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Clinical Therapeutics/Volume 32, Number 3, 2010

Systematic Reviews of Assessment Measures and


Pharmacologic Treatments for Agitation
Scott L. Zeller, MD1; and Robert W. Rhoades, PhD2
1Alameda

County Medical Center, Oakland, California; and 2Steamboat Springs, Colorado

ABSTRACT
Background: Agitation is a common behavioral
emergency associated with high risk of injury to patients and health care professionals. There are a wide
variety of approaches to assessing the severity of agitation and the risk of violence/aggression, and many
different pharmacotherapies have been used to manage this condition.
Objectives: Two systematic reviews were carried
out. The first focused on measures used to assess agitation and predict aggression/violence and/or the need
for medication. The second focused on clinical trials
of the efficacy and tolerability of pharmacotherapies
for agitation.
Methods: Publications relevant to each topic were
identified by searches of MEDLINE through December 24, 2009. The search concerning the assessment of
agitation included the terms agitation AND assessment
AND (scale OR instrument); the search for clinical trials
of pharmacotherapies for agitation included the terms
agitation and treatment AND (emergency OR acute).
Both searches were limited to reports of studies published
in English involving patients aged 18 years.
Results: The literature search identified 13 scales
used to assess the severity of agitation across multiple
patient populations; only 3 of these reports involved
the prediction of aggression/violence in patients with
agitation, and 1 involved prediction of the need for
medication. Thirty-one clinical trials of pharmacotherapy for agitation were identified by the literature
search. Based on their results, orally administered olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, and lorazepam; intramuscularly administered
olanzapine, lorazepam, ziprasidone, haloperidol, aripiprazole, midazolam, and droperidol; and intravenously administered droperidol and lorazepam were
effective for the treatment of agitation. The intramuscular route of administration was associated with a more
rapid onset of action compared with the oral route (eg,
for olanzapine, 30 minutes vs 1 hour, respectively).
March 2010

Conclusions: Agitation is a common behavioral


emergency that may require pharmacotherapy. The
management of agitated patients may be improved
through the use of easy-to-administer instruments that
predict the need for medication and the availability of
rapid-acting treatments that are well accepted by patients and health care professionals. (Clin Ther.
2010;32:403425) 2010 Excerpta Medica Inc.
Key words: agitation, schizophrenia, bipolar
disorder.

INTRODUCTION
Agitation is characterized by excessive motor or verbal activity, irritability, uncooperativeness, threatening
gestures, and, in some cases, assault.1,2 Key features
generally present in patients with agitation include
restlessness with excessive or semipurposeful motor
activity, irritability, heightened responsiveness to internal and external stimuli, and an unstable clinical
course.3 Aggression is not a core feature of agitation,
and the frequency with which agitation is associated
with aggression has not been clearly established.4
As many as 1.7 million emergency department
(ED) visits in the United States per year may involve
agitated patients,5 and 20% to 50% of visits to psychiatric emergency services in the United States may
involve patients who are at risk for agitation.5,6 Approximately 10% of patients encountered in emergency psychiatry settings may become agitated or violent
during assessment.7
Agitation may be associated with psychiatric conditions, including schizophrenia, bipolar disorder,
personality disorder, general anxiety disorder, panic
Accepted for publication January 2, 2010.
Express Track online publication March 3, 2010.
doi:10.1016/j.clinthera.2010.03.006
0149-2918/$ - see front matter
2010 Excerpta Medica Inc. All rights reserved.

403

Clinical Therapeutics
disorder, and major depression.4,8 Agitation may also
be associated with central nervous system diseases,
including Parkinsons disease, Alzheimers disease, and
other types of dementia.8,9 It may also occur in individuals with a wide range of medical conditions (eg,
thyrotoxicosis, encephalitis, meningitis) and in those
with brain trauma or hypoglycemia.8,10 Agitation may
occur in those who abuse substances (eg, alcohol, cocaine, methamphetamine) and may also result from
akathisia after administration of a conventional antipsychotic agent.8,11
Psychoses, including schizophrenia and bipolar
disorder, are common causes of agitation among individuals presenting in the ED.6,12,13 Schizophrenia affects ~2.4 million adults in the United States (1.1%
of those aged 18 years), with bipolar disorder affecting ~5.7 million (2.6% of those aged 18 years).14 It
has been estimated that ~20% of patients with schizophrenia will have episodes of agitation during their
lifetime.15 Agitated patients with schizophrenia are
thought to account for 900,000 annual visits to psychiatric emergency services, or 21% of all psychiatric
emergency visits.16 The frequency of agitation in patients with bipolar disorder has not been reported.
Many different medical specialists (eg, psychiatrists,
emergency physicians, primary care physicians, geriatricians) encounter agitation in their practices.5,17,18
Clinicians in different specialties may view agitation
primarily or exclusively from the perspective of their
own patient population, and consideration of the condition and its treatment may vary greatly across specialties. As described by a psychiatrist, symptoms
of agitation are likely to reflect observations from
agitated patients with either schizophrenia or bipolar
disorder. Conversely, because they are likely to encounter patients with agitation associated with a wide
range of underlying conditions,1820 emergency physicians may describe agitation in terms of a broader
range of symptoms. Similarly, geriatricians descriptions of agitation are likely to reflect syndromes commonly seen in the elderly.21 Regardless of the underlying etiology, there is clear agreement that agitation is
a behavioral emergency that requires immediate intervention to control symptoms and decrease the risk of
injury to the patient, health care personnel, and others
in the immediate treatment area.22,23
This paper reports the results of 2 systematic reviews. The first focused on measures used to assess
agitation and predict aggression/violence and/or the
404

need for medication. The second focused on clinical


trials of the efficacy and tolerability of pharmacotherapies for agitation.

METHODS
Publications relevant to each topic were identified by
searches of MEDLINE through December 24, 2009.
The search concerning measures for the assessment of
agitation included the terms agitation AND assessment AND (scale OR instrument); the search for clinical trials of pharmacotherapies for agitation included
the terms agitation and treatment AND (emergency
OR acute). Both searches were limited to reports of
studies published in English involving patients aged
18 years.
The abstracts of all publications identified by the
searches were reviewed for relevance. For a report to
be included in the review, patients had to be treated
specifically for agitation; exacerbations of schizophrenia or manic episodes without defined agitation were
not included. For each paper included in the analysis, data on the study design, patient characteristics,
drug doses and routes of administration, results for
the primary efficacy variable, and tolerability were
extracted from the full text by one of the authors
(R.W.R.).

INSTRUMENTS FOR THE


ASSESSMENT OF AGITATION
The literature search concerning measures for the
assessment of agitation retrieved 256 citations, of
which 212 were eliminated based on their titles alone.
Of the 44 remaining citations, review of the abstracts
or full text resulted in the elimination of 31 assessment tools developed for and used only in single
populations (eg, the elderly, those managed in an intensive care unit, those with dementia or brain injury).
The 13 remaining scales used in the assessment of
agitation/aggression across multiple treatment settings are listed in Table I. Three reports involved the
prediction of aggression/violence in patients with agitation,28,32,33 and 1 involved prediction of the need for
medication.43
The Aggressive Behavior Scale is a 4-item summary
scale measuring verbal and physical abuse, socially
inappropriate behavior, and resisting care.24 The frequency of each item is scored over 7 days using the
following scale: 0 = not exhibited; 1 = occurred on 1 to
3 days; 2 = occurred on 4 to 6 days; and 3 = occurred
Volume 32 Number 3

S.L. Zeller and R.W. Rhoades

Table I. Tools for the assessment of agitation.


