David Feifel, MD PhD

It is a general rule that established pharmacological treatments for major psychiatric syndromes (e.g., antidepressants for depression, antipsychotics for psychosis and mood stabilizers for mania) require days to weeks of continuous administration to produce resolution or significant improvement in the core symptoms of the respective underlying syndrome. Therefore, psychopharmacological intervention in the acute setting cannot be expected to produce a definitive therapeutic effect for these syndromes, any more than antimicrobial therapy in the acute setting can be expected to produce a definitive resolution of infectious disease processes. However, aside from initiation of definitive therapy, intervention in the acute setting can effectively reduce symptoms of agitation and aggression that frequently accompany the acute presentation of major psychiatric syndromes.

Agitation is a syndrome that can manifest as the most prominent feature during the acute presentation of many psychiatric disorders, including major mood, anxiety and psychotic disorders. Agitation predisposes a patient to aggressive behavior, thereby putting the agitated patient, as well as health care staff and other patients, at risk. Furthermore, agitation inhibits medical and psychiatric assessment and, in so doing, hinders diagnosis and definitive treatment of the underlying etiology. It is not surprising, therefore, that the most common use of psychopharmacological treatment in the acute setting is to target agitation and aggression.

An ideal anti-agitation medication would rapidly reduce behavioral and subjective features of agitation (i.e., tranquilization) without producing excessive sedation or otherwise compromising the patient's ability to remain alert, responsive and lucid. Unfortunately, because the two effects are often co-induced, many clinicians inextricably associate tranquilization with sedation. For this reason, sedation, in its own right, is often viewed as a desirable property for an anti-agitation medication. It is, however, important to keep in mind that while tranquilization facilitates the diagnostic assessment and initiation of definitive treatment of a patient presenting with acute agitation, sedation does not facilitate and, in fact, usually hinders these goals. Based upon the criteria of tranquilization without sedation, an ideal anti-agitation medication does not currently exist. Nevertheless, clinicians have at their disposal a number of standard and emerging treatment options that are effective in the acute management of agitation.

Conventional or typical antipsychotic drugs were historically the first medications to be widely adapted for the treatment of patients presenting with acute agitation, particularly with concomitant psychotic symptoms. Studies have shown that typical antipsychotics are effective for this use (see Allen [2000] for review). Their mechanism of action is via reduction in dopamine transmission in the brain, of which the most pertinent pathways are probably dopamine circuits in the limbic and prefrontal cortical areas. The high-potency antipsychotic haloperidol (Haldol) has been shown to be more effective than the low-potency chlorpromazine (Thorazine) (Gerstenzang and Krulisky, 1977) for the treatment of acute agitation when both are administered parenterally. In addition, the high-potency antipsychotic drugs are associated with less severe side effects, such as hypotension (Man and Chen, 1973). Not surprisingly, therefore, haloperidol in doses of 5 mg to 10 mg has emerged as the most widely used antipsychotic for the treatment of acute agitation in the emergency setting.

The major liability associated with typical antipsychotic medications is the fact that they can produce significant adverse effects even with a single administration in the acute setting. These include akathisia, extrapyramidal symptoms (EPS) and, less frequently, neuroleptic malignant syndrome. In addition to adding to patients' discomfort, these potential side effects may confound subsequent diagnostic assessments. I have observed several cases in which the administration of high-potency neuroleptics to patients with acute agitated psychosis induced a catatonia-like syndrome, which was then misdiagnosed by inexperienced clinicians as being psychogenic in origin. This misdiagnosis typically prompted more aggressive antipsychotic treatment and, in turn, more severe catatonic features. In each of these cases, once the iatrogenic etiology of this syndrome was recognized, the patients' symptoms improved rapidly and dramatically with administration of anticholinergic medication.

Droperidol (Inapsine), a butyrophenone that is structurally related to haloperidol and indicated for use in anesthesia, has a faster onset of action and a shorter duration of action compared to intramuscular (IM) haloperidol (Resnick and Burton, 1984; Thomas et al., 1992). It can only be administered parenterally, as no oral formulation exists. Droperidol is the anti-agitation medication of preference among many clinicians treating agitation in the psychiatric emergency setting, owing to its rapid, potent and predictable effects. However, some clinicians have reported instances of mild hypotension and/or respiratory suppression, as well as acute EPS, with droperidol.

Benzodiazepines have become an important family of medications for the treatment of acute agitation. They were initially introduced in the acute setting as adjuncts to typical antipsychotic drugs. Lorazepam (Ativan) has become the most widely used benzodiazepine for acute treatment of agitation. Studies indicate that, as a monotherapy, lorazepam can produce equal or greater anti-agitation or anti-aggression effects compared to haloperidol monotherapy, with a time course that is as good and often faster (Battaglia et al., 1997; Foster et al., 1997; Salzman et al., 1991). Similar findings have been reported for other benzodiazepines including midazolam (Versed) (Wyant et al., 1990) and flunitrazepam (Rohypnol, not available in the United States) (Dorevitch et al., 1999). The mechanism of action of benzodiazepines is through facilitation of GABA-ergic transmission, which is the major inhibitory neurotransmitter in the brain.

