Systematic Reviews of Assessment Measures And

Clinical Therapeutics/Volume 32, Number 3, 2010

March 2010 403

Accepted for publication January 2, 2010.

Express Track online publication March 3, 2010.doi: 10.1016/j.clinthera.2010.03.0060149-2918/$ - see front matter

2010 Excerpta Medica Inc. All rights reserved.

ABSTRACTBackground: Agitation is a common behavioral

emergency associated with high risk of injury to pa-tients and health care professionals. There are a wide variety of approaches to assessing the severity of agi-tation and the risk of violence/aggression, and many different pharmacotherapies have been used to man-age this condition.

Objectives: Two systematic reviews were carried out. The first focused on measures used to assess agi-tation 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 Decem-ber 24, 2009. The search concerning the assessment of agitation included the terms agitation AND assessmentAND (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 pharmacother-apy for agitation were identified by the literature search. Based on their results, orally administered olan-zapine, risperidone, aripiprazole, quetiapine, halo-peridol, and lorazepam; intramuscularly administered olanzapine, lorazepam, ziprasidone, haloperidol, ari-piprazole, midazolam, and droperidol; and intrave-nously administered droperidol and lorazepam were effective for the treatment of agitation. The intramuscu-lar 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).

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 pa-tients and health care professionals. (Clin Ther.2010;32:403425) 2010 Excerpta Medica Inc.

Key words: agitation, schizophrenia, bipolar disorder.

INTRODUCTIONAgitation is characterized by excessive motor or ver-bal 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 in-ternal 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 psy-chiatric emergency services in the United States may involve patients who are at risk for agitation.5,6 Ap-proximately 10% of patients encountered in emergen-cy psychiatry settings may become agitated or violent during assessment.7

Agitation may be associated with psychiatric con-ditions, including schizophrenia, bipolar disorder, personality disorder, general anxiety disorder, panic

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

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need for medication. The second focused on clinical trials of the efficacy and tolerability of pharmaco-therapies for agitation.

METHODSPublications 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 assess-ment AND (scale OR instrument); the search for clini-cal trials of pharmacotherapies for agitation included the terms agitation and treatment AND (emergencyOR 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 schizophre-nia or manic episodes without defined agitation were not included. For each paper included in the analy-sis, 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 AGITATIONThe 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 assess-ment tools developed for and used only in single populations (eg, the elderly, those managed in an in-tensive care unit, those with dementia or brain injury). The 13 remaining scales used in the assessment of agitation/aggression across multiple treatment set-tings are listed in Table I. Three reports involved the prediction of aggression/violence in patients with agi-tation,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 fre-quency 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

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 indi-viduals 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, co-caine, methamphetamine) and may also result from akathisia after administration of a conventional anti-psychotic agent.8,11

Psychoses, including schizophrenia and bipolar disorder, are common causes of agitation among indi-viduals presenting in the ED.6,12,13 Schizophrenia af-fects ~2.4 million adults in the United States (1.1% of those aged 18 years), with bipolar disorder affect-ing ~5.7 million (2.6% of those aged 18 years).14 It has been estimated that ~20% of patients with schizo-phrenia will have episodes of agitation during their lifetime.15 Agitated patients with schizophrenia are thought to account for 900,000 annual visits to psy-chiatric emergency services, or 21% of all psychiatric emergency visits.16 The frequency of agitation in pa-tients with bipolar disorder has not been reported.

Many different medical specialists (eg, psychiatrists, emergency physicians, primary care physicians, geria-tricians) 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 con-dition and its treatment may vary greatly across spe-cialties. 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 en-counter patients with agitation associated with a wide range of underlying conditions,1820 emergency physi-cians may describe agitation in terms of a broader range of symptoms. Similarly, geriatricians descrip-tions of agitation are likely to reflect syndromes com-monly seen in the elderly.21 Regardless of the underly-ing etiology, there is clear agreement that agitation is a behavioral emergency that requires immediate inter-vention 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 re-views. The first focused on measures used to assess agitation and predict aggression/violence and/or the

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repetitious mannerisms, restlessness, screaming, re-petitive 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 nurs-ing homes, this instrument has been used for the as-sessment of patients being admitted to the hospital for psychiatric services.27

The Brset Violence Checklist (BVC) was devel-oped 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 be-haviors (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 Aggres-sion is a simple instrument based solely on observa-tion 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 medi-cation, although scores on this instrument have been found to be linearly correlated with scores on the Positive and Negative Syndrome ScaleExcited Com-ponent (PANSS-EC).

