1. health and fitness
2. disorders

Citalopram Treatment for Impulsive Aggression in
Children and Adolescents: An Open Pilot Study
JORGE L. ARMENTEROS, M.D., AND JOHN E. LEWIS, PH.D.
ABSTRACT
Objective: To assess the short-term effect and safety of citalopram in the reduction of impulsive aggression in children
and adolescents. Method: Twelve subjects, aged 7 to 15 years, were attending a psychiatric outpatient clinic and had a
profile of impulsive aggression. Subjects were treated in an open trial with citalopram for 6 weeks after a 1-week washout
period. Dosage was regulated individually over a period of 4 weeks. The starting dose was 10 mg/day followed by 10 mg
increments on a weekly basis. The maximum dose was not to exceed 40 mg/day. Outcome measures included the
Modified Overt Aggression Scale (MOAS), the Child Behavioral Checklist (CBCL), and the Clinical Global Impressions
(CGI). Results: Eleven subjects completed the study. Citalopram produced clinically and statistically significant reductions on target symptoms of impulsive aggression, independent of other behavioral problems, as measured by the MOAS,
the CBCL, and the CGI at doses ranging from 20 to 40 mg/day (mean = 27 mg). No major adverse reactions were associated with citalopram use. Conclusion: Citalopram appears to be effective and well tolerated in this sample of children
and adolescents with impulsive aggression. J. Am. Acad. Child Adolesc. Psychiatry, 2002, 41(5):522–529. Key Words:
impulsive aggression, citalopram, psychopharmacology.
Accepted December 18, 2001.
Dr. Armenteros is Director of Pediatric Psychopharmacology, Division of Child
and Adolescent Psychiatry, University of Miami School of Medicine; Dr. Lewis
is Assistant Professor, Department of Psychiatry and Behavioral Sciences, University
of Miami School of Medicine.
Reprint requests to Dr. Armenteros, Division of Child and Adolescent Psychiatry,
University of Miami School of Medicine, 1695 NW 9th Avenue, Suite 1404,
FL 33136; e-mail: j.armenteros@miami.edu.
0890-8567/02/4105–05222002 by the American Academy of Child
and Adolescent Psychiatry.
Several researchers have attempted to define the phenomenology of human aggression and its subtypes
(Barratt et al., 1997; Vitiello et al., 1990; Vitiello and
Stoff, 1997). Two types of aggressive behaviors have
emerged. The first type is considered to have a significant
affective component and to be more impulsive. It is characterized by a hair-trigger response to a stimulus that
results in an agitated state and culminates in an aggressive act. This impulsive aggression is viewed as an overreaction to a minor provocation and is often accompanied
by disinhibition and behavioral dyscontrol. The individual who exhibits impulsive aggression often feels remorse
after the aggressive act and vows not to do it again, yet
they often do repeat the behavior. The second type of
aggression is considered to be nonimpulsive; an instrumental behavior prompted by its anticipated benefits.
Brown et al. (1979) were among the first researchers to
evaluate the concept of impulsive aggression. The authors
found personality disorders generally associated with behavioral impulsivity to have significantly higher aggression
indices. A recent study by Seroczynski et al. (1999) provides further support for this concept. The authors found
genetic associations between impulsivity and aggression.
In children, fight initiation was linked to impulsivity irrespective of whether attention-deficit/hyperactivity disor-
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Aggression is a significant problem in our society, with serious psychological, social, and financial consequences. The
problem is not limited to the adult population; aggressive
behaviors are extremely common in the daily lives of many
juveniles. Aggressive behavior patterns have increased among
psychiatrically referred children and adolescents over the
past 2 decades (Achenbach and Howell, 1993). A recent
study using nationally representative data from the Youth
Risk Behavior Survey showed that physical fighting and
weapon carrying remains at high levels in minority groups
(Brener et al., 1999). In 1991, the U.S. Dept. of Health
and Human Services (Public Health Service, 1991) established a reduction in youth violence as a national health
objective for the year 2000. Unfortunately, the prevalence
of youth violence and aggression is still unacceptably high
as this objective has not been met with success.
CITALOPRAM FOR IMPULSIVE AGGRESSION
der was present or not (Halperin et al., 1995). In addition, impulsivity was related to delinquency, suggesting
that children with poor self-control would steal and fight
on the spur of the moment (White et al., 1994).
In summary, these studies suggest that impulsivity may
be a trigger for aggressiveness. In this model, the aggressive act per se is conceived as the observable behavioral
manifestation of the underlying impulsivity. The construct of impulsive aggression offers a unitary understanding of a common behavioral problem in children.
Although this label has varied among authors (Coccaro
et al., 1989; Linnoila et al., 1983), construct and validity studies (Atkins et al., 1993; Barratt et al., 1997) support the soundness of this concept.
A basic constituent of the impulsive aggression construct is its dimensional quality. As an independent entity,
impulsive aggression does not comprise a separate diagnostic category. Furthermore, no psychiatric diagnosis
subsumes impulsive aggression as a pathognomonic sign.
