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Clinical Therapeutics/Volume 32, Number 3, 2010

Systematic Reviews of Assessment Measures and
Pharmacologic Treatments for Agitation
Scott L. Zeller, MD1; and Robert W. Rhoades, PhD2
1Alameda

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

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

Conclusions: Agitation is a common behavioral
emergency that may require pharmacotherapy. The
management of agitated patients may be improved
through the use of easy-to-administer instruments that
predict the need for medication and the availability of
rapid-acting treatments that are well accepted by patients and health care professionals. (Clin Ther.
2010;32:403–425) © 2010 Excerpta Medica Inc.
Key words: agitation, schizophrenia, bipolar
disorder.

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

403

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

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

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

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

and correctional settings. pushing.25 Brief Agitation Rating Scale26. repetitive sentences or questions.28 It measures 6 clinician-rated variables: confusion. wandering. it has been used for the assessment of agitation in patients presenting to the ED. irritability. habitual behaviors (nonviolent) are scored 0. and complaining. Tools for the assessment of agitation. The Agitated Behavior Scale was developed to assess the nature and extent of agitation during the acute phase of recovery from acquired brain injury. restlessness. This instrument was developed primarily for the assessment of elderly patients in long-term care facilities.25 Its primary purpose is to provide health care professionals with objective feedback on the course of a patient’s agitation.30 It includes descriptions of 29 agitated behaviors. and Risk Management–20 Violence Risk Assessment Scheme32 McNiel-Binder Violence Screening Checklist33 Neurobehavioral Rating Scale–Revised34. 3 = present to a moderate degree.39 Positive and Negative Syndrome Scale–Excited Component40–44 Ryden Aggression Scale45–47 daily.35 Overt Aggression Scale36.37 Overt Agitation Severity Scale38. including history of violence. unpredictable anger. grabbing. pacing or aimless wandering. and Risk Management–20 Violence Risk Assessment Scheme (HCR-20) has been used to assess the risk of violence in a wide range of settings. 405 . and a score ≥2 is predictive of a violent episode in the next 24 hours. and attacks on objects.27 The Brøset Violence Checklist (BVC) was developed primarily for use in the evaluation of psychiatric inpatients. although it has been used for the initial assessment of agitation in patients being admitted to the hospital for psychiatric care. Rhoades Table I. The CMAI is a 29-item caregiver rating questionnaire used for the assessment of agitation in older persons. resistance to restraint.L. Zeller and R. physical threats. The Clinical Global Impression Scale for Aggression is a simple instrument based solely on observation of the patient. or 2 = definitely present.32 It includes 20 items taken from the patient’s medical history or rated by the clinician. violence/threats. For patients who are well known to the clinical staff. impulsivity/impatience. loud/excessive talking. It includes 14 clinician-rated items: attention-related behaviors.31 Historical. Each item is scored as 0 = not present. verbal threats. The sum of scores is then totaled. restlessness. Although this instrument was developed and is used primarily for the assessment of agitation in patients with brain damage. Each item is scored for its presence (1) or absence (0).29 The clinician rates agitation on a scale from 1 = none to 5 = aggressive behavior. This instrument was originally developed for use in long-term care facilities. excessive crying or laughter. All items are rated on the following 4-point scale: 1 = absent. this instrument has been used for the assessment of patients being admitted to the hospital for psychiatric services. and 4 = present to an extreme degree. It has been found to be effective in predicting violent behavior in clinical psychiatric.W. Clinical. repetitive behaviors. and environmental/ support factors that may increase the risk for violence. and self-abusive behavior.S. uncooperativity.31 The Historical. Items are rated from 0 = none to 3 = often or continuous. current clinical status.13 The Brief Agitation Rating Scale (BARS) was developed to allow nurses and other caregivers in nursing homes to rapidly assess a patient’s level of agitation. but it has also been used for the assessment of patients being admitted for acute care. 2 = present to a slight degree. screaming. sudden changes of mood. whereas an increase in the listed behaviors is scored 1. A total score of 0 indicates a low risk of violence. It has not been used to predict violence or the need for medication. March 2010 repetitious mannerisms. forensic. boisterousness.26 It was developed as a subset of the Cohen-Mansfield Agitation Inventory (CMAI). In addition to its use in nursing homes. with a maximum score of 40. Aggressive Behavior Scale24 Agitated Behavior Scale13. 1 = possibly present. although scores on this instrument have been found to be linearly correlated with scores on the Positive and Negative Syndrome Scale–Excited Component (PANSS-EC). Clinical. each rated on a 7-point scale of frequency. It includes 10 items: hitting. making strange noises.27 Brøset Violence Checklist28 Clinical Global Impression Scale for Aggression29 Cohen-Mansfield Agitation Inventory30. self-stimulating behavior.

There were no signifiVolume 32 Number 3 .39 The PANSS-EC is commonly used in the assessment of psychiatric conditions. 31 clinical trials were included in the review.50–54 Monotherapy In a 72-hour. Villari et al48 evaluated haloperidol 5 to 15 mg/d. clinician-based instrument designed to measure neurobehavioral disturbances. as the end point that is most meaningful in clinical practice—patients with a low risk of violence who cooperate with clinical evaluations— may not be completely captured by the measures used to assess the effects of pharmacotherapy in clinical trials. the PANSS-EC has been used in clinical practice to aid in deciding whether to administer psychotropic medication to agitated patients with schizophrenia. planning and mentalflexibility tasks. emotional state. randomized. This instrument has been found to have moderate sensitivity (57. difficulties in expressive and receptive communication. prospective trial. and sexual behavior.33 It includes 5 variables: history of physical attacks or fear-inducing behavior within 2 weeks. Each item is rated on a scale from 1 = nonexistent to 7 = severe. disinhibition. postconcussional symptoms. grimacing).2%) and specificity (70. uncooperativeness. risperidone 2 to 6 mg/d. explanation of proverbs. hostility.38 Each behavior is measured on a scale from 0 = not present to 4 = always present.43 A study in patients with schizophrenia admitted to a psychiatric hospital found that the 41 patients who were assessed using the PANSS-EC during the first 3 days after admission and received medication as needed based in part on the results of this evaluation had a significantly lower risk for episodes of aggression compared with the 35 patients who were not assessed using the PANSS-EC and received medication solely on the basis of clinical observation (P = 0. objects. It has been used primarily as a survey instrument for assessing the prevalence of aggressive behavior in the community and among nursing home residents. male gender. and currently married or living with a partner. absence of suicidal behavior.45 Items are rated on a scale from 0 = never to 5 = ≥1 time daily. impulsivity.021).45–47 Few of the numerous scales developed for the assessment of agitation have been used to assess the efficacy of pharmacotherapy for this condition. This instrument has been validated in psychiatric inpatients. tension. and movements of the lower extremities (eg.43 A response to treatment is considered a 406 ≥40% decrease in PANSS-EC score within 2 hours. multidimensional. Each variable is scored as present or absent. It also involves the clinician’s observations regarding the patient’s fatigability. and quetiapine 300 to 800 mg/d in 101 agitated patients with psychosis. TREATMENT OF AGITATION The literature search for clinical trials of pharmacotherapy for agitation retrieved 169 citations. olanzapine 10 to 20 mg/d.40–43 It includes 5 individual PANSS items: hostility. This instrument has been employed for the assessment of agitation level in patients presenting to the ED. Each variable is scored as present or absent.0%) for predicting violence in patients admitted to a psychiatric inpatient unit. movements of the upper torso and extremities (eg. and disturbance of mood. After evaluation of the abstracts and/or full text of these citations. The scale was developed for use in both adults and pediatric patients in clinical and research settings. rocking). tapping of fingers.44 The Ryden Aggression Scale contains 3 subscales with a total of 25 items concerning physical. Oral Therapy The search identified 7 trials of oral therapy for agitation (Table II). verbal. Although it is primarily a research tool. The Neurobehavioral Rating Scale–Revised (NRS-R) is a 29-item. and others.35 The Overt Aggression Scale (OAS) is a checklist of 16 items that is used to evaluate verbal aggression and physical aggression against self.34 It includes assessments of orientation and memory of recent events.36. visible signs of anxiety. This is an important lack. schizophrenic or manic diagnosis. rater-blinded. 2 assessing antipsychotic monotherapy48. and delayed recall of objects presented at the beginning of a session. toe-tapping. although it can be used to measure agitation and has been extensively used in clinical trials of pharmacotherapy for agitation. The Overt Agitation Severity Scale is used to assess vocalizations (eg. focused attention and concentration.49 and 5 assessing antipsychotic agents in combination with intramuscular lorazepam. agitation.37 It is scored as described in the next paragraph. and excitability.Clinical Therapeutics The McNiel-Binder Violence Screening Checklist is used to predict future violent behavior. kicking at objects) indicative of agitation. whining) and orofacial movements (eg.

