Acute Agitation 2015-11-26, 9:54 PM

Acute Agitation
Kurt Skakum, MD, FRCPC
Jeffrey P. Reiss, MD, MSc, FRCPC, DABPN, DFCPA, DFAPA
Date of Revision: October 2014

Introduction

Acute agitation is a dangerous condition that occurs in 10–20% of hospitalized patients who are acutely ill.1 For the
well-being and safety of patients and caregivers, it is essential that agitated patients are treated quickly, effectively and
safely. As a first step, the underlying cause of agitation must be determined and treated whenever possible.

Acute agitation is defined as a “state of anxiety accompanied by motor restlessness.”2 Aggression, defined as a
“behaviour leading to self assertion”,2 is often mislabeled as agitation and can occur in association with acute agitation.
Agitation can occur in many clinical settings. This chapter will focus on the management of agitation in adults in the
emergency room or in-patient units such as psychiatry or medical/surgical wards.

Agitation can be associated with delirium from any cause, including infection, neurologic conditions (e.g., trauma,
seizure, stroke or tumor), intoxication, drug withdrawal (see Drug Withdrawal Syndromes), adverse drug reactions
such as toxicity, allergy or akathisia, endocrine disorders, blood sugar irregularities, cardiovascular problems and
electrolyte disturbances. Psychiatric conditions that can cause agitation include psychosis, mania, depression, anxiety
and personality disorders. Agitation is also frequently associated with dementia.

As practitioners transition to the DSM-53 they should be aware of several changes to terminology and diagnostic
criteria affecting some of the disorders described in this chapter. Most significantly, the former category of dementia is
removed and has been replaced with the wider category of neurocognitive disorders (NCD). This new category now
includes delirium as well as mild or major NCDs associated with conditions such as Alzheimer’s disease,
frontotemporal neurocognitive disorder, Lewy body disease, vascular neurocognitive disorder, traumatic brain injury,
substance/medication-induced disorder, HIV infection, prion disease, Parkinson’s disease, Huntington’s disease, and
others.

This chapter still refers to dementia and discusses delirium separately from dementia. Agitation in patients with
neurocognitive disorder due to traumatic brain injury deserves separate mention, since significant research is
published on this specific condition. Additionally, other psychiatric conditions associated with agitation will be referred
to by their generic descriptors (e.g., psychosis, mania, depression, anxiety and personality disorders) rather than a
DSM-5 specific diagnosis.

Goals of Therapy
Create a safe environment for the treatment of the agitated patient and other patients
Keep the work environment safe for staff
Ameliorate the agitated state
Prevent further episodes of agitation/aggression

Investigations
Obtain history from the patient and descriptions of the patient's behaviour from staff and other collateral sources.

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Include:
triggers for the behaviour
previous episodes of agitation
description of the nature of the agitation
Review medications and concomitant medical conditions
Determine whether the agitation is accompanied by other symptoms such as confusion, clouded consciousness,
cognitive impairment or physical symptoms such as fever, hypoxia or pain
Mental status examination, a complete physical examination and relevant laboratory investigations are essential
to the diagnosis

Therapeutic Choices
Figure 1 illustrates an algorithm for the management of acute agitation associated with several conditions.

Nonpharmacologic Choices

Give special attention to safety when encountering an acutely agitated/aggressive patient. This includes safety of
the agitated individual, other patients and staff in the environment. Often, both nonpharmacologic and
pharmacologic interventions will be necessary. Address patients in a calm, reassuring yet confident tone of voice.
There should be no hesitancy to have additional staff nearby. Direct patients to attempt to control their behaviour
and reassure them that the environment is safe and that they have no reason to be fearful. Ask what the problem is
and how it can be resolved. If necessary, patients can be asked to take medication to help reduce their distress.

Due to safety concerns or adverse reactions in elderly patients with dementing illnesses, use pharmacologic agents
sparingly. Employ psychosocial interventions in this population where possible.4 Consultation with responsive
behavioural specialists can be beneficial in these cases.

If verbal approaches are unsuccessful, patients may need to be physically restrained or secluded. Details on the
application of restraint and seclusion are not addressed in this chapter.

Pharmacologic Choices

Delirium

Delirium is a condition in which an acute onset of impairment in consciousness and cognition is associated with
a medical/physical cause. The impairment typically fluctuates over the course of the day.