Aggressive Behavior Scale24
Agitated Behavior Scale13,25
Brief Agitation Rating Scale26,27
Brset Violence Checklist28
Clinical Global Impression Scale for Aggression29
Cohen-Mansfield Agitation Inventory30,31
Historical, Clinical, and Risk Management20
Violence Risk Assessment Scheme32
McNiel-Binder Violence Screening Checklist33
Neurobehavioral Rating ScaleRevised34,35
Overt Aggression Scale36,37
Overt Agitation Severity Scale38,39
Positive and Negative Syndrome ScaleExcited
Component4044
Ryden Aggression Scale4547
daily. This instrument was originally developed for
use in long-term care facilities, but it has also been
used for the assessment of patients being admitted for
acute care.
The Agitated Behavior Scale was developed to assess the nature and extent of agitation during the
acute phase of recovery from acquired brain injury.25
Its primary purpose is to provide health care professionals with objective feedback on the course of a
patients agitation. It includes 14 clinician-rated items:
attention-related behaviors, impulsivity/impatience,
uncooperativity, violence/threats, unpredictable anger,
self-stimulating behavior, resistance to restraint, wandering, restlessness, repetitive behaviors, loud/excessive
talking, sudden changes of mood, excessive crying or
laughter, and self-abusive behavior. All items are rated
on the following 4-point scale: 1 = absent; 2 = present
to a slight degree; 3 = present to a moderate degree;
and 4 = present to an extreme degree. Although this
instrument was developed and is used primarily for the
assessment of agitation in patients with brain damage,
it has been used for the assessment of agitation in
patients presenting to the ED.13
The Brief Agitation Rating Scale (BARS) was developed to allow nurses and other caregivers in nursing
homes to rapidly assess a patients level of agitation.26
It was developed as a subset of the Cohen-Mansfield
Agitation Inventory (CMAI). It includes 10 items: hitting, grabbing, pushing, pacing or aimless wandering,
March 2010

repetitious mannerisms, restlessness, screaming, repetitive sentences or questions, making strange noises,
and complaining. Items are rated from 0 = none to
3 = often or continuous. In addition to its use in nursing homes, this instrument has been used for the assessment of patients being admitted to the hospital
for psychiatric services.27
The Brset Violence Checklist (BVC) was developed primarily for use in the evaluation of psychiatric
inpatients.28 It measures 6 clinician-rated variables:
confusion, irritability, boisterousness, physical threats,
verbal threats, and attacks on objects. Each item is
scored for its presence (1) or absence (0). For patients
who are well known to the clinical staff, habitual behaviors (nonviolent) are scored 0, whereas an increase
in the listed behaviors is scored 1. The sum of scores
is then totaled. A total score of 0 indicates a low risk
of violence, and a score 2 is predictive of a violent
episode in the next 24 hours.
The Clinical Global Impression Scale for Aggression is a simple instrument based solely on observation of the patient.29 The clinician rates agitation on a
scale from 1 = none to 5 = aggressive behavior. It has
not been used to predict violence or the need for medication, although scores on this instrument have been
found to be linearly correlated with scores on the
Positive and Negative Syndrome ScaleExcited Component (PANSS-EC).
The CMAI is a 29-item caregiver rating questionnaire used for the assessment of agitation in older
persons.30 It includes descriptions of 29 agitated behaviors, each rated on a 7-point scale of frequency.
This instrument was developed primarily for the assessment of elderly patients in long-term care facilities, although it has been used for the initial assessment of agitation in patients being admitted to the
hospital for psychiatric care.31
The Historical, Clinical, and Risk Management20
Violence Risk Assessment Scheme (HCR-20) has been
used to assess the risk of violence in a wide range of settings.32 It includes 20 items taken from the patients
medical history or rated by the clinician, including history
of violence, current clinical status, and environmental/
support factors that may increase the risk for violence.
Each item is scored as 0 = not present, 1 = possibly present, or 2 = definitely present, with a maximum score
of 40. It has been found to be effective in predicting
violent behavior in clinical psychiatric, forensic, and
correctional settings.
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Clinical Therapeutics
The McNiel-Binder Violence Screening Checklist
is used to predict future violent behavior.33 It includes
5 variables: history of physical attacks or fear-inducing
behavior within 2 weeks, absence of suicidal behavior,
schizophrenic or manic diagnosis, male gender, and
currently married or living with a partner. Each variable is scored as present or absent. This instrument
has been found to have moderate sensitivity (57.2%)
and specificity (70.0%) for predicting violence in patients admitted to a psychiatric inpatient unit.
The Neurobehavioral Rating ScaleRevised (NRS-R)
is a 29-item, multidimensional, clinician-based instrument designed to measure neurobehavioral disturbances.34 It includes assessments of orientation and
memory of recent events, emotional state, postconcussional symptoms, focused attention and concentration, explanation of proverbs, planning and mentalflexibility tasks, and delayed recall of objects presented
at the beginning of a session. It also involves the clinicians observations regarding the patients fatigability,
visible signs of anxiety, disinhibition, agitation, hostility, difficulties in expressive and receptive communication, and disturbance of mood. Each variable is scored
as present or absent. This instrument has been employed for the assessment of agitation level in patients
presenting to the ED.35
The Overt Aggression Scale (OAS) is a checklist of
16 items that is used to evaluate verbal aggression and
physical aggression against self, objects, and others.36,37
It is scored as described in the next paragraph. The
scale was developed for use in both adults and pediatric patients in clinical and research settings.
The Overt Agitation Severity Scale is used to assess
vocalizations (eg, whining) and orofacial movements
(eg, grimacing), movements of the upper torso and extremities (eg, tapping of fingers, rocking), and movements of the lower extremities (eg, toe-tapping, kicking at objects) indicative of agitation.38 Each behavior
is measured on a scale from 0 = not present to 4 =
always present. This instrument has been validated in
psychiatric inpatients.39
The PANSS-EC is commonly used in the assessment
of psychiatric conditions, although it can be used to
measure agitation and has been extensively used in
clinical trials of pharmacotherapy for agitation.4043 It
includes 5 individual PANSS items: hostility, uncooperativeness, impulsivity, tension, and excitability.
Each item is rated on a scale from 1 = nonexistent to
7 = severe.43 A response to treatment is considered a
406

40% decrease in PANSS-EC score within 2 hours.


Although it is primarily a research tool, the PANSS-EC
has been used in clinical practice to aid in deciding
whether to administer psychotropic medication to agitated patients with schizophrenia.43 A study in patients with schizophrenia admitted to a psychiatric
hospital found that the 41 patients who were assessed
using the PANSS-EC during the first 3 days after admission and received medication as needed based in
part on the results of this evaluation had a significantly lower risk for episodes of aggression compared
with the 35 patients who were not assessed using the
PANSS-EC and received medication solely on the basis
of clinical observation (P = 0.021).44
The Ryden Aggression Scale contains 3 subscales
with a total of 25 items concerning physical, verbal,
and sexual behavior.45 Items are rated on a scale from
0 = never to 5 = 1 time daily. It has been used primarily as a survey instrument for assessing the prevalence of aggressive behavior in the community and
among nursing home residents.4547
Few of the numerous scales developed for the assessment of agitation have been used to assess the efficacy of pharmacotherapy for this condition. This is
an important lack, as the end point that is most meaningful in clinical practicepatients with a low risk of
violence who cooperate with clinical evaluations
may not be completely captured by the measures used
to assess the effects of pharmacotherapy in clinical
trials.

TREATMENT OF AGITATION
The literature search for clinical trials of pharmacotherapy for agitation retrieved 169 citations. After
evaluation of the abstracts and/or full text of these citations, 31 clinical trials were included in the review.