3 h Quetiapine 100 mg (n = 7). somnolence (18. prospective. noninferiority Acute exacerbation of schizophrenia or schizoaffective disorder. rater blinded.4%).7%).3%). headache (6. hypotension (17. 72 h Haloperidol 5–15 mg/d (n = 28) Risperidone 2–6 mg/d (n = 27) Olanzapine 10–20 mg/d (n = 24) Quetiapine 300–800 mg/d (n = 22) MOAS total score: decreased with all treatments (P not reported).1%).4%).1%) (continued) 407 S.0%).5%).1%). hyperkinesia (5.4%). age 18–65 y ED. 150 mg (n = 6). abnormal gait (7. prospective. agitation (5. age 18–65 y PES. hypotension (7.1%). Study/ Design Patient Population Setting and Duration of Treatment Interventions Results for Primary Efficacy Measure Most Common AEs (≥5%) Psychosis (unspecified) Mental health department. 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. hypotension (14.0%). rater blinded .3%) Quetiapine: somnolence (32. acute paranoid reaction.0%) Currier et al49 OL Psychosis and at least moderate agitation. 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.W. Rhoades Villari et al48 R. EPS (7. Results of clinical studies of oral treatment for agitation.1%) Risperidone: somnolence (11.March 2010 Table II.0%).3%). hypotension (14. dizziness (18. abnormal gait (7.0%). PG. Zeller and R. abnormal gait (8. mania with psychotic features.001). with no differences between groups Haloperidol: EPS (21.0%). headache (7. with no significant differences between groups Risperidone: somnolence (12. dizziness (12.L.4%) Olanzapine: somnolence (21.8%) Haloperidol: somnolence (12. delusional disorders (DSM-IV).0%). headache (8.

3%). PC. DB. age 18–65 y ED. agitation (9.001). prospective Psychosis (unspecified). somnolence (25. pain (10.6%).001). 90 min Risperidone 2 mg + lorazepam 2 mg IM (n = 10) Haloperidol 5 mg + lorazepam 2 mg IM (n = 10) Lorazepam 2 mg IM (n = 10) PANSS at 30 and 90 min: no significant differences between groups Not reported (continued) Clinical Therapeutics 408 Table II (continued). headache (11. .3%). insomnia (13. agitation (10. schizophreniform or schizoaffective disorder.7%). PG Schizophrenia.7%).0%). age 18–65 y Inpatient psychiatric. nervousness (7.Study/ Design Patient Population Setting and Duration of Treatment Interventions Results for Primary Efficacy Measure Most Common AEs (≥5%) Volume 32 Number 3 Kinon et al51 R.5%). DB. hypertonia (8. prospective Schizophrenia. schizophreniform or schizoaffective disorder.0%). pain (9. with no significant differences between groups Olanzapine: insomnia (5. 5d Olanzapine 20 mg/d + lorazepam to 4 mg/d IM as needed (n = 306) Aripiprazole to 30 mg/d + lorazepam to 4 mg/d IM as needed (n = 298) PANSS-EC: significant decreases from baseline to end of each day with both treatments (P < 0. anxiety (11.0%). increased salivation (8. nervousness (16.2%) Aripiprazole: insomnia (8. insomnia (5.0%). dystonia (8. DB.5%).3%). headache (5. 3 wk Olanzapine 10 mg/d + lorazepam 1–2 mg IM as needed (n = 52) Haloperidol 10 mg/d + lorazepam 1–2 mg IM as needed (n = 48) PANSS Agitation subscale scores at 1–24 h and each wk thereafter: significant improvements at all time points with both treatments (all.6%). age 18–50 y Hospitalized.3%).3%) Kinon et al52 R.7%) Haloperidol: headache (25. P < 0.0%). with no significant differences between groups Olanzapine: somnolence (17.3%) Veser et al53 R.

MOAS = Modified Overt Aggression Scale. nervousness (7%) 409 S. schizoaffective disorder. insomnia (13%). nervousness (11%).March 2010 Table II (continued). dizziness (17%). headache (17%). followed by OL treatment for 3 d Interventions Olanzapine 10 or 20 mg/d + lorazepam 4 mg/d IM as needed during DB treatment period. age 18–55 y Setting and Duration of Treatment PES. ED = emergency department. bipolar I disorder (manic or mixed episode) (DSM-IV). Fourth Edition. schizophreniform disorder. PC = placebo controlled. DB treatment. followed by olanzapine 5–20 mg/d (N = 148) Results for Primary Efficacy Measure Most Common AEs (≥5%) PANSS-EC at 24 h: significant decreases with both treatments (P < 0. PES = psychiatric emergency services. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders. with no significant difference between groups Olanzapine 10 mg/d: somnolence (26%). Zeller and R. DB treatment for 4 d. R = randomized. PANSS-EC = Positive and Negative Syndrome Scale–Excited Component. PG = parallel group.L. . Rhoades AEs = adverse events.001). EPS = extrapyramidal symptoms. OL = open label. OL treatment Patient Population Schizophrenia. followed by R.W. DB = double blind. insomnia (8%). headache (8%). dizziness (7%) Olanzapine 20 mg/d: somnolence (31%). Study/ Design Baker et al54 R.

150 mg (n = 6). The primary efficacy end point in the double-blind portion of the study was improvement in PANSS-EC scores at 24 hours after dosing. Baker et al54 conducted a 4-day. and hypotension (14. in 148 patients with schizophrenia.3%). mania with psychotic features.5%). double-blind. Combination Therapy Currier et al50 conducted a 24-hour. dystonia (8.001). and hyperkinesia (5.0%). pain (10. randomized. double-blind. The most common AEs with olanzapine were somnolence (21.4%).7%). hypotension (14. parallel-group study comparing olanzapine 20 mg/d with aripiprazole 30 mg/d. in 162 patients with an acute exacerbation of schizophrenia or schizoaffective disorder.6%).0%). or delusional disorders. with no significant differences between groups. somnolence (25. Efficacy was evaluated based on PANSS-EC scores from 30 minutes to 24 hours after dosing. or 200 mg (n = 7). Double-blind treatment was followed by 3 days of randomized. The onset of action was not Volume 32 Number 3 .7%). and headache (7. noninferiority trial comparing risperidone 2 mg and haloperidol 5 mg IM. nervousness (7. It measures the same 16 items as the OAS. with no significant difference between them. headache (11.49 patients with psychosis and at least moderate agitation received quetiapine 100 mg (n = 7).4%).0%). All regimens were associated with decreases in PANSS total scores at 30 and 90 minutes after dosing. the onset of action could not be determined. anxiety (11.0%). rater-blinded. both combined with lorazepam up to 4 mg/d IM as needed.1%). hypotension (17. The most common AEs with haloperidol were headache (25. hypertonia (8. and lorazepam 2 mg IM alone in 30 patients with psychosis. Both agents significantly decreased PANSS-EC scores from 30 minutes to 2 hours after dosing (P < 0.3%). and increased salivation (8.8%).3%) and headache (5. nervousness (16.) Because the first postbaseline evaluation took place 3 days after the initiation of therapy.0%). agitation (10.001). 50% of patients had a ≥40% reduction in PANSS-EC scores. Adverse events (AEs) occurring in ≥5% of patients with haloperidol were extrapyramidal symptoms (EPS) (21.0%). with no significant differences between them. prospective study. with no significant differences between groups. prospective.0%). and headache (8.3%). Orthostasis was the most common AE.7%).3%). in 100 patients with schizophrenia or schizophreniform or schizoaffective disorder. dizziness (12. with no significant differences between doses. or bipolar I disorder (manic or mixed episode).7%).0%).4%). open-label trial by Currier et al. open-label treatment.0%). abnormal gait (8.001).0%).6%). headache (6. doubleblind evaluation of the efficacy of olanzapine 10 or 20 mg/d. the most common AEs with aripiprazole were insomnia (8. the most common AEs with haloperidol were somnolence (12.Clinical Therapeutics cant differences between groups with respect to improvement on the Modified OAS. somnolence (18. dizziness (18. randomized. with lorazepam 4 mg/d IM as needed. with each item rated on a 5-point scale from never to >10 times per week. Kinon et al51 conducted a 5-day. The most common AEs with risperidone were somnolence (11. acute paranoid reaction.5%).2%). No tolerability data were reported.1%). The most common AE with risperidone was somnolence (12. occurring in 40% of patients. Both olanzapine doses were associated with significant decreases in PANSS-EC scores at 24 hours (P < 0.001). schizoaffective or schizophreniform disorder. In a 3-week. Both agents significantly decreased PANSS-EC scores from baseline to the end of each day (P < 0. EPS (7. placebocontrolled trial by Veser et al53 compared risperidone 2 mg plus lorazepam 2 mg IM. both with lorazepam 2 mg IM.1%). Kinon et al52 compared olanzapine 10 mg/d and haloperidol 10 mg/d. randomized. The most common AE with olanzapine was insomnia (5. abnormal gait (7. agitation (5. (The Modified OAS is a retrospective version of the OAS intended to cover a 1-week period of behavior.1%). A 90-minute. randomized.0%). The most common AEs with quetiapine were somnolence (32. randomized. the onset of action was not determined. haloperidol 5 mg plus lorazepam 2 mg IM. In a 3-hour.4%). The most common AEs with olanzapine were somnolence (17.5%).3%). Because the first postbaseline evaluation did not take place until 1 day after the initial dose of study medication.3%). agitation (9. abnormal gait (7. in 604 patients with schizophrenia or schizophreniform 410 or schizoaffective disorder. both with lorazepam 1 to 2 mg IM as needed. pain (9. At 2 hours after dosing. insomnia (13.1%). double-blind.3%). and insomnia (5.0%). Each agent was associated with significant improvements in PANSS Agitation subscale scores from 1 to 24 hours after dosing and at subsequent weekly evaluations (P < 0. and hypotension (7.3%).

