CNS NEWS • JUNE 2004 51

Continuing Medical Education

The Challenge of Managing Acute Agitation:

New Approaches
Release Date: June 2004 Expiration Date: June 30, 2005
SUPPORT STATEMENT
This activity is made possible by an unrestricted educational grant from Eli Lilly and Company.
JOINT SPONSORSHIP STATEMENT
Jointly sponsored by the University of Kentucky College of Medicine and
McMahon Publishing Group.
FACULTY
Leslie Citrome, MD, MPH, is director, Clinical Research and Evaluation Facility, Nathan S. Kline Insti-
tute for Psychiatric Research, Orangeburg, New York; and professor of psychiatry, New York University
School of Medicine, New York City, New York. Dr. Citrome has received honoraria from Abbott Labora-
tories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novartis, and Pfizer; is a consultant to Abbott Labo-
ratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Pfizer; has received grant/research support
from Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer; is a stock shareholder in
Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, and Pfizer; and is a member of the speakers’
bureau for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novartis, and Pfizer.
Jay Fawver, MD, is inpatient, outpatient, and consultation psychiatrist, Park Center Community Mental
Health System, Fort Wayne, Indiana; and clinical associate professor of psychiatry, Indiana University
School of Medicine, Indianapolis, Indiana. Dr. Fawver receives honoraria from and is a member of the
speakers’ bureau for AstraZeneca, Eli Lilly, and Pfizer; and is a consultant to Eli Lilly and Pfizer.
NEEDS STATEMENT
Immediate intervention is necessary to prevent injury and ensure optimal treatment in cases of acute
agitation. Second-generation (or atypical) antipsychotic agents are considered first-line therapy in this
endeavor, as they are associated with a lighter side-effect profile than are their predecessors, the first-
generation (or typical) antipsychotic agents. Newer formulations of these medications, such as intra-
muscular versions, may enhance acute treatment through rapid action. It is imperative that clinicians
be updated as to the efficacy of these agents and formulations for both acute and long-term treatment
of agitation in patients with underlying psychiatric disorders and those with refractory symptoms.
ACCREDITATION STATEMENT
Physician: This activity has been planned and implemented in accordance with the Essential Areas and
Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint
sponsorship of University of Kentucky College of Medicine and McMahon Publishing Group.
The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing
medical education for physicians.
The University of Kentucky College of Medicine designates this educational activity for a maximum of
1.0 Category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim
only those hours of credit actually spent in the educational activity.
TARGET AUDIENCE
This educational program is intended for physicians interested in treating acute agitation.
LEARNING OBJECTIVES
1. Discuss the necessity of assessment and immediate treatment for acute agitation.
2. Describe the cases in which long-term treatment may be necessary.
3. Understand the differences among atypical antipsychotic agents and their benefits relative to typical
antipsychotic agents.
4. Explain the relative benefits of adjunctive pharmacologic treatments for agitation.
DISCLOSURE OF UNLABELED USE
This educational activity contains discussion of published and/or investigational uses of multiple
agents at doses above product label recommendations for agitation and aggression. It also discusses
the unlabeled use of various antipsychotic medications, lithium, and anticonvulsant medications for the
treatment of agitation.
DISCLOSURE OF FINANCIAL INTEREST
All faculty members participating in continuing medical education programs sponsored by the Universi-
ty of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office are expected to dis-
close any real or perceived conflict of interest related to the content of their presentations.
The University of Kentucky College of Medicine presents this activity for educational purposes only.
Participants are expected to utilize their own expertise and judgment while engaged in the practice of
medicine. The content of the presentations is provided solely by presenters who have been selected
for presentations because of recognized expertise in their field.
ESTIMATED TIME OF COMPLETION
This activity should take approximately 1 hour to complete.
METHOD OF PARTICIPATION
There are no fees for participating and receiving credit for this activity. The participant should, in order,
read the objectives and monograph and answer the multiple-choice post-test. Participation is available
online at CMEZone.com. Enter the project number "CE137" in the keyword field to directly access
this activity and receive instantaneous participation. Or, complete the answer sheet with registration
and evaluation on page 56 and mail to: Attn: Distance Education, Continuing Education Office,
Colleges of Pharmacy and Medicine, University of Kentucky, 1 Quality St, 6th Fl, Lexington, KY 40507-
1428. Certificates will be mailed to participants in approximately 4 weeks after receipt of the mailed or
faxed submissions. This credit is valid through June 30, 2005.

