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Treatment of Agitation in Mental Illness

13 J Clin Psychiatry 2006;67 (suppl 10)
ness, the U.S. Food and Drug Administration (FDA) Cen-
ter for Drug Evaluation and Research has observed that
several fairly consistent definitions for this behavioral
phenomenon are currently available in the medical litera-
ture.
1
As cited by the FDA, these definitions of agitation
include exceeding restlessness associated with mental
distress (from Dorlands Medical Dictionary) and ex-
cessive motor activity associated with a feeling of inner
tension (from the American Psychiatric Associations
Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition [DSM-IV]).
1
The complex behavioral dis-
turbances that characterize agitation occur in a number of
psychiatric disorders, including schizophrenia, bipolar
disorder, dementia (including Alzheimers disease [AD]),
and substance abuse (drugs and/or alcohol). For example,
agitation is recognized as one of the most common mani-
festations of bipolar mania, occurring with a frequency of
almost 90%.
2
With respect to schizophrenia, it has been
estimated that acutely agitated patients suffering from this
disorder may currently account for as much as 21% of psy-
chiatric emergency visits in the United States (900,000
visits annually).
3
In patients with dementia, agitation oc-
curs in up to 50% of community-dwelling patients with
AD and 70% to 90% of nursing home residents.
4
Among
elderly nursing home residents, the presence of agitation
in concert with dementia may markedly increase the finan-
cial burden of illness, not only by increasing the use of
high-cost medical services, but also by increasing the risk
of acute hospitalizations (by 15.6% over a 3-month study
period).
5
As a behavioral symptom, agitation remains an impor-
tant therapeutic target, not only in the acute and/or emer-
gent setting, but also with respect to the longer-term care
of patients with psychiatric illness.
6
The intent of this
review is to provide a summary of the various methods
(environmental manipulations and/or modifications, phar-
macotherapy, seclusion, and restraints) that are currently
available to treat agitation. In addition, published guide-
lines will be discussed with respect to the treatment of this
relatively common behavioral disturbance in persons with
various forms of mental illness, particularly schizophre-
nia, bipolar mania, and dementia.
INITIAL APPROACH TO THE AGITATED PATIENT
When a patient presents with acute agitation or overt
aggressive behavior, precautions must first be taken
to modify or manipulate the environment to maximize
the safety of all individuals present.
7
Appropriate environ-
A Review of Agitation in Mental Illness:
Treatment Guidelines and Current Therapies
Stephen R. Marder, M.D.
Background: Agitation is an important therapeutic target in the acute and/or emergent setting, as
well as for longer-term care of patients with psychiatric illness. Method: Select reviews and guide-
lines published (from 2000 to 2006) on the treatment of agitation in various psychiatric disorders were
evaluated. Results: After maximizing the safety of all individuals in the presence of an acutely agi-
tated patient, initial therapy generally involves verbal de-escalation. Pharmacologic management of
acute agitation relies on typical antipsychotics, particularly haloperidol; benzodiazepines; and atypi-
cal antipsychotics. The selection of a specific agent (or combination of agents) should be guided
by etiologic considerations, efficacy of the drug(s), side effects, potential drug interactions, and drug
formulation. Seclusion or restraints are treatments of last resort due to safety issues. Conclusion:
Compared with conventional antipsychotics (e.g., haloperidol), preliminary evidence indicates that
atypical antipsychotics effectively reduce agitation, are better tolerated, and have fewer side effects.
After an acute episode, atypical agents also help ease the transition from intramuscular to oral medica-
tion to promote ongoing treatment. (J Clin Psychiatry 2006;67[suppl 10]:1321)
From the Department of Psychiatry, David Geffen School of
Medicine at the University of California Los Angeles, VISN 22
Mental Illness Research, Education, and Clinical Center,
Los Angeles, Calif.
This article was supported by an unrestricted educational
grant from Bristol-Myers Squibb Company and Otsuka
America Pharmaceutical, Inc.
Corresponding author and reprints: Stephen R. Marder,
M.D., Department of Psychiatry, David Geffen School of
Medicine, VISN 22 Mental Illness Research, Education, and
Clinical Center, VA Desert Pacific Healthcare, 5901 E. 7th St.,
Long Beach, CA 90822 (e-mail: Stephen.Marder@med.va.gov).