The CMAI is a 29-item caregiver rating question-naire used for the assessment of agitation in older persons.30 It includes descriptions of 29 agitated be-haviors, each rated on a 7-point scale of frequency. This instrument was developed primarily for the as-sessment of elderly patients in long-term care facili-ties, although it has been used for the initial assess-ment 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 set-tings.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 pres-ent, 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.

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 as-sess 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 profes-sionals 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, wander-ing, 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 devel-oped 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: hit-ting, grabbing, pushing, pacing or aimless wandering,

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



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 agi-tated patients with schizophrenia.43 A study in pa-tients 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 ad-mission and received medication as needed based in part on the results of this evaluation had a signifi-cantly 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 pri-marily as a survey instrument for assessing the preva-lence of aggressive behavior in the community and among nursing home residents.4547

Few of the numerous scales developed for the as-sessment of agitation have been used to assess the ef-ficacy of pharmacotherapy for this condition. This is an important lack, as the end point that is most mean-ingful in clinical practicepatients with a low risk of violence who cooperate with clinical evaluationsmay not be completely captured by the measures used to assess the effects of pharmacotherapy in clinical trials.

TREATMENT OF AGITATIONThe literature search for clinical trials of pharmaco-therapy for agitation retrieved 169 citations. After evaluation of the abstracts and/or full text of these cita-tions, 31 clinical trials were included in the review.

Oral TherapyThe 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

MonotherapyIn a 72-hour, randomized, rater-blinded, prospec-

tive 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 agi-tated patients with psychosis. There were no signifi-

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 vari-able 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 pa-tients admitted to a psychiatric inpatient unit.

The Neurobehavioral Rating ScaleRevised (NRS-R) is a 29-item, multidimensional, clinician-based instru-ment designed to measure neurobehavioral distur-bances.34 It includes assessments of orientation and memory of recent events, emotional state, postconcus-sional symptoms, focused attention and concentra-tion, explanation of proverbs, planning and mental-flexibility tasks, and delayed recall of objects presented at the beginning of a session. It also involves the clini-cians observations regarding the patients fatigability, visible signs of anxiety, disinhibition, agitation, hostili-ty, difficulties in expressive and receptive communica-tion, and disturbance of mood. Each variable is scored as present or absent. This instrument has been em-ployed 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 pediat-ric 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 ex-tremities (eg, tapping of fingers, rocking), and move-ments of the lower extremities (eg, toe-tapping, kick-ing 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, uncoop-erativeness, 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

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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%)

Villari et al48 R, prospective, rater blinded

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)

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Kinon et al51 R, DB, PG

Schizophrenia, schizophreniform or schizoaffective disorder; age 1865 y

Inpatient psychiatric, 5 d

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)

Table II (continued).

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Study/ Design

Patient Population




Baker et al54 R, DB treatment, followed by R, OL treatment

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

PES, DB treatment for 4 d, followed by OL treatment for 3 d

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)

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%)

AEs = adverse events; R = randomized; MOAS = Modified Overt Aggression Scale; EPS = extrapyramidal symptoms; OL = open label; ED = emergency depart-ment; 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.