The major liability with benzodiazepines is the propensity to sedate patients. Also, some patients, particularly those with underlying brain damage, may become "disinhibited" with benzodiazepines. Importantly, benzodiazepines such as lorazepam have a superior safety profile compared to typical antipsychotics in the treatment of acute agitation and will not produce extrapyramidal symptoms or neuroleptic malignant syndrome.

Rather than monotherapy, a common approach to treatment of agitation in the acute setting is to administer haloperidol and lorazepam in combination (usually parenterally within the same syringe). This combination regimen is popular in acute psychiatric settings because the two medications are thought to produce synergistic anti-agitation effects. Results of some studies comparing the combination approach to monotherapy support this notion of synergism (Battaglia et al., 1997; Bieniek et al., 1998). However, these studies have only examined lorazepam in doses of 2 mg or less in conjunction with an antipsychotic. This has prompted some authors to question whether monotherapy with a higher dose of lorazepam would produce the same advantages as the combination, without the side effects associated with antipsychotic use (Allen, 2000; Bieniek et al., 1998).

The introduction of atypical antipsychotics to the marketplace has had a major impact on clinical practice in the treatment of psychosis in the subacute (e.g., inpatient) and chronic settings, due to strong evidence that they produce a greater spectrum of therapeutic effects and a much superior side-effect profile. One reason the impact of atypical antipsychotics on treatment of psychiatric syndromes in the acute setting (e.g., emergency departments [EDs]) has lagged behind is that parenteral administration of medications is frequently employed in an acute setting for the treatment of agitation. This is either due to patient compliance issues or physician belief that parenteral administration may induce a faster response. At this time, atypical antipsychotics are not available in parenteral formulations. However, orally administered atypical antipsychotic medications, such as risperidone (Risperdal) (Currier, 2000), olanzapine (Zyprexa) (Karagianis et al., 2001) and quetiapine (Seroquel) (Goldstein, 1998, as cited in Currier, 2000), are increasingly being used in the acute setting with good outcomes in lieu of typicals like haloperidol.

The atypicals have significant advantages over typical antipsychotics because they generally have a much better safety and tolerability profile, particularly in respect to extrapyramidal and related side effects. A recent small, prospective study suggested that oral risperidone in combination with lorazepam was as effective and as rapid as IM haloperidol plus IM lorazepam in reducing agitation in psychotic patients in an emergency setting (Currier, 2000). A large-scale, multisite study is currently underway trying to replicate these findings. Short-acting IM formulations of two atypical antipsychotic drugs, olanzapine and ziprasidone (Geodon), which are expected to become available in the very near future, both have demonstrated efficacy in acute agitation (Lucey et al., 2000, as cited in Currier, 2000; Jones et al., 2001). These new compounds will add exciting additional options to the armamentarium of physicians treating agitation in the acute setting.

Recent reports suggest that administration of an intravenous formulation of divalproex (Depakote), indicated for treatment of seizure disorders, produced a rapid reduction in acute agitation (Grunze et al., 1999; Hilty et al., 1998). Grunze and colleagues found this treatment not only reduced acute agitation but also produced a rapid reduction in symptoms of mania in patients experiencing acute manic episodes. If further studies concur, intravenous divalproex may become a useful tool in controlling symptoms associated with manic episodes in the acute setting.

Based upon the evidence that lorazepam produces anti-agitation effects equal or superior to antipsychotic medications without the associated side effects, patients requiring anti-agitation treatment for conditions that do not appear to require definitive treatment with antipsychotics, due to the absence of an underlying psychotic disorder (e.g., depression, mania without psychosis, anxiety disorders, alcohol withdrawal), should be managed with 2 mg to 4 mg lorazepam monotherapy (either oral or parenteral).

Patients whose agitation is secondary to disorders that will require definitive treatment with antipsychotics, due to the presence of psychosis, should be managed with antipsychotic medications as monotherapy or in conjunction with lorazepam.

A high-potency atypical antipsychotic, such as risperidone (2 mg to 4 mg) or olanzapine (15 mg to 20 mg), is generally preferred over a typical agent due to improved tolerability as long as the patient is appropriate and amenable to oral medication. In patients where antipsychotics are indicated but oral medications are not appropriate, parenteral formulations of atypical antipsychotics are expected to become available on the market shortly and should offer similar advantages over parenterally administered typical antipsychotic medications.

Allen MH (2000), Managing the agitated psychotic patient: a reappraisal of the evidence. J Clin Psychiatry 61(suppl 14):11-20.
 

Battaglia J, Moss S, Rush J et al. (1997), Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med 15(4):335-340.
 

Bieniek SA, Ownby RL, Penalver A, Dominguez RA (1998), A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy 18(1):57-62.
 

Currier GW (2000), Atypical antipsychotic medications in the psychiatric emergency service. J Clin Psychiatry 61(suppl 14):21-26.
 

Dorevitch A, Katz N, Zemishlany Z et al. (1999), Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. Am J Psychiatry 156(1):142-144.
 

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Gerstenzang ML, Krulisky TV (1977), Parenteral haloperidol in psychiatric emergencies. Double-blind comparison with chlorpromazine. Dis Nerv Syst 38(8):581-583.
 

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There are two goals in the acute treatment setting (e.g., emergency department): initiation of treatment and reducing the symptoms of agitation and aggression that frequently accompany an acute psychotic breakdown. Treatment options and considerations are reviewed.

David Feifel, MD PhD

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