randomized.05).3%). prospective trial. The only AE reported by ≥5% of patients was somnolence in the lorazepam group (10. The most common AEs with ziprasidone 2 mg were somnolence (13. P < 0. and nervousness (7%).69–73 Monotherapy In a 24-hour. lorazepam 1 mg. double-blind trial by Agid et al56 compared ziprasidone 2 and 20 mg in 79 patients with schizophrenia. PANSS-EC scores at 2 hours. Olanzapine was associated with significant decreases in PANSS-EC scores from 15 to 45 minutes compared with haloperidol (P < 0.9%).01). Of these.3%). In a second report from this trial by Daniel et al. Eight patients had a ≥20–mm Hg reduction in systolic blood pressure during treatment. Lorazepam significantly decreased PANSS-EC scores compared with placebo at 2 hours (P ≤ 0.5 to 10 mg with haloperidol 7.2%). dizziness (17%). nausea (12. or unspecified psychotic disorder.05) and 24 hours (P < 0. haloperidol 5 mg.3%).05).8%). double-blind trial by Meehan et al55 compared the effects of olanzapine 2. and sedation were reported in 1 patient each. Acute urinary retention. The most common AEs were insomnia (9.S. randomized. observational study in 92 patients with schizophrenia.W.01) and from 15 minutes to 2 hours compared with placebo (all.01). A 1-day.9%). with a second dose (5 mg) permitted ≥2 hours after the first dose. Centorrino et al61 conducted a 2-hour.57 decreases in BARS scores were significantly greater with ziprasidone 20 mg compared with ziprasidone 2 mg from 30 minutes to 4 hours after administration (P < 0. and headache (6. Haloperidol was associated with significant decreases compared with placebo from 60 minutes to 2 hours (all. In a 24-hour.05). randomized.001). The most common AEs with ziprasidone 20 mg were somnolence (19. P ≤ 0. bipolar disorder. Olanzapine 411 .3%). Ziprasidone 20 mg was associated with significant decreases in the PANSS early psychosis factor score compared with ziprasidone 2 mg at 4 hours (first postbaseline March 2010 assessment) (P < 0.L.01).9%). No AEs were reported for ≥5% of patients treated with olanzapine. open-label. The most common AEs with olanzapine 20 mg/d were somnolence (31%). observational study.001). All olanzapine doses were associated with significant decreases in the primary efficacy measure.3%). Damsa et al60 evaluated olanzapine 10 mg. and placebo in 311 patients with schizophrenia or schizophreniform or schizoaffective disorder.55–68 and 5 involved combination therapy.5%). Examination of pooled results for the 2 doses indicated that ziprasidone was associated with a significant decrease from baseline in BARS score at 4 hours after the initial injection (P < 0. and placebo in 272 patients with Alzheimer’s disease. Olanzapine significantly decreased PANSS-EC scores at 2 hours (first postbaseline assessment) (P < 0.1%) and EPS (5.2%). blurred vision. No AEs were reported in ≥5% of patients receiving olanzapine. P < 0.6%). Zeller and R. or unspecified psychotic disorder. observational study of olanzapine (mean initial dose. San et al62 conducted a nonrandomized.5 to 5 mg. nausea (7. and insomnia (5. P ≤ 0. randomized. headache (8%).5%). insomnia (13%). in 40 patients with agitation. compared with placebo (all. and injection-site pain (7. delusional disorder. schizoaffective disorder.5 mg and placebo in 270 patients with schizophrenia or schizophreniform or schizoaffective disorder.05). The most common AEs with olanzapine 10 mg/d were somnolence (26%).01). dizziness (9. Barak et al58 conducted a 3-day. vascular dementia. Wright et al59 conducted a 24-hour. Olanzapine significantly decreased PANSS-EC scores at 2 hours after administration (the first postbaseline assessment) (P < 0. 9.3%).001). The most common AEs with haloperidol were dystonia (7. bipolar disorder with psychotic features. or mixed dementia. 15 involved monotherapy43. prospective comparison of olanzapine 10 mg. insomnia (8%).7%) and akathisia (7. Intramuscular Therapy Twenty studies were identified that assessed intramuscular administration of antipsychotic agents and/ or benzodiazepines (Table III). Rhoades determined. headache (17%). Olanzapine significantly decreased PANSS-EC scores compared with placebo from 30 minutes to 2 hours after dosing (all. diarrhea (5. nervousness (11%). open-label study of ziprasidone 10 and 20 mg in 21 elderly patients (age ≥60 years) with schizophrenia or schizoaffective disorder. and dizziness (7%).9 mg) in 74 agitated patients with schizophrenia or bipolar disorder. prospective. Breier et al43 compared olanzapine 2. The most common AEs with haloperidol were parkinsonism (16. asthenia (5. arthralgia (7. Olanzapine doses ≥5 mg were associated with significant decreases compared with placebo at 30 minutes (P ≤ 0. A 24-hour.

haloperidol vs placebo from 60 min to 2 h (all. significant decrease.3%)* Agid et al56 R. age ≥18 y Hospitalized.05). 1 d Olanzapine 2. age ≥18 y Hospitalized. P < 0. 24 h Ziprasidone 2 mg (n = 38) Ziprasidone 20 mg (n = 41) PANSS early psychosis factor score: significant decreases. delusional disorder.01).7%). significant decrease. olanzapine vs placebo (all. akathisia (7.5–5 mg (n = 137) Lorazepam 1 mg (n = 68) Placebo (n = 67) PANSS-EC: significant decreases from 30 min to 2 h. all olanzapine doses vs placebo (all. ziprasidone 20 mg vs ziprasidone 2 mg at 4 h (first postbaseline assessment) (P < 0. lorazepam vs placebo (P ≤ 0. 24 h Olanzapine 2. schizoaffective disorder.5–10 mg (n = 185) Haloperidol 7. P ≤ 0. age ≥55 y Hospitalized or in longterm care facility.001) Haloperidol: parkinsonism (16. significant decrease at 2 h. prospective Schizophrenia.5 mg (n = 40) Placebo (n = 45) PANSS-EC at 2 h: significant decreases.05). PC. P ≤ 0. Results of clinical studies of intramuscular treatment for agitation.01) Not reported (continued) Clinical Therapeutics 412 Table III.05) and 24 h (P < 0.9%)* Meehan et al55 R.Study/ Design Patient Population Setting and Duration of Treatment Interventions Results for Primary Efficacy Measure Most Common AEs (≥5%) Volume 32 Number 3 Breier et al43 R.05) Lorazepam: somnolence (10. olanzapine doses ≥5 mg vs placebo at 30 min (P ≤ 0. DB Schizophrenia. prospective Alzheimer’s disease. mixed dementia. DB. bipolar disorder with psychotic features. . vascular dementia. unspecified psychotic disorder (DSM-IV). schizophreniform or schizoaffective disorder (DSM-IV).

mean initial dose 9. Zeller and R. schizoaffective or schizophreniform disorder (DSM-IV). age ≥18 y Hospitalized.5%).9%). 3 d Ziprasidone 10 or 20 mg (N = 21) BARS: significant decrease at 4 h after initial injection (P < 0. observational Patients with agitation (diagnosis not established).W.001) 8 Patients had ≥20–mm Hg reduction in systolic blood pressure Centorrino et al61 OL. EPS (5. headache (6. olanzapine vs placebo from 15 min to 2 h (all. ziprasidone 20 mg vs ziprasidone 2 mg (P < 0.2%).3%). with second dose (5 mg) permitted ≥2 h after the first (N = 40) PANSS-EC: significant decrease at 2 h (first postbaseline assessment) (P < 0.8%). observational Schizophrenia. sedation (1 patient each) Wright et al59 R.01) Ziprasidone 2 mg: somnolence (13.March 2010 Table III (continued). prospective Schizophrenia. 24 h Olanzapine 10 mg. P < 0. insomnia (5. nausea (7.9%). 24 h Olanzapine 10 mg (n = 131) Haloperidol 5 mg (n = 126) Placebo (n = 54) PANSS-EC at 2 h: significant decreases. age 18–65 y PES.05) and vs haloperidol from 15 to 45 min (P < 0. injection-site pain (7.3%) Ziprasidone 20 mg: somnolence (19.2%). age not specified ED.9 mg (N = 74) PANSS-EC at 2 h: significant decrease (P < 0.5%). diarrhea (5. nausea (12. blurred vision. Study/ Design Daniel et al57 Same study population as in Agid et al56 Patient Population Setting and Duration of Treatment Interventions – – Results for Primary Efficacy Measure Most Common AEs (≥5%) – Decrease in BARS: significant difference from 30 min to 4 h. age ≥60 y Admitted to psychiatric ward.01) Haloperidol: dystonia (7. bipolar disorder. arthralgia (7. asthenia (5. 2 h Olanzapine.001) Insomnia (9.L.3%) 413 (continued) S. schizoaffective disorder (DSM-IV). Rhoades Barak et al58 OL .6%)* Damsa et al60 Prospective. PC.1%).01) Acute urinary retention.3%). dizziness (9.3%) Schizophrenia.

