Chapter 11

Science-Based Treatment of
Aggression and Agitation
by Leslie Citrome, M.D., M.P.H., Karen A. Nolan, Ph.D.,
and Jan Volavka, M.D., Ph.D.

Introduction and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-2

The Science-Based Study of Aggression and Agitation—
From Rats to Man . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-3
Aggression Among Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-3
Biology of Human Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-4
Psychopathy and Related Matters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-5
Classification of Assaults: Implications for Treatment . . . . . . . . . . . . . . 11-5
Science-Based Treatment of Agitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-6
Nonpharmacological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-6
Medication: Calming Agents vs. Sedation . . . . . . . . . . . . . . . . . . . . . . . 11-6
Lorazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-7
Haloperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-7
Haloperidol and Lorazepam Combination . . . . . . . . . . . . . . . . . 11-8
Droperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-8
Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-9
Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-9
Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-10
Science-Based Treatment of Persistent Aggressive Behavior . . . . . . . . . . . . . . 11-10
Nonpharmacological Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-11
Behavioral Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-11
Cognitive Behavior Modification . . . . . . . . . . . . . . . . . . . . . . . 11-12
Therapeutic Communities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-12
Dialectical Behavior Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 11-13
Pharmacological Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-13
Dependent Variables Used in Pharmacological Research . . . . . . . . . . . 11-13
Study Designs: From N=1 Case Reports to Randomized
Double-Blind Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-14
The Role of Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-15
Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-15
Clozapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-15
Copyright © 2004 Civic Research Institute, Inc., 4478 US Route 27, Kingston, NJ 08528. This is a
copy of a chapter from The Science, Treatment, and Prevention of Antisocial Behaviors: Evidence-
Based Practice, Diana H. Fishbein, Ed. To order the book, call 609-683-4450, or visit the publish-
er's website: www.civicresearchinstitute.com.
11-2 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-16
Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-17
Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-17
Anticonvulsants and Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-18
Valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-19
Carbamazapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-19
Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-20
Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-20
Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-20
Other Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-20
Beta-Adrenergic Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-21
Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-21
Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-21
Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-22
Adjunctive Electroconvulsive Therapy . . . . . . . . . . . . . . . . . . . 11-23
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-23

INTRODUCTION AND DEFINITIONS

Aggressive and violent behavior is a frequent reason for referral for mental health
treatment. It is often an obstacle for reintegration back into the community or gener-
al population in forensic settings. Aggressive behavior places other patient-offenders
and staff at risk for harm. Fortunately, there has been progress in the past decade in
developing new treatment approaches for this problem. This chapter may serve as a
resource, based on the latest scientific findings, for agencies, clinicians, or correc-
tional facilities attempting to modernize strategies for humanely subduing aggressive
behavior.
Treatment approaches for agitation and aggression center around two strategies:
• The rapid management of acute agitation, and
• The prevention, or reduction in intensity and frequency, of future episodes.
The methods differ in terms of both behavioral interventions and medication
selection. For the former, broad-spectrum sedating/calming agents are used to quell
acute episodes of agitation. For the latter, medication is chosen based on the specific
underlying mental disorder responsible for the aggressive behavior. This is complicat-
ed by diagnostic uncertainty, the presence of comorbid disorders, and failure of med-
ication regimens that otherwise should have resulted in improvement. Diagnostic and
therapeutic challenges are frequently encountered; for example, some offender
patients are violent only when acutely psychotic, while others may be persistently
aggressive and not exhibiting delusions or hallucinations. This may be due to neu-
ropsychiatric deficits, or character pathology (such as psychopathy), or both. Co-
occurring substance abuse may also greatly increase the risk for violence.
In reviewing the literature, the term “agitation” usually denotes excessive motor
or verbal activity. “Aggression” is defined as overt behavior involving intent to deliv-
er noxious stimulation or to behave destructively. Humans demonstrate three main
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-3

subtypes of aggression: verbal aggression, physical aggression against other people,

and physical aggression against objects. “Violence” denotes physical aggression
against other people and thus can be seen as a subtype of aggression. “Hostility” is ill-
defined in the psychiatric literature. Hostility may include agitation, aggression, irri-
tability, suspicion, uncooperativeness, and jealousy, depending on the context in
which the word is used. When hostility is used when describing results from a rating
scale such as the Positive and Negative Syndrome Rating Scale (PANSS) (Kay,
Fiszbein, & Opler, 1987), the definition includes both verbal and physical behavior.
The PANSS definition for the hostility item reads: “Verbal and nonverbal expressions
of anger and resentment, including sarcasm, passive-aggressive behavior, verbal abuse
and assaultiveness.” Ratings range from 1 (“hostility absent”) to 7 (“extreme hostility
that includes marked anger resulting in extreme uncooperativeness, precluding other
interactions, or in episode(s) of physical assault toward others”) (Kay et al., 1987).
This chapter reviews some of the biological underpinnings of aggressive behavior
and discusses treatment approaches that can be applied to an inpatient, an inmate pop-
ulation, or other adult group prone to violence. The emphasis will be on psychophar-
macological approaches. Although the bulk of the evidence discussed here centers
around individuals with schizophrenia and psychiatric disorders often characterized
by aggression, other diagnostic entities, including dementia, are mentioned where
appropriate.

THE SCIENCE-BASED STUDY OF AGGRESSION AND

AGITATION—FROM RATS TO MAN
Aggression Among Animals
Mammals, including humans, share a considerable amount of neurobiology that
underlies aggressive behavior and its control. Studies in animals such as rodents or
nonhuman primates have thus provided information that has implications for the
understanding of human aggression.
Valzelli and Garattini (1968) first discovered the importance of serotonin in the
inhibitory control of aggression in rodents. Experimental suppression of the seroton-
ergic system by a dietary reduction of serotonin precursor (Gibbons, Barr, Bridger, &
Leibowitz, 1979) or by blocking serotonin synthesis (Gibbons, Barr, Bridger, &
Leibowitz, 1978) increases aggressive behavior in the rat. Furthermore, increased
aggression and concomitant decrease of brain serotonin levels were observed in adult
male mice that had been exposed to alcohol during gestation (Krsiak, Elis, Poschlova,
& Masek, 1977).
There is a recent report that a specific gene, Pet-1 ETS, is critical in differentia-
tion of serotonergic neurons and that mice lacking Pet-1 show heightened anxiety-like
and aggressive behavior (Hendricks et al., 2003).
Levels of 5-hydroxyindoleacetic acid (5-HIAA), a principal serotonin metabolite,
can be assayed in the cerebrospinal fluid (CSF). These levels are believed to reflect
serotonergic activity in the brain. Aggressiveness of rhesus monkeys was inversely
related to the CSF levels of 5-HIAA; these observations provided additional evidence
for the role of serotonin in controlling aggression (Higley et al., 1992).
Experimental enhancement of central noradrenergic or dopaminergic function
generally increases aggressive behavior in animals. The inactivation of these cate-
11-4 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

cholamines is effected by catechol-O-methyltransferase (COMT), and by monoamine

oxidase (MAO-A and MAO-B). Since a reduction of the catecholaminergic activity
should lead to decreased aggressiveness, COMT and MAO would be expected to play
a role in the regulation of aggressive behavior: low activity of these enzymes could
increase aggression. Indeed, male mice whose COMT gene (Gogos et al., 1998) or
MAO-A gene (Cases et al., 1995) was experimentally inactivated (knockout mice) did
show increased aggressiveness.

