Agitation and aggression have always been difficult behaviors for our society to manage, and when such behaviors present in medical or psychiatric patients, special approaches and interventions need to be considered. It is not uncommon that patients with central nervous system disorders present with agitation, aggression, and violence. These behaviors may lead to emergency hospitalization and can become an obstacle to discharge planning. In the office, emergency department, and on the in-patient unit, these behaviors can place patients and staff at risk.

A dual approach is necessary when dealing with this clinical problem. The sedating agents that may be helpful in reducing agitation acutely may not be as useful in managing these behaviors over the long-term. Long-term sedation will not improve a patient's level of functioning and may adversely affect compliance with medication. Thus, it is logical to divide the discussion of treatments into 2 parts: acute and chronic. Acute management will focus on calming the agitated patient, whereas chronic management will have as its goal the reduction of the frequency and intensity of episodes of agitation. Long-term treatment is directed toward the underlying disorder. Additional adjunctive medications may be necessary when standard therapeutic approaches are ineffective.

Definitions

Agitation can be defined as excessive verbal and/or motor behavior. It can readily escalate to aggression, which can be either verbal (vicious cursing and threats) or physical (toward objects or people). Technically, violence is defined as physical aggression against other people. The key to safety is to intervene early in order to prevent progression of agitation to aggression and violence. Table 1 shows the various pharmacologic options for acute agitation.

Table 1. Pharmacologic Options for Acute Agitation -- Intramuscular Agents

Agent	Dose (mg)	Comments
Lorazepam	0.5 to 2.0	Will treat underlying alcohol withdrawal. Caution: respiratory depression.
Haloperidol	0.5 to 10	Caution: akathisia, acute dystonic reaction, seizure threshold decrease.
Droperidol	2.5 to 5.0	No FDA-approved psychiatric indication. Caution: prolongation of the QTc interval (removed from UK market, and new black box warning in United States)
Olanzapine*	10 (2.5 for patients with dementia)	Superiority over haloperidol (schizophrenia) and lorazepam (bipolar disorder) in clinical trials. No EPS. Caution: weight gain over time.
Ziprasidone*	10 to 20	Little or no EPS. Caution: prolongation of the QTc interval.

*Intramuscular formulations not yet available in the United States as of May 7, 2002. FDA, US Food and Drug Administration; EPS, extrapyramidal signs and symptoms

Environmental Interventions

Environmental interventions include the removal of objects that can be used as weapons (ashtrays, chairs), making sure that other patients can safely go to another area (it is easier to move several calm patients than one agitated patient), and having several staff members available. Extraneous stimulation can often make things worse; thus, it is important to turn off the television if there is one in the day room or waiting room.

Behavioral Approaches

Behavioral approaches include never turning your back to an agitated patient, talking softly rather than shouting, and inquiring about what specific needs the patient may have. Eye contact may help establish rapport, but it may be necessary to break eye contact if it is making the patient uncomfortable. The tone of the intervention is set in the first few minutes. A genuine sense of concern goes a long way in reducing the occurrence of an assault. Innocuous questions that focus on basic needs, such as asking about appetite and sleeping patterns, can be helpful. The patient should be permitted to ventilate his or her feelings, but this may need to be cut short if the degree of agitation is escalating and there is clear danger to self and others. It is often helpful for the staff member who has the best rapport with the patient to interact with him/her. Figure 1 shows an algorithm for the management of the agitated patient.

Figure 1. Managing the agitated patient.

Medications: Issues in Assessment

Early on, acutely agitated patients should be offered medication. The choice of medication will be dependent on several factors, notably history. An agitated patient on an inpatient unit whose history is well known will be managed differently from an acutely agitated patient brought in to the emergency department. The latter may be acutely withdrawing from alcohol or sedatives and, thus, require very different interventions from someone who is agitated because of a functional psychosis. Note that almost half of all patients with schizophrenia have a drug and/or alcohol abuse problem,^[1] further complicating a differential diagnosis of the cause of agitation.