Oral Therapy
The search identified 7 trials of oral therapy for
agitation (Table II), 2 assessing antipsychotic
monotherapy48,49 and 5 assessing antipsychotic agents
in combination with intramuscular lorazepam.5054

Monotherapy
In a 72-hour, randomized, rater-blinded, prospective trial, Villari et al48 evaluated haloperidol 5 to
15 mg/d, risperidone 2 to 6 mg/d, olanzapine 10 to
20 mg/d, and quetiapine 300 to 800 mg/d in 101 agitated patients with psychosis. There were no signifiVolume 32 Number 3

March 2010

Table II. Results of clinical studies of oral treatment for agitation.

Study/
Design

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Psychosis
(unspecified)

Mental
health
department,
72 h

Haloperidol 515 mg/d


(n = 28)
Risperidone 26 mg/d
(n = 27)
Olanzapine 1020 mg/d
(n = 24)
Quetiapine 300800 mg/d
(n = 22)

MOAS total score:


decreased with all
treatments (P not
reported), with no
differences between
groups

Haloperidol: EPS (21.4%),


somnolence (18.0%),
hypotension (14.0%),
abnormal gait (7.1%),
headache (7.1%)
Risperidone: somnolence
(11.1%), abnormal gait
(7.4%), EPS (7.4%),
hypotension (7.4%)
Olanzapine: somnolence
(21.0%), hypotension (17.0%),
dizziness (12.5%), abnormal
gait (8.3%), headache (8.3%)
Quetiapine: somnolence
(32.0%), dizziness (18.0%),
hypotension (14.0%)

Currier et al49
OL

Psychosis and at least


moderate agitation;
age 1865 y

ED, 3 h

Quetiapine 100 mg
(n = 7), 150 mg (n = 6),
or 200 mg (n = 7)

PANSS-EC at 2 h: 40%
reduction achieved in
50% of patients

Orthostasis in 40% of
patients at 2 h

Currier et al50
R, PG,
prospective,
rater blinded,
noninferiority

Acute exacerbation
of schizophrenia or
schizoaffective
disorder, mania with
psychotic features,
acute paranoid
reaction, delusional
disorders (DSM-IV);
age 1865 y

PES, 24 h

Risperidone 2 mg +
lorazepam 2 mg IM
(n = 83)
Haloperidol 5 mg IM +
lorazepam 2 mg IM
(n = 79)

PANSS-EC from 30 min to


24 h: significant decreases
with both treatments
from 30 min to 24 h
(P < 0.001), with no
significant differences
between groups

Risperidone: somnolence
(12.8%)
Haloperidol: somnolence
(12.7%), headache (6.3%),
agitation (5.1%),
hyperkinesia (5.1%)

(continued)
407

S.L. Zeller and R.W. Rhoades

Villari et al48
R, prospective,
rater blinded

Study/
Design

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Volume 32 Number 3

Kinon et al51
R, DB, PG

Schizophrenia,
schizophreniform or
schizoaffective
disorder;
age 1865 y

Inpatient
psychiatric,
5d

Olanzapine 20 mg/d +
lorazepam to 4 mg/d
IM as needed (n = 306)
Aripiprazole to 30 mg/d +
lorazepam to 4 mg/d
IM as needed
(n = 298)

PANSS-EC: significant
decreases from baseline
to end of each day with
both treatments (P < 0.001),
with no significant
differences between
groups

Olanzapine: insomnia (5.2%)


Aripiprazole: insomnia (8.3%),
headache (5.3%)

Kinon et al52
R, DB,
prospective

Schizophrenia,
schizophreniform or
schizoaffective
disorder;
age 1850 y

Hospitalized,
3 wk

Olanzapine 10 mg/d +
lorazepam 12 mg IM
as needed (n = 52)
Haloperidol 10 mg/d +
lorazepam 12 mg IM
as needed (n = 48)

PANSS Agitation subscale


scores at 124 h and each
wk thereafter: significant
improvements at all time
points with both treatments
(all, P < 0.001), with no
significant differences
between groups

Olanzapine: somnolence
(17.3%), anxiety (11.5%),
headache (11.5%), agitation
(9.6%), pain (9.6%),
nervousness (7.7%),
insomnia (5.7%)
Haloperidol: headache
(25.0%), somnolence
(25.0%), nervousness
(16.7%), insomnia (13.0%),
agitation (10.0%), pain
(10.0%), dystonia (8.3%),
hypertonia (8.3%),
increased salivation (8.3%)

Veser et al53
R, DB, PC,
prospective

Psychosis
(unspecified);
age 1865 y

ED, 90 min

Risperidone 2 mg +
lorazepam 2 mg IM
(n = 10)
Haloperidol 5 mg +
lorazepam 2 mg IM
(n = 10)
Lorazepam 2 mg IM
(n = 10)

PANSS at 30 and 90 min:


no significant differences
between groups

Not reported

(continued)

Clinical Therapeutics

408

Table II (continued).

March 2010
Table II (continued).
Study/
Design
Baker et al54
R, DB
treatment,
followed by R,
OL treatment

Patient
Population
Schizophrenia,
schizoaffective
disorder,
schizophreniform
disorder, bipolar I
disorder (manic or
mixed episode)
(DSM-IV);
age 1855 y

Setting and
Duration of
Treatment
PES, DB
treatment
for 4 d,
followed
by OL
treatment
for 3 d

Interventions
Olanzapine 10 or 20 mg/d +
lorazepam 4 mg/d IM as
needed during DB
treatment period,
followed by olanzapine
520 mg/d
(N = 148)

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

PANSS-EC at 24 h:
significant decreases with
both treatments (P < 0.001),
with no significant
difference between groups

Olanzapine 10 mg/d:
somnolence (26%),
nervousness (11%),
headache (8%), insomnia
(8%), dizziness (7%)
Olanzapine 20 mg/d:
somnolence (31%), dizziness
(17%), headache (17%),
insomnia (13%), nervousness
(7%)

409

S.L. Zeller and R.W. Rhoades

AEs = adverse events; R = randomized; MOAS = Modified Overt Aggression Scale; EPS = extrapyramidal symptoms; OL = open label; ED = emergency department; PANSS-EC = Positive and Negative Syndrome ScaleExcited Component; PG = parallel group; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition; PES = psychiatric emergency services; DB = double blind; PC = placebo controlled.

Clinical Therapeutics
cant differences between groups with respect to improvement on the Modified OAS. (The Modified OAS
is a retrospective version of the OAS intended to
cover a 1-week period of behavior. It measures the
same 16 items as the OAS, with each item rated on
a 5-point scale from never to >10 times per week.)
Because the first postbaseline evaluation took place
3 days after the initiation of therapy, the onset of action was not determined. Adverse events (AEs) occurring in 5% of patients with haloperidol were extrapyramidal symptoms (EPS) (21.4%), somnolence
(18.0%), hypotension (14.0%), abnormal gait (7.1%),
and headache (7.1%). The most common AEs with
risperidone were somnolence (11.1%), abnormal gait
(7.4%), EPS (7.4%), and hypotension (7.4%). The
most common AEs with olanzapine were somnolence
(21.0%), hypotension (17.0%), dizziness (12.5%), abnormal gait (8.3%), and headache (8.3%). The most
common AEs with quetiapine were somnolence
(32.0%), dizziness (18.0%), and hypotension (14.0%).
In a 3-hour, open-label trial by Currier et al,49 patients with psychosis and at least moderate agitation
received quetiapine 100 mg (n = 7), 150 mg (n = 6), or
200 mg (n = 7). At 2 hours after dosing, 50% of patients had a 40% reduction in PANSS-EC scores.
Orthostasis was the most common AE, occurring in
40% of patients.