Introduction
Acute agitation is common in patients presenting to the
emergency and inpatient departments. Immediate inter-
vention is required to prevent these individuals from harm-
ing themselves or others and to provide them with the
best chance for recovery. Initial pharmacologic treatment
choices often can impact continued management of the
disease. For patients with underlying mental disorders
such as schizophrenia, schizoaffective disorder, or bipolar
mania, acute medication treatment for agitation often tran-
sitions into long-term maintenance treatment, so initial
choices often can impact continued management of the
disease. Consideration should be given to newly available
agents—such as second-generation antipsychotics—that
present more favorable side-effect profiles. Also called
atypical antipsychotics, these agents are more tolerable
than older agents and have less potential to cause dysto-
nia and other extrapyramidal symptoms (EPS), neuroleptic
malignant syndrome, and tardive dyskinesia. Additionally,
they have superior efficacy in improving mood, negative
symptoms, and cognition, thus rendering these agents as
the preferred choice for the long-term management of psy-
chotic disorders. Efficacy for the treatment of acute bipo- important to differentiate their meanings. Agitation is defined behavior is important for intervention before it escalates to
lar mania, even in the absence of psychotic symptoms, as excessive motor or verbal activity that is easily identified aggressive or violent behavior.
has also been established for these agents, leading clini- by clinicians and can be a precursor of aggressive behavior. Patients with schizophrenia appear more likely to exhibit
cians to regard second-generation antipsychotics as hav- Aggression can be verbal or physical and can target objects aggressive or violent behavior than those who do not have
ing a broad spectrum of action. or other people. Violence is physical aggression by one per- the disorder. In the Epidemiological Catchment Area pro-
son against others. Hostility is less well defined, as it can ject, researchers interviewed more than 20,000 people in
Agitation: Definitions and Epidemiology include aggression, irritability, suspicion, uncooperativeness, the general population of the United States, collecting data
The terms agitation, aggression, violence, and hostility are and jealousy.1 Keeping these definitions in mind, the practi- from approximately half of interviewees on their exposure to
often used interchangeably but rarely defined. However, it is cal take-home point is that the early identification of agitated violence. They found that the probability of violent behavior
52 CNS NEWS • JUNE 2004

Continuing Medical Education

among individuals with schizophrenia was 5 to 6 times high-

er than in those without a diagnosed mental disorder.2 Epi-
0
Estimated Mean Change in PANSS–EC

demiologic studies done in other countries have reported

similar results.
RIDE (n=72) Agitation may prompt hospitalization, and patients appear
-2 to be most prone to aggressive behavior during the initial
UCP (n=76)
period after hospital admission; one hospital study reported
that 13% of subjects physically assaulted another person dur-
-4 ing the 24 hours after admission.3 A second inpatient study
found that 9% of patients with schizophrenia or schizoaffec-
tive disorder attacked someone at least once within 8 days
-6 after admission.4 Thus, effective treatment should be initiated
as soon as possible during this crucial period.
Research and clinical experience indicate that a relatively
-8 * †
small number of patients are responsible for the majority of
aggressive or violent incidents in treatment settings. In one
study done in the United States, 5% of patients were respon-
sible for more than half of all incidents.5 Similar work from
-10 Australia reported that 12% of all patients accounted for 69%
of all violent acts.6
It must be clearly stated that not all patients with psychot-
-12 ic disorders are aggressive, violent, or hostile, and not all
Day 1 Day 2 Day 3 Day 4
aggression, violence, and hostility can be attributed to
patients with psychotic disorders. As a matter of fact, most
Overall Treatment Effect P=0.006 of the aggressive, violent, and hostile acts witnessed in
*P=0.03 daily life and society at large are perpetrated by people who
†P=0.001 do not have a major mental disorder as defined by the
PANSS, Positive and Negative Syndrome Scale—Excited Component; RIDE, rapid initial dose escalation; Diagnostic and Statistical Manual of Mental Disorders—
UCP, usual clinical practice Fourth Edition (DSM-IV). Nevertheless, a minority of patients
with psychotic disorders are highly prone to persistent
aggressive behavior.1
Figure 1. Olanzapine rapid initial dose escalation vs usual clinical practice.10 While causes are not completely understood, a multifac-
torial etiology appears to be responsible for violent behav-
ior. Violent patients commonly have comorbid substance
abuse or dependence issues and may be under the influ-
ence of these agents when exhibiting aggressive behavior.
Indeed, an estimated half of all patients with schizophrenia
have problems with substance or alcohol abuse. Other fac-
LIM Prior to First Oral Dose 7-Day End Point tors that may influence violent behavior include elements
0.0 of the underlying disease process, such as hallucinations
or delusions, neuropsychiatric deficits, and poor impulse
control. Patients may also have underlying character
Mean Change From Baseline

pathologies and may use violence to achieve their goals.