Various psychiatric disorders, however, are frequently
accompanied by impulsive aggressive behavior. These
include conduct disorder, attention-deficit/hyperactivity
disorder, intermittent explosive disorder, personality disorders, substance abuse, and psychoses (DSM-IV) (American
Psychiatric Association, 1994). The frequency of impulsivity and various forms of aggression was clearly demonstrated by the DSM-IV field trials for disruptive behavior
disorders (Frick et al., 1994). The sample consisted of
440 clinic-referred youths who were consecutively admitted to a heterogeneous group of mental health clinics.
Although the youths were referred for a variety of reasons, impulsive and aggressive behaviors were very frequent. Consistent with these epidemiological data, a study
of 111 children referred to a psychiatric outpatient clinic
found that impulsivity was strongly associated with initiation of fighting (Halperin et al., 1995). More importantly, the children who initiate fights were found to be
impulsive irrespective of the presence or absence of attention-deficit/hyperactivity disorder or any other disruptive disorder. To reduce diagnostic categorical constraints,
impulsive aggression should be considered as a dimensional behavioral disturbance.
The association between serotonin (5-HT) and aggression has been established with the consistent observation
that abnormalities in central 5-HT function correlate
with impulsive aggression, which is supported by an extensive animal literature. Muricidal behavior, shock-induced
fighting, and attack are all increased by the chemical or
electric lesioning of central 5-HT neurons (Katz, 1980;
Sewell et al., 1982; Siegel et al., 1999). Agents that increase
central 5-HT activity reversed these behaviors. Moreover,
a study of free-ranging rhesus monkeys found a strong
negative correlation between cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA), the main metabolite of
serotonin, and aggression (Higley et al., 1992).
The hypothesis that central 5-HT dysfunction contributes to impulsive aggression in humans is also well
supported by research. In 1976, Asberg and associates
published their findings concerning low CSF 5-HIAA
concentration in depressed patients. The investigators
demonstrated that depressed patients with low CSF 5HIAA concentration were more likely to complete suicide using particularly violent means than depressed
patients with higher CSF 5-HIAA concentration.
Subsequently, Brown et al. (1979) found a significant
negative correlation between impulsive aggression and
CSF 5-HIAA within a group of subjects with personality disorder. Moreover, Linnoila et al. (1983) found significantly lower 5-HIAA in the CSF of impulsive violent
offenders when compared with offenders who premeditated their acts. These findings suggest that abnormalities in the brain’s serotonergic functioning predispose
individuals to impulsive aggression rather than to nonimpulsive, premeditated aggressive behaviors.
Using a different strategy, Coccaro et al. (1989) examined the central serotonergic function of patients with
affective and personality disorders by means of a fenfluramine challenge. The authors found a blunted prolactin
response to fenfluramine, indicating a significant reduction in central serotonergic function in patients with
impulsive aggression.
Abnormalities in the serotonergic system also abide by
a dimensional, rather than a categorical, order. Low serotonergic indices have been associated with major depressive disorder (Meltzer and Lowy, 1987), history of suicide
attempt (Asberg et al., 1976; Mann et al., 1995), personality disorders (Brown et al., 1979; Coccaro et al., 1989),
and impulsive aggression as reviewed above. These data
cumulatively suggest that disturbances in serotonergic
function lack nosological specificity and are not linked to
a particular psychiatric disorder (van Praag et al., 1987).
The serotonergic system in children and adolescents
has been studied infrequently because of ethical and practical difficulties in obtaining CSF samples from this pop-
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523
ARMENTEROS AND LEWIS
ulation. Kruesi et al. (1990) extended the adult findings
to children and adolescents by demonstrating reduced 5HIAA in CSF of aggressive juveniles with disruptive behavior disorders. In contrast, Halperin et al. (1994) found a
positive rather than inverse correlation between aggression
ratings and the prolactin response to fenfluramine challenge in children with attention-deficit/hyperactivity disorder. Another study also found a higher, rather than
lower, prolactin response to the fenfluramine challenge
in aggressive children (Pine et al., 1997). It may be possible that a developmental component modulates the relationship between central serotonergic function and
impulsive aggression in children.
Taken together, these data strongly support the association between abnormalities in the brain’s serotonergic
functioning and impulsive aggression, particularly in
adults. However, the association in children and adolescents is inconclusive at the present time.