Combination Therapy
Currier et al50 conducted a 24-hour, randomized,
prospective, rater-blinded, noninferiority trial comparing risperidone 2 mg and haloperidol 5 mg IM,
both with lorazepam 2 mg IM, in 162 patients with an
acute exacerbation of schizophrenia or schizoaffective
disorder, mania with psychotic features, acute paranoid reaction, or delusional disorders. Efficacy was
evaluated based on PANSS-EC scores from 30 minutes to 24 hours after dosing. Both agents significantly
decreased PANSS-EC scores from 30 minutes to 2 hours
after dosing (P < 0.001), with no significant difference
between them. The most common AE with risperidone
was somnolence (12.8%); the most common AEs with
haloperidol were somnolence (12.7%), headache
(6.3%), agitation (5.1%), and hyperkinesia (5.1%).
Kinon et al51 conducted a 5-day, randomized,
double-blind, parallel-group study comparing olanzapine 20 mg/d with aripiprazole 30 mg/d, both combined with lorazepam up to 4 mg/d IM as needed, in
604 patients with schizophrenia or schizophreniform
410

or schizoaffective disorder. Both agents significantly


decreased PANSS-EC scores from baseline to the end
of each day (P < 0.001), with no significant differences between them. Because the first postbaseline
evaluation did not take place until 1 day after the
initial dose of study medication, the onset of action
could not be determined. The most common AE with
olanzapine was insomnia (5.2%); the most common
AEs with aripiprazole were insomnia (8.3%) and
headache (5.3%).
In a 3-week, randomized, double-blind, prospective
study, Kinon et al52 compared olanzapine 10 mg/d
and haloperidol 10 mg/d, both with lorazepam 1 to
2 mg IM as needed, in 100 patients with schizophrenia or schizophreniform or schizoaffective disorder.
Each agent was associated with significant improvements in PANSS Agitation subscale scores from 1 to
24 hours after dosing and at subsequent weekly evaluations (P < 0.001), with no significant differences between groups. The most common AEs with olanzapine
were somnolence (17.3%), anxiety (11.5%), headache
(11.5%), agitation (9.6%), pain (9.6%), nervousness
(7.7%), and insomnia (5.7%). The most common AEs
with haloperidol were headache (25.0%), somnolence
(25.0%), nervousness (16.7%), insomnia (13.0%),
agitation (10.0%), pain (10.0%), dystonia (8.3%),
hypertonia (8.3%), and increased salivation (8.3%).
A 90-minute, randomized, double-blind, placebocontrolled trial by Veser et al53 compared risperidone
2 mg plus lorazepam 2 mg IM, haloperidol 5 mg plus
lorazepam 2 mg IM, and lorazepam 2 mg IM alone
in 30 patients with psychosis. All regimens were associated with decreases in PANSS total scores at
30 and 90 minutes after dosing, with no significant
differences between groups. No tolerability data were
reported.
Baker et al54 conducted a 4-day, randomized, doubleblind evaluation of the efficacy of olanzapine 10 or
20 mg/d, with lorazepam 4 mg/d IM as needed, in
148 patients with schizophrenia, schizoaffective or
schizophreniform disorder, or bipolar I disorder (manic
or mixed episode). Double-blind treatment was followed by 3 days of randomized, open-label treatment.
The primary efficacy end point in the double-blind
portion of the study was improvement in PANSS-EC
scores at 24 hours after dosing. Both olanzapine doses
were associated with significant decreases in PANSS-EC
scores at 24 hours (P < 0.001), with no significant differences between doses. The onset of action was not
Volume 32 Number 3

S.L. Zeller and R.W. Rhoades


determined. The most common AEs with olanzapine
10 mg/d were somnolence (26%), nervousness (11%),
headache (8%), insomnia (8%), and dizziness (7%).
The most common AEs with olanzapine 20 mg/d were
somnolence (31%), dizziness (17%), headache (17%),
insomnia (13%), and nervousness (7%).

Intramuscular Therapy
Twenty studies were identified that assessed intramuscular administration of antipsychotic agents and/
or benzodiazepines (Table III). Of these, 15 involved
monotherapy43.5568 and 5 involved combination
therapy.6973

Monotherapy
In a 24-hour, randomized, prospective trial, Breier
et al43 compared olanzapine 2.5 to 10 mg with haloperidol 7.5 mg and placebo in 270 patients with
schizophrenia or schizophreniform or schizoaffective
disorder. All olanzapine doses were associated with
significant decreases in the primary efficacy measure,
PANSS-EC scores at 2 hours, compared with placebo
(all, P 0.01). Olanzapine doses 5 mg were associated with significant decreases compared with placebo
at 30 minutes (P 0.05). Haloperidol was associated
with significant decreases compared with placebo
from 60 minutes to 2 hours (all, P < 0.001). No AEs
were reported in 5% of patients receiving olanzapine. The most common AEs with haloperidol were
parkinsonism (16.7%) and akathisia (7.9%).
A 1-day, randomized, double-blind trial by Meehan
et al55 compared the effects of olanzapine 2.5 to 5 mg,
lorazepam 1 mg, and placebo in 272 patients with
Alzheimers disease, vascular dementia, or mixed dementia. Olanzapine significantly decreased PANSS-EC
scores compared with placebo from 30 minutes to
2 hours after dosing (all, P 0.05). Lorazepam significantly decreased PANSS-EC scores compared with
placebo at 2 hours (P 0.05). The only AE reported
by 5% of patients was somnolence in the lorazepam
group (10.3%).
A 24-hour, randomized, double-blind trial by Agid
et al56 compared ziprasidone 2 and 20 mg in 79 patients with schizophrenia, schizoaffective disorder,
bipolar disorder with psychotic features, delusional
disorder, or unspecified psychotic disorder. Ziprasidone 20 mg was associated with significant decreases
in the PANSS early psychosis factor score compared
with ziprasidone 2 mg at 4 hours (first postbaseline
March 2010

assessment) (P < 0.05) and 24 hours (P < 0.01). In a


second report from this trial by Daniel et al,57 decreases in BARS scores were significantly greater with
ziprasidone 20 mg compared with ziprasidone 2 mg
from 30 minutes to 4 hours after administration (P <
0.01). The most common AEs with ziprasidone 2 mg
were somnolence (13.2%), nausea (7.9%), asthenia
(5.3%), diarrhea (5.3%), and insomnia (5.3%). The
most common AEs with ziprasidone 20 mg were somnolence (19.5%), nausea (12.2%), dizziness (9.8%),
and injection-site pain (7.3%).
Barak et al58 conducted a 3-day, open-label study
of ziprasidone 10 and 20 mg in 21 elderly patients
(age 60 years) with schizophrenia or schizoaffective
disorder. Examination of pooled results for the 2 doses
indicated that ziprasidone was associated with a significant decrease from baseline in BARS score at 4 hours
after the initial injection (P < 0.01). Acute urinary retention, blurred vision, and sedation were reported
in 1 patient each.
Wright et al59 conducted a 24-hour, randomized,
prospective comparison of olanzapine 10 mg, haloperidol 5 mg, and placebo in 311 patients with schizophrenia or schizophreniform or schizoaffective disorder. Olanzapine was associated with significant
decreases in PANSS-EC scores from 15 to 45 minutes
compared with haloperidol (P < 0.01) and from 15 minutes to 2 hours compared with placebo (all, P < 0.05).
No AEs were reported for 5% of patients treated
with olanzapine. The most common AEs with haloperidol were dystonia (7.1%) and EPS (5.6%).
In a 24-hour, prospective, observational study,
Damsa et al60 evaluated olanzapine 10 mg, with a
second dose (5 mg) permitted 2 hours after the first
dose, in 40 patients with agitation. Olanzapine significantly decreased PANSS-EC scores at 2 hours after
administration (the first postbaseline assessment) (P <
0.001). Eight patients had a 20mm Hg reduction in
systolic blood pressure during treatment.
Centorrino et al61 conducted a 2-hour, open-label,
observational study of olanzapine (mean initial dose,
9.9 mg) in 74 agitated patients with schizophrenia or
bipolar disorder. Olanzapine significantly decreased
PANSS-EC scores at 2 hours (first postbaseline assessment) (P < 0.001). The most common AEs were insomnia (9.5%), arthralgia (7.9%), and headache (6.3%).
San et al62 conducted a nonrandomized, observational study in 92 patients with schizophrenia, bipolar
disorder, or unspecified psychotic disorder. Olanzapine
411