-0.2 Furthermore, a chaotic environment also may influence the
development of aggressive behavior. Structured environ-
ments, such as an inpatient unit, can help to de-escalate
In CGI-S Score

aggressive behavior.1
-0.4
Assessing the Agitated Patient
* Since medical conditions may lead to agitation, the first
-0.6 rule of assessing agitation is to rule out an underlying
somatic etiology, particularly in patients with no history of
aggressive behavior. Comorbid substance abuse disorders,
Ziprasidone (n=90) antisocial personality disorder, and adverse drug effects
-0.8 Haloperidol (n=42) may also influence behavior. Akathisia, for instance, is a
common adverse effect associated with typical antipsy-
chotics, and it can lead to agitated behavior. In assessing
† violence risk with agitated patients, one of the most impor-
-1.0 *P<0.01 vs. haloperidol tant guidelines to remember is that past violence predicts
†
P<0.05 future violence. Ask questions about a history of violent
CGI-S, Clinical Global Impression–Severity; IM, intramuscular; LIM, last IM injection on day 1, 2, or 3 behavior. For patients with a history of criminal behavior,
arrest records may be available to provide documentation
Figure 2. Ziprasidone IM vs haloperidol IM.14 of past behaviors. Other key issues include whether the
patient has access to weapons, and if the patient is psy-
chotic, the content of his/her delusions or hallucinations.1
Agitation in patients with schizophrenia may result from
noncompliance with a medication regimen or from the fail-
ure of medication to adequately treat the underlying disor-
der. A differential diagnosis would include a variety of other
conditions, some of which can coexist with one another.
Abuse of alcohol, cocaine, amphetamines, and other sub-
stances may be factors. The clinical presentation of delirium
raises the possibility of underlying neurologic, infectious,
cardiac, metabolic, or endocrine disturbances. Other possi-
ble differential diagnoses for agitation include antisocial
personality disorder, borderline personality disorder, dys-
thymia, mania, panic disorder, and post-traumatic stress dis-
order. Finally, iatrogenic causes secondary to psychiatric
 CNS NEWS • JUNE 2004 53

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medication may be precipitants for agitation. Akathisia, for

instance, is a common adverse effect associated with older,
first-generation antipsychotics, and it can lead to agitated 0
behavior. A paradoxical disinhibition reaction associated IM OLZ 10 mg

Mean Change in PANSS–EC

with benzodiazepines should also be considered.1 -1
IM HAL 7.5 mg
Treating the Acutely Agitated Patient -2
IM PBO
When an acutely agitated patient presents to the emer- -3
gency department or is admitted to an inpatient unit, inter-
ventions should be initiated as quickly as possible.1 The -4
main goals are to calm the patient, reduce the risk of harm *
to the patient or others, decrease the need for seclusion or -5
restraint, and to treat any underlying psychosis and/or
mania while assessing the patient for the underlying etiolo- -6
gy of the agitation. Calming the patient also allows diagnos-
tic tests or procedures to be conducted. Inducing sleep -7 *
should be avoided, as sleep obstructs proper assessment
and treatment, and can extend the time spent occupying a
bed in the emergency department, delaying transfer to the
-8 *
appropriate treatment unit. -9
Initial treatment steps should include decreasing environ- 0 15 30 45 60 75 90 105 120
mental stimulation to the patient by dismissing people from
the area not directly related to the patient’s care and turning Time (minutes)
off televisions and radios in the room. Due to the risk of *P<0.05 OLZ vs. HAL
aggressive or violent behavior, several staff should be pre-
P<0.001 OLZ vs. PBO at all time points
sent as a show of concern for the patient and a show of
HAL, haloperidol; OLZ, olanzapine; PANSS–EC, Positive and Negative Syndrome Scale—Excited Component; PBO, placebo
force for security. Calming medication should be offered
early. Other interventions should be available, such as
seclusion or, as a last resort, restraints. However, the use of Figure 3. IM olanzapine, haloperidol, and placebo in acute agitation.16
restraints is often a high-risk procedure in terms of patient
and staff safety.