001). 1d Aripiprazole 1. aripiprazole vs placebo (P < 0.75 mg vs placebo (all.05).4%) Haloperidol: somnolence (12.7%). age ≥18 y Hospitalized. somnolence (9.7%). P ≤ 0. significant decreases from 45 min to 2 h.7%). dizziness (7.3%). haloperidol vs placebo (P < 0. schizophreniform disorder (DSM-IV).7%). bipolar disorder.7%) Haloperidol: insomnia (12.1%) Lorazepam: dizziness (13. headache (8. P < 0. dystonia (7. nausea (5.2%). schizoaffective disorder (DSM-IV). or 15 mg (n = 235) Haloperidol 7. haloperidol vs placebo (both. no significant difference.001) No AEs reported in ≥5% of patients Meehan et al63 R.Study/ Design Patient Population Setting and Duration of Treatment Interventions Results for Primary Efficacy Measure Most Common AEs (≥5%) Volume 32 Number 3 San et al62 Nonrandomized.75 mg: headache (10. age 18–70 y PES. olanzapine vs lorazepam (P = 0. lorazepam vs placebo (P = 0. 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.4%). akathisia (10. dizziness (7. 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. and 4 h): Aripiprazole 9.5%). akathisia (5.01) Aripiprazole 9. unspecified psychotic disorder (DSM-IV).0%).4%). observational Schizophrenia.5 mg (n = 185) Placebo (n = 88) PANSS-EC at 2 h: significant decreases from 60 min to 2 h.001) and vs placebo (P < 0. 9. insomnia (5. dizziness (6.05). P = 0. age ≥18 y Hospitalized.053) Olanzapine: somnolence (13.5 mg (n = 60) Placebo (n = 62) PANSS-EC at 2 h: significant decreases from 45 min to 2 h. somnolence (5. PC Schizophrenia. aripiprazole 9.25. significant decreases at 105 min and 2 h. nausea (10.5%) (continued) Clinical Therapeutics 414 Table III (continued).1%). . DB. 2. 24 h Administered up to 3 times (0. prospective Bipolar disorder (mixed or manic episode) (DSMIII-R).75.1%). EPS (5.05) Aripiprazole: headache (7. 5. age ≥18 y PES. dizziness (9. DB Schizophrenia.3%).0%).75 mg (n = 175) Haloperidol 6.8%) Tran-Johnson et al64 R.0%) Andrezina et al65 R.

89% midazolam (P not reported) No AEs reported in ≥5% of patients (continued) 415 S. 2 wk Haloperidol 5–10 mg + promethazine 25– 50 mg (n = 150) Midazolam 15 mg (n = 151) Tranquilized or asleep at 20 min: 67% haloperidol + promethazine. 2 wk Haloperidol 5–10 mg (n = 156) Haloperidol 5–10 mg + promethazine 50 mg (n = 160) Tranquilized or asleep at 20 min: 55% haloperidol vs 72% haloperidol + promethazine at 20 min (P = 0. Zeller and R. midazolam vs lorazepam) No AEs reported in ≥5% of patients Huf et al69 R.002) Haloperidol monotherapy: dystonia (9 patients)* TREC Collaborative Group70 R. P < 0. OL Psychosis (unspecified).W. prospective . age not specified PES. P = 0. 9 ziprasidone. and 32. 24 midazolam Resnick and Burton67 R. age not specified ED. prospective Psychosis (unspecified). age 18–65 y PES Single doses: Droperidol 5 mg (n = 11) Haloperidol 5 mg (n = 16) BPRS agitation score ≤17: 36% droperidol.05 based on 95% CIs) Respiratory depression: 4 patients droperidol. prospective Psychosis (unspecified).L. 81% haloperidol at 30 min (P < 0. prospective Psychosis (unspecified). DB.003. substance abuse. patient blinded. 28.2 min lorazepam (P = 0. 2 h Droperidol 5 mg (n = 50) Altered Mental Status Scale: Ziprasidone 20 mg (n = 46) significant decreases with all Midazolam 5 mg (n = 48) treatments from 15 to 120 min (all. DB. age ≥18 y ED.05) Haloperidol: dystonia (1 patient)* Nobay et al68 R. Study/ Design Patient Population Setting and Duration of Treatment Interventions Results for Primary Efficacy Measure Most Common AEs (≥5%) Undifferentiated agitation. substance abuse. age not specified PES. DB.March 2010 Table III (continued). substance abuse. midazolam vs haloperidol.3 min haloperidol. 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. Rhoades Martel et al66 R.3 min midazolam.039.

Fourth Edition. lorazepam + haloperidol vs lorazepam alone (P = 0. prospective Psychiatric illness (unspecified). 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. 87% olanzapine (P not reported) No AEs reported in ≥5% of patients Bieniek et al72 R. no differences. Clinical Therapeutics 416 Table III (continued). 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. DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders. age not specified PES. Third Edition Revised. DB. combination therapy vs lorazepam at 1 h (P not reported). patient blinded. EPS (6%) Volume 32 Number 3 AEs = adverse events. prospective Psychosis (unspecified). DB = double blind. OL Psychosis. OL = open label. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders. dry mouth (9%) Lorazepam + haloperidol: dry mouth (9%). EPS = extrapyramidal symptoms.Study/ Design Patient Population Setting and Duration of Treatment Interventions Results for Primary Efficacy Measure Most Common AEs (≥5%) Raveendran et al71 R. *The absence of AE data for a comparator indicates that no AEs were reported in ≥5% of patients in that group.04) No AEs reported in ≥5% of patients Battaglia et al73 R. . R = randomized. TREC = Tranquilização Rápida–Ensaio Clínico (Rapid Tranquilization Clinical Trial). age 18–50 y PES. BARS = Brief Agitation Rating Scale. meeting clinical criteria for chemical restraint. PES = psychiatric emergency services. age not specified PES. lorazepam vs haloperidol. PC = placebo controlled. PANSS-EC = Positive and Negative Syndrome Scale–Excited Component. BPRS = Brief Psychiatric Rating Scale. 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. or haloperidol vs lorazepam + haloperidol (P not reported) Lorazepam: dry mouth (16%) Haloperidol: EPS (20%). ED = emergency department.