There may be limited time to conduct a patient assessment. If someone is acutely agitated and is an immediate danger to self or others, emergency measures must be taken to avoid harm. Somatic/medical conditions must be ruled out prior to initiating additional treatment, as an underlying metabolic, toxic, infectious, or other nonpsychiatric cause may need to be treated. This is not as great a concern for the long-term patient whose history is well known to the staff as it is for the relatively unknown patient presenting to the emergency room. Mechanical restraints may be useful while the medical workup is being conducted.

Risk assessment is important. Past history of violence may be the best predictor of future violent behavior.^[2-4] Current ideation -- in particular, delusions -- has been linked to violence.^[5,6]

Sedation. Nonspecific sedation is often used in the management of an acutely agitated patient. In general, intramuscular injection of a sedative has a faster onset of action than oral or sublingual administration. Up to now, choice of intramuscular medication for behavioral emergencies has been limited to intramuscular preparations of typical antipsychotics (such as haloperidol or chlorpromazine) vs intramuscular preparations of benzodiazepines (principally lorazepam). The availability of intramuscular formulations of novel atypical antipsychotics will provide new treatment options for the management of acute agitation in patients with psychosis.^[7] In general, the atypical antipsychotics are better tolerated than the older agents. Of importance is their decreased propensity for inducing akathisia -- a side effect of typical agents that has been associated with agitation and aggression.^[8,9] In addition, these new formulations provide the opportunity for a smooth transition to oral dosing with the same agent once the acute agitation has been appropriately managed.

Benzodiazepines: focus on lorazepam. Lorazepam, the only benzodiazepine that is reliably absorbed when administered intramuscularly, remains a rational choice when treating an acute episode of agitation, especially when the etiology is not clear, such as when a patient with a history of schizophrenia may actually be withdrawing from alcohol.^[10-12] Lorazepam's half-life is short (10 to 20 hours) and its route of elimination produces no active metabolites. The usual dosage of 0.5 to 2.0 mg every 1 to 6 hours may be administered orally, sublingually, intramuscularly, or intravenously. However, respiratory depression may be a complication in vulnerable patients such as obese smokers with pulmonary disease. Lorazepam is not recommended for long-term daily use because of the problems associated with tolerance, dependence, and withdrawal. The concern over paradoxic reactions to benzodiazepines, as exhibited by hostility or violence, may be exaggerated.^[13]

Conventional antipsychotics. The typical antipsychotics cause sedation, given a high enough dose. Haloperidol, a high potency butyrophenone, has been frequently used as an intramuscular as-needed medication for agitation and aggressive behavior in an emergency department setting for a wide variety of patients, both alone,^[14] and in combination with lorazepam.^[15] However, haloperidol is no longer a reasonable choice for treating psychosis, given the problem of extrapyramidal side effects, tardive dyskinesia, and inferior efficacy compared with typical antipsychotics in patients with a history of suboptimal response to conventional antipsychotics.^[16]

Droperidol, another antipsychotic in the butyrophenone class, is not approved by the US Food and Drug Administration for psychiatric conditions but has been used for sedating agitated patients in an emergency room setting.^[17] However, droperidol causes a dose-dependent prolongation of the QT interval,^[18] and concern over this has led to the withdrawal of this product in the UK market, and a "black-box" warning in the United States.

Olanzapine. Olanzapine, available in the United States since 1996 as an oral agent, is now available in fast-disintegrating tablet (Zydis), and the intramuscular preparation has been recommended for approval for the treatment of agitation in schizophrenia, bipolar disorder, and dementia. The main advantage of the intramuscular formulation is the very rapid achievement of a high peak plasma concentration, correlating with efficacy as early as 15-30 minutes postinjection. Half-life is the same as with oral dosing. Efficacy in controlling agitation was established in 4 double-blind controlled pivotal trials involving more than 1000 patients.^[19] The majority of patients required only 1 olanzapine injection to control their agitation. Intramuscular olanzapine was superior to intramuscular haloperidol (in patients with schizophrenia) and intramuscular lorazepam (in patients with bipolar disorder) at the earliest time point measured. As expected, intramuscular olanzapine exhibited less extrapyramidal side effects compared with intramuscular haloperidol. The optimal dose appears to be 10 mg. However, for patients with dementia, the recommended dose is 2.5 mg.