The first step is to determine and remove the underlying cause of delirium. If agitation persists because the
cause cannot be identified or the patient does not respond, it may be necessary to treat the patient
pharmacologically. Antipsychotics (see Table 1) are first-line medications in these instances. Haloperidol is the
most studied and effective medication for decreasing agitation in delirious patients. It can be given by mouth or
by im/iv injection. Small, regularly scheduled doses are preferred over “as needed” dosing. The mid-potency
first-generation antipsychotic loxapine and second-generation antipsychotics such as olanzapine, risperidone
and quetiapine have also been used to treat delirium.5 Risperidone or olanzapine oral disintegrating tablets
may be beneficial for patients who are not willing to swallow tablets.6 Olanzapine immediate-acting injection
may be required for highly agitated or uncooperative patients who cannot or are unwilling to take oral
medications.

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When used for several weeks to months, antipsychotics have been associated with an increased risk of stroke
and death in elderly patients with dementia. To manage acute confusional states with agitation or aggression in
the elderly, use antipsychotics (for the briefest possible duration) only when the benefits clearly outweigh the
risks.7,8 See also Dementia, below.

Reserve benzodiazepines (preferably those with a longer half-life such as diazepam or chlordiazepoxide) for
cases where symptoms are attributed to alcohol or benzodiazepine withdrawal. More information about
managing drug withdrawal syndromes can be found in Drug Withdrawal Syndromes.

Dementia

Patients with various forms of dementia frequently exhibit agitation. Management of behavioural problems in
older adults with dementia is also discussed in the Dementia chapter (see Dementia).These behaviours can be
disruptive to the care environment and are potentially dangerous. Always document the occurrence, frequency
and nature of the behavioural disturbance and any recognizable triggers. If medications are necessary they
should be prescribed following the “start low, go slow” principle, and reassessed regularly.

Considering the potential increased risks (e.g., stroke, death) and the limited tolerability and benefit in many
patients, the decision to use antipsychotic agents for agitation or aggression in patients with dementia needs to
be made on an individual basis and with caregiver support and consent (see also Dementia).8,9,10 Because of a
more favourable side effect profile, the use of second-generation antipsychotics is increasing over first-
generation antipsychotics.11 Risperidone has a favourable effect on agitation and other behavioural symptoms
(total behaviour, aggression and psychosis) associated with Alzheimer's disease.12 Initiate risperidone at a
dose of 0.25 mg daily and titrate to a usual effective daily dose of 1 mg, with an upper limit of 2 mg. The higher
dosage may offer an efficacy advantage but does so at the risk of increased side effects including falls.
Olanzapine can be started at 2.5 mg daily and titrated to 5–10 mg per day to reduce aggressiveness, anxiety
and euphoria.12 Olanzapine immediate-acting injection may be helpful for patients who refuse or are unable to
take oral medications. There is little evidence on the use of quetiapine in the control of agitation and
aggression in patients with dementia.

Although haloperidol can be effective in reducing aggression in patients with dementia, its routine use in this
setting is not recommended.13

Patients with major or mild NCD with Lewy bodies have enhanced sensitivity to first- and second-generation
antipsychotic medications.14 These medications are best avoided in these patients. Aggression may be
responsive to cholinesterase inhibitors or memantine.15

Other medications have also been studied, including trazodone, SSRIs, cholinesterase inhibitors,
memantine and benzodiazepines. Data to support the efficacy of trazodone for behavioural problems in
patients with dementia are less clear. While a Cocharane review has found no significant benefit for trazodone
compared to placebo,16 an uncontrolled study demonstrated some benefit especially with lowering irritability, 17
and one small study suggested that trazodone was effective in managing aggression and negativism in care-
giving situations.18 There is better evidence to show that trazodone is helpful as a hypnotic and is beneficial in
elderly patients with dementia and sleep disorder problems.19 Postural hypotension associated with trazodone
can lead to an increased risk of falls. A review of antidepressant efficacy and safety in elderly patients with
dementia concluded that the SSRIs citalopram or sertraline provided only a modest reduction in agitation and
psychosis compared with placebo.20 Memantine21 and cholinesterase inhibitors such as donepezil22 may
reduce behavioural disturbances associated with Alzheimer's disease. Benzodiazepines can be useful and
effective for treating acute anxiety and agitation,23 but must be used cautiously because of an increased risk of
falls, impaired cognition and disinhibition. Lorazepam and oxazepam are the oral benzodiazepines of choice in

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this setting because they have no active metabolites and their metabolism is minimally affected by aging. When
an injectable benzodiazepine is required, lorazepam is the only acceptable choice.