On the basis of the existing data, one would expect
drugs that selectively affect central serotonergic function
to be effective for impulsive aggression. More precisely,
the candidate drug should be effective, irrespective of a
syndromal or nosological framework. Various psychopharmacological approaches have been used for the treatment of impulsive aggression. An early study of tryptophan,
a precursor required for serotonin synthesis, demonstrated
a reduced need for injection of antipsychotic medications
and sedatives in aggressive psychiatric inpatients
(Volavka et al., 1990). Because of the ability of lithium
to increase brain tryptophan concentrations and enhance
serotonergic activity, it was also studied in the treatment
of impulsive aggression (Sheard et al., 1976). Lithium
was as effective as haloperidol in reducing aggressiveness
and explosiveness in hospitalized children with conduct
disorder and a profile of aggressive and explosive behavior (Campbell et al., 1984). Eltoprazide, a mixed serotonin 5-HT1 agonist, was found to be effective in reducing
aggressive behavior in a group of patients with schizophrenia (Tiihonen et al., 1993).
Theoretically, selective serotonin reuptake inhibitors
(SSRIs) should be effective in reducing impulsive aggression, but data on this issue are limited. Clomipramine, a
relatively selective serotonin reuptake inhibitor, was superior to placebo in reducing anger in autistic children
(Gordon et al., 1993). Among 30 adults with autism, fluvoxamine was also found to be more effective than placebo
in reducing aggression (McDougle et al., 1996). A study
of depressed adult patients with anger attacks found treat-
ment with fluoxetine to be effective in eliminating these
attacks in 71% of the patients (Fava et al., 1993). Interestingly, the presence of anger attacks predicted a greater
treatment efficacy with fluoxetine irrespective of depressed
symptomatology. Using a double-blind crossover design,
Vartiainen et al. (1995) examined the effect of citalopram
in 14 schizophrenic patients known to be impulsive and
aggressive. Citalopram (20–60 mg/day) or placebo was
administered as an adjuvant to current neuroleptic medication for a 24-week period. The authors found a reduced
frequency of aggressive incidents during citalopram treatment. Moreover, the decrease in aggressive behavior was
independent of a decrease in any other mental symptom.
Side effects were reported to be mild.
For our study, we have chosen citalopram in the treatment of impulsive aggression for several important reasons. First, citalopram is the most specific SSRI for the
inhibition of serotonin reuptake (Hyttel, 1982). This will
avoid possible unwanted effects on other neurotransmitter systems. The greater the biochemical specificity of
a drug, the greater the chance it will be effective against
the dimension of impulsive aggression across diagnoses.
Second, the plasma concentration of citalopram is proportional to the dose administered (i.e., it has linear pharmacokinetics). This eliminates the problem of metabolic
autoinhibition. Third, food intake or times of dosing do
not affect the pharmacokinetics of citalopram. Fourth,
the mean terminal half-life of citalopram is 33 hours.
This makes a single daily dose possible and avoids most
discontinuation adverse effects. Lastly, the inhibition of
hepatic cytochrome P450 (CYP2D6) isoenzymes caused
by citalopram is clinically insignificant.
This study presents data concerning the effects of citalopram in the treatment of impulsive aggression in children and adolescents. Our study departs from the generic
approach in treating impulsive aggression. Instead of targeting symptoms with no connection to a specific functional hypothesis, our pharmacotherapy emerges from
our current understanding of the underlying neurobiology of impulsive aggression.
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METHOD
Patient Selection Criteria
Participants in the trial were male and female children and adolescents (at least 7 but younger than 16 years of age) who were referred
for psychiatric services to the Child and Adolescent Psychiatry outpatient clinic at the University of Miami School of Medicine. To be
CITALOPRAM FOR IMPULSIVE AGGRESSION
enrolled in the study, patients must have had an established pattern
of aggressive behavior of at least 6-months duration with a minimum
of three acts of aggression in the past week, two of which had to be
acts of physical aggression against other people, objects, or self.
Impulsivity needed to be part of the clinical picture, thus inclusion
criteria required subjects to score at least one standard deviation beyond
a normative sample of peers on either “commission errors,” “hit reaction time,” or “risk taking” on the Conner’s Continuous Performance
Test (CPT) (Conners, 1995). In addition, patients were required to
have a score greater than or equal to 4 on the Clinical Global Impressions
(CGI)-Severity scale. Patients were also required to have laboratory
results without significant abnormalities. Children who scored below
75 on Verbal and Performance IQ, measured with the Kaufman Brief
Intelligence Test (Kaufman and Kaufman, 1990), were excluded.
Previous treatments were assessed by means of the Prior Medication
Record (Psychopharmacology Bulletin, 1985).
DSM-IV diagnoses were made by means of a semistructured psychiatric interview using the Child and Adolescent Symptom Inventories4 (Gadow and Sprafkin, 2000). These are behavior rating scales that
screen for a full range of DSM-IV disorders usually first diagnosed in
infancy, childhood, or adolescence. A few exceptions are learning disorders, motor skills disorders, communication disorders, and selective
mutism, which are not elicited by the instrument. Using a symptom
count scoring procedure, we identified patients with a minimum number of symptoms necessary for a DSM-IV diagnosis. The final diagnoses were assigned through a best-estimate process. The research team,
composed of two child and adolescent psychiatrists, reviewed the information obtained from the parent and the youth reports in conjunction with all other clinical information available. The information was
summarized, and possible DSM-IV diagnoses were outlined. We arrived
at a consensus best-estimate diagnoses for each subject.
