Clinical Challenges in the Pharmacologic Management of Agitation

FEATURE ARTICLE
Primary Psychiatry. 2010;17(8):46-52
A.T. Ng, S.L. Zeller, R.W. Rhoades
Clinical Challenges in the Pharmacologic
Management of Agitation
Anthony T. Ng, MD, FAPA, Scott L. Zeller, MD, and Robert W. Rhoades, PhD
ABSTRACT
Agitation, characterized by motor restlessness and accompany-
ing mental tension that may escalate into violence, is a serious
behavioral emergency encountered often in the emergency set-
ting. Behavioral intervention (eg, verbal de-escalation, seclu-
sion) should be the initial approach for management of agitated
patients, but when these techniques are ineffective, pharmaco-
logic treatment becomes necessary. This article reviews the clini-
cal challenges in managing agitation in the emergency setting.
An ideal agent for the acute treatment of agitated patients should
be easy to administer and not traumatic; provide tranquilization
without excessive sedation that may interfere with patient interac-
tion, diagnosis, and selection of additional therapy; have a rapid
onset of action and a sufficient duration of action to allow for
transport of patients to appropriate services; and have low risk
for significant adverse reactions and drug interactions. Currently
available pharmacologic treatments for agitation do not fulfill all
of these criteria, and there are significant unmet needs for novel
antiagitation treatments that are rapid in onset, accepted by
patients and staff, less invasive (as compared with intramuscular
or intravenous formulations), and easy and safe to administer.
INTRODUCTION
Agitation in adults is a psychiatric/medical emergency that
requires rapid and effective intervention to avoid harm to
patients, their families, other individuals receiving care in the
Primary Psychiatry
46
emergency setting, and healthcare professionals. Ineffectively
managed agitation can also greatly increase the overall cost
of patient treatment and create additional expenses that may
result from injury and time lost from work.
Agitation is characterized by excessive motor or verbal
activity, which may include irritability, uncooperativeness,
threatening gestures, and assault. 1,2 It is a common
clinical challenge in the emergency setting that may lead
to violent, destructive behavior and cause extreme personal
distress, while posing a physical risk to the patient, caregivers,
nursing staff, and others. 3 As many as 1.7 million
medical emergency room visits per year may involve agitated
patients, 4 and 20% to 50% of emergency psychiatry
visits in the United States may involve patients who are
at risk for agitation. 4,5 Approximately 10% of patients
encountered in emergency psychiatry settings may become
agitated or violent during assessment. 6
Schizophrenia and bipolar disorder are very common
causes of agitation for individuals who present in the
Dr. Ng is Medical Director of Psychiatric Emergency Services at Acadia Hospital in Bangor, Maine. Dr. Zeller is Chief of Psychiatric Emergency Services at Alameda County Medical Center in Oakland, California.
Dr. Rhoades is a medical writer in Steamboat Springs, Colorado.
Disclosure: Dr. Ng has served as a consultant to Alexza Pharmaceuticals. Dr. Zeller is on the speakers’ bureaus of Eli Lilly and Pfizer and is a consultant to Alexza Pharmaceuticals. Dr. Rhoades is a paid consultant
to Alexza Pharmaceuticals.
Off-label disclosure: This article includes discussion of unapproved/investigational treatments for agitation.
FOCUS POINTS
• Agitation demands rapid treatment that frequently precludes
a thorough evaluation of etiology, therefore requiring
rapidly acting treatments that are effective and safe.
• While nonpharmacologic intervention should be attempted
whenever possible, medication may be administered voluntarily
or under duress, with the aim of safely and swiftly
making the patient less agitated and hostile.
• There are significant unmet needs for novel antiagitation
treatments that are rapid in onset, accepted by patients
and staff, less invasive (as compared with intramuscular or
intravenous formulations), and easy and safe to administer.
Please direct all correspondence to: Anthony T. Ng, MD, FAPA, Medical Director, Psychiatric Emergency Services, Acadia Hospital, 268 Stillwater Ave, Bangor, Maine 04401; Tel: 207-973-6345;
Fax: 207-973-7328; E-mail: atng@emh.org.