Study/
Design

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Volume 32 Number 3

Breier et al43
R, prospective

Schizophrenia,
schizophreniform
or schizoaffective
disorder (DSM-IV);
age 18 y

Hospitalized,
24 h

Olanzapine 2.510 mg
(n = 185)
Haloperidol 7.5 mg
(n = 40)
Placebo (n = 45)

PANSS-EC at 2 h: significant
decreases, all olanzapine doses vs
placebo (all, P 0.01); significant
decrease, olanzapine doses 5 mg
vs placebo at 30 min (P 0.05);
significant decrease, haloperidol
vs placebo from 60 min to 2 h
(all, P < 0.001)

Haloperidol:
parkinsonism (16.7%),
akathisia (7.9%)*

Meehan et al55
R, DB, PC,
prospective

Alzheimers disease,
vascular dementia,
mixed dementia;
age 55 y

Hospitalized
or in longterm care
facility, 1 d

Olanzapine 2.55 mg
(n = 137)
Lorazepam 1 mg (n = 68)
Placebo (n = 67)

PANSS-EC: significant decreases


from 30 min to 2 h, olanzapine vs
placebo (all, P 0.05); significant
decrease at 2 h, lorazepam vs
placebo (P 0.05)

Lorazepam:
somnolence (10.3%)*

Agid et al56
R, DB

Schizophrenia,
schizoaffective
disorder, bipolar
disorder with
psychotic features,
delusional disorder,
unspecified
psychotic disorder
(DSM-IV); age 18 y

Hospitalized,
24 h

Ziprasidone 2 mg (n = 38)
Ziprasidone 20 mg
(n = 41)

PANSS early psychosis factor


score: significant decreases,
ziprasidone 20 mg vs ziprasidone
2 mg at 4 h (first postbaseline
assessment) (P < 0.05) and 24 h
(P < 0.01)

Not reported

(continued)

Clinical Therapeutics

412
Table III. Results of clinical studies of intramuscular treatment for agitation.

March 2010

Table III (continued).


Study/
Design
Daniel et al57
Same study
population as
in Agid et al56

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Decrease in BARS: significant


difference from 30 min to 4 h,
ziprasidone 20 mg vs ziprasidone
2 mg (P < 0.01)

Ziprasidone 2 mg:
somnolence (13.2%),
nausea (7.9%),
asthenia (5.3%),
diarrhea (5.3%),
insomnia (5.3%)
Ziprasidone 20 mg:
somnolence (19.5%),
nausea (12.2%),
dizziness (9.8%),
injection-site pain
(7.3%)

Schizophrenia,
schizoaffective
disorder (DSM-IV);
age 60 y

Admitted to
psychiatric
ward, 3 d

Ziprasidone 10 or 20 mg
(N = 21)

BARS: significant decrease at 4 h


after initial injection (P < 0.01)

Acute urinary
retention, blurred
vision, sedation
(1 patient each)

Wright et al59
R, PC,
prospective

Schizophrenia,
schizoaffective or
schizophreniform
disorder (DSM-IV);
age 18 y

Hospitalized,
24 h

Olanzapine 10 mg
(n = 131)
Haloperidol 5 mg
(n = 126)
Placebo (n = 54)

PANSS-EC at 2 h: significant
decreases, olanzapine vs placebo
from 15 min to 2 h (all, P < 0.05)
and vs haloperidol from 15 to
45 min (P < 0.01)

Haloperidol: dystonia
(7.1%), EPS (5.6%)*

Damsa et al60
Prospective,
observational

Patients with
agitation (diagnosis
not established);
age not specified

ED, 24 h

Olanzapine 10 mg, with


second dose (5 mg)
permitted 2 h after
the first (N = 40)

PANSS-EC: significant decrease


at 2 h (first postbaseline
assessment) (P < 0.001)

8 Patients had
20mm Hg
reduction in systolic
blood pressure

Centorrino
et al61
OL,
observational

Schizophrenia,
bipolar disorder;
age 1865 y

PES, 2 h

Olanzapine, mean initial


dose 9.9 mg (N = 74)

PANSS-EC at 2 h: significant
decrease (P < 0.001)

Insomnia (9.5%),
arthralgia (7.9%),
headache (6.3%)

413

(continued)

S.L. Zeller and R.W. Rhoades

Barak et al58
OL

Study/
Design

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Volume 32 Number 3

San et al62
Nonrandomized,
observational

Schizophrenia,
bipolar disorder,
unspecified
psychotic disorder
(DSM-IV);
age 1870 y

PES, 24 h

Olanzapine 10 mg (N = 92)

PANSS-EC from 2 to 24 h:
significant decrease at 2 h (first
postbaseline assessment) and
24 h (both, P = 0.001)

No AEs reported in
5% of patients

Meehan et al63
R, prospective

Bipolar disorder
(mixed or manic
episode) (DSMIII-R); age 18 y

PES, 24 h

Olanzapine 10 mg (n = 99)
Lorazepam 2 mg (n = 51)
Placebo (n = 51)

PANSS-EC Agitation subscale


score at 2 h: significant decrease,
olanzapine vs lorazepam (P = 0.001)
and vs placebo (P < 0.001); no
significant difference, lorazepam vs
placebo (P = 0.053)

Olanzapine:
somnolence (13.1%),
dizziness (9.1%)
Lorazepam: dizziness
(13.7%), somnolence
(9.8%)

Tran-Johnson
et al64
R, DB, PC

Schizophrenia,
schizophreniform
disorder (DSM-IV);
age 18 y

Hospitalized,
1d

Aripiprazole 1, 5.25, 9.75,


or 15 mg (n = 235)
Haloperidol 7.5 mg
(n = 60)
Placebo (n = 62)

PANSS-EC at 2 h: significant
decreases from 45 min to 2 h,
aripiprazole 9.75 mg vs placebo
(all, P 0.05); significant
decreases at 105 min and 2 h,
haloperidol vs placebo (both,
P < 0.01)

Aripiprazole 9.75 mg:


headache (10.7%),
nausea (10.7%),
dizziness (7.1%),
akathisia (5.4%),
somnolence (5.4%)
Haloperidol:
somnolence (12.3%),
akathisia (10.5%),
dizziness (7.0%),
dystonia (7.0%)

Andrezina
et al65
R, DB

Schizophrenia,
schizoaffective
disorder (DSM-IV);
age 18 y

Hospitalized,
24 h

Administered up to 3 times
(0, 2, and 4 h):
Aripiprazole 9.75 mg
(n = 175)
Haloperidol 6.5 mg
(n = 185)
Placebo (n = 88)

PANSS-EC at 2 h: significant
decreases from 60 min to 2 h,
aripiprazole vs placebo (P < 0.05);
significant decreases from 45 min
to 2 h, haloperidol vs placebo
(P < 0.05)

Aripiprazole: headache
(7.4%), dizziness
(6.3%), insomnia
(5.7%), nausea (5.7%)
Haloperidol: insomnia
(12.0%), headache
(8.2%), EPS (5.5%)
(continued)

Clinical Therapeutics

414

Table III (continued).

March 2010

Table III (continued).