Brain Injury

Give priority to minimizing the potential side effects when choosing a treatment in patients with brain injury.
Many medications from different classes have been used in this setting, though conclusive evidence is lacking.
A Cochrane review of the treatment of agitation and aggression in patients with acquired brain injury (e.g.,
anoxic brain injury, encephalitis, trauma; stroke not included)24 found that the best evidence, though still limited,
was for beta-adrenergic antagonists. High doses of propranolol were effective in reducing the incidence of
aggression. Useful Info? Antiepileptic drugs such as carbamazepine and divalproex are also used. There is
concern about paradoxical disinhibition when benzodiazepines are used in brain-injured patients.
Antipsychotics seem to have a generally anti-aggressive effect regardless of the etiology.
Small studies have evaluated several other medications in this patient population. The evidence is not strong
enough to recommend the use of tricyclic antidepressants, SSRIs, amantadine, buspirone, stimulants and
lithium as first-line agents.

Mental Illness-associated Agitation

Psychosis

With acutely psychotic individuals, short-acting parenteral formulations of antipsychotics either alone or in
combination with parenteral lorazepam are recommended (see also Psychoses).

Do not combine im olanzapine with benzodiazepines because of the associated cardiac and respiratory
complications.

Rapidly dissolving or liquid formulations of second-generation antipsychotics with or without

benzodiazepines are an effective alternative to im medications,25,26 but are not practical for uncooperative
patients. Risperidone is available in liquid and rapidly dissolving tablet preparations. Olanzapine is
available in a rapidly dissolving wafer form. Several first-generation antipsychotics are also available in oral
liquid formulations.

Mania

The acute control of severe agitation in patients with mania involves both short-term treatment and initiation
of longer term mood stabilizers. Initially, second-generation antipsychotics (risperidone, olanzapine,
quetiapine, aripiprazole or ziprasidone) are effective in establishing control of agitated behaviour. If oral
medications cannot be administered, im injection is an effective alternative; im olanzapine, alone or a first-
generation antipsychotic with a benzodiazepine can be used. Generally speaking, benzodiazepines should
not be used as monotherapy.27 Initiation of a mood stabilizer should also be undertaken in the acute phase
of treatment (see Bipolar Disorder).

Situational Agitation/Aggression

Agitation/aggression that is not attributable to any of the previously discussed causes, but more related to
personality factors, is a common occurrence in emergency rooms. There is a relative lack of well-studied

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interventions in this setting. Nonpharmacologic interventions are essential. The most common medications
used are first-generation antipsychotics along with a benzodiazepine, either by oral administration or im
injection (e.g., haloperidol 5 mg po/im plus lorazepam 2 mg po/im). Emerging evidence supports the use of
second-generation antipsychotics in this setting.28

Choices during Pregnancy and Breastfeeding

Agitation is usually an acute and short-lived condition. Employ nonpharmacologic methods as a first-line treatment in
any patient displaying agitation, especially those who are pregnant or breastfeeding. Use pharmacologic treatments for
agitation only in situations where there is significant risk of harm to the patient, infant, staff or other patients on the
treatment unit, and with informed consent.

If agitation during pregnancy or postpartum is associated with a chronic mental illness (e.g., due to nonadherence with
medication), discuss with the patient and/or their next of kin the risks and benefits of restarting or continuing the
specific medication. Information on the use of antipsychotics and antidepressants during pregnancy or breastfeeding
can be found in Depression and Psychoses.

A discussion of general principles on the use of medications in these special populations, such as obtaining informed
consent, can be found in Drug Use during Pregnancy and Drug Use during Breastfeeding. Other specialized reference
sources are also provided in these appendices.