Starting oral olanzapine at 20 to 40 mg/day may result in the reduction of agitation that can be seen when patients initially present for treatment. Results of a multicenter study of a loading-dose strategy for olanzapine were recently reported, whereby patients were randomized to receive either up to 40 mg/day or up to 10 mg/day at the initiation of therapy (N=148).^[20] Patients were enrolled with a diagnosis of schizophrenia, schizoaffective, schizophreniform disorder, or bipolar I disorder and were randomized to 4 days of double-blind oral olanzapine treatment administered by 2 different dosing strategies. One strategy was "Rapid Initial Dose Escalation" (RIDE), consisting of olanzapine 20 mg then 2 additional olanzapine 10 mg oral doses as needed (up to 40 mg/day) on days 1 and 2, followed by 1 additional olanzapine 10 mg oral dose as needed (up to 30 mg/day) on days 3 and 4. The other strategy was "Usual Clinical Practice" (UCP), consisting of olanzapine 10 mg then 2 additional lorazepam 2 mg oral doses as needed (10 mg olanzapine and up to 4 mg lorazepam) on days 1 and 2, followed by 1 additional lorazepam 2 mg oral dose as needed (10 mg olanzapine and up to 2 mg lorazepam) on days 3 and 4. After 4 days of double-blind treatment, all patients were treated openly with standard olanzapine doses (5-20 mg on days 5-7). Although improvement on measures of excitement occurred in both groups, RIDE dosing was significantly more effective than UCP (P = .019), and this difference was first significant at the 24-hour rating (P = .04). No significant differences between groups existed in treatment-emergent adverse events or potentially clinically significant laboratory abnormalities. Thus, it appears that in the acute care of the agitated patient, initiating olanzapine at a 20-mg dose followed if needed by further doses up to 40 mg/day in the first 1-2 days may offer clinicians a rapid and effective treatment strategy.

Ziprasidone. Ziprasidone has been available in the United States since 2001. Although clinical experience with ziprasidone is more limited than with olanzapine, it is an option that may be helpful for selected patients. An obstacle for its use is the association with prolongation of the QTc interval. This issue has led to a warning on the product prescribing information sheet (package insert) that ziprasidone should be avoided in combination with other drugs that are known to prolong the QTc interval, in patients with congenital long QT syndrome, and in patients with a history of cardiac arrhythmias. For these reasons, ziprasidone treatment should only be started after an EKG evaluation if any risk factors are present. On the other hand, in contrast to other atypical antipsychotics (including olanzapine), ziprasidone has not been associated with weight gain over time.^[21] Intramuscular ziprasidone has been recommended for approval for the control of agitation in patients with schizophrenia or schizoaffective disorder. Peak plasma concentrations after an intramuscular dose of ziprasidone are achieved in 30-45 minutes (with half-life of 2.2 to 3.4 hours).^[22] Efficacy was established in 2 double-blind controlled pivotal clinical trials involving approximately 200 patients. The recommended dose is 20 mg.^[23] Overall, ziprasidone was well tolerated and almost free of extrapyramidal side effects, when given by intramuscular injection, at doses up to 80 mg per day.^[22]

Once the acute agitation is managed, longer-term strategies are required. Specialized units such as secure care or psychiatric intensive care units^[24] can provide a structured environment that optimizes staff and patient safety. It is not unusual for overt physical aggression to be greatly diminished in such an environment, only to reappear in a more chaotic setting. Medication treatment remains the mainstay of therapy of persistent aggressive behavior. Choice of a first-line agent is dependent upon the specific underlying disorder. Additional adjunctive medications may be needed if monotherapy fails. Medications that have demonstrated efficacy in preventing or reducing the intensity and frequency of aggressive episodes include atypical antipsychotics, mood stabilizers, and beta-adrenergic blockers. Serotonin-specific reuptake inhibitors may also be helpful. Table 2 shows the pharmacologic options for persistent aggressive behavior.