A
lthough expert consensus is currently lacking as to
a precise definition of agitation in psychiatric ill-
COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
Stephen R. Marder
14 J Clin Psychiatry 2006;67 (suppl 10)
mental modifications and/or manipulations
7
may include
any or all of the following:
Assuring that the patient is physically comfortable
Decreasing external stimuli through the use of
relative isolation (a quiet room or an individual ex-
amination room)
Minimizing waiting time
Communicating a safe, respectful, and caring
attitude
Removing all potentially dangerous objects
Monitoring the way in which staff members ap-
proach the patient
Even the design of accessible toilet and shower units
must be assessed and modified to limit the risk that parts
will be broken off for the purpose of inflicting injury to
self or others.
8
With respect to approaching the agitated
patient, medical personnel and other staff should be edu-
cated to maintain calm, keep a safe distance, identify cues
for violence, respect the patients personal space, avoid di-
rect confrontation, refrain from prolonged or intense direct
eye contact, and avoid any body language that might be
interpreted as threatening or confrontational.
7,8
The first therapeutic approach to the agitated patient
generally involves verbal de-escalation (defusing or
talking down), with staff appearing calm and in control
while simultaneously conveying empathy, professional
concern for the patients well-being, and assurances that
the patient is safe from harm.
7
At this juncture, consulta-
tions from experts in pastoral care or social work also may
be helpful for select patients.
3
If, despite initial interventions, a patients agitation be-
comes so severe that the threat of assault to self or others
becomes an immediate concern, the first goal of treatment
is to do only what is necessary to assure the safety of the
patient and others while simultaneously facilitating the re-
sumption of more normal interpersonal relations.
9,10
Later,
once the patient has calmed, there should be improved op-
portunities to understand the patients problems and, hope-
fully, chart his or her subsequent treatment course.
9,10
PHARMACOLOGIC MANAGEMENT
OF THE AGITATED PATIENT
Pharmacologic management of the agitated patient may
serve either as primary therapy or as an adjunct to other
efforts at de-escalation as just described.
7
Recent discus-
sions have brought several important issues to the fore in
the delineation of appropriate pharmacologic management
of the agitated patient.
Definition of Treatment Endpoint
Prospective endpoints for the treatment of agitation
have not been well defined. Although sleep is sometimes
used as a valid treatment target for agitation reduction,
6
it
often does not guarantee safety and it definitely conflicts
with the goal of patient participation in treatment plan-
ning.
11
Moreover, sleep has not been found to be a condi-
tion that is essential for either improvement in patient
agitation or a decrease in core psychotic symptoms. In-
stead, tranquilization (a calming process separate from
total sleep induction) is now viewed by many clinicians as
the therapeutic endpoint for the treatment of agitation.
12
Variability in Assessment Instruments
In clinical studies, definitions of agitation have often
lacked precision.
13
To date, a wide variety of scales have
been used to measure agitation, including the Brief Psychi-
atric Rating Scale, the Overt Aggression Scale, the Overt
Agitation Severity Scale, the Agitated Behavior Scale, and
modified versions of these instruments.
11
Also, as of the
year 2000, many investigators have begun assessing agita-
tion by means of 10 items on the Positive and Negative
Syndrome Scale (PANSS) described as the excitement/
hostility component.
11
Unfortunately, the lack of agreement
and/or standardization of assessment instruments for the
study of agitation has sometimes made it difficult to com-
pare efficacy results across studies. The various agitation
scales differ significantly in their assessment approaches
10
;
hence, consolidation or extrapolation of efficacy findings
toward a unified clinical conclusion is challenging.
Issues Regarding Informed Consent
Informed consent or informed refusal of care poses
unique challenges with respect to the treatment of agitated
psychiatric patients.
3
The most important element of in-
formed consent is the assessment of decisional capacity,
for example, through the use of the Mini-Mental State Ex-
amination.
3
The mere existence of a particular preexisting
diagnosis or therapy does not preclude the ability of the
patient to participate in medical decision-making. With that
said, however, the ability of a highly agitated patient to
truly provide informed consent prior to participation in a
clinical trial has recently been questioned. The underlying
issue may be summarized as follows: If the patient were
sufficiently competent to absorb and understand informa-
tion about the trial and voluntarily decide to participate,
would his or her level of agitation be truly high, even in
light of reportedly high agitation scale scores? Future dis-
cussion and resolution of this issue remain of great impor-
tance in the valid interpretation of efficacy results from
treatment studies involving agitated patients, especially pa-
tients with the most severe symptoms.