© MBL Communications Inc. August 2010

emergency department. 5,7,8 Patients with psychoses result
in ~900,000 emergency department visits annually. 5
Schizophrenia is disproportionately common among homeless
people, with an incidence of 27%, which contributes to
their high frequency of presentation with agitation in the
emergency department. 7 It is important to note that agitation
among patients with schizophrenia or bipolar disorder
may be precipitated or exacerbated by both patient-related
factors (eg, male, younger age, history of substance abuse,
poor adherence to antipsychotics, history of physically
aggressive behavior, 9-12 and the characteristics of the environment
in which they are managed (eg, an overcrowded
emergency department). 13 Unpremeditated violence in
patients with agitation is often preceded by a prodromal
period of 30–60 minutes, during which they may exhibit
increased pacing or loud speech. 14 Recognizing these prodromal
symptoms provides an opportunity for early deescalation
and/or offering pharmacologic treatment.
Several tools have been developed to assist in the identification
of patients who are likely to become violent in
different treatment settings. The Brøset Violence Checklist
(BVC) measures confusion, irritability, boisterousness, physical
threats, verbal threats, and attacks on objects with each
scored for its presence (1) or absence (0). The sum of scores
is then totaled with a total score of 0, suggesting that the
risk of violence is small; scores 1 and 2 suggest that the risk
of violence is moderate, and preventive measures should
be taken; and scores ≥3 indicate that the risk of violence is
very high and that action should be taken. 15 The Historical,
Clinical, and Risk Management Violence Risk Assessment
Scheme is a 20-item scale that gathers information about
past history of violence, current clinical status, and environmental/support
factors that may increase risk for violence. 16
It has been shown to be useful for the clinical psychiatric,
forensic, and correctional settings. 16 A third tool that
may be useful for prediction of violence in the emergency
department is the McNeil-Binder Checklist, which evaluates
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 together status, to predict violent behavior. It has been
shown to have a sensitivity of 57.2% and a specificity of
70.0% for prediction of violence in psychiatric inpatients. 17
None of these prediction tools have been evaluated in the
emergency department and all but the BVC require at least
some information about the patient’s history.
The occurrence of agitation and violence significantly
impacts the agitated individual, other patients around him
or her, and healthcare personnel. 18 Results from one survey
of psychiatric emergency services in the US indicated
that agitation resulted in an average of 8 patient-to-staff
assaults per facility each year. 19 Most of these episodes
Clinical Challenges in the Pharmacologic Management of Agitation
caused injuries to personnel that were sufficiently severe to
result in absences from work. 19 Results from one study 20 of
violence in the emergency department indicated that 80%
of respondents reported that at least one staff member had
been injured by a violent patient in the preceding 5 years,
and 43% reported physical attacks on staff at least once per
month. Results from another survey 21 of 106 emergency
department personnel indicated that 57% were physically
assaulted, 48% reported impaired job performance for the
rest of the shift or the rest of the week after an incident
of violence, 73% were afraid of patients as a result of violence,
and 25% took days off because of violence.
The symptoms of agitation may be very similar across
a wide range of diagnoses, including medical conditions,
toxicity, and psychiatric illness (Table 1). 22-27 The terms
used to define agitation typically include increased psychomotor
activity; aggression; disinhibition/impulsivity;
and irritable, anxious, or labile mood. 28 Numerous different
definitions for agitation have been put forward in the
medical literature, and they vary based on the condition
(eg, dementia, traumatic brain injury, schizophrenia, bipolar
disorder) believed to underlie patients’ symptoms. 28 It
has been suggested that the lack of a uniform and precise
definition of agitation may contribute to misrecognition
(both over- and underrecognition) of this condition and
misdetermination of its causes in the acute care setting. 28
The etiology of agitation is not completely understood, but
TABLE 1
CONDITIONS ASSOCIATED WITH AGITATION 22-27
Medical causes:
• Thyrotoxicosis
• Encephalitis
• Meningitis
• Sepsis
• Brain trauma
• Dementia
• Delirium
• Seizure disorders
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© MBL Communications Inc. August 2010
Toxicity:
• Intoxication (alcohol, cocaine, methamphetamine)
• Alcohol withdrawal
Psychiatric disease:
• Schizophrenia
• Schizoaffective disorder
• Schizophreniform disorder
• Brief psychotic disorder
• Bipolar disorder
• Borderline personality disorder
• Obsessive-compulsive disorder
• Panic disorder
• Posttraumatic stress disorder
Ng AT, Zeller SL, Rhoades RW. Primary Psychiatry. Vol 17, No 8. 2010.