Study/
Design

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Undifferentiated
agitation; age 18 y

ED, 2 h

Droperidol 5 mg (n = 50) Altered Mental Status Scale:


Ziprasidone 20 mg (n = 46) significant decreases with all
Midazolam 5 mg (n = 48) treatments from 15 to 120 min
(all, P < 0.05 based on 95% CIs)

Respiratory depression:
4 patients droperidol,
9 ziprasidone,
24 midazolam

Resnick and
Burton67
R, DB,
prospective

Psychosis
(unspecified);
age 1865 y

PES

Single doses:
Droperidol 5 mg (n = 11)
Haloperidol 5 mg (n = 16)

BPRS agitation score 17: 36%


droperidol, 81% haloperidol at 30
min (P < 0.05)

Haloperidol: dystonia
(1 patient)*

Nobay et al68
R, DB,
prospective

Psychosis
(unspecified),
substance abuse; age
not specified

ED, 1 d

Midazolam 5 mg (n = 42)
Haloperidol 5 mg (n = 42)
Lorazepam 2 mg (n = 27)

Mean time to sedation on


Modified Thomas Combativeness
Scale: 18.3 min midazolam,
28.3 min haloperidol, and 32.2 min
lorazepam (P = 0.039, midazolam vs
haloperidol; P = 0.003, midazolam
vs lorazepam)

No AEs reported in
5% of patients

Huf et al69
R, OL

Psychosis
(unspecified),
substance abuse; age
not specified

PES, 2 wk

Haloperidol 510 mg
(n = 156)
Haloperidol 510 mg +
promethazine 50 mg
(n = 160)

Tranquilized or asleep at
20 min: 55% haloperidol vs
72% haloperidol + promethazine
at 20 min (P = 0.002)

Haloperidol
monotherapy:
dystonia
(9 patients)*

TREC
Collaborative
Group70
R, patient
blinded,
prospective

Psychosis
(unspecified),
substance abuse; age
not specified

PES, 2 wk

Haloperidol 510 mg +
promethazine 25
50 mg (n = 150)
Midazolam 15 mg
(n = 151)

Tranquilized or asleep at 20 min:


67% haloperidol + promethazine,
89% midazolam (P not reported)

No AEs reported in
5% of patients

(continued)
415

S.L. Zeller and R.W. Rhoades

Martel et al66
R, DB,
prospective

Study/
Design

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Raveendran
et al71
R, patient
blinded,
prospective

Psychiatric illness
(unspecified); age not
specified

PES, 2 wk

Haloperidol 10 mg +
promethazine 25
50 mg (n = 150)
Olanzapine 10 mg
(n = 150)

Tranquilized or asleep at 15 min:


91% haloperidol + promethazine,
87% olanzapine (P not reported)

No AEs reported in
5% of patients

Bieniek et al72
R, OL

Psychosis, meeting
clinical criteria for
chemical restraint;
age 1850 y

PES, 180-min
duration of
observation

Lorazepam 2 mg (n = 11)
Lorazepam 2 mg +
haloperidol 5 mg (n = 9)

Overt Aggression Scale:


significant decrease at 60 min,
lorazepam + haloperidol vs
lorazepam alone
(P = 0.04)

No AEs reported in
5% of patients

Battaglia et al73
R, DB,
prospective

Psychosis
(unspecified); age
not specified

PES, 24 h

Lorazepam 2 mg (n = 31)
Haloperidol 5 mg (n = 35)
Lorazepam 2 mg +
haloperidol 5 mg
(n = 32)

Agitated Behavior Scale at 1 h:


greater decrease, combination
therapy vs lorazepam at 1 h
(P not reported); no differences,
lorazepam vs haloperidol, or
haloperidol vs lorazepam +
haloperidol (P not reported)

Lorazepam:
dry mouth (16%)
Haloperidol:
EPS (20%),
dry mouth (9%)
Lorazepam +
haloperidol: dry
mouth (9%), EPS
(6%)

Volume 32 Number 3

AEs = adverse events; R = randomized; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; PANSS-EC = Positive and Negative Syndrome
ScaleExcited Component; DB = double blind; PC = placebo controlled; BARS = Brief Agitation Rating Scale; OL = open label; EPS = extrapyramidal symptoms;
ED = emergency department; PES = psychiatric emergency services; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised; BPRS = Brief
Psychiatric Rating Scale; TREC = Tranquilizao RpidaEnsaio Clnico (Rapid Tranquilization Clinical Trial).
*The absence of AE data for a comparator indicates that no AEs were reported in 5% of patients in that group.

Clinical Therapeutics

416
Table III (continued).

S.L. Zeller and R.W. Rhoades


significantly decreased PANSS-EC scores at 2 hours
(first postbaseline assessment) and 24 hours after dosing (both, P < 0.001). No AEs were reported in 5%
of patients.
In a 24-hour, randomized, prospective study, Meehan et al63 compared olanzapine 10 mg, lorazepam
2 mg, and placebo in 201 agitated patients with bipolar disorder (mixed or manic episode). Olanzapine
was associated with significant decreases in PANSS-EC
Agitation subscale scores at 2 hours after administration (first postbaseline assessment) compared with
lorazepam (P = 0.001) and placebo (P < 0.001). There
was no significant difference between lorazepam and
placebo. The most common AEs with olanzapine were
somnolence (13.1%) and dizziness (9.1%). The most
common AEs with lorazepam were dizziness (13.7%)
and somnolence (9.8%).
In a 1-day, randomized, double-blind study in
357 patients with schizophrenia or schizophreniform
disorder, Tran-Johnson et al64 compared aripiprazole
1, 5.25, 9.75, and 15 mg; haloperidol 7.5 mg; and
placebo. Aripiprazole 9.75 mg was associated with
significant decreases in PANSS-EC scores compared
with placebo from 45 minutes to 2 hours after administration (all, P 0.05); haloperidol was associated
with significant decreases compared with placebo at
105 minutes and 2 hours (both, P < 0.01). The most
common AEs with aripiprazole were headache
(10.7%), nausea (10.7%), dizziness (7.1%), akathisia
(5.4%), and somnolence (5.4%). The most common AEs
with haloperidol were somnolence (12.3%), akathisia
(10.5%), dizziness (7.0%), and dystonia (7.0%).
Andrezina et al65 conducted a 24-hour, randomized,
double-blind comparison of aripiprazole 9.75 mg,
haloperidol 6.5 mg, and placebo, each administered
up to 3 times (0, 2, and 4 hours), in 448 patients with
schizophrenia or schizoaffective disorder. Aripiprazole
was associated with significant decreases in PANSS-EC
scores compared with placebo at 60 minutes through
2 hours (P < 0.05), and haloperidol was associated
with significant decreases compared with placebo at
45 minutes through 2 hours (P < 0.05). The most
common AEs with aripiprazole were headache (7.4%),
dizziness (6.3%), insomnia (5.7%), and nausea (5.7%).
The most common AEs with haloperidol were insomnia (12.0%), headache (8.2%), and EPS (5.5%).
Martel et al66 compared droperidol 5 mg, ziprasidone 20 mg, and midazolam 5 mg in 144 patients with
undifferentiated agitation. All treatments significantly
March 2010

decreased Altered Mental Status Scale scores from


15 minutes to 2 hours after dosing (all, P < 0.05
[based on 95% CIs]). Respiratory depression occurred
in 4 patients treated with droperidol, 9 treated with
ziprasidone, and 24 treated with midazolam.
A randomized, double-blind study by Resnick and
Burton67 compared single doses of droperidol 5 mg
and haloperidol 5 mg in 27 patients with agitation
and unspecified psychosis. Based on a Brief Psychiatric Rating Scale score 17, there were significant reductions in agitation at 30 minutes in 36% of patients
treated with droperidol and 81% of those treated
with haloperidol (P < 0.05). No AEs were reported in
5% of patients receiving droperidol. Dystonia was
reported in 1 patient receiving haloperidol.
In a 1-day, randomized, double-blind, prospective
study, Nobay et al68 compared midazolam 5 mg, haloperidol 5 mg, and lorazepam 2 mg in 111 patients
with unspecified psychosis or substance abuse. As measured on the Modified Thomas Combativeness Scale,
the mean times to sedation were 18.3 minutes for midazolam, 28.3 minutes for haloperidol, and 32.2 minutes for lorazepam (P = 0.039, midazolam vs haloperidol; P = 0.003, midazolam vs lorazepam). No AEs
were reported in 5% of patients in any treatment
group.