SPECIFIC PHARMACOLOGIC TREATMENTS
FOR AGITATION
The pharmacologic management of acute agitation has
traditionally employed 3 separate classes of medications:
COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
Treatment of Agitation in Mental Illness
15 J Clin Psychiatry 2006;67 (suppl 10)
typical antipsychotics, particularly haloperidol; benzo-
diazepines; and, most recently, atypical antipsychotics.
Each class of medication is discussed separately in the fol-
lowing section. At the conclusion of that discussion, an
overview of guidelines applicable to the use of these medi-
cations in various subtypes of agitated patients is provided.
Typical Antipsychotics
Typical antipsychotics exert their antianxiety effect by
inhibiting dopaminergic transmission in the brain.
6
Taken
collectively, the literature published worldwide suggests
that haloperidol is one of the most frequently used typical
antipsychotics administered for the treatment of acute agi-
tation,
6
and many authors
3
consider this drug to be the
treatment of choice for this behavioral problem. Haloperi-
dol can be administered orally, intramuscularly (IM), or
intravenously (IV). When administered intramuscularly or
intravenously, the drug has an onset of action within 30 to
60 minutes, an elimination half-life of up to 12 to 36 hours,
and a duration of effect of up to 24 hours.
14
Important adverse events associated with the use of
typical antipsychotics (e.g., haloperidol) may include ex-
trapyramidal symptoms (EPS), cardiac arrhythmias, and
neuroleptic malignant syndrome (NMS).
Extrapyramidal symptoms. Haloperidol may produce
EPS, including dystonia, akathisia, and parkinsonian-like
effects (rigidity of the limbs, resting tremors, slowed
movements, etc.).
3
These events are of major concern, not
only because of their impact on the patients physical
symptoms, but also because of their potential to increase
patient distress and medication refusal.
6
Dystonic reac-
tions are particularly common following intramuscular ad-
ministration of haloperidol, especially in muscular young
men. To decrease the risk of EPS, anticholinergic med-
ications, such as benztropine, diphenhydramine, or tri-
hexyphenidyl, may be used to address these symptoms
prophylactically.
6
Akathisia is also a concern because this
side effect can be difficult to assess in patients who are al-
ready restless.
Cardiac arrhythmias. All typical antipsychotics have
quinidine-like cardiac effects, potentially increasing the
risk for cardiac arrhythmias through prolongation of the
corrected QT interval (QTc).
6
Although there have been re-
ports of sudden death occurring during tranquilization with
typical antipsychotics, including haloperidol, the
role played by the antipsychotic in these deaths re-
mains an unsettled issue since most fatalities had
multiple probable causative factors.
6,15,16
Some pub-
lished reports have linked haloperidol with cardiac
arrhythmias; however, among the typical antipsy-
chotics, haloperidol is considered to have a rela-
tively low risk for increasing QTc.
6
Neuroleptic malignant syndrome. Although
NMS is generally a rare complication of typical
antipsychotic use (0.2% of patients treated), the risk
of this problem may increase in highly agitated patients,
especially when relatively large amounts of an typical
antipsychotic are given over a short period of time.
6
This
is particularly true for patients who are poorly hydrated,
restrained, and kept in poorly ventilated holding areas.
6,11
In recognition of the potential adverse events that may
occur with typical antipsychotic use, it is imperative that
any patient treated for acute agitation should have peri-
odic monitoring of vital signs, together with evaluations
for EPS, particularly muscular rigidity.
Atypical Antipsychotics
The most recent milestone in the treatment of advanced
psychotic illness involves the development of atypical
antipsychotics, a family of second-generation agents that
are associated with reduced EPS. Table 1 lists available
atypical antipsychotics and their various formulations for
the treatment of agitation.
1721
As alternatives to haloperidol, preliminary evidence
indicates that these agents are effective in reducing agita-
tion, better tolerated, and have fewer side effects.
7,22,23
Af-
ter resolution of an acute episode, atypical antipsychotics
also help ease the patients transition from intramuscular
to oral medication and promote ongoing treatment.
7,22,23
In
terms of gauging patient satisfaction, it has been reported
that a small percentage of agitated patients treated with in-
tramuscular atypical antipsychotics have voluntarily re-
quested another dose of the medication during the acute
phase.