A.T. Ng, S.L. Zeller, R.W. Rhoades
it is believed that abnormalities in the biogenic amines—serotonin,
dopamine, and norepinephrine—as well as the inhibitory
neurotransmitter γ-aminobutyric acid (GABA) are all
involved. 29-31 It has been suggested that agitation associated
with psychosis, mania, and substance abuse may be correlated
with elevated dopaminergic neurotransmission, and that
decreased GABAergic transmission is characteristic of agitation
associated with dementia, depression, and anxiety. 32
Agitation demands rapid treatment that frequently precludes
a thorough evaluation of etiology. Clinicians therefore
require rapidly acting treatments that are effective and
safe, regardless of the genesis of agitation. It is important
to note that treatment requirements and unmet needs for
the management of patients with agitation vary from one
setting to another and that those in the emergency department
are very different from those for a patient presenting
to a psychiatric clinic. 33-36 The etiology of agitation for the
patient in the emergency department may be unknown,
while some patient history is likely to be available to personnel
in the psychiatric clinic. Treatment selection may
be more difficult in the emergency department versus the
psychiatric clinic because healthcare professionals in the
psychiatric clinic may have more information about efficacy
of prior treatments in a given patient.
ACUTE MANAGEMENT OF THE
AGITATED PATIENT
Diagnosis and establishment of the acute treatment
plan for the agitated patient is difficult because of the
immediate need for intervention, which may increase
diagnostic difficulty.
Establishment of a provisional diagnosis is a crucial step in
the management of the agitated patient, and medical causes
of agitation and substance abuse should be ruled out, if possible,
before assuming a psychiatric etiology. Patient characteristics
that increase the probability of a non-psychiatric
cause of agitation include lack of prior psychiatric history,
older age, and new or pre-existing medical complaints. 37,38 It
has been suggested that a brief medical work-up be carried
out in patients without a psychiatric history, with features
not consistent with a psychiatric diagnosis (eg, lethargy,
confusion), with abnormal vital signs, with sudden onset of
agitation, and who are known to have recently started any
new medications (eg, anticholinergics, steroids). 39
Ideally, initial intervention in the agitated patient should
be as nonrestrictive as possible. Techniques such as verbal
de-escalation (“talking the patient down”) or destimulation
(placing the patient in a quiet room ) are effective in some
agitated individuals and should be attempted prior to more
forceful interventions. 14,40
While nonpharmacologic intervention should be
attempted whenever possible as a first step in the acute
management of agitated patients, it is often ineffective
in some individuals who present in the emergency setting.
18 Rapid and safe tranquilization of aggressive/violent
patients is often necessary; medication may be given voluntarily
or under duress, with the aim of safely and swiftly
making the patient less agitated and hostile. It should be
noted that offering the agitated patient medication can
go hand-in-hand with non-restrictive interventions such
as verbal de-escalation and providing the patient with an
opportunity for time in a quiet environment. 41 Involuntary
administration of medication should be considered coercive
in the same sense as forced seclusion or restraint.
The goal of acute pharmacologic treatment for agitation
is to calm the patient while avoiding excessive sedation that
can interfere with the ability to continue the psychiatric
evaluation and intervention. 42,43 Excessive sedation that
results in a requirement for continuous observation and/or
assistance with toileting also increases the burden on emergency
department staff. 36 Prompt administration of effective
medications to the agitated patient has the potential
to reduce the probability of harm to self or others, permit
accomplishment of needed diagnostic tests, attenuate psychosis,
and reduce the requirement for restraint. 36
The choice of medication for a patient with agitation
should be guided by the etiology underlying the episode if
it is known. For example, agitation resulting from organic
causes (eg, hypoglycemia, hypoxia, thyroid storm) should
not be treated with an antipsychotic, while administration
of an antipsychotic and/or benzodiazepine is appropriate
for agitation that has a psychiatric etiology. 39 The remainder
of this article focuses on treatment of agitated patients
using antipsychotics and benzodiazepines.