Table 2. Pharmacologic Options for Persistent Aggressive Behavior

Class	Comments
Atypical antipsychotics	Clozapine superior to risperidone and haloperidol.
Mood stabilizers	Limited evidence from randomized clinical trials, but more exists for valproate and carbamazepine.
Beta-blockers	Most evidence is from patients with organic mental disorders.
Antidepressants	SSRIs may be helpful -- one randomized clinical trial of adjunctive citalopram in schizophrenia. Caution: rapid cycling in patients with bipolar disorder.
Benzodiazepines	Negative trial of adjunctive clonazepam in schizophrenia is cautionary. Leads to physiologic tolerance over the long term.

SSRI, selective serotonin reuptake inhibitor

A common theme may be the serotonergic system. A disturbance of this system has been implicated in impulsive violence in humans.^[25,26] A disturbance of the serotonergic system has been inferred from low levels of the 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF),^[27-30] or from a blunted response to neuroendocrine challenges.^[31] This work was done largely in aggressive patients with personality disorders and substance use disorders.

Atypical Antipsychotics

The role of the serotonergic system in the pathogenesis of schizophrenia has recently received increased research attention, stimulated by the success of atypical antipsychotics that have serotonergic effects. However, there is only limited information on the serotonergic system and its functioning in aggressive patients with schizophrenia. Measures of serotonergic function in humans, such as the CSF 5-HIAA assays and neuroendocrine challenges, yield results that can be distorted by concomitant medication, including antipsychotics. The CSF levels of 5-HIAA in a small sample of aggressive schizophrenics (N=10) were not different from those obtained in matched controls.^[32] In this study, the authors were unable to discontinue antipsychotic treatment of the subjects for an adequate period of time. This problem may have contributed to the negative result. However, in spite of the lack of specific information on the role of serotonin in aggression in schizophrenia, the serotonin hypothesis has been a theoretical mainstay of the antiaggressive treatment in this disorder.

It has been observed that atypical antipsychotics, especially clozapine, appear to specifically target aggressive behavior. This has been demonstrated in several retrospective studies.^[33-39] The reductions of hostility^[40] and aggression^[41] after clozapine treatment were selective in the sense that they were (statistically) independent of the general antipsychotic effects of clozapine. This was confirmed in a double blind 14-week randomized clinical trial comparing the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, or haloperidol in 157 inpatients with schizophrenia or schizoaffective disorder with a history of suboptimal treatment response to conventional antipsychotics.^[42] Clozapine had a significantly greater antihostility effect than haloperidol or risperidone. The effect on hostility was independent of antipsychotic effect on delusional thinking, formal thought disorder, or hallucinations, and independent of sedation. Neither risperidone nor olanzapine showed superiority over haloperidol. The failure of risperidone to demonstrate superiority to haloperidol in treatment-refractory patients is in direct contrast to an earlier study with treatment-responsive patients participating in a pivotal registration protocol.^[43] Regardless of this, an important limitation shared by these 2 studies^[42,43] is that subjects were not specifically selected because of a history of aggressive and hostile behavior, and that overt hostility was largely demonstrated by verbal expression of resentment rather than by overt physical assault.

Quetiapine may also preferentially reduce hostility and aggression in treatment-responsive acute schizophrenia. Utilizing the data gathered in a pivotal registration study, both quetiapine and haloperidol were found to be superior to placebo in reducing positive symptoms, but only quetiapine was superior to placebo in the measures of aggression and hostility.^[44] This is supported by a case report describing a dramatic response to quetiapine monotherapy in a persistently aggressive patient who had failed to respond to numerous other medications.^[45]

Another post-hoc subanalysis, this time of olanzapine compared with haloperidol, was conducted using the data from a pivotal multicenter clinical trial that enrolled treatment-responsive patients.^[46] Olanzapine-treated patients experienced a significantly greater improvement in behavioral agitation than did the haloperidol-treated patients.