Biology of Human Aggression

The vast literature on this subject has been reviewed elsewhere (Volavka, 2002);
here we provide a basic introduction. Twin studies have provided evidence of genetic
effects on aggressive behavior, impulsiveness, and irritability (Coccaro, Bergeman,
Kavoussi, & Seroczynski, 1997; Miles & Carey, 1997). These genetic effects interact
with prenatal and postnatal environmental factors. Prenatal factors that may lead to
aggression and other antisocial activities in adolescence and adulthood include mater-
nal smoking (Brennan, Grekin, Mortensen, & Mednick, 2002) and malnutrition
(Neugebauer, Hoek, & Susser, 1999) during pregnancy. Postnatal factors include brain
injuries, particularly those affecting the ventromedial frontal areas (Grafman et al.,
1996).
The role of serotonin in the inhibitory control of aggression has been document-
ed in humans. CSF 5-HIAA levels were inversely related to the lifetime history of
aggression in young human males (Brown, Goodwin, Ballenger, Goyer, & Major,
1979), a finding strikingly similar to that reported in rhesus monkeys (Higley et al.,
1992). The association between impulsive aggression and a dysfunction of the sero-
tonergic system has been repeatedly replicated.
Since aggressive behavior is heritable and serotonin is implicated, genes that code
for proteins involved in serotonergic activity are candidates for roles in the regulation
of aggression. Studies focusing on the genes coding for tryptophan hydroxylase and
serotonin transporter are yielding promising results that need to be replicated.
Human studies of catecholamines in aggression have been less extensive than
those of serotonin. It appears that irritability, and perhaps increased readiness to
engage in overt aggression, are mediated by noradrenergic mechanisms. Impulsive
assaultive behavior was reported in eight related males with a mutation affecting the
MAO-A gene, with a corresponding reduction of the MAO-A activity (Brunner,
Nelen, Breakefield, Ropers, & van Oost, 1993); this observation is consistent with the
report on MAO-A knockout mice (Cases et al., 1995).
A common bi-allelic polymorphism in the COMT gene is associated with a three-
to fourfold difference in the COMT enzymatic activity between homozygous subjects.
Males with schizophrenia who have a history of persistent aggressive behavior are
more likely to have the allele that codes for the low COMT enzymatic activity
(Lachman, Nolan, Mohr, Saito, & Volavka, 1998; Strous, Bark, Parsia, Volavka, &
Lachman, 1997; Kotler et al., 1999). These findings are consistent with the observa-
tions in knockout mice (Gogos et al., 1998), but they have not been replicated in at
least one study of schizophrenia (Jones et al., 2001). Molecular genetic studies of
aggression are in progress. Such studies may ultimately result in novel methods for
prevention and treatment of aggressive behavior.
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-5

Psychopathy and Related Matters

Antisocial personality disorder (ASPD) and psychopathy are closely related terms
and are often (but mistakenly) used interchangeably. The psychopathic personality is
characterized by superficial charm, unreliability, insincerity, lack of remorse, and
pathological egocentricity and incapacity for love (Cleckley, 1955). Current criteria
for psychopathy include these personality traits as well as a history of repeated viola-
tion of social norms (Hare, 1991). The Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV-TR; American Psychiatric Association, 2000) diagnostic criteria
for ASPD emphasize overt antisocial behaviors rather than personality traits per se.
Most psychopaths also meet the criteria for ASPD. However, psychopathy is a nar-
rower concept and a diagnosis of ASPD does not necessarily imply that the full crite-
ria for psychopathy are met (Hare, 1996).
ASPD and psychopathy are both strongly associated with criminality and violence
(Alm et al., 1996; Belmore & Quinsey, 1994; Hare, 1988) and specifically with vio-
lent crime (Blackburn & Coid, 1999). Convictions for violent crime are more common
among psychopaths (85 percent) than nonpsychopaths (54 percent) and psychopaths
are responsible for more violence in prisons (Hare & McPherson, 1984). Formally
diagnosed psychopathy is a strong predictor of violent recidivism (Grann, Långström,
Tengström, & Kullgren, 1999). A diagnosis of psychopathy is associated with three-
to fourfold increase in risk for violent reoffending after release (Hare, 1991; Harris,
1993).
Both genetic and environmental factors appear to influence the development of
antisociality (Caspi et al., 2002; Rhee & Waldman, 2002). It has been hypothesized
that autonomic underarousal (reflected by, e.g., low resting heart rate), which is a hall-
mark of psychopathic/antisocial populations, confers a predisposition for the devel-
opment of “fearlessness,” leading to violent and antisocial behavior (Raine, 1997).
Fearlessness and stimulation-seeking at age three has been correlated with aggressive
behavior at age eleven (Raine, Reynolds, Venables, Mednick, & Farrington, 1998b).
Antisocial subjects have also been found to have reduced autonomic response to stres-
sors and heightened autonomic arousal may exert a protective effect against the devel-
opment of criminality (Brennan et al., 1997). Some studies have reported poor per-
formance on measures of executive/prefrontal function in antisocial/psychopathic
subjects (Bergvall, Wessely, Forsman, & Hansen, 2001; Dolan, Deakin, Roberts, &
Anderson, 2002). Siever (1998) has suggested that a combination of abnormalities
affecting both prefrontal cortex and serotonergic regulation provide the key substrates
for aggressive psychopathy.

Classification of Assaults: Implications for Treatment

As illustrated above, there are numerous causes of aggression. The causal classi-
fication of acts of violence therefore offers a potential means for targeting anti-aggres-
sive treatments to particular type(s) of aggression. The distinction between impulsive
and premeditated aggression appears to be a valid one: individuals who commit
impulsive acts of violence differ from those whose violence is premeditated in terms
of neurocognitive abilities and psychophysiological measures of information process-
ing (Barratt, Kent, & Felthous, 1997a), in regional brain glucose metabolism (Raine
11-6 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

et al., 1998a), and in response to pharmacologic intervention (Barratt, Stanford,

Felthous, & Kent, 1997b). However, dichotomous classifications may obscure the fact
that a single aggressive act may arise from a mixture of causes and motivations. We
recently completed a study (Nolan et al., 2003) in which we attempted to learn the rea-
sons for assaults committed by psychiatric inpatients. We hypothesized that assaultive
behavior in this population could be related to positive psychotic symptoms, disor-
dered impulse control, and psychopathy, and we constructed an interview-based mea-
sure to elicit information regarding the reasons for assaults from assailants, victims,
and witnesses. Both consensus clinical ratings and factor analysis of the interview
data indicated that approximately 20 percent of the assaults were directly related to
positive psychotic symptoms. Factor analysis revealed two additional factors: one was
related to psychotic confusion and disorganization and the other differentiated impul-
sive versus psychopathic assaults. Many assaults had high scores on more than one
factor and multiple contributing causes could be discerned.
Although further research is needed to evaluate the degree to which an individ-
ual’s aggressive behavior is dominated by one or more of these factors, these obser-
vations suggest that the effectiveness of anti-aggressive treatment strategies may be
enhanced by identifying and targeting specific causal contributors.

SCIENCE-BASED TREATMENT OF AGITATION

Nonpharmacological Interventions
Behavioral and psychological interventions are used simultaneously with medica-
tion approaches (Citrome & Green, 1990). Minimizing use of restraint or seclusion
may be possible by intervening early. If restraint or seclusion is ultimately necessary,
this is the time when the risk for injury for both staff and offending patients is highest.
General advice includes the need to survey the environment for potential
weapons, to not turn your back on the agitated offender, and to have other staff avail-
able. Take verbal threats seriously and be alert to physical premonitory signs such as
a clenched fist and pacing.
Initially, an agitated patient-offender should be isolated from other patient-offend-
ers and from distractions, because extraneous stimulation can intensify psychosis in
an offender who may be hallucinating, paranoid, and agitated. Moreover, other
patient-offenders may intentionally or inadvertently interfere with treatment.
Generally it is easier to clear the area of many calm patient-offenders than to move
one dangerous individual.

Medication: Calming Agents vs. Sedation

Sedation has been the mainstay in the management of acute agitation. However,
excessive sedation makes it difficult, if not impossible, to conduct a thorough psychi-
atric examination. Thus a more therapeutic goal is to produce a state of calmness,
rather than drowsiness.
Early intervention is important to arrest the progression of agitation to frank
aggression or violence. In addition to behavioral interventions enumerated above,
medication should be offered early.
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-7

Intramuscular administration of a medication results in a higher maximum plasma

concentration (Cmax) in a shorter period of time (Tmax). It is believed that the higher
the plasma concentration, the greater the calming or sedating effect. The recommend-
ed dosing outlined below usually results in adequate efficacy, but certain vulnerable
populations such as children, adolescents, the elderly, and the medically ill, may need
substantially lower doses to avoid oversedation. Others may need higher or repeated
doses to obtain a therapeutic response. The use of an intramuscular formulation must
be balanced against the possibility of using an oral formulation that may be more read-
ily acceptable to the patient-offender. It is also not uncommon for a patient-offender to
readily calm down after an oral dose, even before plasma levels are measurable.
Until recently, the choices of intramuscular agents for behavioral emergencies has
been limited. First generation typical antipsychotics (such as haloperidol or chlorpro-
mazine) as well as benzodiazepines (notably lorazepam) have been commonly used.
In 2002, an intramuscular formulation of ziprasidone was commercially released, and
in 2004 an intramuscular formulation of olanzapine became available. These atypical
antipsychotics provide a new treatment option for the management of agitation
(Citrome, 2002). The principal distinguishing feature between typical and atypical
antipsychotics is that these newer agents have a much lower propensity to cause
extrapyramidal symptoms (EPS). Thus the risk of an acute dystonic reaction is great-
ly diminished when using atypical antipsychotics compared to older agents such as
haloperidol. The risk of akathisia is also diminished, eliminating an iatrogenic cause
for agitation. These new formulations of atypical antipsychotics also provide the
opportunity for a smooth transition to oral dosing to the same agent once the acute
agitation is appropriately managed, which may be an advantage in preventing future
episodes of agitation. Intramuscular formulations of commonly used agents are out-
lined in Table 11.1.