dizziness (6.4%).2%). The TREC (Tranquilização Rápida–Ensaio Clínico [Rapid Tranquilization Clinical Trial]) Collaborative Group conducted a 2-week. Rhoades significantly decreased PANSS-EC scores at 2 hours (first postbaseline assessment) and 24 hours after dosing (both.3%).4%). Combination Therapy Huf et al69 conducted a randomized. No AEs were reported in ≥5% of patients in any treatment group. Aripiprazole was associated with significant decreases in PANSS-EC scores compared with placebo at 60 minutes through 2 hours (P < 0. Martel et al66 compared droperidol 5 mg. randomized. each administered up to 3 times (0.1%) and dizziness (9. The proportions of patients in the haloperidol and haloperidol-plus-promethazine groups who were tranquilized or asleep within 20 minutes were 55% and 72%. akathisia (10. ziprasidone 20 mg. patientblinded.3 minutes for haloperidol.7%). Dystonia was reported in 9 patients treated with haloperidol monotherapy. randomized. Based on a Brief Psychiatric Rating Scale score ≤17. Andrezina et al65 conducted a 24-hour. midazolam vs lorazepam). The most common AEs with haloperidol were somnolence (12. and midazolam 5 mg in 144 patients with undifferentiated agitation.01). and dystonia (7.039. Respiratory depression occurred in 4 patients treated with droperidol. A randomized. In a 24-hour. and nausea (5.7%). 28.7%) and somnolence (9. respectively (P = 0.8%). P < 0.3%). Aripiprazole 9. 2.05 [based on 95% CIs]). double-blind. No AEs were reported in ≥5% of patients.W.25. P < 0. and 15 mg. The most common AEs with aripiprazole were headache (7. The most common AEs with lorazepam were dizziness (13. 67% of those who received haloperidol plus promethazine and 89% of those who received midazolam were tranquilized or asleep (P not reported).L. double-blind study in 357 patients with schizophrenia or schizophreniform disorder.05).001).05).7%). 5. haloperidol was associated with significant decreases compared with placebo at 105 minutes and 2 hours (both. the mean times to sedation were 18.05). and 24 treated with midazolam.05). akathisia (5. 417 . The most common AEs with olanzapine were somnolence (13. Nobay et al68 compared midazolam 5 mg.S. All treatments significantly March 2010 decreased Altered Mental Status Scale scores from 15 minutes to 2 hours after dosing (all. randomized.70 At 20 minutes. Zeller and R.4%).5 mg.0%). and haloperidol was associated with significant decreases compared with placebo at 45 minutes through 2 hours (P < 0. and somnolence (5.002).3 minutes for midazolam. The most common AEs with aripiprazole were headache (10. lorazepam 2 mg. There was no significant difference between lorazepam and placebo.001) and placebo (P < 0. prospective study. The most common AEs with haloperidol were insomnia (12. P < 0. haloperidol 6. Olanzapine was associated with significant decreases in PANSS-EC Agitation subscale scores at 2 hours after administration (first postbaseline assessment) compared with lorazepam (P = 0. Meehan et al63 compared olanzapine 10 mg. P = 0. 9 treated with ziprasidone.0%). and EPS (5. dizziness (7.75. No AEs were reported in ≥5% of patients receiving droperidol.2 minutes for lorazepam (P = 0.75 mg.0%). and lorazepam 2 mg in 111 patients with unspecified psychosis or substance abuse. In a 1-day. dizziness (7. prospective study. As measured on the Modified Thomas Combativeness Scale. Dystonia was reported in 1 patient receiving haloperidol. randomized. there were significant reductions in agitation at 30 minutes in 36% of patients treated with droperidol and 81% of those treated with haloperidol (P < 0. open-label comparison of haloperidol 5 to 10 mg and haloperidol 5 to 10 mg plus promethazine 50 mg in 316 agitated patients with unspecified psychosis or substance abuse. insomnia (5. In a 1-day. midazolam vs haloperidol. P ≤ 0.5%). Tran-Johnson et al64 compared aripiprazole 1.7%).1%). 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. and placebo.5 mg.001). No AEs were reported in ≥5% of patients. haloperidol 7.5%).1%). and 32. 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. haloperidol 5 mg. headache (8. nausea (10. in 448 patients with schizophrenia or schizoaffective disorder. and placebo. and placebo in 201 agitated patients with bipolar disorder (mixed or manic episode). double-blind comparison of aripiprazole 9. 9.003.75 mg was associated with significant decreases in PANSS-EC scores compared with placebo from 45 minutes to 2 hours after administration (all. randomized. and 4 hours).

There were no differences between lorazepam and haloperidol or between haloperidol and combination treatment. 3 = awake and cooperative.5 minutes for midazolam. patients receiving droperidol had significantly better sedation scores from 10 through 60 minutes compared with lorazepam (all.5 to 5 mg and lorazepam 2 to 4 mg in 202 patients with unspecified psychosis or drug abuse. Patients receiving droperidol had significantly better sedation scores compared with lorazepam from 10 through 60 minutes (all.0 minutes for droperidol and 6.05) and 10 minutes (P < 0.78. prospective comparison of lorazepam 2 mg. 4 = decreased agitation. As measured on the same 6-point scale as in the previous study. 1 = settled.81 Assessment of the severity of agitation and prediction of whether it is likely to lead to aggressive/violent behavior are important to guiding treatment decisions in both the emergency and nonemergency settings. and the most common AEs for lorazepam plus haloperidol were dry mouth (9%) and EPS (6%). double-blind. double-blind. No AEs were reported in ≥5% of patients. the most common AEs for haloperidol were EPS (20%) and dry mouth (9%).to 60-minute prodromal period during which they may exhibit increased pacing or loud speech.4%). The most common AEs with midazolam were hypotension (5. No AEs were reported in ≥5% of patients. prospective comparison of droperidol 5 mg and midazolam 5 mg in 153 patients with psychiatric illness or substance abuse. No AEs were reported in ≥5% of patients. 4 = highly aroused. The median time to sedation was 8. randomized. 2 = mildly aroused and pacing. Richards et al75 compared droperidol 2. Droperidol was associated with significantly greater sedation compared with placebo at 5 minutes (P = 0. Sedation was measured on a 6-point scale (6 = combative/violent. all involving comparisons between droperidol monotherapy and a benzodiazepine74–76 or placebo77 (Table IV). Patients receiving combination therapy had greater reductions in Agitated Behavior Scale scores at 1 hour compared with lorazepam (P not provided). 1 = deep sleep). There is evidence that the severity of untreated agitation increases with time in at least some patients. P < 0.001). 2 = somnolent. 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. Rosen et al77 conducted a 1-day. double-blind. 1 = no agitation). 3 = decreasing agitation. No AEs were reported in ≥5% of patients treated with droperidol. No AEs were reported in ≥5% of patients in either treatment group. No AEs were reported in ≥5% of patients. haloperidol plus lorazepam was significantly more effective in improving OAS scores at 60 minutes compared with lorazepam monotherapy (P = 0. 2 = slight agitation. At 15 minutes. open-label trial. Intravenous Therapy Four reports of intravenous treatment for agitation were identified. randomized. DISCUSSION Agitation may be present in patients with a wide range of medical and psychiatric disorders. P < 0. Sedation was measured based on a score of 2 on a 6-point scale (5 = highly aroused and violent.001). Bieniek et al72 conducted a randomized. prospective study comparing droperidol 5 mg with placebo in 46 combative patients. The Volume 32 Number 3 . randomized. patient-blinded. 3 = moderately aroused. 91% of patients who received haloperidol plus promethazine and 87% of those who received olanzapine were tranquilized or asleep (P not reported).79 The continuum of agitation can be described as proceeding from anxiety to high anxiety to agitation to aggression. haloperidol 5 mg. 418 In a 1-hour.Clinical Therapeutics A 2-week.04). Richards et al76 conducted another study of the same design comparing droperidol 2. 5 = very anxious/agitated.001). randomized. The most common AE with lorazepam was dry mouth (16%). and their combination in 98 patients with unspecified psychosis.4%) and hypoxia (5.8 Agitation can be viewed in terms of a 2-dimensional framework—duration and severity—with symptoms that vary over time and according to the changing characteristics of the patient’s internal state and environment during the episode. Over 180 minutes of observation.5 to 5 mg with lorazepam 2 to 4 mg in 146 patients with methamphetamine abuse. Battaglia et al73 conducted a 24-hour. 4 = anxious.80 Unpremeditated violence in patients with agitation may be preceded by a 30. and 0 = asleep). randomized. Knott et al74 conducted a 1-hour. Efficacy was measured on a 5-point agitation scale (5 = violently agitated. prospective trial by Raveendran et al71 compared haloperidol 10 mg plus promethazine 25 to 50 mg with olanzapine 10 mg in 300 patients with unspecified psychiatric illness.

hypoxia (5.001) No AEs reported in ≥5% of patients Rosen et al77 R. P < 0. ED = emergency department. R = randomized. DB = double blind.March 2010 Table IV. Study/ Design Patient Population Setting and Duration of Treatment Interventions Results for Primary Efficacy Measure Most Common AEs (≥5%) Psychiatric illness.5 min midazolam (P = 0. 419 S.05) and 10 min (P < 0.001) No AEs reported in ≥5% of patients AEs = adverse events. Results of clinical studies of intravenous treatment for agitation. droperidol vs lorazepam (all. substance abuse. OL.4%). droperidol vs lorazepam (all. prospective Methamphetamine abuse. age 18–65 y ED. OL.5–5 mg (n = 102) Lorazepam 2–4 mg (n = 100) Sedation score: significant differences at 10–60 min. Rhoades Knott et al74 R. DB. 1 h Droperidol 2. Zeller and R. DB. drug abuse. P < 0. 1 h Droperidol 2. age ≥18 y ED. 1 d Droperidol 5 mg (n = 23) Placebo (n = 23) Sedation score: significant difference. *The absence of AE data for a comparator indicates that no AEs were reported in ≥5% of patients in that group.5–5 mg (n = 72) Lorazepam 2–4 mg (n = 74) Sedation score: significant differences at 10–60 min.0 min droperidol. age ≥18 y ED. droperidol vs placebo at 5 min (P = 0. prospective Psychosis (unspecified).L.075) Midazolam: hypotension (5.W. OL = open label. prospective Combative.4%)* Richards et al75 R. prospective . 6.001) No AEs reported in ≥5% of patients Richards et al76 R. age 18–54 y ED. 1 h Droperidol 5 mg until sedated (n = 79) Midazolam 5 mg until sedated (n = 74) Median time to sedation: 8.