Pharmacologic Interventions

Medication should be offered early in order to decrease

agitation and avoid further escalation to aggressive or vio-
lent behavior. Choices include older agents such as Agitated patient
lorazepam and typical antipsychotics such as haloperidol.
New alternatives are atypical antipsychotics. The latter have
significant advantages, as discussed below.
Lorazepam is among the most commonly used agents Simultaneous
for the treatment of agitation. Currently available in oral,
sublingual, injectable (intramuscular [IM] or intravenous
[I.V.]) formulations, lorazepam produces rapid, nonspecific
sedation. It has a short half-life of 10 to 20 hours, and has Environmental and behavioral Medication
no active metabolites. Dosing is simple with lorazepam: 0.5
interventions: interventions—
to 2 mg per dose, as needed, every 1 to 6 hours. It has the
advantage of also treating withdrawal from alcohol or seda- • Decrease stimulation offer early:
tives. However, lorazepam can cause respiratory depres- • Allow patient to verbalize • Assess medical
sion and, in some patients, a paradoxical disinhibition that thoughts and feelings condition
results in further deterioration in aggressive behavior. Other • “Talking down”
significant drawbacks include the development of toler-
ance, which precludes long-term use, and a lack of effect
on the core symptoms of psychosis.1
Antipsychotics address these limitations, not leading to Remains agitated and a Withdrawal from alcohol
tolerance or respiratory depression and improving the core danger to self or others or sedatives?
symptoms of psychosis. First-generation—or typical—antipsy-
chotics include haloperidol and chlorpromazine, agents that
have been in use for decades and are available in various YES NO YES
formulations, including oral and IM. An injection of IM
haloperidol rapidly allows for a high plasma level of the drug
and universally produces sedation given a high enough
dose. However, typical antipsychotics also have several limi- Seclusion and/ 1st choice: SGA PO/IM Lorazepam
tations including side effects such as postural hypotension, or restraint 2nd Choice: PO/IM
a lowering of the seizure threshold, acute dystonia, akathisia, Haloperidol ± lorazepam PO/IM
and tardive dyskinesia (TD). Dystonia, for one, can frighten
patients and lead to treatment noncompliance. Droperidol, a
preanesthetic agent that has a structural similarity to
haloperidol, has been associated with QTc prolongation, a Persistent aggressive behavior: SGA ± mood stabilizer ± ß-blocker
potentially dangerous change in cardiac rhythm. It now car-
ries a black box warning in the United States and has been
withdrawn from the market in the United Kingdom.7 IM, intramuscular; SGA, second-generation antipsychotic; PO, oral
A combination commonly used to treat acute agitation is
IM haloperidol (5 mg) and lorazepam (2 mg). This combina- Figure 4. Acute agitation: a treatment algorithm.20
tion is more effective and faster acting than either agent
alone, and can be administered in the same syringe. Inter-
estingly, this combination is less likely to cause EPS than
haloperidol used alone. However, haloperidol is not an ideal
54 CNS NEWS • JUNE 2004
Continuing Medical Education
candidate for long-term treatment, because of concerns
over EPS, TD, and limited (or no efficacy) for negative symp-
toms and cognitive dysfunction.
Second-Generation Antipsychotics
Second-generation antipsychotics have emerged during
the last 15 years. More recently, several have become
available in liquid, rapidly disintegrating tablet, and IM for-
mulations. The atypical agents are associated with signifi-
cantly lower rates of EPS and TD, thus avoiding one of the
major barriers to treatment adherence. The second-gener-
ation agents also are more effective for the treatment of
the broad spectrum of symptoms of chronic mental ill-
ness—particularly negative symptoms, mood disturbances,
and cognitive impairment.7
The first atypical antipsychotic to be formally tested as an
emergency treatment for agitation was risperidone. Liquid
risperidone was evaluated in a prospective, naturalistic
study conducted with agitated subjects in a large, urban
emergency department.8 This study compared risperidone
liquid concentrate (2 mg) plus oral lorazepam (2 mg) with
IM haloperidol (5 mg) plus IM lorazepam (2 mg). The results
demonstrated the utility of the oral formulations in treating
acute agitation. Both treatment groups showed rapid, signifi-
cant, and equivalent reductions in agitation scores on the
Positive And Negative Syndrome Scale—Excited Compo-
nent (PANSS-EC). These reductions were significant within
30 minutes of treatment. Based upon this study, the IM for-
mulations did not provide a faster onset of response than
the oral formulations.
Olanzapine has also been assessed for the treatment of
agitation. Current formulations include a regular oral pill,
oral rapidly disintegrating tablets and a rapid-acting IM
preparation. Both the regular oral preparation and the IM
formulation have been formally tested in agitated patients. A
double-blind, randomized clinical trial tested a loading dose
strategy of oral olanzapine in 148 acutely agitated subjects
with schizophrenia, schizoaffective disorder, schizophreni-
form disorder, or bipolar I mania. Subjects were randomized
to 2 groups: the rapid initial dose escalation (RIDE) group,
and the usual clinical practice (UCP) group. Treatment for
RIDE patients consisted of olanzapine (20 mg PO) for days
1 to 4 with an additional 10 mg added as needed (up to 40
mg per day for days 1 and 2, and up to 30 mg per day for
days 3 and 4). The UCP group received olanzapine (10 mg
PO) for days 1 to 4, and up to 4 mg lorazepam (PO) on
days 1 and 2, or up to 2 mg lorazepam on days 3 and 4.
After day 4, all patients were treated in open fashion with