At this time, the weight of the evidence favors clozapine as specific antiaggressive treatment for schizophrenia patients,^[47] with demonstrated superiority to haloperidol and perhaps risperidone.

Mood Stabilizers

Mood stabilizers are the drugs of choice in the treatment of bipolar disorder. Their efficacy in mood regulation, and perhaps in reducing impulsivity, has led to their use in other disorders, including schizophrenia. Such use has been increasing over time, and in one report of New York State Psychiatric Centers, in 1998, 2134 out of 4922 (43.4%) inpatients diagnosed with schizophrenia received a mood stabilizer, with valproate most commonly prescribed (1724 or 35.0%).^[48] Expert consensus guidelines suggest the use of adjunctive mood stabilizers in patients with schizophrenia with agitation, excitement, aggression, or violence,^[49] but there is little in the way of evidence in the form of randomized clinical trials for these patients. A recent review of the use of valproate to counter violence and aggressive behaviors in a variety of diagnoses^[50] did reveal a 77.1% response rate (defined by a 50% reduction in target behavior) based on 17 reports (164 patients), but included only 16 patients with schizophrenia. Only 1 double-blind study was found, and it consisted of 16 patients with borderline personality disorder.^[51] Since that review, there have been additional reports, including a double-blind placebo-controlled trial of valproate in 20 children and adolescents with explosive temper and mood lability where valproate was superior to placebo,^[52] and a 1-year open-label prospective trial of adjunctive valproate with olanzapine in 10 patients with paranoid schizophrenia, demonstrating statistically significant reductions in hostility.^[53]

Recently completed is a large, multicenter, randomized, double-blind, clinical trial of adjunctive valproate in patients recently hospitalized with an acute exacerbation of schizophrenia.^[54] A total of 249 patients with schizophrenia were randomized to receive over a 4-week period either olanzapine and valproate, olanzapine and placebo, risperidone and valproate, or risperidone and placebo. Subjects were required to have a minimum threshold of certain symptoms (hostility and uncooperativeness, or excitement and tension). Monotherapy with an antipsychotic was compared with combination therapy with an antipsychotic and valproate. Adjunctive valproate was well tolerated and resulted in faster improvement in psychopathology (as measured by the Positive and Negative Syndrome Scale), including positive symptoms. Valproate significantly enhanced antipsychotic efficacy as early as treatment day 3. This study is important because it is the first large-scale randomized clinical trial that focuses on valproate in schizophrenia. It is anticipated that this will inspire further work that will examine the use of adjunctive valproate on more refractory populations and over longer lengths of time.

Adjunctive lithium has also been used for aggressive behavior. However, the data for the use of lithium in patients with schizophrenia is mixed. When lithium was added to antipsychotics for the treatment of resistant schizophrenic patients classified as "dangerous, violent, or criminal," no benefits were seen after 4 weeks of adjunctive lithium.^[55] However, another group found that lithium was useful as a single agent in ameliorating psychosis in 3 schizophrenic patients who suffered from marked akathisia with accompanying agitation, restlessness, and irritability when on standard antipsychotics.^[56]

Carbamazepine may be a useful adjunct to antipsychotic therapy^[57] and may lower aggression in a broad spectrum of disorders.^[58] However, carbamazepine as an antiaggressive agent has been studied in only a limited number of patients.^[59-65] The largest of these studies is a multifacility double-blind protocol comparing the effect of a 4-week trial of adjunctive carbamazepine vs placebo with standard antipsychotic treatment in 162 patients, 78% of them with a Diagnostic and Statistical Manual of Mental Disorders, 3rd edition diagnosis of schizophrenia (the remainder with schizoaffective disorder), all with excited states or aggressive/violent behavior that responded unsatisfactorily to antipsychotic treatment.^[64] There was no statistically significant difference in response among the patients with schizophrenia receiving either adjunctive carbamazepine or placebo, but a trend toward moderate improvement with carbamazepine was noted (P < .10).