A basic constituent of the impulsive aggression construct is its
dimensional quality; therefore, diagnoses for participants included
attention-deficit/hyperactivity disorder, oppositional defiant disorder, major depression, social phobia, generalized anxiety disorder, and
conduct disorder as defined by the DSM-IV. Patients were excluded
from the study if they had any of the following comorbid disorders:
schizophrenia, other psychotic disorders, bipolar I or II disorder, major
depression with psychotic features, delirium, dementia, and alcohol
or substance abuse/dependence.
Patient’s parents or guardians gave their permission for participation in the study and signed an informed consent document approved
by the University of Miami School of Medicine Institutional Review
Board. Patients also provided assent for their participation.
Study Design
then summed to yield a total aggression score. We only rated the occurrence of impulsive aggressive events over the previous 1-week period.
The MOAS also measures two categories of irritability, subjective and
overt, which are summed to yield a total irritability score. Parents/guardians
were the respondents for this scale with the child providing information on subjective irritability.
We also used the Aggression Questionnaire (AQ) to classify aggression into “predatory” and “affective” subtypes (Malone et al., 1998;
Vitiello et al., 1990; Vitiello and Stoff, 1997). The AQ is a 16-item
scale consisting of eight items that assess predatory aggression and
eight items that assess affective aggression. Items are scored as not true
(0), partly true (1), or very true (2). Predatory and affective scores are
obtained by adding the corresponding items with a possible range of
0 to 16. The Predatory-Affective index is calculated by subtracting
the affective score from the predatory score. Higher index scores indicate a predominantly predatory type of aggression, while lower scores
indicate primarily an affective or impulsive subtype. Severity of illness and improvement were assessed weekly on the CGI. The CPT
was administered at baseline and endpoint. The CPT consists of a
series of letters presented on a computer screen in rapid succession.
The subject is required to press a key whenever a target stimulus is
presented, and to refrain from pressing the key when the nontarget
stimulus is presented. The CPT generates separate measures of inattention and impulsivity. In addition, the parents completed the Child
Behavioral Checklist (CBCL) (Achenbach and Howell, 1993) at baseline and endpoint.
Adverse events, heart rate, blood pressure, and body weight were
determined at each weekly visit. Routine clinical laboratory studies
included complete blood cell count and differential, electrolytes, thyroid and kidney function tests, and urine analysis for toxicology and
pregnancy (females). These were conducted during the screening phase
and at week 6, or upon study withdrawal.
Statistical Method
Frequency and descriptive statistics were calculated to check all relevant characteristics of the data. The aggression and irritability scores
on the MOAS, the AQ, the CGI-Severity of Illness, and the CPT
were analyzed using repeated measures analysis of variance in a general linear model design. Mauchly’s (1940) test of sphericity was used
to evaluate the form of the variance–covariance matrix of the data
and whether the test was significant, and then the Greenhouse-Geisser
Epsilon adjustment was used when the sphericity assumption was violated. When a significant overall within-subjects F value was obtained,
marginal means were used to assess pairwise comparisons with the
least significant difference from the baseline value to the value at each
follow-up time point. Data on the CPT and CBCL, reported only at
baseline and discharge, were analyzed with paired-sample t tests. The
significance level for all analyses was p = .05.
After a 1-week washout period, subjects entered a 6-week open trial
of citalopram under careful clinical and laboratory monitoring. The
dose of citalopram was individually adjusted to obtain maximum benefits with minimal adverse effects. The initial dose of citalopram was
10 mg/day with weekly adjustments of 10 mg in either direction
depending on the prevalence of impulsive aggressive behaviors or the
emergence of side effects. No other psychotropic medications were
allowed during the trial.
Subjects were seen at weekly intervals and evaluated with standardized instruments and global assessments for efficacy. The primary
efficacy measure was the Modified Overt Aggression Scale (MOAS)
(Coccaro et al., 1991). The MOAS retrospectively measures four categories of aggression: (1) verbal aggression, (2) physical aggression
against self, (3) physical aggression against objects, and (4) physical
aggression against other people. The most severe aggressive event
within each category is multiplied by its designated weight factor and
Twelve subjects (10 males and 2 females) were enrolled
into the protocol. Their ages ranged from 7 to 15 years
old (mean = 10.22 years). Table 1 summarizes demographic
characteristics and baseline severity of disease on these
subjects. Their scores on the AQ predatory-affective index
ranged from –11 to 2, indicating that the primary subtype
of aggression was impulsive/affective. Therapeutic doses
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525
RESULTS
ARMENTEROS AND LEWIS
TABLE 1
Baseline Demographic Characteristics and Severity of Disease in 12 Subjects With Impulsive Aggression
Subject
Age
Gender
1
2
3
4
5
6
7
8
9
10
11
12 a
15
10
7
8
8
9
15
8
12
8
12
7
F
M
M
M
M
M
F
M
M
M
M
M
DSM-IV
Diagnoses
PredatoryAffective
Index
CGI
Severity
Maximum
Dose
(mg/day)
–4
–2
–6
–2
2
–11
–6
–6
–8
–1
–3
–4
5
4
5
4
5
6
5
6
5
5
5
5
20
30
30
40
20
40
40
40
40
40
20
20
ODD, CD
ADHD-C, CD
ODD, CD
ODD, CD, SP
ADHD-C, ODD, CD
ADHD-C, ODD, CD
ODD, CD, GA, SP
ADHD-C, ODD, CD
CD
ADHD-C, ODD, CD
ADHD-I, ODD, CD
ADHD-C
Note: ADHD-C = attention-deficit/hyperactivity disorder, combined; ADHD-I = attention-deficit/hyperactivity disorder,
inattentive; CD = conduct disorder; ODD = oppositional defiant disorder; SP = social phobia; GA = generalized anxiety disorder.