24
Currently, accurate assessment of the anti-agitation
utility of atypical antipsychotics has been limited by the
fact that recent clinical trials involving these agents have
typically focused on the treatment of medically stable,
nonintoxicated, protocol-compliant patients who were
able to consent to treatment.
6
Given that limitation, a re-
cent 2006 Clinical Policy Statement issued from the
American College of Emergency Physicians
25
has cited
the following efficacy results in published reports.
Ziprasidone. Ziprasidone, the first atypical antipsy-
chotic available in a fast-acting intramuscular preparation,
reaches peak plasma concentrations in 30 to 45 minutes
and has an elimination half-life of 2 to 4 hours.
26
Ziprasi-
done (20 mg IM) reduced symptoms of acute agitation
in patients with known psychotic disorders
27
and showed
Table 1. Atypical Antipsychotic Formulations for the Treatment of
Agitation
Orally
Oral Disintegrating Intramuscular
Agent Solution Tablets Injection Tablets Capsules
Risperidone
17

Olanzapine
18

Ziprasidone
19

Aripiprazole
20

Quetiapine
21

COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
Stephen R. Marder
16 J Clin Psychiatry 2006;67 (suppl 10)
efficacy comparable to that of traditional therapies (usu-
ally haloperidol with lorazepam) in undifferentiated pa-
tients with agitation.
24
Olanzapine. Olanzapine is a dopamine/serotonin an-
tagonist belonging to the thienobenzodiazepine class. It
reaches maximum concentration in 15 to 45 minutes and
has an elimination half-life of 30 hours and a duration of
action of up to 24 hours.
28
Intramuscular olanzapine was
found to be equivalent to haloperidol in reducing symp-
toms of acute agitation in 2 studies involving patients with
schizophrenia.
29,30
In patients with bipolar mania, olanza-
pine (10 mg) produced a greater reduction in agitation
scores than lorazepam (2 mg) at 2 hours, although results
of the different therapies were equivalent at 24 hours.
31
Risperidone. Risperidone is a benzisoxazole derivative
with a high affinity for dopamine/serotonin receptors.
Risperidone (2 mg orally) given in combination with lora-
zepam (2 mg) appeared to be comparable to the combina-
tion of haloperidol (5 mg) plus lorazepam (2 mg) for the
short-term treatment of agitated psychosis in patients
who would accept oral medications.
25
However, inter-
pretation of the results from this trial is complicated
by possibly higher levels of agitation in the haloperidol-
lorazepam group as compared with the risperidone-
lorazepam group.
25
Aripiprazole. Aripiprazole, the most recent atypical
antipsychotic to become available, is a dopamine D
2
par-
tial agonist with serotonin 5-HT
1A
partial agonist and
5-HT
2A
antagonist activity. Theoretically, by increasing
dopamine activity in hypodopaminergic regions while de-
creasing dopamine activity in hyperdopaminergic areas of
the brain, aripiprazole will confer potent antipsychotic ac-
tivity without the side effects of conventional antipsy-
chotic medications. Aripiprazole is currently approved for
the treatment of schizophrenia and the treatment of acute
mania and mixed episodes associated with bipolar dis-
order. As reviewed elsewhere in this supplement (see
Caine, pp. 2231), a recently presented analysis of drug-
manufacturer data (a total of 9 FDA registration and post-
marketing trials) has shown that aripiprazole, along with
several other atypical antipsychotics evaluated, is effec-
tive in consistently controlling agitation in schizophrenic
patients with high baseline levels of agitation (as mea-
sured by PANSS excitement component) in patients with
bipolar mania (as measured by decreases in total Young
Mania Rating Scale scores), and in patients with highly
agitated AD and associated psychosis.
In terms of side effects, an open-label, randomized,
prospective study by Harrigan and colleagues
32
concluded
that, like with haloperidol, maximum-recommended daily
dosages of olanzapine, ziprasidone, quetiapine, and ris-
peridone prolonged the QTc at the steady-state peak
plasma concentration. Prolongation of the QTc was least
for olanzapine, and none of the antipsychotics resulted in a
QTc that exceeded 500 ms. For olanzapine, a 20-mg de-
crease in systolic blood pressure has been noted in ap-
proximately 12% of patients,
25
necessitating the careful
monitoring of orthostatic vital signs, especially if repeated
dosages of olanzapine are to be administered. In light of
European reports
6,25
of 8 fatalities following combination
therapies that utilized olanzapine, intramuscular olanza-
pine should not be coadministered with other medications,
especially benzodiazepines or other central nervous sys-
tem depressants.