Combination Therapy
Huf et al69 conducted a randomized, open-label
comparison of haloperidol 5 to 10 mg and haloperidol 5 to 10 mg plus promethazine 50 mg in 316 agitated patients with unspecified psychosis or substance
abuse. The proportions of patients in the haloperidol and haloperidol-plus-promethazine groups who
were tranquilized or asleep within 20 minutes were
55% and 72%, respectively (P = 0.002). Dystonia
was reported in 9 patients treated with haloperidol
monotherapy.
The TREC (Tranquilizao RpidaEnsaio Clnico
[Rapid Tranquilization Clinical Trial]) Collaborative
Group conducted a 2-week, randomized, patientblinded, prospective comparison of the combination
of haloperidol 5 to 10 mg plus promethazine 25 to
50 mg and midazolam 15 mg in 301 patients with
unspecified psychosis or substance abuse.70 At 20 minutes, 67% of those who received haloperidol plus
promethazine and 89% of those who received midazolam were tranquilized or asleep (P not reported).
No AEs were reported in 5% of patients.
417

Clinical Therapeutics
A 2-week, randomized, patient-blinded, prospective trial by Raveendran et al71 compared haloperidol
10 mg plus promethazine 25 to 50 mg with olanzapine 10 mg in 300 patients with unspecified psychiatric
illness. At 15 minutes, 91% of patients who received
haloperidol plus promethazine and 87% of those who
received olanzapine were tranquilized or asleep (P not
reported). No AEs were reported in 5% of patients.
Bieniek et al72 conducted a randomized, open-label
comparison of lorazepam 2 mg and lorazepam 2 mg
plus haloperidol 5 mg in 20 patients with psychosis
who met the clinical criteria for chemical restraint.
Over 180 minutes of observation, haloperidol plus
lorazepam was significantly more effective in improving OAS scores at 60 minutes compared with lorazepam monotherapy (P = 0.04). No AEs were reported
in 5% of patients in either treatment group.
Battaglia et al73 conducted a 24-hour, randomized,
double-blind, prospective comparison of lorazepam
2 mg, haloperidol 5 mg, and their combination in
98 patients with unspecified psychosis. Patients receiving combination therapy had greater reductions in
Agitated Behavior Scale scores at 1 hour compared
with lorazepam (P not provided). There were no differences between lorazepam and haloperidol or between haloperidol and combination treatment. The
most common AE with lorazepam was dry mouth
(16%); the most common AEs for haloperidol were
EPS (20%) and dry mouth (9%); and the most common AEs for lorazepam plus haloperidol were dry
mouth (9%) and EPS (6%).

Intravenous Therapy
Four reports of intravenous treatment for agitation
were identified, all involving comparisons between
droperidol monotherapy and a benzodiazepine7476 or
placebo77 (Table IV).
Knott et al74 conducted a 1-hour, randomized,
double-blind, prospective comparison of droperidol
5 mg and midazolam 5 mg in 153 patients with psychiatric illness or substance abuse. Sedation was measured
based on a score of 2 on a 6-point scale (5 = highly
aroused and violent; 4 = highly aroused; 3 = moderately aroused; 2 = mildly aroused and pacing; 1 = settled; and 0 = asleep). The median time to sedation was
8.0 minutes for droperidol and 6.5 minutes for midazolam. No AEs were reported in 5% of patients treated
with droperidol. The most common AEs with midazolam were hypotension (5.4%) and hypoxia (5.4%).
418

In a 1-hour, randomized, open-label trial, Richards


et al75 compared droperidol 2.5 to 5 mg with lorazepam 2 to 4 mg in 146 patients with methamphetamine
abuse. Sedation was measured on a 6-point scale (6 =
combative/violent; 5 = very anxious/agitated; 4 = anxious; 3 = awake and cooperative; 2 = somnolent; 1 =
deep sleep). Patients receiving droperidol had significantly better sedation scores compared with lorazepam from 10 through 60 minutes (all, P < 0.001). No
AEs were reported in 5% of patients.
Richards et al76 conducted another study of the
same design comparing droperidol 2.5 to 5 mg and
lorazepam 2 to 4 mg in 202 patients with unspecified
psychosis or drug abuse. As measured on the same
6-point scale as in the previous study, patients receiving droperidol had significantly better sedation scores
from 10 through 60 minutes compared with lorazepam (all, P < 0.001). No AEs were reported in 5%
of patients.
Rosen et al77 conducted a 1-day, randomized,
double-blind, prospective study comparing droperidol
5 mg with placebo in 46 combative patients. Efficacy was measured on a 5-point agitation scale (5 = violently agitated; 4 = decreased agitation; 3 = decreasing
agitation; 2 = slight agitation; 1 = no agitation). Droperidol was associated with significantly greater sedation compared with placebo at 5 minutes (P = 0.05)
and 10 minutes (P < 0.001). No AEs were reported in
5% of patients.

DISCUSSION
Agitation may be present in patients with a wide
range of medical and psychiatric disorders.8 Agitation
can be viewed in terms of a 2-dimensional frameworkduration and severitywith symptoms that
vary over time and according to the changing characteristics of the patients internal state and environment
during the episode.78,79 The continuum of agitation
can be described as proceeding from anxiety to high
anxiety to agitation to aggression. There is evidence
that the severity of untreated agitation increases with
time in at least some patients.80 Unpremeditated violence in patients with agitation may be preceded by a
30- to 60-minute prodromal period during which they
may exhibit increased pacing or loud speech.81
Assessment of the severity of agitation and prediction of whether it is likely to lead to aggressive/violent
behavior are important to guiding treatment decisions
in both the emergency and nonemergency settings. The
Volume 32 Number 3

March 2010
Table IV. Results of clinical studies of intravenous treatment for agitation.

Study/
Design

Patient
Population

Setting and
Duration of
Treatment

Interventions

Results for Primary


Efficacy Measure

Most Common
AEs (5%)

Psychiatric illness,
substance abuse;
age 1865 y

ED, 1 h

Droperidol 5 mg until
sedated (n = 79)
Midazolam 5 mg until
sedated (n = 74)

Median time to sedation:


8.0 min droperidol, 6.5 min
midazolam (P = 0.075)

Midazolam: hypotension
(5.4%), hypoxia (5.4%)*

Richards et al75
R, OL,
prospective

Methamphetamine
abuse; age 18 y

ED, 1 h

Droperidol 2.55 mg (n = 72)


Lorazepam 24 mg (n = 74)

Sedation score: significant


differences at 1060 min,
droperidol vs lorazepam (all,
P < 0.001)

No AEs reported in 5%
of patients

Richards et al76
R, OL,
prospective

Psychosis
(unspecified), drug
abuse; age 18 y

ED, 1 h

Droperidol 2.55 mg (n = 102)


Lorazepam 24 mg (n = 100)

Sedation score: significant


differences at 1060 min,
droperidol vs lorazepam (all,
P < 0.001)

No AEs reported in 5%
of patients

Rosen et al77
R, DB,
prospective

Combative; age
1854 y

ED, 1 d

Droperidol 5 mg (n = 23)
Placebo (n = 23)

Sedation score: significant


difference, droperidol vs
placebo at 5 min (P = 0.05)
and 10 min (P < 0.001)

No AEs reported in 5%
of patients

AEs = adverse events; R = randomized; DB = double blind; ED = emergency department; OL = open label.
*The absence of AE data for a comparator indicates that no AEs were reported in 5% of patients in that group.