a
Subject 12 was discontinued from the study because of his high level of hyperactivity, requiring treatment with a stimulant medication.
nificantly different from baseline (F7 = 4.98, p < .001).
The weekly scores on the MOAS Aggression Against
Objects subscale were also significantly lower from baseline (F6 = 7.9, p < .001). The scores on the MOAS Verbal
Aggression, Aggression Against Self, and Aggression Against
Other People subscales were nonsignificantly different.
Total irritability scores were significantly reduced on weeks
1, 2, 5, and 6 compared with baseline (F7 = 2.95, p = .02).
Aggressive behaviors also decreased significantly as
measured by the parent’s report on the CBCL. Delinquent
behaviors, which are associated with predatory aggres-
of citalopram at endpoint ranged from 20 mg/day to 40
mg/day (mean = 27 mg/day). One subject was discontinued from the study because of his high level of hyperactivity, requiring treatment with a stimulant medication.
Medications used immediately before the trial and thus
required a washout period included methylphenidate, dextroamphetamine, sertraline, and carbamazepine.
For the 11 subjects who completed the study, marked
improvement was observed on measures of both overt
aggression and irritability on the MOAS (Table 2 and Fig.
1). Each weekly mean total score for aggression was sig-
TABLE 2
Modified Overt Aggression Scale (MOAS) Total Scores of Subjects Treated With Citalopram
Total Aggression Scores
Subject
1
2
3
4
5
6
7
8
9
10
11
Mean
SD
Total Irritability Scores
Baseline
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5
Wk 6
Baseline
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5
Wk 6
22
15
21
14
31
24
18
28
12
16
14
0
18
5
18
10
8
3
22
6
19
9
11
13
2
14
7
NA
10
NA
9
13
3
2
7
15
6
4
14
8
19
17
13
9
2
8
25
8
10
8
2
22
15
18
3
10
6
1
0
7
6
2
25
10
NA
6
3
3
2
0
9
3
1
6
15
25
3
8
6
5
5
6
6
7
5
5
3
6
2
1
3
6
0
6
0
6
2
8
9
1
4
1
7
0
NA
5
NA
6
6
3
2
3
5
2
6
6
1
5
8
6
7
0
4
6
5
0
2
4
6
6
7
3
0
2
0
2
2
6
2
6
7
NA
1
3
3
0
2
1
3
4
1
5
4
3
19.55
6.20
10.73
7.36
9.11
4.34
10.36
5.55
11.00
7.97
7.30
7.10
6.36
7.50
5.64
1.29
3.91
3.21
3.67
2.55
4.64
2.29
3.91
2.43
2.80
2.57
2.64
1.50
Note: Wk = week of study; NA = data are not available.
526
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CITALOPRAM FOR IMPULSIVE AGGRESSION
subjects who completed the protocol, only 4 experienced
mild adverse effects that included somnolence, headache,
drowsiness, and nightmares. In every case of somnolence,
the medication was shifted from morning administration
to bedtime administration. This strategy eliminated all
complaints of daytime somnolence. Treatment was not
discontinued in any of these cases because of adverse side
effects. Throughout the study, complete blood cell count
and differential, electrolytes, and thyroid and kidney function tests remained within normal limits.
DISCUSSION
Fig. 1 Temporal assessment of change in Modified Overt Aggression Scale
(MOAS) total aggression and irritability scores during a 6-week course of
citalopram in children and adolescents with impulsive aggression.
In this small, open trial of citalopram, children and
adolescents with several DSM-IV diagnoses had clinically
and statistically significant reductions in impulsive aggression from baseline to end of treatment across all measures. Citalopram affected both aggression and irritability
in 9 out of 11 subjects who completed the study, as measured by the MOAS. Moreover, our results suggest that
the effect of citalopram treatment on impulsive aggression is independent of other comorbid behavioral problems. Clinical improvement was confirmed by parental
reports on the CBCL.