Lorazepam. Lorazepam is the only benzodiazepine that is reliably absorbed when

administered intramuscularly and is commonly used as a treatment for agitation. It has
a relatively short half-life and no active metabolites (Salzman, 1988; Greenblatt et al.,
1979; Greenblatt, Divoll, Harmatz, & Shader, 1982). Because of the cross-tolerance
of benzodiazepines with alcohol, using lorazepam may be ideal when managing an
agitated patient-offender withdrawing from alcohol. Caution is required when respi-
ratory depression is a possibility, for example in the obese patient with pulmonary dis-
ease or with a history of sleep apnea. Because of the problems associated with toler-
ance, dependence, and withdrawal, lorazepam is not recommended for long-term daily
use. Paradoxical reactions to benzodiazepines, as exhibited by hostility or violence are
uncommon (Dietch & Jennings, 1988), occurring perhaps somewhat more frequently
in the elderly.

Haloperidol. Haloperidol is perhaps the most commonly used typical antipsychotic.

It is available in a short-acting intramuscular formulation, and this formulation is fre-
quently used as a sedating agent (Clinton, Sterner, Stelmachers, & Ruiz, 1987). Its
advantage over the low potency typical antipsychotics (e.g., chlorpromazine) is that it
causes less hypotension, fewer anticholinergic side effects, and less of a decrease in
the seizure threshold. However, the use of haloperidol carries the risk of an acute dys-
tonic reaction, which is quite distressing for the patient and can lead to reluctance to
11-8 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

Table 11.1
Pharmacological Options for Acute Agitation—Intramuscular Agents

Agent Dose (mg) Half-life (hours) Comments

Lorazepam 0.5 to 2.0 10–20 Useful for withdrawal

from alcohol, but no
significant antipsychot-
ic effect.
Haloperidol 0.5 to 7.5 12–36 Propensity toward
EPS, including acute
dystonia and akathisia.
Can combine with
lorazepam in the same
syringe.
Droperidol 2.5-5.0 2 QTc prolongation.
Withdrawn in UK.
Ziprasidone 10-20 2.2 – 3.4 Favorable EPS profile.
Bolded warning for
QTc prolongation in
product labeling.
Olanzapine 10 (2.5 for patients 34–38 Favorable EPS profile.
with dementia) No significant effect on
QTc.

take any antipsychotic medication. Haloperidol can also cause akathisia, whose atten-
dant feeling of inner restlessness may itself provoke violent behavior (Keckich, 1978;
Siris, 1985).

Haloperidol and Lorazepam Combination. Another alternative is to combine

haloperidol (5 mg) and lorazepam (2 mg) in the same syringe. This combination has
a lower propensity for extrapyramidal side effects than haloperidol alone and a faster
onset of action, and fewer injections are necessary to achieve the desired amount of
sedation (Battaglia et al., 1997; Hughes, 1999). However, the continued use of
haloperidol is suboptimal in the treatment of offenders with persistent aggressive
behavior (see below).

Droperidol. Droperidol is not FDA-approved for psychiatric conditions but has been
used for sedating agitated patient-offenders in an emergency room setting (Thomas,
Schwartz, & Petrilli, 1992). Structurally similar to haloperidol, it is used most often
for the induction of anesthesia. It has a rapid onset of action and a less severe
extrapyramidal side effects profile compared with haloperidol. However, droperidol
causes a dose-dependent prolongation of the QT interval (Lischke et al., 1994), and
concern over this has led to the withdrawal of this product in the United Kingdom
market and a new “black box” warning in the product’s labeling in the United States.
The use of droperidol as treatment for agitation is declining.
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-9

Ziprasidone. Oral ziprasidone was commercially released in 2001, and the intramus-
cular formulation became generally available in 2002. Premarketing clinical trials
demonstrated efficacy of both a 10 mg and a 20 mg dose in reducing acute agitation
in approximately 200 patients with schizophrenia and schizoaffective disorder
(Lesem, Zajecka, Swift, Reeves, & Harrigan, 2001; Daniel, Potkin, Reeves, Swift, &
Harrigan, 2001). Peak plasma concentrations after an intramuscular dose of ziprasi-
done are achieved in thirty to forty-five minutes, compared with eight hours (with
half-life of 3.8 hours) with oral dosing (Pfizer, 2001). Cmax was higher with a 20 mg
injection of ziprasidone compared with a 10 mg injection, probably explaining the
greater efficacy of the higher dose. Significant improvement with 20 mg was
observed at thirty minutes post-injection (Daniel et al., 2001). The improvement with
the 20 mg dose increased until two hours and was maintained until at least four hours
post-dose. The number of 20 mg injections needed to achieve the desired outcome was
one (42 percent) or two (37 percent) (Daniel et al., 2001). Overall intramuscular
ziprasidone was well tolerated and almost free of extrapyramidal side effects at doses
up to 80 mg per day (Pfizer, 2001).
The most common treatment-emergent adverse events at the 10 mg and 20 mg
doses are nausea, headache, and dizziness. As per the product package insert, the rec-
ommended dose is 10 to 20 mg, administered as required, up to a maximum dose of
40 mg per day. Doses of 10 mg may be administered every two hours and of 20 mg
every four. The practice of co-administration of oral and intramuscular ziprasidone is
not recommended. The magnitude of QTc, or QT (corrected), increases with intra-
muscular ziprasidone is comparable to that described for oral ziprasidone. Because of
this effect, the product package insert contains a warning that ziprasidone should not
be used with other drugs that are known to prolong the QTc interval, in patients with
congenital long QT syndrome, and in those with a history of cardiac arrhythmias,
often seen in cocaine addicts. However, the actual clinical significance of these
changes in QTc interval remains in doubt. No clinically meaningful changes in QTc
interval were noted with either ziprasidone or haloperidol in a six-week open-label
study comparing sequential IM/oral ziprasidone with sequential IM/oral haloperidol
(Brook, 2003).

Olanzapine. Oral olanzapine was commercially released in 1996, and the intramus-
cular formulation became available in 2004. Premarketing clinical trials demonstrat-
ed efficacy of olanzapine in reducing acute agitation in approximately 1,050 patients
with schizophrenia, schizoaffective disorder, bipolar disorder, and dementia (Eli Lilly,
2001; Wright et al., 2001, Breier et al., 2002; Meehan et al., 2001, 2002). Peak plas-
ma concentrations after an intramuscular dose of olanzapine are achieved in fifteen to
thirty minutes, compared with three to six hours with oral dosing (Eli Lilly, 2001).
Onset of efficacy of intramuscular olanzapine (10 mg) is rapid, occurring as early as
fifteen minutes, and superior to intramuscular haloperidol (7.5 mg) among patients
with schizophrenia (Wright et al., 2001). An analogous study with bipolar mania
revealed similar findings with onset of efficacy seen as early as thirty minutes, with
superiority to intramuscular lorazepam (2 mg) (Meehan et al., 2001). Intramuscular
olanzapine exhibited less extrapyramidal side effects compared with intramuscular
haloperidol. No adverse event was significantly more frequent for intramuscular olan-
zapine than intramuscular haloperidol or intramuscular lorazepam. A single injection
11-10 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

of olanzapine 10 mg achieved the desired outcome in 76 percent of the cases (Breier

et al., 2002). Current product labeling recommends a dose of 10 mg per injection for
adults with agitation associated with schizophrenia or bipolar mania. Intramuscular
olanzapine is not yet FDA-approved for agitation associated with dementia; however,
the dose likely to be recommended should approval be granted for that indication is
2.5 mg per injection. In contrast to ziprasidone, there is no evidence for any signifi-
cant QTc interval prolongations with olanzapine (Lindborg, Beasley, Alaka, & Taylor,
2003).
Oral olanzapine has also been used in the treatment of agitation. Baker, Kinon,
Maguire, Liu, and Hill (2003) recently reported the results of a double-blind, multi-
center study of a loading-dose strategy for olanzapine, in which 148 patients with
schizophrenia, schizoaffective, schizophreniform disorder, or bipolar I disorder were
randomized to receive either a minimum of olanzapine 20 mg/day (up to 40 mg on the
first and second day and up to 30 mg on the third and fourth) or olanzapine 10 mg/day
(with lorazepam as needed). Although improvement on measures of agitation
occurred in both groups, higher olanzapine dosing was significantly more effective,
and this difference was first significant at the twenty-four-hour rating. No statistical-
ly significant differences between groups existed in treatment-emergent adverse
events or potentially clinically significant laboratory abnormalities. However, the
patients in the high dose group were twice as likely to experience headache and dizzi-
ness. Additional work in this area is anticipated, including the use of a new rapidly dis-
integrating tablet of olanzapine commercially available since 2000.