Benzodiazepines
Benzodiazepines are thought to exert their anti-
agitation effects through the facilitation of !-aminobutyric
acid (GABA) neurotransmission.
6
Some available evi-
dence suggests that in the context of agitation, ben-
zodiazepines are either as effective as the typical
antipsychotic haloperidol
11
or are superior to that drug,
especially in the treatment of psychotic or manic agita-
tion.
3336
Among the benzodiazepines, lorazepam is gener-
ally the most popular choice for use in agitation. It is the
only benzodiazepine with complete and rapid intramuscu-
lar absorption, an elimination half-life of 12 to 15 hours,
and a duration of action of 8 to 10 hours.
37
Lorazepam has
few drug-drug interactions and requires no involvement of
the cytochrome P450 system. When compared with halo-
peridol (5 mg), lorazepam (2 mg) has been shown to be
superior to the typical antipsychotic on measures of both
aggression
36
and clinical global improvement.
34
While lorazepam remains the most popular benzo-
diazepine for use in agitation, other benzodiazepines (e.g.,
clonazepam, diazepam, chlordiazepoxide, midazolam, and
flunitrazepam [not available in the United States]) have
been studied as single-agent therapy for acute agitation
and have demonstrated tranquilizing effects comparable to
those of haloperidol.
6
Although midazolam has been found
to be superior to haloperidol on measures of motor agita-
tion, most patients fell asleep after intramuscular adminis-
tration (2.5 to 15 mg) of this drug, and the duration of
effect was short (12 hours).
38
With respect to diazepam
and chlordiazepoxide, the use of these medications is
complicated by their erratic intramuscular absorption rates
and by the fact that they generate active metabolites that
have long half-lives.
6
Clonazepam, a high-potency ben-
zodiazepine with a long elimination half-life (20 to 80
hours), has complete but inconsistent intramuscular ab-
sorption,
37
and its mechanism of action is poorly under-
stood.
6
Overall, it appears to have limited efficacy for the
treatment of agitation.
6
In terms of side effects, benzodiazepines produce EPS
less frequently as compared with typical antipsychotics
11
and do not have significant cardiac effects.
6
However,
benzodiazepines do have the capacity to cause respiratory
depression, ataxia, excessive sedation, or paradoxical dis-
inhibition.
6
In light of this safety profile, clinicians often
avoid using benzodiazepines in patients with chronic
COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
Treatment of Agitation in Mental Illness
17 J Clin Psychiatry 2006;67 (suppl 10)
obstructive pulmonary disease or conditions that limit pul-
monary reserve.
39
Likewise, dose adjustments may be nec-
essary in elderly patients who, as a special subpopulation,
are generally more susceptible to excessive sedation and
ataxia.
40
GUIDELINES FOR PHARMACOTHERAPY
IN AGITATION
The selection of a specific agent (or combination of
agents) for the management of agitation should be guided
by diagnostic or etiologic considerations. Acutely agitated
patients often have major psychiatric illness that promotes
the agitated behavior, with severe agitation commonly
observed in psychotic illnesses, such as schizophrenia,
schizoaffective disorder, and the manic phase of bipolar
disorder. Other diagnoses associated with the occurrence
of severe agitation are drug- (cocaine, amphetamines, and
hallucinogens) and alcohol-intoxicated states. Because
these diagnoses present special considerations, evidence-
based guidelines suggest that drug- or alcohol-induced de-
lirium should be approached according to the underlying
etiology, if that etiology is known.
11,41
One of the reasons
for this approach is the fact that anticholinergic properties
often are associated with substances of abuse (e.g., hallu-
cinogens); hence, psychotropic medications such as anti-
psychotics (which have their own anticholinergic effects)
may potentiate the toxicity of the drugs of abuse. As a rule,
antipsychotics should be avoided when anticholinergic
delirium is suspected.
11
Instead, benzodiazepines may be a
better choice, especially when the potential for seizures
exists, as with cocaine toxicity.