In the present study, the subjects received several DSMIV diagnoses, and all had long standing histories of impulsive aggressive behavior. In all cases, the impulsive aggressive
behavior had failed to respond to other treatments.
All subjects enrolled in the study completed the 6-week
protocol with the exception of subject 12, resulting in a
modest attrition rate of 8.3%. The medication was very
well tolerated. We did not encounter the agitation and
behavioral disinhibition commonly associated with SSRI
sion (Vitiello et al., 1990; Vittiello and Stoff, 1997), were
nonsignificantly different. Internalizing problems, like
anxiety or depression, were also nonsignificantly different. We found a significant reduction in the total problems score on the CBCL, which resulted primarily from
a decrease in aggressive behaviors (Table 3).
Ratings on the CGI-Severity of illness, which consider
the total clinical experience of the rater with this particular population, also declined significantly at the end of
citalopram treatment (F7 = 5.78, p < .001). On the Global
Improvement item of the CGI at endpoint, which compares the current condition to the subject’s condition before
treatment, five subjects were rated as “Much Improved,”
four as “Improved,” zero as “Slightly Improved,” and two
as “Unchanged.” Citalopram had no effect on CPT scores.
Citalopram was generally well tolerated in this sample
and most adverse effects were not serious. Out of the 11
TABLE 3
Mean Child Behavior Checklist Scores of Subjects Treated With Citalopram
Baseline
Endpoint
Subscale
Mean
SD
Mean
SD
p Value
Withdrawn
Somatic Complaints
Anxious/Depressed
Social Problems
Thought Problems
Attention Problems
Delinquent Behavior
Aggressive Behavior
Internalizing Problems
Externalizing Problems
Total Problems
69.18
60.18
68.73
67.73
71.55
75.18
71.00
77.27
68.27
73.91
74.55
10.61
9.47
11.82
9.38
13.66
14.05
7.04
13.48
11.46
8.60
8.66
64.45
58.09
63.64
63.36
69.73
69.64
66.00
70.64
63.18
68.55
68.82
10.92
7.42
11.69
8.98
10.78
11.73
10.67
13.34
11.56
11.48
9.57
NS
NS
NS
NS
NS
p = .04
NS
p = .01
NS
p < .03
p < .02
Note: NS = not significant.
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527
ARMENTEROS AND LEWIS
treatment in children and adolescents. Subjects who
responded were continued on citalopram at the end of
the protocol. Follow-up of subjects after the protocol
ended was strictly clinical; therefore, research assessments
(e.g., MOAS or CGI) were not repeated. Our best clinical impression is that the benefits of citalopram were
maintained and adverse effects did not emerge anew for
up to a 4-month period.
These data support the hypothesis that a central serotonergic dysfunction leading to impulsive aggression could
be ameliorated by treatment with a specific SSRI. Further
studies need to correlate abnormalities on biological measures of central serotonergic functioning to demonstrate
clearly that the mechanism for reduced impulsive aggression is in fact an improvement in serotonergic functioning.
Reports of controlled clinical trials suggest that the
aggressive behaviors of many children with conduct disorder are significantly reduced during periods of baseline
inpatient hospitalization (Campbell et al., 1984; Cueva
et al., 1996; Malone et al., 1997). The aggressive behaviors are clearly affected by the change in environment,
because these children left their homes and were hospitalized, and by the hospital milieu and structure. Although
the participants in our study continued to live in the same
home environments, the possibility exists that weekly visits to the outpatient clinic could exert a therapeutic effect
on impulsive aggressive behaviors. This putative effect
would be independent of the psychopharmacological effect
of citalopram and similar to the “placebo effect” reported
elsewhere. A rigorous double-blind and placebo-controlled
study would be required to discern these competing effects.
The literature review and clinical experience indicate
that stimulants may be effective in reducing mild (Werry
and Aman, 1975), but not severe, forms of aggression
(Conners et al., 1971). More recent research indicates
that methylphenidate is effective in a clinical population
of children diagnosed with conduct disorder (Klein et al.,
1997). In this study, however, aggression was not a target symptom, and the instrument used, the Inattention/
Overactivity With Aggression Conners Teacher Rating
Scale (Goyette et al., 1978), does not differentiate between
predatory and impulsive types of aggression. Certainly,
in milder cases of aggressive behavior, a trial of stimulants would be indicated.
and the lack of multiple blind raters. Because the study
was not controlled, the observed improvement could have
been attributable solely to nonspecific treatment factors
(e.g., frequent visits to the clinic, attention to behavioral
problems) or the passage of time. However, in spite of these
shortcomings, our findings are in agreement with a controlled study of fluoxetine in adults with personality disorder and impulsive aggression (Coccaro et al., 1997). Our
results need to be replicated in a larger sample of patients
under double-blind and placebo-controlled conditions.