standard doses of olanzapine (5 to 20 mg per day for days
5 to 7).9 Both treatments produced substantial reductions in
agitation as measured by the PANSS-EC. However, the RIDE
dosing produced significantly greater reductions than did
the UCP dosing as early as 24 hours (Figure 1, page 52).
Importantly, there were no statistically significant differences
between groups in treatment-emergent adverse events.
Thus, the administration of up to 40 mg per day of olanzap-
ine during the first 48 hours of treatment produced faster
reductions in agitation than did “usual” doses of olanzapine.
Rapidly disintegrating olanzapine tablets may also be use-
ful for the treatment of agitation. Dissolving quickly in the
patient’s mouth or in a liquid drink, these tablets can reduce
the potential for “cheeking” or spitting, as may happen with
noncompliant and ambivalent patients. Over the long term,
these tablets are bioequivalent to regular olanzapine tablets,
but within the first 2 hours, a more rapid absorption of med-
ication occurs with the rapidly dissolving tablet.10 While this
pharmacokinetic difference may have benefits in the acute
phase of treatment, this formulation has not yet been formal-
ly tested in clinical trials of acute agitation.
Second-Generation Antipsychotics:
Intramuscular Formulations
The new atypical antipsychotic ziprasidone is available in
an IM formulation for the indication of agitation associated
with schizophrenia, and several studies have examined its
use in agitated patients. According to initial pharmacokinet-
ics studies, IM ziprasidone displays linear pharmacokinet-
ics, bioavailability of 100%, time to maximum serum
concentrations (Tmax) of 30 to 45 minutes, and terminal half-
life of 2 to 5 hours.11 Two trials compared different doses of
ziprasidone IM: 2 mg versus 10 mg in one study,12 and 2
mg versus 20 mg in the second.13 In both, the higher dose
was significantly superior to the lower dose according to
scores on the Behavioral Activity Rating Scale (BARS) and
in percentage of responders (defined as improvement of ≥2
in BARS 2 hours after the first injection). Response
appeared to be greatest with the 20-mg dose. Similarly, sig-
nificantly greater improvement was achieved on the PANSS
agitation items and the Clinical Global Impression–Severity
(CGI-S) scale 4 hours after the first injection with the 20-mg
dose than with the 2-mg dose.13
An open-label study comparing IM ziprasidone with IM
haloperidol for the treatment of acute agitation demon-
strated substantial advantages for ziprasidone.14 The
results, as measured on the CGI-S, demonstrated signifi-
cantly greater reductions in agitation with ziprasidone than
with haloperidol during both the initial IM and transitional
oral phases (Figure 2, page 52).
Overall, the IM ziprasidone formulation was safe and
effective for the treatment of agitation. The majority of
patients in clinical trials required only 1 or 2 injections in the
first 24 hours to control symptoms of agitation, and signifi-
cant improvement was demonstrated within 30 minutes.
Rates of EPS in these studies were similar to those associ-
ated with placebo, and there were fewer cases of dystonia
with ziprasidone than with haloperidol.15 Although the prod-
uct label for IM ziprasidone warns of the risk of QTc prolon-
gation, the studies performed found that QTc changes were
similar to those seen with IM haloperidol.7
The IM formulation of olanzapine became commercially
available in 2004, and is FDA approved for the indication of
agitation associated with schizophrenia or bipolar mania. It
has been studied extensively in schizophrenia, bipolar
mania, and dementia, with data available for approximately
1,000 patients in four registration studies. Pharmacokinetic
analysis from initial studies indicated that IM olanzapine has
a much shorter Tmax and a higher maximum serum concen-
tration than does the oral formulation.16 In clinical trials,
these characteristics translated into a rapid reduction in agi-
tation, comparable to IM haloperidol or IM lorazepam.16
For example, a comparison of IM olanzapine (10 mg)
with IM haloperidol (7.5 mg) and IM placebo in patients with
schizophrenia demonstrated statistically superior reductions
in scores on the PANSS-EC with IM olanzapine compared
with placebo. In contrast to what was observed with IM
haloperidol, this difference was statistically significant for IM
olanzapine within the first 15 minutes after treatment (Figure
3). By the end of the 2-hour observation period, both active
treatments resulted in similar reductions in agitation.17
A similar study in acutely agitated patients with bipolar
mania compared IM olanzapine (10 mg) with IM lorazepam
(2 mg) and IM placebo. Within the first 30 minutes, IM olan-
zapine produced significantly greater reductions in scores
on the PANSS-EC than did lorazepam (P=0.05).18 Statistical
superiority continued throughout the 2-hour study period
(P<0.001 olanzapine vs lorazepam and placebo at all other
time points). Importantly, these reductions in agitation did
not appear to result solely from the antipsychotic effects of
olanzapine. A secondary analysis of data from this study
demonstrated that olanzapine significantly reduced PANSS-
EC scores in both psychotic and nonpsychotic patients rela-
tive to placebo (P<0.05).16
Overall, clinical trials of IM olanzapine have demonstrat-
ed that it works faster than IM formulations of haloperidol or
lorazepam and is effective in agitated patients with a variety
of diseases. The majority of patients in these studies
required only 1 injection of olanzapine in 24 hours to con-
trol their agitation, and efficacy was evident within 15 to 30
minutes. Although olanzapine is best known as an antipsy-
chotic, it has proven to be effective in both psychotic and