Risperidone. Oral risperidone liquid has been used as an alternative to intramuscular

injections of haloperidol. Currier and Simpson (2001) demonstrated this use in a
prospective, nonrandomized, rater-blinded study of sixty patients that compared the
combination of liquid risperidone (2 mg) and oral lorazepam (2 mg) to the combina-
tion of intramuscular haloperidol (5 mg) and intramuscular lorazepam (2 mg) for
treatment of psychotic agitation. They reported no adverse events for the oral treat-
ment group, but one patient in the intramuscular haloperidol treatment group devel-
oped acute dystonia within twenty-four hours. One patient receiving oral risperidone
treatment required intramuscular haloperidol for continued agitation; otherwise
results between the two approaches were comparable. Currier, Gharabawi, Morein,
Mahmoud, and Simpson (2002) compared these treatments again in a recently report-
ed randomized multicenter clinical trial involving 162 patients and using blinded
raters. Oral risperidone was as effective as intramuscular haloperidol in controlling
acute psychotic behavioral disorders in an acute setting, without the over-sedation
sometimes observed with haloperidol. Further studies with risperidone monotherapy
are anticipated, including the use of a rapidly disintegrating tablet that became com-
ercially available in 2003.

SCIENCE-BASED TREATMENT OF PERSISTENT AGGRESSIVE

BEHAVIOR
Once the acute episode of agitation is appropriately managed the goal is to
decrease the frequency and intensity of future aggressive behavior. This may require
special treatment settings such as secure or psychiatric intensive care units (Musisi,
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-11

Wasylenki, & Rapp, 1989; Goldney, Bowes, Spence, Czechowicz, & Hurley, 1985;
Warneke, 1986; Citrome, Green, & Fost, 1995; Maier, Stava, Morrow, Van Rybroek,
& Bauman, 1987) whose staff are trained to provide this specialized care in a highly
structured environment that optimizes staff and patient-offender safety.

Nonpharmacological Treatments
There are a variety of nonpharmacological approaches to the problem of persis-
tent aggressive behavior. They can be used in tandem with medication treatments. The
strategies outlined here include simple behavioral modification, more complex token
economies, cognitive behavior modification, behavior contracts, therapeutic commu-
nities, and dialectical behavior therapy. Selection of the appropriate intervention will
depend on the underlying diagnosis and the individual’s cognitive and intellectual
capacity. As will be discussed, some approaches may be counterproductive in certain
patient-offenders such as those with psychopathy.

Behavioral Treatments. Behavioral treatments, based on principles of classical and

operant conditioning and social learning theories, aim to reduce the occurrence of
undesirable aggressive behaviors and increase the occurrence of appropriate prosocial
replacement behaviors. In their simplest form, behavior modification techniques
involve identifying a specific problem behavior (e.g., hitting) and instituting a formal
plan of aversive consequences for the unwanted behavior and reinforcement for appro-
priate behavior. Consistent adherence to the treatment plan is critical but is often
impeded by lack of knowledge and training among direct care staff (Donat, 1998).
Systematic monitoring of the frequency of aggressive behavior both before and dur-
ing treatment allows continuous assessment of the effectiveness of the intervention,
which is very important since it is possible to inadvertently reward the undesirable
behavior. An example of this is a patient-offender who enjoys a time-out that allows
him to be alone and exempts his participating in a group activity, but whose rate of
aggressive behavior actually increases on instituting the intervention. In addition, fre-
quency monitoring provides objective evidence of behavioral change that can be rein-
forcing, both for the patient-offender and the staff.
These techniques have been applied to a wide range of behavioral problems, rang-
ing from smoking cessation to the reduction of physical aggression, in various popu-
lations including the developmentally disabled, hyperactive children, oppositional
adolescents, and psychiatric patients. Behavioral interventions to reduce aggressive
behavior have been successfully applied among developmentally disabled children in
residential and classroom settings. However, the utility of simple behavioral treatment
is limited in that there is little evidence generalizable to behaviors other than the spe-
cific target behavior or of long-term maintenance of the effects of treatment (Hughs,
1993).
The likelihood of aggressive behavior can be increased by environmental factors.
Overcrowding, noise, and lack of privacy have been implicated in aggression in inpa-
tient settings (Daffern & Howells, 2002). Of course this is unavoidable in a correc-
tional environment. Social environment can foster or discourage aggressive respond-
ing. Lax structure on a ward, other treatment facility, or prison—including lack of clear
rules or inconsistent enforcement of rules—all contribute to aggressive behaviors.
11-12 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

Token economies may be useful. A token economy is based on delayed reinforce-

ment; token rewards (e.g., points) for appropriate behavior can be accumulated and
exchanged at regular intervals for specific reinforcers of the patient’s choosing (e.g.,
food). Some token economies also include a “response cost” component, in which
inappropriate behaviors are punished by loss of tokens. Token economies are widely
used and have been shown to be effective in increasing ward (or classroom) structure
and decreasing aggression (Bellus, Vergo, Kost, Stewart, & Barkstrom, 1999).

Cognitive Behavior Modification. Cognitive behavior modification (CBM) applies

the techniques of behavior therapy to underlying cognition to teach strategies, such as
anger control, which can be applied in various situations. CBM emphasizes self-con-
trol as opposed to reliance on external controls, the latter being less effective in elic-
iting long-term, generalized change. The model CBM paradigm introduced by
Meichenbaum and Goodman (1971) taught subjects to use verbal self-instruction
(first overt, then gradually faded to covert) to improve attention and performance on
cognitive tasks. A number of studies of antiaggressive CBM interventions in children
have produced positive results and, most encouragingly, have shown lasting effects up
to three years later (Robinson, Smith, Miller, & Brownell, 1999).
Behavioral contracts, or written agreements between a patient-offender and his
therapist, are sometimes used to treat aggression. In these contracts, the offender par-
ticipates actively with the therapist in defining goals (e.g., a period of time without
aggressive behavior), rewards for meeting goals, and penalties for failing to meet
them. To develop a reasonable behavioral contract with attainable goals, a therapist
must know the frequency of the aggressive behavior and the appropriately desirable
rewards and penalties to motivate the individual. The period of time covered by the
contract must also be adjusted to the frequency of aggressive behavior. Behavioral
contracts have been found effective in reducing juvenile offenders’ criminal behaviors
(Lipsey & Wilson, 1993).

Therapeutic Communities. Therapeutic communities (TCs) are based on a social

learning model in which peer support plays an important role in the development of
problem solving abilities to avoid aggressive or antisocial responses to stressors. The
TC approach attempts to enhance insight and to foster prosocial behaviors such as
cooperation, empathy, and responsibility. A number of studies have formally evaluat-
ed the outcome of participation in prison-based drug treatment programs (Hartmann,
Wolk, Johnston, & Colyer, 1977). Inmates who complete such programs are less like-
ly to be rearrested or report using drugs after discharge. There is relatively little data
on the efficacy of TCs in the reduction of aggressive behavior per se, but some stud-
ies report good outcomes related to treatment programs for offenders with personali-
ty disorders, at least in terms of reductions in the number of serious incidents in the
facilities (Dolan, 1998). On a cautionary note, however, participation in such pro-
grams may actually increase a highly psychopathic individual’s dangerousness. In one
study, TC treatment was associated with lower recidivism (especially violent recidi-
vism) for nonpsychopaths and higher violent recidivism for psychopaths (Rice et al.,
1992). Psychopaths in TC settings may learn to appear more empathic and then use
this information to manipulate and deceive others.
Low self-esteem has frequently been cited as an important cause of aggression
and antisocial behavior. Many TC programs include components designed to raise
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-13

participants’ self-esteem. However, individuals with inflated self-evaluations may be

most prone to encountering threats to their ego and to reacting with violence toward
such threats (Baumeister et al., 1996). Thus, for some individuals, participation in a
TC program that enhances self-esteem may actually increase aggression.