Clinical Implications and Conclusions
Although these considerations may limit our findings
with regard to efficacy, this study presents the first systematic report of citalopram in children and adolescents
with impulsive aggression. Clearly, a more extensive evaluation of the reliability and validity of the impulsive
aggression model would be necessary.
In this study, citalopram 20 to 40 mg daily was associated with clinically and statistically significant reduction in the impulsive aggression dimension irrespective
of DSM-IV diagnostic category. These preliminary results
are favorable and suggest that citalopram is effective and
well tolerated in children and adolescents. A critical assessment of efficacy and safety of citalopram under doubleblind and placebo-controlled conditions seems justified.
REFERENCES
Some of the limitations of this study include the small
number of subjects, the uncontrolled nature of the trial,
Achenbach TM, Howell CT (1993), Are American children’s problems getting worse? A 13-year comparison. J Am Acad Child Adolesc Psychiatry
32:1145–1154
American Psychiatric Association (1994), Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSM-IV). Washington, DC: American
Psychiatric Association
Asberg M, Traksman L, Thoren P (1976), 5 HIAA in the cerebrospinal fluid:
a biochemical suicide predictor? Arch Gen Psychiatry 33:1193–1197
Atkins MS, Stoff DM, Osborne ML, Brown K (1993), Distinguishing instrumental and hostile aggression: does it make a difference? J Abnorm Child
Psychol 21:355–365
Barratt ES, Stanford MS, Kent TA, Felthous A (1997), Neuropsychological
and cognitive psychophysiological substrates of impulsive aggression. Biol
Psychiatry 41:1045–1061
Brener ND, Simon TR, Krug EG, Lowry R (1999), Recent trends in violencerelated behaviors among high school students in the United States. JAMA
282:440–446
Brown GL, Goodwin FK, Ballenger JC, Goyer PF, Major LF (1979), Aggression
in humans correlates with cerebrospinal fluid amine metabolites. Psychiatry
Res 1:131–139
Campbell M, Small AM, Green WH et al. (1984), Behavioral efficacy of haloperidol and lithium carbonate: a comparison in hospitalized aggressive
children with conduct disorder. Arch Gen Psychiatry 41:650–656
Coccaro EF, Harvey PD, Kupsaw-Lawrence E, Herbert JL, Bernstein DP
(1991), Development of neuropharmacologically based behavioral assessments of impulsive aggressive behavior. J Neuropsychiatry Clin Neurosci
3:S44–S51
528
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 5 , M AY 2 0 0 2
Limitations
CITALOPRAM FOR IMPULSIVE AGGRESSION
Coccaro EF, Kavoussi RJ (1997), Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 54:1081–1088
Coccaro EF, Siever LJ, Klar HM et al. (1989), Serotonergic studies in patients
with affective and personality disorders. Arch Gen Psychiatry 46:587–599
Conners CK (1995), Conners’ Continuous Performance Test II: Computer Program
for Windows; Technical Guide and Software Manual. Toronto: Multi-Health
Systems
Conners CK, Kramer R, Rothschild GH, Schwartz L, Stone A (1971), Treatment
of young delinquent boys with diphenylhydantoin sodium and methylphenidate. Arch Gen Psychiatry 24:156–160
Cueva JE, Overall JE, Small AM, Armenteros JL, Perry R, Campbell M (1996),
Carbamazepine in aggressive children with conduct disorder: a doubleblind and placebo-controled study. J Am Acad Child Adolesc Psychiatry
35:480–490
Fava M, Rosenbaum JF, Pava JA, McCarthy MK, Steingard RJ, Bouffides E
(1993), Anger attacks in unipolar depression, I: clinical correlates and
response to fluoxetine treatment. Am J Psychiatry 150:1158–1163
Frick PJ, Lahey BB, Applegate B et al. (1994), DSM-IV field trials for the disruptive behavior disorders: symptom utility estimates. J Am Acad Child
Adolesc Psychiatry 33:529–539
Gadow KD, Sprafkin J (2000), Child Symptom Inventories Manual. Stony
Brook, NY: Checkmate Plus
Gordon CT, State RC, Nelson JE, Hamburger SD, Rapoport JL (1993), A
double-blind comparison of clomipramine, desipramine, and placebo in
the treatment of autistic disorder. Arch Gen Psychiatry 50:441–447
Goyette CH, Connors CK, Ulrich RF (1978), Normative data on revised
Conners parent and teacher rating scales. J Abnorm Child Psychol 6:221–236
Halperin JM, Newcorn JH, Matier K, Bedi G, Hall S, Sharma V (1995),
Impulsivity and the initiation of fights in children with disruptive behavior disorders. J Child Psychol Psychiatry 36:1199–1211
Halperin JM, Sharma V, Siever LJ et al. (1994), Serotonergic function in aggressive and nonaggressive boys with attention deficit hyperactivity disorder.