completion of the HCR-20 may take several hours and requires access to the patient’s medical history. The AAEP expert panel also emphasizes the importance of speed of onset and reliability of delivery when choosing a route of administration. Although several scales have been found useful in predicting violent behavior.32. or selection of additional therapy.90 A final important consideration with any medication used in the ED is that it must control agitation in patients with underlying conditions that 420 may not be fully understood at the time treatment is administered.78. haloperidol and lorazepam) that have been the standard of care for many years. risperidone alone or combined with a benzodiazepine. For agitated but cooperative patients. of newly admitted psychiatric patients. Treatment guidelines from the Joint Commission on Accreditation of Healthcare Organizations and the Centers for Medicare and Medicaid Services recommend the use of oral rather than intramuscular preparations of antipsychotics and benzodiazepines (eg. Current guidelines support a wide range of pharmacologic interventions for patients with agitation. the ACEP guidelines support monotherapy with either an atypical antipsychotic or conventional neuroleptic. a rapid onset of action.91 The guidelines recommend use of a benzodiazepine when no data are available on the condition underlying the emergency or when evaluation of the patient indicates intoxication.94 Volume 32 Number 3 . the NRS-R and CMAI each take ~15 to 20 minutes to complete.35. They state that no single atypical antipsychotic should be considered a general replacement for haloperidol and that haloperidol should be used in combination with a benzodiazepine.84–87 It should also be noted that experienced psychiatrists and psychiatric nurses are able to accurately predict violent behavior without the use of specific assessment tools. diagnosis. tranquilization without excessive sedation that may interfere with interaction with the patient. For oral treatment of agitation related to schizophrenia or mania. with little interpatient variability in pharmacokinetics and pharmacodynamics. a sufficient duration of effect for patients to be transported to the appropriate service. respectively. it must be stressed that an assessment based on these or any other scales provides only a snapshot of the patient’s condition at a given time and that the severity of an episode may change over time depending on both the external environment and the evolution of the patient’s internal condition. For example. the combination of an oral benzodiazepine (lorazepam) and an oral antipsychotic (risperidone) is recommended.28. both for managing agitation and as initial drug therapy.93 In patients with known psychiatric illness in whom antipsychotic use is indicated. the BVC requires ~5 minutes to complete and is based entirely on currently observed behavior. with no associated pain or need for restraint. and BVC have been found effective in predicting aggression/violence among psychiatric inpatients and in the correctional setting.28 Other instruments fall between these extremes.Clinical Therapeutics 13 assessment tools reviewed here vary substantially in their suitability for use in the assessment of agitation in the emergency setting. An expert consensus statement on the acute management of agitated patients in the ED from the American Association for Emergency Psychiatry (AAEP) provides detailed recommendations for the management of behavioral emergencies.79.88 The characteristics of an ideal medication for the acute management of agitation include easy preparation and nontraumatic administration (no needles).92 The American College of Emergency Physicians’ (ACEP) recommendations for the pharmacologic management of patients with agitation in the ED include use of a benzodiazepine (lorazepam or midazolam) or a conventional antipsychotic (haloperidol) as initial monotherapy in patients whose condition is unknown. and haloperidol plus a benzodiazepine. In contrast. The HCR-20.40.82 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. and the importance of maintaining the physician–patient relationship in long-term care.33.89. the guidelines recommend first-line treatment with olanzapine alone. One study found that psychiatrists and psychiatric nurses correctly predicted violent behavior in 82% and 84%. the high priority of controlling aggressive behavior during an emergency. McNiel-Binder Violence Screening Checklist. Intramuscular olanzapine is recommended as the first choice when a parenteral agent is needed.83 The PANSS-EC has been used in clinical practice to evaluate whether psychotropic medication should be administered to agitated patients with schizophrenia. and a low risk for adverse reactions and drug interactions.

with 52 patients accepting oral medication and intramuscular medication administered to 48 patients. Use of restraints and pharmacotherapy in academic psychiatric emergency services. Results of a survey of 59 patients who had used psychiatric emergency services indicated that as pharmacotherapy for episodes of agitation. Currier GW. Postgrad Med. 2000. The most common intramuscular medication was olanzapine (46%).23. Allen MH. 6. CNS Spectr. Rhoades is a paid consultant for Alexza Pharmaceuticals.12(Suppl 17): 5–11. intramuscular.61(Suppl 14):5–10. Oral agents are well accepted. the studies reviewed support a more rapid onset of action with intramuscular compared with oral administration. and involve them in treatment decisions. followed by olanzapine (33%).96 and inserting an intravenous line may be difficult and potentially dangerous in an agitated patient. and the combination of a benzodiazepine and an atypical antipsychotic (6%). placement of an intravenous line). 4. Atypical antipsychotics for acute agitation. 2002. Allen MH. intramuscular and intravenous administration of conventional or atypical antipsychotic agents may be associated with an increased risk of AEs and more patient objections (eg. Citrome L. A report of 100 consecutive agitated patients treated in the ED indicated that drug treatment was employed in every case. In general. followed by haloperidol (25%).L.S. Patient preference is an important consideration in the acute treatment of agitation. Mountain View. Management of agitated patients in the emergency setting could be facilitated by development of an easy-to-administer instrument that can predict the risk for violence/aggression in agitated patients. CNS Drugs.95 Another potential limitation of oral medications is that patients may “cheek” tablets.26:42–49. 2007. benzodiazepines (2%). REFERENCES 1. and the combination of a benzodiazepine with either an atypical or conventional antipsychotic (13%).23. as well as performance of comparative studies aimed at defining an approach to the treatment of agitation that is well accepted by health care providers and patients. respondents preferred pills or capsules.”89 Responders also stressed the importance March 2010 of having staff treat them with respect. 2008. Marco CA. holding them in the mouth without swallowing them.23:767– 776.99 Another potentially important limitation of the search procedure was that it was limited to published papers and did not include meeting posters and abstracts. California. J Clin Psychiatry. 2005.112:85–88. Emergency management of agitation in schizophrenia. and intravenous treatment may all be effective for the treatment of agitation. The authors have indicated that they have no other conflicts of interest with regard to the content of this article. Pharmacological control of acute agitation: Focus on intramuscular preparations. Reports concerning newer treatments for agitation were not identified by the literature search. Managing the acutely agitated and psychotic patient. Vaughan J. Rhoades The findings of this review of clinical trials of pharmacotherapy for agitation suggest that oral. 5. risperidone (8%). Dr. 3. Zeller and R. and with intravenous compared with intramuscular administration. Zimbroff DL. Gen Hosp Psychiatry. followed by liquid medication and then “an injection I agree to. resistance to needles. Am J Emerg Med. 2004.97 The literature search identified few studies of how agitated patients are actually managed in the ED. although onset of action differs according to the route of administration. ziprasidone (15%). New intramuscular options offer advantages.89 although their relatively slow onset of action may limit their utility in some patients. Lindenmayer JP. The pathophysiology of agitation.89 There is also concern that the use of injected medications may compromise the physician–patient relationship. ACKNOWLEDGMENTS Preparation of this article was supported by Alexza Pharmaceuticals.22: 199–212. CONCLUSIONS The results of this review highlight the numerous options for the assessment and treatment of patients with agitation. 421 . talk and listen to them. Other treatments for agitation may not have been identified because of the well-known bias against publication of negative clinical-trial results. Nordstrom K. benzodiazepines (15%).90 Compared with oral administration.W. 2. Zeller is a member of speakers’ bureaus for Eli Lilly and Company and Pfizer Inc. Dr. 94–96.90 Intravenous or intramuscular administration of medications to an agitated patient has also been associated with the risk for needle-stick injuries to ED staff.98 The most commonly used oral medication was haloperidol (38%).