Dialectical Behavior Therapy. Dialectical behavior therapy (DBT) was developed

primarily to treat individuals with borderline personality disorder, among whom para-
suicidal and impulsive aggression are serious behavior problems (Linehan, 1987).
DBT includes aspects of operant conditioning and cognitive behavior therapy strate-
gies in a time-limited and highly structured method. Patient-offenders participate in
both individual and group therapy organized around a hierarchy of behavioral goals
and emphasizing the development of problem-solving skills. DBT includes telephone
contact with the therapist and consultation between therapists. It has been reported
effective in reducing borderline symptomatology such as parasuicidal behaviors,
although data on long-term efficacy are limited (Westen, 2000). DBT is seen as a
promising treatment strategy for violent and antisocial behavior. Although the results
of pilot studies in forensic and violent mentally ill populations are encouraging
(McCann, Ball, & Ivanoff, 2003; Trupin, Stewart, Beach, & Boesky, 2002), more for-
mal research is needed in this area. DBT can be expensive, as it is labor intensive,
requiring extensive training and continuous professional and supportive supervision
of the therapists.
The choice of treatment approach is, of necessity, predicated on both patient-
offender characteristics and resource availability. CBM and more complex behavioral
approaches require greater cognitive capacity than simple behavior modification tech-
niques. The TC treatment appears to be more effective for younger, nonpsychopathic
individuals. DBT requires a high degree of motivation and commitment from both
patient-offenders and therapists.

Pharmacological Treatments
Medication is an essential component in the treatment of persistent aggressive
behavior among individuals with psychiatric disorders. Although pharmacotherapy
for the longer-term management of aggressive behavior is somewhat dependent on the
individual’s underlying diagnosis, clinical management is often complicated and can
entail the use of several co-prescribed medications. At the core of impulsive aggres-
sive behavior may be a dysregulation of the serotonergic neurotransmitter system, and
this may explain the possible ameliorative effects of agents such as atypical antipsy-
chotics and the serotonin specific reuptake inhibitors.

Dependent Variables Used in Pharmacological Research

Although overt physical aggression against other persons would be the most direct
outcome measure when assessing the efficacy of anti-aggressive agents, these events
are highly undesirable. Fights and assaults are actively discouraged in research set-
tings, and hence particularly infrequent. More common, but still undesirable, is physi-
cal aggression against objects. This can take the form of punching a wall, breaking a
television set, or kicking a wastebasket. These events are relatively infrequent com-
pared to overt verbal aggression. This latter behavior can be quite useful in assessing
11-14 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

the efficacy of different treatments because it is relatively common and measurable.

Moreover, there is already an established relationship between verbal and physical
aggression so that verbal aggression may serve as a useful proxy measure (Rabinowitz,
Avnon, & Rosenberg, 1996). Staff need to be sensitized to take notice of verbal aggres-
sion as it may be ingrained and accepted in the ward or prison culture. One approach
in a treatment facility or prison is to make a checklist that includes all the names of the
patient-offenders on the inpatient unit or cell block, divided in a grid of thirty-minute
blocks. When an episode of verbal aggression (or other form of aggression) is noted,
the therapist makes a check in a designated box and writes details on the reverse of the
sheet for future follow-up. The authors are currently using this method to trigger fur-
ther review and completion of more standardized rating scales and tools such as the
Overt Aggression Scale (Yudofsky, Silver, Jackson, Endicott, & Williams, 1986).
Seclusion and restraint rates can be used as a proxy measure for aggressive behav-
ior, the assumption being that patient-offenders placed in these restrictive measures
have been assaultive or self-destructive. Outcomes are often reported on in retrospec-
tive record reviews.
Hostility and aggression items on rating scales are also useful to assess efficacy
of medications. Examiners can use retrospective reviews where scales such as the
Brief Psychiatric Rating Scale were mandatory for clinicians wishing to prescribe
clozapine (Volavka, Zito, Vitrai, & Czobor, 1993). More commonly, this outcome
measure is used in planned (Citrome et al., 2001b) and post hoc analyses (Czobor,
Volavka, & Meibach, 1995; Cantillon & Goldstein, 1998) of randomized clinical tri-
als. This method of using psychopathology rating scales has the advantage of being
able to control for other antipsychotic effects, such as those on hallucinations and
delusions. If information on sedation is available, this can be controlled for as well. A
disadvantage is that these rating scales do not measure overt physical aggression per
se and ratings may reflect mere hostility. Moreover, patients enrolled in these ran-
domized clinical trials are not usually selected because of problems with hostility and,
in fact, aggressivity usually excludes them from participating.

Study Designs: From N=1 Case Reports to Randomized

Double-Blind Clinical Trials
Usually the first signal that an agent may be efficacious is contained in a case
report or case series. These usually take the form of a letter to the editor in a special-
ty journal. An example is a case report of quetiapine (Citrome, Krakowski, Greenberg,
Andrade, & Volavka, 2001a; see below). These reports are generally followed by ret-
rospective record reviews that measure outcomes such as numbers of incidents or
episodes of seclusion or restraints. Typically a “before and after” comparison is made,
and this has been typical of many of the reports regarding the introduction of clozap-
ine in state-operated hospitals (see below). Taken alone, a single retrospective study is
not compelling, but when replicated several-fold, it provides a strong signal that an
agent is probably effective.
The gold standard is the randomized double-blind clinical trial. Designs may
involve parallel arms (controls are different subjects) or crossover (subjects serve as
their own controls). At times the gold standard is approximated by randomized open-
label studies with blinded raters. Randomized clinical trials are difficult to design and
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-15

implement, especially in samples of aggressive individuals where consent bias and

other selection biases are perhaps unavoidable. Other operational difficulties include
the length of the baseline period and the relative rarity of measurable events (Volavka
& Citrome, 1999).

The Role of Diagnosis

Conventional wisdom is that medications should be targeted to the underlying
diagnosis. For example antidepressants would be prescribed for major depression,
mood stabilizers for bipolar disorder, and antipsychotics for schizophrenia. This is
complicated when disorders co-occur or when monotherapy fails to relieve symptoms.
Moreover, diagnostic entities such as schizophrenia may actually be composed of dif-
ferent subtypes of disease processes, and the different treatment domains may need to
be independently targeted. Thus for schizophrenia, the treatment domains of positive
symptoms, negative symptoms, mood, cognition, and hostility may all require some-
what different treatment considerations when selecting antipsychotic medications
(Citrome & Volavka, 2002a).
The pharmacological treatments for persistent aggressive behavior outlined below
appear useful for a variety of diagnoses, including schizophrenia, bipolar disorder, and
dementia. This raises at least two possibilities: the agents themselves are broad-spec-
trum and/or hostility shares a common biological pathway regardless of diagnosis.

Atypical Antipsychotics
Several atypical antipsychotics are available in the United States today (Table
11.2). The FDA-approved indications include schizophrenia (all), bipolar disorder
(olanzapine, risperidone, quetiapine), and recurrent suicidal behavior (clozapine). The
latter two indications demonstrate a broader spectrum of action for the atypical
antipsychotics than originally anticipated and have led to the use of these agents for a
variety of conditions that do not necessarily include psychotic symptoms. Atypical
antipsychotics appear to have efficacy for negative symptoms, cognitive dysfunction,
mood dysregulation, and as we will detail below, hostility (Citrome & Volavka,
2002a).
In addition to their use in patient-offenders with schizophrenia, schizoaffective
disorder, and bipolar disorder, atypical antipsychotics have also been used to manage
aggression and behavioral dyscontrol among patients with dementia. Evidence sup-
porting this indication will also be discussed.

