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Clinically Significant Acute Agitation: Consensus Update

Brenda Wood, BSPharm, PharmD
Clinician and Medical Writer
Rancho Santa Fe, California


US Pharm. 2010;35(11):HS-9-HS-15.

A behavioral emergency--also known as clinically significant acute agitation--typically is a dynamic, unpredictable encounter with a patient in whom the diagnosis is unknown or preliminary. Class I studies are limited or nonexistent, possibly because of the emergent need for treatment in highly agitated patients.1,2 Several lower-level class II and class III studies have been conducted.2-16 It is for this reason that the Expert Consensus Guidelines were developed. The guidelines were formulated based on responses to a statistically designed written survey that was administered to 48 experts in the field.1 Clinically significant acute agitation that required emergency intervention was defined as involving “explosive and/or unpredictable anger; intimidating behavior; restlessness, pacing, or excessive movement; physical and/or verbal self-abusiveness; demeaning or hostile verbal behavior; uncooperative or demanding behavior or resistance to care; and impulsive or impatient behavior or low tolerance to pain or frustration.”1

Expert Consensus Guidelines

The treatment of choice endorsed by the Expert Consensus Guidelines is to calm the patient without sedation.1 Second-line treatment is mild sedation to the point of drowsiness, but not sleep; third-line treatment is heavy sedation or sleep. In general, the recommendations are based on a preliminary diagnosis. Clinically significant acute agitation should be treated with an agent that will effectively treat the underlying condition.1

Historically, lorazepam and haloperidol have been used most often for treating clinically significant acute agitation.17 Of the agents listed in the Expert Consensus Guidelines, 100% of survey respondents considered intramuscular (IM) and oral formulations of lorazepam and haloperidol to be appropriate.1 Thirty-eight percent of respondents considered diazepam to be inappropriate for emergency treatment, followed by oral ziprasidone (31% of respondents), oral quetiapine (25%), IM ziprasidone (9%), IM olanzapine (2%), and oral risperidone (2%).1 TABLES 1 and 2 list the appropriate first- and high second-line oral and parenteral agents, respectively, while TABLE 3 gives appropriate choices for special patient populations. TABLE 4 describes the dosing specified by the consensus survey. Refer to the Expert Consensus Guidelines for additional recommendations regarding failure of initial treatment.1

Within the limits of the expert opinion, the Consensus Guidelines suggest that benzodiazepines are first-line therapy when there is no clear diagnosis, when there is stimulant intoxication, and when parenteral therapy is needed for a personality disorder.1 Benzodiazepines are a high second-line option if medication must be used for alcohol intoxication.1 Lorazepam is recommended as first-line therapy if the following comorbid conditions exist: cardiac arrhythmia or conduction defect; obesity; or diabetes or hyperglycemia.1 Haloperidol and ziprasidone are also recommended as first-line therapy for diabetes or hyperglycemia.1 Lorazepam and clonazepam are first-line therapy if the patient has a history of akathisia, amenorrhea and/or galactorrhea, seizures, extrapyramidal symptoms, tardive dyskinesia, or neuroleptic malignant syndrome.1 Risperidone is recommended as first-line therapy for delirium, dementia, mental retardation, and drug abuse or dependence.1 Olanzapine, haloperidol, and ziprasidone are recommended as first-line agents for drug abuse or dependence.1

It is unclear whether combination therapy with a benzodiazepine and an antipsychotic confers greater efficacy, a more rapid onset of action, or reduced side effects. The literature does not support the use of combination therapy to lower the dose of each medication.1 However, within the limits of the expert opinion, the Consensus Guidelines suggest that second-generation antipsychotics, alone or in combination with a benzodiazepine, are first-line or high second-line treatment when acute agitation is the result of a primary psychiatric condition such as schizophrenia, mania, or psychotic depression.1