Table II (continued).



or schizoaffective disorder. Both agents significantly decreased PANSS-EC scores from baseline to the end of each day (P < 0.001), with no significant differ-ences 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 schizophre-nia or schizophreniform or schizoaffective disorder. Each agent was associated with significant improve-ments in PANSS Agitation subscale scores from 1 to 24 hours after dosing and at subsequent weekly evalu-ations (P < 0.001), with no significant differences be-tween 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, placebo-controlled 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 as-sociated 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, double-blind 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 fol-lowed 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 dif-ferences between doses. The onset of action was not

cant differences between groups with respect to im-provement 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 ac-tion was not determined. Adverse events (AEs) occur-ring in 5% of patients with haloperidol were ex-trapyramidal 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%), ab-normal 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 pa-tients 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 pa-tients had a 40% reduction in PANSS-EC scores. Orthostasis was the most common AE, occurring in 40% of patients.

Combination TherapyCurrier et al50 conducted a 24-hour, randomized,

prospective, rater-blinded, noninferiority trial com-paring 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 para-noid reaction, or delusional disorders. Efficacy was evaluated based on PANSS-EC scores from 30 min-utes 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 olan-zapine 20 mg/d with aripiprazole 30 mg/d, both com-bined with lorazepam up to 4 mg/d IM as needed, in 604 patients with schizophrenia or schizophreniform

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assessment) (P < 0.05) and 24 hours (P < 0.01). In a second report from this trial by Daniel et al,57 de-creases 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 som-nolence (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 signifi-cant decrease from baseline in BARS score at 4 hours after the initial injection (P < 0.01). Acute urinary re-tention, blurred vision, and sedation were reported in 1 patient each.

Wright et al59 conducted a 24-hour, randomized, prospective comparison of olanzapine 10 mg, halo-peridol 5 mg, and placebo in 311 patients with schizo-phrenia or schizophreniform or schizoaffective dis-order. Olanzapine was associated with significant decreases in PANSS-EC scores from 15 to 45 minutes compared with haloperidol (P < 0.01) and from 15 min-utes 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 halo-peridol 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 signifi-cantly 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 assess-ment) (P < 0.001). The most common AEs were insom-nia (9.5%), arthralgia (7.9%), and headache (6.3%).

San et al62 conducted a nonrandomized, observa-tional study in 92 patients with schizophrenia, bipolar disorder, or unspecified psychotic disorder. Olanzapine

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 TherapyTwenty studies were identified that assessed intra-

muscular administration of antipsychotic agents and/or benzodiazepines (Table III). Of these, 15 involved monotherapy43.5568 and 5 involved combination therapy.6973

MonotherapyIn a 24-hour, randomized, prospective trial, Breier

et al43 compared olanzapine 2.5 to 10 mg with halo-peridol 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 associ-ated 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 olanza-pine. 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 de-mentia. Olanzapine significantly decreased PANSS-EC scores compared with placebo from 30 minutes to 2 hours after dosing (all, P 0.05). Lorazepam signifi-cantly 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 pa-tients with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, delusional disorder, or unspecified psychotic disorder. Ziprasi-done 20 mg was associated with significant decreases in the PANSS early psychosis factor score compared with ziprasidone 2 mg at 4 hours (first postbaseline

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

Study/ Design

Patient Population




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 long-term 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)

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Study/ Design

Patient Population




Daniel et al57 Same study population as in Agid et al56

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%)

Barak et al58

OLSchizophrenia, 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%)

(continued)

Table III (continued).

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Study/ Design

Patient Population




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) (DSM-III-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, 1 d

Aripiprazole 1, 5.25, 9.75, or 15 mg (n = 235)


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)


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)


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Study/ Design

Patient Population




Martel et al66 R, DB, prospective

Undifferentiated agitation; age 18 y

ED, 2 h Droperidol 5 mg (n = 50)Ziprasidone 20 mg (n = 46) Midazolam 5 mg (n = 48)

Altered Mental Status Scale: significant decreases with all treatments from 15 to 120 min (all, P < 0.05 based on 95% CIs)

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

Resnick andBurton67

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)


Huf et al69 R, OL


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


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)


(continued)


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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)


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)


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%)

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.