Current drugs used for the acute treatment of agitation may
be administered orally, intravenously (IV), or by injections
into the muscle (intramuscular [IM]). 44 Each of these routes of
delivery may have important limitations. Administration of an
oral agent may not be possible in a very agitated patient and this
route of administration often results in a slow onset of action. 44
Intravenous administration of medications may result in a very
rapid onset of action, but establishing an IV line may be very
difficult and potentially dangerous in the agitated patient. In
addition, IV administration of some medications used to treat
agitation may result in cardiac and/or respiratory complications.
44 Results from one study 45 have shown further that IM
administration of haloperidol did not result in more rapid
resolution of agitation than delivery of an oral concentrate.
Similarly, comparison of the combination of oral risperidone
and oral lorazepam versus IM haloperidol plus IM lorazepam in
patients with agitation indicated no significant between-treatment
differences in onset of action. 46 Nevertheless, IM drug
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administration generally achieves therapeutic concentrations
more rapidly than oral delivery. 47 A recent systematic review 48
of clinical trials focused on the acute treatment of agitation
indicated generally more rapid onset of action for IM versus
oral administration of the same agents.
Intramuscular injections are easier to administer than IV
infusions, and some patients will agree to this route of delivery
for medications to more rapidly control their agitation.
However, the onset of action with IM injection of a given
medication may be slower and the pharmacologic effects
more variable than those observed after IV administration
of the same drug. 49,50 For example, the onset of action with
midazolam for calming agitated patients is 1–5 minutes for
IV delivery versus 18 minutes for IM administration. 51,52
Additionally, the pain associated with IM injection may be
poorly tolerated by some patients. 44 Any intervention that is
aversive to the patient, particularly if it is administered involuntarily,
may be viewed as punishment and has the potential
to impair the physician-patient relationship and effective longer-term
management after resolution of the episode of agitation.
42 Further, approaching the patient with a needle may
increase stress for both patients and their families and escalate
agitation. 53 Both IV and IM administration of medications to
the agitated patient are also associated with the risk for needlestick
injuries to emergency department staff. 54 Despite these
limitations, the relatively rapid onset of action for IM and IV
administration of antipsychotics and/or benzodiazepines is an
important advantage when the behavior of an agitated patient
poses an imminent risk to himself and others, and parenteral
drug administration is the only feasible treatment alternative.
The characteristics of an ideal medication for the acute
management of agitated patients have been set forth by
several investigators (Table 2). 55,56 They include easy preparation
by staff and nontraumatic administration (no needles)
with no associated pain or requirement for restraint;
rapid onset of action with little interpatient variability in
pharmacokinetics and pharmacodynamics; sufficient duration
of effect for transport of patients to appropriate services;
tranquilization without excessive sedation that may
interfere with patient interaction, diagnosis, and selection
of additional therapy; and low risk for significant adverse
reactions and drug interactions. 55,56
GUIDELINES FOR ACUTE MANAGEMENT OF
AGITATION IN THE EMERGENCY SETTING
Several guidelines for the acute management of agitated
patients have been published; those from the Joint Commission
on Accreditation of Healthcare Organizations as well as the
Centers for Medicare and Medicaid Services indicate that
nonphysical forms of behavior management (eg, verbal inter-
Clinical Challenges in the Pharmacologic Management of Agitation
vention or show of force) are the appropriate first-line strategy.