The clinical policy of the American College of Emergency Physicians (ACEP) differs from that of the Expert Consensus Guidelines in that the ACEP recommends droperidol as an agent of choice and suggests that “rapid sedation” may also be obtained with droperidol.2 The Expert Consensus Guidelines do not recommend the use of droperidol for the treatment of behavioral emergencies even if the expert panel did not consider any risk with droperidol use.1 The expert panel, in contrast to the ACEP, strongly endorsed the goal of emergency treatment to “calm the patient without sedation.”1

At the time of the survey, the expert panel did not have a consensus on the use of IM aripiprazole, and the ACEP did not address the use of aripiprazole; therefore, the dosing is not listed in TABLE 4.1 Studies in patients with acute agitation who have Alzheimer's disease, vascular or mixed dementia, bipolar disorder, or schizophrenia indicate that aripiprazole is effective and well tolerated.18-20 The single IM aripiprazole dose in these studies was 9.75 mg to 15 mg. Although there was no consensus on the use of aripiprazole, those experts who used aripiprazole recommended a minimum single dose of approximately 11 mg, a maximum single dose of approximately 25.5 mg, a minimum wait-time interval between doses of 75 minutes, and a maximum total dose in the first 24 hours of approximately 31.50 mg.1

Medication Safety

Important safety concerns with the use of medications used to treat clinically significant acute agitation include the potential for drug interactions, cardiotoxic effects, cerebrovascular effects, and hypotension. When a clinician is deciding whether to administer these agents acutely with the intent to begin long-term therapy, the effects that they may have on blood glucose and lipid profiles should be considered.21 Torsades de pointes has been reported with IV haloperidol at high oral doses (420-1,000 mg).21 However, definitive cases have not been reported with risperidone, olanzapine, or ziprasidone even though a change in the QTc may be seen with atypical antipsychotics. A black box warning exists for aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. The warning states that there is an “increased risk of death and increased incidence of cerebrovascular adverse events” in elderly patients with dementia-related psychosis.22

Hypotension may be seen with lorazepam at low levels. Haloperidol alone does not appear to confer a significant risk of hypotension, but severe hypotension can occur with haloperidol in combination with antihypertensives, leading in rare cases to cardiac arrest. Other side effects seen with use of haloperidol and other atypical antipsychotics in the acute setting may include extrapyramidal symptoms, akathisia, and dystonic reactions.17

Important Drug Interactions

Risperidone and Olanzapine: These drugs are metabolized via CYP2D6. There may be an increased effect with either agent when strong inhibitors of CYP2D6 (fluoxetine, paroxetine, high-dose sertraline) are used concomitantly.23 Olanzapine is metabolized primarily via CYP1A2, and it may result in a decreased response if it is administered to a patient who smokes cigarettes.23

Ziprasidone and Quetiapine: These agents are metabolized via CYP3A4. Agents that induce CYP3A4 (carbamazepine, phenytoin) or inhibit it (ketoconazole, protease inhibitors) can affect ziprasidone and quetiapine concentrations.23

Aripiprazole: Aripiprazole is metabolized via CYP3A4 and CYP2D6. Adjustments should be made when enzyme inducers or inhibitors are used concomitantly.24

Haloperidol: Significant interactions can be seen with the administration of haloperidol plus carbamazepine, lithium, or serotonin reuptake inhibitors.25


The primary goal in treating patients with clinically significant acute agitation is to calm the patient without sedation. This can facilitate the patient-physician relationship and aid in proper diagnosis of the underlying disease, thus allowing for initiation of appropriate first-line therapy. Haloperidol is still recommended as a first-line or high second-line choice in many cases, and the benzodiazepine most widely recommended by the Expert Consensus Guidelines is lorazepam. The guidelines recommend second-generation antipsychotics alone or in combination with a benzodiazepine as first-line or high second-line therapy when acute agitation is the result of a primary psychiatric condition such as schizophrenia, mania, or psychotic depression. Data are inconclusive concerning greater efficacy, more rapid onset of action, or reduced side effects with the use of combination therapy. The literature does not support using combination therapy to lower the dose of each medication.


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