Therapeutic Tips
Implement measures to prevent delirium (and any attendant agitation) in hospitalized patients (e.g., provide aids
such as clocks and calendars to keep patients orientated, mobilize patients early following surgery, prevent sleep
deprivation, optimize functioning and communication with eyeglasses/hearing aids).
In elderly patients with dementia, use antipsychotics only when nonpharmacologic measures have failed, and if
patients are severely agitated, psychotic and/or a danger to themselves or others.
Use lower doses of antipsychotics in older patients; re-evaluate the need for continued therapy regularly.

Algorithm
Figure 1: Management of Acute Agitation

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Drug Table

Table 1: Drugs Used for the Management of Acute Agitation

Class Drug Dosage Adverse Drug Costa
Effects Interactions

Antidepressants trazodone Brain injury: 25– Sedation, May potentiate $

generics 50 mg HS po nausea, effects of other
Maximum: 200 headache, dry CNS depressants
mg HS mouth, and augment
orthostatic hypotensive
Dementia (for hypotension, effects of
sedation): 25– priapism antihypertensives.
100 mg/day po (rare).

Antiepileptic carbamazepine Mania: 800– Rash, Induces $

Drugs immediate- 1200 mg/day po cognitive cytochrome P450
release in 2–4 divided impairment, enzymes; may
Tegretol, doses sedation, increase
generics Target serum hyponatremia. clearance of
levels (based on many other drugs
data for seizure such as oral
contraceptives,

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control): 17–50 lovastatin,

µg/L meperidine,
Brain injury: morphine,
200–300 mg nifedipine,
BID–TID po oxycodone,
trazodone.

Antiepileptic divalproex Brain injury: Nausea, Inhibits $

Drugs sodium 250–500 mg TID tremor, glucuronidation;
Epival, po sedation; may decrease
generics Target serum rarely, edema. clearance of other
level (based on drugs such as
data for seizure lamotrigine and
control): 400– lorazepam.
700 µmol/L

Antipsychotics, haloperidol Delirium: 0.5–2.5 Sedation, Additive effects $–$$

First-generation generics mg BID po/im parkinsonism, with other CNS
Dementia: 0.5–1 akathisia, depressants,
mg BID po acute antagonism of
dystonia, dopamine
Psychosis: 5–10 neuroleptic agonists.
mg/day po/im malignant Haloperidol:
Mania: 5–10 syndrome. Avoid combining
mg/day po/im Haloperidol: with other drugs
QTc that increase QTc
prolongation. interval.

Antipsychotics, loxapine Delirium: 12.5– Sedation, Additive effects $

First-generation Xylac, generics 50 mg/day po parkinsonism, with other CNS
Psychosis: 25– akathisia, depressants,
50 mg/day po acute antagonism of
dystonia, dopamine
neuroleptic agonists.
malignant
syndrome.

Antipsychotics, zuclopenthixol Psychosis: 50– Sedation, Additive effects $$$-

First-generation acetate, 150 mg im; parkinsonism, with other CNS $$$$$/2–3
intramuscular duration of action akathisia, depressants, days
Clopixol- 2–3 days acute antagonism of
Acuphase dystonia, dopamine
neuroleptic agonists.
malignant
syndrome.

Antipsychotics, aripiprazole Mania: 15 Akathisia, Carbamazepine $

Second- Abilify mg/day po as dizziness, (or other strong
generation acute orthostatic inducers of
monotherapy; hypotension, CYP2D6 or
10–15 mg/day if headache, GI CYP3A4 such as

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used as co- complaints, phenytoin,

therapy with tremor, rifampin) can
lithium or sedation. decrease
valproate aripiprazole levels
Psychosis: 10– significantly.
15 mg/day po Ketoconazole,
quinidine,
fluoxetine or
paroxetine (or
other strong
inhibitors of
CYP2D6 or
CYP3A4) can
increase levels
substantially.

Antipsychotics, olanzapine, Delirium: 5–10 Anticholinergic Additive sedation $–$$

Second- oral mg/day po effects, with CNS
generation Zyprexa, Dementia: 2.5–5 akathisia, depressants;
Zyprexa Zydis, mg/day po dizziness, antagonism of
generics neuroleptic dopamine
Psychosis: 10– malignant agonists; may
30 mg/day po syndrome. potentiate
Mania: 5–20 antihypertensive
mg/day po drug effects.