8(Suppl 3):309–315.160:831–835. 31.shtml. Bryois C. et al. Lesser JM. Rev Med Suisse. 2005. Lambert J. J Am Geriatr Soc. 2003. Agitation III: Pharmacologic treatment of agitation. Neurobehavioral Rating Scale–revised.75:197– 213. 30. Shah A. 14.11:261–277. National Institute of Mental Health. Int Psychogeriatr.18:579–586. et al.8: 1051–1055. 2008. Downey LV. The epidemiology of the homeless population and its impact on an urban emergency department. Mazaux JM.pdf.com/ hcr20annotated. Sensitivity. Guy LS. New treatments for agitation. J Interpers Violence. Assessment of neuropsychologic impairments after head injury: Interrater reliability and factorial and criterion validity of the Neurobehavioral Rating Scale-Revised. Bourdinaud V.81:796– 806. Emergency Psychiatry: Principles and Practice. Predicting clinical and social outcome of patients attending ‘real world’ mental health services: A 6-year multi-wave follow-up study. Pa: Wolters Kluwer Health/Lippincott Williams & Wilkins. Prim Care Companion J Clin Psychiatry. 35. 2009.Clinical Therapeutics 7. Anderson RL. 1998. The Brøset Violence Checklist. The aggressive behavior scale: A new scale to measure aggression based on the minimum data set. 2008. Davidoff DA. Br J Psychiatry. 1992. Finkel SI. Piechniczek-Buczek J. 2007: 16–30. 1994. Zoupanos BN. Verma SD. Allen MH. J Clin Psychiatry.com/viewer?a=v&q= cache:ot2tT7tiT9AJ:www. Lasalvia A. 2006. Schizophr Res. 8. 28. Cristofalo D. 2009.org/Toolbox%2520test/Neuro behavioral%2520Rating%2520 Scale-R. Chiang W. Kambhampati KK.nimh. Psychiatr Q. Conceptualization of agitation: Results based on the Cohen-Mansfield Agitation Inventory and the Agitation Behavior Mapping Instrument. 22. Patients in a state of agitation at the admission service of a Rouen hospital emergency department [in French]. 29. Accessed December 25. and disinhibition in Alzheimer’s disease: Definitions and treatment options. Huber CG. Hung O. and interrater reliability.65:1207–1222. Parkash N.41:50–52. Corrigan JD. Ring H.29:470–474. Emerg Med Clin North Am. Citrome L. 422 18. 2000. 26. 16. 32. 9. Diabetes Metab Res Rev.gov/health/publications/thenumbers-count-mental-disordersin-america/index. 33. 29:89–98. Alexander J. Alderfer BS. Pilowsky LS. et al. Development of a scale for assessment of agitation following traumatic brain injury. Haloperidol plus promethazine for psychosis induced aggression. A brief agitation rating scale (BARS) for nursing home elderly. Zun LS. Frequency of alternative to restraints and seclusion and uses of agitation reduction techniques in the emergency department. Rapid tranquillisation. Weir J. Presse Med. Hughes S.10:108–113.violence-risk. Geriatrics. http://www. Gonzales SJ. 1993. Naber D. 2004. Allen MH. nih. Screening for risk of inpatient violence. Douglas KS. eds. Psychosis. J Am Geriatr Soc. Treatment of agitation in bipolar disorder across the life cycle. McNiel DE. http:// docs. Binder RL. Evans H. 2003. 21. Law Hum Behav. Pochard F. Zun LS. Battaglia J. Woods P. 2007. Cohen-Mansfield J. Volume 32 Number 3 .24:467–490. Bauer F. Almvik R. D’Amore J. http://www. Philadelphia. et al. 27. 17. Encephale. Warren RE. A survey of emergency prescribing in a general psychiatric hospital. Vanier M. 1998.28:1630– 1634. Cochrane Database Syst Rev. 2005. 1999. Citrome L. Level of agitation of psychiatric patients presenting to an emergency department. Moritz F. et al. 13. specificity. In: Glick RL. The Numbers Count: Mental Disorders in America. Management of the agitated elderly patient in the nursing home: The role of the atypical antipsychotics. 25.nihtool box. 1989. Hirdes JP. Berlin AB. Treatment of agitation in the emergency room [in French]. Acad Emerg Med. 2005. Validation of a Clinical Global Impression Scale for Aggression (CGI-A) in a sample of 558 psychiatric patients.(1) CD005146.+neurobeha vioral+rating+scale+revised&hl=en &gl=us&sig=AHIEtbS9aYwd3d S-F7kU9je4kijqz7VqDw. J Clin Psychiatry. 2008:137–147. The symptoms of hyperglycaemia in people with insulin-treated diabetes: Classification using principal components analysis. viii. Accessed December 25. 24. Evaluation of three aggression/agitation behaviour rating scales for use on an acute admission and assessment psychogeriatric ward.pdf+mccauley. 2003. Huf G. Deary IJ. Int J Geriatr Psychiatry. Psychiatric emergencies in the elderly population.1: 1810–1813. Pharmacological management of acute agitation. Bonetto C. 2008. Survey of management methods for patients in a state of agitation at admission and emergency departments in France [in French]. Drugs. 2001. Goldfrank L. HCR20 violence risk assessment scheme: Overview and annotated bibliography. Rasmussen K. Perlman CM. 12. Gen Hosp Psychiatry. 61:14–20. McCauley SR. 2000. Zeller SL. 23. Downey LV. Lambert M. 11. 100:342–348. Acta Psychiatr Scand Suppl. J Clin Exp Neuropsychol. 1996. 19.56:2298–2303. 15:1284–1296. Fishkind AB. 2009. 10. 2009. agitation. Shine PJ.google. Psychosisrelated disturbances. Accessed November 18.59(Suppl 19):50–55.13:415–420. Arch Phys Med Rehabil. Lyons JS. 34. 15. Frier BM. 20.64(Suppl 4):3–9. Boyer A.19:408–414. 2006.

Intramuscular olanzapine in patients with schizophrenia: An observational study in an emergency room. Meehan KM. 40. Kapur S. Utility of decision support tools for assessing acute risk of violence. 57. 1997. Int J Geriatr Psychiatry. et al. The Overt Aggression Scale for the objective rating of verbal and physical aggression. J Neuropsychiatry Clin Neurosci. Stauffer VL. et al. GutierrezEsteinou R. Neuropsychopharmacology. 2004. Kopecky HJ. A double-blind. Arch Gen Psychiatry.L. et al. The Overt Agitation Severity Scale for the objective rating of agitation. randomized trial. McNiel DE. Wrigley M. Kopecky CR. et al. Plopski I. Lau GS. randomized.9:541–548. Hum Psychopharmacol. Meehan K. J Clin Psychiatry. Breier A. double-blind. and placebo: A double-blind. David SR. 1998. 56. Kinon BJ. et al. Yudofsky SC. Baker RW.26:494–504. 2006. placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Citrome LL. J Consult Clin Psychol. Kwon Y. Barak Y. Am J Emerg Med. 2007. Lazignac C. et al. 1997. Meyers AL. Daniel DG. 2007. Gannon M. Marder SR. Ahl J. in combination with lorazepam. 2008. 2006. Birkett M. Centorrino F. 49. Warrington L. Psychiatr Q. 58. Chou JC. et al. 2008.22:181–186.34:1451–1459. et al.158:1149–1151. A naturalistic multicenter study of intramuscular olanzapine in the treat- 423 . Silver JM. Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. 2007. McMullen E.12:384–388. Double-blind. randomized study in acutely agitated patients with dementia. Rhoades 36. J Psychiatr Pract. Acute treatment of psychotic agitation: A randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. A pilot. Oral risperidone. Arranz B. Eom M. Currier GW. Alzheimer Dis Assoc Disord. 43. Comparison of rapidly acting intramuscular olanzapine. Sachs GS. medication.143:35–39. Taehan Kanho Hakhoe Chi. 54. 2008. Yudofsky SC. Jackson W. 1986. 2003.68:1377–1383. 1988. Gregory AL.65: 386–394. Ahl J. Mazeh D. Kinon BJ. J Clin Psychopharmacol. et al. Bull Soc Sci Med Grand Duche Luxemb. Risperidone versus haloperidol.23:342–348. 38. Intramuscular ziprasidone treatment of acute psychotic agitation in elderly patients with schizophrenia. Am J Geriatr Psychiatry. et al. 2006. placebo-controlled clinical trials. Chaichan W. et al. Walsh PG. et al. Oh H. et al. van Wijngaarden E. Adam E. 61. placebo-controlled trial.28:601–607. et al.102: 241–248. David SR. J Clin Psychiatry. 51. A study of aggression among referrals to a community-based psychiatry of old age service. 155:128–134. et al. 45. West B. Querejeta I. olanzapine and quetiapine versus haloperidol in psychotic agitation.68:662–668. Aggressive behavior in persons with dementia who live in the community. Olanzapine versus aripiprazole for the treatment of agitation in acutely ill patients with schizophrenia. 44. Kinon BJ. 60. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: A double-blind.14:105–113. openlabel safety study of quetiapine for treatment of moderate psychotic agitation in the emergency setting. A study on aggressive behavior among nursing home residents with cognitive impairment. March 2010 46.W. Schizophr Res. Effectiveness of rapid initial dose escalation of up to forty milli- 55. Lam JN. Evaluation of the use of the positive and negative syndrome scale-excited component as a criterion for administration of p. 2007. 2002. placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Rocca P. Gibbons P. Damsa C.13:159–169. Rotelli MD. 2003.12:223–228. Birkett M. grams per day of oral olanzapine in acute agitation.S. Wright P. Am J Psychiatry.22:455–462.12:103– 108. Villari V. Efficacy of accelerated dose titration of olanzapine with adjunctive lorazepam to treat acute agitation in schizophrenia. 2004. Veser FH. J Clin Psychopharmacol. et al. 2008:209–216. Zeller and R. 62. Antimanic response to aripiprazole in bipolar I disorder patients is independent of the agitation level at baseline.2:342–355. An observational study of the effectiveness and safety of intramuscular olanzapine in the treatment of acute agitation in patients with bipolar mania or schizophrenia/schizoaffective disorder. 59. KollackWalker S. 2004. Feifel D. Kopecky HJ. 39. Ryden MB. 37. Trenton AJ. 2001. 50. Baruch Y. Currier GW. Psychopharmacology (Berl). Agid O. Wang H. Potkin SG. Zimbroff DL. 41. Reeves KR.69:301–323. 2008. J Psychiatr Pract. Gaulin BD. 47. Prog Neuropsychopharmacol Biol Psychiatry. San L. 42. Reliability and validity of the Overt Agitation Severity Scale in adult psychiatric inpatients.14: 629–633. 52. Intramuscular aripiprazole in the control of agitation.r. J Psychiatr Pract. lorazepam. 2002. et al. et al. Yudofsky SC. 48. 32:405–413. Currier GW. Maguire GA. Fonzo V. Aripiprazole effects in patients with acute schizophrenia experiencing higher or lower agitation: A post hoc analysis of 4 randomized. Veser BD.n.59:441–448. in the treatment of acute agitation and psychosis: A pilot. 53. J Clin Psychiatry. et al.71:945– 953. Kunik M. Am J Psychiatry. McMullan JT. J Psychiatr Pract. 2001.