Am J Psychiatry 151:243–248
Higley JD, Mehlman PT, Taub DM et al. (1992), Cerebrospinal fluid monoamine
and adrenal correlates of aggression in free-ranging rhesus monkeys. Arch
Gen Psychiatry 49:436–441
Hyttel J (1982), Citalopram: pharmacological profile of a specific serotonin
uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol
Biol Psychiatry 6:277–295
Katz RJ (1980), Role of serotonergic mechanisms in animal models of predation. Prog Neuropsychopharmacol Biol Psychiatry 4:219–231
Kaufman AS, Kaufman NL (1990), Kaufman Brief Intelligence Test. Circle
Pines, MN: American Guidance Services
Klein RG, Abikoff H, Klass E, Ganeles D, Seese LM, Pollck S (1997), Clinical
efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Arch Gen Psychiatry 54:1073–1080
Kruesi MJ, Rapoport JL, Hamburger S et al. (1990), Cerebrospinal fluid
monoamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents. Arch Gen Psychiatry 47:419–426
Linnoila M, Virkunen M, Scheinin M, Nuutila A, Rimon R, Goodwin FK
(1983), Low cerebrospinal fluid 5-hydroxyindolacetic acid concentration
differentiates impulsive from nonimpulsive violent behavior. Life Sci
33:2609–2614
Malone RP, Bennett DS, Luebbert JF et al. (1998), Aggression classification
and treatment response. Psychopharmacol Bull 34:41–45
Malone RP, Luebbert JF, Delaney MA et al. (1997), Nonpharmacological
response in hospitalized children with conduct disorder. J Am Acad Child
Adolesc Psychiatry 36:242–247
Mann JJ, McBride PA, Malone KM, DeMeo MD, Keilp J (1995), Blunted
serotonergic responsivity in depressed patients. Neuropsychopharmacology
13:53–64
Mauchly JW (1940), Significance test for sphericity of a normal n-variate distribution. Annu Math Stat 11:204–209
McDougle C, Nylor S, Cohen D, Volkmar F, Heninger G, Price L (1996), A
double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 53:1001–1008
Meltzer HY, Lowy MT (1987), The serotonin hypothesis of depression. In:
Psychopharmacology: Third Generation of Progress, Meltzer HY, ed. New
York: Raven, pp 513–526
Pine DS, Coplan JD, Wasserman GA et al. (1997), Neuroendocrine response
to fenfluramine challenge in boys: associations with aggressive behavior
and adverse rearing. Arch Gen Psychiatry 54:839–846
Psychopharmacology Bulletin (1985), Special feature: rating scales and assessment instruments for use in pediatric psychopharmacology research
21:731–733
Public Health Service (1991), Healthy People 2000: National Health Promotion
and Disease Prevention Objectives—Full Report With Commentary. Washington,
DC: US Department of Health and Human Services
Seroczynski AD, Bergeman CS, Coccaro EF (1999), Etiology of the impulsivity/aggression relationship: genes or environment? Psychiatry Res 86:41–57
Sewell RG, Galus JA, Gault FP, Cleary JP (1982), P-Chlorophenylalanine
effects on shock-induced attack and pressing responses in rats. Pharmacol
Biochem Behav 17:337–340
Sheard MH, Marini JL, Bridges CI, Wagner E (1976), The effect of lithium
on impulsive aggressive behavior in man. Am J Psychiatry 133:1409–1413
Siegel A, Roeling T, Gregg TR, Kruk MR (1999), Neuropharmacology of
brain-stimulation-evoked aggression. Neurosci Biobehav Rev 23:359–389
Tiihonen J, Schwartz E, Petrilli R (1993), Eltoprazine for aggression in schizophrenia and mental retardation. Lancet 341:307
van Praag HM, Kahn RS, Asnis GM et al. (1987), Denosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric
disorders. J Affect Disord 13:1–8
Vartiainen H, Tiihonen J, Putkonen A et al. (1995), Citalopram, a selective
serotonin reuptake inhibitor, in the treatment of aggression in schizophrenia. Acta Psychiatr Scand 91:348–351
Vitiello B, Behar D, Hunt J, Stoff D, Ricciuti A (1990), Subtyping aggression
in children and adolescents. J Neuropsychiatry Clin Neurosci 2:189–192
Vitiello B, Stoff DM (1997), Subtypes of aggression and their relevance to
child psychiatry. J Am Acad Child Adolesc Psychiatry 36:307–315
Volavka J, Crowner M, Brizer D (1990), Tryptophan treatment of aggressive
psychiatric inpatients. Biol Psychiatry 28:728–732
Werry JS, Aman MG (1975), Methylphenidate and haloperidol in children:
effects on attention, memory and activity. Arch Gen Psychiatry 32:790–795
White JL, Moffitt TE, Caspi A, Bartuch JB, Needles DJ, Stouthamer-Loeber
M (1994), Measuring impulsivity and examining its relationship to delinquency. J Abnorm Psychol 103:192–205
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 1 : 5 , M AY 2 0 0 2
529