Antipsychotics, olanzapine, Delirium or Anticholinergic Additive sedation $$$-$$$$$

Second- intramuscular mania: 2.5–10 effects, with CNS
generation Zyprexa mg im; repeat in akathisia, depressants;
Intramuscular 2 h and 6 h PRN dizziness, antagonism of
to a maximum of neuroleptic dopamine
30 mg/24 h malignant agonists; may
Use maximum of syndrome. potentiate
2.5 mg/dose in antihypertensive
debilitated drug effects.
patients, 5 mg in Should not be
elderly patients administered
simultaneously
with parenteral
benzodiazepines
due to reports of
cardiac and
respiratory
problems
including deaths.

Antipsychotics, quetiapine Delirium: 25–100 Sedation, Additive sedation $

Second- Seroquel, mg/day po dizziness, with CNS
generation generics Dementia: 12.5– neuroleptic depressants;
50 mg/day po malignant antagonism of
syndrome. dopamine
Psychosis: 300– agonists; may

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800 mg/day po potentiate

Mania: start with antihypertensive
100 mg/day po; drug effects.
increase by 100
mg/day as
needed to 300–
600 mg/day
divided BID

Antipsychotics, risperidone Delirium: 0.5–2 Akathisia, Additive sedation $

Second- Risperdal mg/day po dizziness, with CNS
generation Preparations, Psychosis: 2–8 neuroleptic depressants;
generics mg/day po malignant antagonism of
syndrome. dopamine
Dementia: 0.25– agonists; may
2 mg/day po potentiate
Mania: 2–3 antihypertensive
mg/day po drug effects.

Antipsychotics, ziprasidone Mania: start with Insomnia, Carbamazepine $

Second- Zeldox 40 mg BID po; extrapyramidal decreases
generation increase as side effects; ziprasidone levels
needed up to 80 consider ECG significantly; do
mg BID po at baseline not use with other
Psychosis: start and drugs that prolong
with 40 mg BID periodically to the QTc interval.
po; increase as monitor effect
needed up to 80 on QTc
mg BID po interval.

Benzodiazepines clonazepam Mania: 0.25–0.5 Sedation, Additive sedation $

Rivotril, mg BID–TID po dizziness, and possibly
generics cognitive cardiorespiratory
impairment; depression with
rarely, other CNS
respiratory depressants.
depression
can occur in
this setting.

Benzodiazepines lorazepam Dementia: 0.5–1 Sedation, Additive sedation $

Ativan, mg Q6–8H po dizziness, and possibly
generics Mania/psychosis, cognitive cardiorespiratory
adjunctively with impairment; depression with
antipsychotics: rarely, other CNS
1–2 mg po/im respiratory depressants.
depression
can occur in
this setting.

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Benzodiazepines oxazepam Dementia: 10–15 Sedation, Additive sedation $

generics mg TID po dizziness, and possibly
cognitive cardiorespiratory
impairment; depression with
rarely, other CNS
respiratory depressants.
depression
can occur in
this setting.

Beta1-adrenergic propranolol Brain injury: 20– Bradycardia, Additive $

Antagonists generics 40 mg daily po; hypotension, hypotension with
increase by 20 heart block, other
mg/day sedation. antihypertensives;
Maximum: 640 additive sedation
mg/day with other CNS
depressants.
Monitor heart
rate and blood
pressure

a Cost of 1-day supply unless otherwise specified; includes drug cost only.
Dosage adjustment may be required in renal impairment; see Dosage Adjustment in Renal Impairment.
Legend: $ < $5 $–$$ < $5–15 $$ $5–15 $$$ $15–25 $$$-$$$$$ $15– 45 $$$$ $25–35
$$$$$ $35–45

Suggested Readings
Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. J Clin Psychiatry
2006;67(Suppl 10):13-21.

Nassisi D, Korc B, Hahn S et al. The evaluation and management of the acutely agitated elderly patient. Mt Sinai J
Med 2006;73(7):976-84.

Stern TA, Rosenbaum JF, Fava M et al. Chapter 18: Delirium. In: Massachusetts General Hospital comprehensive
clinical psychiatry. 1st ed. Philadelphia (PA): Mosby/Elsevier; 2008. p. 217-29.

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