If medication is required, the use of oral drugs rather than IM
preparations is recommended. 57 The Expert Consensus Panel
for Behavioral Emergencies consensus regarding the acute
management of agitated patients in the emergency department
setting differs somewhat from these guidelines. This consensus,
based on responses to a survey completed by 48 experts
in the acute management of agitated patients, indicated that
first-line oral options for the acute treatment of agitation associated
with schizophrenia are olanzapine alone, risperidone
alone or combined with a benzodiazepine, and haloperidol
plus a benzodiazepine. Parenteral agents supported by experts
included IM olanzapine and IM ziprasidone. The experts
recommended initial use of benzodiazepines when no information
was available about the patient’s condition, when there
was no specific treatment available for the patient’s condition,
or when the patient was intoxicated. Haloperidol was viewed
as being as effective as any currently available antipsychotic,
and it was recommended that it should be administered
alone or with a benzodiazepine unless the patient is medically
compromised. 42 While these expert recommendations
provide guidance for optimal use of existing medications for
the acute treatment of agitated patient, none of the currently
recommended approaches meets all of the criteria for an ideal
treatment set forth above (Table 2). 33-35,55,56
LIMITATIONS OF CURRENT
PHARMACOLOGIC TREATMENT OPTIONS
Oral Drug Administration
Oral agents, particularly atypical or second-generation
antipsychotics, have been used extensively for the acute treat-
TABLE 2
CHARACTERISTICS OF AN IDEAL MEDICATION FOR ACUTE
MANAGEMENT OF THE AGITATED PATIENT 55,56
• Easy preparation by staff and nontraumatic administration (no needles)
with no associated pain or requirement for restraint; possibility for self
administration.
• Rapid onset of action with little interpatient variability in pharmacokinetics
and pharmacodynamics.
• Offset sufficiently slow for transport of patient to appropriate services.
• Provides tranquilization without excessive sedation that may interfere with
patient interaction, diagnosis, and selection of additional therapy.
• Low risk for significant adverse reactions (acute movement disorders,
especially dystonia, hypotension, cardiovascular events, dysphoria, neurologic
events [eg, seizures]) and drug interactions.
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A.T. Ng, S.L. Zeller, R.W. Rhoades
ment of agitation, 36 but they may be limited by slow onset
of action. 58 Results from controlled clinical trials indicate
that the shortest onset of action for oral olanzapine or haloperidol
in patients experiencing an episode of agitation is ~1
hour. 59 The combinations of oral risperidone and lorazepam
or haloperidol and lorazepam have been reported to have
onsets of action of 30 minutes in patients with agitation. 60
Another potential limitation of oral medications is patients
“cheeking” (taking, but not swallowing) oral tablets. 55
While not specifically approved for the treatment of
agitation, orally disintegrating formulations of several antipsychotics
(eg, risperidone, olanzapine, aripiprazole) have
been developed. 59,61,62 This formulation may facilitate antipsychotic
delivery to agitated patients, particular those who
might not comply with treatment, but their pharmacokinetic
profiles, including time to maximum plasma concentration,
are equivalent to those for conventional tablets. 61,63,64
Intramuscular Injection
Intramuscular administration of conventional or atypical
antipsychotics provides more rapid onset of action than
oral delivery, but may be associated with higher risk for
adverse events and patient objections. Intramuscular ziprasidone
has been shown to have an onset of action of ~30
minutes in agitated patients in one study. 65 Intramuscular
olanzapine is also rapidly absorbed and produces significant
reductions in agitation within 30 minutes, but has
been associated with significant reductions in systolic and
diastolic blood pressure and pulse rate. 66,67
Objection to IM injection may create a barrier to this
approach to acute treatment of agitation in many patients.
Results from one survey indicated that patients most preferred
pills or capsules, followed by liquid medication,
and then “an injection I agree to.” 56 Physicians are also
concerned that injected medication will compromise the
physician-patient relationship. 55
Excessive Sedation
While tranquilizing or calming the agitated patient is
the central aim of pharmacotherapy, avoiding excessive
sedation that may interfere with further evaluation and
treatment is now also recognized as an important aspect
of intervention. Heavy sedation of patients may help to
ensure the safety of both patients and staff, but it also
makes it difficult or impossible to elicit useful information
from them. 3 Review of randomized clinical trial data indicated
that oral ziprasidone and quetiapine (not approved
for treatment of agitation) and IM olanzapine have higher
dose-related sedative potential while oral risperidone (not
approved for treatment of agitation) and IM aripiprazole
have lower sedative potential. 68 However, other studies
have suggested that IM olanzapine may have low risk for
sedation in the acute treatment setting. 69,70
While the risk with IM administration of antipsychotics
for excessive sedation that may interfere with further
patient evaluation and intervention appears to be lower
than that after oral delivery, 36,55 results from several studies
have indicated that IM formulations of some atypical
antipsychotics do have at least some liability for excessive
sedation. In contrast to the conclusions from Cañas, 68
results from a study 28 comparing IM aripiprazole and
IM lorazepam indicated excessive sedation (Agitation-
Calmness Evaluation Scale score of 8 or 9) during the
initial 2 hours after first injection in 17.3% and 19.1% of
aripiprazole- and lorazepam-treated patients, respectively.