11
Although benzodiaze-
pines are recommended for alcohol withdrawal states,
these medications should be used with caution because the
sedative and respiratory depressant effects are additive
with those of alcohol and other central nervous system
depressants.
11
In addition to etiology, other important factors in the
choice of pharmacologic therapy for agitation include the
efficacy of a specific drug (or combination of drugs),
known side effect profile, and potential drug interac-
tions.
11,41
For practical purposes in the clinical setting,
drug formulation is also of vital importance because it
not only affects the route of administration (a factor that
particularly impacts the treatment of the agitated, uncoop-
erative patient), but also the onset and duration of the
therapeutic effect.
Table 2 summarizes select reviews and guidelines re-
garding the pharmacologic treatment of agitation in vari-
ous psychiatric disorders published between 2000 and
2006.
2,3,68,11,25,4246
As may be appreciated from a review of
the citations presented in this table, the treatment of agita-
tion has drawn the attention of experts from diverse
specialties, including psychiatry, emergency medicine, ge-
riatrics, internal medicine, and general practice. In terms
of therapeutic recommendations, a 2000 review by Allen
11
indicated that during the period between 1960 and 1990,
the most common approach to rapid tranquilization in the
emergency setting was a combination of haloperidol and
lorazepam. Likewise, in a more recent review,
6
haloperi-
dol and lorazepam were similarly found to be the most
widely used agents. This is especially true in the case
of agitated, uncooperative patients whose medication his-
tory (with respect to prior exposure to antipsychotics) is
unknown
43
or for acutely agitated, undifferentiated pa-
tients.
25
For patients with known psychiatric illness (i.e.,
schizophrenia) for which antipsychotic treatment is indi-
cated, an extra dose of the same typical or atypical agent
that the patient is already on has been recently recom-
mended by a subcommittee of the American College of
Emergency Physicians.
25
Conversely, in the psychiatric
emergency services setting, an earlier consensus survey
indicated that benzodiazepines may be the initial choice of
therapy for the agitated, uncooperative patient with a his-
tory of prior exposure to antipsychotics.
43
With respect to
atypical antipsychotics, a 2005 review by Marco and
Vaughan
3
concluded that due to the recent introduction of
parenteral forms of these drugs, atypical antipsychotics
are gaining in popularity as first-line drugs in the treat-
ment of agitation.
Regarding alternate forms of therapy for special popu-
lations, patients with bipolar disorder may be treated with
lithium, divalproex sodium, or carbamazepine for an acute
manic episode.
2,42
Antipsychotics and benzodiazepines are
considered adjunctive treatments in this population.
2
For
the geriatric patient with psychotic mania, a 2004 survey
of geriatric specialists
44
favored the combination of a
mood stabilizer plus an antipsychotic. However, a later re-
view by Young
42
favored the use of a mood stabilizer and
the elimination of other, unnecessary psychotropic agents.
For agitated geriatric patients with dementia, mono-
therapy with an atypical antipsychotic was favored in a
2004 survey of geriatric specialists.
44
Moreover, as of
2005, Hansberry and colleagues
47
observed that atypical
antipsychotics, especially risperidone and olanzapine, had
come to be the de facto preferred treatment for agitation in
patients with dementia, with or without psychosis. With
respect to aripiprazole, Mintzer and colleagues
48
recently
demonstrated that aripiprazole produced overall clinical
improvement and significant decreases in agitation symp-
toms in long-term (10-week) studies of highly agitated pa-
tients with AD and associated psychosis.
Despite the apparent efficacy and utility of atypical
antipsychotics in treating agitation associated with de-
mentia, the off-label use of these atypical agents, which
are approved only for the treatment of schizophrenia and
mania, recently has generated concern from the FDA due
to reports of higher death rates, as compared to placebo,
among elderly patients with dementia.
49
Consequently, the
drug labeling of atypical antipsychotics must now include
COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2006 PHYSICIANS POSTGRADUATE PRESS, INC.
Stephen R. Marder
18 J Clin Psychiatry 2006;67 (suppl 10)
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Treatment of Agitation in Mental Illness
19 J Clin Psychiatry 2006;67 (suppl 10)
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Stephen R. Marder
20 J Clin Psychiatry 2006;67 (suppl 10)
a boxed warning describing this risk and noting that these
drugs are not approved for the treatment of behavioral
symptoms in elderly patients.