Clozapine. After clozapine was introduced, several investigators reported a reduction

in the number of violent incidents and/or a decrease in the use of seclusion or restraint
among inpatients once they began clozapine treatment (Wilson & Claussen, 1995;
Ratey, Leveroni, Kilmer, Gutheil, & Swartz, 1993; Chiles, Davidson, & McBride,
1994; Mallya, Roos, & Roebuck-Colgan, 1992; Spivak, Mester, Wittenberg, Maman,
& Weizman, 1997; Maier, 1992; Ebrahim, Gibler, Gacono, & Hayes, 1994). The
reductions in hostility (Volavka et al., 1993) and aggression (Buckley et al., 1995)
after clozapine treatment were selective in the sense that they were (statistically) inde-
pendent of the general antipsychotic effects of clozapine. These uncontrolled studies
11-16 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

Table 11. 2
Atypical Antipsychotics Available in the USA

Antipsychotic Year Launched in USA FDA Approved Indications

Clozapine 1989 Treatment-resistant schizophre-

nia; recurrent suicidal behavior
in schizophrenia
Risperidone 1994 Schizophrenia; bipolar mania
Olanzapine 1996 Schizophrenia; bipolar mania;
bipolar maintenance
Quetiapine 1997 Schizophrenia; bipolar mania
Ziprasidone 2001 Schizophrenia
Aripiprazole 2002 Schizophrenia

Source: Physicians’ Desk Reference (58 ed.). Montvale, NJ: Thomson, 2004, and updates supplied by the manu-
facturer.

provided a strong signal that clozapine provided an advantage in the management of

persistent aggressive behavior, which led to a randomized double-blind clinical trial
supporting this conclusion. This fourteen-week study compared the specific anti-hos-
tility effects of clozapine with those of olanzapine, risperidone, or haloperidol in 157
inpatients with schizophrenia or schizoaffective disorder (Citrome et al., 2001a) and
found that clozapine had significantly greater anti-hostility effect than haloperidol or
risperidone. This effect on hostility was specific: it was independent of antipsychotic
effect on delusional thinking, formal thought disorder, or hallucinations, and inde-
pendent of sedation.
Further analyses of these data, including measures of overt aggression (Volavka
et al., 2004), showed that patients exhibiting overt aggression had less overall
improvement of psychopathology, but that antipsychotic efficacy of clozapine was
greatest in aggressive patients, whereas the opposite was true for risperidone and olan-
zapine. A key finding was that a therapeutic dose of clozapine was necessary to
achieve superior effects on the frequency and the severity of overt aggression. Since
it can take many days to titrate clozapine to a therapeutic dose, it is important not to
terminate a clozapine trial prematurely.

Risperidone. In a post-hoc analysis of a phase III randomized clinical registration

trial, risperidone also demonstrated a selective effect on hostility that was superior to
haloperidol (Czobor et al., 1995). Although this was supported by a review of the
impact of risperidone on seclusion and restraint in seventy-four patients receiving
risperidone (average risperidone dose 5.1 mg/day) at a state psychiatric hospital
(Chengappa et al., 2000), this effect was not evident in a retrospective case-control
study of twenty-seven patients with schizophrenia or schizoaffective disorder (average
risperidone dose 6.8 mg/day) (Buckley et al., 1997), and in another negative report of
a group of twenty forensic patients with chronic schizophrenia (minimum risperidone
dose 6 mg/day, average dose not reported) (Beck et al., 1997).
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-17

A large, twelve-week, double-blind, placebo-controlled study of risperidone in the

treatment of psychotic and behavioral symptoms in 625 institutionalized elderly
patients with dementia revealed significantly greater reductions in aggressiveness
scores in patients receiving 0.5, 1, and 2 mg/day of risperidone than in placebo
patients (Katz et al., 1999). This was replicated in another study of 344 patients in
which low-dose risperidone (mean 1.1 mg/d) was well tolerated and associated with
reductions in the severity and frequency of behavioral symptoms, particularly aggres-
sion, in elderly patients with dementia (De Deyn et al., 1999).

Olanzapine. Kinon, Roychowdhury, Milton, and Hill (2001) found olanzapine to be

superior to haloperidol on measures of agitation as determined by a post-hoc analysis
of a phase III randomized clinical registration trial in patients with schizophrenia, but
selectivity of effect was not reported.
Street and colleagues (2000) found low-dose olanzapine (5 and 10 mg/d) to be
significantly superior to placebo and well tolerated in treating agitation/aggression in
a multicenter, double-blind, placebo-controlled, six-week study conducted with 206
elderly nursing home residents with dementia. Edell and Tunis (2001) also reported
the effectiveness of olanzapine in improving behavioral/psychological symptoms of
dementia in hospitalized dementia patients in a 998-patient open study comparing
olanzapine, risperidone, and haloperidol.

Quetiapine. Quetiapine may also preferentially reduce hostility and aggression. In a

post-hoc analysis of a phase III randomized clinical registration trial (Chengappa et
al., 2003), quetiapine treatment had a direct and significant effect on agitation that was
independent of the improvement in psychotic symptoms. Quetiapine treatment
reduced agitation scores significantly among patients with acute psychoses compared
with placebo, but the authors observed only a slight (and non-statistically significant)
reduction in agitation scores when haloperidol treatment was compared with placebo.
This advantage for quetiapine is supported by a case report describing a dramatic
response to quetiapine monotherapy in a persistently aggressive patient with schizoaf-
fective disorder who had failed to respond to numerous other medications (Citrome et
al., 2001a), and in a case report of quetiapine combined with valproate in a patient
with treatment-resistant schizophrenia (Brooks, 2001).
Scharre and Chang’s (2002) prospective open-label twelve-week pilot study in
outpatients with dementia with psychosis or aggressive behaviors shows a significant
decrease of delusions, aggression, and overall behaviors after giving doses ranging
from 50 to 150 mg of quetiapine. As with analogous studies with risperidone and olan-
zapine, these doses of quetiapine are lower than those commonly used for the treat-
ment of schizophrenia (Citrome & Volavka, 2002b).
The effect of atypical antipsychotics on aggressive behavior among nondemented
patients is summarized in Table 11.3. At this time, the weight of the evidence favors
clozapine as specific antiaggressive treatment (Glazer & Dickson, 1998), with
demonstrated superiority to haloperidol and risperidone in patients with schizophre-
nia or schizoaffective disorder (Citrome et al., 2001b). More research is needed to
compare the other atypical antipsychotics with clozapine for this indication. Ideally,
such studies need to be done double-blind with subjects specially selected because of
their aggressive behavior. This is quite difficult to do because of a number of factors,
including the relative rarity of aggressive events and consequent need for a large sam-
11-18 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

Table 11.3
Evidence for Using Atypical Antipsychotics for Aggressive Behavior
(Excluding Patients with Dementia

Rx Studies Outcome
CLO >10 Open Retrospective Record Decrease in seclusion/restraint,
Reviews (N=~1000); NIMH- improvement in security
funded RCT (vs. OLZ, RIS, HAL) level/discharge, clinical
(N=157) improvement in medical record,
decrease in aggressive
incidents, improvement in
BPRS, improvement in NOSIE,
specific decrease in PANSS
Hostility Item
RIS Post-Hoc Subanalysis of Phase Improvement in PANSS
III RCT (vs. HAL) (N=513); 3 Hostility Item and BPRS Factor
Open Label Comparisons 4 (uncontrolled hostility/
(N=~100 ) excitement); decrease in seclu-
sion/restraint. Two reports were
negative (no difference/
improvement seen).
OLZ Post-Hoc Subanalysis of Phase Improvement in agitation
III RCT (vs. HAL) (N=388)
QUE Post-Hoc Subanalysis of Phase Improvement in BPRS Hostility
III RCT (vs. HAL) (N=257); case Item; improvement in PANSS
reports (N=2)

CLO – Clozapine RCT – Randomized clinical trial

RIS – Risperidone BPRS – Brief psychiatric rating scale
OLZ – Olanzapine NOSIE – Nursing Observation Scale for Inpatient
QUE – Quetiapine Evaluation
HAL – Haloperidol PANSS – Positive and negative syndrome scale

ple size and lengthy baseline and trial periods, as well as selection/consent bias
(Volavka & Citrome, 1999). One large federally funded double-blind, randomized
study comparing clozapine, olanzapine, and haloperidol among assaultive patients is
currently underway at our facility (Krakowski, 1999).

Anticonvulsants and Lithium

Mood stabilizers such as lithium and anticonvulsants are extensively used among
patient-offenders with a diagnosis of schizophrenia, with rates of use approaching 50
percent for this group (Citrome, Jaffe, & Levine, 2002). There is an expectation that
adjunctive mood stabilizers can reduce aggressive and impulsive behavior (Citrome,
1995). There are expert consensus guidelines suggesting the use of adjunctive mood
stabilizers in those with schizophrenia with agitation, excitement, aggression, or vio-
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-19

lence (McEvoy, Scheifler, & Frances, 1999), but the supporting evidence for this indi-
cation is based almost entirely on uncontrolled studies and case reports.