Tharyan P. 65. Martel M. et al. 73. Richards JR. Droperidol vs. 79. BMJ. et al. Moss S. Ownby RL. J Clin Psychiatry.16:187–195. 2009. Berlin AB. Tran-Johnson TK. 78. 2005. Philadelphia. Miner J. J Emerg Med. A prospective. Factors relevant to patient assaultive behavior and assault in acute inpatient psychiatric units in Taiwan. Wolfe RE. Sterzinger A. Arch Psychiatr Nurs. 2006. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Zeller S. emergency department study. Levitt MA. Rush J. et al. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Current treatments of agitation and aggression. Duncan DR. Alexander J. randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Cohen-Mansfield J. In: Glick RL. 72. 81. 2006.11: 744–749.uk/Cohen%20Mansf ield %20Agitation%20Inventory. double-blind. J Clin Psychopharmacol. Rapid tranquillisation in psychiatric emergency settings in India: Pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. 82. Needham I. 2007. Citrome L. 2002. BMJ. haloperidol in the initial management of acutely agitated patients. Chemical restraint for the agitated patient in the emergency department: Lorazepam versus droperidol. BMC Psychiatry. Chou KR. doubleblind. or both for psychotic agitation? A multicenter. et al. 85. Accessed November 18.47:61–67.pdf. Nobay F. Dresden GM. et al. 86. Huf G. Josiassen RC. 84. or placebo in treating acutely agitated patients diagnosed with bipolar mania. Accessed December 25. Raveendran NS. In: Glick RL. Taylor DM.Clinical Therapeutics 63. Bieniek SA. Andrezina R. Rosen CL. Knott JC.13:233]. 75. 2007. co. 76. Meehan K. Acad Emerg Med. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: A randomised trial of midazolam versus haloperidol plus promethazine. et al.327:708–713. Berlin AB. Sack DA.12:1167–1172. for the TREC Collaborative Group. Menchetti M. 2006. 64. Derlet RW. Beck C. Mao WC.188:281–292. Emergency Psychiatry: Principles and Practice.63:1121– 1128.21:389–397. Fishkind A. Predictors of noncompliance in patients with schizophrenia. placebo-controlled comparison with intramuscular haloperidol. prospective. eds. David S. Agitation I: Overview of agitation and violence. eds. randomized comparison of the efficacy and safety of intramuscular injections of olanzapine. Fishkind AB. Rapid tranquillisation in psychiatric emergency settings in Brazil: Prag- 424 70. 66. 77. Burton BT. Ratliff AF. J Emerg Med. 2001. Fishkind AB. 2004. Tonti C. 1997.335:869. for the TREC-India II Collaborative Group. Marcus RN. Adams CE.18:57–62. Castle DJ. lorazepam.com/viewpr ogr am/ 1866. Haloperidol.335:865. Zhang F. Eur J Emerg Med. Emergency Psychiatry: Principles and Practice. http://wanderingnetwork. Lu RB. Escalation/de-escalation patterns of behavioral symptoms of persons with dementia. 2008:125–136. TREC Collaborative Group. double-blind. Psychopharmacology (Berl). Battaglia J. 1998. 2006. Dassen T. ment of acutely agitated manic or schizophrenic patients. 80. 2008. Marcus RN. Psychiatry Clin Neurosci. Agitation II: Deescalation of the aggressive patient and avoiding coercion.6: 17. 2003.68:111– 119. 1984.4:130–135. BMJ. placebo-controlled trial. Pharmacotherapy. matic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. J Clin Psychiatry. 1998. A double-blind. 2006.21:539–543. 71. 69. Perkins DO. 2008:117–124. 1997. Adams CE. Penalver A. Aging Ment Health. 2004. Predicting inpatient violence using an extended version of the Brøset-Violence-Checklist: Instrument development and clinical application. Duncan DR. 67. Pa: Wolters Kluwer Health/Lippincott Williams & Wilkins. The efficacy of intravenous droperidol in the prehospital setting. Management of acute undifferentiated agitation in the emergency department: A randomized doubleblind trial of droperidol.15:335–340. Coutinho ES. Am J Emerg Med. 1997. ziprasidone. 74. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: A randomized. 8:126–132. 68.16:567– 573. Dominguez RA. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: A double-blind. et al. Resnick M. 2002. Bruch SM.15:13–17. Zeller SL. lorazepam. Simon BC. Philadelphia. Richards JR. 2009. 2007. Ann Emerg Med. Pa: Wolters Kluwer Health/Lippincott Williams & Wilkins.62:247–255. http://cme. and midazolam [published correction appears in Acad Emerg Med.45:298– 299. Methamphetamine toxicity: Treatment with a benzodiazepine versus a butyrophenone. Derlet RW. Abderhalden C. et al. Volume 32 Number 3 . J Clin Psychiatry. medscape. Cohen-Mansfield Agitation Inventory (CMAI)–long form. Predictors of violent behavior among acute psychiatric patients: Clinical study. Zeller SL. Eur Psychiatry. Rapp CG. 83. Woods DL. Acad Emerg Med. Amore M.

Publication bias in clinical trials due to statistical significance or direction of trial results. 2002.47:79–99. Edlow JA. Sorock GS. 9:39–58. What do consumers say they want and need during a psychiatric emergency? J Psychiatr Pract. J Psychiatr Pract. 2006. The expert consensus guideline series. 2009. Madre M. 91. 93. 2002. Lereya J.11(Suppl 1):5–108. Treatment of behavioral emergencies: A summary of the expert consensus guidelines. The agitated psychotic patient: Guidelines to ensure staff and patient safety. TREC-Rio trial: A randomised controlled trial for rapid tranquillisation for agitated patients in emergency psychiatric rooms [ISRCTN44153243]. Clinical policy: Critical issues in the diagnosis and management of the adult psychiatric patient in the emergency department. 2009. Palmstierna T. Predictions made by psychiatrists and psychiatric nurses of violence by patients.W. 1991. E-mail: szellermd@gmail. Clinical management of agitation. Sharps-related injuries in health care workers: A casecrossover study. Zimbroff DL. Allen MH. CA 94602.com 425 . com/viewprogram/2311.(1) MR000006. Pascual JC.8:171–178. Fisman DN. Carpenter D.8(Suppl 4):S2– S8. Rabinowitz J. et al. Wolf SJ.L. 2003. for the Expert Consensus Panel for Behavioral Emergencies 2005. Allen MH.2:11. 2006. Wistedt B. 1411 East 31st Street.114: 688–694. Currier GW. et al. Rhoades 87. Allen MH. 2002. Cochrane Database Syst Rev. Oakland. Treatment of behavioral emergencies 2005. Carpenter D. 92. et al.medscape. Hopewell S. Neuropsychopharmacol Hung. Accessed November 18. 97. J Am Psychiatr Nurses Assoc. Murphy MC. 2005. 89. Psychiatr Serv. Ann Emerg Med. March 2010 96. Harris AD. Hosp Community Psychiatry. Fennig S. Loudon K. for the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Critical Issues in the Diagnosis and Management of the Adult Psychiatric Patient in the Emergency Department. Lukens TW. et al. Mittleman MA.53:622–624. New formulations of olanzapine in the treatment of acute agitation [in Hungarian]. Clarke MJ. A naturalistic study: 100 Consecutive episodes of acute agitation in a psychiatric emergency department [in Spanish]. Haim R.42:1237–1240. 88. 95. Huf G. Puigdemont D. Alameda County Medical Center. Zeller.34:239–244. Currier GW. Coutinho ES. Hughes DH.S. Sheets JL. et al. http://cme. MD. Actas Esp Psiquiatr. Adams CE. Am J Med. Huitfeldt B. 98. BMC Psychiatry. 99. Zeller and R. 2003. Bartkó G. Address correspondence to: Scott L. 2003. 2006. 94. et al. The relationship of crowding and aggressive behavior on a psychiatric intensive care unit.9:16–38. 90. J Psychiatr Pract. for the TREC-Rio Trial.