nonpsychotic patients. Furthermore, IM olanzapine was safe
and well tolerated; it was not associated with excessive or
undesirable sedation, rates of EPS were similar to placebo
in all trials, and there were no cases of acute dystonia. In
addition, no clinically significant changes in laboratory val-
ues, including the QTc interval, were observed. Although
mild and transient changes in blood pressure and heart
rate were noted in some patients, there were no substantial
differences between treatment groups in relevant adverse
events, such as syncope or dizziness.7
Long-Term Approaches to Treatment
A minority of patients experience recurrent episodes of
agitation and aggression, requiring both acute and long-
term treatment. However, sedation per se is not a suitable
long-term strategy because it prevents patients from being
able to function adequately, reenter the community, and
participate in normal activities. A number of strategies
may be helpful for managing such patients, although
sometimes the primary long-term treatment does not suffi-
ciently treat the underlying mental disorder. The evolving
use of second-generation antipsychotics provides an alter-
native for patients who do not show improvement on the
older first-generation agents for the treatment of recurrent
agitation and aggression. Adjunctive medication may also
be necessary.
Evidence supporting the use of second-generation
antipsychotics in the long-term prevention of aggressive
episodes varies from agent to agent. In the only trial of its
kind, clozapine was demonstrated statistically superior to
haloperidol and risperidone on measures of hostility in
patients who were refractory to first-generation antipsy-
chotics.19 In addition, more than 10 open-label, retrospec-
tive studies have reviewed the efficacy of clozapine in
long-term use, generally reporting a decreased need for
seclusion or restraint, lower discharge rates, and fewer
aggressive incidents.20
A specific antihostility effect for risperidone has been
examined in several comparisons including a post hoc
subanalysis of a Phase III randomized trial, in which
risperidone was determined superior to haloperidol and
placebo. Specific findings from these studies included
improvement in the PANSS Hostility Item and the Brief
Psychiatric Rating Scale Factor 4 (uncontrolled
hostility/excitement).20 However, this was not seen in a
more treatment-resistant group of patients.19
Fewer data regarding long-term reductions in aggression
are available for olanzapine, quetiapine, ziprasidone, and
aripiprazole, although post hoc analyses of randomized tri-
als with these agents have usually reported improvements
in agitation and hostility measures.
Investigators are currently pursuing studies comparing
various antipsychotics for the management of persistent
aggressive behavior. These studies are very logistically diffi-
cult to do.21 For example, since inpatient units actively work
to provide a treatment milieu to discourage violence,
aggressive events are relatively rare, requiring such studies
to recruit a large sample and follow it over an extended peri-
od. Consent is also an issue in this patient population. Final-
ly, a placebo monotherapy group cannot be easily
accommodated.
Adjunctive Treatments
Adjunctive treatments—such as with lithium, anticonvul-
sant medications, β-blockers, selective serotonin reuptake
inhibitors (SSRIs), and benzodiazepines—may be used to
augment the effects of antipsychotics and help prevent the
recurrence of aggression. The practice is very common. A
study of trends in adjunctive medication use for inpatients
in New York state hospitals from 1994 to 2001 found that
nearly 50% of inpatients with schizophrenia received lithium
or an anticonvulsant in addition to an antipsychotic—most
commonly valproate.22 The best-studied adjunctive mood
stabilizers/anticonvulsant medications in schizophrenia are
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lithium, carbamazepine, valproate, and lamotrigine, with the
strength of the evidence supporting valproate and lamotrig-
ine, with a smaller effect seen for carbamazepine. Conflict-
ing results were observed with lithium.23
Adjunctive use of β-blockers may be helpful in managing
persistent aggressive behavior.20 Several reports examined
the use of propranolol in patients with organic brain dis-
ease. In addition, pindolol and nadolol were tested under
double-blind, placebo-controlled conditions in 3 studies.
When using β-blockers, however, care must be taken to
monitor blood pressure and pulse, as these medications
can cause hypotension, bradycardia, respiratory difficulty,
ataxia, and other side effects. Caution should be used with
patients who are diabetic or asthmatic.
The SSRIs have been shown effective for impulsive and
compulsive behaviors, and initial studies suggest that they
may also be useful as add-on agents for the long-term man-
agement of aggression. Open-label trials of fluoxetine sug-
gest that this SSRI may have antiaggressive effects in
personality disorders24 and in schizophrenia.25 A double-
