J., Stroup, T. S., . . . Lieberman, J. A. (2008). Com-
parison of antipsychotic medication effects on reducing violence
in people with schizophrenia. British Journal of Psychiatry, 193,
37– 43.
Tandon, R., Carpenter, W. T., & Davis, J. M. (2007). First- and
second-generation antipsychotics: Learning from CUtLASS and
CATIE. Archives of General Psychiatry, 64, 977–988.
Toren, P., Ratner, S., Laor, N., & Weizman, A. (2004). Benefit-
risk assessment of atypical antipsychotics in the treatment of
schizophrenia and comorbid disorders in children and adoles-
cents. Drug Safety, 27, 1135–1156.
Tremblay, R. E., Nagin, D. S., Seguin, J. R., Zoccolillo, M.,
Zelazo, P. D., Boivin, M., . . . Japel, C. (2004). Physical aggres-
sion during early childhood: Trajectories and predictors. Pedi-
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
atrics, 114, 43–50.
This document is copyrighted by the American Psychological Association or one of its allied publishers.
U.S. Food and Drug Administration. (2004a). Suicidality in chil-
dren and adolescents being treated with antidepressant medica-
tions. Retrieved from http://www.fda.gov/Drugs/DrugSafety/
PublicHealthAdvisories/ucm161679.htm
U.S. Food and Drug Administration. (2004b). Worsening depres-
sion and suicidality in patients being treated with antidepres-
sants. Retrieved from http://www.fda.gov/Drugs/DrugSafety/
PublicHealthAdvisories/ucm161696.htm
U.S. Food and Drug Administration. (2004, February). Meeting of
the Psychopharmacological Drugs Advisory Committee and the
Pediatric Subcommittee of the Anti-Infective Drugs Advisory
Committee.
201
Vedantam, S. (2004, February 3). FDA links antidepressants,
youth suicide risk. The Washington Post, p. A01.
Vetter, V. L., Elia, J., Erickson, C., Berger, S., Blum, N., Uzark,
K., . . . Webb, C. L. (2008). Cardiovascular monitoring of chil-
dren and adolescents with heart disease receiving stimulant
drugs. A scientific statement from the American Heart Associ-
ation Council on cardiovascular disease in the young congenital
cardiac defects committee and the Council on Cardiovascular
Nursing. Circulation, 117, 2407–2423.
Wada, A., Yokoo, H., Yanagita, T., & Kobayashi, H. (2005).
Lithium: Potential therapeutics against acute brain injuries and
chronic neurodegenerative diseases. Journal of Pharmacologi-
cal Sciences, 99, 307–321.
Washburn, J. J., McMahon, S. D., King, C. A., Reinecke, M. A.,
& Silver, C. (2004). Narcissistic features in young adolescents:
Relations to aggression and internalizing symptoms. Journal of
Youth and Adolescence, 33, 247–260.
Werner, N. E., & Nixon, C. L. (2005). Normative beliefs and
relational aggression: An investigation of the cognitive bases of
adolescent aggressive behavior. Journal of Youth and Adoles-
cence, 34, 229 –243.
Yan, J. (2009, May 15). Short, intensive ADHD treatments are not
long-term panacea. Psychiatric News, 44, 1, 20.
Received June 7, 2009
Revision received September 10, 2009
Accepted October 8, 2009 䡲