Parenterally administered benzodiazepines have also been
associated with excessive sedation. 71 The combination of
these drugs with a conventional or atypical antipsychotic
may further increase the risk for excessive sedation versus
treatment with single agents.
Other Adverse Events Associated with Current
Acute Treatments for Agitation
All agents currently used for the acute treatment of agitation
have the potential for clinically important adverse events.
Conventional antipsychotics (eg, haloperidol) may produce
dysphoria, dystonia, and akathisia (in up to 33% of patients),
as well as postural hypotension leading to syncope, and possible
cardiac events. In addition to being aversive to patients,
the symptoms of akathisia may be confused with the underlying
agitation. 36 This has the potential to lead to inappropriate
increases in drug dosing. Conventional neuroleptics (eg, haloperidol)
often require the use of concomitant anticholinergics
to prevent or treat extrapyramidal symptoms, and administration
of these drugs can lead to cognitive disturbances.
Treatment with conventional neuroleptics may also lead to
neuroleptic malignant syndrome, particularly when administered
in high doses to agitated patients. 72 Acute dystonic
reactions, which may be life threatening, have been reported
to occur in 9% of agitated patients treated with haloperidol. 73
Due in large part to these limitations, the use of conventional
antipsychotics is no longer considered “best practice” for any
of the major conditions contributing to agitation. 55,74
Administration of atypical antipsychotics may also result
in significant adverse events when used in the acute care
setting. Treatment with olanzapine may lead to bradycardia,
orthostatic hypotension, and increased somnolence
when administered with lorazepam. 55 Risperidone may be
associated with the development of extrapyramidal symptoms.
75 Ziprasidone may produce nausea, headache, dizziness,
and possible risk for QTc prolongation. 55 Quetiapine
may result in orthostatic hypotension. 76 Aripiprazole may
produce nausea and vomiting. 77
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Medications used for the acute treatment of agitation
also have the potential for clinically significant drug-drug
interactions; this is especially important in patients with
comorbid medical conditions. Lorazepam has a substantial
potential for interactions with prescription drugs, drugs of
abuse, and alcohol. 78 Haloperidol, ziprasidone, aripiprazole,
and quetiapine are all metabolized, at least partially, by cytochrome
P450 (CYP) 3A4 and may interact with agents that
induce or inhibit this enzyme, including carbamazepine,
valproate, phenytoin, phenobarbital, rifampicin, quinidine,
glucocorticoids, and macrolide antibiotics. 79-81 Olanzapine is
metabolized by CYP 2D6 and 1A2, and it may interact with
fluvoxamine, fluoxetine, sertraline, and grapefruit juice. 79,80
Risperidone is partially metabolized by CYP 2D6, but has
little risk for clinically significant drug interactions. 79,80
NEW ALTERNATIVES FOR ACUTE
TREATMENT OF THE AGITATED PATIENT
While conventional or atypical antipsychotics, used
alone or in combination with a benzodiazepine, have been
shown to be effective for the acute treatment of agitation,
the results summarized in the preceding sections indicate
that there is a clear need for new options for the initial
pharmacologic management of the agitated patient who
presents in the emergency setting. The magnitude of
this need is clearly reflected by survey results indicating
that 8.5% of patients who present with agitation require
restraint during psychiatric emergency visits, 56 suggesting
that current approaches to treatment are far from optimal
for rapidly calming these individuals.
Asenapine sublingual tablets are a new option for the
treatment of acute episodes of schizophrenia and for treatment
of acute manic or mixed episodes of bipolar I disorder.
Bioavailability is 35% when taken sublingually, but

A.T. Ng, S.L. Zeller, R.W. Rhoades
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