blind, crossover study of adjunctive citalopram also demon-
strated anti-aggressive effects in patients with
schizophrenia.26 While preliminary, these data suggest that
SSRIs may be effective as adjunctive therapy for the preven-
tion of aggressive behavior. In general, SSRIs should be ini-
tiated at low doses for add-on therapy and then titrated
carefully as needed.
Benzodiazepines are often used for the long-term man-
agement of patients with panic disorder, bipolar disorder,
and other mental conditions. However, benzodiazepines do
not appear to be effective in the long-term treatment of
aggression. Evidence actually suggests that this class of
agents may have a negative impact on these patients. A
double-blind, placebo-controlled study in patients who were
receiving an antipsychotic for schizophrenia reported no
additional benefit with the addition of the benzodiazepine
clonazepam.27 Although consensus guidelines recommend
the continued use of lorazepam in patients with schizophre-
nia and agitation or excitement but no history of substance
abuse,28 such long-term use can lead to physiologic toler-
ance. Tolerance develops fairly quickly with repeated use
and can lead to withdrawal symptoms and increased agita-
tion if a dose is missed.
A Treatment Algorithm
A treatment algorithm showing the simultaneous and
immediate provision of environmental and medical inter-
ventions can assist in the appropriate care of agitated
patients (Figure 4). When selecting an initial agent, physi-
cians should assess each patient for withdrawal from alco-
hol or sedatives. For a case in which withdrawal is
anticipated, lorazepam remains the best choice. Other-
wise, second-generation antipsychotics are the best
agents available, in either oral or IM formulations. Contin-
ued use of second-generation antipsychotics is preferred
over first-generation antipsychotics because of a favorable
EPS profile and a broader spectrum of efficacy that
includes treatment of negative symptoms and cognitive
dysfunction as well as mood stabilization. For patients
who remain aggressive over the long term, treatment may
require adjunctive therapies such as with lithium, anticon-
vulsants, β-blockers, or SSRIs.
Summary
Acute agitation is common and should be considered
a psychiatric emergency. Immediate treatment of patients
exhibiting agitation is crucial to prevent escalation and
the progression to aggressive or violent behaviors. Initial
treatments should be aimed at calming the patient and
should combine medication with environmental approach-
es, such as eliminating stimulation or the use of seclusion.
Intramuscular formulations of lorazepam and the typical
antipsychotic haloperidol are commonly used to
treat acute agitation. However, neither agent is a good
CNS NEWS • JUNE 2004 55
candidate for long-term treatment. Haloperidol carries a
heavy burden of potential side effects and does not treat
the negative symptoms of schizophrenia; lorazepam can
lead to tolerance and does not usually treat the underlying
mental disorder.
Fortunately, new formulations of olanzapine, risperidone,
and ziprasidone are becoming available for use in acute
treatment. Studies thus far indicate that these agents are at
least as effective as are haloperidol and lorazepam, and
that they may also have a quicker onset of action. Because
these newer antipsychotics are more tolerable to the
patient—causing little EPS or TD, for example—they are
excellent candidates for the long-term treatment of psy-
chosis, and may be useful in the prevention of aggression
in patients prone to recurrences. For the minority of patients
who repeatedly demonstrate aggressive behavior, adjunc-
tive therapies with lithium, anticonvulsant agents, β-block-
ers, and SSRIs may be required.
References
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advantages. Postgrad Med. 2002;112:85-88,94-96.
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intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agi-
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done 20 mg is effective in reducing acute agitation associated with psychosis: a dou-
ble-blind, randomized trial. Psychopharmacology (Berl). 2001;155:128-134.
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haloperidol in the treatment of acute psychosis. Ziprasidone I.M. Study Group. J Clin
Psychiatry. 2000;61:933-941.
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Rockville, Maryland: FDA Psychopharmacological Drugs Advisory Committee;
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ine for injection). Rockville, Maryland: US Dept of Health and Human Services;
January 11, 2001.
17. Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of
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tion in schizophrenia. Am J Psychiatry. 2001;158:1149-1151.
18. Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the effi-
cacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in
treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharma-
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56 CNS NEWS • JUNE 2004