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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 Psychiat-ric Rating Scale score 17, there were significant re-ductions 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, halo-peridol 5 mg, and lorazepam 2 mg in 111 patients with unspecified psychosis or substance abuse. As mea-sured on the Modified Thomas Combativeness Scale, the mean times to sedation were 18.3 minutes for mid-azolam, 28.3 minutes for haloperidol, and 32.2 min-utes for lorazepam (P = 0.039, midazolam vs haloperi-dol; P = 0.003, midazolam vs lorazepam). No AEs were reported in 5% of patients in any treatment group.

Combination TherapyHuf et al69 conducted a randomized, open-label

comparison of haloperidol 5 to 10 mg and haloperi-dol 5 to 10 mg plus promethazine 50 mg in 316 agi-tated patients with unspecified psychosis or substance abuse. The proportions of patients in the haloperi-dol 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, patient-blinded, 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 min-utes, 67% of those who received haloperidol plus promethazine and 89% of those who received mid-azolam were tranquilized or asleep (P not reported). No AEs were reported in 5% of patients.

significantly decreased PANSS-EC scores at 2 hours (first postbaseline assessment) and 24 hours after dos-ing (both, P < 0.001). No AEs were reported in 5% of patients.

In a 24-hour, randomized, prospective study, Mee-han et al63 compared olanzapine 10 mg, lorazepam 2 mg, and placebo in 201 agitated patients with bi-polar disorder (mixed or manic episode). Olanzapine was associated with significant decreases in PANSS-EC Agitation subscale scores at 2 hours after administra-tion (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 admin-istration (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 insom-nia (12.0%), headache (8.2%), and EPS (5.5%).

Martel et al66 compared droperidol 5 mg, ziprasi-done 20 mg, and midazolam 5 mg in 144 patients with undifferentiated agitation. All treatments significantly



In a 1-hour, randomized, open-label trial, Richards et al75 compared droperidol 2.5 to 5 mg with loraze-pam 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 = anx-ious; 3 = awake and cooperative; 2 = somnolent; 1 = deep sleep). Patients receiving droperidol had signifi-cantly better sedation scores compared with loraze-pam 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 receiv-ing droperidol had significantly better sedation scores from 10 through 60 minutes compared with loraze-pam (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. Effica-cy was measured on a 5-point agitation scale (5 = vio-lently agitated; 4 = decreased agitation; 3 = decreasing agitation; 2 = slight agitation; 1 = no agitation). Dro-peridol was associated with significantly greater seda-tion compared with placebo at 5 minutes (P = 0.05) and 10 minutes (P < 0.001). No AEs were reported in 5% of patients.

DISCUSSIONAgitation 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 frame-workduration and severitywith symptoms that vary over time and according to the changing charac-teristics 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 vio-lence 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 predic-tion 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

A 2-week, randomized, patient-blinded, prospec-tive trial by Raveendran et al71 compared haloperidol 10 mg plus promethazine 25 to 50 mg with olanza-pine 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 improv-ing OAS scores at 60 minutes compared with loraze-pam 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 re-ceiving combination therapy had greater reductions in Agitated Behavior Scale scores at 1 hour compared with lorazepam (P not provided). There were no dif-ferences between lorazepam and haloperidol or be-tween 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 com-mon AEs for lorazepam plus haloperidol were dry mouth (9%) and EPS (6%).

Intravenous TherapyFour 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 psychi-atric 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 = moder-ately aroused; 2 = mildly aroused and pacing; 1 = set-tled; and 0 = asleep). The median time to sedation was 8.0 minutes for droperidol and 6.5 minutes for midazo-lam. No AEs were reported in 5% of patients treated with droperidol. The most common AEs with midazo-lam were hypotension (5.4%) and hypoxia (5.4%).

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

Study/ Design

Patient Population




Knott et al74 R, DB, prospective

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)


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)


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)


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.



may not be fully understood at the time treatment is administered.