Valproate. The most commonly used mood stabilizer is valproate (Citrome, Levine,
& Allingham, 2000; Citrome et al., 2002). A recent review of the use of valproate in
violence and aggressive behaviors in a variety of diagnoses (Lindenmayer &
Kotsaftis, 2000) did reveal a 77.1 percent response rate (defined by a 50 percent
reduction in target behavior) based on seventeen reports (164 patients, approximately
one-half with dementia). There are two extant double-blind studies favoring valproate
for aggression: one with sixteen patients with borderline personality disorder
(Hollander et al., 2001) and one with twenty children and adolescents with explosive
temper and mood lability (Donovan et al., 2000). Recently there was a report of a one-
year open-label prospective trial of adjunctive valproate with olanzapine in ten
patients with paranoid schizophrenia, demonstrating statistically significant reduc-
tions in hostility (Littrell, Petty, Hilligoss, Kirshner, & Johnson, 2004).
Positive symptoms were reduced with adjunctive valproate in a twenty-eight-day,
double-blind, randomized study with olanzapine and risperidone among 249 patients
with an acute episode of schizophrenia (Casey et al., 2003). A post-hoc secondary
analysis (Citrome et al., 2004) found that combination therapy with divalproex had sig-
nificantly greater anti-hostility effect at three and seven days than antipsychotic
monotherapy (P < .05), as measured by the PANSS hostility item. The effect on hos-
tility appears statistically independent of antipsychotic effect on other PANSS items
that reflect delusional thinking, a formal thought disorder, or hallucinations. The mean
dose of adjunctive valproate was approximately 2300 mg/day, and was well tolerated,
with little in the way of differences in adverse events between monotherapy with an
antipsychotic or combination therapy with valproate. Adequate dosing may be impor-
tant, and may explain why valproate 480 mg per day did not differentiate from place-
bo on measures of aggressive behavior in a three-week randomized, placebo controlled,
double-blind, crossover study of forty-two patients with dementia (Sival, Haffmans,
Jansen, Duursma, & Eikelenboom, 2002).

Carbamazepine. The rate of carbamazepine use has been decreasing (Citrome et al.,
2002), perhaps because alternatives such as valproate are easier to manage, as carba-
mazepine induces its own metabolism. Nonetheless, carbamazepine has been used for
the management of persistent aggressive behavior. The evidence for efficacy comes
from small trials or case reports (Luchins, 1984; Yassa & Dupont, 1983; Hakola &
Laulumaa, 1982; Neppe, 1983; Dose, Apelt, & Emrich, 1987; Okuma et al., 1989;
Hesslinger et al., 1999). Although the largest randomized clinical trial of carba-
mazepine of 162 patients with schizophrenia (Okuma et al., 1989) failed to detect sig-
nificant improvement on the total Brief Psychiatric Rating Scale, differences did
emerge among the items of suspiciousness, uncooperativeness, and excitement.
In a six-week, randomized, multisite, parallel-group study of fifty nursing home
patients with agitation and dementia, individualized doses of carbamazepine were
compared with placebo (Tariot et al., 1998). This controlled study showed significant
short-term efficacy of carbamazepine for agitation and aggression with generally
good safety and tolerability. The modal carbamazepine dose at six weeks was 300
mg/day, and a mean serum level of 5.3 micrograms/ml was achieved.
11-20 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

With rare exceptions, the published studies of carbamazepine and aggressivity are
not blinded and are uncontrolled for placebo effect. In addition, plasma levels of con-
comitant antipsychotics are not measured, leaving open the possibility for undetected
pharmacokinetic interactions. Despite these limitations, carbamazepine, as an adjunc-
tive agent, does appear useful (Simhandl & Meszaros, 1992) and may lower aggres-
sion in a broad spectrum of disorders (Young & Hillbrand, 1994).
Lithium. Lithium is widely used for the treatment of bipolar or schizoaffective disor-
der. As such it can be expected to reduce manic symptoms. In the absence of mania,
lithium may not be efficacious in reducing aggressive behavior, as evidenced in a
study where lithium was added to antipsychotics for the treatment of resistant schizo-
phrenic patients classified as “dangerous, violent or criminal” (Collins, Larkin, &
Shubsachs, 1991). However, in another population, lithium treatment reduced the
number of violent infractions in sixty-six nonpsychotic, impulsively aggressive pris-
oners in a double-blind, placebo-controlled study (Sheard, Marini, Bridges, & Wagner,
1976). In addition, there are case reports of lithium being helpful in cases of akathisia
among patients with schizophrenia (Shalev, Hermesh, & Munitz, 1987). There are also
case reports of patients with paranoid schizophrenia with aggressive or disorderly
behaviors who have responded to the addition of lithium to their antipsychotic treat-
ment, then deteriorated after the lithium was discontinued but subsequently improved
when it was reinstituted (Prakash, 1985). Thus an empirical trial may be warranted if
there has been a failure on adjunctive valproate or adjunctive carbamazepine.
Gabapentin. In 1998, gabapentin use exceeded that for carbamazepine in patients with
schizophrenia hospitalized within psychiatric centers operated by the State of New York
(Citrome et al., 2000). Ryback and Ryback (1995) have suggested that this agent may
be useful in managing behavior dyscontrol. There may be a role for using this agent in
nursing home patients with dementia and aggressive and agitated behaviors, as evi-
denced by a retrospective chart review of twenty-four patients (Hawkins, Tinklenberg,
Sheikh, Peyser, & Yesavage, 2000). In an open-trial of adjunctive gabapentin in four
patients with schizophrenia, four with schizoaffective disorder, two with bipolar disor-
der, and one with pervasive developmental disorder, the gabapentin helped reduce agi-
tation within the context of a long-term, psychosocial rehabilitation unit of a New York
State psychiatric hospital (Megna, Devitt, Sauro, & Dewan, 2002). These case reports
will need to be replicated and systematic controlled studies need to be done.
Lamotrigine. A recent report by Tiihonen and colleagues (2003) of a double-blind,
placebo-controlled, crossover trial of adjunctive lamotrigine in thirty-four treatment
refractory patients who failed clozapine monotherapy demonstrates improvement in
the positive symptoms of schizophrenia. Subjects received lamotrigine (200 mg/day)
for up to twelve weeks. Any specific effect on hostility has not been reported.
Other Anticonvulsants. A report regarding three patients receiving topiramate is cau-
tionary in that the patients suffered deterioration in both positive and negative symp-
toms of schizophrenia (Millson, Owen, Lorberg, & Tackaberry, 2002). No reports
have been found, anecdotal or otherwise, regarding the adjunctive use of oxcar-
bazepine in patients with schizophrenia.
The mood stabilizers described above can be considered as primary treatment for
patient-offenders with bipolar disorder, and they may be useful as adjunctive agents
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-21

for those with schizophrenia or schizoaffective disorder. More evidence exists for the
use of valproate or carbamazepine than for lithium, gabapentin, or lamotrigine for the
indication of aggressive behavior in psychotic disorders. As with the atypical antipsy-
chotics, mood stabilizers can also be a successful strategy for the treatment of aggres-
sion among patients with dementia.

Beta-Adrenergic Blockers
Propranolol is the most extensively studied beta-adrenergic blocker in the context
of managing persistent aggressive behavior, with the majority of the work done with
brain-injured offenders (Yudofsky, Williams, & Gorman, 1981; Yudofsky, Stevens,
Silver, Barsa, & Williams, 1984). Propranolol has also been used as an adjunctive
treatment for schizophrenia with a finding of a reduction in symptoms, including
aggression (Sheppard, 1979). However, the use of propranolol is complicated by the
necessarily slow titration rate (to avoid excessive hypotension and bradycardia) and
time lag to the onset of efficacy. Other agents may be simpler to prescribe, and adjunc-
tive nadolol was also found to be helpful in patient-offenders with schizophrenia and
aggression. In a double-blind, placebo-controlled study of adjunctive nadolol (40–120
mg/day) in forty-one patients, twenty-nine of whom were schizophrenic, Ratey and
colleagues (1992) found a decline in the frequency of aggression compared to con-
trols. In a preliminary report of a double-blind, placebo-controlled study of adjunctive
nadolol (80-120 mg/day) in thirty violent inpatients, of whom twenty-three were schiz-
ophrenic, Alpert et al. (1990) found a trend demonstrating lower hostility for the active
treatment group. The authors also noted a decrease in extrapyramidal symptoms, lead-
ing to the conclusion that antiaggression and anti-akathisia effects were associated,
although this association was not maintained in the investigators’ final report of thir-
ty-four acutely aggressive male schizophrenic patients (Allan et al.,1996).