Continuing Medical Education

25. Goldman MB, Janecek HM. Adjunctive fluoxetine improves global function in chronic 4. To calm an acutely agitated patient, ___________ c. A dosage of 2 mg was shown in studies to be most
schizophrenia. J Neuropsychiatry Clin Neurosci. 1990;2:429-431. should be avoided when possible. effective.
26. Vartiainen H, Tiihonen J, Putkonen A, et al. Citalopram, a selective serotonin reuptake a. calming blankets d. Time to maximum serum concentration is
inhibitor, in the treatment of aggression in schizophrenia. Acta Psychiatr Scand. b. lorazepam 15 minutes.
1995;91:348-351.
c. restraints
27. Karson CN, Weinberger DR, Bigelow L, Wyatt RJ. Clonazepam treatment of chronic d. seclusion
schizophrenia: negative results in a double-blind, placebo-controlled trial. Am J Psychi- 8. ___________ has been shown effective in the long-
atry. 1982;139:1627-1628. term treatment of agitation.
5. In the treatment of acute agitation, a combination a. Clozapine
28. McEvoy JP, Scheifler PL, Frances A, eds. The Expert Consensus Guideline Series:
Treatment of Schizophrenia. J Clin Psychiatry. 1999;60(suppl 11):1-80. of lorazepam and haloperidol ___________ . b. Fluoxetine
a. is more effective than either agent alone c. Sedation
CME Questions b. works more slowly than either agent alone d. Haloperidol
c. cannot be administered in the same syringe
1. Agitation is defined as ___________ . d. is more likely to cause extrapyramidal symptoms than
either agent alone 9. Adjunctive treatments for the long-term manage-
a. excessive motor or verbal activity ment of aggression include ___________ .
b. physical aggression by one person against others a. selective serotonin reuptake inhibitors (SSRIs)
c. irritability, suspicion, and jealousy 6. The administration of up to ___________ of olanzap-
ine during the first 24 hours of treatment produced b. benzodiazepines
d. a general feeling of hopelessness c. SSRIs and β-blockers
the fastest reductions in agitation in a rapid initial
2. Aggressive behavior appears to stem from _______ . dose escalation study. d. SSRIS and benzodiazepines
a. comorbid substance abuse a. 20
b. hallucinations and delusions b. 25 10. According to the acute agitation treatment
c. a chaotic environment c. 30 algorithm, ___________ .
d. all of the above d. 40 a. lorazepam is recommended for patients in whom
alcohol or sedative withdrawal is anticipated
3. In assessing an acutely agitated patient, the first 7. Which of the following is true about the intramuscu- b. second-generation antipsychotics are recommended
step is to ___________ . lar formulations of ziprasidone? for patients in whom alcohol or sedative withdrawal is
a. administer an atypical antipsychotic agent a. The majority of patients require 3 or 4 injections in not anticipated
b. ask about the content of a patient’s delusions the first 24 hours. c. adjunctive treatment is recommended for patients
c. rule out a somatic cause b. A dosage of 20 mg was shown in studies to be most who remain aggressive over the long term
d. ask whether the patient has access to a weapon effective. d. all of the above

✃
ANSWER SHEET & EVALUATION FORM
The Challenge of Managing Acute Agitation: New Approaches
Release Date: June 2004 Expiration Date: June 30, 2005

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CE137