49
SECLUSION AND RESTRAINTS
If the agitated patient continues to exhibit emergent
and imminently dangerous behavior despite the pre-
cautions and therapies described in this report, some
practitioners suggest the use of seclusion or restraints,
7
al-
though each of these modalities is often considered a
treatment-of-last-resort.
8
Currently, seclusion rooms are
used in a minority of emergency departments across the
United States, and the use of seclusion has been declining,
possibly due to regulatory concerns and complications as-
sociated with the practice.
50
Regarding complications re-
ported in conjunction with the use of seclusion, a recent
survey of U.S. emergency department medical directors
50
concluded that patient escape from seclusion (30.1% of all
complications) was the most common adverse event, fol-
lowed by staff injury (29.2%), patient injury (19.8%), and
increased harmful behavior (11.3%).
Although it has been estimated that physical restraints
are currently employed in the treatment of approximately
8.5% of patients in emergency departments,
43
their use re-
mains a potentially dangerous management option and
should be employed sparingly.
8
While restrained, highly
agitated patients may develop significant medical com-
plications or sustain serious physical harm.
8
In terms of
clinical guidelines, the use of physical restraints should be
limited to cases in which the safety of the patient, other pa-
tients, or the hospital staff is threatened.
3
When applied,
physical restraints should be employed in the least restric-
tive manner possible and for the least amount of time (as
mandated by the clinical situation).
3
Also, as required by
the Joint Commission of Accreditation of Healthcare Or-
ganizations, institutions must have policies in place that
deal with the use of restraints, stipulating physician or-
ders, nursing documentation, types of restraints, and pa-
tient monitoring and assessment.
3
SUMMARY
Agitation is a complex behavioral disturbance that may
occur in a number of psychiatric disorders. When a patient
presents with acute agitation or overt aggressive behavior,
precautions must be taken first to modify the patients en-
vironment so as to maximize the safety of all individuals
present. Next, initial attempts at therapy generally involve
verbal de-escalation (defusing or talking down), with
staff appearing calm and in control while simultaneously
conveying empathy, concern, and assurances that the pa-
tient is safe from harm. At this juncture, consultations
from experts in pastoral care or social work also may
be helpful. If the agitated patient continues to exhibit
emergent and imminently dangerous behavior, some prac-
titioners suggest the use of seclusion or restraints, al-
though these modalities are generally considered as
treatments of last resort due to serious safety issues. With
respect to pharmacologic management, pharmacotherapy
may serve either as primary therapy or as an adjunct to
other efforts at de-escalation. Pharmacologic management
of acute agitation has traditionally employed 3 separate
classes of medications: typical antipsychotics, particularly
haloperidol; benzodiazepines; and, most recently, atypical
antipsychotics. The selection of a specific agent (or com-
bination of agents) for the management of agitation should
be guided by diagnostic or etiologic considerations. Other
important factors include efficacy, side effect profile, po-
tential drug interactions, and available formulations (the
determinant of the route of administration). In the year
2000, the most common approach to rapid tranquilization
in the emergency setting was a combination of haloperidol
and lorazepam, and these agents continue to be widely
used, especially in acutely agitated, undifferentiated pa-
tients and agitated, uncooperative patients with no known
medication history. For patients with a known psychiatric
illness for which antipsychotic treatment is indicated,
antipsychotic monotherapy (typical or atypical) has been
recommended, although some practitioners favor benzo-
diazepines as an initial choice. With respect to atypical
antipsychotics, the recent introduction of parenteral forms
of these drugs has led to their increasing popularity as
first-line treatments for agitation.
3
Because all medica-
tions used to treat agitation carry a risk of side effects, it is
imperative that any patient receiving pharmacotherapy for
acute agitation be closely monitored for the onset of ad-
verse reactions.
Drug names: aripiprazole (Abilify), benztropine (Cogentin and others),
carbamazepine (Carbatrol, Equetro, and others), chlordiazepoxide
(Librium and others), clonazepam (Klonopin and others), clozapine
(FazaClo, Clozaril, and others), diazepam (Valium and others),
diphenhydramine (Benadryl and others), divalproex sodium (Depa-
kote), droperidol (Inapsine and others), haloperidol (Haldol and
others), lithium (Lithobid, Eskalith, and others), lorazepam (Ativan
and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone
(Risperdal), trazodone (Desyrel and others), ziprasidone (Geodon).
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