An empirical trial of adjunctive valproate, lithium, or carbamazepine may be considered for patients with schizophrenia and persistent aggressive behavior, but chronic use, without demonstrable benefit, only exposes the patient to the possibility of side effects.

Beta Blockers

Beta-adrenergic blockers -- in particular, propranolol -- have been used in the treatment of aggressive behavior in brain-injured patients ^[66,67] and, to a limited extent, in schizophrenia.^[68] A chart review of chronically assaultive schizophrenic patients receiving nadolol or propranolol revealed a 70% decrease in actual assaults for 4 of the 7 patients.^[69] A double-blind, placebo-controlled study of adjunctive nadolol (40-120 mg/day) in 41 patients, 29 of whom were schizophrenic, found a decline in the frequency of aggression compared with controls.^[70] In a report of a double-blind, placebo-controlled study of adjunctive nadolol (80-120 mg/day) in 30 violent inpatients, of whom 23 were schizophrenic, a trend was found demonstrating lower hostility for the active treatment group.^[71]

Benzodiazepines

Despite a positive anecdotal report demonstrating the usefulness of adjunctive clonazepam in reducing aggression,^[72] a double-blind, placebo-controlled trial of adjunctive clonazepam in 13 schizophrenic patients receiving antipsychotics revealed no additional therapeutic benefit; in fact, 4 patients demonstrated violent behavior during the course of clonazepam treatment.^[73] This finding is in contrast to the clinical utility of clonazepam in carefully selected patients with bipolar disorder.

Although the consensus guidelines recommend continued use of lorazepam for patients with schizophrenia with agitation or excitement (but with no history of substance abuse),^[49] such use can be problematic because of physiological tolerance. Missing scheduled doses of lorazepam may result in withdrawal symptoms that can lead to agitation or excitement, as well as irritability and a greater risk for aggressive behavior.

Antidepressants

Impulsive aggression against self and others may be influenced by effects on serotonin (5-HT) receptors. Specific serotonin reuptake inhibitors have been reported to be useful in reducing aggression. In a retrospective, uncontrolled study, adjunctive fluoxetine was given to 5 patients with chronic schizophrenia with a decrease in violent incidents observed for 4 cases.^[74] In another case report, fluvoxamine added to risperidone was reported to be effective in managing aggression in schizophrenia.^[75] A double-blind, placebo-controlled, crossover study of adjunctive citalopram in violent patients with schizophrenia found that the number of aggressive incidents decreased during the active citalopram treatment.^[76] Care must be taken when prescribing antidepressants in patients with bipolar disorder, as they may precipitate mania or lead to rapid cycling.

Adjunctive Electroconvulsive Therapy (ECT)

Adjunctive ECT may be helpful in patients who have inadequately responsive psychotic symptoms.^[77] An open trial of ECT in combination with risperidone in male patients with schizophrenia and aggression resulted in a reduction in aggressive behavior for 9 of the 10 patients.^[78] In a case report of a patient with treatment-resistant schizophrenia receiving adjunctive ECT (together with clozapine and olanzapine), the authors reported a significant amelioration of aggressive behavior (Greenberg et al., unpublished data, 2002).

The treatment of agitation, aggression, and violence begins with the successful management of the acute episode, followed by strategies designed to reduce the intensity and frequency of subsequent episodes. Short-term medication therapies include the use of lorazepam and/or antipsychotics. Intramuscular preparations of atypical antipsychotics are an improvement over what has been available. Lorazepam for long-term daily use is not recommended because of problems associated with tolerance, dependence, and withdrawal. Long-term treatment is directed toward the underlying disorder. When standard therapeutic approaches fail, adjunctive medications can be considered. Clozapine appears to be the most effective antipsychotic in reducing aggression in patients with schizophrenia. Adjunctive mood stabilizers can also be used to decrease the intensity and frequency of agitation and poor impulse control. Adjunctive beta-blockers, serotonin specific reuptake inhibitors, and ECT may be considered for patients in whom other approaches have failed.

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