419

S.L. Zeller and R.W. Rhoades

Knott et al74
R, DB,
prospective

Clinical Therapeutics
13 assessment tools reviewed here vary substantially
in their suitability for use in the assessment of agitation in the emergency setting. For example, completion of the HCR-20 may take several hours and requires access to the patients medical history. In
contrast, the BVC requires ~5 minutes to complete
and is based entirely on currently observed behavior.28 Other instruments fall between these extremes;
the NRS-R and CMAI each take ~15 to 20 minutes to
complete.35,82
There are differences in the extent to which these
instruments have been evaluated for their ability to
predict violent behavior and/or the requirement for
intervention to prevent aggressive/violent behavior.
The HCR-20, McNiel-Binder Violence Screening
Checklist, and BVC have been found effective in predicting aggression/violence among psychiatric inpatients and in the correctional setting.28,32,33,83 The
PANSS-EC has been used in clinical practice to evaluate whether psychotropic medication should be administered to agitated patients with schizophrenia.
Although several scales have been found useful in
predicting violent behavior, it must be stressed that an
assessment based on these or any other scales provides
only a snapshot of the patients condition at a given
time and that the severity of an episode may change
over time depending on both the external environment and the evolution of the patients internal
condition.40,78,79,8487 It should also be noted that experienced psychiatrists and psychiatric nurses are able
to accurately predict violent behavior without the use
of specific assessment tools. One study found that
psychiatrists and psychiatric nurses correctly predicted violent behavior in 82% and 84%, respectively, of
newly admitted psychiatric patients.88
The characteristics of an ideal medication for the
acute management of agitation include easy preparation and nontraumatic administration (no needles),
with no associated pain or need for restraint; a rapid
onset of action, with little interpatient variability in
pharmacokinetics and pharmacodynamics; a sufficient duration of effect for patients to be transported
to the appropriate service; tranquilization without
excessive sedation that may interfere with interaction
with the patient, diagnosis, or selection of additional
therapy; and a low risk for adverse reactions and drug
interactions.89,90 A final important consideration with
any medication used in the ED is that it must control
agitation in patients with underlying conditions that
420

may not be fully understood at the time treatment is


administered.
Current guidelines support a wide range of pharmacologic interventions for patients with agitation.
An expert consensus statement on the acute management of agitated patients in the ED from the American Association for Emergency Psychiatry (AAEP)
provides detailed recommendations for the management of behavioral emergencies.91 The guidelines recommend use of a benzodiazepine when no data are
available on the condition underlying the emergency
or when evaluation of the patient indicates intoxication. They state that no single atypical antipsychotic
should be considered a general replacement for haloperidol and that haloperidol should be used in combination with a benzodiazepine. For oral treatment of
agitation related to schizophrenia or mania, the guidelines recommend first-line treatment with olanzapine
alone, risperidone alone or combined with a benzodiazepine, and haloperidol plus a benzodiazepine. Intramuscular olanzapine is recommended as the first
choice when a parenteral agent is needed. The AAEP
expert panel also emphasizes the importance of speed
of onset and reliability of delivery when choosing a
route of administration, the high priority of controlling aggressive behavior during an emergency, and the
importance of maintaining the physicianpatient relationship in long-term care.92
The American College of Emergency Physicians
(ACEP) recommendations for the pharmacologic
management of patients with agitation in the ED include use of a benzodiazepine (lorazepam or midazolam) or a conventional antipsychotic (haloperidol) as
initial monotherapy in patients whose condition is
unknown.93 In patients with known psychiatric illness
in whom antipsychotic use is indicated, the ACEP
guidelines support monotherapy with either an atypical antipsychotic or conventional neuroleptic, both
for managing agitation and as initial drug therapy. For
agitated but cooperative patients, the combination of
an oral benzodiazepine (lorazepam) and an oral antipsychotic (risperidone) is recommended. Treatment
guidelines from the Joint Commission on Accreditation of Healthcare Organizations and the Centers for
Medicare and Medicaid Services recommend the use
of oral rather than intramuscular preparations of antipsychotics and benzodiazepines (eg, haloperidol and
lorazepam) that have been the standard of care for
many years.94
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S.L. Zeller and R.W. Rhoades


The findings of this review of clinical trials of pharmacotherapy for agitation suggest that oral, intramuscular, and intravenous treatment may all be effective
for the treatment of agitation, although onset of action differs according to the route of administration.
In general, the studies reviewed support a more rapid
onset of action with intramuscular compared with
oral administration, and with intravenous compared
with intramuscular administration. Oral agents are
well accepted,23,89 although their relatively slow onset
of action may limit their utility in some patients.95
Another potential limitation of oral medications is
that patients may cheek tablets, holding them in
the mouth without swallowing them.90 Compared with
oral administration, intramuscular and intravenous administration of conventional or atypical antipsychotic
agents may be associated with an increased risk of
AEs and more patient objections (eg, resistance to
needles, placement of an intravenous line).23,89 There
is also concern that the use of injected medications
may compromise the physicianpatient relationship.90
Intravenous or intramuscular administration of medications to an agitated patient has also been associated
with the risk for needle-stick injuries to ED staff,96
and inserting an intravenous line may be difficult and
potentially dangerous in an agitated patient.97
The literature search identified few studies of how
agitated patients are actually managed in the ED. A
report of 100 consecutive agitated patients treated in
the ED indicated that drug treatment was employed in
every case, with 52 patients accepting oral medication
and intramuscular medication administered to 48 patients.98 The most commonly used oral medication
was haloperidol (38%), followed by olanzapine
(33%), benzodiazepines (15%), risperidone (8%), and
the combination of a benzodiazepine and an atypical
antipsychotic (6%). The most common intramuscular
medication was olanzapine (46%), followed by haloperidol (25%), ziprasidone (15%), benzodiazepines
(2%), and the combination of a benzodiazepine with
either an atypical or conventional antipsychotic
(13%).
Patient preference is an important consideration in
the acute treatment of agitation. Results of a survey of
59 patients who had used psychiatric emergency services indicated that as pharmacotherapy for episodes
of agitation, respondents preferred pills or capsules,
followed by liquid medication and then an injection
I agree to.89 Responders also stressed the importance
March 2010

of having staff treat them with respect, talk and listen


to them, and involve them in treatment decisions.
Reports concerning newer treatments for agitation
were not identified by the literature search. Other
treatments for agitation may not have been identified
because of the well-known bias against publication
of negative clinical-trial results.99 Another potentially
important limitation of the search procedure was that
it was limited to published papers and did not include
meeting posters and abstracts.

CONCLUSIONS
The results of this review highlight the numerous options for the assessment and treatment of patients
with agitation. Management of agitated patients in
the emergency setting could be facilitated by development of an easy-to-administer instrument that can
predict the risk for violence/aggression in agitated
patients, as well as performance of comparative studies aimed at defining an approach to the treatment of
agitation that is well accepted by health care providers
and patients.

ACKNOWLEDGMENTS
Preparation of this article was supported by Alexza
Pharmaceuticals, Mountain View, California.
Dr. Zeller is a member of speakers bureaus for Eli
Lilly and Company and Pfizer Inc. Dr. Rhoades is a
paid consultant for Alexza Pharmaceuticals. The authors have indicated that they have no other conflicts
of interest with regard to the content of this article.

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Cochrane Database Syst Rev. 2009;(1)
MR000006.

Address correspondence to: Scott L. Zeller, MD, Alameda County


Medical Center, 1411 East 31st Street, Oakland, CA 94602. E-mail:
szellermd@gmail.com
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