Other Agents
Benzodiazepines. Although the consensus guidelines recommend continued use of
lorazepam for patients with schizophrenia with agitation or excitement (but with no
history of substance abuse) (McEvoy et al., 1999), such use can be problematic
because of physiological tolerance. Missing scheduled doses of lorazepam may result
in withdrawal symptoms that can lead to agitation or excitement, as well as irritabili-
ty and a greater risk for aggressive behavior.
Clonazepam, a high potency benzodiazepine that is also classified as an anticon-
vulsant, has been used as monotherapy and as adjunctive treatment for patient-offend-
ers with bipolar disorder. Keats and Mukherjee (1988) also reported its usefulness as
an antiaggressive agent in a case report of a schizophrenic patient with a seizure dis-
order. In this particular case, both phenytoin and carbamazepine were ineffective. The
patient did best on a combination of haloperidol and clonazepam. This result is in con-
trast to Karson, Weinberger, Bigelow, and Wyatt’s (1982) double-blind, placebo-con-
trolled trial of adjunctive clonazepam in thirteen schizophrenic patients receiving
antipsychotics, in which the authors observed no additional therapeutic benefit and, in
fact, that four patients demonstrated violent behavior during the course of clonazepam
treatment.
Thus, caution is urged when contemplating long-term benzodiazepine use for the
11-22 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

management of persistent aggressive behavior. Because of tolerance, it is expected

that larger quantities of the medication will eventually be needed to achieve the
desired effect. Reduction of the dose and discontinuation of the agent may involve a
prolonged period of time. Because benzodiazepines have abuse potential and signifi-
cant street value, some jurisdictions, including New York State, require the use of spe-
cially tracked prescription pads when prescribing benzodiazepines. This may become
an obstacle where an individual is seeking an emergency renewal or refill from an
unfamiliar practitioner or from a hospital emergency department.

Antidepressants. The current interest in certain antidepressants’ role in aggression is

based on the crucial role of serotonergic regulation of impulsive aggression against
self and others (see Chapter 9, this volume, for a discussion of its relation to post-
traumatic stress disorder). Now that antidepressants with specific effects on serotonin
receptors are available, a number of reports have emerged. In a retrospective, uncon-
trolled study, adjunctive fluoxetine was given to five patients with chronic schizo-
phrenia; a decrease in violent incidents was observed in four cases (Goldman &
Janecek, 1990). In a case report, fluvoxamine added to risperidone was reported to be
effective in managing aggression in schizophrenia (Silver & Kushnir, 1998).
Citalopram was tested for antiaggressive effects in fifteen chronically violent,
hospitalized schizophrenic patients (Vartiainen et al., 1995). This double-blind, place-
bo-controlled, crossover study lasted forty-eight weeks—twenty-four weeks on active
citalopram (20-60 mg/day) and twenty-four weeks on citalopram placebo. The
researchers added the trial medication to the concurrent antipsychotic treatment. The
number of aggressive incidents decreased during the active citalopram treatment. This
is consistent with another study of citalopram, this time done with patients diagnosed
with a DSM-IV cluster B personality disorder or intermittent explosive disorder
(Reist, Nakamura, Sagart, Sokolski, & Fujimoto, 2003). In this open-label design, the
researchers gave twenty-five patients citalopram at doses ranging from 20 to 60
mg/day, with a mean daily dose of 45.5 mg. They found statistically significant
decreases on rating scales measuring aggression. In a double-blind, placebo-con-
trolled, twelve-week clinical trial of fluoxetine in the treatment of impulsive aggres-
sive behavior in forty non-major depressed, non-bipolar or schizophrenic, personality
disordered individuals, fluoxetine (at daily doses ranging 20–60 mg) had significant
antiaggressive effects, independent of any antidepressant effects (Coccaro &
Kavoussi, 1997). Thus across diagnoses, antidepressants may have a role in decreas-
ing aggressive behavior.
Reports in the lay press have indicated that antidepressants may play a role in
causing aggression. Fluoxetine has been blamed for inducing murder or suicide and
was used as a legal defense and as a plaintiff’s argument in seeking compensatory and
punitive damages in a variety of court cases (Burton, 1991; Grinfeld, 1995). The exist-
ing scientific literature does not support this link, however. The reported cases are
complicated by co-existing factors that would increase the risk for behavioral dyscon-
trol (Citrome &Volavka, 1999). This topic is reviewed in detail elsewhere, where all
published papers on Medline and other databases linking serotonin, selective sero-
tonin reuptake inhibitors (SSRIs), and aggression were reviewed (Walsh & Dinan,
2001). The authors note that a small proportion of patients treated with SSRIs may
become akathisic and others may show increases in anxiety in the initial phase of
 SCIENCE-BASED TREATMENT OF AGGRESSION AND AGITATION 11-23

treatment, but no increased susceptibility to aggression or suicidality can be connect-

ed with fluoxetine or any other SSRI. There is, however, new information indicating
that children may be more susceptible to these untoward effects (Abbott, 2003;
Wooltorton, 2003). The U.S. Food and Drug Administration (2003) issued a public
health advisory regarding reports of suicidality in pediatric patients being treated with
antidepressant medications for major depressive disorder, but noted it was difficult to
disentangle possible drug effects from the underlying disease.

Adjunctive Electroconvulsive Therapy. Although electroconvulsive therapy (ECT)

is often considered a treatment for mood disorders, adjunctive ECT may help individ-
uals who have inadequately responsive psychotic symptoms (Fink & Sackeim, 1996),
in particular patient-offenders with persistent aggressive behavior. An open trial of
ECT in combination with risperidone in male patients with schizophrenia and aggres-
sion resulted in a reduction in aggressive behavior for nine of the ten patients (Hirose,
Ashby, & Mills, 2001). In that series of patients, bilateral ECT was administered five
times a week, with a mean total number of 6.6 treatments. Of the six patients with pos-
itive symptoms at baseline, five experienced a rapid diminution of their aggressive
behavior within twelve days. The four remaining patients in the sample had no posi-
tive symptoms at baseline, yet also experienced a rapid elimination of aggressive
behavior, this time within ten days. The authors report that these outcomes were sus-
tained for at least six months.
Persistent aggressive behavior was successfully treated with adjunctive ECT
(together with clozapine and olanzapine) in a patient with treatment-resistant schizo-
phrenia (Greenberg, Citrome, Nolan, Hill, & Volavka, 2000). Thirty-one treatments
were given over five and one-half months and resulted in significant amelioration of
aggressive behavior that was sustained for at least another five and one-half months.

CONCLUSIONS
Agitation and aggression are frequent reasons for referral for treatment. There are
two aspects to the rational management of this clinical problem. The first is to be able
to effectively manage acute episodes of agitation. The second is to decrease the inten-
sity and frequency of future episodes. Although sedation can be used to control acute
agitation, sedation per se is suboptimal in reducing agitation in the long-term because
of its negative impact on overall functioning. Animal and human research informs us
that the serotonergic and catecholaminergic (e.g., norepinephrine and dopamine) sys-
tems are implicated in the modulation of aggressive behavior, however other factors
are involved, including psychosis and psychopathy. It is not uncommon for all three
factors to be present in the same individual, necessitating a multi-pronged treatment
approach that involves both nonpharmacological behavioral and psychological
approaches together with medication treatment.
Strategies to control acute agitation include the use of mechanical restraints and
the administration of parenteral medication. Early intervention is important to avoid
further escalation to violence. The new intramuscular formulations of atypical
antipsychotics hold promise to quickly and efficaciously control acute agitation, with-
out the side effect burdens of the older typical antipsychotics. Lorazepam remains an
option, particularly for patient-offenders withdrawing from alcohol.
11-24 THE SCIENCE, TREATMENT, AND PREVENTION OF ANTISOCIAL BEHAVIORS

Longer-term management requires treatment for the underlying disorder.

Clozapine appears to be the most effective antipsychotic in reducing aggressivity in
patient-offenders with schizophrenia and schizoaffective disorder. Evidence also
exists for the use of the other atypical antipsychotics, particularly for those with
dementia. Anticonvulsants such as valproate and carbamazepine are also used, com-
monly together with antipsychotics, to decrease the intensity and frequency of agita-
tion and to treat poor impulse control. Beta-blockers and SSRIs may also be helpful.
Adjunctive ECT, together with atypical antipsychotics, may be considered for patient-
offenders who have failed other approaches. An effective pharmacologic treatment for
aggression related to psychopathy has yet to be discovered and tested.

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