Current guidelines support a wide range of phar-macologic interventions for patients with agitation. An expert consensus statement on the acute manage-ment of agitated patients in the ED from the Ameri-can Association for Emergency Psychiatry (AAEP) provides detailed recommendations for the manage-ment of behavioral emergencies.91 The guidelines rec-ommend use of a benzodiazepine when no data are available on the condition underlying the emergency or when evaluation of the patient indicates intoxica-tion. They state that no single atypical antipsychotic should be considered a general replacement for halo-peridol and that haloperidol should be used in combi-nation with a benzodiazepine. For oral treatment of agitation related to schizophrenia or mania, the guide-lines recommend first-line treatment with olanzapine alone, risperidone alone or combined with a benzodi-azepine, and haloperidol plus a benzodiazepine. Intra-muscular 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 control-ling aggressive behavior during an emergency, and the importance of maintaining the physicianpatient rela-tionship in long-term care.92

The American College of Emergency Physicians (ACEP) recommendations for the pharmacologic management of patients with agitation in the ED in-clude use of a benzodiazepine (lorazepam or midazo-lam) 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 atypi-cal 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 anti-psychotic (risperidone) is recommended. Treatment guidelines from the Joint Commission on Accredita-tion of Healthcare Organizations and the Centers for Medicare and Medicaid Services recommend the use of oral rather than intramuscular preparations of an-tipsychotics and benzodiazepines (eg, haloperidol and lorazepam) that have been the standard of care for many years.94

13 assessment tools reviewed here vary substantially in their suitability for use in the assessment of agita-tion in the emergency setting. For example, comple-tion of the HCR-20 may take several hours and re-quires access to the patients medical history. In contrast, the BVC requires ~5 minutes to complete and is based entirely on currently observed behav-ior.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 pre-dicting aggression/violence among psychiatric inpa-tients and in the correctional setting.28,32,33,83 The PANSS-EC has been used in clinical practice to evalu-ate whether psychotropic medication should be ad-ministered 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 environ-ment and the evolution of the patients internal condition.40,78,79,8487 It should also be noted that ex-perienced 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 predict-ed 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 prepara-tion 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 suffi-cient 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

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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.

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

ACKNOWLEDGMENTSPreparation 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 au-thors have indicated that they have no other conflicts of interest with regard to the content of this article.

REFERENCES1. Zimbroff DL. Pharmacological control of acute agitation:

Focus on intramuscular preparations. CNS Drugs. 2008;22: 199212.

2. Citrome L. Atypical antipsychotics for acute agitation. New intramuscular options offer advantages. Postgrad Med. 2002;112:8588, 9496.

3. Lindenmayer JP. The pathophysiology of agitation. J Clin Psychiatry. 2000;61(Suppl 14):510.

4. Nordstrom K, Allen MH. Managing the acutely agitated and psychotic patient. CNS Spectr. 2007;12(Suppl 17): 511.

5. Allen MH, Currier GW. Use of restraints and pharmaco-therapy in academic psychiatric emergency services. Gen Hosp Psychiatry. 2004;26:4249.

6. Marco CA, Vaughan J. Emergency management of agitation in schizophrenia. Am J Emerg Med. 2005;23:767 776.

The findings of this review of clinical trials of phar-macotherapy for agitation suggest that oral, intramus-cular, and intravenous treatment may all be effective for the treatment of agitation, although onset of ac-tion 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 ad-ministration 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 medi-cations 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 pa-tients.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 halo-peridol (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 ser-vices 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



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28. Almvik R, Woods P, Rasmussen K. The Brset Violence Checklist. Sen-sitivity, specificity, and interrater reliability. J Interpers Violence. 2000; 15:12841296.

29. Huber CG, Lambert M, Naber D, et al. Validation of a Clinical Global Impression Scale for Aggression (CGI-A) in a sample of 558 psychi-atric patients. Schizophr Res. 2008; 100:342348.

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Address correspondence to: Scott L. Zeller, MD, Alameda County Medical Center, 1411 East 31st Street, Oakland, CA 94602. E-mail: [email protected]

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